Pathology of Childhood and Adolescence: An Illustrated Guide [1 ed.] 9783662591673, 9783662591697

Table of contents :
Foreword
Foreword
Preface
Contents
1: Cardiovascular System
1.1 Developmental and Genetics
1.2 Congenital Heart Disease
1.2.1 Sequential Segmental Cardio-Analysis
1.2.2 Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Atrioventricular Septal Defect (AVSD), Patent Ductus Arteriosus (PDA), and Ebstein’s Tricuspid Anomaly (ETA)
1.2.2.1 Atrial Septal Defect (ASD)
1.2.2.2 Ventricular Septal Defect (VSD)
1.2.2.3 Atrioventricular Septal Defect (AVSD)
1.2.2.4 Patent Ductus Arteriosus (PDA)
1.2.2.5 Ebstein’s Tricuspid Anomaly (ETA)
1.2.3 Tetralogy of Fallot (TOF) and Double Outlet Right Ventricle (DORV)
1.2.3.1 Tetralogy of Fallot (TOF)
Aortopulmonary Collateral Arteries (APCAs)
Pulmonary Arterial Changes in VSD and Severe Pulmonary Hypertension
1.2.3.2 Double Outlet Right Ventricle
1.2.4 Hypoplastic Right Heart Syndrome
1.2.4.1 PAVSD
1.2.4.2 PSIVS/PAIVS
1.2.4.3 HRHTA
1.2.5 Transposition of the Great Arteries
1.2.6 Common Trunk (Persistent Truncus Arteriosus)
1.2.7 Total Anomalous Pulmonary Venous Return
1.2.8 Scimitar Syndrome
1.2.9 Hypoplastic Left Heart Syndrome and Coarctation of Aorta
1.2.9.1 Hypoplastic Left Heart Syndrome (HLHS)
1.2.9.2 Coarctation of the Aorta
1.2.10 Heterotaxy Syndrome
1.2.11 Common Genetic Syndromes with Congenital Heart Disease
1.3 Myocarditis and Nonischemic Cardiomyopathies
1.3.1 Myocarditis
1.3.2 Dilated Cardiomyopathy
1.3.2.1 Angiotensin I-Converting Enzyme (ACE) Gene
1.3.2.2 Angiotensin II Type 1 Receptor (AGTR1) Gene
1.3.2.3 Angiotensinogen (AGT) Gene
1.3.2.4 Tumor Necrosis Factor-α (TNF-α) Gene
1.3.2.5 Phospholamban (PLN) Gene
1.3.2.6 Bone Morphogenetic Protein-10 (BMP10) Gene
1.3.2.7 Titin/Connectin Gene
1.3.2.8 Human Leukocyte Antigen (HLA) Gene
1.3.2.9 Alpha2C-Adrenoceptor Gene
1.3.2.10 β1-Adrenoceptor Gene
1.3.2.11 β2-Adrenoceptor Gene
1.3.2.12 Beta-Myosin Heavy Chain Gene
1.3.2.13 Myosin Binding Protein-C (MYBPC3) Gene
1.3.2.14 Cardiac Troponin I (TNNI3) Gene
1.3.2.15 Cardiac Troponin T (TNNT2) Gene
1.3.2.16 Alpha-Cardiac Actin Gene
1.3.2.17 Endothelin-1, Endothelin-A (ETA), and Endothelin-B (ETB) Receptor Genes
1.3.2.18 Apolipoprotein E (ApoE) Gene
1.3.2.19 SCN5A Gene
1.3.2.20 Myotrophin Gene
1.3.2.21 Vinculin and Metavinculin Genes
1.3.2.22 Lamin A/C Gene
1.3.2.23 Adenosine Monophosphate Deaminase-1 (AMPD1) Gene
1.3.2.24 Cypher/ZASP Gene
1.3.2.25 β-Sarcoglycan (SGCB) and δ-Sarcoglycan (SGCD) Genes
1.3.2.26 Polyadenylate-Binding Protein 2 (PABP2) Gene
1.3.2.27 Genes Encoding the Four Major Components of the Heart Calcineurin Pathway, PPP3CA, PPP3CB, GATA4, and NFATC4
1.3.2.28 Dystrophin Gene
1.3.2.29 Gene for Platelet-Activating Factor Acetylhydrolase (PAF-AH)
1.3.2.30 Transforming Growth Factor β1 (TGF-β1) Gene
1.3.2.31 G4.5 Gene
1.3.2.32 HS426 (Nebulette) Gene
1.3.2.33 Human Cardiotrophin-1 Gene (CTF1)
1.3.2.34 Desmin Gene
1.3.2.35 Endothelial Nitric Oxide Synthase (NOS3) Gene
1.3.2.36 Skeletal Muscle Alpha-Actin Gene (ACTA1)
1.3.2.37 Locus on Chromosome 6q12–q16 for Autosomal Dominant DCM
1.3.2.38 A-Dystrobrevin (DTNA)
1.3.2.39 Manganese Superoxide Dismutase Gene (SOD2)
1.3.2.40 Mitochondrial DNA Abnormalities
1.3.2.41 Dilated Cardiomyopathy Due to Chemotherapy-Related Cardiotoxicity
1.3.3 Hypertrophic Cardiomyopathy
1.3.4 Infiltrative/Restrictive Cardiomyopathies
1.3.4.1 Sarcoidosis
1.3.5 Left Ventricular Non-compaction
1.3.6 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C)
1.3.7 Lamin A/C Cardiomyopathy
1.3.8 Mitochondrial Cardiomyopathies
1.3.8.1 mtDNA Depletion Syndrome
1.3.9 Cardiac Channelopathies and Sudden Cardiac Death
1.4 Ischemic Heart Disease, Myocardial Dysfunction, and Heart Failure
1.4.1 Ischemic Heart Disease
1.4.2 Myocardial Dysfunction
1.4.3 Heart Failure
1.5 Valvular Heart Disease
1.5.1 Endocarditis and Valvar Vegetation
1.5.2 Mitral Valve Prolapse
1.5.3 Calcific Mitral Annulus and Calcific Aortic Stenosis
1.5.4 Rheumatic Heart Disease (RHD)
1.5.5 Prosthetic Valves
1.6 Transplantation
1.6.1 Allograft Cellular Rejection
1.6.2 Allograft Humoral Rejection
1.6.3 Cardiac Allograft Vasculopathy
1.6.4 Extracardiac Posttransplant Lympho-proliferative Disorders (PTLD) Following HTX
1.7 Tumors
1.7.1 Benign Tumors
1.7.1.1 Myxoma
1.7.1.2 Lipoma, Valve Fibrolipoma, and Lipomatous Hypertrophy of the Interatrial Septum (LHIAS)
1.7.1.3 Papillary Fibroelastoma (PFE) and Fibroma
Papillary Fibroelastoma
Fibroma
1.7.1.4 Rhabdomyoma
1.7.1.5 Hemangioma
1.7.1.6 Inflammatory Myofibroblastic Tumor
1.7.1.7 Paraganglioma
1.7.1.8 Cardiac Hamartoma
1.7.1.9 Histiocytoid CM (HICM)/Purkinje Cell Hamartoma
1.7.1.10 Congenital Polycystic Tumor of Atrioventricular Node (AVN)
1.7.1.11 Calcified Amorphous Tumor
1.7.1.12 Mesothelial/Monocytic Incidental Excrescences (MICE)
1.7.1.13 Mural Thrombi
1.7.1.14 Rare Non-cardiac Benign Tumors
1.7.2 Malignant Tumors
1.7.2.1 Epithelioid Hemangioendothelioma
1.7.2.2 Angiosarcoma
1.7.2.3 Rhabdomyosarcoma
1.7.2.4 Synovial Sarcoma
1.7.2.5 Others
1.7.3 Metastatic Tumors
1.8 Pericardial Disease
1.8.1 Non-neoplastic Pericardial Disease
1.8.1.1 Pericardial Sac Fluid Storage Through Frank Accumulation Through Tamponade
1.8.1.2 Pericarditis
1.8.2 Neoplastic Pericardial Disease
1.9 Non-neoplastic Vascular Pathology
1.9.1 Congenital Anomalies
1.9.1.1 Arteriovenous Malformations
1.9.1.2 Berry Aneurysm
1.9.1.3 Media Dysplasia
1.9.2 Fibromuscular Dysplasia
1.9.3 Arteriosclerosis
1.9.3.1 Vasculitides
1.9.4 Large-Vessel Vasculitis
1.9.4.1 Takayasu Arteritis
1.9.4.2 Horton Arteritis (Cranial Arteritis, Giant Cell Arteritis)
1.9.5 Medium-Vessel Vasculitis
1.9.5.1 Kawasaki Disease
1.9.5.2 Polyarteritis Nodosa (PAN)
1.9.6 Small-Vessel Vasculitis
Multiple Choice Questions and Answers
References and Recommended Readings
2: Lower Respiratory Tract
2.1 Development and Genetics
2.2 Dysmorphology and Perinatal Congenital Airway Diseases
2.2.1 Foregut Cysts of Bronchogenic Type
2.2.2 Agenesis, Aplasia, and Hypoplasia Pulmonis (Pulmonary Hypoplasia)
2.2.3 CPAM and Congenital Lobar Emphysema
2.2.4 Tracheal and Bronchial Anomalies
2.2.4.1 Laryngeal Web
2.2.4.2 Tracheoesophageal Fistula
2.2.4.3 Tracheal Stenosis/Atresia
2.2.5 Sequestrations and Vascular Anomalies
2.3 Infantile and Pediatric NILD
2.3.1 Neonatal Respiratory Distress Syndrome
2.3.2 “Old” and “New” Bronchopulmonary Dysplasia (OBPD and NBPD)
2.3.3 Atelectasis
2.3.4 Cystic Fibrosis
2.4 Infantile and Pediatric ILD
2.4.1 Diffuse Lung Development-Associated ILD
2.4.1.1 Congenital Acinar Dysgenesis/Dysplasia
2.4.1.2 Congenital Alveolar Dysgenesis/Dysplasia
2.4.1.3 Alveolar Capillary Dysplasia With/Without Misalignment of Pulmonary Veins (ACD/MPV)
2.4.2 Trisomy 21 (Down Syndrome)-Associated ILD
2.4.3 ILD Related to Other Chromosomal/Genomic Microdeletion Disorders
2.4.4 Neuroendocrine Hyperplasia of Infancy (NEHI)
2.4.5 Pulmonary Interstitial Glycogenosis (PIG)
2.4.6 Surfactant Dysfunction Disorders
2.4.6.1 Dysfunctional SP-B-Related ILD
2.4.6.2 Dysfunctional SP-C-Related ILD
2.4.6.3 Dysfunctional ABCA3-Related ILD
2.4.6.4 Lysinuric Protein Intolerance
2.4.7 Pulmonary Alveolar Proteinosis
2.5 “Adult” ILD of the Youth
2.5.1 Diffuse Alveolar Damage (DAD)
2.5.2 Cryptogenic Organizing Pneumonia (COP)
2.5.3 Usual Interstitial Pneumonia/Pneumonitis (UIP)
2.5.4 Nonspecific Interstitial Pneumonia/Pneumonitis (NSIP)
2.5.5 Desquamative Interstitial Pneumonia/Pneumonitis
2.5.6 Respiratory Bronchiolitis ILD
2.5.7 Pulmonary Langerhans Cell Histiocytosis
2.5.8 Lymphoid Interstitial Pneumonia/Pneumonitis (LIP)
2.5.9 Hypersensitivity Pneumonia/Pneumonitis (HSP)
2.5.10 Acute Eosinophilic Pneumonia/Pneumonitis
2.5.11 Progressive Massive Fibrosis
2.6 Inflammation: Tracheobronchial
2.6.1 Laryngotracheitis
2.6.2 Acute Bronchitis
2.6.3 Bronchial Asthma
2.6.4 Pulmonary Hyperinflation
2.6.5 Bronchiectasis
2.6.6 Neoplasms
2.7 Inflammation: Infectious (Pneumonia/Pneumonitis)
2.7.1 Lobar Pneumonia
2.7.2 Bronchopneumonia
2.7.3 Interstitial Pneumonia
2.7.4 Primary Atypical Inflammation (Pneumonia)
2.8 Inflammation: Non-infectious (Pneumonia vs. Pneumonitis)
2.8.1 Aspiration and Chemical Pneumonitis
2.8.2 Lipoid Pneumonia
2.8.3 Diffuse Pulmonary Hemorrhagic Syndromes
2.8.3.1 Goodpasture Syndrome
2.8.3.2 Idiopathic Pulmonary Hemosiderosis
2.8.3.3 Vasculitis-Associated Hemorrhage (Necrotizing Capillaritis)
2.9 Inflammation: Infectious/Non-infectious Granulomatous/Nongranulomatous
2.9.1 Primary Pulmonary Tuberculosis
2.9.2 Sarcoidosis
2.9.3 Aspergillosis
2.9.4 Others
2.10 Chronic Obstructive Pulmonary Disease of the Youth
2.10.1 Chronic Bronchitis
2.10.2 Emphysema
2.11 “Adult” Pneumoconiosis of the Youth
2.11.1 Silicosis
2.11.2 Asbestosis
2.11.3 Non-silico Asbestosis-Related Pneumoconiosis
2.12 Pulmonary Vascular Disorders
2.12.1 Pulmonary Congestion and Edema
2.12.2 Pulmonary Embolism/Infarction
2.12.3 Pulmonary Arterial Hypertension (PAH)
2.13 Transplantation-Related Disorders
2.13.1 Acute Rejection
2.13.2 Chronic Rejection
2.14 Pediatric Tumors and Pseudotumors
2.14.1 Pulmonary Teratoma
2.14.2 Inflammatory Myofibroblastic Tumor
2.14.3 Pulmonary Hamartoma
2.14.4 Pulmonary Sclerosing Hemangioma
2.14.5 Pulmonary Carcinoid
2.14.6 Lymphangioma-(Leo)-Myomatosis (LAM)
2.14.7 Kaposiform Lymphangiomatosis
2.14.8 Pleuropulmonary Blastoma
2.14.9 Metastatic Tumors
2.15 “Adult”-Type Neoplasms in Childhood/Youth
2.15.1 “Adult”-Type Preneoplastic Lesions
2.16 Pleural Diseases
2.16.1 Pleural Effusions and Pleuritis
2.16.2 Pneumothorax
2.16.3 Neoplastic Pleural Diseases
2.16.3.1 Solitary Fibrous Tumor of Pleura
2.16.3.2 Benign Mesothelioma
2.16.3.3 Malignant Mesothelioma
2.17 Posttransplant Lymphoproliferative Disorders (PTLD)
2.18 Non-thymic Mediastinal Pathology
2.18.1 Anterior Mediastinal Pathology
2.18.2 Middle Mediastinal Pathology
2.18.3 Posterior Mediastinal Pathology
Multiple Choice Questions and Answers
References and Recommended Readings
3: Gastrointestinal Tract
3.1 Development and Genetics
3.2 Esophagus
3.2.1 Esophageal Anomalies
3.2.1.1 Esophageal Atresia ± Tracheoesophageal Fistula (EA-TEF)
3.2.1.2 Esophageal Duplication
3.2.1.3 Ectopia/Heterotopia
3.2.1.4 Obstructive Disorders
3.2.1.5 Acquired Anomalies of Low or Eumotility
3.2.1.6 Acquired Anomalies with Dysmotility
3.2.2 Esophageal Vascular Changes
3.2.3 Esophageal Inflammatory Diseases
3.2.3.1 Reflux Esophagitis
GERD in Children with Severe Neurological Impairment
3.2.3.2 Eosinophilic Esophagitis
3.2.3.3 Infectious Esophagitis
3.2.3.4 Injury-Associated Esophagitis
3.2.3.5 Esophagitis in Systemic Disorders
3.2.3.6 Graft-Versus-Host Disease
Endoscopic and Histological Criteria
3.2.3.7 Inflammation-Associated Lining Changes
3.2.4 Esophageal Tumors
3.2.4.1 Benign Esophageal Tumors
3.2.4.2 Malignant Esophageal Tumors
Squamous Cell Carcinoma
Adenocarcinoma
Other Tumors of the Esophagus
3.3 Stomach
3.3.1 Gastric Anomalies
3.3.1.1 Gastric Agenesis and Dystopias
3.3.1.2 Gastric Duplications
3.3.1.3 Ectopia/Heterotopia
3.3.1.4 Obstructive Disorders
3.3.1.5 Acquired Anomalies with Dysmotility
3.3.2 Gastric Vascular Changes
3.3.2.1 Hyperemia
3.3.2.2 Gastric Antral Vascular Ectasia
3.3.3 Gastric Inflammatory Diseases
3.3.3.1 Acute Gastritis
3.3.3.2 Chronic Gastritis
3.3.3.3 Specific Gastritides
Lymphocytic Gastritis
Granulomatous Gastritis
Eosinophilic Gastritis
Helicobacter heilmannii Gastritis
3.3.4 Tissue Continuity Damage-Related Gastric Degenerations
3.3.4.1 Gastric Ulcers
Stress Ulcers
Peptic Ulcers
3.3.4.2 Gastric Hyperplasia
Menetrier Disease
Zollinger-Ellison Syndrome
3.3.4.3 Metaplasias
3.3.5 Gastric Tumors
3.3.5.1 Benign Epithelial Neoplasms
3.3.5.2 Malignant Epithelial Neoplasms
Adenocarcinoma
Other Carcinomas
3.3.5.3 Neuroendocrine Tumors
3.3.5.4 Lymphoproliferative Lesions
Gastrointestinal B-NHL
Mantle Cell Lymphoma
Follicular Lymphoma
Burkitt Lymphoma
Diffuse Large B-Cell Lymphoma
Extranodal Marginal Zone B-Cell Lymphoma of MALT (ENMZL/MALT)
Immunoproliferative Small Intestine Disease (IPSID)
Gastrointestinal T-NHL
Enteropathy-Associated T-Cell Lymphoma (EATL)
Nonnasal NK/T-Cell NHL
Pseudolymphoma
3.3.5.5 Stromal Tumors and Smooth Muscle-Differentiating Tumors
GIST: Gastrointestinal Stromal Tumor
Smooth Muscle Tumors
3.3.5.6 Nonstroma/Smooth Muscle-Differentiating Tumors
3.3.5.7 Secondary Tumors
3.4 Small Intestine
3.4.1 Small Intestinal Anomalies
3.4.1.1 Infantile Colic
3.4.2 Abdominal Wall Defects (Median-Paramedian)
3.4.2.1 Omphalocele
3.4.2.2 Gastroschisis
3.4.3 Continuity Defects of the Intestinal Lumen
3.4.3.1 Atresia
3.4.3.2 Stenosis
3.4.3.3 Meconium Plug Syndrome
3.4.4 Intestinal Muscular Wall Defects
3.4.4.1 Diverticula
Mesenteric Diverticulum
Anti-mesenteric (Meckel’s) Diverticulum
3.4.4.2 Segmental Dilatation
3.4.5 Small Intestinal Dystopias
3.4.5.1 Intussusception
3.4.5.2 Volvulus
3.4.5.3 Nonrotation and Malrotation
3.4.6 Composition Abnormalities of the Intestinal Wall
3.4.6.1 Pancreas Heterotopia
3.4.6.2 Gastric Heterotopia
3.4.6.3 Endometrial Heterotopia (Endometriosis)
3.4.7 Small Intestinal Vascular Changes
3.4.7.1 Non-NEC Vascular Necrosis
Acute Intestinal Ischemia
Chronic Intestinal Ischemia
3.4.8 Inflammation and Malabsorption
3.4.8.1 Necrotizing Enterocolitis
Animal Models
3.4.8.2 Gluten-Sensitive Enteropathy
3.4.8.3 Non-GSE Causes of Malabsorption
Giardiasis/Lambliasis
Tropical Sprue
Whipple Disease
Anisakiasis
3.4.8.4 Intractable Diarrhea of Infancy
Microvillous Inclusion Disease (MVID)
Intestinal Epithelial Dysplasia/Tufting Enteropathy (IED-TE)
Syndromic Diarrhea of Infancy (SDI)
Autoimmune Enteropathy (AIE)
IPEX Syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-Linkage)
Systemic Disease with Enteric Manifestations
Food Protein-Induced Enterocolitis Syndrome (FPIES)
3.4.8.5 Crohn Disease
3.4.8.6 Peptic Ulceration-Associated Diseases
Radiation Enteritis
Nonsteroidal Anti-inflammatory Drug-Induced Gut Lesions
3.4.9 Short Bowel Syndrome/Intestinal Failure
3.4.10 Small Intestinal Transplantation
3.4.11 Graft-Versus-Host Disease (GVHD) of the Gut
3.4.12 Small Intestinal Neoplasms
3.4.12.1 Adenoma
3.4.12.2 Adenocarcinoma
3.4.12.3 Carcinoma of the Ampulla of Vater
Neuroendocrine Neoplasm
3.4.12.4 Gangliocytic Paraganglioma
3.4.12.5 Other Tumors
3.5 Appendix
3.5.1 Appendiceal Anomalies
3.5.2 Appendiceal Vascular Changes
3.5.3 Appendicitis
3.5.4 Appendiceal Metabolic and Degenerative Changes
3.5.5 Appendiceal Neoplasms
3.5.5.1 Mucinous Cystadenoma
3.5.5.2 Mucinous Cystadenocarcinoma
3.5.5.3 Adenocarcinoma
3.5.5.4 Carcinoid Tumor
3.6 Large Intestine
3.6.1 Large Intestinal Anomalies
3.6.1.1 Congenital Atresia: Stenosis of the Colon
3.6.1.2 Acquired “Pseudo-Atresia” of the Colon
3.6.1.3 Cloacal Membrane Teratogenesis
3.6.1.4 Caudal Dysgenesis Syndrome (CDS)
3.6.1.5 Recto-colonic Dysmotility Syndromes
Aganlionosis (HSCR, HirSChspRung Disease)
Neural Crest Migration
3.6.1.6 Non-Hirschsprung Recto-colonic Dysmotility Syndromes
Rectal Biopsy as Gold Standard
3.6.1.7 Constipation and Chronic Intestinal Pseudo-obstruction
Animal Models and What’s Going on in Research?
3.6.1.8 Colon Diverticulosis
3.6.2 Large Intestinal Vascular Changes
3.6.2.1 Ischemic Colitis
3.6.2.2 Angiodysplasia and Heyde Syndrome
3.6.3 Large Intestinal Inflammatory Disorders
3.6.3.1 Ulcerative Colitis
Colon-Rectal Dysplasia = Intraepithelial Neoplasia
Backwash Ileitis
3.6.3.2 Infectious Colitides
3.6.3.3 “Microscopic Colitis”
3.6.3.4 Others
3.6.4 Colon-Rectum Neoplasms
3.6.4.1 Adenomatous and Serrated Polyps
3.6.4.2 Non-neoplastic, Nonserrated Polyps
Juvenile (Retention) Polyps
Hamartomatous (Peutz-Jeghers-Type) Polyps
Pseudopolyps
Inflammatory Fibroid Polyps
Solitary Rectal Ulcer
Lymphoid Polyps
3.6.4.3 Polyposis Syndromes
FAP
Cowden Syndrome
Gardner Syndrome
Juvenile Polyposis Syndrome (JPS)
Peutz-Jeghers Syndrome (PJS)
Turcot Syndrome
Cronkhite-Canada Syndrome
3.6.4.4 Familial vs. Sporadic Colorectal Neoplasia
3.6.4.5 Adenocarcinoma
Carcinoid Tumor
3.7 Anus
3.7.1 Anal Anomalies
3.7.1.1 Anorectal Defects
3.7.2 Inflammatory Anal Diseases
3.7.2.1 Crohn Disease
3.7.2.2 Ulcerative Colitis
3.7.2.3 Lymphoid Polyp
3.7.3 Benign Anal Tumors and Non-neoplastic Anal Lesions (Pseudotumors)
3.7.4 Anal Pre- and Malignant Lesions
3.7.4.1 Condyloma Acuminatum
Dysplasia (Anal Intraepithelial Neoplasia, AIN)
3.7.4.2 Anal Carcinoma
Anal Carcinoma Histologic Variants
3.7.4.3 Paget Disease
3.7.4.4 Nonanal Carcinoma Neoplasms
3.7.4.5 Secondary Tumors
3.7.4.6 TNM Staging and CAP Guidelines
3.8 Peritoneum
3.8.1 Cytology
3.8.2 Non-neoplastic Peritoneal Pathology
3.8.3 Neoplastic Peritoneal Pathology
Multiple Choice Questions and Answers
References and Recommended Readings
4: Parenchymal GI Glands: Liver
4.1 Development and Genetics (Figs. 4.1 and 4.2)
4.2 Hepatobiliary Anomalies
4.2.1 Ductal Plate Malformation (DPM)
4.2.2 Congenital Hepatic Fibrosis
4.2.3 Biliary Hamartoma (von Meyenburg Complex)
4.2.4 Caroli Disease/Syndrome
4.2.5 ADPKD-Related Liver Cysts
4.3 Hyperbilirubinemia and Cholestasis
4.3.1 Hyperbilirubinemia
4.3.1.1 The Increase of Bilirubin Production
4.3.1.2 The Decrease of Bilirubin Uptake by the Hepatocytes
4.3.2 Decreased Bilirubin Conjugation and Unconjugated Hyperbilirubinemia
4.3.2.1 Abnormal Intracellular (Intrahepatocytic) Binding or Storage of Bilirubin
4.3.2.2 The Inefficiency of the (Intrahepatocyte) Conjugation System
4.3.3 Conjugated Hyperbilirubinemia
4.3.3.1 Abnormal Excretion of the Conjugated Bilirubin into the Intrahepatic Biliary Tract
4.3.3.2 Structural Abnormalities of the Intra- and Extrahepatic Biliary System
4.3.3.3 Abnormalities of the Enterohepatic Circulation
4.4 Infantile/Pediatric/Youth Cholangiopathies
4.4.1 Biliary Atresia
4.4.2 Non-BA Infantile Obstructive Cholangiopathies (NBAIOC)
4.4.3 The Paucity of the Intrahepatic Biliary Ducts (PIBD)
4.4.4 Neonatal Hepatitis Group (NAG)
4.4.4.1 Bile Acid Synthesis Disorders (BASD)
4.4.4.2 Defects of the Intracellular Transport of Conjugated Bilirubin
4.4.4.3 Infection-Related Neonatal Hepatitis
4.4.4.4 Non-BASD Metabolic Dysregulation-Related Neonatal Hepatitis
4.4.4.5 Endocrine Dysregulation-Based Neonatal Hepatitis (EDNH)
4.4.4.6 Miscellaneous/Idiopathic NAG
4.4.5 Primary Sclerosing Cholangitis (PSC)
4.4.6 Primary Biliary Cirrhosis (PBC)
4.4.7 Pregnancy-Related Liver Disease (PLD)
4.5 Genetic and Metabolic Liver Disease
4.5.1 Endoplasmic Reticulum Storage Diseases (ERSDs)
4.5.1.1 Alpha-1-antitrypsin Deficiency (AATD)
4.5.1.2 Non-AATD Endoplasmic Reticulum Storage Diseases
4.5.2 Congenital Dysregulation of Carbohydrate Metabolism
4.5.2.1 Glycogen Storage Diseases
4.5.2.2 Lafora Progressive Myoclonic Epilepsy
4.5.2.3 Galactosemia
4.5.2.4 Hereditary Fructose Intolerance
4.5.2.5 Congenital Disorders of Glycosylation (CDG)
4.5.3 Lipid/Glycolipid and Lipoprotein Metabolism Disorders
4.5.3.1 Niemann-Pick Disease (NPD)
4.5.3.2 Gaucher Disease
4.5.3.3 Mucolipidoses
4.5.4 Amino Acid Metabolism Disorders
4.5.4.1 Tyrosinemia
4.5.5 Mitochondrial Hepatopathies
4.5.5.1 Electron Transport (Respiratory Chain) Defects
4.5.5.2 Fatty Acid Oxidation and Transport Defects
4.5.5.3 Urea Cycle Enzyme Defects
4.5.5.4 Secondary Mitochondrial Hepatopathies
4.5.6 Peroxisomal Disorders
4.5.7 Iron Metabolism Dysregulation
4.5.8 Copper Metabolism Dysregulation
4.5.8.1 Wilson Disease
4.5.8.2 Menkes Syndrome
4.5.9 Porphyria-Related Hepatopathies
4.5.10 Shwachman-Diamond Syndrome (SDS)
4.5.11 Chronic Granulomatous Disease (CGD)
4.5.12 Albinism-Related Liver Diseases
4.6 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection
4.6.1 Acute Viral Hepatitis
4.6.2 Chronic Viral Hepatitis
4.6.3 Autoimmune Hepatitis
4.6.4 Drug-Induced Liver Disease (Chemical Injury) and TPN
4.6.5 Granulomatous Liver Disease
4.6.6 Alcoholic Liver Disease
4.6.7 Non-alcoholic Steatohepatitis
4.6.8 Acute and Chronic Rejection Post-Liver Transplantation
4.7 Hepatic Vascular Disorders
4.7.1 Acute and Chronic Passive Liver Congestion
4.7.2 Ischemic Hepatocellular Necrosis
4.7.3 Shock-Related Cholestasis
4.8 Liver Failure and Liver Cirrhosis
4.9 Portal Hypertension
4.10 Bacterial and Parasitic Liver Infections
4.10.1 Pyogenic Abscess
4.10.2 Helminthiasis
4.11 Liver Tumors
4.11.1 Benign Tumors (Figs. 4.31, 4.32, and 4.33)
4.11.1.1 Nodular Regenerative Hyperplasia (NRH)
4.11.1.2 Partial Nodular Transformation (PNH)
4.11.1.3 Focal Nodular Hyperplasia (FNH)
4.11.1.4 Macro-Regenerative Nodule (or Nodularity) (MRN)
4.11.1.5 Liver Cell Adenoma (LCA)
4.11.1.6 Hepatocellular Dysplasia
4.11.1.7 Bile Duct Hamartoma (BDH)
4.11.1.8 Bile Duct Adenoma (BDA)
4.11.1.9 Biliary Cystadenoma (BCA)
4.11.1.10 Biliary Papillomatosis
4.11.1.11 Cavernous Hemangioma
4.11.1.12 Infantile Hemangioendothelioma
4.11.1.13 Peliosis Hepatis
4.11.1.14 Hepatic Mesenchymal Hamartoma
4.11.1.15 Teratoma
4.11.1.16 Angiomyolipoma
4.11.2 Malignant Tumors (Figs. 4.34, 4.35, 4.36, 4.37, 4.38, 4.39, 4.40, and 4.41)
4.11.2.1 Hepatoblastoma
4.11.2.2 Hepatocellular Carcinoma (HCC)
4.11.2.3 Cholangiocellular Carcinoma (CCA)
4.11.2.4 Hepatic Angiosarcoma (HAS)
4.11.2.5 Undifferentiated Embryonal Liver Sarcoma (UELS)
4.11.2.6 Hepatic Leiomyosarcoma (HLMS) and Hepatic Rhabdomyosarcoma (HRMS)
4.11.2.7 Rhabdoid Tumor of the Liver
4.11.3 Metastatic Tumors
Multiple Choice Questions and Answers
References and Recommended Readings
5: Parenchymal GI Glands (Gallbladder, Biliary Tract, and Pancreas)
5.1 Development and Genetics
5.2 Biliary and Pancreatic Structural Anomalies
5.2.1 Choledochal Cysts
5.2.2 Gallbladder Congenital Abnormalities
5.2.3 Pancreas Congenital Anomalies
5.2.3.1 Agenesis/Aplasia/Hypoplasia (Both Exocrine and Endocrine Components)
5.2.3.2 Restricted Exocrine Hypoplasia (aka “lipomatous pseudohypertrophy of the pancreas”)
5.2.3.3 Ductal Abnormalities
5.2.3.4 Heterotopia Pancreatitis (Gr. ἕτερος or “Other, Different” and τόπος “Place”)
5.2.3.5 Annular Pancreas
5.2.3.6 Cystic Dysplasia
5.2.3.7 Congenital Cysts of the Pancreas
5.3 Gallbladder and Extrahepatic Biliary Tract
5.3.1 Cholesterolosis and Cholelithiasis
5.3.1.1 Cholelithiasis
5.3.2 Acute and Chronic Cholecystitis
5.3.2.1 Cholecystitis
Acute
5.3.2.2 Chronic Cholecystitis
Variants
5.3.3 Gallbladder Proliferative Processes and Neoplasms
5.3.3.1 Metaplasia
5.3.3.2 Dysplasia
5.3.3.3 Neoplasms
5.3.3.4 Gallbladder Carcinoma
5.3.4 Extrahepatic Bile Duct Tumors and Cholangiocellular Carcinoma
5.3.4.1 Carcinoma of the Extrahepatic Bile Ducts
5.3.4.2 Embryonal Rhabdomyosarcoma
5.4 Pancreas Pathology
5.4.1 Congenital Hyperinsulinism and Nesidioblastosis
5.4.2 Acute and Chronic Pancreatitis
5.4.2.1 Acute Pancreatitis
5.4.2.2 Chronic Pancreatitis
Pancreatitis Variants/Special Types
Pancreatitis, Lymphoplasmacytic Sclerosing Type
Pancreatitis, Granulocytic Epithelial Lesion Type
5.4.3 Pancreatoblastoma and Acinar Cell Carcinoma in Childhood and Youth
5.4.3.1 Pancreatoblastoma
5.4.3.2 Acinar Cell Carcinoma in Childhood and Youth
5.4.4 Cysts and Cystic Neoplastic Processes of the Pancreas
5.4.4.1 Pancreas Pseudocysts (PPC)
5.4.5 PanIN and Solid Pancreas Ductal Carcinoma
5.4.6 Other Tumors
5.4.7 Degenerative Changes and Transplant Pathology
5.4.7.1 Diabetes Mellitus
5.4.7.2 Pancreas Transplant
Multiple Choice Questions and Answers
References and Recommended Readings
6: Kidney, Pelvis, and Ureter
6.1 Development and Genetics
6.2 Non-cystic Congenital Anomalies
6.2.1 Disorders of Number
6.2.2 Disorders of Rotation
6.2.3 Disorders of Position
6.2.4 Disorders of Separation
6.3 Cystic Renal Diseases
6.3.1 Classifications
6.3.2 Autosomal Dominant Polycystic Kidney Disease
6.3.3 Autosomal Recessive Polycystic Kidney Disease
6.3.4 Medullary Sponge Kidney
6.3.5 Multicystic Dysplastic Kidney (MCDK)
6.3.6 Hydronephrosis/Hydroureteronephrosis
6.3.7 Simple Renal Cysts
6.3.8 Acquired Cystic Kidney Disease (CRD-Related)
6.3.9 Genetic Syndromes and Cystic Renal Disease
6.4 Primary Glomerular Diseases
6.4.1 Hypersensitivity Reactions and Major Clinical Syndromes of Glomerular Disease
6.4.2 Post-infectious Glomerulonephritis
6.4.3 Rapidly Progressive Glomerulonephritis
6.4.4 Minimal Change Disease
6.4.5 (Diffuse) Mesangial Proliferative GN
6.4.6 Focal and Segmental Glomerulosclerosis
6.4.7 Membranous Glomerulonephritis
6.4.8 Membranoproliferative (Membrane-Capillary) Glomerulonephritis
6.5 Secondary Glomerular Diseases
6.5.1 SLE/Lupus Nephritis
6.5.2 Henoch-Schönlein Purpura
6.5.3 Amyloidosis
6.5.4 Light Chain Disease
6.5.5 Cryoglobulinemia
6.5.6 Diabetic Nephropathy
6.6 Hereditary/Familial Nephropathies
6.6.1 Fabry Nephropathy
6.6.2 Alport Syndrome
6.6.3 Nail-Patella Syndrome
6.6.4 Congenital Nephrotic Syndrome
6.6.5 Thin Glomerular Basement Membrane Nephropathy (TBMN)
6.7 Tubulointerstitial Diseases
6.7.1 Acute Tubulointerstitial Nephritis (ATIN)
6.7.1.1 Acute Pyelonephritis
6.7.1.2 Pyonephrosis
6.7.1.3 Acute Hypersensitivity Nephritis (AHN)
6.7.1.4 Renal Papillary Necrosis
6.7.2 Chronic Tubulointerstitial Nephritis (CTIN)
6.7.3 Acute Tubular Necrosis
6.7.4 Chronic Renal Failure (CRF)
6.7.5 Nephrolithiasis and Nephrocalcinosis
6.7.6 Osmotic Nephrosis and Hyaline Change
6.7.7 Hypokalemic Nephropathy
6.7.8 Urate Nephropathy
6.7.9 Cholemic Nephropathy/Jaundice-Linked Acute Kidney Injury
6.7.10 Myeloma Kidney
6.7.11 Radiation Nephropathy
6.7.12 Tubulointerstitial Nephritis and Uveitis (TINU)
6.8 Vascular Diseases
6.8.1 Benign Nephrosclerosis
6.8.2 Malignant Nephrosclerosis
6.8.3 Renal Artery Stenosis
6.8.4 Infarcts
6.8.5 Vasculitis
6.8.6 Hemolytic Uremic Syndrome
6.8.7 Thrombotic Thrombocytopenic Purpura
6.9 Renal Transplantation
6.9.1 Preservation Injury
6.9.2 Hyperacute Rejection
6.9.3 Acute Rejection
6.9.4 Chronic Rejection
6.9.5 Humoral (Acute/Chronic) Rejection
6.9.6 Antirejection Drug Toxicity
6.9.7 Recurrence of Primary Disorder
6.10 Hereditary Cancer Syndromes Associated with Renal Tumors
6.10.1 Beckwith-Wiedemann Syndrome
6.10.2 WAGR Syndrome
6.10.3 Denys-Drash Syndrome
6.10.4 Non-WT1/Non-WT2 Pediatric Syndromes
6.10.5 Von Hippel Lindau Syndrome
6.10.6 Tuberous Sclerosis Syndrome
6.10.7 Hereditary Papillary Renal Carcinoma Syndrome
6.10.8 Hereditary Leiomyoma Renal Carcinoma Syndrome
6.10.9 Birt-Hogg-Dube Syndrome
6.11 Pediatric Tumors (Embryonal)
6.11.1 Wilms Tumor (Nephroblastoma)
6.11.2 Cystic Partially Differentiated Nephroblastoma (CPDN) and (Pediatric) Cystic Nephroma
6.11.3 Congenital Mesoblastic Nephroma
6.11.4 Clear Cell Sarcoma
6.11.5 Rhabdoid Tumor
6.11.6 Metanephric Tumors
6.11.7 XP11 Translocation Carcinoma
6.11.8 Ossifying Renal Tumor of Infancy
6.12 Non-embryonal Tumors of the Young
6.12.1 Clear Cell Renal Cell Carcinoma
6.12.2 Chromophobe Renal Cell Carcinoma
6.12.3 Papillary Adenoma and Renal Cell Carcinoma
6.12.4 Collecting Duct Carcinoma
6.12.5 Renal Medullary Carcinoma
6.12.6 Angiomyolipoma
6.12.7 Oncocytoma
6.12.8 Other Epithelial and Mesenchymal Tumors
6.13 Non-neoplastic Pathology of the Pelvis and Ureter
6.13.1 Anatomy and Physiology Notes
6.13.2 Congenital Pelvic-Ureteral Anomalies
6.13.3 Congenital Ureteric Anomalies
6.13.4 Lower Urinary Tract Abnormalities
6.14 Tumors of the Pelvis and Ureter
6.14.1 Neoplasms
6.14.2 Genetic Syndromes
Multiple Choice Questions and Answers
References and Recommended Readings
7: Lower Urinary and Male Genital System
7.1 Development and Genetics
7.1.1 Urinary Bladder and Ureter
7.1.2 Testis, Prostate, and Penis
7.2 Lower Urinary and Genital System Anomalies
7.2.1 Lower Urinary System Anomalies
7.2.1.1 Double Ureters
7.2.1.2 Urinary Bladder Diverticula
7.2.1.3 Persistence of the Urachus
7.2.1.4 Urinary Bladder Exstrophy
7.2.2 Male Genital System Anomalies
7.2.2.1 Anorchia/Anorchism
7.2.2.2 Testicular Regression Syndrome
7.2.2.3 Cryptorchidism and Polyorchidism (Polyorchism)
7.2.2.4 Heterotopias and Heterotopia-Mimickers
7.2.2.5 Bifid Scrotum
7.2.2.6 Prostate Gland Agenesis/Dysgenesis
7.2.2.7 Phimosis and Paraphimosis
7.2.2.8 Urethral Meatus Abnormalities
7.2.2.9 Size and Numerical Abnormalities of the Penis
7.3 Urinary Tract Inflammatory and Degenerative Conditions
7.3.1 Cystitis, Infectious
7.3.2 Cystitis, Non-infectious
7.3.3 Malacoplakia of the Young
7.3.4 Urinary Tract Infections and Vesicoureteral Reflux
7.3.5 Megacystis, Megaureter, Hydronephrosis, and Neurogenic Bladder
7.3.6 Urinary Tract Endometriosis
7.3.7 Tumorlike Lesions (Including Caruncles)
7.4 Preneoplastic and Neoplastic Conditions of the Urinary Tract
7.4.1 Urothelial Hyperplasia (Flat and Papillary)
7.4.2 Reactive Atypia, Atypia of Unknown Significance, Dysplasia, and Carcinoma In Situ (CIS)
7.4.3 Noninvasive Papillary Urothelial Neoplasms
7.4.4 Invasive Urothelial Neoplasms
7.4.5 Non-urothelial Differentiated Urinary Tract Neoplasms
7.5 Male Infertility-Associated Disorders
7.5.1 Spermiogram and Classification
7.6 Inflammatory Disorders of the Testis and Epididymis
7.6.1 Acute Orchitis
7.6.2 Epidermoid Cysts
7.6.3 Hydrocele
7.6.4 Spermatocele
7.6.5 Varicocele
7.7 Testicular Tumors
7.7.1 Germ Cell Tumors
7.7.1.1 Intratubular Germ Cell Neoplasia (ITGCN)
7.7.1.2 Seminoma
7.7.1.3 Embryonal Carcinoma (Testicular EC or TEC)
7.7.1.4 Teratoma
7.7.1.5 Yolk Sac Tumor (YST)/ Endodermal Sinus Tumor (EST)
7.7.1.6 Polyembryoma
7.7.1.7 Choriocarcinoma
7.7.2 Tumors of Specialized Gonadal Stroma
7.7.2.1 Leydig Cell Tumor (LeCT)
7.7.2.2 Sertoli Cell Tumors, Pseudotumors, and Related Lesions
7.7.3 Rhabdomyosarcoma and Rhabdoid Tumor of the Testis
7.7.4 Secondary Tumors
7.8 Tumors of the Epididymis
7.8.1 Adenomatoid Tumor
7.8.2 Papillary Cystadenoma
7.8.3 Rhabdomyosarcoma
7.8.4 Mesothelioma
7.9 Inflammatory Disorders of the Prostate Gland
7.9.1 Acute Prostatitis
7.9.2 Chronic Prostatitis
7.9.3 Granulomatous Prostatitis
7.9.4 Prostatic Malakoplakia of the Youth
7.10 Prostate Gland Overgrowths
7.10.1 Benign Nodular Hyperplasia of the Young and Fibromatosis
7.10.2 Rhabdomyosarcoma, Leiomyosarcoma, and Other Sarcomas (e.g., Ewing Sarcoma)
7.10.3 Prostatic Carcinoma Mimickers
7.10.4 Prostatic Intraepithelial Neoplasia (PIN)
7.10.5 Prostate Cancer of the Young
7.10.6 Hematological Malignancies
7.10.7 Secondary Tumors
7.11 Inflammatory and Neoplastic Disorders of the Penis
7.11.1 Infections
7.11.1.1 Balanoposthitis
7.11.1.2 Syphilis
7.11.1.3 Lymphogranuloma Venereum
7.11.1.4 Others
7.11.2 Non-infectious Inflammatory Diseases
7.11.2.1 Balanitis Xerotica Obliterans
7.11.2.2 Balanitis Circumscripta Plasmacellularis
7.11.2.3 Peyronie Disease
7.11.3 Penile Cysts and Noninvasive Squamous Cell Lesions
7.11.4 Penile Squamous Cell Carcinoma of the Youth
7.11.5 Non-squamous Cell Carcinoma Neoplasms of the Penis
Multiple Choice Questions and Answers
References and Recommended Readings
8: Female Genital System
8.1 Development and Genetics
8.2 Congenital Anomalies of the Female Genital System
8.3 Ovarian Inflammatory and Degenerative Conditions
8.3.1 Oophoritis
8.3.2 Torsion
8.3.3 Non-neoplastic Cystic Lesions
8.3.3.1 Germinal Inclusion Cysts
8.3.3.2 Follicular Cysts
8.3.3.3 Corpus Luteum Cysts
8.3.3.4 Polycystic Change
8.3.3.5 Hyperreactio Luteinalis
8.3.3.6 Epidermoid Cysts
8.3.4 Non-neoplastic Proliferations
8.3.4.1 Endometriosis
8.3.4.2 Endosalpingiosis
8.3.4.3 Stromal Hyperplasia and Stromal Hyperthecosis
8.3.4.4 Hilus Cell Hyperplasia
8.3.4.5 Ectopic Decidual Reaction
8.3.4.6 Massive Edema of the Ovary
8.3.4.7 Fibromatosis Ovarii
8.3.4.8 Pregnancy Luteoma
8.4 Infectious Diseases of the Female Genital System
8.4.1 Viral Diseases
8.4.1.1 Herpes Genitalis
8.4.1.2 Condyloma Acuminatum
8.4.2 Bacterial Diseases
8.4.2.1 Syphilis
8.4.2.2 Gonorrhea
8.4.2.3 Chlamydia Infections
8.4.2.4 Chancroid
8.4.2.5 Granuloma Inguinale
8.4.3 Fungal Diseases
8.4.3.1 Candidiasis
8.4.4 Parasitic Diseases
8.4.4.1 Trichomoniasis
8.5 Inflammatory, Reactive Changes and Degenerative Conditions of Vulva, Vagina, Cervix, Uterus, and Tuba
8.5.1 Non- and Preneoplastic Vulvar and Vaginal Lesions
8.5.1.1 Cystic Lesions of the Vulva
8.5.1.2 Vulvitis, Neovagina, and Urothelial Metaplasia
8.5.1.3 Vulvar Dystrophies
8.5.1.4 Vaginal Adenosis
8.5.1.5 Benign Discolored Lesions of the Vulva
8.5.1.6 Vaginal Pseudotumors
8.5.1.7 Endometriosis Vulvae Sive Vaginae Vel Vulvovagine
8.5.2 Inflammation-Associated Cervical Lesions
8.5.2.1 Infective Cervicitis
8.5.2.2 Non-infective Cervicitis
8.5.2.3 Papillary Endocervicitis
8.5.3 Reactive Changes of the Cervix
8.5.4 Cyst-Associated Cervical Lesions
8.5.5 Ectopia-Associated Cervical Lesions
8.5.6 Pregnancy-Associated Cervical Lesions
8.5.7 Cervical Metaplasias
8.5.8 Non-neoplastic and Preneoplastic Uterine Lesions
8.5.8.1 Dysfunctional Uterine Bleeding
8.5.8.2 Endometritis
8.5.8.3 Endometrial Metaplasias
8.5.8.4 Adenomyosis and Endometriosis
8.5.9 Non-neoplastic Abnormalities of the Tuba
8.6 Tumors of the Ovary
8.6.1 Germ Cell Tumors
8.6.1.1 Dysgerminoma
8.6.1.2 Teratoma
8.6.1.3 Yolk Sac Tumor (YST)/ Endodermal Sinus Tumor (EST)
8.6.1.4 Embryonal Carcinoma
8.6.1.5 Polyembryoma
8.6.1.6 Choriocarcinoma
8.6.2 Surface Epithelial Tumors
8.6.2.1 Serous Tumors
Serous Cystadenoma/Cystadenofibroma
Serous Borderline (Proliferative) Tumors (LMP)
Ovarian Implants and Benign Mimics
Ovarian Serous (Cyst-) Adenocarcinoma (OSCAC/OSAC)
Low-Grade vs. High-Grade Serous Carcinoma
TP53 Gene Mutational Status and Gene Product Expression (p53 IHC)
8.6.2.2 Mucinous Tumors
8.6.2.3 Endometrioid Tumors
8.6.2.4 Clear Cell (Mesonephroid) Tumors
8.6.2.5 Brenner (Transitional Cell) Tumors
8.6.3 Sex Cord-Stromal Tumors
8.6.3.1 Granulosa Cell Tumor
8.6.3.2 Sertoli-Leydig Cell Tumor
8.6.3.3 Steroid/Lipid Cell-Rich Tumor Group
8.6.3.4 Fibroma/Thecoma Group
8.6.3.5 Sclerosing Stromal Tumor
8.6.3.6 Sex Cord Tumor with Annular Tubules
8.6.3.7 Gynandroblastoma
8.6.4 Other Primary Ovarian and Secondary Tumors
8.6.4.1 Gonadoblastoma
8.7 Tumors of the Tuba
8.7.1 Benign Neoplasms
8.7.2 Malignant Neoplasms
8.8 Tumors of the Uterus
8.8.1 Type I/Type II EC
8.8.2 Non-type I/Non-type II EC
8.8.3 Uterine Leiomyoma (ULM) and Variants
8.8.4 Uterine Leiomyosarcoma (ULMS)
8.8.5 Uterine Adenomatoid Tumor
8.8.6 Uterine Lymphangiomyomatosis (ULAM)
8.8.7 Uterine Stroma Tumors
8.8.8 Hematological Malignancies and Secondary Tumors
8.9 Tumors of the Cervix
8.9.1 Benign Neoplasms
8.9.2 Precancerous Conditions and Malignant Neoplasms
8.9.2.1 Cervical Dysplasia
8.9.2.2 Cervical Epidermoid Carcinoma
8.9.2.3 Cervical Adenocarcinoma and Variants
Minimal Deviation Adenocarcinoma
Villoglandular Papillary Carcinoma
Basaloid Carcinoma
Adenoid Basal Carcinoma
Clear Cell Carcinoma
Mesonephric Carcinoma
Adenosquamous (Mixed) Carcinoma
Glassy Cell Carcinoma
Adenoid Cystic Carcinoma
8.9.2.4 Cervical Neuroendocrine Carcinoma (CNEC)
8.10 Tumors of the Vagina
8.10.1 Benign Tumors
8.10.1.1 (Müllerian) Papilloma
8.10.1.2 Vaginal Fibroepithelial Polyp
8.10.1.3 Vaginal Postoperative Spindle (Cell) Nodule (POSN)
8.10.1.4 Other Vaginal Benign Tumors
8.10.2 Precancerous Conditions and Malignant Tumors
8.10.2.1 Vaginal Intraepithelial Neoplasia (VAIN I–III)
8.10.2.2 Vaginal Epidermoid Carcinoma
8.10.2.3 Vaginal Adenocarcinoma
8.10.2.4 Vaginal Rhabdomyosarcoma of Botryoid Type (B-ERMS)
8.10.2.5 Vaginal Yolk Sac Tumor (YST) or Endodermal Sinus Tumor (EST)
8.10.2.6 Other Vaginal Malignant Neoplasms
8.11 Tumors of the Vulva
8.11.1 Benign Neoplasms
8.11.1.1 Condyloma Acuminatum
8.11.1.2 Ectopic Mammary Tissue and Hidradenoma Papilliferum
8.11.1.3 Squamous Papilloma, Vulvar/Vestibular Squamous Papillomatosis, and Fibroepithelial Polyp (Acrochordon)
8.11.1.4 Vulvar Melanocytic Nevi
8.11.1.5 Vulvar Angiomyofibro
8.11.1.6 Vulvar Cellular Angiofibroma (CAF)
8.11.1.7 Other Benign Lesions of the Vulva
8.11.2 Malignant Tumors
8.11.2.1 Precancerous Malignant Conditions
Vulvar Intraepithelial Neoplasia (VIN)
8.11.2.2 Vulvar Epidermoid Carcinoma
8.11.2.3 Vulvar Epidermoid Carcinoma Variants
8.11.2.4 Extramammary Paget disease (EMPD) of the Vulva or Vulvar Paget Disease (VPD)
8.11.2.5 Bartholin Gland Carcinoma and Other Carcinomas
8.11.2.6 Vulvar Aggressive Angiomyxoma
8.11.2.7 Vulvar Epithelioid Sarcoma and Other Sarcomas
8.11.2.8 Vulvar Malignant Melanoma
Multiple Choice Questions and Answers
References and Recommended Readings
9: Breast
9.1 Development and Genetics
9.2 Congenital Anomalies, Inflammatory, and Related Disorders
9.2.1 Amastia, Atelia, Synmastia, Polymastia, and Politelia
9.2.2 Asymmetry, Hypotrophy, and Hypertrophy
9.2.3 Dysmaturity and Precocious Thelarche
9.2.4 Acute Mastitis, Abscess, and Phlegmon
9.2.5 Duct Ectasia, Periductal Mastitis, and Granulomatous Mastitis
9.2.6 Necrosis, Calcifications, and Mondor Disease
9.3 Pathology of the Female and Young Adult
9.3.1 Fibrocystic Disease
9.3.2 Soft Tissue Tumors and Hematological Malignancies
9.3.3 Fibroadenoma
9.3.4 Adenoma
9.3.4.1 Tubular Adenoma
9.3.4.2 Lactating Adenoma
9.3.4.3 Nipple Duct Adenoma (NDA)
9.3.4.4 Syringomatous Adenoma of the Nipple (SAN)
9.3.4.5 Intraductal Papilloma, Papillomatosis, and “Encysted Intraductal Papillary Carcinoma”
9.3.4.6 Ductal Adenoma
9.3.4.7 Apocrine Adenoma
9.3.5 Genetic Background of Breast Cancer
9.3.6 In Situ and Invasive Ductal Breast Carcinoma
9.3.6.1 Ductal Carcinoma In Situ
9.3.6.2 Invasive Ductal Carcinoma
9.3.7 In Situ and Invasive Lobular Breast Carcinoma
9.3.8 WHO Variants of the Infiltrating Ductal Carcinoma
9.3.9 Sweat Gland-Type Tumors and Myoepithelial Tumors
9.3.10 Phyllodes Tumor
9.4 Cancer Mimickers
9.4.1 Hyperplasia, Ductal and Lobular
9.4.2 Adenosis
9.5 Male Breast Disease
9.5.1 Gynecomastia
9.5.2 Breast Cancer of the Male
Multiple Choice Questions and Answers
References and Recommended Readings
10: Hematolymphoid System
10.1 Development and Genetics
10.2 Red Blood Cell Disorders
10.2.1 Anemia
10.2.1.1 Anemia Due to Excessive Blood Turnover
10.2.1.2 Anemia Due to Failure of Blood Production
10.2.2 Polycythemia
10.2.2.1 Primary Polycythemia (aka Polycythemia vera)
10.2.2.2 Secondary Polycythemia
10.3 Coagulation and Hemostasis Disorders
10.3.1 Coagulation and Hemostasis
10.3.2 Coagulation Disorders
10.3.2.1 Coagulation Disorders
10.3.2.2 Acquired Disorders
10.3.3 Platelet Disorders
10.3.3.1 Primary (Essential) Thrombocythemia
10.4 White Blood Cell Disorders
10.4.1 Leukocytopenias and Leukocyte Dysfunctionalities
10.4.2 Non-neoplastic Leukocytosis
10.4.3 Leukemia (Neoplastic Leukocytosis) or Virchow’s “Weisses Blut”
10.4.3.1 Acute Lymphoblastic (Lymphocytic) Leukemia (ALL)
10.4.3.2 Chronic Lymphocytic Leukemia (CLL)
10.4.3.3 Acute Myeloblastic (Myelocytic) Leukemia (AML)
10.4.3.4 Chronic Myelocytic Leukemia (CML)
10.4.3.5 Myeloid Sarcoma
10.4.3.6 Hairy Cell Leukemia (HCL)
10.4.3.7 Transient Atypical Myelopoiesis (TAM)
10.4.4 Myelodysplastic Syndromes
10.4.5 Hodgkin Lymphoma
10.4.6 Non-Hodgkin Lymphomas
10.4.7 Follicular Lymphoma
10.4.8 Small Lymphocytic Lymphoma
10.4.9 Mantle Cell Lymphoma (MCL)
10.4.10 Marginal Cell Lymphoma
10.4.11 Diffuse Large B-Cell Lymphoma (DLBCL)
10.4.12 Lymphoblastic Lymphoma
10.4.13 Burkitt Lymphoma
10.4.14 Peripheral T-Cell Lymphoma
10.4.15 Anaplastic Large Cell Lymphoma
10.4.16 Adult T-Cell Leukemia/Lymphoma
10.4.17 Cutaneous T-Cell Lymphoma (CTCL)
10.4.18 Angiocentric Immunoproliferative Lesions
10.4.19 Extranodal NK-/T-Cell Lymphoma
10.5 Disorders of the Monocyte-Macrophage System and Mast Cells
10.5.1 Hemophagocytic Syndrome
10.5.2 Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease)
10.5.3 Langerhans Cell Histiocytosis
10.5.4 Histiocytic Medullary Reticulosis
10.5.5 True Histiocytic Lymphoma
10.5.6 Systemic Mastocytosis
10.6 Plasma Cell Disorders
10.6.1 Multiple Myeloma
10.6.2 Solitary Myeloma
10.6.3 Plasma Cell Leukemia
10.6.4 Waldenstrom’s Macroglobulinemia
10.6.5 Heavy Chain Disease
10.6.6 Monoclonal Gammopathy of Undetermined Significance (MGUS)
10.7 Benign Lymphadenopathies
10.7.1 Follicular Hyperplasia
10.7.1.1 Nonspecific Reactive Lymphadenitis
10.7.1.2 Toxoplasmosis
10.7.1.3 Rheumatoid Arthritis and Sjögren Disease
10.7.1.4 Systemic Lupus Erythematosus (SLE) Lymphadenopathy
10.7.1.5 Necrotizing Lymphadenitis (Kikuchi-Fujimoto Lymphadenitis)
10.7.1.6 Cat-Scratch Disease
10.7.1.7 Lymphogranuloma Venereum
10.7.1.8 Kimura Disease
10.7.1.9 Syphilis
10.7.1.10 Castleman Disease
10.7.1.11 Progressive Transformation of Germinal Centers (PTGC)
10.7.1.12 AIDS-Related Lymphadenopathy
10.7.2 Diffuse (Paracortical) Hyperplasia
10.7.2.1 ALPS
10.7.2.2 Postvaccinal Viral Lymphadenitis
10.7.2.3 Infectious Mononucleosis
10.7.2.4 Dermatopathic Lymphadenitis
10.7.3 Sinus Pattern
10.7.3.1 Sinus Histiocytosis
10.7.3.2 Sinus Histiocytosis with Massive Lymphadenopathy
10.7.3.3 Lipophagic Reactions
10.7.3.4 Vascular Transformation of LN Sinuses
10.7.4 Predominant Granulomatous Pattern
10.7.4.1 Tuberculosis
10.7.4.2 Atypical Mycobacteriosis
10.7.4.3 Sarcoidosis (See Lung) Lymphadenopathy
10.7.4.4 Fungal Infections
10.7.4.5 Chronic Granulomatous Disease
10.7.5 Other Myxoid Patterns
10.7.5.1 Kawasaki Disease
10.7.5.2 Leprosy
10.7.5.3 Mesenteric Lymphadenitis
10.7.6 Angioimmunoblastic Lymphadenopathy with Dysproteinemia (AILD)
10.8 Disorders of the Spleen
10.8.1 White Pulp Disorders of the Spleen
10.8.1.1 Reactive Follicular Hyperplasia
10.8.1.2 Reactive Non-follicular Lymphoid Hyperplasia
10.8.1.3 Chronic Lymphocytic Anemia
10.8.1.4 Malignant Lymphomas
10.8.2 Red Pulp Disorders of the Spleen
10.8.2.1 Congestion
10.8.2.2 Infection
10.8.2.3 Leukemia
10.8.2.4 Histiocytic Proliferations
10.9 Disorders of the Thymus
10.9.1 Thymic Cysts and Thymolipoma
10.9.2 True Thymic Hyperplasia and Thymic Follicular Hyperplasia
10.9.3 HIV Changes
10.9.4 Thymoma
Multiple Choice Questions and Answers
References and Recommended Readings
11: Endocrine System
11.1 Development and Genetics
11.2 Pituitary Gland Pathology
11.2.1 Congenital Anomalies of the Pituitary Gland
11.2.2 Vascular and Degenerative Changes
11.2.3 Pituitary Adenomas and Hyperpituitarism
11.2.3.1 Classification of Pituitary Adenomas
11.2.3.2 Pituitary Tumor Morphology
11.2.3.3 Clinical Course of Pituitary Neoplasia
11.2.4 Genetic Syndromes Associated with Pituitary Adenomas
11.2.5 Hypopituitarism (Simmonds Disease)
11.2.6 Empty Sella Syndrome (ESS)
11.2.7 Neurohypophysopathies (Disorders of the Posterior Pituitary Gland)
11.2.7.1 Diabetes Insipidus
11.2.7.2 ADH Hypersecretion
11.3 Thyroid Gland Pathology
11.3.1 Congenital Anomalies, Hyperplasia, and Thyroiditis
11.3.2 Congenital Anomalies, Goiter, and Dysfunctional Thyroid Gland
11.3.2.1 Congenital Anomalies of the Thyroid Gland
11.3.2.2 Dysfunctional Thyroid Gland and Dyshormonogenetic Goiter
11.3.2.3 Graves Disease (Diffuse Hyperplasia)
11.3.2.4 Multinodular Goiter
11.3.3 Inflammatory and Immunologic Thyroiditis
11.3.3.1 Acute Thyroiditis
11.3.3.2 Granulomatous (Subacute) Thyroiditis
11.3.3.3 Autoimmune Thyroiditis
11.3.3.4 IgG4-Related Thyroiditis and Riedel’s Thyroiditis
11.3.4 Epithelial Neoplasms of the Thyroid Glands
11.3.4.1 Follicular Thyroid Adenoma
11.3.4.2 Follicular Thyroid Carcinoma
11.3.4.3 Papillary Thyroid Carcinoma
11.3.4.4 Medullary Thyroid Carcinoma
11.3.4.5 Hürthle Cell Tumors
11.3.4.6 Poorly Differentiated Thyroid Carcinoma
11.3.4.7 Anaplastic Thyroid Carcinoma
11.3.4.8 Other Epithelial Tumors
11.3.4.9 Non-epithelial Neoplasms
11.3.4.10 Secondary (Metastatic) Tumors
11.4 Parathyroid Gland Pathology
11.4.1 Congenital Anomalies of the Parathyroid Glands
11.4.2 Parathyroid Gland Hyperplasia
11.4.3 Parathyroid Gland Adenoma
11.4.4 Parathyroid Gland Carcinoma
11.5 Adrenal Gland Pathology
11.5.1 Congenital Anomalies of the Adrenal Gland and Paraganglia
11.5.2 Dysfunctional Adrenal Gland
11.5.3 Adrenalitis
11.5.4 Neoplasms of the Adrenal Gland and Paraganglia
11.5.4.1 Adrenocortical Adenoma
11.5.4.2 Adrenal Cortical Carcinoma
11.5.4.3 Neuroblastoma, Ganglioneuroblastoma, and Ganglioneuroma
11.5.4.4 Pheochromocytoma and Paraganglioma
11.5.4.5 Other Tumors and Secondary Tumors
11.5.5 Syndromes Associated with Adrenal Cortex Abnormalities
Multiple Choice Questions and Answers
References and Recommended Readings
12: Soft Tissue
12.1 Development and Genetics
12.2 Vascular and Inflammatory Changes of Soft Tissue
12.2.1 Hyperemia
12.2.2 Necrotizing Fasciitis
12.2.3 Vasculitis-Associated Soft Tissue Changes
12.2.4 Miscellaneous
12.3 Soft Tissue Neoplasms: Scoring
12.4 Adipocytic Tumors
12.4.1 Lipoma
12.4.2 Lipoma Subtypes
12.4.3 Lipomatosis
12.4.4 Lipoblastoma
12.4.5 Hibernoma
12.4.6 Locally Aggressive and Malignant Adipocytic Tumors
12.4.6.1 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
12.4.6.2 Myxoid/Round Cell Liposarcoma
12.4.6.3 Pleomorphic Liposarcoma
12.4.6.4 Dedifferentiated Liposarcoma
12.5 Fibroblastic/Myofibroblastic Tumors
12.5.1 Fasciitis/Myositis Group
12.5.1.1 Nodular Fasciitis
12.5.2 Fibroma Group
12.5.2.1 Nuchal-Type Fibroma (NTF)
12.5.2.2 Gardner Fibroma
12.5.2.3 Nasopharyngeal Fibroma
12.5.2.4 Ovarian Fibroma
12.5.2.5 Fibroma of Tendon Sheath
12.5.2.6 Elastofibroma
12.5.2.7 “Genital” Cellular Angiofibroma (GCAF)
12.5.2.8 Keloid
12.5.3 Fibroblastoma Classic and Subtypes
12.5.3.1 Desmoplastic Fibroblastoma (DFB)
12.5.3.2 Giant Cell Fibroblastoma (GCFB)
12.5.3.3 Angio-Myofibroblastoma (AMFB)
12.5.3.4 Mammary-Type Myofibroblastoma (MTMFB)
12.5.4 Fibrous Hamartoma of Infancy (FHI)
12.5.5 Fibromatosis of Childhood
12.5.5.1 Fibromatosis Colli (FCO)
12.5.5.2 Infantile Digital Fibromatosis
12.5.5.3 Infantile Fibromatosis, Desmoid Type
12.5.5.4 Juvenile Hyaline Fibromatosis
12.5.5.5 Gingival Fibromatosis
12.5.6 Infantile Myofibroma/Myofibromatosis
12.5.7 Fibroblastic/Myofibroblastic Tumors with Intermediate Malignant Potential
12.5.7.1 Solitary Fibrous Tumor, Hemangiopericytoma, and Giant Cell Angiofibroma
Giant Cell Angiofibroma (GCAF)
12.5.7.2 Inflammatory Myofibroblastic Tumor
12.5.7.3 Low-Grade Myofibroblastic Sarcoma (LGMFS)
12.5.7.4 Myxo-inflammator Fibroblastic Sarcoma (MIFS)
12.5.7.5 Infantile Fibrosarcoma
12.5.8 Malignant Fibroblastic/Myofibroblastic Tumors
12.5.8.1 Adult Fibrosarcoma (AFS)
12.5.8.2 Myxofibrosarcoma
12.5.8.3 Low-Grade Fibro-Myxoid Sarcoma (LGFMS)
12.5.8.4 Sclerosing Epithelioid Fibrosarcoma
12.6 Fibrohistiocytic Tumors
12.6.1 Histiocytoma
12.6.1.1 Juvenile Xanthogranuloma
12.6.1.2 Reticulohistiocytoma
12.6.2 Benign Fibrous Histiocytoma
12.6.2.1 Dermatofibroma
12.6.2.2 Giant Cell Tumor of Tendon Sheath (GCTTS)
12.6.2.3 Pigmented Villonodular Synovitis or Diffuse-Type Giant Cell Tumor
12.6.2.4 Cellular Fibrous Histiocytoma
Plexiform Fibrohistiocytic Tumor
Giant Cell Tumor of Soft Tissues
12.6.3 Borderline Fibrous Histiocytoma
12.6.4 Malignant Fibrous Histiocytoma
12.7 Smooth Muscle Tumors
12.7.1 Leiomyoma
12.7.2 EBV-Related Smooth Muscle Tumors
12.7.3 Leiomyosarcoma
12.8 Pericytic Tumors
12.8.1 Glomus Tumor
12.8.2 Glomangiosarcoma
12.8.3 Myopericytoma
12.9 Skeletal Muscle Tumors
12.9.1 Rhabdomyomatous Mesenchymal Hamartoma (RMH)
12.9.2 Rhabdomyoma
12.9.3 Rhabdomyosarcoma
12.9.3.1 Embryonal RMS
12.9.3.2 Botryoid RMS
12.9.3.3 Spindle-Cell RMS
12.9.3.4 Alveolar RMS
12.9.4 Pleomorphic RMS
12.9.4.1 Late Effects of Childhood Cancer Therapy
12.10 Vascular Tumors
12.10.1 Benign Vascular Tumors
12.10.1.1 Hemangioma
12.10.1.2 Hemangioma Variants
12.10.1.3 Lymphangioma
12.10.2 Vascular Tumors with Intermediate Malignant Potential
12.10.2.1 Hemangioendothelioma
Hemangioendothelioma Variants
12.10.2.2 Kaposi Sarcoma
12.10.3 Malignant Vascular Tumors
12.10.3.1 Epithelioid Hemangioendothelioma
12.10.3.2 Angiosarcoma
12.10.4 Genetic Syndromes Associated with Vascular Tumors
12.11 Chondro-Osteoforming Tumors
12.11.1 Extraskeletal Chondroma
12.11.2 Extraskeletal Myxoid Chondrosarcoma
12.11.3 Mesenchymal Chondrosarcoma
12.11.4 Extraskeletal Aneurysmatic Bone Cyst
12.11.5 Extraskeletal Osteosarcoma (ESOS)
12.11.6 Extraskeletal Chordoma
12.12 Tumors of Uncertain Differentiation
12.12.1 Myxoma
12.12.2 Myoepithelial Carcinoma
12.12.3 Parachordoma
12.12.4 Synovial Sarcoma
12.12.5 Epithelioid Sarcoma
12.12.6 Alveolar Soft Part Sarcoma
12.12.7 Clear Cell Sarcoma
12.12.8 Extraskeletal Myxoid Chondrosarcoma (ESMC)
12.12.9 PNET/Extraskeletal Ewing Sarcoma (ESES)
12.12.10 Desmoplastic Small Round Cell Tumor
12.12.11 Extrarenal Rhabdoid Tumor
12.12.12 Malignant Mesenchymoma
12.12.13 PEComa
12.12.14 Extrarenal Wilms’ Tumor
12.12.15 Sacrococcygeal Teratoma and Extragonadal Germ Cell Tumor and Yolk Sac Tumor
Multiple Choice Questions and Answers
References and Recommended Readings
13: Arthro-Skeletal System
13.1 Development and Genetics
13.2 Osteochondrodysplasias
13.2.1 Nosology and Nomenclature
13.2.2 Groups of Genetic Skeletal Disorders
13.2.2.1 Thanatophoric Dysplasia
13.3 Metabolic Skeletal Diseases
13.3.1 Rickets, and Osteomalacia
13.3.1.1 Vitamin D Deficiency
13.3.2 Osteoporosis of the Youth
13.3.3 Paget Disease of the Bone
13.3.4 Juvenile Paget Disease
13.4 Osteitis and Osteomyelitis
13.4.1 Osteomyelitis
13.5 Osteonecrosis
13.5.1 Bony Infarct and Osteochondritis Dissecans
13.5.1.1 Bony Infarct
13.5.1.2 Osteochondritis Dissecans
13.6 Tumorlike Lesions and Bone/Osteoid-Forming Tumors
13.6.1 Myositis Ossificans
13.6.2 Fibrous Dysplasia and Osteofibrous Dysplasia
13.6.2.1 Fibrous Dysplasia
13.6.2.2 Osteofibrous Dysplasia (OFD)
13.6.3 Non-ossifying Fibroma (NOF)
13.6.4 Bone Cysts
13.6.4.1 Simple Bone Cyst
13.6.4.2 Aneurysmal Bone Cyst
13.6.5 Osteoma, Osteoid Osteoma, and Giant Osteoid Osteoma
13.6.5.1 Osteoma
13.6.5.2 Osteoid Osteoma
13.6.5.3 Giant Osteoid Osteoma (GOO)
13.6.6 Giant Cell Tumor
13.6.7 Osteosarcoma
13.7 Chondroid (Cartilage)-Forming Tumors
13.7.1 Osteochondroma
13.7.2 Enchondroma
13.7.3 Chondroblastoma
13.7.4 Chondromyxoid Fibroma
13.7.5 Chondrosarcoma
13.8 Bone Ewing Sarcoma
13.9 Miscellaneous Bone Tumors
13.9.1 Chordoma
13.9.2 Adamantinoma
13.9.3 Langerhans Cell Histiocytosis
13.9.4 Vascular, Smooth Muscle, and Lipogenic Tumors
13.9.5 Hematologic Tumors
13.10 Metastatic Bone Tumors
13.11 Juvenile Rheumatoid Arthritis and Juvenile Arthropathies
13.11.1 Rheumatoid Arthritis and Juvenile Rheumatoid Arthritis
13.11.1.1 Rheumatoid Arthritis
13.11.1.2 Juvenile Rheumatoid Arthritis
13.11.2 Infectious Arthritis
13.11.3 Gout, Early-Onset Juvenile Tophaceous Gout and Pseudogout
13.11.3.1 Gout
13.11.3.2 Early-Onset Juvenile (Tophaceous) Gout (EOJG)
13.11.3.3 Pseudogout
13.11.4 Bursitis, Baker Cyst, and Ganglion
13.11.4.1 Bursitis
13.11.4.2 Baker Cyst
13.11.4.3 Ganglion
13.11.5 Pigmented Villonodular Synovitis and Nodular Tenosynovitis
13.11.5.1 Pigmented Villonodular Synovitis (PVNS)
13.11.5.2 Nodular Tenosynovitis (NTS)
Multiple Choice Questions and Answers
References and Recommended Readings
14: Head and Neck
14.1 Development
14.2 Nasal Cavity, Paranasal Sinuses, and Nasopharynx
14.2.1 Congenital Anomalies
14.2.2 Inflammatory Lesions
14.2.2.1 Nasal Polyposis
14.2.3 Tumors
14.2.3.1 Benign Epithelial Tumors
Sinonasal Papilloma
14.2.3.2 Malignant Epithelial Tumors
Nasopharyngeal Carcinoma
14.2.3.3 Benign Mesenchymal Tumors
Nasopharyngeal Angiofibroma (NAF)
14.2.3.4 Other Tumors
Bone/Cartilaginous Forming Tumors
Hematolymphoid Tumors
Extranodal NK/T-Cell Lymphoma (EN-NK/T-NHL)
Diffuse Large B-Cell Lymphoma (DLBCL)
Extramedullary Myeloid Sarcoma (EMS)
Langerhans Cell Histiocytosis (LCH)
Neuroectodermal Tumors
PNET/Ewing Sarcoma
Esthesioneuroblastoma
Melanotic Neuroectodermal Tumor of Infancy (MNETI)
Mucosal Malignant Melanoma
Germ Cell Tumors
Secondary Tumors
14.3 Larynx and Trachea
14.3.1 Congenital Anomalies
14.3.1.1 Thyroglossal Duct Cyst and Laryngeal Disturbances
14.3.1.2 Laryngomalacia
14.3.2 Cysts and Laryngoceles
14.3.3 Inflammatory Lesions and Non-neoplastic Lesions
14.3.3.1 Acute Epiglottitis
14.3.3.2 Chronic Laryngitis
14.3.3.3 Granulomatous Laryngitis
14.3.3.4 Laryngeal Nodule
14.3.3.5 Contact Ulcers of Larynx
14.3.4 Tumors
14.3.4.1 Papilloma (Juvenile Laryngeal Papilloma)
14.3.4.2 Laryngeal Carcinoma
14.4 Oral Cavity and Oropharynx
14.4.1 Congenital Anomalies
14.4.1.1 Gingival Cysts
14.4.1.2 Epstein Pearls
14.4.1.3 Bohn’s Nodules
14.4.1.4 Eruption Cyst
14.4.1.5 Epidermoid and Dermoid Cysts
14.4.1.6 Maxillary Osteomyelitis of the Newborn
14.4.1.7 Neonatal Herpes Simplex Virus Infection
14.4.1.8 Neonatal Candidiasis
14.4.1.9 Mucocele
14.4.1.10 Ranula
14.4.1.11 Riga-Fede Disease
14.4.1.12 Neonatal Pemphigus Vulgaris
14.4.1.13 Oral Choristoma
14.4.2 Branchial Cleft Cysts
14.4.3 Inflammatory Lesions
14.4.4 Tumors
14.4.4.1 Epithelial Precursor Lesions
14.4.4.2 Benign Epithelial Tumors
14.4.4.3 Malignant Epithelial Tumors
14.4.4.4 Soft Tissue Tumors
Congenital Epulis of Newborn
Pyogenic Granuloma (Lobular Capillary Hemangioma)
Hemangioma
Lymphangioma
Langerhans Cell Histiocytosis X (LCH)
14.4.4.5 Hematolymphoid Tumors, Non-LCH
Extramedullary Myeloid Sarcoma (EMS)
14.4.4.6 Other Malignant Neoplasms
14.5 Salivary Glands
14.5.1 Congenital Anomalies
14.5.2 Inflammatory Lesions and Non-neoplastic Lesions
14.5.3 Tumors
14.5.3.1 Benign Tumors
14.5.3.2 Malignant Epithelial Tumors
14.5.3.3 Soft Tissue Tumors
14.5.3.4 Hematolymphoid Tumors
14.5.3.5 Secondary Tumors
14.6 Mandible and Maxilla
14.6.1 Odontogenic Cysts
14.6.1.1 Radicular Cyst
14.6.1.2 Paradental Cyst
14.6.1.3 Dentigerous (Follicular) Cyst
14.6.1.4 Odontogenic Keratocyst
14.6.2 Odontogenic Tumors
14.6.2.1 Ameloblastoma (Adamantinoma)
14.6.2.2 Calcifying Epithelial Odontogenic Tumor
14.6.2.3 Odontogenic Fibroma
Mixed Odontogenic Tumors
14.6.3 Bone-Related Lesions
14.7 Ear
14.7.1 Congenital Anomalies
14.7.2 Inflammatory Lesions and Non-neoplastic Lesions
14.7.2.1 Acute Otitis Media (AOM)
14.7.3 Tumors
14.7.3.1 Tumors of the External Ear
RMS and Bony Lesions
14.7.3.2 Tumors of the Middle Ear
14.7.3.3 Tumors of the Inner Ear
14.8 Eye and Ocular Adnexa
14.8.1 Congenital Anomalies
14.8.2 Inflammatory Lesions and Non-neoplastic Lesions
14.8.3 Tumors
14.8.3.1 Retinoblastoma and Related Lesions
14.9 Skull
Multiple Choice Questions and Answers
References and Recommended Readings
15: Central Nervous System
15.1 Development: Genetics
15.1.1 Development and Genetics
15.1.2 Neuromeric Model of the Organization of the Embryonic Forebrain According to Puelles and Rubenstein
15.2 Congenital Abnormalities of the Central Nervous System
15.2.1 Ectopia
15.2.2 Neural Tube Defects (NTDs)
15.2.2.1 Spina Bifida
15.2.2.2 Meningocele/Meningomyelocele
15.2.2.3 Arnold-Chiari Malformation (ACM)/Chiari II Malformation
15.2.2.4 Anencephaly
15.2.3 Prosencephalon Defects
15.2.4 Vesicular Forebrain (Pseudo-aprosencephaly)
15.2.5 Ventriculomegaly/Hydrocephalus
15.2.6 Agenesis of the Corpus Callosum (ACC)
15.2.7 Cerebellar Malformations
15.2.8 Agnathia Otocephaly Complex (AGOTC)
15.2.9 Telencephalosynapsis (Synencephaly) and Rhombencephalon Synapsis
15.2.10 CNS Defects in Acardia
15.2.11 CNS Defects in Chromosomal and Genetic Syndromes
15.2.11.1 Cornelia De Lange Syndrome (CDLS)
15.2.12 Neuronal Migration Disorders
15.2.13 Phakomatoses
15.2.13.1 Tuberous Sclerosis Complex (TSC)
15.2.13.2 Neurofibromatosis (NF)
15.2.13.3 Von Hippel-Lindau Syndrome (VHLS)
15.2.13.4 Sturge-Weber Syndrome (SWS)
15.2.13.5 Wyburn-Mason Syndrome (WMS)
15.3 Vascular Disorders of the Central Nervous System
15.3.1 Intracranial Hemorrhage
15.3.1.1 Intraparenchymal Hemorrhage (IPH)
15.3.1.2 Subarachnoidal Hemorrhage (SAH)
15.3.1.3 Subdural Hemorrhage (SDH)
15.3.1.4 Epidural Hemorrhage (EDH)
15.3.2 Vascular Malformations
15.3.2.1 Arteriovenous Malformations (AVM)
15.3.3 Aneurysms
15.3.3.1 Berry Aneurysms
15.3.3.2 Mycotic Aneurysms
15.3.3.3 Arteriosclerotic Aneurysms
15.3.4 Thrombosis of Venous Sinuses and Cerebral Veins
15.3.5 Pediatric and Inherited Neurovascular Diseases
15.3.5.1 Cerebral Cavernous Malformations (CCM)
15.3.5.2 Hereditary Hemorrhagic Telangiectasia (HHT)
15.4 Infections of the CNS
15.4.1 Suppurative Infections
15.4.1.1 Acute Suppurative (Lepto-)Meningitis
15.4.1.2 Brain Abscess
15.4.1.3 Septic Thrombophlebitis
15.4.2 Tuberculous (Lepto-)Meningitis
15.4.3 Neurosyphilis
15.4.4 Viral Infections
15.4.4.1 Poliomyelitis
15.4.4.2 Rabies
15.4.4.3 Herpes Simplex Encephalitis
15.4.4.4 Subacute Sclerosing Panencephalitis (SSPE)
15.4.4.5 Progressive Multifocal Leukoencephalopathy (PML)
15.4.4.6 Human Immunodeficiency Virus (HIV): Infection
15.4.5 Toxoplasmosis
15.4.6 Fungal Infections
15.5 Metabolic Disorders Affecting the CNS
15.5.1 Pernicious Anemia
15.5.2 Wernicke Encephalopathy
15.6 Trauma to the Head and Spine
15.7 Head Injuries
15.7.1 Epidural Hematoma
15.7.2 Subdural Hematoma
15.7.3 Subarachnoidal Hemorrhage
15.7.3.1 Brain Concussion
15.7.3.2 Brain Contusion
15.7.3.3 Brain Laceration
15.7.4 Spinal Injuries
15.7.5 Intervertebral Disk Herniation
15.8 Demyelinating Diseases Involving the Central Nervous System
15.8.1 Multiple Sclerosis
15.8.2 Leukodystrophies
15.8.2.1 Metachromatic Leukodystrophy
15.8.2.2 Globoid Cell Leukodystrophy (Krabbe Disease)
15.8.2.3 Adrenoleukodystrophy
15.8.3 Amyotrophic Lateral Sclerosis
15.8.4 Werdnig-Hoffmann Disease
15.8.5 Syringomyelia
15.8.6 Parkinson Disease and Parkinson Disease-Associated, G-Protein-Coupled Receptor 37 (GPR37/PaelR)-Related Autism Spectrum Disorder
15.8.7 Creutzfeldt-Jakob Disease (sCJD or Sporadic), CJD-Familial and CJD-Variant
15.8.8 West Syndrome/Infantile Spasms, ACTH Therapy, and Sudden Death
15.9 Neoplasms of the Central Nervous System
15.9.1 Astrocyte-Derived Neoplasms
15.9.1.1 Astrocytoma
15.9.1.2 Pilocytic Astrocytoma
15.9.1.3 Glioblastoma Multiforme (GBM)
15.9.1.4 Oligodendroglioma
15.9.2 Ependymoma
15.9.3 Medulloblastoma
15.9.4 Meningioma
15.9.5 Hemangioblastoma and Filum Terminale Hamartoma
15.9.6 Schwannoma
15.9.7 Craniopharyngioma
15.9.8 Chordoma
15.9.9 Tumors of the Pineal Body
15.9.10 Hematological Malignancies
15.9.11 Other Tumors and Metastatic Tumors
Multiple Choice Questions and Answers
References and Recommended Readings
16: Peripheral Nervous System
16.1 Development
16.2 Disorders of the Peripheral Nervous System
16.2.1 Peripheral Neuropathy
16.2.2 Traumatic Neuropathy
16.2.3 Vascular Neuropathy
16.2.4 Intoxication-Related Neuropathy
16.2.5 Infiltration (e.g., Amyloid) Related Neuropathy
16.2.6 Neoplasms of the Peripheral Nervous System
16.2.6.1 Schwannoma
16.2.6.2 Neurofibroma (Figs. 16.2 and 16.3)
16.2.6.3 Malignant Peripheral Nerve Sheath Tumor (Figs. 16.4, 16.5, 16.6, 16.7, and 16.8)
16.3 Neuromuscular Disorders
16.3.1 Muscle Biopsy Test
16.3.2 Neurogenic Disorders
16.3.2.1 Denervation (Figs. 16.9 and 16.10)
16.3.2.2 Myasthenia Gravis
16.3.3 Myopathic Disorders
16.3.3.1 Muscular Dystrophies
16.3.3.2 Congenital Myopathies
16.3.4 Glycogen Storage Diseases
16.3.5 Mitochondrial Myopathies (Fig. 16.11)
16.3.6 Inflammatory Myopathies: Non-infectious
16.3.7 Inflammatory Myopathies: Infectious
Multiple Choice Questions and Answers
References and Recommended Readings
17: Skin
17.1 Development, General Terminology, and Congenital Skin Defects
17.1.1 Development
17.1.2 General Terminology
17.1.3 Lethal Congenital Contractural Syndromes
17.2 Spongiotic Dermatitis
17.2.1 Conventional Spongiosis
17.2.1.1 Atopic Dermatitis
17.2.1.2 Allergic Contact Dermatitis
17.2.1.3 Seborrheic Dermatitis
17.2.1.4 Nummular Dermatitis
17.2.1.5 Stasis Dermatitis
17.2.1.6 Pityriasis Alba
17.2.1.7 Pityriasis Rosea
17.2.1.8 Papular Acrodermatitis of Gianotti-Crosti
17.2.1.9 Erythema Neonatorum
17.2.1.10 Incontinentia Pigmenti
17.2.2 Eosinophilic Spongiosis
17.2.3 Follicular Spongiosis
17.2.4 Miliarial Spongiosis
17.3 Interface Dermatitis
17.3.1 Vacuolar Interface Dermatitis
17.3.1.1 Lupus: SLE/Discoid Lupus
17.3.1.2 Dermatomyositis
17.3.1.3 Pityriasis Lichenoides Et Varioliformis Acuta (PLEVA)
17.3.1.4 Erythema Multiforme
17.3.1.5 Toxic Epidermal Necrolysis (TEN)/Stevens-Johnson Syndrome (SJS)
17.3.1.6 Graft Versus Host Disease (GVHD)
17.3.1.7 Fixed Drug Eruption
17.3.1.8 Lichen Sclerosus et Atrophicus (LSA)
17.3.1.9 Infections
17.3.2 Lichenoid Interface Dermatitis
17.4 Psoriasis and Psoriasiform Dermatitis
17.4.1 Psoriasis
17.4.2 Psoriasiform Dermatitis
17.5 Perivascular In Toto Dermatitis (PID)
17.5.1 Urticaria
17.5.2 Non-urticaria Superficial and Deep Perivascular Dermatitis
17.5.2.1 Autoinflammatory Syndromes
17.6 Nodular and Diffuse Cutaneous Infiltrates
17.6.1 Granuloma Annulare
17.6.2 Necrobiosis Lipoidica Diabeticorum (NLD)
17.6.3 Rheumatoid Nodule
17.6.4 Sarcoid
17.7 Intraepidermal Blistering Diseases
17.7.1 Pemphigus Vulgaris, Pemphigus Foliaceus, and Pemphigus Paraneoplasticus
17.7.1.1 Pemphigus Vulgaris
17.7.1.2 Pemphigus Foliaceus
17.7.1.3 Pemphigus Paraneoplasticus
17.7.2 IgA Pemphigus and Impetigo
17.7.2.1 IgA Pemphigus
17.7.2.2 Impetigo
17.7.3 Intraepidermal Blistering Diseases
17.7.3.1 Darier Disease
17.7.3.2 Grover Disease
17.7.3.3 Hailey-Hailey Disease
17.8 Subepidermal Blistering Diseases
17.8.1 Bullous Pemphigoid and Epidermolysis Bullosa
17.8.1.1 Bullous Pemphigoid
17.8.1.2 Epidermolysis Bullosa
17.8.2 Erythema Multiforme and Toxic Epidermal Necrolysis
17.8.3 Hb-Related Porphyria Cutanea Tarda, Herpes Gestationis, and Dermatitis Herpetiformis
17.8.4 Lupus (Systemic Lupus Erythematodes)
17.9 Vasculitis
17.10 Cutaneous Appendages Disorders
17.11 Panniculitis
17.11.1 Septal Panniculitis
17.11.1.1 Erythema Nodosum
17.11.2 Lobular Panniculitis
17.11.2.1 Vasculitis-Associated Lobular Panniculitis (Erythema induratum)
17.12 Cutaneous Adverse Drug Reactions
17.12.1 Exanthematous CADR
17.12.1.1 Urticaria-Like CADR
17.12.1.2 Fixed Drug Eruptions
17.12.1.3 Photosensitivity-Driven CADR (P-CADR)
17.12.1.4 Serum Sickness- Like CADR (SSLR)
17.13 Dyskeratotic, Non-/Pauci-Inflammatory Disorders
17.14 Non-dyskeratotic, Non-/Pauci-Inflammatory Disorders
17.15 Infections and Infestations
17.16 Cutaneous Cysts and Related Lesions
17.17 Tumors of the Epidermis
17.17.1 Epidermal Nevi and Related Lesions
17.17.1.1 Morphea
17.17.2 Pseudoepitheliomatous Hyperplasia (PEH)
17.17.3 Acanthoses/Acanthomas/Keratoses
17.17.3.1 Acrochordons
17.17.3.2 Fibrokeratoma, Acquired, Digital
17.17.3.3 Lichenoid Keratosis
17.17.3.4 Cutaneous Horn
17.17.3.5 Acanthosis Nigricans
17.17.3.6 Leukoplakia
17.17.3.7 Seborrheic Keratosis
17.17.3.8 Actinic (Solar) Keratosis
17.17.4 Keratinocyte Dysplasia
17.17.5 Intraepidermal Carcinomas
17.17.5.1 Bowen Disease
17.17.5.2 Erythroplasia of Queyrat
17.17.5.3 Bowenoid Papulosis
17.17.6 Keratoacanthoma
17.17.7 Malignant Tumors
17.17.7.1 Invasive Squamous Cell Carcinoma
17.17.7.2 Basal Cell Carcinoma
17.17.7.3 Paget Disease
17.18 Melanocytic Lesions
17.18.1 Lentigines, Solar Lentigo, Lentigo Simplex, and Melanotic Macules (Box 17.8)
17.18.2 Melanocytic Nevi
17.18.3 Variants of Melanocytic Nevi
17.18.4 Spitz Nevus and Variants
17.18.5 Atypical Melanocytic (Dysplastic) Nevi
17.18.6 Malignant Melanoma and Variants
17.19 Sebaceous and Pilar Tumors
17.19.1 Sebaceous Hyperplasia
17.19.2 Nevus Sebaceous (of Jadassohn) (NSJ)
17.19.3 Sebaceous Adenoma, Sebaceoma, and Xanthoma
17.19.4 Sebaceous Carcinoma
17.19.5 Benign Hair Follicle Tumors
17.19.5.1 Pilar Sheath Acanthoma
17.19.5.2 Trichilemmoma
17.19.5.3 Trichofolliculoma
17.19.5.4 Trichoepithelioma
17.19.5.5 Pilomatrixoma
17.19.5.6 Piloleiomyoma
17.19.6 Malignant Hair Follicle Tumors
17.20 Sweat Gland Tumors
17.20.1 Eccrine Gland Tumors
17.20.1.1 Cylindroma
17.20.1.2 Syringoma
17.20.1.3 Chondroid Syringoma
17.20.1.4 Eccrine Poroma
17.20.1.5 Eccrine Acrospiroma
17.20.1.6 Eccrine Spiradenoma
17.20.1.7 Eccrine Carcinoma
17.20.2 Apocrine Gland Tumors
17.20.2.1 Syringocystadenoma Papilliferum
17.20.2.2 Apocrine Tubular Adenoma
17.20.2.3 Hidradenoma Papilliferum
17.21 Fibrous and Fibrohistiocytic Tumors
17.21.1 Hypertrophic Scar and Keloid
17.21.2 Dermatofibroma
17.21.3 Juvenile Xanthogranuloma
17.21.4 Dermatofibrosarcoma Protuberans
17.22 Vascular Tumors (Fig. 17.13)
17.23 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone
17.24 Neural and Neuroendocrine Tumors
17.24.1 Merkel Cell Carcinoma
17.24.2 Paraganglioma
17.25 Hematological Skin Infiltrates
17.25.1 Pseudolymphomas
17.25.2 Benign and Malignant Mastocytosis
17.26 Solid Tumor Metastases to the Skin
Multiple Choice Questions and Answers
References and Recommended Readings
18: Placenta, Abnormal Conception, and Prematurity
18.1 Development and Useful Pilot Concepts and Tables
18.2 Pathology of the Early Pregnancy
18.2.1 Disorders of the Placenta Formation
18.2.1.1 Partial Mole (Partial Molar Degeneration)
18.2.1.2 Complete Mole (Complete Molar Degeneration)
18.2.1.3 Hydropic Abortus/Hydropic Molar Degeneration (HMD)
18.2.2 Disorders of the Placenta Maturation
18.2.3 Disorders of the Placenta Vascularization
18.2.4 Disorders of the Placenta Implantation Site
18.2.5 Twin and Multiple Pregnancies
18.3 Pathology of the Late Pregnancy
18.3.1 Acute Diseases
18.3.1.1 Abruptio Placentae
18.3.1.2 Bleeding of the Fetus (Fetal Maternal Hemorrhage, FMH)
18.3.1.3 Cord Integrity Damage
18.3.2 Subacute Diseases
18.3.2.1 Amniotic Fluid Infection (AFI)/Acute Chorioamnionitis (ACA)
18.3.2.2 Meconium-Stained Amniotic Fluid-Related Disorders (MAFD)
18.3.2.3 Fetomaternal Hemorrhage (FMH) ± Intervillous Thrombus(i)
18.3.2.4 S/P Prolonged/Repetitive Hypoxia
18.3.3 Chronic Diseases
18.3.3.1 Maternal Vascular Underperfusion (MVUP) (Figs. 18.24, 18.25, 18.26, and 18.27)
18.3.3.2 Fetal Thrombotic Vasculopathy (FTV)
18.3.3.3 Chronic Villitis of Infectious Type (CVI) and Villitis of Unknown Etiology (VUE)
18.3.3.4 Massive Perivillous Fibrin Deposition (MPFD) and “Maternal Floor Infarction”
18.3.3.5 “Chronic” Placental Abruption (CPA)
18.3.3.6 Villous Capillary Proliferation Disorders (VCPD)
18.3.3.7 Distal Villous Immaturity (DVI)
18.3.4 Fetal Growth Restriction
18.4 Non-neoplastic Trophoblastic Abnormalities
18.4.1 Placental Site Nodule
18.4.2 Exaggerated Placental Site
18.5 Gestational Trophoblastic Diseases, Pre- and Malignant
18.5.1 Invasive Mole
18.5.2 Placental Site Trophoblastic Tumor
18.5.3 Epithelioid Trophoblastic Tumor
18.5.4 Choriocarcinoma
18.6 Birth Defects
18.6.1 Birth Defects: Taxonomy Principles
18.6.2 Birth Defects: Categories
18.6.3 Birth Defects: Pathogenesis (Macro- and Micromechanisms)
18.6.4 Birth Defects: Etiology (Mendelian, Chromosomal, Multifactorial)
18.7 Infection in Pregnancy, Prom, and Dysmaturity
18.7.1 Infection in Pregnancy
18.7.2 Premature Rupture of Membranes (PROM)
18.7.3 Fetal Growth Restriction (FGR) and Dysmaturity
18.8 IUFD and Placenta
18.8.1 Fetal Death Syndrome (Intrauterine Fetal Demise, IUFD)
18.8.2 Step-by-Step Approach in the Examination of a Placenta
Multiple Choice Questions and Answers
References and Recommended Readings
Index

Citation preview

Matthew P. Lungren Michael R.B. Evans Editors

Pathology Clinical Medicine of Childhood and Adolescence Covertemplate An Illustrated Subtitle for Guide Clinical Medicine Consolato M. SergiCovers T3_HB Second Edition

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Pathology of Childhood and Adolescence

Consolato M. Sergi

Pathology of Childhood and Adolescence An Illustrated Guide

Consolato M. Sergi University of Alberta Edmonton, AB Canada

ISBN 978-3-662-59167-3    ISBN 978-3-662-59169-7 (eBook) https://doi.org/10.1007/978-3-662-59169-7 © Springer-Verlag GmbH Germany, part of Springer Nature 2020 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer-Verlag GmbH, DE part of Springer Nature. The registered company address is: Heidelberger Platz 3, 14197 Berlin, Germany

To my patients and their families, to my family, and to my students and fellows

Foreword

University hospitals, major hospitals, and medical care centers must have a pathological institute, and this is a long-standing requirement. This facility is the prerequisite for the adequate diagnosis of most of the diseases that need to be treated. Since most major hospitals also have pediatric and pediatric and adolescent surgery, the affiliated pathological institute should either have a department for pediatric pathology or at least one or two, better three, designated pathologists of childhood pathology to meet the child-specific pathological diagnosis. It is well known that this is not always the case. There are very few institutes of pathology that have their department or division of pediatric pathology or at least have a pediatric pathologist. The well-known sentence “children are not small adults” is often not taken into account. At present, at least in the German-speaking world, pediatric pathology is only a subdiscipline of pathology. It is carried out often by general pathologists who are particularly interested with this field, who receive their training on their initiative, by rotating in several renowned institutions and participating to congresses and meetings of the Society for Pediatric Pathology or Pediatric Pathology Society as well as national meetings of pediatric pathology. What is the challenge for pediatric pathologists? The field of work comprises a vast field of diagnostic tasks, which implies two interlinked fields of knowledge: on the one hand, knowledge of physiological development processes, i.e., the continually changing processes for growth reasons, and typical findings of the various tissues of the human body, starting with the embryo and ending in adolescents and late youth, and on the other hand, knowledge of the possible deviating pathological findings for the respective age group. This means that the ever-changing morphology of healthy development represents an additional dynamic dimension in the evaluation of pathological changes that reduce the diagnostic effort of pediatric pathologists compared to that of general pathologists. An additional, not less critical, area of pediatric pathology is the fetal diagnosis, primarily because it can be used to clarify congenital malformations and intrauterine, perinatal, and postpartum deaths. Finally, placenta diagnosis should not be forgotten, as it can be used to detect relevant evidence not only for intra- and perinatal deaths or possible diseases in the newborn but also for pregnancy complications. In summary, in addition to diagnostics, the participation of the pediatric pathologists in the context of rare or unusual findings with discussion in the vii

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setting of multidisciplinary team meetings with general and subspecialized pediatricians, pediatric surgeons, obstetricians, and human geneticists is very well welcomed. It is surprising that the children’s pathology, although its diagnostic-scientific spectrum and its cooperation in the clinical implementation of its findings differ sizably from that of general pathology, is usually covered in very few textbooks. There is virtually no truly comprehensive, clinical, and molecular biology-oriented up-to-date manual that includes detailed information for all stakeholders. Due to the far-reaching prerequisites mentioned, a great deal of courage is required to commit to the task of writing a handbook for children’s pathology because, as mentioned above, children’s pathology not only requires a comprehensive spectrum of knowledge per se but also requires solid knowledge of the physiological processes of the growing body and – in connection with diagnostics  – also specific ideas regarding pediatric or pediatric surgical treatment options. These requirements make the creation of a manual an almost unmanageable challenge if all these criteria are to be considered efficiently. Consolato Sergi is in the field of pediatric pathology for more than 30 years collecting experiences and acquiring knowledge. He took up this challenge, as he told me about a year ago, after much consideration. His decision for this endeavor was born out of the idea of putting his extensive pediatric pathological knowledge on paper in order to fill the bibliographical gap that exists in this respect. In this context, I would like to mention a few of my memories that connect me with the author of this book. Between 2004 and 2008, Sergi was employed as a pediatric pathologist at the Pathological Institute of the Medical University of Innsbruck, Austria. As director of the Department of Pediatrics and Adolescent Surgery, I had to deal with him very often, as we had to cope with a quite significant number of surgical patients. On the one hand, we repeatedly discussed not only critical problems of our shared patients (often not sparing any day of the week including Saturday and Sunday) but also scientific projects. On the other hand, we met fortnightly or weekly within the framework of multidisciplinary team meetings. The “case ideas” and discussions were very profitable and sustainable since Dr. Sergi, who is also pediatrician, already had, at that time, an extensive theoretical and clinical knowledge. Therefore, he was able to contribute a lot to the clinical discussions, which was generally well praised. It was obvious that I remained in contact with him, who has proven himself to this day, after his departure from Innsbruck due to our excellent cooperation. I congratulated him on his decision to write up this textbook, which will complement the library of not only pathologists and pediatric pathologists but also pediatricians, pediatric surgeons, and human geneticists. Because of his knowledge and well-balanced scientific curriculum, I was sure he would be able to complete this project. In reading the table of the contents of his book, I saw my opinion confirmed. He had compiled a textbook covering all relevant pediatric pathological topics. What is important to mention in this context is the fact that not only had he brought his vast wealth of knowledge into text but also didactically presented his theoretical and practical knowledge with a lot of pictorial material so informative that it would benefit

Foreword

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not only morphologists but also clinicians. Consequently, it represents for all those who are involved – directly – in the pathological diagnosis with all its facets and in the resulting treatment of sick children or adolescents who are involved in diagnostics and research in the field of pediatric pathology as well as trainees and fellows, an essential and comprehensive source of information. Medical University of Innsbruck, Innsbruck, Austria

Josef Hager

Foreword

Pediatrics, the “Medicine of Children,” is an area of medical study that is very broad, diverse, and challenging. Unlike different specialties and subspecialties, pediatrics does not deal with an organ, system, or specialty of function but with a developing organism, the human organism in its total entirety, genetics, embryonal, fetal, neonate to adolescent. The development through this continuum presents with a diversity of pathophysiology. The Department of Pediatrics, at the University of Alberta, has recognized the research and education opportunities to answer clinically important questions that make a difference in the health of children throughout the age spectrum. In collaboration with all our child health colleagues, including Dr. Sergi, the Department of Pediatrics is a leading recipient of national tri-council funding and through research truly making a clinical difference. Dr. Sergi’s book is a compilation of pathological illustrations and molecular biology data put together for the benefit of all who care for the newborn, child, and adolescent, including physicians, trainees, and allied Pediatric health providers. Clinical acumen depends predominantly on logical deduction but also on lateral interaction with disciplines that help to understand the biology of the developing human organism. Pediatric pathology is unique because it helps pediatricians to understand not only the pathological basis of disease but also inquire into molecular biological pathogenesis. Dr. Sergi’s marvelous textbook in pediatric pathology is the crown of more than 30 years of the interaction of him with pediatricians. Joining the University of Alberta in 2008 as full professor of pathology and adjunct professor of pediatrics allowed me to interact with him very often as chair of the Department of Pediatrics at the University of Alberta, and importantly as a colleague in hepatology and liver transplantation. For over a decade I have had the professional opportunity to interact clinically with Dr. Sergi. His clear explanation of concepts of pathophysiology to not only myself but to our multidisciplinary team, and most importantly our trainees, has enriched all of our intellect, and ongoing management of patients. I know that the value of such a compilation relies on extensive and thorough effort, as is witnessed in this textbook. The generosity of Dr. Sergi’s dedication, and that of his family, for the advancement of pediatric medicine and pediatric pathology is immeasurable.

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I wish all readers, my fellows and colleagues and myself will have the opportunity to interact more with Dr. Sergi and acquire the invaluable steps in progressing the knowledge in pediatrics. Susan M. Gilmour, MD, MSc, FRCPC Professor Pediatrics, Pediatric Gastroenterology/Hepatology Department Chair 2009–2019 University of Alberta Edmonton Canada

Preface

The pediatric patient may be mistakenly considered an adult in miniature, but the precise definitions of diseases uniquely appearing in infancy, childhood, and adolescence make this field of medicine astoundingly rich in notions and knowledge ranging from the early intrauterine life to adolescence and youth. Pediatric pathology is one of the fastest growing subspecialties in medicine. Pediatric pathology is also unique because a few diseases that were earlier confined to adults are now occurring in childhood, adolescence, and youth. There may be several reasons, including the optimization of imaging technology, better surgical and clinical pathology criteria, but also some external factors are likely playing some role. The environment has become more and more impregnated with dangerous molecular compounds that are not only carcinogenic but also endocrine and metabolism disruptors. The pediatric pathology clubs, born in the United Kingdom and the United States, have seen growing number of participants in the last few years. The current pediatric pathology society (PPS) and societies of pediatric pathology (SPP) have reached an enormous interest not only in residents in pathology but also in pediatrics, obstetrics, gynecology, as well as other medical and surgical specialties. Long before the founding of the pediatric pathology clubs and their transformation into PPS and SPP, the German embryological schools played an unarguable and incontrovertible role in the expansion of our knowledge of perinatal medicine and congenital defects in the twentieth century. Three figures have motivated me in collecting and producing this book. They are Guido Fanconi, Klaus Goerttler, and Harald P.  Schmitt. Guido Fanconi is regarded as one of the founders of the modern pediatrics for his contributions to biochemistry and how biochemistry helped reshape modern pediatrics. His contributions to the pathology of pediatrics were numerous, and several diseases have been nominated after him. He was head of the Kinderspital in Zurich, Switzerland, for about 45 years and recognized Down syndrome years before the chromosomal identification. In 1934, the first patients affected with mucoviscidosis or cystic fibrosis of the pancreas were described in a doctoral thesis written under his direction. His contributions to pediatrics are countless, and some of these are highlighted in the present book. A few years ago, Stephan Lobitz, from the Department of Pediatric Oncology and Hematology, Charité–University Medicine Berlin, Berlin, Germany, and Eunike Velleuer, from the Department of Pediatric Oncology, Hematology and Immunology, University of Düsseldorf, Germany, wrote an outstanding contribution on Professor Fanconi. Most probably, one of the xiii

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most paramount contributions for understanding the magnitude of Fanconi to pediatrics and the many mentees is a handwritten note kindly made available to Dr. Lobitz and Dr. Velleuer by Fanconi’s son. Fanconi wrote “Forschen: Aufdeckung und Deutung eines neuen Tatbestandes ist an eine Idee gebunden, der eine Unsumme fleissiger Arbeit folgt. Sie setzt einen ideenreichen Kopf und einen fleissigen, systematischen Arbeiter voraus. Ferner ist es wichtig, dass ein gründliches Wissen zugrunde liegt.” (“Research: the discovery and interpretation of new facts are bound to an idea which is followed by an enormous amount of hard work. It presupposes a creative mind and a diligent, systematic worker. A sound knowledge base is also important.”) This sentence has been a path to many pediatric pathologists who contributed to the self-determination, development, and autonomy of pediatric pathology starting about the second half of last century and continuing in this century. The stature of Professor Klaus Goerttler as top-ranking cardiac embryologist and pediatric pathologist has extensively contributed to the German embryology school, pediatric cardiology, and pediatric pathology. The German embryology school laid fundamental notions for the development of numerous concepts of knowledge in pediatric pathology. The clarification of the embryology of heart and its defects by the Heidelberg professor are milestones in the interpretation of the current pediatric cardiology and cardiac surgery as may be identified in his book Normale und pathologische Entwicklung des menschlichen Herzens (Normal and Pathologic Development of the Human Heart) of 1958. Hypoxia is a dreadful teratogen, causing disruption, particularly of neurulation if it interferes with early stages of embryonic development. Numerous experimental studies performed in amphibian and chick embryos showed that hypobaric-mediated hypoxia determines disruptions of the heart as well as head and brain. Most of the disruptions are induced at the beginning of gastrulation, i.e., before the onset of neurulation, when oxygen consumption is known to be exceptionally high. In these experiments, the underlying developmental mechanisms responsible for the malformations occurring with hypoxia were multiple. They include (1) the disturbance of the migration of blastema, or an alteration of the “Topogenese” (topogenesis” of the German embryological school according to Lehmann and of the “integrated cell and tissue movements” according to Gilbert), (2) the decreased induction of the altered blastema, and (3) the disturbance of the organ anlage or primordial organ to further differentiate. These studies continued the Spemann-Mangold experiments successfully on organizers and found that amphibian and chick investigations can also be extrapolated to humans. Professor Schwalbe highly influenced professor Goerttler and early pediatric pathologists worldwide. Ernst Theodor Karl Schwalbe (1871–1920) was a German pathologist, born in Berlin, who specialized in teratology. His medical study crossed three of the most prestigious universities (Strasbourg, Berlin, and Heidelberg). His habilitation (higher Ph.D. degree) was with a thesis on blood coagulation. In Heidelberg, Dr. Schwalbe worked as an assistant under Julius Arnold. As prosector and head of the pathology-bacteriology clinic, he worked at the city hospital in Karlsruhe in 1907/08. He worked for 12 years at the University of Rostock until 1920 when he was killed while serving as a volunteer during the Kapp Lüttwitz Putsch, which aimed to dis-

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engage the German Revolution of 1918–1919; overthrow the Weimar Republic, in governmental position after World War I; and establish an autocratic government in its place. In my opinion, Professor Schwalbe is probably one of the founders of pediatric pathology in general, and his studies have helped to shape the birth of several pediatric pathology clubs worldwide. Professor Horst P. Schmitt was my teacher in neuropathology during my residency in pathology. Professor Schmitt allowed me to revise several diseases in neuropathology and stimulated me in broadening my knowledge in developmental biology and pathology not only of humans but also of vertebrates. The book Pathology of Childhood and Adolescence is not only a book of pathology for pathologists or surgeons (adult and pediatric pathologists) or residents in these disciplines but also contains a molecular biology approach to some of the very challenging diseases in pediatrics. This book came after 12 years work and tight cooperation with Springer Publisher. I am very grateful to Mr. Karthik Periyasamy, who looked at the production for several years; all the Springer team; to my colleague, Dr. Atilano Lacson; and my mentors (Francesco Callea, Walter J Hofmann, Herwart F.  Otto, Axel von Herbay, Peter Sinn, Philipp Schnabel, Gregor Mikuz, Moorghen Morgan, Josef Hager, Lothar Bernd Zimmerhackl, Ulrich Schweigmann, and Brian Chiu, among others). I am also grateful to numerous adult and pediatric pathology colleagues and clinical colleagues who sent me consultation cases and advised me over the years. In this book, 18 chapters summarize and illustrate the pathology of childhood and youth comprehensively, including diseases of the cardiovascular system and respiratory tract, gastrointestinal tract, liver, pancreas and biliary tract, upper and lower urinary system, gynecological tract, breast, hematolymphoid system, endocrine system, soft tissues, arthro-skeletal system, central and peripheral nervous system, dermatological system, and placenta with pathology of the fetus and newborn. Pediatric pathology is not the search of the curiosities and does not involve the collection of rare specimens or the taking care of a cabinet of teratological cases. The pediatric pathologist tries to address specifically congenital defects in a context that may help to advance medicine and discover new cures. Most of the genes involved in morphogenesis may play a crucial role in carcinogenesis as identified most recently by pharmacology studies. Apart from being a pathologist, several pediatric pathologists are engaged in various humanitarian missions. Several pediatric pathologists hold a second specialty in pediatrics or gynecology and membership in pediatric or gynecology societies. Our job as pathologist involves an impressive work for advocacy of children and families. Rudolf Virchow, who is probably one of the founders of cellular pathology, was particularly active in social medicine and public health. In 1902, the British Medical Journal suggested that Berlin was one of the most hygienic cities in Europe due to Professor Virchow’s efforts on social milieu and social reforms in Germany. The increasingly authoritarian nature of his Imperial country moved Virchow to demand democracy and social welfare programs. Following the steps of Virchow’s deep sense of humanitarianism, several pediatric pathologists are now engaged in middle- or low-income countries to improve the public health qualities in these geographic areas. Sir William Osler, first Baronet, FRS

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FRCP (1849–1919), was a Canadian physician and one of the four founding fathers of Johns Hopkins Hospital in Maryland, United States. As a student, Sir William Osler spent some time in Berlin learning the art of the autopsy from Virchow and, on the pathologist’s 70th birthday, emphasized that his consistent humanitarianism amplified Virchow’s scientific achievements. Such Canadian esprit has permeated the twenty-first century as well. In 2006, Jean Vanier, a Canadian philanthropist, who recently passed away, gave a talk at Concordia University in the city of Montreal. He argued that the Western culture of the individualism which values beauty, money, and success also creates a gap between the healthy and the disabled. In this century, healthcare is going to go through financial and technological challenges. It is imperative that the pediatric pathologist is prone to support social initiatives. Pathologists provide strong support to patients and physicians alike as they face the battle with cancer, and the Springer team and I hope that our pages provide the concepts and the foundation for the future of cancer prevention and therapy as we move to the era of personalized molecular oncology. I hope that our book will help the students to learn some pediatric pathology skills and that the physicians are motivated in continuing learning programs. We have employed a coded format that we consider is fruitful and powerful for achieving optimal learning and memorization (DEF, definition; AKA/SYN, also known as/synonyms; EPI, epidemiology; EPG, etio-pathogenesis; CLI, clinics; GRO, gross findings; CLM, conventional light microscopy; TEM, transmission electron microscopy, HSS, histochemical special stains; IHC, immunohistochemistry; FNA, fine-needle aspiration; CMB, cytogenetics and molecular biology; DDX, differential diagnosis; TRT, treatment; PGN, prognosis). We think that the reader will enjoy this book and forgive me if some areas have not been emphasized enough. I trust this book can be a good help for many colleagues in their daily practice. We are eager to share this book with all our health professional colleagues across the world honestly hoping the reader will find the content of pertinence and interest to the care of all children. Edmonton, AB, Canada

Consolato M. Sergi

Coda All health is global health, and all medicine is social medicine, and, in this setting, pediatrics plays a significant role for the well-being and health of all children no matter their origin, the skin color they have, the religion they profess, or the orientation their parents have. Pediatric pathology is at the basis of the diseases that can be discovered before birth and after birth. This book is a solid basis that can be useful not only for pediatricians and pathologists involved in the healthcare of developed countries but also for low- and middleincome developing countries. Thus, most of the profit of the author will go to charities involving children. Pediatric pathologists and pediatricians remain essential leaders in the advocacy for pediatric patients and their families. Many of us have been engaged in teaching and providing healthcare services in the setting of the World Health Organization integrated management solutions and nongovernmental organizations, and their efforts have paved the roads for suggesting improvements for better healthcare in low- and middleincome countries. We hope that the application of experience from resource-rich settings to resource-limited settings will be followed by voracious readers able to gather information and notes from this book for the continuing medical education in global health. Disclaimer Medicine is an evolving field of knowledge. Thus, please be advised of the following disclaimer. Here, I inform readers of this book that the views and opinions expressed in the text belong solely to the author. They do not necessarily belong to the author’s employer, organization, committee, or other group or individual. Moreover, I do not make any warranties about the completeness, reliability, and accuracy of this information. Please verify your current standards of practice in your country of practice. Any action you take upon the information on this book is strictly at your own risk, and by reading and understanding this disclaimer, I will not be liable for any losses and damages in connection with the use of the text of this book.

Contents

1 Cardiovascular System������������������������������������������������������������������    1 1.1 Developmental and Genetics��������������������������������������������������    2 1.2 Congenital Heart Disease��������������������������������������������������������    6 1.2.1 Sequential Segmental Cardio-Analysis����������������������    8 1.2.2 Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Atrioventricular Septal Defect (AVSD), Patent Ductus Arteriosus (PDA), and Ebstein’s Tricuspid Anomaly (ETA)��������������������   11 1.2.3 Tetralogy of Fallot (TOF) and Double Outlet Right Ventricle (DORV)����������������������������������   18 1.2.4 Hypoplastic Right Heart Syndrome����������������������������   24 1.2.5 Transposition of the Great Arteries����������������������������   26 1.2.6 Common Trunk (Persistent Truncus Arteriosus)��������   31 1.2.7 Total Anomalous Pulmonary Venous Return��������������   32 1.2.8 Scimitar Syndrome�����������������������������������������������������   32 1.2.9 Hypoplastic Left Heart Syndrome and Coarctation of Aorta��������������������������������������������   33 1.2.10 Heterotaxy Syndrome ������������������������������������������������   41 1.2.11 Common Genetic Syndromes with Congenital Heart Disease��������������������������������������������������������������   41 1.3 Myocarditis and Nonischemic Cardiomyopathies������������������   48 1.3.1 Myocarditis ����������������������������������������������������������������   48 1.3.2 Dilated Cardiomyopathy��������������������������������������������   48 1.3.3 Hypertrophic Cardiomyopathy ����������������������������������   66 1.3.4 Infiltrative/Restrictive Cardiomyopathies ������������������   66 1.3.5 Left Ventricular Non-compaction ������������������������������   78 1.3.6 Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C) ��������������������������������������   79 1.3.7 Lamin A/C Cardiomyopathy��������������������������������������   81 1.3.8 Mitochondrial Cardiomyopathies ������������������������������   81 1.3.9 Cardiac Channelopathies and Sudden Cardiac Death�������������������������������������������������������������   83 1.4 Ischemic Heart Disease, Myocardial Dysfunction, and Heart Failure��������������������������������������������������������������������   85 1.4.1 Ischemic Heart Disease����������������������������������������������   85 1.4.2 Myocardial Dysfunction ��������������������������������������������   85 1.4.3 Heart Failure ��������������������������������������������������������������   85 xix

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1.5 Valvular Heart Disease������������������������������������������������������������   87 1.5.1 Endocarditis and Valvar Vegetation����������������������������   87 1.5.2 Mitral Valve Prolapse��������������������������������������������������   91 1.5.3 Calcific Mitral Annulus and Calcific Aortic Stenosis������������������������������������������������������������   91 1.5.4 Rheumatic Heart Disease (RHD)��������������������������������   91 1.5.5 Prosthetic Valves ��������������������������������������������������������   92 1.6 Transplantation������������������������������������������������������������������������   92 1.6.1 Allograft Cellular Rejection����������������������������������������   92 1.6.2 Allograft Humoral Rejection��������������������������������������   95 1.6.3 Cardiac Allograft Vasculopathy����������������������������������   97 1.6.4 Extracardiac Posttransplant Lympho-proliferative Disorders (PTLD) Following HTX����������������������������  100 1.7 Tumors������������������������������������������������������������������������������������  100 1.7.1 Benign Tumors������������������������������������������������������������  102 1.7.2 Malignant Tumors������������������������������������������������������  109 1.7.3 Metastatic Tumors������������������������������������������������������  112 1.8 Pericardial Disease������������������������������������������������������������������  115 1.8.1 Non-neoplastic Pericardial Disease����������������������������  115 1.8.2 Neoplastic Pericardial Disease������������������������������������  116 1.9 Non-neoplastic Vascular Pathology����������������������������������������  116 1.9.1 Congenital Anomalies������������������������������������������������  116 1.9.2 Fibromuscular Dysplasia��������������������������������������������  117 1.9.3 Arteriosclerosis ����������������������������������������������������������  117 1.9.4 Large-Vessel Vasculitis ����������������������������������������������  119 1.9.5 Medium-Vessel Vasculitis ������������������������������������������  123 1.9.6 Small-Vessel Vasculitis ����������������������������������������������  125 Multiple Choice Questions and Answers����������������������������������������  125 References and Recommended Readings����������������������������������������  127 2 Lower Respiratory Tract��������������������������������������������������������������  139 2.1 Development and Genetics ����������������������������������������������������  141 2.2 Dysmorphology and Perinatal Congenital Airway Diseases����������������������������������������������������������������������  145 2.2.1 Foregut Cysts of Bronchogenic Type��������������������������  146 2.2.2 Agenesis, Aplasia, and Hypoplasia Pulmonis (Pulmonary Hypoplasia) ��������������������������������������������  148 2.2.3 CPAM and Congenital Lobar Emphysema����������������  148 2.2.4 Tracheal and Bronchial Anomalies ����������������������������  151 2.2.5 Sequestrations and Vascular Anomalies����������������������  152 2.3 Infantile and Pediatric NILD��������������������������������������������������  155 2.3.1 Neonatal Respiratory Distress Syndrome ������������������  157 2.3.2 “Old” and “New” Bronchopulmonary Dysplasia (OBPD and NBPD)������������������������������������  157 2.3.3 Atelectasis ������������������������������������������������������������������  158 2.3.4 Cystic Fibrosis������������������������������������������������������������  158 2.4 Infantile and Pediatric ILD������������������������������������������������������  159 2.4.1 Diffuse Lung Development-Associated ILD��������������  159 2.4.2 Trisomy 21 (Down Syndrome)-Associated ILD��������  161

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2.4.3 ILD Related to Other Chromosomal/Genomic Microdeletion Disorders ��������������������������������������������  163 2.4.4 Neuroendocrine Hyperplasia of Infancy (NEHI)��������  163 2.4.5 Pulmonary Interstitial Glycogenosis (PIG)����������������  164 2.4.6 Surfactant Dysfunction Disorders������������������������������  164 2.4.7 Pulmonary Alveolar Proteinosis ��������������������������������  166 2.5 “Adult” ILD of the Youth��������������������������������������������������������  167 2.5.1 Diffuse Alveolar Damage (DAD) ������������������������������  167 2.5.2 Cryptogenic Organizing Pneumonia (COP) ��������������  170 2.5.3 Usual Interstitial Pneumonia/Pneumonitis (UIP)�������  173 2.5.4 Nonspecific Interstitial Pneumonia/ Pneumonitis (NSIP)����������������������������������������������������  175 2.5.5 Desquamative Interstitial Pneumonia/Pneumonitis����  176 2.5.6 Respiratory Bronchiolitis ILD������������������������������������  177 2.5.7 Pulmonary Langerhans Cell Histiocytosis������������������  179 2.5.8 Lymphoid Interstitial Pneumonia/ Pneumonitis (LIP)������������������������������������������������������  180 2.5.9 Hypersensitivity Pneumonia/Pneumonitis (HSP) ������  181 2.5.10 Acute Eosinophilic Pneumonia/Pneumonitis��������������  182 2.5.11 Progressive Massive Fibrosis��������������������������������������  184 2.6 Inflammation: Tracheobronchial��������������������������������������������  184 2.6.1 Laryngotracheitis��������������������������������������������������������  184 2.6.2 Acute Bronchitis ��������������������������������������������������������  184 2.6.3 Bronchial Asthma�������������������������������������������������������  184 2.6.4 Pulmonary Hyperinflation������������������������������������������  188 2.6.5 Bronchiectasis ������������������������������������������������������������  189 2.6.6 Neoplasms������������������������������������������������������������������  189 2.7 Inflammation: Infectious (Pneumonia/Pneumonitis)��������������  190 2.7.1 Lobar Pneumonia��������������������������������������������������������  190 2.7.2 Bronchopneumonia ����������������������������������������������������  191 2.7.3 Interstitial Pneumonia ������������������������������������������������  193 2.7.4 Primary Atypical Inflammation (Pneumonia)������������  193 2.8 Inflammation: Non-­infectious (Pneumonia vs. Pneumonitis) ��������������������������������������������������������������������������  193 2.8.1 Aspiration and Chemical Pneumonitis�����������������������  193 2.8.2 Lipoid Pneumonia������������������������������������������������������  195 2.8.3 Diffuse Pulmonary Hemorrhagic Syndromes ������������  196 2.9 Inflammation: Infectious/Non-infectious Granulomatous/Nongranulomatous����������������������������������������  197 2.9.1 Primary Pulmonary Tuberculosis��������������������������������  197 2.9.2 Sarcoidosis������������������������������������������������������������������  200 2.9.3 Aspergillosis ��������������������������������������������������������������  201 2.9.4 Others��������������������������������������������������������������������������  202 2.10 Chronic Obstructive Pulmonary Disease of the Youth������������  202 2.10.1 Chronic Bronchitis������������������������������������������������������  203 2.10.2 Emphysema����������������������������������������������������������������  203

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2.11 “Adult” Pneumoconiosis of the Youth������������������������������������  204 2.11.1 Silicosis����������������������������������������������������������������������  205 2.11.2 Asbestosis ������������������������������������������������������������������  206 2.11.3 Non-silico Asbestosis-Related Pneumoconiosis ��������  207 2.12 Pulmonary Vascular Disorders������������������������������������������������  207 2.12.1 Pulmonary Congestion and Edema����������������������������  208 2.12.2 Pulmonary Embolism/Infarction��������������������������������  208 2.12.3 Pulmonary Arterial Hypertension (PAH)��������������������  210 2.13 Transplantation-Related Disorders ����������������������������������������  212 2.13.1 Acute Rejection����������������������������������������������������������  212 2.13.2 Chronic Rejection ������������������������������������������������������  212 2.14 Pediatric Tumors and Pseudotumors��������������������������������������  215 2.14.1 Pulmonary Teratoma ��������������������������������������������������  215 2.14.2 Inflammatory Myofibroblastic Tumor������������������������  215 2.14.3 Pulmonary Hamartoma ����������������������������������������������  217 2.14.4 Pulmonary Sclerosing Hemangioma��������������������������  217 2.14.5 Pulmonary Carcinoid��������������������������������������������������  217 2.14.6 Lymphangioma-(Leo)-Myomatosis (LAM)���������������  217 2.14.7 Kaposiform Lymphangiomatosis��������������������������������  219 2.14.8 Pleuropulmonary Blastoma����������������������������������������  220 2.14.9 Metastatic Tumors������������������������������������������������������  222 2.15 “Adult”-Type Neoplasms in Childhood/Youth�����������������������  222 2.15.1 “Adult”-Type Preneoplastic Lesions��������������������������  226 2.16 Pleural Diseases����������������������������������������������������������������������  230 2.16.1 Pleural Effusions and Pleuritis������������������������������������  230 2.16.2 Pneumothorax ������������������������������������������������������������  234 2.16.3 Neoplastic Pleural Diseases����������������������������������������  235 2.17 Posttransplant Lymphoproliferative Disorders (PTLD)����������  237 2.18 Non-thymic Mediastinal Pathology����������������������������������������  240 2.18.1 Anterior Mediastinal Pathology����������������������������������  241 2.18.2 Middle Mediastinal Pathology������������������������������������  242 2.18.3 Posterior Mediastinal Pathology ��������������������������������  242 Multiple Choice Questions and Answers����������������������������������������  242 References and Recommended Readings����������������������������������������  244 3 Gastrointestinal Tract��������������������������������������������������������������������  255 3.1 Development and Genetics ����������������������������������������������������  256 3.2 Esophagus ������������������������������������������������������������������������������  258 3.2.1 Esophageal Anomalies������������������������������������������������  258 3.2.2 Esophageal Vascular Changes������������������������������������  263 3.2.3 Esophageal Inflammatory Diseases����������������������������  263 3.2.4 Esophageal Tumors����������������������������������������������������  274 3.3 Stomach����������������������������������������������������������������������������������  277 3.3.1 Gastric Anomalies������������������������������������������������������  277 3.3.2 Gastric Vascular Changes��������������������������������������������  280 3.3.3 Gastric Inflammatory Diseases ����������������������������������  281 3.3.4 Tissue Continuity Damage-­Related Gastric Degenerations������������������������������������������������  286 3.3.5 Gastric Tumors������������������������������������������������������������  287

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3.4 Small Intestine������������������������������������������������������������������������  304 3.4.1 Small Intestinal Anomalies ����������������������������������������  304 3.4.2 Abdominal Wall Defects (Median-Paramedian)��������  306 3.4.3 Continuity Defects of the Intestinal Lumen����������������  312 3.4.4 Intestinal Muscular Wall Defects��������������������������������  316 3.4.5 Small Intestinal Dystopias������������������������������������������  317 3.4.6 Composition Abnormalities of the Intestinal Wall������  317 3.4.7 Small Intestinal Vascular Changes������������������������������  318 3.4.8 Inflammation and Malabsorption��������������������������������  319 3.4.9 Short Bowel Syndrome/Intestinal Failure������������������  336 3.4.10 Small Intestinal Transplantation ��������������������������������  336 3.4.11 Graft-Versus-Host Disease (GVHD) of the Gut ��������  339 3.4.12 Small Intestinal Neoplasms����������������������������������������  340 3.5 Appendix��������������������������������������������������������������������������������  343 3.5.1 Appendiceal Anomalies����������������������������������������������  343 3.5.2 Appendiceal Vascular Changes����������������������������������  343 3.5.3 Appendicitis����������������������������������������������������������������  349 3.5.4 Appendiceal Metabolic and Degenerative Changes����������������������������������������������������������������������  351 3.5.5 Appendiceal Neoplasms���������������������������������������������  351 3.6 Large Intestine������������������������������������������������������������������������  353 3.6.1 Large Intestinal Anomalies ����������������������������������������  353 3.6.2 Large Intestinal Vascular Changes������������������������������  373 3.6.3 Large Intestinal Inflammatory Disorders��������������������  374 3.6.4 Colon-Rectum Neoplasms������������������������������������������  380 3.7 Anus����������������������������������������������������������������������������������������  387 3.7.1 Anal Anomalies����������������������������������������������������������  388 3.7.2 Inflammatory Anal Diseases ��������������������������������������  389 3.7.3 Benign Anal Tumors and Non-­neoplastic Anal Lesions (Pseudotumors) ������������������������������������  389 3.7.4 Anal Pre- and Malignant Lesions ������������������������������  390 3.8 Peritoneum������������������������������������������������������������������������������  393 3.8.1 Cytology����������������������������������������������������������������������  393 3.8.2 Non-neoplastic Peritoneal Pathology��������������������������  394 3.8.3 Neoplastic Peritoneal Pathology ��������������������������������  394 Multiple Choice Questions and Answers����������������������������������������  399 References and Recommended Readings����������������������������������������  402 4 Parenchymal GI Glands: Liver����������������������������������������������������  425 4.1 Development and Genetics ����������������������������������������������������  426 4.2 Hepatobiliary Anomalies��������������������������������������������������������  430 4.2.1 Ductal Plate Malformation (DPM) ����������������������������  431 4.2.2 Congenital Hepatic Fibrosis����������������������������������������  435 4.2.3 Biliary Hamartoma (von Meyenburg Complex) ��������  435 4.2.4 Caroli Disease/Syndrome�������������������������������������������  435 4.2.5 ADPKD-Related Liver Cysts��������������������������������������  435 4.3 Hyperbilirubinemia and Cholestasis ��������������������������������������  436 4.3.1 Hyperbilirubinemia ����������������������������������������������������  436

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4.3.2 Decreased Bilirubin Conjugation and Unconjugated Hyperbilirubinemia����������������������  437 4.3.3 Conjugated Hyperbilirubinemia���������������������������������  438 4.4 Infantile/Pediatric/Youth Cholangiopathies����������������������������  439 4.4.1 Biliary Atresia ������������������������������������������������������������  440 4.4.2 Non-BA Infantile Obstructive Cholangiopathies (NBAIOC)������������������������������������������������������������������  443 4.4.3 The Paucity of the Intrahepatic Biliary Ducts (PIBD)��������������������������������������������������������������  444 4.4.4 Neonatal Hepatitis Group (NAG) ������������������������������  444 4.4.5 Primary Sclerosing Cholangitis (PSC) ����������������������  456 4.4.6 Primary Biliary Cirrhosis (PBC)��������������������������������  458 4.4.7 Pregnancy-Related Liver Disease (PLD)��������������������  459 4.5 Genetic and Metabolic Liver Disease ������������������������������������  460 4.5.1 Endoplasmic Reticulum Storage Diseases (ERSDs) ������������������������������������������������������  461 4.5.2 Congenital Dysregulation of Carbohydrate Metabolism ����������������������������������������������������������������  464 4.5.3 Lipid/Glycolipid and Lipoprotein Metabolism Disorders������������������������������������������������  467 4.5.4 Amino Acid Metabolism Disorders����������������������������  471 4.5.5 Mitochondrial Hepatopathies��������������������������������������  471 4.5.6 Peroxisomal Disorders������������������������������������������������  477 4.5.7 Iron Metabolism Dysregulation����������������������������������  479 4.5.8 Copper Metabolism Dysregulation ����������������������������  483 4.5.9 Porphyria-Related Hepatopathies ������������������������������  485 4.5.10 Shwachman-Diamond Syndrome (SDS)��������������������  485 4.5.11 Chronic Granulomatous Disease (CGD)��������������������  485 4.5.12 Albinism-Related Liver Diseases��������������������������������  486 4.6 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection ����������������������������������������������������������  486 4.6.1 Acute Viral Hepatitis��������������������������������������������������  486 4.6.2 Chronic Viral Hepatitis ����������������������������������������������  488 4.6.3 Autoimmune Hepatitis������������������������������������������������  489 4.6.4 Drug-Induced Liver Disease (Chemical Injury) and TPN����������������������������������������������������������  490 4.6.5 Granulomatous Liver Disease������������������������������������  495 4.6.6 Alcoholic Liver Disease����������������������������������������������  496 4.6.7 Non-alcoholic Steatohepatitis ������������������������������������  498 4.6.8 Acute and Chronic Rejection Post-Liver Transplantation�����������������������������������������������������������  498 4.7 Hepatic Vascular Disorders ����������������������������������������������������  503 4.7.1 Acute and Chronic Passive Liver Congestion������������  503 4.7.2 Ischemic Hepatocellular Necrosis������������������������������  505 4.7.3 Shock-Related Cholestasis������������������������������������������  505 4.8 Liver Failure and Liver Cirrhosis��������������������������������������������  505 4.9 Portal Hypertension����������������������������������������������������������������  508 4.10 Bacterial and Parasitic Liver Infections����������������������������������  509

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4.10.1 Pyogenic Abscess��������������������������������������������������������  509 4.10.2 Helminthiasis��������������������������������������������������������������  510 4.11 Liver Tumors��������������������������������������������������������������������������  510 4.11.1 Benign Tumors������������������������������������������������������������  510 4.11.2 Malignant Tumors������������������������������������������������������  517 4.11.3 Metastatic Tumors������������������������������������������������������  534 Multiple Choice Questions and Answers����������������������������������������  538 References and Recommended Readings����������������������������������������  540 5 Parenchymal GI Glands (Gallbladder, Biliary Tract, and Pancreas) ��������������������������������������������������������������������������������  551 5.1 Development and Genetics ����������������������������������������������������  551 5.2 Biliary and Pancreatic Structural Anomalies��������������������������  553 5.2.1 Choledochal Cysts������������������������������������������������������  553 5.2.2 Gallbladder Congenital Abnormalities ����������������������  553 5.2.3 Pancreas Congenital Anomalies����������������������������������  553 5.3 Gallbladder and Extrahepatic Biliary Tract����������������������������  556 5.3.1 Cholesterolosis and Cholelithiasis������������������������������  556 5.3.2 Acute and Chronic Cholecystitis��������������������������������  557 5.3.3 Gallbladder Proliferative Processes and Neoplasms������������������������������������������������������������  558 5.3.4 Extrahepatic Bile Duct Tumors and Cholangiocellular Carcinoma������������������������������  561 5.4 Pancreas Pathology ����������������������������������������������������������������  561 5.4.1 Congenital Hyperinsulinism and Nesidioblastosis���������������������������������������������������  561 5.4.2 Acute and Chronic Pancreatitis����������������������������������  563 5.4.3 Pancreatoblastoma and Acinar Cell Carcinoma in Childhood and Youth����������������������������  566 5.4.4 Cysts and Cystic Neoplastic Processes of the Pancreas������������������������������������������������������������  567 5.4.5 PanIN and Solid Pancreas Ductal Carcinoma������������  571 5.4.6 Other Tumors��������������������������������������������������������������  571 5.4.7 Degenerative Changes and Transplant Pathology������  571 Multiple Choice Questions and Answers����������������������������������������  574 References and Recommended Readings����������������������������������������  575 6 Kidney, Pelvis, and Ureter������������������������������������������������������������  579 6.1 Development and Genetics ����������������������������������������������������  581 6.2 Non-cystic Congenital Anomalies������������������������������������������  589 6.2.1 Disorders of Number��������������������������������������������������  589 6.2.2 Disorders of Rotation��������������������������������������������������  591 6.2.3 Disorders of Position��������������������������������������������������  591 6.2.4 Disorders of Separation����������������������������������������������  591 6.3 Cystic Renal Diseases ������������������������������������������������������������  591 6.3.1 Classifications ������������������������������������������������������������  591 6.3.2 Autosomal Dominant Polycystic Kidney Disease������  591 6.3.3 Autosomal Recessive Polycystic Kidney Disease������  596 6.3.4 Medullary Sponge Kidney������������������������������������������  597

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6.3.5 Multicystic Dysplastic Kidney (MCDK)��������������������  597 6.3.6 Hydronephrosis/Hydroureteronephrosis ��������������������  597 6.3.7 Simple Renal Cysts����������������������������������������������������  598 6.3.8 Acquired Cystic Kidney Disease (CRD-Related)������  598 6.3.9 Genetic Syndromes and Cystic Renal Disease ����������  598 6.4 Primary Glomerular Diseases ������������������������������������������������  599 6.4.1 Hypersensitivity Reactions and Major Clinical Syndromes of Glomerular Disease����������������  599 6.4.2 Post-infectious Glomerulonephritis����������������������������  600 6.4.3 Rapidly Progressive Glomerulonephritis��������������������  602 6.4.4 Minimal Change Disease��������������������������������������������  604 6.4.5 (Diffuse) Mesangial Proliferative GN������������������������  604 6.4.6 Focal and Segmental Glomerulosclerosis ������������������  604 6.4.7 Membranous Glomerulonephritis ������������������������������  606 6.4.8 Membranoproliferative (Membrane-Capillary) Glomerulonephritis ����������������������������������������������������  609 6.5 Secondary Glomerular Diseases ��������������������������������������������  610 6.5.1 SLE/Lupus Nephritis��������������������������������������������������  610 6.5.2 Henoch-Schönlein Purpura ����������������������������������������  611 6.5.3 Amyloidosis����������������������������������������������������������������  613 6.5.4 Light Chain Disease����������������������������������������������������  614 6.5.5 Cryoglobulinemia ������������������������������������������������������  614 6.5.6 Diabetic Nephropathy ������������������������������������������������  614 6.6 Hereditary/Familial Nephropathies����������������������������������������  615 6.6.1 Fabry Nephropathy ����������������������������������������������������  615 6.6.2 Alport Syndrome��������������������������������������������������������  615 6.6.3 Nail-Patella Syndrome������������������������������������������������  617 6.6.4 Congenital Nephrotic Syndrome��������������������������������  617 6.6.5 Thin Glomerular Basement Membrane Nephropathy (TBMN)������������������������������������������������  617 6.7 Tubulointerstitial Diseases������������������������������������������������������  618 6.7.1 Acute Tubulointerstitial Nephritis (ATIN)������������������  618 6.7.2 Chronic Tubulointerstitial Nephritis (CTIN)��������������  622 6.7.3 Acute Tubular Necrosis����������������������������������������������  623 6.7.4 Chronic Renal Failure (CRF)��������������������������������������  623 6.7.5 Nephrolithiasis and Nephrocalcinosis������������������������  624 6.7.6 Osmotic Nephrosis and Hyaline Change��������������������  625 6.7.7 Hypokalemic Nephropathy ����������������������������������������  625 6.7.8 Urate Nephropathy������������������������������������������������������  625 6.7.9 Cholemic Nephropathy/Jaundice-Linked Acute Kidney Injury ��������������������������������������������������  625 6.7.10 Myeloma Kidney��������������������������������������������������������  625 6.7.11 Radiation Nephropathy ����������������������������������������������  626 6.7.12 Tubulointerstitial Nephritis and Uveitis (TINU)��������  626 6.8 Vascular Diseases��������������������������������������������������������������������  626 6.8.1 Benign Nephrosclerosis����������������������������������������������  626 6.8.2 Malignant Nephrosclerosis ����������������������������������������  626 6.8.3 Renal Artery Stenosis��������������������������������������������������  626

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6.8.4 Infarcts������������������������������������������������������������������������  627 6.8.5 Vasculitis ��������������������������������������������������������������������  627 6.8.6 Hemolytic Uremic Syndrome ������������������������������������  628 6.8.7 Thrombotic Thrombocytopenic Purpura��������������������  630 6.9 Renal Transplantation ������������������������������������������������������������  630 6.9.1 Preservation Injury������������������������������������������������������  630 6.9.2 Hyperacute Rejection��������������������������������������������������  630 6.9.3 Acute Rejection����������������������������������������������������������  631 6.9.4 Chronic Rejection ������������������������������������������������������  632 6.9.5 Humoral (Acute/Chronic) Rejection��������������������������  632 6.9.6 Antirejection Drug Toxicity����������������������������������������  633 6.9.7 Recurrence of Primary Disorder ��������������������������������  633 6.10 Hereditary Cancer Syndromes Associated with Renal Tumors������������������������������������������������������������������  633 6.10.1 Beckwith-Wiedemann Syndrome ������������������������������  633 6.10.2 WAGR Syndrome ������������������������������������������������������  633 6.10.3 Denys-Drash Syndrome����������������������������������������������  634 6.10.4 Non-WT1/Non-WT2 Pediatric Syndromes����������������  634 6.10.5 Von Hippel Lindau Syndrome������������������������������������  634 6.10.6 Tuberous Sclerosis Syndrome������������������������������������  634 6.10.7 Hereditary Papillary Renal Carcinoma Syndrome��������������������������������������������������������������������  634 6.10.8 Hereditary Leiomyoma Renal Carcinoma Syndrome��������������������������������������������������������������������  634 6.10.9 Birt-Hogg-Dube Syndrome����������������������������������������  634 6.11 Pediatric Tumors (Embryonal)������������������������������������������������  634 6.11.1 Wilms Tumor (Nephroblastoma)��������������������������������  634 6.11.2 Cystic Partially Differentiated Nephroblastoma (CPDN) and (Pediatric) Cystic Nephroma ����������������  645 6.11.3 Congenital Mesoblastic Nephroma����������������������������  646 6.11.4 Clear Cell Sarcoma ����������������������������������������������������  646 6.11.5 Rhabdoid Tumor ��������������������������������������������������������  647 6.11.6 Metanephric Tumors ��������������������������������������������������  647 6.11.7 XP11 Translocation Carcinoma����������������������������������  647 6.11.8 Ossifying Renal Tumor of Infancy�����������������������������  650 6.12 Non-embryonal Tumors of the Young������������������������������������  650 6.12.1 Clear Cell Renal Cell Carcinoma��������������������������������  650 6.12.2 Chromophobe Renal Cell Carcinoma ������������������������  653 6.12.3 Papillary Adenoma and Renal Cell Carcinoma����������  653 6.12.4 Collecting Duct Carcinoma����������������������������������������  656 6.12.5 Renal Medullary Carcinoma ��������������������������������������  656 6.12.6 Angiomyolipoma��������������������������������������������������������  656 6.12.7 Oncocytoma����������������������������������������������������������������  656 6.12.8 Other Epithelial and Mesenchymal Tumors ��������������  659 6.13 Non-neoplastic Pathology of the Pelvis and Ureter����������������  661 6.13.1 Anatomy and Physiology Notes���������������������������������  661 6.13.2 Congenital Pelvic-Ureteral Anomalies ����������������������  661 6.13.3 Congenital Ureteric Anomalies����������������������������������  661 6.13.4 Lower Urinary Tract Abnormalities����������������������������  662

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6.14 Tumors of the Pelvis and Ureter ��������������������������������������������  666 6.14.1 Neoplasms������������������������������������������������������������������  666 6.14.2 Genetic Syndromes ����������������������������������������������������  666 Multiple Choice Questions and Answers����������������������������������������  667 References and Recommended Readings����������������������������������������  668 7 Lower Urinary and Male Genital System������������������������������������  673 7.1 Development and Genetics ����������������������������������������������������  674 7.1.1 Urinary Bladder and Ureter����������������������������������������  674 7.1.2 Testis, Prostate, and Penis������������������������������������������  675 7.2 Lower Urinary and Genital System Anomalies����������������������  676 7.2.1 Lower Urinary System Anomalies������������������������������  676 7.2.2 Male Genital System Anomalies��������������������������������  678 7.3 Urinary Tract Inflammatory and Degenerative Conditions ������������������������������������������������������������������������������  684 7.3.1 Cystitis, Infectious������������������������������������������������������  684 7.3.2 Cystitis, Non-infectious����������������������������������������������  684 7.3.3 Malacoplakia of the Young ����������������������������������������  686 7.3.4 Urinary Tract Infections and Vesicoureteral Reflux��������������������������������������������������������������������������  686 7.3.5 Megacystis, Megaureter, Hydronephrosis, and Neurogenic Bladder ��������������������������������������������  687 7.3.6 Urinary Tract Endometriosis��������������������������������������  688 7.3.7 Tumorlike Lesions (Including Caruncles)������������������  689 7.4 Preneoplastic and Neoplastic Conditions of the Urinary Tract����������������������������������������������������������������  690 7.4.1 Urothelial Hyperplasia (Flat and Papillary)����������������  690 7.4.2 Reactive Atypia, Atypia of Unknown Significance, Dysplasia, and Carcinoma In Situ (CIS)����������������������������������������������������������������  691 7.4.3 Noninvasive Papillary Urothelial Neoplasms ������������  691 7.4.4 Invasive Urothelial Neoplasms ����������������������������������  693 7.4.5 Non-urothelial Differentiated Urinary Tract Neoplasms ��������������������������������������������������������  696 7.5 Male Infertility-Associated Disorders������������������������������������  696 7.5.1 Spermiogram and Classification ��������������������������������  696 7.6 Inflammatory Disorders of the Testis and Epididymis������������  696 7.6.1 Acute Orchitis ������������������������������������������������������������  697 7.6.2 Epidermoid Cysts��������������������������������������������������������  697 7.6.3 Hydrocele��������������������������������������������������������������������  700 7.6.4 Spermatocele��������������������������������������������������������������  700 7.6.5 Varicocele��������������������������������������������������������������������  704 7.7 Testicular Tumors��������������������������������������������������������������������  704 7.7.1 Germ Cell Tumors������������������������������������������������������  704 7.7.2 Tumors of Specialized Gonadal Stroma ��������������������  720 7.7.3 Rhabdomyosarcoma and Rhabdoid Tumor of the Testis ����������������������������������������������������������������  727 7.7.4 Secondary Tumors������������������������������������������������������  727

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7.8 Tumors of the Epididymis������������������������������������������������������  727 7.8.1 Adenomatoid Tumor ��������������������������������������������������  727 7.8.2 Papillary Cystadenoma ����������������������������������������������  728 7.8.3 Rhabdomyosarcoma����������������������������������������������������  728 7.8.4 Mesothelioma��������������������������������������������������������������  728 7.9 Inflammatory Disorders of the Prostate Gland ����������������������  728 7.9.1 Acute Prostatitis����������������������������������������������������������  728 7.9.2 Chronic Prostatitis������������������������������������������������������  728 7.9.3 Granulomatous Prostatitis������������������������������������������  729 7.9.4 Prostatic Malakoplakia of the Youth ��������������������������  729 7.10 Prostate Gland Overgrowths ��������������������������������������������������  729 7.10.1 Benign Nodular Hyperplasia of the Young and Fibromatosis��������������������������������������������������������  729 7.10.2 Rhabdomyosarcoma, Leiomyosarcoma, and Other Sarcomas (e.g., Ewing Sarcoma) ��������������  729 7.10.3 Prostatic Carcinoma Mimickers����������������������������������  730 7.10.4 Prostatic Intraepithelial Neoplasia (PIN)��������������������  732 7.10.5 Prostate Cancer of the Young��������������������������������������  733 7.10.6 Hematological Malignancies��������������������������������������  739 7.10.7 Secondary Tumors������������������������������������������������������  739 7.11 Inflammatory and Neoplastic Disorders of the Penis ������������  739 7.11.1 Infections��������������������������������������������������������������������  739 7.11.2 Non-infectious Inflammatory Diseases����������������������  740 7.11.3 Penile Cysts and Noninvasive Squamous Cell Lesions����������������������������������������������������������������  741 7.11.4 Penile Squamous Cell Carcinoma of the Youth����������  741 7.11.5 Non-squamous Cell Carcinoma Neoplasms of the Penis������������������������������������������������������������������  744 Multiple Choice Questions and Answers����������������������������������������  744 References and Recommended Readings����������������������������������������  746 8 Female Genital System������������������������������������������������������������������  757 8.1 Development and Genetics ����������������������������������������������������  758 8.2 Congenital Anomalies of the Female Genital System������������  760 8.3 Ovarian Inflammatory and Degenerative Conditions��������������  761 8.3.1 Oophoritis ������������������������������������������������������������������  761 8.3.2 Torsion������������������������������������������������������������������������  761 8.3.3 Non-neoplastic Cystic Lesions ����������������������������������  763 8.3.4 Non-neoplastic Proliferations ������������������������������������  763 8.4 Infectious Diseases of the Female Genital System ����������������  764 8.4.1 Viral Diseases�������������������������������������������������������������  764 8.4.2 Bacterial Diseases ������������������������������������������������������  765 8.4.3 Fungal Diseases����������������������������������������������������������  767 8.4.4 Parasitic Diseases��������������������������������������������������������  767 8.5 Inflammatory, Reactive Changes and Degenerative Conditions of Vulva, Vagina, Cervix, Uterus, and Tuba ��������  767 8.5.1 Non- and Preneoplastic Vulvar and Vaginal Lesions����������������������������������������������������  767 8.5.2 Inflammation-Associated Cervical Lesions����������������  769

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8.5.3 Reactive Changes of the Cervix����������������������������������  770 8.5.4 Cyst-Associated Cervical Lesions������������������������������  770 8.5.5 Ectopia-Associated Cervical Lesions ������������������������  770 8.5.6 Pregnancy-Associated Cervical Lesions��������������������  770 8.5.7 Cervical Metaplasias��������������������������������������������������  771 8.5.8 Non-neoplastic and Preneoplastic Uterine Lesions ����������������������������������������������������������  771 8.5.9 Non-neoplastic Abnormalities of the Tuba ����������������  773 8.6 Tumors of the Ovary ��������������������������������������������������������������  773 8.6.1 Germ Cell Tumors������������������������������������������������������  774 8.6.2 Surface Epithelial Tumors������������������������������������������  779 8.6.3 Sex Cord-Stromal Tumors������������������������������������������  790 8.6.4 Other Primary Ovarian and Secondary Tumors����������  798 8.7 Tumors of the Tuba ����������������������������������������������������������������  798 8.7.1 Benign Neoplasms������������������������������������������������������  798 8.7.2 Malignant Neoplasms ������������������������������������������������  798 8.8 Tumors of the Uterus��������������������������������������������������������������  798 8.8.1 Type I/Type II EC ������������������������������������������������������  799 8.8.2 Non-type I/Non-type II EC ����������������������������������������  799 8.8.3 Uterine Leiomyoma (ULM) and Variants������������������  799 8.8.4 Uterine Leiomyosarcoma (ULMS) ����������������������������  799 8.8.5 Uterine Adenomatoid Tumor��������������������������������������  804 8.8.6 Uterine Lymphangiomyomatosis (ULAM)����������������  804 8.8.7 Uterine Stroma Tumors����������������������������������������������  804 8.8.8 Hematological Malignancies and Secondary Tumors������������������������������������������������  804 8.9 Tumors of the Cervix��������������������������������������������������������������  805 8.9.1 Benign Neoplasms������������������������������������������������������  805 8.9.2 Precancerous Conditions and Malignant Neoplasms������������������������������������������������������������������  805 8.10 Tumors of the Vagina��������������������������������������������������������������  811 8.10.1 Benign Tumors������������������������������������������������������������  811 8.10.2 Precancerous Conditions and Malignant Tumors������������������������������������������������������������������������  813 8.11 Tumors of the Vulva����������������������������������������������������������������  816 8.11.1 Benign Neoplasms������������������������������������������������������  816 8.11.2 Malignant Tumors������������������������������������������������������  818 Multiple Choice Questions and Answers����������������������������������������  823 References and Recommended Readings����������������������������������������  825 9 Breast����������������������������������������������������������������������������������������������  833 9.1 Development and Genetics ����������������������������������������������������  834 9.2 Congenital Anomalies, Inflammatory, and Related Disorders ������������������������������������������������������������  836 9.2.1 Amastia, Atelia, Synmastia, Polymastia, and Politelia����������������������������������������������������������������  836 9.2.2 Asymmetry, Hypotrophy, and Hypertrophy����������������  836 9.2.3 Dysmaturity and Precocious Thelarche����������������������  838 9.2.4 Acute Mastitis, Abscess, and Phlegmon ��������������������  838

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9.2.5 Duct Ectasia, Periductal Mastitis, and Granulomatous Mastitis ��������������������������������������  839 9.2.6 Necrosis, Calcifications, and Mondor Disease ����������  839 9.3 Pathology of the Female and Young Adult������������������������������  840 9.3.1 Fibrocystic Disease ����������������������������������������������������  840 9.3.2 Soft Tissue Tumors and Hematological Malignancies ��������������������������������������������������������������  840 9.3.3 Fibroadenoma ������������������������������������������������������������  840 9.3.4 Adenoma ��������������������������������������������������������������������  841 9.3.5 Genetic Background of Breast Cancer������������������������  844 9.3.6 In Situ and Invasive Ductal Breast Carcinoma ����������  847 9.3.7 In Situ and Invasive Lobular Breast Carcinoma ��������  849 9.3.8 WHO Variants of the Infiltrating Ductal Carcinoma ������������������������������������������������������������������  849 9.3.9 Sweat Gland-Type Tumors and Myoepithelial Tumors������������������������������������������������������������������������  850 9.3.10 Phyllodes Tumor ��������������������������������������������������������  851 9.4 Cancer Mimickers������������������������������������������������������������������  852 9.4.1 Hyperplasia, Ductal and Lobular��������������������������������  852 9.4.2 Adenosis����������������������������������������������������������������������  855 9.5 Male Breast Disease����������������������������������������������������������������  855 9.5.1 Gynecomastia��������������������������������������������������������������  855 9.5.2 Breast Cancer of the Male������������������������������������������  855 Multiple Choice Questions and Answers����������������������������������������  856 References and Recommended Readings����������������������������������������  857 10 Hematolymphoid System��������������������������������������������������������������  861 10.1 Development and Genetics ��������������������������������������������������  862 10.2 Red Blood Cell Disorders ����������������������������������������������������  864 10.2.1 Anemia����������������������������������������������������������������������  864 10.2.2 Polycythemia������������������������������������������������������������  867 10.3 Coagulation and Hemostasis Disorders��������������������������������  869 10.3.1 Coagulation and Hemostasis������������������������������������  869 10.3.2 Coagulation Disorders����������������������������������������������  869 10.3.3 Platelet Disorders������������������������������������������������������  870 10.4 White Blood Cell Disorders��������������������������������������������������  871 10.4.1 Leukocytopenias and Leukocyte Dysfunctionalities ����������������������������������������������������  871 10.4.2 Non-neoplastic Leukocytosis������������������������������������  871 10.4.3 Leukemia (Neoplastic Leukocytosis) or Virchow’s “Weisses Blut” ������������������������������������  872 10.4.4 Myelodysplastic Syndromes ������������������������������������  878 10.4.5 Hodgkin Lymphoma ������������������������������������������������  878 10.4.6 Non-Hodgkin Lymphomas���������������������������������������  887 10.4.7 Follicular Lymphoma������������������������������������������������  888 10.4.8 Small Lymphocytic Lymphoma��������������������������������  890 10.4.9 Mantle Cell Lymphoma (MCL)��������������������������������  891 10.4.10 Marginal Cell Lymphoma ��������������������������������������  891

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10.4.11 Diffuse Large B-Cell Lymphoma (DLBCL)����������  892 10.4.12 Lymphoblastic Lymphoma ������������������������������������  894 10.4.13 Burkitt Lymphoma��������������������������������������������������  896 10.4.14 Peripheral T-Cell Lymphoma����������������������������������  902 10.4.15 Anaplastic Large Cell Lymphoma��������������������������  903 10.4.16 Adult T-Cell Leukemia/Lymphoma������������������������  903 10.4.17 Cutaneous T-Cell Lymphoma (CTCL) ������������������  904 10.4.18 Angiocentric Immunoproliferative Lesions������������  905 10.4.19 Extranodal NK-/T-Cell Lymphoma������������������������  906 10.5 Disorders of the Monocyte-­Macrophage System and Mast Cells����������������������������������������������������������  907 10.5.1 Hemophagocytic Syndrome��������������������������������������  907 10.5.2 Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-­Dorfman Disease)����������  908 10.5.3 Langerhans Cell Histiocytosis����������������������������������  908 10.5.4 Histiocytic Medullary Reticulosis����������������������������  909 10.5.5 True Histiocytic Lymphoma ������������������������������������  910 10.5.6 Systemic Mastocytosis����������������������������������������������  910 10.6 Plasma Cell Disorders����������������������������������������������������������  910 10.6.1 Multiple Myeloma����������������������������������������������������  911 10.6.2 Solitary Myeloma�����������������������������������������������������  912 10.6.3 Plasma Cell Leukemia����������������������������������������������  912 10.6.4 Waldenstrom’s Macroglobulinemia��������������������������  912 10.6.5 Heavy Chain Disease������������������������������������������������  912 10.6.6 Monoclonal Gammopathy of Undetermined Significance (MGUS)�����������������������������������������������  913 10.7 Benign Lymphadenopathies��������������������������������������������������  913 10.7.1 Follicular Hyperplasia����������������������������������������������  914 10.7.2 Diffuse (Paracortical) Hyperplasia����������������������������  918 10.7.3 Sinus Pattern ������������������������������������������������������������  919 10.7.4 Predominant Granulomatous Pattern������������������������  920 10.7.5 Other Myxoid Patterns����������������������������������������������  921 10.7.6 Angioimmunoblastic Lymphadenopathy with Dysproteinemia (AILD)������������������������������������  921 10.8 Disorders of the Spleen��������������������������������������������������������  921 10.8.1 White Pulp Disorders of the Spleen��������������������������  922 10.8.2 Red Pulp Disorders of the Spleen ����������������������������  922 10.9 Disorders of the Thymus������������������������������������������������������  924 10.9.1 Thymic Cysts and Thymolipoma������������������������������  924 10.9.2 True Thymic Hyperplasia and Thymic Follicular Hyperplasia����������������������������������������������  924 10.9.3 HIV Changes������������������������������������������������������������  925 10.9.4 Thymoma������������������������������������������������������������������  925 Multiple Choice Questions and Answers����������������������������������������  927 References and Recommended Readings����������������������������������������  930 11 Endocrine System��������������������������������������������������������������������������  933 11.1 Development and Genetics ��������������������������������������������������  934 11.2 Pituitary Gland Pathology����������������������������������������������������  938

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11.2.1 Congenital Anomalies of the Pituitary Gland ����������  939 11.2.2 Vascular and Degenerative Changes ������������������������  939 11.2.3 Pituitary Adenomas and Hyperpituitarism����������������  939 11.2.4 Genetic Syndromes Associated with Pituitary Adenomas ����������������������������������������������������������������  941 11.2.5 Hypopituitarism (Simmonds Disease)����������������������  942 11.2.6 Empty Sella Syndrome (ESS)����������������������������������  943 11.2.7 Neurohypophysopathies (Disorders of the Posterior Pituitary Gland) ����������������������������������������  943 11.3 Thyroid Gland Pathology������������������������������������������������������  943 11.3.1 Congenital Anomalies, Hyperplasia, and Thyroiditis����������������������������������������������������������  946 11.3.2 Congenital Anomalies, Goiter, and Dysfunctional Thyroid Gland����������������������������  946 11.3.3 Inflammatory and Immunologic Thyroiditis������������  948 11.3.4 Epithelial Neoplasms of the Thyroid Glands������������  949 11.4 Parathyroid Gland Pathology������������������������������������������������  965 11.4.1 Congenital Anomalies of the Parathyroid Glands ����������������������������������������������������������������������  965 11.4.2 Parathyroid Gland Hyperplasia��������������������������������  965 11.4.3 Parathyroid Gland Adenoma������������������������������������  966 11.4.4 Parathyroid Gland Carcinoma����������������������������������  966 11.5 Adrenal Gland Pathology������������������������������������������������������  967 11.5.1 Congenital Anomalies of the Adrenal Gland and Paraganglia����������������������������������������������  967 11.5.2 Dysfunctional Adrenal Gland ����������������������������������  969 11.5.3 Adrenalitis����������������������������������������������������������������  969 11.5.4 Neoplasms of the Adrenal Gland and Paraganglia��������������������������������������������������������  974 11.5.5 Syndromes Associated with Adrenal Cortex Abnormalities������������������������������������������������  996 Multiple Choice Questions and Answers����������������������������������������  997 References and Recommended Readings����������������������������������������  998 12 Soft Tissue �������������������������������������������������������������������������������������� 1003 12.1 Development and Genetics �������������������������������������������������� 1004 12.2 Vascular and Inflammatory Changes of Soft Tissue ������������ 1005   12.2.1 Hyperemia�������������������������������������������������������������� 1005   12.2.2 Necrotizing Fasciitis ���������������������������������������������� 1005   12.2.3 Vasculitis-Associated Soft Tissue Changes������������ 1005   12.2.4 Miscellaneous �������������������������������������������������������� 1005 12.3 Soft Tissue Neoplasms: Scoring ������������������������������������������ 1009 12.4 Adipocytic Tumors���������������������������������������������������������������� 1010   12.4.1 Lipoma�������������������������������������������������������������������� 1011   12.4.2 Lipoma Subtypes���������������������������������������������������� 1011   12.4.3 Lipomatosis������������������������������������������������������������ 1012   12.4.4 Lipoblastoma���������������������������������������������������������� 1012   12.4.5 Hibernoma�������������������������������������������������������������� 1012

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  12.4.6 Locally Aggressive and Malignant Adipocytic Tumors�������������������������������������������������� 1013 12.5 Fibroblastic/Myofibroblastic Tumors������������������������������������ 1017   12.5.1 Fasciitis/Myositis Group���������������������������������������� 1019   12.5.2 Fibroma Group�������������������������������������������������������� 1020   12.5.3 Fibroblastoma Classic and Subtypes���������������������� 1021   12.5.4 Fibrous Hamartoma of Infancy (FHI)�������������������� 1023   12.5.5 Fibromatosis of Childhood ������������������������������������ 1023   12.5.6 Infantile Myofibroma/Myofibromatosis������������������ 1027   12.5.7 Fibroblastic/Myofibroblastic Tumors with Intermediate Malignant Potential������������������� 1027   12.5.8 Malignant Fibroblastic/Myofibroblastic Tumors�������������������������������������������������������������������� 1033 12.6 Fibrohistiocytic Tumors�������������������������������������������������������� 1036   12.6.1 Histiocytoma ���������������������������������������������������������� 1036   12.6.2 Benign Fibrous Histiocytoma �������������������������������� 1037   12.6.3 Borderline Fibrous Histiocytoma���������������������������� 1039   12.6.4 Malignant Fibrous Histiocytoma���������������������������� 1039 12.7 Smooth Muscle Tumors�������������������������������������������������������� 1040   12.7.1 Leiomyoma ������������������������������������������������������������ 1040   12.7.2 EBV-Related Smooth Muscle Tumors�������������������� 1040   12.7.3 Leiomyosarcoma���������������������������������������������������� 1040 12.8 Pericytic Tumors ������������������������������������������������������������������ 1041   12.8.1 Glomus Tumor�������������������������������������������������������� 1041   12.8.2 Glomangiosarcoma ������������������������������������������������ 1042   12.8.3 Myopericytoma ������������������������������������������������������ 1042 12.9 Skeletal Muscle Tumors�������������������������������������������������������� 1044   12.9.1 Rhabdomyomatous Mesenchymal Hamartoma (RMH)������������������������������������������������ 1044   12.9.2 Rhabdomyoma�������������������������������������������������������� 1046   12.9.3 Rhabdomyosarcoma������������������������������������������������ 1046   12.9.4 Pleomorphic RMS�������������������������������������������������� 1055 12.10 Vascular Tumors�������������������������������������������������������������������� 1059 12.10.1 Benign Vascular Tumors ���������������������������������������� 1059 12.10.2 Vascular Tumors with Intermediate Malignant Potential������������������������������������������������ 1062 12.10.3 Malignant Vascular Tumors������������������������������������ 1066 12.10.4 Genetic Syndromes Associated with Vascular Tumors���������������������������������������������� 1068 12.11 Chondro-Osteoforming Tumors�������������������������������������������� 1069 12.11.1 Extraskeletal Chondroma���������������������������������������� 1069 12.11.2 Extraskeletal Myxoid Chondrosarcoma������������������ 1069 12.11.3 Mesenchymal Chondrosarcoma������������������������������ 1070 12.11.4 Extraskeletal Aneurysmatic Bone Cyst������������������ 1070 12.11.5 Extraskeletal Osteosarcoma (ESOS)���������������������� 1070 12.11.6 Extraskeletal Chordoma������������������������������������������ 1070 12.12 Tumors of Uncertain Differentiation������������������������������������ 1071 12.12.1 Myxoma������������������������������������������������������������������ 1071 12.12.2 Myoepithelial Carcinoma��������������������������������������� 1072

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12.12.3 Parachordoma �������������������������������������������������������� 1072 12.12.4 Synovial Sarcoma �������������������������������������������������� 1074 12.12.5 Epithelioid Sarcoma������������������������������������������������ 1076 12.12.6 Alveolar Soft Part Sarcoma������������������������������������ 1076 12.12.7 Clear Cell Sarcoma ������������������������������������������������ 1079 12.12.8 Extraskeletal Myxoid Chondrosarcoma (ESMC) ������������������������������������������������������������������ 1080 12.12.9 PNET/Extraskeletal Ewing Sarcoma (ESES) �������� 1081 12.12.10 Desmoplastic Small Round Cell Tumor �������������� 1083 12.12.11 Extrarenal Rhabdoid Tumor���������������������������������� 1084 12.12.12 Malignant Mesenchymoma���������������������������������� 1084 12.12.13 PEComa���������������������������������������������������������������� 1084 12.12.14 Extrarenal Wilms’ Tumor ������������������������������������ 1085 12.12.15 Sacrococcygeal Teratoma and Extragonadal Germ Cell Tumor and Yolk Sac Tumor���������������� 1085 Multiple Choice Questions and Answers���������������������������������������� 1090 References and Recommended Readings���������������������������������������� 1091 13 Arthro-Skeletal System������������������������������������������������������������������ 1095 13.1 Development and Genetics �������������������������������������������������� 1096 13.2 Osteochondrodysplasias�������������������������������������������������������� 1097 13.2.1 Nosology and Nomenclature������������������������������������ 1097 13.2.2 Groups of Genetic Skeletal Disorders���������������������� 1098 13.3 Metabolic Skeletal Diseases ������������������������������������������������ 1103 13.3.1 Rickets, and Osteomalacia���������������������������������������� 1103 13.3.2 Osteoporosis of the Youth ���������������������������������������� 1104 13.3.3 Paget Disease of the Bone���������������������������������������� 1106 13.3.4 Juvenile Paget Disease���������������������������������������������� 1108 13.4 Osteitis and Osteomyelitis���������������������������������������������������� 1109 13.4.1 Osteomyelitis������������������������������������������������������������ 1109 13.5 Osteonecrosis������������������������������������������������������������������������ 1113 13.5.1 Bony Infarct and Osteochondritis Dissecans������������ 1113 13.6 Tumorlike Lesions and Bone/Osteoid-Forming Tumors������ 1115 13.6.1 Myositis Ossificans �������������������������������������������������� 1115 13.6.2 Fibrous Dysplasia and Osteofibrous Dysplasia�������� 1116 13.6.3 Non-ossifying Fibroma (NOF) �������������������������������� 1118 13.6.4 Bone Cysts���������������������������������������������������������������� 1120 13.6.5 Osteoma, Osteoid Osteoma, and Giant Osteoid Osteoma������������������������������������������������������ 1124 13.6.6 Giant Cell Tumor������������������������������������������������������ 1127 13.6.7 Osteosarcoma������������������������������������������������������������ 1128 13.7 Chondroid (Cartilage)-Forming Tumors������������������������������ 1136 13.7.1 Osteochondroma ������������������������������������������������������ 1137 13.7.2 Enchondroma������������������������������������������������������������ 1139 13.7.3 Chondroblastoma������������������������������������������������������ 1140 13.7.4 Chondromyxoid Fibroma������������������������������������������ 1143 13.7.5 Chondrosarcoma ������������������������������������������������������ 1145 13.8 Bone Ewing Sarcoma������������������������������������������������������������ 1147

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13.9 Miscellaneous Bone Tumors������������������������������������������������ 1149 13.9.1 Chordoma������������������������������������������������������������������ 1149 13.9.2 Adamantinoma���������������������������������������������������������� 1150 13.9.3 Langerhans Cell Histiocytosis���������������������������������� 1151 13.9.4 Vascular, Smooth Muscle, and Lipogenic Tumors���������������������������������������������������������������������� 1153 13.9.5 Hematologic Tumors������������������������������������������������ 1153 13.10 Metastatic Bone Tumors ������������������������������������������������������ 1153 13.11 Juvenile Rheumatoid Arthritis and Juvenile Arthropathies������������������������������������������������������������������������ 1154 13.11.1 Rheumatoid Arthritis and Juvenile Rheumatoid Arthritis���������������������������������������������� 1154 13.11.2 Infectious Arthritis�������������������������������������������������� 1156 13.11.3 Gout, Early-Onset Juvenile Tophaceous Gout and Pseudogout���������������������������������������������� 1157 13.11.4 Bursitis, Baker Cyst, and Ganglion������������������������ 1159 13.11.5 Pigmented Villonodular Synovitis and Nodular Tenosynovitis ������������������������������������ 1159 Multiple Choice Questions and Answers���������������������������������������� 1161 References and Recommended Readings���������������������������������������� 1162 14 Head and Neck ������������������������������������������������������������������������������ 1167 14.1 Development ������������������������������������������������������������������������ 1168 14.2 Nasal Cavity, Paranasal Sinuses, and Nasopharynx������������� 1171 14.2.1 Congenital Anomalies���������������������������������������������� 1171 14.2.2 Inflammatory Lesions ���������������������������������������������� 1173 14.2.3 Tumors���������������������������������������������������������������������� 1174 14.3 Larynx and Trachea�������������������������������������������������������������� 1183 14.3.1 Congenital Anomalies���������������������������������������������� 1183 14.3.2 Cysts and Laryngoceles�������������������������������������������� 1184 14.3.3 Inflammatory Lesions and Non-neoplastic Lesions���������������������������������������������������������������������� 1185 14.3.4 Tumors���������������������������������������������������������������������� 1186 14.4 Oral Cavity and Oropharynx������������������������������������������������ 1189 14.4.1 Congenital Anomalies���������������������������������������������� 1189 14.4.2 Branchial Cleft Cysts������������������������������������������������ 1195 14.4.3 Inflammatory Lesions ���������������������������������������������� 1197 14.4.4 Tumors���������������������������������������������������������������������� 1197 14.5 Salivary Glands �������������������������������������������������������������������� 1203 14.5.1 Congenital Anomalies���������������������������������������������� 1203 14.5.2 Inflammatory Lesions and Non-neoplastic Lesions���������������������������������������������������������������������� 1203 14.5.3 Tumors���������������������������������������������������������������������� 1205 14.6 Mandible and Maxilla ���������������������������������������������������������� 1209 14.6.1 Odontogenic Cysts���������������������������������������������������� 1210 14.6.2 Odontogenic Tumors������������������������������������������������ 1216 14.6.3 Bone-Related Lesions ���������������������������������������������� 1218

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14.7 Ear ���������������������������������������������������������������������������������������� 1218 14.7.1 Congenital Anomalies���������������������������������������������� 1218 14.7.2 Inflammatory Lesions and Non-neoplastic Lesions���������������������������������������������������������������������� 1218 14.7.3 Tumors���������������������������������������������������������������������� 1220 14.8 Eye and Ocular Adnexa�������������������������������������������������������� 1226 14.8.1 Congenital Anomalies���������������������������������������������� 1226 14.8.2 Inflammatory Lesions and Non-neoplastic Lesions���������������������������������������������������������������������� 1226 14.8.3 Tumors���������������������������������������������������������������������� 1226 14.9 Skull�������������������������������������������������������������������������������������� 1230 Multiple Choice Questions and Answers���������������������������������������� 1233 References and Recommended Readings���������������������������������������� 1235 15 Central Nervous System���������������������������������������������������������������� 1243 15.1 Development: Genetics �������������������������������������������������������� 1244 15.1.1 Development and Genetics �������������������������������������� 1244 15.1.2 Neuromeric Model of the Organization of the Embryonic Forebrain According to Puelles and Rubenstein ���������������������������������������� 1246 15.2 Congenital Abnormalities of the Central Nervous System�������������������������������������������������������������������� 1247 15.2.1 Ectopia���������������������������������������������������������������������� 1247 15.2.2 Neural Tube Defects (NTDs)������������������������������������ 1250 15.2.3 Prosencephalon Defects�������������������������������������������� 1252 15.2.4 Vesicular Forebrain (Pseudo-aprosencephaly)���������� 1254 15.2.5 Ventriculomegaly/Hydrocephalus���������������������������� 1257 15.2.6 Agenesis of the Corpus Callosum (ACC)���������������� 1257 15.2.7 Cerebellar Malformations ���������������������������������������� 1258 15.2.8 Agnathia Otocephaly Complex (AGOTC)���������������� 1259 15.2.9 Telencephalosynapsis (Synencephaly) and Rhombencephalon Synapsis ������������������������������������ 1259 15.2.10 CNS Defects in Acardia������������������������������������������ 1261 15.2.11 CNS Defects in Chromosomal and Genetic Syndromes������������������������������������������ 1263 15.2.12 Neuronal Migration Disorders�������������������������������� 1264 15.2.13 Phakomatoses���������������������������������������������������������� 1264 15.3 Vascular Disorders of the Central Nervous System�������������� 1267 15.3.1 Intracranial Hemorrhage ������������������������������������������ 1267 15.3.2 Vascular Malformations�������������������������������������������� 1272 15.3.3 Aneurysms���������������������������������������������������������������� 1273 15.3.4 Thrombosis of Venous Sinuses and Cerebral Veins���������������������������������������������������� 1274 15.3.5 Pediatric and Inherited Neurovascular Diseases������ 1274 15.4 Infections of the CNS������������������������������������������������������������ 1275 15.4.1 Suppurative Infections���������������������������������������������� 1276 15.4.2 Tuberculous (Lepto-)Meningitis ������������������������������ 1279 15.4.3 Neurosyphilis������������������������������������������������������������ 1280 15.4.4 Viral Infections��������������������������������������������������������� 1280

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15.4.5 Toxoplasmosis���������������������������������������������������������� 1282 15.4.6 Fungal Infections������������������������������������������������������ 1282 15.5 Metabolic Disorders Affecting the CNS ������������������������������ 1282 15.5.1 Pernicious Anemia���������������������������������������������������� 1283 15.5.2 Wernicke Encephalopathy���������������������������������������� 1283 15.6 Trauma to the Head and Spine���������������������������������������������� 1284 15.7 Head Injuries������������������������������������������������������������������������ 1284 15.7.1 Epidural Hematoma�������������������������������������������������� 1284 15.7.2 Subdural Hematoma������������������������������������������������� 1284 15.7.3 Subarachnoidal Hemorrhage������������������������������������ 1285 15.7.4 Spinal Injuries ���������������������������������������������������������� 1285 15.7.5 Intervertebral Disk Herniation���������������������������������� 1286 15.8 Demyelinating Diseases Involving the Central Nervous System�������������������������������������������������������������������� 1286 15.8.1 Multiple Sclerosis ���������������������������������������������������� 1286 15.8.2 Leukodystrophies������������������������������������������������������ 1287 15.8.3 Amyotrophic Lateral Sclerosis �������������������������������� 1288 15.8.4 Werdnig-Hoffmann Disease�������������������������������������� 1288 15.8.5 Syringomyelia ���������������������������������������������������������� 1289 15.8.6 Parkinson Disease and Parkinson Disease-­Associated, G-Protein-­Coupled Receptor 37 (GPR37/PaelR)-Related Autism Spectrum Disorder �������������������������������������� 1289 15.8.7 Creutzfeldt-Jakob Disease (sCJD or Sporadic), CJD-­­Familial and CJD-Variant �������������� 1290 15.8.8 West Syndrome/Infantile Spasms, ACTH Therapy, and Sudden Death�������������������������������������� 1290 15.9 Neoplasms of the Central Nervous System�������������������������� 1291 15.9.1 Astrocyte-Derived Neoplasms���������������������������������� 1291 15.9.2 Ependymoma������������������������������������������������������������ 1294 15.9.3 Medulloblastoma������������������������������������������������������ 1295 15.9.4 Meningioma�������������������������������������������������������������� 1299 15.9.5 Hemangioblastoma and Filum Terminale Hamartoma���������������������������������������������������������������� 1299 15.9.6 Schwannoma ������������������������������������������������������������ 1300 15.9.7 Craniopharyngioma�������������������������������������������������� 1300 15.9.8 Chordoma������������������������������������������������������������������ 1300 15.9.9 Tumors of the Pineal Body �������������������������������������� 1302 15.9.10 Hematological Malignancies���������������������������������� 1302 15.9.11 Other Tumors and Metastatic Tumors�������������������� 1304 Multiple Choice Questions and Answers���������������������������������������� 1309 References and Recommended Readings���������������������������������������� 1311 16 Peripheral Nervous System ���������������������������������������������������������� 1321 16.1 Development ������������������������������������������������������������������������ 1321 16.2 Disorders of the Peripheral Nervous System������������������������ 1322 16.2.1 Peripheral Neuropathy���������������������������������������������� 1322 16.2.2 Traumatic Neuropathy���������������������������������������������� 1323 16.2.3 Vascular Neuropathy������������������������������������������������ 1323

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16.2.4 Intoxication-Related Neuropathy������������������������������ 1323 16.2.5 Infiltration (e.g., Amyloid) Related Neuropathy������ 1323 16.2.6 Neoplasms of the Peripheral Nervous System���������� 1323 16.3 Neuromuscular Disorders ���������������������������������������������������� 1333 16.3.1 Muscle Biopsy Test�������������������������������������������������� 1333 16.3.2 Neurogenic Disorders ���������������������������������������������� 1335 16.3.3 Myopathic Disorders������������������������������������������������ 1337 16.3.4 Glycogen Storage Diseases�������������������������������������� 1339 16.3.5 Mitochondrial Myopathies���������������������������������������� 1339 16.3.6 Inflammatory Myopathies: Non-infectious�������������� 1341 16.3.7 Inflammatory Myopathies: Infectious���������������������� 1341 Multiple Choice Questions and Answers���������������������������������������� 1341 References and Recommended Readings���������������������������������������� 1342 17 Skin�������������������������������������������������������������������������������������������������� 1345 17.1 Development, General Terminology, and Congenital Skin Defects������������������������������������������������ 1347 17.1.1 Development ������������������������������������������������������������ 1347 17.1.2 General Terminology������������������������������������������������ 1348 17.1.3 Lethal Congenital Contractural Syndromes�������������� 1348 17.2 Spongiotic Dermatitis ���������������������������������������������������������� 1352 17.2.1 Conventional Spongiosis������������������������������������������ 1352 17.2.2 Eosinophilic Spongiosis�������������������������������������������� 1354 17.2.3 Follicular Spongiosis������������������������������������������������ 1354 17.2.4 Miliarial Spongiosis�������������������������������������������������� 1354 17.3 Interface Dermatitis�������������������������������������������������������������� 1355 17.3.1 Vacuolar Interface Dermatitis ���������������������������������� 1355 17.3.2 Lichenoid Interface Dermatitis �������������������������������� 1360 17.4 Psoriasis and Psoriasiform Dermatitis���������������������������������� 1360 17.4.1 Psoriasis�������������������������������������������������������������������� 1360 17.4.2 Psoriasiform Dermatitis�������������������������������������������� 1360 17.5 Perivascular In Toto Dermatitis (PID)���������������������������������� 1361 17.5.1 Urticaria�������������������������������������������������������������������� 1361 17.5.2 Non-urticaria Superficial and Deep Perivascular Dermatitis �������������������������������������������� 1362 17.6 Nodular and Diffuse Cutaneous Infiltrates���������������������������� 1363 17.6.1 Granuloma Annulare������������������������������������������������ 1363 17.6.2 Necrobiosis Lipoidica Diabeticorum (NLD)������������ 1364 17.6.3 Rheumatoid Nodule�������������������������������������������������� 1364 17.6.4 Sarcoid���������������������������������������������������������������������� 1364 17.7 Intraepidermal Blistering Diseases �������������������������������������� 1364 17.7.1 Pemphigus Vulgaris, Pemphigus Foliaceus, and Pemphigus Paraneoplasticus������������������������������ 1364 17.7.2 IgA Pemphigus and Impetigo ���������������������������������� 1366 17.7.3 Intraepidermal Blistering Diseases �������������������������� 1366 17.8 Subepidermal Blistering Diseases���������������������������������������� 1367 17.8.1 Bullous Pemphigoid and Epidermolysis Bullosa���������������������������������������������������������������������� 1367 17.8.2 Erythema Multiforme and Toxic Epidermal Necrolysis������������������������������������������������ 1368

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17.8.3 Hb-Related Porphyria Cutanea Tarda, Herpes Gestationis, and Dermatitis Herpetiformis �������������� 1368 17.8.4 Lupus (Systemic Lupus Erythematodes)������������������ 1369 17.9 Vasculitis ������������������������������������������������������������������������������ 1369 17.10 Cutaneous Appendages Disorders���������������������������������������� 1369 17.11 Panniculitis���������������������������������������������������������������������������� 1369 17.11.1 Septal Panniculitis�������������������������������������������������� 1369 17.11.2 Lobular Panniculitis������������������������������������������������ 1370 17.12 Cutaneous Adverse Drug Reactions�������������������������������������� 1370 17.12.1 Exanthematous CADR�������������������������������������������� 1371 17.13 Dyskeratotic, Non-/Pauci-­Inflammatory Disorders�������������� 1372 17.14 Non-dyskeratotic, Non-/Pauci-Inflammatory Disorders ������ 1372 17.15 Infections and Infestations���������������������������������������������������� 1372 17.16 Cutaneous Cysts and Related Lesions���������������������������������� 1372 17.17 Tumors of the Epidermis������������������������������������������������������ 1373 17.17.1 Epidermal Nevi and Related Lesions���������������������� 1373 17.17.2 Pseudoepitheliomatous Hyperplasia (PEH)������������ 1376 17.17.3 Acanthoses/Acanthomas/Keratoses������������������������ 1376 17.17.4 Keratinocyte Dysplasia ������������������������������������������ 1377 17.17.5 Intraepidermal Carcinomas������������������������������������ 1378 17.17.6 Keratoacanthoma���������������������������������������������������� 1378 17.17.7 Malignant Tumors�������������������������������������������������� 1378 17.18 Melanocytic Lesions ������������������������������������������������������������ 1381 17.18.1 Lentigines, Solar Lentigo, Lentigo Simplex, and Melanotic Macules (Box 17.8)������������������������ 1381 17.18.2 Melanocytic Nevi���������������������������������������������������� 1381 17.18.3 Variants of Melanocytic Nevi �������������������������������� 1382 17.18.4 Spitz Nevus and Variants���������������������������������������� 1384 17.18.5 Atypical Melanocytic (Dysplastic) Nevi���������������� 1385 17.18.6 Malignant Melanoma and Variants ������������������������ 1385 17.19 Sebaceous and Pilar Tumors ������������������������������������������������ 1387 17.19.1 Sebaceous Hyperplasia ������������������������������������������ 1387 17.19.2 Nevus Sebaceous (of Jadassohn) (NSJ)������������������ 1387 17.19.3 Sebaceous Adenoma, Sebaceoma, and Xanthoma �������������������������������������������������������� 1388 17.19.4 Sebaceous Carcinoma �������������������������������������������� 1388 17.19.5 Benign Hair Follicle Tumors���������������������������������� 1388 17.19.6 Malignant Hair Follicle Tumors������������������������������ 1390 17.20 Sweat Gland Tumors������������������������������������������������������������ 1390 17.20.1 Eccrine Gland Tumors�������������������������������������������� 1391 17.20.2 Apocrine Gland Tumors������������������������������������������ 1393 17.21 Fibrous and Fibrohistiocytic Tumors������������������������������������ 1394 17.21.1 Hypertrophic Scar and Keloid�������������������������������� 1394 17.21.2 Dermatofibroma������������������������������������������������������ 1394 17.21.3 Juvenile Xanthogranuloma ������������������������������������ 1394 17.21.4 Dermatofibrosarcoma Protuberans������������������������� 1396

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17.22 Vascular Tumors�������������������������������������������������������������������� 1396 17.23 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone ������������������������������������������������������������������������������ 1396 17.24 Neural and Neuroendocrine Tumors������������������������������������ 1396 17.24.1 Merkel Cell Carcinoma������������������������������������������ 1396 17.24.2 Paraganglioma�������������������������������������������������������� 1399 17.25 Hematological Skin Infiltrates���������������������������������������������� 1400 17.25.1 Pseudolymphomas�������������������������������������������������� 1400 17.25.2 Benign and Malignant Mastocytosis���������������������� 1400 17.26 Solid Tumor Metastases to the Skin�������������������������������������� 1400 Multiple Choice Questions and Answers���������������������������������������� 1403 References and Recommended Readings���������������������������������������� 1405 18 Placenta, Abnormal Conception, and Prematurity�������������������� 1409 18.1 Development and Useful Pilot Concepts and Tables������������ 1410 18.2 Pathology of the Early Pregnancy���������������������������������������� 1422 18.2.1 Disorders of the Placenta Formation������������������������ 1423 18.2.2 Disorders of the Placenta Maturation ���������������������� 1431 18.2.3 Disorders of the Placenta Vascularization���������������� 1434 18.2.4 Disorders of the Placenta Implantation Site������������� 1434 18.2.5 Twin and Multiple Pregnancies�������������������������������� 1442 18.3 Pathology of the Late Pregnancy������������������������������������������ 1449 18.3.1 Acute Diseases���������������������������������������������������������� 1450 18.3.2 Subacute Diseases���������������������������������������������������� 1457 18.3.3 Chronic Diseases������������������������������������������������������ 1468 18.3.4 Fetal Growth Restriction������������������������������������������ 1482 18.4 Non-neoplastic Trophoblastic Abnormalities ���������������������� 1485 18.4.1 Placental Site Nodule������������������������������������������������ 1485 18.4.2 Exaggerated Placental Site���������������������������������������� 1485 18.5 Gestational Trophoblastic Diseases, Pre- and Malignant ���� 1486 18.5.1 Invasive Mole������������������������������������������������������������ 1486 18.5.2 Placental Site Trophoblastic Tumor�������������������������� 1486 18.5.3 Epithelioid Trophoblastic Tumor������������������������������ 1486 18.5.4 Choriocarcinoma������������������������������������������������������ 1486 18.6 Birth Defects ������������������������������������������������������������������������ 1488 18.6.1 Birth Defects: Taxonomy Principles ������������������������ 1490 18.6.2 Birth Defects: Categories������������������������������������������ 1493 18.6.3 Birth Defects: Pathogenesis (Macro- and Micromechanisms)���������������������������������������������������� 1496 18.6.4 Birth Defects: Etiology (Mendelian, Chromosomal, Multifactorial) ���������������������������������������������������������� 1515 18.7 Infection in Pregnancy, Prom, and Dysmaturity ������������������ 1533 18.7.1 Infection in Pregnancy���������������������������������������������� 1533 18.7.2 Premature Rupture of Membranes (PROM) ������������ 1541 18.7.3 Fetal Growth Restriction (FGR) and Dysmaturity���� 1541 18.8 IUFD and Placenta���������������������������������������������������������������� 1546

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18.8.1 Fetal Death Syndrome (Intrauterine Fetal Demise, IUFD)������������������������������������������������������������������������ 1546 18.8.2 Step-by-Step Approach in the Examination of a Placenta�������������������������������������������������������������� 1548 Multiple Choice Questions and Answers���������������������������������������� 1552 References and Recommended Readings���������������������������������������� 1554 Index�������������������������������������������������������������������������������������������������������� 1571

1

Cardiovascular System

Contents 1.1

Developmental and Genetics

 ongenital Heart Disease C Sequential Segmental Cardio-Analysis Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Atrioventricular Septal Defect (AVSD), Patent Ductus Arteriosus (PDA), and Ebstein’s Tricuspid Anomaly (ETA) 1.2.3 Tetralogy of Fallot (TOF) and Double Outlet Right Ventricle (DORV) 1.2.4 Hypoplastic Right Heart Syndrome 1.2.5 Transposition of the Great Arteries 1.2.6 Common Trunk (Persistent Truncus Arteriosus) 1.2.7 Total Anomalous Pulmonary Venous Return 1.2.8 Scimitar Syndrome 1.2.9 Hypoplastic Left Heart Syndrome and Coarctation of Aorta 1.2.10 Heterotaxy Syndrome 1.2.11 Common Genetic Syndromes with Congenital Heart Disease

1.2 1.2.1 1.2.2

 2  6  8  11  18  24  26  31  32  32  33  41  41  48  48  48  66  66  78

1.3.7 1.3.8 1.3.9

 yocarditis and Nonischemic Cardiomyopathies M Myocarditis Dilated Cardiomyopathy Hypertrophic Cardiomyopathy Infiltrative/Restrictive Cardiomyopathies Left Ventricular Non-compaction Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy (ARVD/C) Lamin A/C Cardiomyopathy Mitochondrial Cardiomyopathies Cardiac Channelopathies and Sudden Cardiac Death

1.4 1.4.1 1.4.2 1.4.3

I schemic Heart Disease, Myocardial Dysfunction, and Heart Failure Ischemic Heart Disease Myocardial Dysfunction Heart Failure

 85  85  85  85

1.5 1.5.1 1.5.2 1.5.3 1.5.4 1.5.5

 alvular Heart Disease V Endocarditis and Valvar Vegetation Mitral Valve Prolapse Calcific Mitral Annulus and Calcific Aortic Stenosis Rheumatic Heart Disease (RHD) Prosthetic Valves

 87  87  91  91  91  92

1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.6

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_1

 79  81  81  83

1

1  Cardiovascular System

2

Transplantation  llograft Cellular Rejection A Allograft Humoral Rejection Cardiac Allograft Vasculopathy Extracardiac Posttransplant Lympho-proliferative Disorders (PTLD) Following HTX

 100

1.7 1.7.1 1.7.2 1.7.3

Tumors  enign Tumors B Malignant Tumors Metastatic Tumors

 100  102  109  112

1.8 1.8.1 1.8.2

Pericardial Disease  on-neoplastic Pericardial Disease N Neoplastic Pericardial Disease

 115  115  116

1.9 1.9.1 1.9.2 1.9.3 1.9.4 1.9.5 1.9.6

Non-neoplastic Vascular Pathology  ongenital Anomalies C Fibromuscular Dysplasia Arteriosclerosis Large-Vessel Vasculitis Medium-Vessel Vasculitis Small-Vessel Vasculitis

 116  116  117  117  119  123  125

1.6 1.6.1 1.6.2 1.6.3 1.6.4

1.1

 92  92  95  97

Multiple Choice Questions and Answers

 125

References and Recommended Readings

 127

Developmental and Genetics

The developing embryo has the cardiovascular system as the first system to function, and the blood begins to circulate by the end of the third week. Septation is key and is defined as a division between cavities. It evolves continuously and plays a major role in the construction as parts of an organism take progressively shape by partitions. The milestones of cardiac development are described in Box 1.1 (Fig. 1.1). The cardiac crescent is indeed the first stage of the development of the heart before the end of the gastrulating embryo. Remarkably, it is characterized by the commitment of the mesodermal cells of the anterior lateral plate to the cardiogenic lineage. These cells are devoutly committed to migrate and organize in the structure, which is called the cardiac crescent. The commitment of these cells is under the influence of mostly BMP, FGF, and WNT proteins (BMP, bone morphogenetic proteins; FGF, fibroblast growth factor; WNT, portmanteau of Wingless and Int-1). In addition to these three cell signaling pathways, cardiac morphogenesis is also regulated by NOTCH, TGF, and

VEGF. Specific knockout mice give origin to a particular phenotype that may be useful for the understanding of the multiplicity of congenital heart disease. In particular, the linear heart is the second stage of development of the heart, which is the first functional organ in the embryo. In the elongated heart, there is migration and fusion along the ventral midline of the precursors of the cardiac crescent. Cardia bifida is the result of a failure of the fusion of these cell aggregates. One of the critical transcription factors playing a significant role in the second stage is GATA-4, which is synergistical with the SMAD proteins, several intracellular effectors of the TGF/BMP signaling pathway to activate NKX2.5 transcription. Chamber formation occurs in the third and fourth stage of cardiac development and includes specification, septation, and trabeculation of the chambers. KO mouse technology is being pillared in identifying several pathogenetic pathways. It has allowed identifying several transcription factors that play a significant role during this stage. A secondary or anterior heart field (AHF), other than heart tube-derived cardiomyocytes, accompanies the development of the heart. AHF myo-

1.1 Developmental and Genetics

Box 1.1 Heart Development

Day 15th: –– Lateral mesoderm-derived first heart field (TBX5, HAND1) develops in the left ventricle. –– Second heart field (FGF-10, HAND2) aims to form the right ventricle outflow tract and atria. Day 20th: –– Initial crescent-derived beating tube loops to the right side of the forming embryo. Day 28th: –– Heart chambers steadily delineate. –– Neural crest cells migrate with septation of the outflow tracts. –– Aortic arches form. –– Extracellular matrix swells up for the formation of the endocardial cushions. Day 50th: –– Four-chambered heart forms. Notes: FGF-10, Fibroblast Growth Factor 10; Hand1, Heart And Neural Crest Derivatives Expressed 1; Hand2, Heart And Neural Crest Derivatives Expressed 2; TBX5, T-Box Transcription Factor 5.

cytes derive from the pharyngeal mesoderm and are incorporated in the developing heart tube during the looping stage at both the venous and arterial poles. The “cardiogenic area” of the splanchnic mesenchyme represents the area where cardiac development enters into the scene and precisely on day 16–19 of embryo development. The heart takes shape as two side-by-side longitudinal cell strands that are labeled cardiogenic cords. The canalization of the cardiogenic cords is key to form the endocardial tubes of the forming heart. These two tubular structures fuse together to form a single tubular heart or heart tube. On day 23–24 of embryo development, the bulboventricular loop progressively forms introducing asymmetry in the cardiac structure. The paired aortic arches

3

are responsible for the development of the arterial system, while the venous end of the heart is responsible for the development of the venous system. In week 3 of the embryo development, the vascular system originates from mesodermal cells of the “blood islands.” The peripheral cellular component of these structures is responsible for the formation of the endothelium, while the central portion gives rise to hematopoietic elements. Subsequently, pericytes from the surrounding mesenchyme will join the first blood vessels. They differentiate into the wall layers. The histology of the heart changes from pre- to postnatal state. In the fetal stage, the heart shows a significant amount of glycogen, while the heart in children and, mainly, adolescents is quite similar to young adults. The cardiomyocyte in the adult mammalian organism is a differentiated postmitotic cell with no significant proliferative potential due to its inability to reactivate the cell cycle. It is known that the G0 phase of a cell is a period of the cell cycle in which cell does exist in an inactive, non-­cycling state. Although cells were previously thought to enter G0 by default, this state is now considered as a way for cells to preserve essential and extremely precious cell physiology functions over time. In response to extrinsic stimuli, some of the G0 cells may proliferate by reentering the cell cycle. In G1 phase, there is a restriction point (R-point) with a dichotomic fate. Mammalian cells can enter the G0 phase before the R-point but are committed to mitosis after the R-point. The lack of G1 cyclin/cyclin-dependent kinases (Cdk), which are essential positive cellcycle modulators, and the deficiency of high levels of cell-cycle inhibitors, including the retinoblastoma proteins pRb/p130 and the Cdk inhibitors p21/p27, limit the mitotic capacity of mature cardiomyocytes. Thus, the adult mammalian heart is functionally incapable of repairing itself after ischemic injury. In fact, cardiomyocytes that survive the insult suffer from cell enlargement, myofibrillar disarray, and re-expression of some fetal transcription factors and genes. Although the molecular mechanisms underlying heart failure are poorly understood, it is known that this process is a significant pathway. Cell hypertrophy with the disarray of the myofibrils and re-expression of some fetal transcription factors and genes are associated with con-

1  Cardiovascular System

4

a

b

1.1 Developmental and Genetics

5

siderable morbidity and mortality and remains at long-term an inefficient mechanism to let differentiated postmitotic cells to survive. This process, which does not provide adequate or appropriate adjustment to the environment or situation with time, leads to the development of heart failure. The most exciting result linking to the heart transcriptome is its regulation by the guardian of the human genome, the TP53 gene, which is located on the short arm of chromosome 17 (17p13.1). After several decades of research into TP53, there is substantial evidence that the tumor suppressor guardian of live, better known as p53, inhibits cell growth after acute stress by regulating the transcription of genes. It has been recently identified an intriguing and sensational role for p53 in the heart as a master regulator of the cardiac transcriptome. The TP53 gene spans 20 kB, with a noncoding exon 1 and a 10-kB-long first intron. The regulation of tumor-free survival is based on p53, which is a transcription factor that translates growth and survival signals into specific gene expression patterns. In cells that are in regular status, the E3 ubiquitin ligase Mdm2 keeps p53 expression at low levels by targeting p53 for proteasomal degradation. Mdm2 results inactivated in response to acute stress factors. The Mdm2 inactivation results in increased levels of p53 with the fate of cell division and apoptosis. There is a negative feedback that limits p53 by activating Mdm2 transcription using p53. This negative feedback loop defines p53 activity. Tumorigenesis is one of the consequences of having p53 mutated. In this setting, there is a prolif-

eration of aberrant clones of genetically unstable cells, as shown in the p53 knockout mouse. Conversely, Mdm2 knockout mice die during embryogenesis through p53-­induced apoptosis. This balance between p53 and Mdm2 is critical for the organism and tumorigenesis. In end-stage heart failure, high levels of p53 correlate with apoptosis of cardiomyocytes and cell hypertrophy. The normal by-products of 36-ATP-linked aerobic respiration are reactive oxygen species (ROS), which induce DNA damage and cellular defense systems. In fact, p53 plays a significant role in the cardiac transcriptome, because it acts as a pleiotropic regulator of the cardiac function as Mak et al. recently described. The activation of process-specific transcription factors (Mef2a, Myocd, Pgc-1α, Tfam) results from p53 loss. The presence of Esrrγ, Gata4, and Mef2a in p53 immunoprecipitates from adult hearts of experimental animals may suggest complex formation between p53 and some processspecific transcription factors (TFs), and endogenous p53 protein specifically binds to these promoters in oligonucleotide precipitation experiments and PCR chromatin immunoprecipitation (ChIP) assays. This high degree of connectivity of p53 with TFs is probably a fascinating event and may represent a working platform for future studies. In animal models, some master transcription factors (Gata4, c-Myc, Nfat3, NF-κB) are linked to the development of HF. It has been demonstrated that physical exercise is crucial in increasing the expression of these specific gene sets. These very recent studies reinforce the postulation

Fig. 1.1  Cardiac crescent formation with transcription factor activation during early development and abnormalities of endocardial cushion development. (a) From the beginning of the cardiac crescent through the maturation/ septation, there are a number of transcription factors that are activated. In (b) there is the representation of the endocardial cushion defects illustrating the variations of the Rastelli types (CITED, CREB-binding protein/p300-interacting transactivator with Asp/Glu-rich C-terminal domain; FOG-2 “FRIEND OF GATA2” or ZINC FINGER PROTEIN, MULTITYPE 2 / ZFPM2, GATA4 and GATA5, transcription factors characterized by their ability to bind to the DNA sequence “GATA”; TBX5, T-box tran-

scription factor 5; dHAND and, eHNAD, basic helixloop-helix transcription factors; HEY2, Hes Related Family BHLH Transcription Factor With YRPW Motif 2; NF-ATC, Nuclear Factor of Activated T Cells; PITX2, Pituitary homeobox 2; MEF2C, Myocyte-specific enhancer factor 2C, aka MADS box transcription Enhancer Factor 2; MESP 1/2, Mesoderm Posterior BHLH Transcription Factor 1 and 2; NKX 2-5, NK2 Homeobox 5; RXR-A, Retinoid X Receptor Alpha; SOX4, SRY-Box Transcription Factor 4; TBX1, T-Box Transcription Factor 1; TEF-1, Transcription-al enhancer factor 1; ZIC3, a member of the Zinc finger of the cerebellum (ZIC) protein family)

1  Cardiovascular System

6

of a rheostat-like role for p53 with significant changes of the p53/Mdm2 circuitry. It seems evident that the circulatory benefit derived from physical exercise arises not only from muscular activity and efficiency of the pump function, but also from a well orchestrated cascade of cytokines. In mouse and human, there are, probably, more than 2 × 103 TFs, which modulate the mRNA profiles corresponding to 23,000 genes. DNA-binding TFs are thought to be crucial in getting significant insights into the regulation of the cardiac transcriptome. Thus, we strongly need a systems biology based approach to magnificently complement the single-­ gene-focused biology of the last three decades.

1.2

Congenital Heart Disease

Congenital heart surgery has seen a rapid growth in the last three decades showing some new procedures emphasizing how cardiac pathology is a rapidly evolving field. Enhancement of patients’ outcome has been witnessed not only in well-­ developed countries but also in developing countries. The introduction of life support devices such as the Berlin heart and the increase in knowledge in cardiac physiology integrated with new laboratory data is probably by this advancement. Pharmacologic intervention and hemodynamic support have petrified milestones in medicine. The extracorporeal membrane oxygenation provides better patient outcomes than decades ago. Congenital heart disease has become increasingly complex and affects nearly 1% of births per year in several well-developed countries. The prevalence of some congenital disabilities involving the heart, especially mild types, is increasing, while it seems that the prevalence of other types remains stable. The ventricular septal defect is the most common type of heart defect, which may be quite mild. However, 1/4 of newborns with a congenital heart disease present with a critical heart illness, and these infants usually need surgery or a palliative corrective procedure in their first year of life. The cause is multifactorial, although the increase of some environmental etiologies may be alarming. Right-to-left shunt with cyanotic heart disease is mostly seen in cardiovascular defects, such as the transposition of the great arteries (TGA) and the

Box 1.2 Congenital Heart Disease

1.2.1. Sequential Segmental CardioAnalysis 1.2.2. Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD), Atrioventricular Septal Defect (AVSD), Patent Ductus Arteriosus (PDA), and Ebstein’s Tricuspid Anomaly (ETA) 1.2.3. Tetralogy of Fallot and Double Outlet Right Ventricle (DORV) 1.2.4. Hypoplastic Right Heart Syndrome 1.2.5. Transposition of Great Arteries (TGA) 1.2.6. Common Trunk (“Persistent Truncus Arteriosus”) 1.2.7. Total Anomalous Pulmonary Venous Return (TAPVR) 1.2.8. Scimitar Syndrome 1.2.9. Hypoplastic Left Heart Syndrome and Coarctation of Aorta 1.2.10. Heterotaxy Syndrome 1.2.11. Common Genetic Syndromes with Congenital Heart Disease

tetralogy of Fallot (TOF). Left-to-right shunt is seen in atrial (ASD) or ventricular (VSD) septal defects and patent ductus arteriosus (PDA). These defects are also recognized as cyanotic heart diseases of late-type because the shunt induces pulmonary hypertension with consequent right ventricular hypertrophy and progressively inversion of the shunt from left to right into the right to left, a condition labeled Eisenmenger syndrome. Disorders contemplating the clinical morphology and the association of molecular genetic disorders became an essential part of the study of both a pediatrician and a pediatric pathologist. In this section, the critical anomalies in the congenital heart disease are highlighted following the presentation of the method to investigate such defects. Indeed, the investigative method and its principles are crucial to correctly identify these defects both intra vitam and at time of post mortem examination. The proposed program to orientate into congenital heart disease is shown in Box 1.2, although the reader should familiarize himself/herself with the normal configuration of the heart (Fig. 1.2).

1.2 Congenital Heart Disease

a

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b

c

d

e

Fig. 1.2  View of the normal heart at fetal age with illustration of the right and left chambers. In (a) the anterosuperior face of the heart is seen with two cut opening the right and left chambers. In (b) the arrow points to the right ventricle with the high trabeculated septal wall, while in

(c) the right ventricle (arrow) and its outflow tract are shown. In (d) the arrows points to the left ventricle showing the smooth parietal wall characterizing anatomically the left ventricle. In (e) the outflow tract of the left ventricle with the aortic valve are shown

8

1.2.1 Sequential Segmental Cardio-Analysis Disorders involving an abnormal formation of the heart are better investigated if the cardiac specimen is studied schematically. Cardiac anomalies are one of the most frequent anomalies and may occur singly or in the setting of a multiple congenital anomaly syndrome. The recognition of a single cardiac anomaly, e.g., aortic stenosis, may represent a non-difficult task, but probably complex cardiac defects may pose a challenge for non-pediatric pathologists. Both the Bostonian school of segmental notation of single parts of the heart developed from the teaching of Professor Van Praagh, and the impulses and directions derived from the European school of sequential segmental analysis (SSA) with Professor Robert Anderson and Professor Becker have been fundamental in cardiac anatomy teaching. These approaches allow us to assess cardiac specimens that can be considered reproducible and of great value for gynecologists and cardiologists (Fig. 1.2). Sequential segmental analysis (SSA) is a careful step-by-step approach to describe the cardiac anatomy analytically and is necessarily useful for all cardiac malformations leading to a systematic approval of its pathophysiology. SSA was developed between the late 1970s and early 1980s of the last century and is based on a method deriving from the separate analysis of three essential elements, including atria, ventricles, and great arteries. All three s­egments need to be described independently from their position, i.e., they should have supportive findings indicating if they are morphologically right or left and which great artery is. The anatomical features dominate the “crime scene,” rather than their spatial orientation. The separation of the three segments needs the identification of two planes of partition, including the fibrous tissue plane of the atrioventricular (AV) junction of the valves separating the atria from the ventricles and the attachment of the arterial valves to the ventricles or ventriculoarterial (VA) connections separating the ventricular masses from the great arteries. First, the atrial situs is individualized by ascertaining the position of each atrium about each other within the chest cavity. Second,

1  Cardiovascular System

the AV and VA connections of the heart are determined. A segment can be right- or left-sided and, independently, morphologically right or left (Carvalho et al. 2005). Thus, the question is to identify the morphology of the single parts of the heart and is at the basis of the terminology used in SSA, which has been now used for decades by gynecologists, cardiologists, and pathologists. In SSCA, the analysis using SSA is complemented with transcriptomic analysis, which may be crucial in understanding pediatric versus adult failing hearts (Jana et al. 2018). SSCA may also be defined sequential segmental chemical analysis. The atrial arrangement or situs is the initial approach describing the heart. In pediatric cardiology, the atrial situs is recognized by the method of the abdominal major blood vessels concerning the spinal column. In obstetrics, fetal laterality is the first category to ascertain. Situs is defined as the location that an organ occupies in a symmetric bilateral system. The morphologically right or left atrium is determined by the most constant anatomic feature, which is the atrial appendage. A broad-based triangular atrial appendage (“Snoopy’s nose”-like) defines the atrial segment, which lodges the appendage, as for the right. Conversely, a narrow-based trapezoidal atrial appendage (“Snoopy’s ear”-like) defines the atrial segment as left. There are three possible types of sites, including (1) situs solitus, (2) situs inversus, and (3) situs ambiguus. The situs solitus is the usual atrial arrangement, the situs inversus is the mirror-image arrangement, and the situs ambiguus presents with isomerism of right or left atrial appendages, i.e., in other words, two morphologically right or two morphologically left atrial appendages. Isomerism means paired, mirror image sets of ordinarily single or nonidentical organ systems (atria, lungs, and other organs), frequently associated with other abnormalities (vide infra). In right isomerism both large vessels of the abdomen, i.e., aorta and IVC, are located on the same side of the spinal column (either left or right) with IVC on the front and aorta on the back. On the contrary, in left isomerism, the IVC shows an interruption. There is azygos continuation, which is represented as a venous structure posterior to the aorta. The hepatic venous flow only reaches, usually, the right atrium from below through IVC. In the azygos continua-

1.2 Congenital Heart Disease

tion, the IVC is interrupted distal to its passage through the liver, and blood flow reaches the right atrium through an azygos vein, which may be quite large, connecting the IVC to the SVC.  In fact, an essential marker of left isomerism is an interrupted IVC with azygos continuation (Carvalho et al. 2005). The aorta is more centrally located, and the azygos vein is on either the right or left side. Usually, bilateral right-­sidedness is peculiarly distinguished with the absence of leftsided structures, such as the spleen (asplenia), while bilateral left-sidedness with a surplus of leftsided structures, namely, more spleens or polysplenia. Paired morphologically correct structures identify right isomerism or asplenia syndrome: absence of the spleen, bilateral right bronchi, bilateral trilobed (right) lungs, two morphologic right atria, and multiple anomalies of systemic and pulmonary venous connections as well as other complex cardiac and non-cardiac abnormalities. Left isomerism or polysplenia syndrome is characterized by paired, morphologically left structures: multiple bilateral spleens, bilateral left bronchi, bilateral bilobed (left) lungs, midline liver, two morphologic left atria, and complex congenital cardiac and non-­cardiac defects. Thus, in autopsies restricted to heart and lungs, as often happens in post-cardiac surgical procedures or induced interruptions of pregnancy, a review of the intra vitam imaging is essential for a correct evaluation and pathology report. It is crucial to stress how important the relationship between the cardiologist and the pathologist is. Failure of communication or conflicts of interest at this level may have disastrous consequences. Moreover, the pathologist needs to rely on the support from the cardiologist in addressing more resources for the pathologist aiming to be an advocate for cardiac pathology in public health economics and politics. The description of the atria also foresees the correct identification of the coronary sinus, Koch’s triangle, and Thebesian valve. These structures should also be shown to the cardiologist or the cardiac surgeon at the time of the presentation of the autopsy findings. There are two possible options for AV connections, either biventricular AV connection with each atrium connecting to its ventricle or univentricular AV connection when each atrium is not

9

related to a separate ventricular chamber. Biventricular AV connection also needs to be subdivided into concordant, discordant, or ambiguus. Univentricular AV connection needs to be further classified as absent right AV connection or absent left AV connection or double-inlet ventricle (DIV) with a ventricle that can be morphologically right or left. In biventricular AV connection, there can be concordance or discordance of the AV connection. Concordant biventricular AV connection is characterized by a morphologically right atrium connecting to a morphologically right ventricle with a morphologically left atrium connected to a morphologically left ventricle. On the other hand, discordant biventricular AV connection is characterized by a morphologically right atrium connected to a morphologically left ventricle and a morphologically left atrium connected to a morphologically right ventricle. Three components characterize each ventricle, including an inlet, apical, and outlet components. All three need to be carefully (often magnification-lens-aided) evaluated before labeling a ventricle as right or left. The apical portion is the most constant part of a ventricle because the inlet and the outlet can be absent. The right sidedness of a ventricle is characterized by a tricuspid valve as AV junction with the tension apparatus attached to both the septal wall and to the papillary muscle. Moreover, coarse trabeculation at the apex and over the entire septal fence is found, and the arterial valve is supported by an infundibulum, which is entirely muscular and is separated from the AV valve by the muscle. Typically, there is also a muscular bar in the right ventricle, the moderator band, which connects the IVS to the anterior papillary muscle crossing the lower portion of the right ventricular chamber and acting as a primary conduction pathway to the free wall originating from the right bundle branch. The left-sides or laterality of a ventricle is characterized by an AV junction guarded by a bicuspid valve (mitral) with the attachment of the tension apparatus (chordae) to the papillary muscles. Moreover, fine, crisscrossing trabeculations at the apex and a smooth upper septal surface, as well as a fibrous continuity between arterial and AV valve, are seen. Concordant and discordant connections can only be seen in heart specimens with lateralization of

10

the atria, while heart specimens with atrial isomerism, a biventricular connection, are labeled as ambiguus which underlines the absence of lateralization of the atria. In this common congenital heart disease, the pulmonary venous circulation drains correctly into the left atrium and then into left-sided morphological right ventricle, but from this ventricle, blood is directed toward the systemic circulation through the aorta, which regarding SSA is indicated as A-V-Discordance  +  V-Art-Discordance or l-TGA. This type of TGA is different from d-TGA with A-V-Concordance + V-Art-­Discordance, i.e., the ventricles are connected to the wrong, great artery and acronym for this defect. Hence, d-TGA is not to be confused with l-TGA or Levo-TGA, where there are both atrioventricular and ventriculoarterial discordance (AVD + VAD). Univentricular AV connection is defined in case one or two atrial chambers connect to one ventricle, which is also called “main” or “dominant” ventricle. Double-inlet ventricle consists of both atria, no matter of their arrangement, connecting to the single ventricle. If one of the atria does not show any connection and only an atrium connects to the ventricle, the condition is called right or left absent AV connection. The other minor or absent ventricle is usually rudimentary and usually lacks the inlet component. The rudimentary right ventricle is located anterior and superior, if the dominant ventricle is of left ventricular morphology, and may acquire a right- or left-sided or directly anterior position. The rudimentary left ventricle has a posterior and ­ inferior position if the dominant ventricle is of right ventricular morphology and may be either right- or left-sided. Very rarely, there may be an occasion of a ventricle of general morphology, but their existence has been a matter of debate. An additional describing parameter in the SSA of heart specimens regards the fashion or mode of AV connection. There are four possibilities, including (1) two perforate valves, (2) one perforate and one without perforation, (3) a common AV valve, and (4) straddling and overriding valves. In the setting of an AVSD, there is neither a true mitral nor a correct tricuspid valve, but a 5-leaflet A-V valve guards a single atrioventricular orifice, in the severe form. A “right A-V valve”

1  Cardiovascular System

comprises the right anterosuperior leaflet, the right inferior leaflet, the right portions of the superior, and the inferior bridging leaflets. Conversely, a “left A-V valve” includes the left portions of the superior (anterior) and inferior (posterior) bridging leaflets and the left lateral leaflet. Cleft AV valve is characterized by a defect involving the left AV valve in AVSD designed by the unification of the superior and inferior bridging leaflets. Something similar but morphogenetically distinct entity may occur concerning the anterior or rarely posterior leaflet of the mitral valve in otherwise healthy hearts. Overriding is defined by the condition characterized by an AV valve overriding the interventricular septum above a VSD and emptying into both ventricles. The disease characterized by an AV valve with the anomalous insertion of valvar tensor apparatus into the contralateral ventricle is called straddling and is usually accompanied by a VSD. The examination of the VA connections also belongs to SSA and aims to identify which great artery connects to which ventricle. An abnormal condition is truncus arteriosus communis or common arterial trunk with a single great artery arising from the ventricular chambers and giving rise to coronary arteries, pulmonary arteries, and head and neck blood vessels. VA connections can be of four types, including (1) concordant, (2) discordant, (3) double-outlet, and (4) single-­ outlet. Concordant VA connections are junctions between morphologically right ventricle connecting to the pulmonary artery and morphologically left ventricle connecting to the aorta. Discordant VA connections are characterized by morphologically right ventricle connecting to the aorta and morphologically left ventricle connecting to the pulmonary artery. Double-outlet VA connection occurs when both great arteries arise predominantly from a ventricle of right, left, or indeterminate morphology. In DORV, there is usually no fibrous continuity between the semilunar and the AV valves, and there is an associated VSD. If the VSD is located in subaortic position without RV outflow tract obstruction, the cardiac physiology simulates a pure VSD, while in case of RV outflow tract obstruction, the cardiac physiology simulates tetralogy of Fallot. A VSD located in the subpulmonary

1.2 Congenital Heart Disease

position (Taussig-Bing anomaly) determines cardiac physiology, affecting a complete transposition of the great arteries with VSD. Substantially, the Taussing-Bing anomaly includes a transposition of the aorta to the right ventricle in addition to a malposition of the pulmonary artery with an obvious subpulmonary VSD.  A single-outlet is represented by either a common arterial trunk (persistent truncus arteriosus) or be associated with pulmonary or aortic atresia. About the cardiac conduction system preparation, the sinus node is a small “cigar”-shaped structure located just subepicardial in the terminal groove laterally to the junction SVC and RA and is generally inferior to the crest of the appendage of the atrium. The AV node is located at the apex of the Koch’s triangle. As indicated above, the sides of the triangle of Koch are the tendon of Todaro, which is the continuation of the valvula eustachii of the IVC (or its remnant) and the axis of the septal leaflet of the right AV valve. The coronary sinus and the sub-Thebesian sinus, which is also called valvula sinus coronarii thebesii, form the base of the triangle. Between the membranous and muscular components of the ventricular septum runs the AV bundle. Finally, the SSA includes the investigation of associated anomalies of the atria, AV and VA connections, e.g., bilateral SVC, TAPVC, and coarctation of the aorta. In the chest, the cardiac position is independent of the chamber connections with three possibilities, including dextrocardia, levocardia, or mesocardia, if the heart is located in the right chest or left chest or centrally placed, respectively. In situs solitus, the center is in the left chest with the apex pointing to the left, while in situs inversus, the heart is in the right chest with the top usually leading to the right. Numerous aspects of the delivery of care are probably trying to measure the cardiac anatomy comprehensively. Some may have an impact on the outcome. The sequential segmental analysis and the new approach associated with transcriptomics or sequential segmental cardio-analysis (chemical analysis) of heart specimens examined following transplantation or complete or limited autopsy are crucial for the progress of pediatric cardiology and the understanding of congenital heart disease in the adolescent and adulthood.

11

1.2.2 A  trial Septal Defect (ASD), Ventricular Septal Defect (VSD), Atrioventricular Septal Defect (AVSD), Patent Ductus Arteriosus (PDA), and Ebstein’s Tricuspid Anomaly (ETA) 1.2.2.1 Atrial Septal Defect (ASD) • DEF: Defect of separation of the atria with interatrial communication (four types), including ostium primum (5%) or low in septum, adjacent to AV valves; ostium secundum (90%), at the site of the foramen ovale; sinus venosus (5%), divided in superior (near SVC) and inferior (near IVC) sinus venosus defect; and unroofed coronary sinus (Fig. 1.3). • EPI: 10% congenital cardiac defects, 1:1500 live births. • ETP: Deficiency of the septum interatriale cordis due to different causes, including trisomy 21 syndrome (Down syndrome), Ebstein’s anomaly, fetal alcohol syndrome, Holt-Oram syndrome, and Lutembacher’s syndrome. • CLI: Asymptomatic, mostly, but untreated defects can yield right atrial enlargement, cardiac arrhythmias, and heart failure as time progresses. • EKG: Prolonged PR interval (a first-degree heart block) due to the enlargement of the atria and the increased distance due to the defect itself. Moreover, there is a left axis deviation of the QRS complex with a primum ASD, while there is a right axis deviation of the QRS complex with a secundum ASD and a left axis deviation of the P wave in case of a sinus venosus ASD. A common finding in the ECG is the presence of an incomplete right bundle branch block. • Echo: Jet of blood from the left atrium to the right atrium. • TRT: Secundum, primum, and coronary sinus defects with small shunts (Qp: Qs 50%; moderate to extreme LAD of the QRS axis; usual with atypical QRS configuration, rSr′ or rsR′; atrial enlargement, possible LAE; and ventricular hypertrophy, uncommon in partial; BVH in complete; RVH with Eisenmenger syndrome.

1.2 Congenital Heart Disease

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Fig. 1.5  This patient shows a large atrioventricular septal defect as identified first in the prenatal ultrasound (a). The figure (b) shows the anterosuperior face of the heart and the superior part of the congenital heart defect (c), while (d) demonstrates the large atrioventricular septal defect.

In (e, f) is shown the small right ventricle with a stenosis of the pulmonary atresia. Figures (g, h) show the pulmonary venous return from the lungs to the left atrium and the trachea and its bifurcation, respectively

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• Echo: Evidence of the defect using 2-­ dimensional echocardiography with color flow and Doppler studies. • TRT: Surgical repair involving the closure of the atrial and ventricular septal defects and restoration of a competent left AV valve. • PGN: Repair of the AVSD should be performed by age 2–4  months because of the heart failure and failure to thrive. In some patients, repair may be delayed up to 6 months, if they grow well, but not over this time to prevent the development of pulmonary vascular disease, specifically in patients with trisomy 21 syndrome (Down syndrome). Complications include a leaky mitral valve with consequent heart failure. In cases with proper treatment, most infants with AVSD grow up to have healthy lives. Endocarditis prophylaxis is required only for the first 6 months after repair or if there is a residual defect, which is located adjacently to a surgical patch.

1.2.2.4 Patent Ductus Arteriosus (PDA) • DEF: Persistence of the unique blood vessel between the main pulmonary artery and the aorta in extrauterine life closing ­spontaneously by day 4 of age (↑O2 tension) ± VSD, CoA. • SYN: Ductus arteriosus Botalli apertus • EPI: 12% of CHDs; incidence: 2/10,000 and 6/100,000 of live newborns; ♂ 10,000  feet), premature babies 50 mm Hg or > 2/3 of systemic pressures or percutaneous balloon valvuloplasty for palliatively relieving the valvular obstruction. • PGN: Mild PSIVS harboring patients have a normal lifespan, moderate PSIVS may present with easy fatigability, and dyspnea on exercise while severe PSIVS/PAIVS harboring patients manifest with severe cyanosis, and right-sided CHF in early life. Other conditions that may be encountered in this setting of RVTO are infundibular pulmonary stenosis without VSD and distal pulmonary stenosis (supravalvar pulmonary stenosis, peripheral pulmonary stenosis, and absence of a pulmonary artery).

1.2.4.3 HRHTA • DEF: Complete atresia of the tricuspid valve (right AV valve) with two subtypes depending upon the relationship of the great arteries (HRHTA I without TGA and HRHTA II with TGA). • EPI:  2b > 2c).

1.2 Congenital Heart Disease

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Fig. 1.12  Congenital heart disease showing a left (corrected) transposition of the great arteries with ventricular septal defect, pulmonary hypertension, and Eisenmenger syndrome. In (a) is a cartoon showing the corrected transposition of the great arteries with atrioventricular discordance and ventriculoarterial discordance. Figures (b–h)

show the several segments of the atrioventricular discordance on both sides with a probe in (f) inserted in the ventricular septal defect. Figure (i) shows some additional lung hemorrhage that can be fatal as seen in our patient, and besides there is the physiopathology cascade of the L-TGA

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Fig. 1.13  Figures (a–h) show another example of transposition of the great arteries

1.2 Congenital Heart Disease

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Fig. 1.14  Congenital heart disease with TGA. Figures (a–h) show another example of transposition of the great arteries. In this example, there is concordance between atria and ventricles (atrioventricular concordance)

1  Cardiovascular System

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Fig. 1.15  Histopathology of transposition of the great arteries (TGA). Figures (a–h) show the histopathology associated with patients with TGA. Myocardial tissue is demonstrated in (a–c), while the remaining histologic

photographs show the lung pathology with hemorrhage. In the heart, signs of cardiomyocyte hypertrophy accompany interstitial edema and fibrosis

1.2 Congenital Heart Disease

• PEX: Tachypnea (hypoxia), tachycardia, murmur absent in 1a but present in 1b, 2a, and 2b due to the pulmonary stenosis and in 2c due to the VSD, palpable RV impulse and accentuated S2. • CXR: Mild cardiomegaly, mild ↑pulmonary vascular markings, and “egg-on-string/side” appearance to the cardiac silhouette. • EKG: It is of little definite help, although the absence of positive findings of other defects, such as a left axis deviation of TA-HRH, may provide some information. • Echo: Posterior great artery arises from LV and divides into RPA and LPA, while the aorta is anterior and appears from RV. • TRT: Cardiac catheterization is performed to characterize the defect in preparation for corrective surgery further but also to perform a Rashkind septostomy (aka balloon atrial septostomy or BAS) once the cardiologist has identified the TGA with two well-developed ventricles. The BAS may be complicated by arrhythmias, inadequate or excessive size of the tear, and rupture of the left atrium. The Rashkind procedure is performed with PGE1 infusion to maintain PDA. Since 1958, the year when Senning introduced his surgical procedure for d-TGA or atrial switch ­operation, the prognosis for children born with TGA has changed dramatically. S ­ ubsequently, an alternative technique was proposed by Mustard. In the Senning procedure, the venous return is directed to the contralateral atrioventricular valve and ventricle using an atrial baffle or deflector made of the patient’s septal tissue. In Mustard’s technique, the atrial septum is excised, and a pericardial or synthetic baffle is created to direct the venous return. Senning procedure was popular in Europe, while Mustard technique was favorite in Canada and the USA.  Late complications associated with these techniques include mostly atrial arrhythmias and right ventricular dysfunction. SCD remains a leading cause of death in many series, and the history of tachyarrhythmias is considered an independent predictive factor for mortality. Thus, the Arterial Switch Operation (ASO) or Jatene’s procedure started to be used in the mid-1980s and is currently

31

used for TGA. There is still considerable interest in the outcome of TGA patients operated with ­Senning or Mustard procedures, and both techniques may be used in cases in which atrial repair is not feasible. Rastelli repair for TGA is an operation for repair of complete TGA in association with a large VSD and pulmonary stenosis and consists of a neo-communication between the LV and the aorta via the VSD using a baffle within the RV, which is connected to the pulmonary artery using a valved conduit and finally by obliteration of the LV-PA connection. Thus, Rastelli repair allows the left ventricle to support the systemic circulation. Although atrial switch operation was performed worldwide is not done anymore, patients with heart corrected are still alive, and the permission for an autopsy may be granted. Thus, this knowledge is always essential to have. Rastelli can be performed with low mortality at an early stage, but later substantial rates of morbidity and mortality are associated with this procedure. Fatal consequences include conduit obstruction, left ventricular outflow tract obstruction, and arrhythmia. Thus, the first two structures need to be investigated by the pathologist. The current early and late results of the ASO are excellent. ASO has reduced the application of the Rastelli repair to an alternative when LVOTO is not prone to be relief at the time of ASO. • PGN: Without surgery, congestive heart failure is common, because of the high cardiac output, inadequate oxygenation of the myocardium, and systemic pressure in both ventricles.

1.2.6 Common Trunk (Persistent Truncus Arteriosus) • DEF: Developmental failure of separation of the aorta and MPA with a single large vessel. The Collett and Edwards classification divides the PTA into four types. Type I shows the main pulmonary artery arising from the truncus and then dividing into the right and left pulmonary arteries. Type II is identified by the right and left pulmonary arteries, which arise distinctly from the

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• •

•

•

posterior aspect of the trunk. Type III shows the right and left pulmonary arteries arising from the lateral parts of the root of the trunk. Finally, type IV, which is now reclassified as TOF with pulmonary atresia, shows both pulmonary arteries supplied by collateral vessels from the aorta descendens. Van Praagh updated this classification identifying a type A (truncus arteriosus with VSD) and a type B (truncus arteriosus without VSD). Van Praagh subdivided type A into four subtypes: A1 (the main pulmonary artery arises from the trunk and subsequently divides into right and left pulmonary arteries), A2 (the right and left pulmonary arteries to originate separately from the posterior part of the trunk), A3, and A4. In A3, one lung is supplied by a pulmonary artery branch that arises from the truncus, while a ductus-like collateral artery supplies the other lung. Finally, the subtype A4 is characterized by a truncus, which is a large pulmonary artery, and there is an aortic arch, which is interrupted or coarctation is existing. EPI: 1:10,000 newborns. ETP: Embryologically, the primitive truncus remains undivided into the pulmonary artery and aorta, i.e., there is a single, large, arterial trunk that overlies a large VSD, which is malaligned and perimembranous in localization. CLI: There is a mixture of oxygenated and nonoxygenated blood with resulting cyanosis and heart failure. The children show poor feeding, diaphoresis, and tachypnea. There is a typical first heart sound (S1) and a loud, single second heart sound (S2) and variable murmurs. PGN: Surgical management consists of complete repair. The VSD is closed so that the left ventricle ejects into the truncal root, and the continuity between the ventricle (right) and the confluence of the pulmonary arteries is permitted using a conduit with or without a valve.

1.2.7 T  otal Anomalous Pulmonary Venous Return • DEF: Abnormal drainage of the oxygenated pulmonary blood flow directly or indirectly into the right atrium instead of the left atrium

• •

•

•

• • •

with mixing in the right atrium of systemic (hypoxygenated) and pulmonary (oxygenated) venous blood in association with either an ASD or a PDA and consequent right-to-left shunt and cyanosis with TAPVR: supracardiac (I), cardiac (II), infradiaphragmatic (III), or mixed (IV) types. The vascular connections are visualized in the Darling classification. EPI: 1.5% of all CHD, ♂:♀ = 3:1, isolated CHD in 2/3, but combined CHD in 1/3 of patients. EPG: –– Persistence ≥1 veins that join to the right SVC left vertical vein/innominate (brachiocephalic) vein or umbilical/vitelline vein/portal vein is due to failure of the common pulmonary vein to connect with the pulmonary venous plexus. –– Direct connection to the RA is due to either failure of the septum primum to usually form or abnormal septation of the sinus venosus. CLI: RA and RV enlargement due to the pulmonary venous return connecting to the systemic venous system, and in the case of pulmonary venous obstruction, RVH takes place. ASD or PDA are associated with defects that will allow life in maintaining a left ventricular outflow. Signs and symptoms include cyanosis, failure to thrive, tachypnea, and susceptibility to lower respiratory infections. IMG: RA and RV enlargement with lung edema and “8”/“Snowman”-CXR pattern and abnormal PPVVs connections using echo, angiography, and MRI. EKG: RVH signs. TRT: Surgery (reconstruction of the abnormal drainage RA → LA) and closure of ASD/PDA. PGN: CHF (RHF), arrhythmias, pneumonia/ bronchopneumonia, and pulmonary HTN.

1.2.8 Scimitar Syndrome • DEF: Hypoplastic lung syndrome due to abnormal venous return draining the right lower lobe of the ipsilateral lung entering the IVC (typically), the portal vein, the hepatic vein, or the right atrium instead of the left atrium and showing a small pulmonary artery

1.2 Congenital Heart Disease

a

33

b

c

d

Fig. 1.16  In Scimitar syndrome, there is an association of congenital cardiopulmonary anomalies consisting of a partial anomalous pulmonary venous connection of the right lung to the inferior vena cava (a), right lung hypoplasia (b), dextro-

position of the heart, and anomalous systemic arterial supply to the right lung. In this patient, the Scimitar syndrome was also accompanied by adhesion to the diaphragm (c) and thrombi (d) seen in the right and left pulmonary circulation

and potentially showing a less common lung systemic arterial supply (Fig. 1.16). • SYN: Hypogenesis lung syndrome, hypogenetic lung, and pulmonary venolobar syndrome. • CXR/Echo: “Scimitar shadow” (anomalous vein draining into the IVC). • DDX: Pulmonary sequestration, which is a disconnected bronchopulmonary mass with systemic arterial supply (contralateral mediastinal shift, focal lung consolidation, more common systemic arterial supply, and less common abnormal venous drainage).

1.2.9 H  ypoplastic Left Heart Syndrome and Coarctation of Aorta 1.2.9.1 Hypoplastic Left Heart Syndrome (HLHS) • DEF: Life-threatening defect, which causes still 25% of infants’ deaths due to multiple etiologies, including maternal, gestational, and familial/genetic/chromosomal conditions as well as fetal exposure to teratogens and active maternal infections. There is an abnormal

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development of the left-sided structures of the heart with blood flow obstruction at the level of the outflow tract of the left ventricular chamber. Although terminologically controversially debated, HLHS is probably a better-­accepted term for this condition, including underdevelopment (hypoplasia/stenosis through atresia) of the mitral valve, aorta, and aortic arch. HLHS may show a considerable inconsistency in expressivity with variable degrees of left ventricular outflow tract obstruction (LVOTO), AV valve involvement, and aortic hypoplasia (Figs. 1.17, 1.18, 1.19, 1.20, and 1.21). • EPI: 0.016–0.036% of all live births (≥ about 2:10,000). • CLI: Full-term babies, apparently healthy (S2 is loud and single) until the closure of arterial duct, when left atrial hypertension may develop quite quickly if there is a restriction of blood flow from the left to the right atrium due to an absent or inadequate atrial communication. There are also marked parasternal lift with poor peripheral perfu-

sion, cyanosis, and missing or barely palpable pulses. • DGN: CXR, EKG, and echo. • DDX: Aortic stenosis, CoA, and IAA (structural cardiac diseases). • MNG: Either heart TX or three-staged palliative procedures: 1. Norwood operation during the first week of life including the following steps: –– The central PA is divided with the distal stump closed with a patch, and the DA is ligated. –– One of the two alternatives to increase blood flow incrementing O2 saturation is performed. –– 1st: Right-sided modified Blalock-­ Taussig shunt (anastomosis between an SCA and RPA). –– 2nd: Sano shunt (RVOT-PA conduit). –– The atrial septum is distended, and the proximal MPA and hypoplastic aorta are joint together with an aortic or PA allograft/homograft (neo-aorta).

a

b

c

d

Fig. 1.17  Hypoplastic left heart syndrome (or better known as hypoplastic left heart). Figures (a–d) show a hypoplastic left heart in a fetus, and the rudimentary cavity is shown in (d)

1.2 Congenital Heart Disease

a

35

b

c

e

f

g

h

i

j

Fig. 1.18  This panel shows a cartoon (a) and several views of a hypoplastic left heart with status post Norwood and Glenn anastomosis between the superior caval vein

d

k

and the pulmonary artery (b–i). Figure (j) shows a thrombus in the right coronary artery, while figure (k) shows the full right ventricular cavity

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a

b

c

d

Fig. 1.19  Congenital heart disease showing several internal views of a hypoplastic left heart with large right ventricular cavity

1.2 Congenital Heart Disease

37

a

b

c

d

Fig. 1.20  Congenital heart disease showing a hypoplastic left heart with a tiny left ventricular cavity

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a

b

c

d

e

f

g

h

Fig. 1.21  Congenital heart disease with a hypoplastic left heart and pathologic changes identified in the organs. Several hemorrhages are shown in several organs from (a–h), including the lung (a), liver (b), kidney (c) on gross examination, and lung (d–e) with an hemorrhagic infarc-

tion, liver (f) with congestion of the sinusoids and rarefaction of the liver trabeculae, spleen (g) with congestion of the red pulp and relative reduction of the white pulp, and kidney (h) with hemorrhage and calcifications on histologic examination

1.2 Congenital Heart Disease

2. Bi-directional Glenn operation (SVC to the RPA, end-to-side anastomosis) at 3–6 months. 3. Fontan operation (a baffle directs IVC flow within the RA into the lower part of the SVC that is divided or the RAA, which is connected to the PA; the upper portion of the SVC is jointed superiorly to PA) at 18–36 months. • PGN: SR is 75% for stage 1, 95% for stage 2, and 90% for stage 3. Overall 5YSR: 70% after surgical correction. Factors: (1) low diastolic blood pressure in the aortic root is associated with decrease in coronary arterial perfusion (myocardial ischemia!), (2) bleeding with coagulopathy is a Norwood complication, and (3) neurodevelopmental disabilities (genetics or overt/occult CNS hypoperfusion due to thromboemboli). Recurrence risk in siblings is 0.5%, but accompanied by other forms of CHD, it raises to 13.5%. Genetic syndromes include Turner syndrome, Noonan syndrome, Smith-Lemli-Opitz syndrome, Holt-­ Oram syndrome, etc. Antenatal diagnosis is based on a fetal echo at 18–22 weeks of gestation.

1.2.9.2 Coarctation of the Aorta • DEF: Narrowing of a section of the aorta most commonly between the left subclavian artery and the ductus arteriosus (Isthmus aortae) to an abnormal width. In the fetus and neonate, the aortic isthmus, the portion of the aorta between the left subclavian artery and the ductus arteriosus, usually is usually narrowed, and the lumen is about 2/3 of the ascending-descending parts of the developing aorta until 6–9 months of age when the narrowing indeed vanishes. Tubular hypoplasia is found in the aortic isthmus and is often referred to as preductal or infantile coarctation of the aorta. Interrupted aortic arch (IAA) is classified according to Celoria-Patton and can be subtyped in three types, A, B, and C.  Type A involves interruptions distal to the left subclavian artery. Type B involves interruptions distal to the left common carotid artery, and, finally, type C involves interruptions distal to the innominate artery (proximal to the left common carotid arterial origin). Type A and

39

•

•

•

•

type B have a similar frequency, despite some reports indicate that type B is the most common type, while type C is exceptionally uncommon. Each type is divided into three subtypes: 1: normal subclavian artery, 2: aberrant subclavian artery, and 3: isolated subclavian artery that arises from the ductus arteriosus Botalli. In CoA, there is a posterior eccentric fold (posterior shelf) inside the isthmus, opposite to the orifice of the arterial duct, which closing at birth or soon afterward, further narrows remarkably the aortic lumen. Bonnet classification: infantile or preductal (isthmic) form and adult or juxtaductal form (Fig. 1.22). EPI: 6% congenital cardiac anomalies, ♂:♀ = 3:1, ±Turner syndrome and a­ ccompanied by other defects in 50% of cases (PDA, bicuspid aortic valve, AS, ASD, VSD). Other associations include DiGeorge syndrome, truncus arteriosus, aortopulmonary septal “window”, TGA, DORV, and functional single ventricle. ETP: The embryology of coarctation indicates that the fourth arch persists on the left side of the body to connect ventral aorta to dorsal aorta and form the aortic arch, while the sixth arch develops distally into ductus arteriosus. Coarctation of aorta results from the fourth and sixth arch. There are, commonly, two ETP hypotheses, including (1) the ductal tissue theory suggesting that the aortic narrowing is due to migration of ductal smooth muscle cell into the aorta and (2) the hemodynamic theory implying that the reduction is due to reduced flow through the aortic arch. The tubular hypoplasia of the aortic isthmus may be indeed related to blood flow paucity in the intrauterine life, which improves postnatally. CLI: From asymptomatic to congestive heart failure in early infancy with early symptoms of decreased exercise tolerance and fatigability in early childhood, pulse lag in lower extremities, ABP UEX > LEX (≥20 mmHg), and blowing systolic murmur in the interscapular area of the back (ABP, arterial blood pressure; UEX, upper estremities; LEX, lower extremities). CXR: Multiple signs including the “3” sign, rib notching of posterior third of ribs 3–8,

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a

b

c

d

e

f

g

h

Fig. 1.22  Cross sections of several aortic specimens taken at several levels in different patients (a–h) showing marked fibrointimal hyperplasia and luminal stenosis

1.2 Congenital Heart Disease

Box 1.3 Complications of the Coarctation of the Aorta

• Aortic Rupture • Bleeding of Extracardiac Type (e.g., Intracranial or Cerebrovascular Stroke) • Congestive Heart Failure • Disseminated (Sepsis) or Localized Infection (Endocarditis of Subacute Type)

• • •

•

“E”-shaped esophagus on barium swallow (the first arc of the E is due to dilatation of the aorta just proximal to the coarctation, the middle bar of the E is expected to coarctation itself, while the second arch of the E is due to post-stenotic dilatation of the aorta), infantile cardiomegaly with LV enlargement, and infantile pulmonary congestion. EKG: Normal to LVH signs ± RVH signs with or without congestive heart failure. Echo: Visualization of the CoA with data of pressure gradients, LVH, and anatomy details. TRT: Surgery but deferral of definitive correction may be opted in some cases using intravenous nitroprusside or propranolol to reduce the afterload. PGN: If not corrected, 60% die before age 40, often of aortic rupture (Box 1.3). The patients who survive the neonatal period without developing heart failure seem that they should do quite well throughout childhood and adolescence.

1.2.10 Heterotaxy Syndrome • DEF: Abnormal arrangement of the internal organs in the chest and abdomen affecting the heart, lungs, liver, spleen, intestines, and other organs (ἕτερος, ‘different’ and τάξις, ‘arrangement’). Situs solitus is the typical arrangement of the organs. The situs inversus is when the orientation of the internal organs is entirely flipped from right to left, and the situs ambiguus is when the direction of the internal organs is mixed. The affected organs may show three or two lung lobes bilaterally, two morphologi-

41

cally left/right chambers, right-located liver or located across the middle of the body, left/right stomach, a-splenia/poly-splenia, and malrotation of the intestines (Figs.  1.23, 1.24, and 1.25). Life is conditional on the organs involved. Signs and symptoms of heterotaxy syndrome can include cyanosis, breathing difficulties, an increased risk of infections, and food digesting difficulties. The most severe complications are generally determined by critical heart disease, a group of complex heart defects that are present from birth. Heterotaxy syndrome is often life-threatening in infancy or childhood, even with treatment, although its severity depends on the specific abnormalities involved. • SYN: HTX, Ivemark syndrome, left/right isomerism, situs ambiguus, situs ambiguus viscerum, and visceral heterotaxy. • EPI: 3% of all CHD, 1  in 10,000 people worldwide, and black/Hispanic > white.

1.2.11 Common Genetic Syndromes with Congenital Heart Disease The development of the heart characterizes the period ranging from the third and the seventh week of gestation. In this time, complex folding and looping of the described initially as ‘horseshoe’-­shaped tube give rise to the four-­ chambered cardiac pump; there are also some other organs that are forming and may be involved in phenotype leading to common congenital syndromes. In this period, both exogenous factors (e.g., rubella, CMV, alcohol, drugs, cannabis, cocaine, etc.) and intrinsic factors (genes and epigenetics) may play an etiopathogenetic role. In about 1/5 of all children born with a cardiac defect, there are extracardiac defects. A chromosomal, subchromosomal (microdeletion), or genetic disorder (monogenic), which is either inherited from the biologic parents or occurred spontaneously, may be the underlying common factor. Indeed, a genetic cause can be supposed if a cardiovascular defect or syndrome occurs frequently or recurrently in one family. Numerous reviews are highlighting congenital syndromes with congenital heart disease. Here, some of the

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a

b

c

d

e

f

g

Fig. 1.23  Ivemark syndrome in a child with heterotaxy syndrome (a) showing a common atrium (b), left loop and unbalanced atrioventricular septal defect. There is malrotation or dislocation of the internal organs with prominent

abdomen (c). The morphology of the heart is abnormal harboring a common atrium (d–e) as better shown on (f). In (g), the liver is located on the left side of the abdominal site

most critical congenital syndromes are summarized (Figs. 1.26 and 1.27). More congenital syndromes are also described in other chapters of this book.

developmental defects of the brain, eyes, palate, heart (>90% of patients have CHD, mostly VSD), urinary, and gastrointestinal systems. • Trisomy 21 syndrome (Down syndrome): 1:650 births, appropriate for the delivery date, and mild to severe developmental defects of the heart (up to 50% of patients, mostly AVSD, ASD, VSD) and gastrointestinal system (atresia, aganglionosis, or Hirschsprung disease). • Monosomy X0 syndrome (Ullrich-Turner syndrome): 1:2000 births (female, 45, X0) with

• Trisomy 13 syndrome (Patau syndrome): 1:10,000 births, small for date, severe developmental defects of the brain, heart (80% of patients, mostly VSD, heterotaxy), urinary, and gastrointestinal systems. • Trisomy 18 syndrome (Edwards syndrome): 1:3000/1:10,000, small for date, and severe

1.2 Congenital Heart Disease

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a

b

c

d

e

f

g

h

Fig. 1.24  Ivemark syndrome with hypoplastic right heart syndrome, pulmonary atresia, and ventricular septal defect as shown in several views of the heart dissection (a–h)

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a

b

c

d

e

f

Fig. 1.25  Congenital heart disease with right atrial isomerism, double outlet right ventricle, balanced atrioventricular septal defect, and total anomalous pulmonary

venous return as well as asplenia as shown in these several views of this heart dissection (a–f)

urogenital defects (underdeveloped “streak • 22q11.2 microdeletion syndrome (DiGeorge gonads”) and cardiovascular defects (aortic and Shprintzen syndrome): 1:4000–1:6000 isthmus stenosis). births with cardiovascular defects other than • 1p36 deletion syndrome (1p36 monosomy): somatic (85% RVOT defects, including the 2/10,000 births, severe disruptive psychosocommon trunk, VSD, TOF), thyroid, and paracial behavior with cerebral seizures and self-­ thyroid gland defects with resultant disorders destructive phenotype, general hypotonia, of calcium metabolism, thymus agenesis, and feeding problems, vision disturbances and psychological development. hearing loss, and cardiovascular defects in • 4p- syndrome (Wolf-Hirschhorn syndrome): 40% of the affected children (PDA, TOF, 1:50,000 births, loss of a short arm of one of ASD, VSD, ECA), who may start or evolve the chromosomes 4, 1:50,000 births, VLBW into dilated cardiomyopathy (DCM). infants with microcephaly and typical facial

1.2 Congenital Heart Disease

a

d

45

b

c

f

e

Fig. 1.26  VACTERL association is an association of multiple congenital anomalies including vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, and/or esophageal atresia, as well as renal and radial anomalies and limb defects. In (a) are shown several types of atrial communication in a cartoon and two heart specimen preparations, fresh (b) and post-formalin fixation (c),

showing an atrial septum defect of type II. In (d) is shown a tracheostomy, which is often necessary in these patients. Moreover, these children may develop thoracal lymphomegaly that may contribute to breathing difficulties (e). In (f) there is joining of the lower poles of both kidneys (“horseshoe kidney”)

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a

b

c

d

Fig. 1.27  Catch 22 syndrome is a genetic syndrome including cardiac defects, abnormal facial features with cleft palate, thymic hypoplasia with T-cell deficiencies, calcification of periventricular basal ganglia, and hypocalcemia. The second letter “C” of the acronym is also often used to designate the cleft palate. Catch 22 syndrome results from a deletion within chromosome 22q11 and includes DiGeorge syndrome, conotruncal anomaly face syndrome, and velocardiofacial syndrome. In (a) is shown the 22q11.2 region, while (b) shows a characteristic FISH of a patient harboring Catch 22 syndrome. The normal

chromosome 22 shows a hybridization signal in band 22q11.2, the Catch 22 region, being marked by an arrow. No signal is observed in the other chromosome 22, indicating a microdeletion of the region 22qll.2 (arrow head). Both chromosomes 22 reveal signals for the control region. Hybridization on the distal long arm 22q13.3 was used as control. Karyotype (500 G- and Q-banding): 46, XX.ish del (22) (q11.2 q11.2) (D22S75-). In (c, d) there is the preparation of the heart showing tetralogy of Fallot, a frequent congenital heart defect of children affected with Catch 22 syndrome

features with hypertelorism, eyelids that slant down, broad nose, micrognathia, turned-down mouth, and ear tags or pits, mental retardation with seizures, failure to thrive. CHD includes ASD or VSD. 1-YSR  G tRNAThr mutation is connected with respiratory enzyme deficiency, mitochondrial myopathy, and cardiomyopathy. The tRNAArg—c.10458  T  >  C mutation is described as a known sequence polymorphism. In the D-loop region, several sequence alterations could be detected. The c.16189 T > C variant that is associated with susceptibility to DCM could be detected in the Caucasian cohort in 15.6% of patients with DCM and 9.7% of the control subjects. Some 17.2% of the c.16189 T > C variant in Caucasians with DCM versus 8.8% in controls have also been detected. A significant difference could be found in new mtDNA mutations in protein-coding genes of patients with DCM. Some of the mutations were found to be potentially pathogenic to DCM because they substituted evolutionarily conserved residues which might alter the function of the respective protein subunits. Mutations altering the function of the subunits of the respiratory chain can be responsible for the pathogenesis of DCM.

1.3.2.41 Dilated Cardiomyopathy Due to Chemotherapy-­ Related Cardiotoxicity This form of DCM is likely to be secondary to some nutritional deficiency associated with the administration of adriamycin (doxorubicin). Histologically, there is patchy myocardial interstitial fibrosis with scattered vacuolated cardiomyocytes (“Adria cells”), fibroblastic proliferation, histiocytic infiltration (CD68+), partial/total loss of myofibrils, and vacuolar degeneration of the cells. The vacuolization of cardiomyocytes is due to dilation of the sar-

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cotubular system as the earliest change, and the Adria cell shows loss of cross striations, homogeneous basophilic staining, and loss of myofilaments. The DCM due to chemotherapy-related cardiotoxicity is more often observed in young ­ adults, either intra vitam (during life) by asymptomatic murmur on a routine physical exam or following sudden death during strenuous exercise. In conclusion, DCM is a primary myocardial disease that causes considerable morbidity and mortality. Although this cardiomyopathy is clinically heterogeneous, genetic factors play an essential role in its etiology and pathogenesis. As demonstrated above, the association between gene polymorphisms and DCM has been investigated for various genes. The genetic contributions to heart failure can be broadly grouped into causative and modifier genes. Numerous components of the cytoskeletal system have been implicated as genes that cause DCM.  In contrast, modifier genes become active after the disease is present and thus influence clinical course. The identification of genetic risk factors is essential for better understanding the pathogenesis of DCM.  Up to now, several chromosomal loci and disease genes have been identified. But the data suggests that nearly all of the disease genes account for a relatively small proportion of all cases of DCM.  As no significant gene or loci have been identified in DCM, it may be speculated that many morbid genes remain to be determined.

1.3.3 Hypertrophic Cardiomyopathy • DEF: Multigenic/polygenic disorder mostly involving the interventricular septum but also an extension on some degree of left ventricular outflow tract obstruction (Fig. 1.33). • SYN: Idiopathic hypertrophic subaortic stenosis (IHSS), asymmetric septal hypertrophy (ASH). • EPI: ~0.2% (1:500) of young adults. Sarcomere protein mutations known to cause HCM are quite common in the general population. • ETP: AD inheritance but also sporadic. Concentric (not asymmetric) left ventricular hypertrophy has been independently associated

•

• •

•

•

with an increase of the risk to have sudden cardiac death (SCD). Remarkably, the density of connexin 43 gap junctions at the intercalated disc in individuals with LVH + SCD and individuals with LVH  +  unnatural death is quite similar. An increase in the number of connexin 43-labeled gap junctions with an increase in the myocyte cross section may be found. These gap junctions may be at the basis of conduction of the electrical activity in the transverse orientation. The maintenance of gap junctions at the intercalated disc as an expected number and the longitudinal conduction properties in cardiomyocytes should remain intact, but the transverse conduction properties of the hypertrophied cardiomyocytes may be altered and be at the basis of SCD, at least in some cases. CLI: HCM remains a diagnosis of exclusion. Thus, secondary causes of left ventricular hypertrophy such as systemic hypertension, valvular/subvalvular aortic stenosis, and infiltrative cardiomyopathies must be ruled out. If echocardiography, computed tomography (CT), or cardiac magnetic resonance (CMR) in the absence of a secondary cause identify a wall thickness of ≥15 mm, this finding is consistent with HCM. GRO: Left ventricular hypertrophy. CLM: Myofiber hypertrophy, myofiber disarray, and interstitial fibrosis with intramyocardial located coronary vessels (~50%) and frequent endocardial fibrosis of the outflow tract are the essential characteristics for diagnosis. TEM reveals derangement of the cardiac cell anatomy at the subcellular level, including the loss of the normal alignment of myofibrils and Z disks. PGN: Disease progression is difficult to envisage, and genetic screening is jeopardized because there are differences in penetrance and expressivity.

1.3.4 Infiltrative/Restrictive Cardiomyopathies Cardiomyopathies consisting of any disorder, which implicates a restriction of the ventricular filling phase of the cardiac pump, are grouped

1.3 Myocarditis and Nonischemic Cardiomyopathies

a

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b

c

d

e

f

Fig. 1.33  The relationship between the heart and the brain is complex. Certain pathological conditions can interfere with the normal brain-heart regulatory mechanisms and result in impaired cardiovascular function and

dilated cardiomyopathy. In neurogenic cardiomyopathy, there is dilatative form (a–c) with fibro-fatty infiltration of the myocardium at places (d–f)

under the label “infiltrative /restrictive cardiomyopathies.” Although the main problem is the abnormal filling of the heart, the heart may not pump blood vigorously when the cardiovascular disease progresses. The abnormal cardiologic function can affect extracardiac organs. Restrictive cardiomyopathy may affect a single ventricle or both of the ventricles. Although restrictive cardiomyopathy is rare, the cardiologist and pathologist need to consider two of the most common causes, which are amyloidosis and glycogenosis. Other causes entail carcinoid heart disease, endomyocardial fibrosis, and Loeffler syndrome, iron over-

load (hemochromatosis or hemosiderosis), sarcoidosis, scarring after radiation or chemotherapy, scleroderma, and neoplasms of the heart (Figs.  1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.40, 1.41, 1.42, 1.43, and 1.44). As part of systemic amyloidosis (AA type of amyloid) or isolated as in senile cardiac amyloidosis (AF type of amyloid [transthyretin]), amyloidosis may be an essential component of restrictive CM. The result of the immunologic mechanisms involved in a multifactorial fashion with different types of amyloid. Substantially, it is a disorder of protein misfolding with at least 23 different pro-

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a

b

Fig. 1.34  In the hypertrophic cardiomyopathy, the ventricular septum is usually thicker than the left ventricular free wall (greater than 1.5 cm) (a). Histologically, there is

a

Fig. 1.35  Sarcoidosis is a multisystem, granulomatous disease of unknown etiology, and there is evidence that an immunological response to an unidentified antigenic trigger in genetically susceptible persons is present.

c

myocardial disarray with interdigitating myocardial fibers. Although this finding is not pathognomonic for hypertrophic cardiomyopathy, it is indeed quite characteristic (b, c)

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Noncaseating granulomas are the histopathological hallmark (b–g), but the Schaumann bodies or asteroid bodies (h) are quite characteristic, although nonspecific

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Fig. 1.35 (continued)

a

Fig. 1.36  Altered pattern of cytochrome c oxidase and succinate dehydrogenase (complex II) immunohistochemistry reveals a mosaic pattern of cytochrome c oxidase-­deficient and cytochrome c oxidase-positive cardiomyocytes (top panel) with reduced succinate dehydro-

b

genase staining (bottom panel) in the MELAS myocardium (right, top, and bottom) compared to a non-failing control (NFC) myocardium (left top and bottom). All the microphotographs have been taken at ×400 as original magnification

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Fig. 1.36 (continued)

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Fig. 1.37  Mitochondrial DNA cardiomyopathies with characteristic ultrastructural features on electron microscopy (EM). These features may range from large, subsarcolemmal accumulations of mitochondria to myofibers containing disordered myofibrils, degenerating mitochondria and vacuoles (a). One of the most frequent characteristic features of the abnormal mitochondria is the presence of very peculiar paracrystalline inclusions (b, c). The mitochondrial inclusions are sometimes described as having a “parking lot” appearance (b). Another characteristic feature is the presence of lipid droplets (c) together with these mitochondrial accumulations. Membranous whorled mitochondria can also be found. In the relaxed state, the wide gap between two Z lines is about 2.2 μm and is the functional basic unit of muscle, which is also referred to as sarcomere. In isotonic, i.e., associated with a muscle shortening, contraction shortens the length of sarcomeres of a muscle fiber at the same time. Nemaline inclusion myopathy is a congenital myopathy characterized by gross hypotonia in early infantile cases with cardiopulmonary insufficiency. The predominant fea-

e

ture is the presence of nemaline rods. Nemaline rods are identified within the cytoplasm and can also be demonstrated with a modified Gomori trichrome staining using histochemistry. Nemaline rods can be present as dense, irregular bodies in a random orientation just beneath the sarcolemma. On EM, they present as thickenings of the Z-lines within type I fibers. The nemaline rods are derived from Z-band material and have also been characterized immunohistochemically with an antibody anti-alpha-actinin. At higher magnification, nemaline rods show variable rod length in the longitudinal section. Thin filaments extending from each end interdigitate with thicker filaments. Inclusion body myositis contains a variety of inclusions (f, g) ranging from abnormal filaments to myelin figures (membranous whorls). Filaments can be identified within both the nucleus (l) and cytoplasm (g) of muscle fibers. In the cytoplasmic body myopathy (i), there is a sharply defined dense structure (i), which characteristically shows radiation of thin filaments from the center of the inclusion

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Fig. 1.37 (continued)

teins that aggregate forming fibrils with the appearance of amyloid. The red-green dichroism or birefringence is due to the dye Congo red, which binds to the amyloid-forming fibrils. Congo red is a water-soluble organic compound and its use in pathology is still en vogue. The endomyocardial fibrosis of children and young adults, which often occurs in Africa, is characterized by endocardial fibrosis extending from apex into outflow tracts of the left and right ventricle. The scarring may extend into inner 1/3 of myocardium and may involve tricuspid and mitral valves. Microscopically, varying amounts of inflammation, including eosinophils, often seen at the edge of scarring can be demonstrated. Loeffler endocarditis may be seen as early as 2-year-old infants and is similar to EMF spectrum with three stages: acute myocarditis (necrotic), organizing thrombus, and endomyocardial fibrosis. Eosinophilic infiltration of other organs may be observed, and the outcome may reveal a rapid downhill course to death. Grossly, endocardial fibroelastosis shows pearly-white thickening of the endocardium due to an increase in collagen and elastic fibers on the surface, mostly in the left ventricle.

1.3.4.1 Sarcoidosis Cardiac involvement of this idiopathic multisystemic granulomatous disease is seen in ~ ¼ of patients with systemic disease (mostly autopsy). Sarcoidosis involves the lymph nodes, lungs, eyes, kidneys, central nervous system and skin, and occasionally heart. Cardiac symptoms occur in less than 5% of patients with sarcoidosis and include papillary muscle dysfunction, congestive heart failure, pericarditis, and conduction abnormalities, and SCD as well as occasionally sarcoid myocarditis, which can mimic ARVC.  The differential diagnosis of granulomas in the heart includes tuberculosis, toxoplasmosis, rheumatic fever, fungal, and idiopathic giant cell myocarditis, among others. Special stains are mandatory in these cases and include PAS, PASD, Giemsa, GMS, ZN, auramine-rhodamine, and Fite staining. IHC is also important and the pathologist should have in his repertoire antibodies against T. gondii. Thalassemia major is the most dreadful form of β-thalassemia, which is a hematologic disorder that reduces the production of hemoglobin. The β-thalassemia is classified into two types depending on the severity of symptoms, including thal-

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72 Fig. 1.38 Glycogenosis cardiomyopathy is often found in Pompe’s disease. There is vacuolation of the cardiomyocytes with (a) or without (b) signs of cardiomyocyte hypertrophy and increase of the nuclear size of the cardiomyocytes. The ultrastructural features of glycogenosis are an accumulation in the lysosomes (Pompe’s disease) or in the cytoplasm of the cardiomyocytes (c)

a

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Fig. 1.39  Fabry disease is a lysosomal storage disease which involves dysfunctional metabolism of sphingolipids (sphingolipidosis). Cardiomyocytes show multiple vacuolated cells or perinuclear vacuoles on hematoxylin and eosin (H&E) staining (a, b), periodic acid Shiff (PAS) negativity (c), interstitial fibrosis on Movat pentachrome

staining or trichromic stain (d), and ultrathin slide sections showing enlarged secondary lysosomes packed with storage material, which has a somewhat heterogeneous appearance and displacement of the mitochondria, which may show vacuolation and loss of cristae (e, f)

assemia major (or Cooley anemia, aka “Mediterranean anemia”) and thalassemia intermedia. Thalassemia minor is also widely known as β-thalassemia trait. The β-thalassemia is caused by mutations in the HBB gene, which is located on 11p15.5. HBB provides instructions for making a protein called beta-­globin (β-globin). Beta thalassemia occurs most often in Mediterranean countries, North Africa, Middle East, India, Central Asia, and Southeast Asia. One of the significant complications of

thalassemia-­driven microcytic anemia with the early destruction of the abnormal erythrocytes in these patients is excessive siderosis. This complication, if untreated or poorly treated, can determine iron deposition in major organs, including the liver and heart. Cardiac iron accumulation is the precise cause of intractable cardiac failure if no treatment is started. However, despite iron chelating agents, patient survival may be reduced due to the intrinsic damage related to the deposition of iron in the cardiac muscle, causing sec-

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Fig. 1.40  Sanfilippo cardiomyopathy is a rare mucopolysaccharidosis. Accumulation of partially degraded GAGs progressively affects multiple organ systems including the heart. There is dilatation of the right chambers and hyper-

trophy of the left ventricle (a). On histology, there is infiltration of the myocardium of cells containing foamy cells (b–d) that illustrate concentric multilamellar bodies on electron microscopy (e)

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Fig. 1.41  Unusual combination of patient with restrictive cardiomyopathy due to siderosis-related myelodysplastic syndrome and Caroli disease. The cardiomyocytes

show perinuclear and accumulation of hemosiderin (Fe) and interstitial fibrosis (a–h) at places or diffusely

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Fig. 1.42  Early amyloidosis of the heart of a young patient with fibrosis (a, b), Congo red positivity (c, e) and birefringence (d, f). At places, the amyloidosis is quite marked at level of the blood vessels (g, h)

ondary cytologic myocardial cell dysfunction. analyzed by routine histology, transmission elecThus, myocardial biopsies may be taken to inves- tron microscopy, and Perls Prussian blue (PPB) tigate iron deposition and quantify hyper-­ histochemical stain for detecting iron deposits in siderosis using either histochemical the cardiac tissue. PPB is a commonly used assessment-based or X-ray microanalysis-­method in histology, histopathology, and clinical standardized scores. Cardiac biopsies should be pathology to identify the presence of Fe in tissue

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a

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Fig. 1.43  Chloroquine toxicity of the cardiomyocytes in a young patient with restrictive cardiomyopathy showing pathology images of endomyocardial biopsy specimens. Light microscopy using hematoxylin and eosin stain demonstrates vacuolization of cardiomyocytes at ×200 magnification (a); light microscopy using periodic acid-Schiff stain at ×200 magnification shows that the vacuoles are periodic acid-Schiff-negative at ×200 magnification (b); there is an impressive interstitial fibrosis of the myocar-

dium as highlighted using Movat pentachrome staining at ×200 magnification (c); electron microscopy at ×25,500 magnification demonstrates myeloid and curvilinear myeloid bodies, as well as vacuolated cytoplasm characteristic of chloroquine-associated cardiomyocyte damage (d). Myeloid and curvilinear myeloid bodies, as well as vacuolated cytoplasm characteristic of chloroquine-­ associated cardiomyocyte damage

or cell samples. This last method is the most used and cheaper method for follow-up patients. Masson trichrome histochemical stain is also useful for evaluating the extent of fibrosis, which may be related to early heart failure. The Buja and Roberts schema is highly reproducible and generally used in the routine diagnostics to quantify the visualized iron deposits in the cardiomyocytes. It has been suggested that an immunohistochemistry procedure may be used to highlight the iron-laden macrophages using antibodies against the CD68 antigen of the macrophages, but obviously histochemistry is cheaper than immunohistochemistry. Moreover, cardiomyocytes can be detected using antihuman desmin antibodies. Electron microscopy may also be very helpful revealing the presence of electrondense cytoplasmic pleomorphic granules within cardiomyocytes, which correspond to small primary and large secondary lysosomes distributed

randomly in the cytoplasm of the cardiac muscle cell. The dysfunctional cardiomyocytes often show discontinuities in the structure of sarcomeres and loss of myofilaments. There is also the loss of the sarcomeric arrangement by many siderosomes that disrupt the cardiac muscle cell and damage of both thick and thin filaments and disorganization of the Z-bands with the disappearance of the intercalated discs at places. Mitochondria show swelling and very few cristae. It does not seem that electron-dense ironcontaining particles are found within other cytoplasmic organelles, such as Golgi apparatus. Nuclear changes are also observed and include elongation, an increase of the electron density, and increase of heterochromatin but no iron-containing particles. Basement membranes and cell membranes appear to be intact. X-ray microanalysis may be used to confirm the presence of iron inside of the primary lysosomes.

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Fig. 1.44  Restrictive cardiomyopathy due to myofibrillar myopathy. In (a, b) dilatation of the heart, while (c–f) show the characteristic features of the cardiomyocytes exhibiting abnormal intracellular protein inclusions,

which may be single or multiple. The inclusions are eosinophilic and may be congophilic (c–f), which may poses some differential diagnosis in older patients

1.3.5 Left Ventricular Non-compaction

LVNC can also be inherited as an X-linked inherited recessive disease. • CLI: Symptoms vary considerably according to the degree of the involvement of the heart. In consideration of the malfunction, symptoms frequently overlap with those associated with dilated, hypertrophic, or restrictive cardiomyopathy. • GRO: The cross sections of a cardiac specimen with LVNC show deep recesses extending to the inner half of the ventricle. These

• DEF: Spongy degeneration of the cardiac musculature with weak functionality and predisposing to heart failure due to an impaired ability to pump blood (Figs. 1.45 and 1.46). • EPI: 8–12 per one million individuals per year. • ETP: Mutations in the MYH7 gene and MYBPC3 gene account for about 1/3 of cases.

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(2) coarse trabecula like many papillary muscles, and (3) interlacing smaller muscle bundles or compressed invaginations, which are identified chiefly microscopically. • CLM: Two patterns of myocardial structure in the superficial noncompacted layer are recognized, but in most hearts, the patterns overlap. The first pattern is characterized by anastomosing muscle bundles forming irregularly branching endocardial recesses with a staghorn appearance, while the second pattern reminds many small papillary muscles, creating an irregular appearance to the surface. • PGN: It depends on the severity of the condition, but cardiac transplantation seems to be the only option when the heart fails.

1.3.6 Arrhythmogenic Right Ventricular Dysplasia/ Cardiomyopathy (ARVD/C) • DEF: Inherited, genetically determined CM characterized by structural and functional abnormalities, predominantly of the right ventricle resulting from progressive, fibrofatty replacement of the myocardium starting from the epicardium with an AD pattern and variable expressivity (Fig. 1.46). • SYN: Uhl anomaly. • EPI: 1:1000–1:5000 in the general population but accounts for up to 17% of all SCD of the youth. • ETP: Point mutations in genes encoding for Fig. 1.45  Left-ventricle non-compaction (LVNC) with desmosomal proteins are the underlying gross features characteristic of this syndrome, which is a genetic dysregulation. A triad of ARVC, palrelatively rare congenital disorder characterized by promimoplantar keratosis, and woolly hair characnent trabeculations and intertrabecular recesses. There is terize an AR-inherited subtype (Naxos the potential for thromboembolism, cardiac arrhythmias, and sudden cardiac death as adverse early or late effects disease). • CLI: RV dilatation, arrhythmias, and SCD are the characteristic triad. CT angiography is parrecesses are most conspicuously in the mid-­ ticularly useful for the detection of akinetic or ventricle and toward the apex cordis. The dyskinetic bulging in the triangle of dysplasia, gross appearance may vary from anastomosbut MRI with gadolinium enhancement is ing trabecula to a quite smooth endocardial superb for its potential in detecting regional and surface with narrow beginnings of the recesses diastolic ventricular dysfunctions, which can be to the cavity of the ventricle. The patterns of the early signs of ARVD/C. Two primary criterecesses may be divided into three types, ria or one major plus two minor criteria or four including (1) anastomosing broad trabecula, c

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Fig. 1.46  Histology of LVNV showing the recesses and trabeculations using hematoxylin-eosin and connective tissue stain (a, b). In (c) are presented the clinical procedures. In the early stages, a vacuolation may be prominent. It has been proved that early metabolic stabilization and regular cardiac evaluation are a must for the young

affected infants with LVNC.  A surveillance plan for patients harboring Barth syndrome (a rare X-linked inherited disorder characterized by cardioskeletal myopathy, peripheral neutropenia, psychomotor and growth retardation, and 3-methylglutaconic aciduria) before heart transplantation has been suggested

minor criteria are essential for the diagnosis of ARVD/C.  Six categories include global and regional dysfunction and structural alterations (I), wall morphology (II), re-/depolarization, conduction disturbances, arrhythmias (III–V), and family history (VI) (Marcus et  al., 2010). The significant rules of category I include severe dilatation and reduction of RV ejection fraction with no/mild LV dysfunction, localized RV aneurysms, and severe segmental RV ­dilatation.

The minor criteria of category I entail mild global RV dilatation and ejection fraction reduction with normal LV function, mild segmental dilatation of the RV, and regional RV hypokinesia. Category II includes fibrofatty replacement of the myocardium (only one major criterion), while categories III–V involve one primary criterion of ε-waves or localized prolongation of the QRS complex in the right precordial leads and three minor criteria, including inversion of

1.3 Myocarditis and Nonischemic Cardiomyopathies

•

•

• •

T-waves in the right precordial leads, late potentials, left bundle branch reentrant ventricular tachycardia, and recurrent ventricular extrasystoles. Finally, category IV relies on the family history confirmed at autopsy or surgery (primary) and family history of premature SCD in a young ( IMB); eccentric atheromatous plaques with the superimposed intimal proliferation; fibrinoid necrosis of the media (IMB); T lymphocytes, macrophages, and foamy cells (epicardial > IMB); vascular thrombosis (IMB); and vasculitis, endothelialitis, and ACR (IMB). The examination of the myocardium often shows an ischemic injury on both sides of the heart with inherent patchiness. This acute and healing ischemic injury is at the basis of the ­concept that intramyocardial branches are entirely or subtotal occluded before the large epicardial branches are stenosed. The pathology of CAV does not differ substantially between children and adults, although the underlying lipid profile may play an aggravating role often observed in adults.

1.6.4 Extracardiac Posttransplant Lympho-proliferative Disorders (PTLD) Following HTX Heart transplantation (HTX) is associated with a burden of immunosuppression, and there is the risk of posttransplant lymphoproliferative disorders (PTLDs). In Fig.  1.60, some extracardiac posttransplant lymphoproliferative disorders have been collected. PTLD occurs between 1.2% and 9% of cardiac transplant patients across ages and gender. The first year of transplantation is the most vulnerable time to develop PTLDs. Risk factors for developing PTLDs are the infection with Epstein-Barr

virus (EBV) and some immunosuppressive regimens, such as OKT3. EBV is a ubiquitous γ-herpesvirus able to establish lifelong persistent infection and can be intermittently shed in the saliva. EBV has a characteristic dual tropism for both B lymphocytes and epithelial cells. EBV exhibits a biphasic life cycle. Although the infection is often benign, EBV is associated with some lymphomas and carcinomas that arise in several anatomical sites. It has been questioned if EBV is a carrier or a driver for the oncogenesis. Currently, EBV is considered a carcinogenetic cofactor in cellular environments due to its ability to immortalize B lymphocytes and its occurrence in a subgroup of tumors considering that EBV may act more as an agent of tumor progression rather than tumor initiation. The majority of PTLDs are malignant B-cell lymphomas (Fig.  1.60). In a previous study, our group could identify heterogeneity of PTLD after heart transplantation. Our study confirmed the heterogeneity of PTLD and the involvement of multiple anatomic sites. The significant manifestation of PTLD in the aerodigestive tract is impressive and may be related to the immunologic reactions in mucosa-associated lymphoid tissues (MALT) in these sites. In many transplantation centers, we consider EBV to be a crucial etiologic agent in the development of PTLD.  The emerging EBV-­ negative PTLD cases may warrant an investigation into other causal agents with different mechanisms of malignant transformation.

1.7

Tumors

Cardiac tumors are rare, although the exact incidence seems to be unknown. Several autopsy studies indicate a rate ranging from 0.0017% to 0.33%. In 90% of cardiac tumors in adulthood, myxomas and sarcomas play a contributive role, while in childhood, rhabdomyomas and fibromas comprise a vast majority of cardiac neoplasms (Figs. 1.61–1.63). Symptomatology of cardiac tumors is observed in four settings, including 1. Intracavitary growth causing either partial or occlusive obstruction of the blood flow

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Fig. 1.61  Cardiac myxoma in a patient with Carney complex. Carney complex includes spotty skin pigmentation, myxomas, endocrine overactivity, and other conditions. Carney complex is inherited as an autosomal dominant trait and is caused by mutation of the PRKAR1A gene in about two-thirds of the cases. Grossly, cardiac myxomas are pedunculated nodules or masses, often

attached to left atrial wall of the heart by a pedicle (a, b). Histologically, cardiac myxomas are endothelial cells in fibromyxoid matrix (c–e). Immunohistochemically, the tumor cells are mostly positive for S100 (f, g, ×200 as original magnification) and HLA-DR (h, ×100 as original magnification)

obstruction or interference with valvar functionality with different symptomatologies if the valves involved are atrioventricular or ventriculoarterial 2. Intramyocardial growth causing refractory arrhythmias, sudden cardiac death (SCD), and pericardial effusions up to tamponade 3 . Embolization with transient ischemic attacks (TIA), strokes, and scotomas

4. Systemic or constitutional symptoms, which may be quite variable Primary cardiac tumors may be detected as an abnormal finding of a chest x-ray or another imaging test performed for an unrelated reason. The more detailed anatomy and pathology of cardiac tumors are carried out using echocardiography, magnetic resonance imaging, and computed tomography.

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Fig. 1.62  Heart with fibrous hamartoma (a, hematoxylin and eosin staining, ×100 original magnification), fibroma (b, Movat pentachrome staining, 12.5 original magnifica-

tion), and immunohistochemical evidence of actin (c, antiactin immunostaining, avidin-biotin-complex, ×100), and evidence of elastic fibers (d, Elastic-Van Gieson, ×100)

1.7.1 Benign Tumors

cies, which are different in the lifespan from infancy to adolescence and adulthood. Moreover, some entities are also linked to genetic syndromes, and appropriate genetic counseling may need to be addressed. In infancy and childhood, rhabdomyoma, fibroma, and histiocytoid cardiomyopathy (also called Purkinje cell hamartoma) comprise a vast majority of cardiac tumors. In adulthood, ¾ of primary cardiac tumors are benign, and approximately half of these are myxomas, while the rest consists of lipomas, papillary fibroelastoma, and rhabdomyoma.

Cardiac disorders with neoplastic significance but also including tumorlike conditions with variable presentation and prognosis (e.g., recurrence) depending on size, localization, invasiveness, friability, growth rate, and histologic variety. Benign tumors of the heart can be classified as either cardiac specific or non-cardiac specific. The latter category comprises tumors that have a pattern similar to their counterparts in the body and will only be listed in this chapter. Some conditions need to be carefully distinguished from each other because morphology can remarkably be quite similar. An important differential diagnosis is the correct identification of fatty-appearing tumors of the heart, which include lipoma, fibrolipoma, lipomatous hypertrophy of the IAS, hemangioma, and rhabdomyoma. The differential diagnosis is crucial, and it is important to keep in mind the most frequent malignancies, including angiosarcoma, liposarcoma, synovial sarcoma, and the metastasis to the heart from malignan-

1.7.1.1 Myxoma • DEF: Most common primary cardiac tumor (~50% of all primary cardiac neoplasms) presenting with heart failure, stroke, and constitutional symptoms and harboring chromosomal abnormalities, variable DNA content, and microsatellite instability supporting the concept of neoplasm rather than a reactive process (Fig. 1.61). • EPI: Sporadic (~95%) and familial types (~5%): Carney or myxoma complex (skin pigmentation

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Fig. 1.63  Papillary fibroelastoma with the characteristic avascular branching papillae (a, e, hematoxylin and eosin staining; b, c, d, f, Masson’s trichromic stain)

with lentigines and blue nevi, calcifying SertoliLeydig testicular tumors, cutaneous myxomas, psammomatous melanotic schwannoma, myxoid fibroadenomas of the breast, pigmented adrenal cortical hyperplasia, pituitary hyperactivity, and neoplasms of the thyroid gland) caused by PRKAR1A  (protein kinase cAMPdependent regulatory type 1α) gene mutations. Sporadic (single, 40–60 years, ♂  ♀, left atrium in ~2/3, recur in 1/3). • GRO: Pedunculated tumor with irregular, nonhomogeneous lucencies on echo and divided

into two types – solid (smooth and lobular) and papillary (friable and irregular with organized thrombi) and heterogeneity (cut surface) with cysts, calcifications, necrosis, and hemorrhage. • CLM: Lepidic (Gr. λεπίς, scaly) cells (stellate cells with ovoid nucleus and ± distinct nucleoli and bulky eosinophilic cytoplasm with indistinct cell borders) singly, in cords or in pseudo vascular arrangement embedded in a gel-like mucopolysaccharide-­ rich stroma ± BV, extravasated RBC, recent and old hemorrhage, hemosiderin, calcifications (e.g., Gamna-­ Gandy bodies), and inflammatory cells ± heterologous component (columnar

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epithelium with or without glands, extramedullary hematopoiesis, and thymic tissue). • IHC: (±) Calretinin and vimentin. • DDX: Organizing thrombus (lepidic cells in cords or ring structures forming vessels) and myxosarcoma (invasion of the tumor stalk and substantial areas of hypercellularity, necrosis, and cellular atypia). • PGN: After surgery, possible recurrence (e.g., multicentric) and embolization risk and genetic counseling in the familial type.

1.7.1.2 Lipoma, Valve Fibrolipoma, and Lipomatous Hypertrophy of the Interatrial Septum (LHIAS) • Lipoma: Well-localized, encapsulated, yellow, spherical/elliptical, subendo-/subepi-/subpericardial or intramyocardial, anywhere, with cardiomegaly and dyspnea, made of mature fat cells ± fat necrosis and histiocytes (DDX: WD-lipoma-like LPS showing lipoblasts!). • Valve Fibrolipoma: Lipomatous “hamartoma” of the AV valve (properly neoplasm, because fat is not a standard component of the valve) with an admixture of mature fat cells, fibrosis, and thin-walled BV. • LHIAS: Unencapsulated dumbbell mass of the IAS  ±  cardiac hypertrophy and arrhythmias and constituted by mature and brown fat cells and degenerated entrapped cardiomyocytes that typically spares the fossa ovalis. 1.7.1.3 Papillary Fibroelastoma (PFE) and Fibroma Papillary Fibroelastoma • DEF: First most common valvular and second most common primary benign cardiac tumor, which presents as small, stalky, homogenous valvular mass on echo causing blood flow turbulence. It has been suggested to be an exaggerated form of Lambl excrescence. • EPI: Any age (~60 years), ♂ = ♀, with embolization risk (tumor or thrombus), usually ventricular surface of valves and the atrial surface of AV valves (R > L in children and R mitral>tricuspid>p ulmonary) or endocardium. • CLM: Three layers constituted by central fibroelastic stroma (+ EvG), outer myxoid, proteoglycan-rich matrix, and overlying hyperplastic endothelium (+ CD34/CD31/FVIIIRA). • DDX: Lambl excrescences (along with the lines of closure – nodules of Arantii – of cardiac valves), vegetations, and valvular myxomas (-EvG). • PGN: Conservatively (anticoagulants)/surgery with leaflet repair or valve replacement. Fibroma • DEF: The fibroma is the second most common pediatric primary cardiac tumor after rhabdomyoma with possible association with Gorlin syndrome or NBCCS (PTCH1 on 9q22.3, multiple BCC of the skin, jaw cysts, and bifid ribs, frequently discovered in utero or infancy (Fig. 1.63). • CLI: Large, noncontractile, solid mass with heterogeneity on echo mimicking HCM in a setting of heart failure, arrhythmias, SCD or incidentally. • GRO: Small-to-large, firm, white, well-­ circumscribed (nonencapsulated), or ­infiltrative mass of the free walls of the ventricles or IVS. • CLM: Fibromatosis-like appearance with spindle cells harboring a bland-looking morphology embedded in collagen (children: cellularity > collagen deposition; adults: cellularity < collagen deposition) ± scattered inflammatory cells and central dystrophic calcification. • HSS/IHC: (+) EvG, VIM, SMA, but B-cat (−). • DDX: fibromatosis (B-cat +), fibrosarcoma ((+) VIM, P53, Coll. Type 1, MIB1), synovial sarcoma (+) VIM, TLE1, CKs, EMA, Bcl2, β-Cat, CD99, CD56, CD57, CALR, SYT, ZO-1, Claudin-1, and occludin). Immunostaining for SYT and TLE1 proteins discriminates synovial sarcoma from other soft tissue tumors, because recent studies evidence that more tumors may have TLE1 positivity. Glandular component of

1.7 Tumors

most biphasic cases are also usually positive for ZO-1, Claudin-1, and occludin. • PGN: Surgery and no recurrence in partial resection; cardiac TX for unresectable lesions.

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(atypia, necrosis, mitoses, pericardial extension), lipoma, fibrolipoma. • PGN: Usually good with surgery but also spontaneous regression and regression after steroids.

1.7.1.4 Rhabdomyoma • DEF: Most common pediatric primary cardiac 1.7.1.6 Inflammatory Myofibroblastic Tumor tumor, which is associated with tuberous sclerosis (TSC1 on 9q34/TSC2 on 16p13), discov- • DEF: Rare tumor with obscure etiology (reacered in utero (e.g., stillbirth) or in the first year tive, autoimmunity, neoplastic), which presof life, often multiple, ± arrhythmias/valvular ents as a polypoid mass with a broad base, anomalies/LVOTO, but the tendency to sponattached to the endocardium and covered with taneous regression. fibrin as well as constitutional symptoms • GRO: Small, firm, gray-white, well-­ mostly in children and adolescents. circumscribed myocardial nodules/masses are • GRO: Circumscribed, not encapsulated whitprotruding into ventricular chamber. ish mass with whorled fleshy or myxoid cut • CLM: Mixture of large polygonal cells with surface and occasional foci of hemorrhage, glycogen-rich cytoplasmic vacuoles sepanecrosis, or calcification. rated by strands of cytoplasm radiating from • CLM: There is an admixture of myofibrocell center or nucleus (spider cells) in chilblasts, fibroblasts, and inflammatory cells in a dren prompting to the direction of a hamarmyxoid or poorly collagenous stroma without toma but + in adults indicating a benign significant pleomorphism and atypia. tumor. • IHC: (+) SMA, VIM, calponin, but (−) CD34 • IHC: (+)  PAS; ACT, DES, MGB, VIM; and ALK1 (differently from non-cardiac IMT). apoptosis-­ associated ubiquitin; HMB-45; • DDX: Fibroma (non-endocardial, calcificahamartin, tuberin; remarkably MIB1/Ki67 –. tion, whorls of bland-appearing homogeneous • PGN: Spontaneous regression or surgery if + fibroblast), fibrosarcoma (pleomorphism and symptoms (arrhythmias, valvular atypical mitoses), myxoma (no multinucleobstruction). ated syncytia or perivascular rings, CD34+). • PGN: Usually good with surgery but also spon1.7.1.5 Hemangioma taneous regression and regression after steroids. • DEF: Benign vascular neoplasm, which is usually localized at the right atrium or ven- 1.7.1.7 Paraganglioma tricular septum, ± association with other cuta- • DEF: Rare extra-adrenal pheochromocytoma, neous or visceral angiomas (diffuse which originates from paraganglia cells and angiomatosis) and may present with arrhythtypically found within the atrial walls mias, pericardial effusion, heart failure, and (Fig. 1.65). sudden cardiac death. • EPI: Third to fourth decade of life. • EPI: Any age, although more often seen in • CLI: Mass in the roof of the right atrium ± adults, ♂ > ♀. symptoms hyper-catecholaminemia (HTN, • GRO: 2–4 cm sessile or polypoid, red-purple headache, sweating, palpitations, and dysnodule. pnea) and positive 131I-MIBG scintigraphy • CLM: Capillary, cavernous, arteriovenous or (MIBG, metaiodobenzylguanidine). intramuscular pattern, which may also have • GRO: Soft, fleshy, tan-to-brown, poorly cirfat and fibrous tissue (Fig. 1.64). cumscribed mass with a broad base. • DDX: Epithelioid hemangioma/epithelioid • CLM: ‘Zellballen’ pattern constituted by nests hemangioendothelioma, angiosarcoma, of large polygonal epithelioid chromaffin cells

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Fig. 1.64  Cardiac angioma with a semisolid vascular mass (a, b) and histological evidence of proliferating blood vessels (c–h). In (f) is shown the immunohistochemical expression of CD31 (×50, original magnifica-

tion). In (g) is shown the immunohistochemical evidence of actin (×50, original magnification), and in (h) is shown the negative staining with antibody against calretinin, a mesothelial marker (×50, original magnification)

(+NSE, CGA, SYN) separated by sustentacular cells (+S100). • DDX: Other extracardiac locations of paragangliomas/pheochromocytoma • PGN: Usually good with surgery but potential local invasion and metastasis → malignancy.

1.7.1.8 Cardiac Hamartoma • DEF: Rare, disorganized overgrowth of mature cardiomyocytes with abnormal development of embryonic cellularity. • EPI: Any age, ♂ > ♀. • CLI: Arrhythmias or incidentally.

1.7 Tumors

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Fig. 1.65  Chemodectoma at the glomus aorticus showing (all figures are hematoxylin-eosin-stained). Chemodectoma has an appearance similar to the normal paraganglia with the tendency to form nests of 15–20

chief cells, which are arranged haphazardly within a moderately to very rich vascular stroma (a–h). Ultrastructural features include the presence of neurosecretory-like granules in the chief cells

• GRO: Small-to-large firm, pale white, poorly demarcated mass. • CLM: Haphazardly or herringbone/whorling organization of mature hypertrophic cardiomyocytes ± thick-walled BV, fibrosis, and fatty tissue.

• DDX. Myocardial infarction (healing or scars), hypertrophic CM (diffuse process), fibroma (fibroblasts and collagen), and rhabdomyoma (no spider cells). • PGN: Surgery with no recurrence.

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1.7.1.9 Histiocytoid CM (HICM)/ Purkinje Cell Hamartoma • DEF: It is a heterogeneous genetic mitochondrial disorder of cardiomyocytes. Although some controversy exists about the origin of HCM, it is being considered a first genetic CM according to AHA and not as a developmental anomaly of the atrioventricular conduction system, a multifocal tumor of Purkinje cells, or as a developmental arrest of cardiomyocytes. • EPI: Mostly infant (< 2 years) girls (♂  left).

1.7.3 Metastatic Tumors Cardiac metastases have been reported to be up to 100-fold more common than primaries. The heart may be reached by four different pathways, including direct extension from mediastinal neoplasms (per contiguitatem), hematological spread, intra-

1.7 Tumors Fig. 1.69 Cardiac angiosarcoma with gross features of invasion (a) and histopathologic features of malignant cells and proliferation of blood vessels (b–c). There is a high rate of mitotic figures

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Fig. 1.70  Pericardial synovial sarcoma with interlacing tumor cells. There is one fibrous type, spindle or sarcomatous cell, with relatively small and uniform morphology and one epithelial in appearance with a classical synovial sarcoma of biphasic appearance (a–b). Immunohistochemically, the tumor cells show positivity

for vimentin (c, ×200 original magnification), CD34 (d, ×200 original magnification), Bcl-2 (e, ×200 original magnification), CD99 (f, ×200 original magnification), actin (g, ×200 original magnification), but negativity for calretinin (h, ×200 original magnification)

1.8 Pericardial Disease

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Fig. 1.71  Supraaortic metastasis of a follicular thyroid carcinoma with infiltration of atypical thyroidal cells in a stroma

cavitary expansion from the IVC, and through lymphatics. The bronchial carcinoma is the most frequent secondary tumor of the heart. In order of frequency following lung carcinomas, there is carcinoma of breast, melanoma, lymphoma, leukemia, renal cell carcinoma, and choriocarcinoma. A secondary tumor may often involve the pericardium, be multifocal, or produce an intracavitary lesion. In children and adolescents, secondary tumors are extremely rare (Fig. 1.71).

1.8

Pericardial Disease

1.8.1 Non-neoplastic Pericardial Disease 1.8.1.1 Pericardial Sac Fluid Storage Through Frank Accumulation Through Tamponade 30–50  cc thin, transparent, straw-colored fluid ordinarily present in the pericardial sac with ­epicardium lining the myocardium of the heart and the proper pericardial layer on the heart.

Pericardial effusion can be: –– Serous: congestive heart failure, hypoproteinemia –– Serosanguinous: blunt chest trauma, CPR –– Chylous: lymphatic obstruction (benign or malignant) –– Cholesterol-rich: myxedema Hemopericardium rupture of heart or intrapericardial aorta following MI, dissecting aneurysm, or acute chest trauma. The factors underlying a hemopericardium in children and adolescents include chest wall PNET (Askin tumor), dermatomyositis, dissecting aortic aneurysm (thoracic), heart attack (acute MI), heart failure, heart surgery (post-surgery), heart tumors, heart wounds, iatrogenic (e.g., placement of central lines), renal failure, leukemia/lymphoma, pericarditis (following bacterial or viral infections), radiation therapy to the chest, recent invasive heart procedures (nonsurgical), systemic lupus erythematosus (SLE), and dysfunctional (underactive) thyroid gland.

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Tamponade occurs with the simultaneous or independent occurrence of either fluid accumulation > pericardial sac capacity and when the collection does take place rapidly. Tamponade can cause cardiac compression and SCD.  Pericardial effusion gives to the heart space, which is less than usual. Thus, the heart is unable to expand causing pump dysfunction. The fluid-filled pericardial sac can range from a few hundred ml to liter. Conversely, tamponade is filling with liquid in the sac but faster than effusion and more than emanation. Few hundred ml filled suddenly would induce a maladaptation of the heart, which decreases in contractility. In the end, the body goes into shock.

1.8.1.2 Pericarditis Currently, the most important and practical question about the classification of pericardial disease is the distinction between viral pericarditis and autoreactive pericarditis. While the autoreactive forms benefit of systemic and intrapericardial corticosteroid treatment, their use in viral forms remains currently contraindicated. Anatomic-pathologic classification has minor significance indeed. This classification includes fibrinous pericarditis, seen in the post-­myocardial infarct, rheumatic fever, trauma, uremia, ­radiation, SLE, and severe pneumonia characterized histologically by an intertwined mass of thin eosinophilic fibers or sizeable amorphous mass and clinically evidenced by a loud friction rub. It may resolve or become organized to produce adhesive pericarditis (cor villosum → “Panzerherz” of the German literature). Serous pericarditis is encountered in rheumatic fever, SLE, systemic scleroderma, tumors, uremia, virus, or TB. Histologically, there is mild inflammation of epicardial and pericardial surfaces with both acute and chronic inflammatory cells. In the suppurative (purulent) inflammation, bacteria, fungi, or parasites are the most common etiologic factors. The pathogenesis follows direct extension, hematogenous seeding, lymphatic spread, and iatrogenic seeding with potential fatal mediastinitis. A sequel of the purulent pericarditis is the constrictive pericarditis.

• Caseous pericarditis: TB. • Constrictive pericarditis: Idiopathic as a sequela of previous serous, fibrinous, or caseous pericarditis with eliminated pericardial space and substituted by a thick scar tissue of up to 10  mm in thickness with potential dystrophic calcification, causing encasement of the heart pump with restrictive mal-­ functionality (concretio cordis). The adhesion from the pericardial sac into the mediastinum is also a common event. The mal-functionality of the heart pump may induce hypertrophy and dilation of the heart according to the remaining free space and if the heart is not tightly adherent to the pericardium.

1.8.2 Neoplastic Pericardial Disease It is mostly associated with metastasis by small round blue cell tumors in childhood and youth.

1.9

Non-neoplastic Vascular Pathology

1.9.1 Congenital Anomalies 1.9.1.1 Arteriovenous Malformations An abnormal communication between arterial and venous systems (without passing through capillaries) that may be encountered in infancy, childhood, and youth. If the arterio-venous malformation (AVM) is large, it can induce heart failure. Apart from the natural forms, acquired forms include AVM as a result of penetrating injury, inflammatory necrosis, and aneurysmal rupture.

1.9.1.2 Berry Aneurysm The most common vascular malformation of cerebral vessels is at the polygon of Willis at the basis of the brain. They are called a berry aneurysm due to the shape and account for 95% of cerebral aneurysms. The rupture of berry aneu• Hemorrhagic pericarditis: Iatrogenic (post-­ rysms may cause SCD. Such a breach is a signifiopen heart surgery) or non-iatrogenic (TB or cant component of the etiologies of SCD and malignancy from the lung or breast). needs to be ruled out with a complete autopsy.

1.9 Non-neoplastic Vascular Pathology

Typically, berry aneurysm occurs at the bifurcation of major arteries.

1.9.1.3 Media Dysplasia Ehlers-Danlos (EDS) and Marfan syndrome (MFS) are multisystemic diseases. These diseases are genetically inherited and mainly affect the soft connective tissues. EDS is heterogeneous and characterized by hyperextensibility of the skin, atrophic scar, joint hypermobility, and tissue fragility. The etiology relies on mutations in genes encoding fibrillar collagens or collagen-­modifying enzymes. MFS is an AD-inherited disorder that affects the cardiovascular, ocular, and skeletal system. There are aortic root dissection, ectopia lentis, and bone overgrowth. Mutations in the FBN1 gene cause MFS, encoding the microfibrillar protein fibrillin-1 (Figs. 1.72, and 1.73).

1.9.2 Fibromuscular Dysplasia • DEF: Non-atherosclerotic, noninflammatory vasculopathy, which shows abnormal growth within the wall of an artery, mainly the renal and carotid arteries. Its pathogenesis is unknown. There is no necrosis, calcification, inflammation, and arteriosclerosis. Typically, FMD develops by 20–30  years of age and involves large- and medium-sized muscular arteries: renal, carotid, axillary, and mesenteric BVs. Microscopically, there is an unusual arrangement of cellular and extracellular elements of the wall, particularly media, with disorderly proliferation and distortion of the vascular lumen (Fig. 1.74). Six types are distinct, including: 1. Intimal fibroplasia, which is blurry from the proliferative stage of atherosclerosis but no discernible lipid deposition 2. Medial fibroplasia, characterized by “string of beads,” i.e., alternating stenosis (intimal fibrosis and medial thickening) and building of mural aneurysms 3. Medial hyperplasia characterized by an increase in cells of the tunica media 4. Perimedial fibroplasia, which involves fibrosis of outer half of the tunica media, being the inner portion regular – with cir-

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cumferential and uniform thickening of vessel and narrowing of the lumen of the blood vessel 5. Medial dissection with medial fibrosis and dissecting aneurysms 6 . Periarterial fibroplasia, which includes perivascular fibrosis and inflammation

1.9.3 Arteriosclerosis This process is not dissimilar from the adult pathology, but it does not seem to play any major role in pediatrics. The Mönckeberg arteriosclerosis refers to a medial calcific sclerosis with calcifications in media of medium to small arteries with no associated inflammation and potential ossification and rare in adolescents and youth. The cystic medial necrosis refers to an accumulation of amorphous material in the media often forming cysts or mucoid pools. We have a disruption of the structure of the tunica media by the appearance of small clefts filled with a slightly basophilic ground substance. The cystic medial necrosis is observed in Marfan syndrome and predisposes to vascular dissections. Pregnancy significantly augments the risk of vascular events. There is a several-fold higher risk of venous thromboembolism, myocardial infarction, and stroke than nonpregnant women of childbearing age. These risks are not minimal but extend for several months into the postpartum period and need to be known by the general practitioners. Aortic rupture and complications in pregnancy have been described in Marfan syndrome, Loeys-Dietz syndrome, EhlersDanlos syndrome, Turner syndrome, a bicuspid aortic valve (Fig. 1.75). On the other hand, aortic complications have also been reported in pregnant women without any other known risk factors and the risk of aortic dissection or rupture in pregnancy has been recently investigated (Kamel et al. 2016). These authors found that there is an absolute increase in the risk of aortic dissection or rupture attributable to pregnancy in ≈4 per million pregnancies. This data are helpful when counseling patients about the risks of pregnancy and when evaluating thoracal symptoms in pregnant or postpartum patients.

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Fig. 1.72  Genetics and histopathology of Ehlers-Danlos syndrome (EDS) with myxoid degeneration and fibrillar degeneration (a–b). EDS is a group of genetic connective tissue disorders with symptoms including loose joints, stretchy skin, and abnormal scar formation and complications including aortic dissection, joint dislocations, and scoliosis/osteoarthritis. Figure (c) shows the rupture of the

fibers by Movat pentachrome staining (×100, original magnification). Figures (d, e) show the rupture of the elastic fibers by Vierhoff staining (×50, original magnification). Figures (f, g) show the myxoid degeneration of the aorta using the Alcian Blue-periodic acid-Schiff special stain (f, ×100 original magnification; g, ×200 original magnification)

1.9 Non-neoplastic Vascular Pathology

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Fig. 1.73 Histopathology of Marfan syndrome with lacunae in the wall of the aorta (a, Hematoxylin and Eosin staining, ×50 and b, periodic acid-Schiff staining, ×100). An Ellis Van Gieson staining can show the differences between an aorta of a patient with Marfan syndrome (c, Ellis Van Gieson ×50 original magnification) and a normal age-matched control aorta (d, Ellis Van Gieson ×50

1.9.3.1 Vasculitides The vasculitides are presented here (Box 1.6).

1.9.4 Large-Vessel Vasculitis 1.9.4.1 Takayasu Arteritis • DEF: Chronic granulomatous arteritis involving media and adventitia accompanied with intimal fibrosis and fibrous thickening of the aortic arch and marked focal narrowing depending from the location from the origins

original magnification). Figure (e) shows a high magnification of the rupture of the elastic fibers (Ellis Van Gieson ×100 original magnification). Figure (f) shows the myxoid degeneration with accumulation of mucopolysaccharides (Alcian Blue-periodic acid-Schiff staining, ×100 original magnification)

Box 1.6 Vasculitides

1.9.4. Large-Vessel Vasculitis (Takayasu Arteritis, Horton Arteritis) 1.9.5. Medium-Vessel Vasculitis (Kawasaki Disease, Polyarteritis Nodosa) 1.9.6. Small-Vessel Vasculitis (Wegener Granulomatosis, EGPA or ChurgStrauss Syndrome, Microscopic Polyangiitis) Note: EGPA, Eosinophilic Granulo­ matosis with Polyangiitis.

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Fig. 1.74  Arterial fibromuscular dysplasia. The cartoon shows arterial fibromuscular dysplasia (a, b). Figures (c– e) show the fibromuscular dysplasia histologically (c, Hematoxylin and Eosin stain, ×12.5 original magnification; d, Hematoxylin and Eosin stain, ×50 original magni-

fication; e, Movat pentachrome stain, ×50 original magnification; f, Movat pentachrome stain, ×50 original magnification; g, Movat pentachrome stain, ×50 original magnification; h, Alcian Blue periodic acid-Schiff stain, ×50 original magnification). See text for details

1.9 Non-neoplastic Vascular Pathology

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Fig. 1.75  Dissecting aortic aneurysms in labor is a tragedy that occurs rarely. In a and b, the gross photographs of such a dissection are presented. Histologic microphoto-

graphs (c, d) show the dissecting aneurysms. Figure (e) shows the underlying causes of a dissecting aneurysms in labor

of the arch vessels to the distal aorta (Fig. 1.76). • EPI: Asian>Western, 15–45  years-old, ♂:♀ = 1:3, HLA-DR4 + (often). • EPG: Autoimmune. • CLI: Ocular disturbances, weakened pulses in upper limbs (“pulseless disease”), subclavian bruits, hypertension, syncope, hemiplegia

• IMG: Angiographically, the type I involves only the branches of the aortic arch, while the type IIa involves the ascending aorta, aortic arch, and its branches. The type IIb involves the ascending aorta, aortic arch, and its branches as well as the descending thoracic aorta. Type III affects the descending thoracic aorta, the abdominal aorta, and/or the renal

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Fig. 1.76  Vasculitis schema (a, b) and Takayasu aortitis shown with microphotographs (c–e: Hematoxylin and Eosin stain, ×40, ×100, and ×400 original magnification, respectively)

arteries, while type IV involves only the abdominal aorta and/or the renal arteries, and, finally, the type V, which is the most common type, has combined features of both types IIb and IV. Moreover, the optional involvement of

the coronary and pulmonary arteries is indicated as C+ and P+, respectively. • TRT: Glucocorticosteroids starting at a high dose and tapered over weeks and months and cytotoxic drugs (e.g., methotrexate and azathio-

1.9 Non-neoplastic Vascular Pathology

prine) as well as antitumor necrosis factor drugs such as infliximab. Surgery may be necessary to relieve blocked arteries or repair aneurysms. • PGN: Mortality rate is 5%, but complications include stenosis of blood vessels, myocarditis, pericarditis, endocarditis, heart failure, an aneurysm in the aorta, arterial hypertension, ischemic stroke or transient ischemic attack (TIA), myocardial infarct, and pulmonary artery dysfunction.

1.9.4.2 Horton Arteritis (Cranial Arteritis, Giant Cell Arteritis) • DEF: Chronic granulomatous arteritis with optional necrosis of medium and small arteries of the head and neck region with the destruction of the internal and external elastic laminae. • EPI: Western>Asian, elderly, ♂:♀  =  1:3, HLA-DR4 + (often). • EPG: Autoimmune. • CLI: Headache, scalp tenderness, jaw pain, visual loss, ↑ESR. • GRO: Hardening of the arterial segment in a temporal biopsy in 60% of patients. • CLM: Chronic granulomatous arteritis with giant cells (see definition). • TRT: Steroids. • PGN: Rapid remission with steroid therapy.

1.9.5 Medium-Vessel Vasculitis 1.9.5.1 Kawasaki Disease • DEF: Acute systemic vasculitis of unknown cause (Fig. 1.77). • SYN: Mucocutaneous lymph node syndrome. • EPI: In the USA, 19:100,000 children T) and coding region (A92T) of the human cardiotrophin-1 gene (CTF1) in patients with dilated cardiomyopathy. Hum Mutat. 2000;16(5):448. Ewing CK, Loffredo CA, Beaty TH.  Paternal risk factors for isolated membranous ventricular septal defects. Am J Med Genet. 1997a;71(1):42–6. PubMed PMID:9215767 Ewing CK, Loffredo CA, Beaty TH.  Paternal risk factors for isolated membranous ventricular septal defects. Am J Med Genet. 1997b;71(1):42–6. PubMed PMID:9215767 Faé KC, Drigo SA, Cunha-Neto E, Ianni B, Mady C, Kalil J, Goldberg AC. HLA and beta-myosin heavy chain do not influence susceptibility to Chagas disease cardiomyopathy. Microbes Infect. 2000;2(7):745–51. Familiari A, Morlando M, Khalil A, Sonesson SE, Scala C, Rizzo G, et  al. Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound: A Systematic Review and Meta-Analysis. Circulation. 2017;135(8):772–85. https://doi.org/10.1161/ CIRCULATIONAHA.116.024068. Epub 2016 Dec 29. Review. PubMed PMID:28034902 Fantel AG, Person RE. Involvement of mitochondria and other free radical sources in normal and abnormal fetal development. Ann N Y Acad Sci. 2002;959:424–33. Review. PubMed PMID:11976215 Feinstein JA, Benson DW, Dubin AM, Cohen MS, Maxey DM, Mahle WT, Pahl E, Villafañe J, Bhatt AB, Peng LF, Johnson BA, Marsden AL, Daniels CJ, Rudd NA, Caldarone CA, Mussatto KA, Morales DL, Ivy DD, Gaynor JW, Tweddell JS, Deal BJ, Furck AK, Rosenthal GL, Ohye RG, Ghanayem NS, Cheatham JP, Tworetzky W, Martin GR.  Hypoplastic left heart syndrome: current considerations and expectations. J Am Coll Cardiol. 2012;59(1 Suppl):S1–42. Review. Erratum in: J Am Coll Cardiol. 2012 Jan 31;59(5):544. PubMed PMID:22192720 Finsterer J. Histiocytoid cardiomyopathy: a mitochondrial disorder. Clin Cardiol. 2008;31(5):225–7. Review. PubMed PMID:18473377

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137 Thiru Y, Pathan N, Bignall S, Habibi P, Levin M. A myocardial cytotoxic process is involved in the cardiac dysfunction of meningococcal septic shock. Crit Care Med. 2000;28(8):2979–83. PubMed PMID:10966282 Thomas-de-Montpréville V, Nottin R, Dulmet E, Serraf A.  Heart tumors in children and adults: clinicopathological study of 59 patients from a surgical center. Cardiovasc Pathol. 2007;16(1):22–8. PubMed PMID:17218211 Thude H, Gerlach K, Richartz B, Krack A, Brenke B, Pethig K, Figulla HR, Barz D. No association between transmembrane protein-tyrosine phosphatase receptor type C (CD45) exon A point mutation (77C>G) and idiopathic dilated cardiomyopathy. Hum Immunol. 2005;66(9):1008–12. Tiago AD, Badenhorst D, Skudicky D, Woodiwiss AJ, Candy GP, Brooksbank R, Sliwa K, Sareli P, Norton GR.  An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy. Cardiovasc Res. 2002;54(3):584–9. Tidake A, Gangurde P, Mahajan A.  Gerbode Defect-A Rare Defect of Atrioventricular Septum and Tricuspid Valve. J Clin Diagn Res. 2015;9(9):OD06–8. https:// doi.org/10.7860/JCDR/2015/14259.6531. Epub 2015 Sep 1. PMID: 26500939; PMCID:PMC4606268 Tiret L, Mallet C, Poirier O, Nicaud V, Millaire A, Bouhour JB, Roizès G, Desnos M, Dorent R, Schwartz K, Cambien F, Komajda M.  Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study. J Am Coll Cardiol. 2000;35(1):29–35. Tsubata S, Bowles KR, Vatta M, Zintz C, Titus J, Muhonen L, Bowles NE, Towbin JA.  Mutations in the human delta-sarcoglycan gene in familial and sporadic dilated cardiomyopathy. J Clin Invest. 2000;106(5):655–62. PubMed PMID:10974018; PubMed Central PMCID: PMC381284 Turillazzi E, Fineschi V, Palmiere C, Sergi C.  Cardiovascular Involvement in Sepsis. Mediators Inflamm. 2016;2016:8584793. https:// doi.org/10.1155/2016/8584793. Epub 2016 May 18. PubMed PMID: 27293322; PubMed Central PMCID:PMC4887644 Turillazzi E, La Rocca G, Anzalone R, Corrao S, Neri M, Pomara C, Riezzo I, Karch SB, Fineschi V. Heterozygous nonsense SCN5A mutation W822X explains a simultaneous sudden infant death syndrome. Virchows Arch. 2008;453(2):209–16. https:// doi.org/10.1007/s00428-008-0632-7. PubMed PMID:18551308 Tynan D, Alphonse J, Henry A, Welsh AW.  The Aortic Isthmus: A Significant yet Underexplored Watershed of the Fetal Circulation. Fetal Diagn Ther. 2016;40(2): 81–93. https://doi.org/10.1159/000446942. Epub 2016 Jul 6. Review. PubMed PMID:27379710 Tynan MJ, Becker AE, Macartney FJ, Jimenez MQ, Shinebourne EA, Anderson RH.  Nomenclature and classification of congenital heart disease. Br Heart J. 1979;41:544–53.

138 Valtuille L, Paterson I, Kim DH, Mullen J, Sergi C, Oudit GY.  A case of lamin A/C mutation cardiomyopathy with overlap features of ARVC: a critical role of genetic testing. Int J Cardiol. 2013;168(4):4325–7. https://doi.org/10.1016/j.ijcard.2013.04.177. PubMed PMID:23684604 Van Praagh R, Bernhard WF, Rosenthal A, Parisi LF, Fyler DC. Interrupted aortic arch: surgical treatment. Am J Cardiol. 1971;27:200–11. Van Praagh R, David I, Van Praagh S.  What is a ventricle? The single-ventricle trap. Pediatr Cardiol. 1982;2:79–84. Van Praagh R.  Terminology of congenital heart disease. Glossary and commentary. Circulation. 1977;56:139–43. Van Praagh R.  The segmental approach to diagnosis in congenital heart disease. Birth Defects Orig Artic Ser. 1972;8:4–23. Vancura V, Hubácek J, Málek I, Gebauerová M, Pitha J, Dorazilová Z, Langová M, Zelízko M, Poledne R. Does angiotensin-converting enzyme polymorphism influence the clinical manifestation and progression of heart failure in patients with dilated cardiomyopathy? Am J Cardiol. 1999;83(3):461–2. A10 Villard E, Duboscq-Bidot L, Charron P, Benaiche A, Conraads V, Sylvius N, Komajda M.  Mutation screening in dilated cardiomyopathy: prominent role of the beta myosin heavy chain gene. Eur Heart J. 2005;26(8):794–803. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20(5):1262–75. Vranes M, Velinovic M, Kovacevic-Kostic N, Savic D, Nikolic D, Karan R.  Pregnancy-related aortic aneurysm and dissection in patients with Marfan’s syndrome: medical and surgical management during pregnancy and after delivery. Medicina (Kaunas). 2011;47(11):604–6. PubMed PMID:22286575 Wagoner LE, Craft LL. Singh B, Suresh DP, Zengel PW, McGuire N, Abraham WT, Chenier TC, Dorn GW 2nd, Liggett SB. Polymorphisms of the beta(2)-adrenergic receptor determine exercise capacity in patients with heart failure. Circ Res. 2000;86(8):834–40. Wang D, Shah KR, Um SY, Eng LS, Zhou B, Lin Y, Mitchell AA, Nicaj L, Prinz M, McDonald TV, Sampson BA, Tang Y.  Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths. Forensic Sci Int. 2014;237:90–9. https:// doi.org/10.1016/j.forsciint.2014.01.014. PubMed PMID:24631775 Wang DG, Fan JB, Siao CJ, Berno A, Young P, Sapolsky R, Ghandour G, Perkins N, Winchester E, Spencer J, Kruglyak L, Stein L, Hsie L, Topaloglou T, Hubbell E, Robinson E, Mittmann M, Morris MS, Shen N, Kilburn D, Rioux J, Nusbaum C, Rozen S, Hudson TJ, Lipshutz R, Chee M, Lander ES. Large-­scale identification, mapping, and genotyping of single-­nucleotide polymorphisms in the human genome. Science. 1998;280(5366):1077–82.

1  Cardiovascular System Wang ZJ, Reddy GP, Gotway MB, Yeh BM, Hetts SW, Higgins CB.  CT and MR imaging of pericardial disease. Radiographics. 2003;23(Spec):S167–80. Review. PubMed PMID:14557510 Webster WS, Abela D.  The effect of hypoxia in development. Birth Defects Res C Embryo Today. 2007;81(3):215–28. Review. PubMed PMID:17963271 Weigang E, Görgen C, Kallenbach K, Dapunt O, Karck M, GERAADA Study Group. German Registry for Acute Aortic Dissection Type A (GERAADA) – new software design, parameters and their definitions. Thorac Cardiovasc Surg. 2011;59(2):69–77. https:// doi.org/10.1055/s-0030-1250748. Review. PubMed PMID:21384302 Weitzman JB.  Electronic medical devices: a primer for pathologists. Arch Pathol Lab Med. 2003;127(7):814– 25. Review. PubMed PMID:12823035 Wenzel K, Felix SB, Bauer D, Heere P, Flachmeier C, Podlowski S, Köpke K, Hoehe MR.  Novel variants in 3 kb of 5′UTR of the beta 1-adrenergic receptor gene (−93C>T, −210C>T, and −2146T>C): −2146C homozygotes present in patients with idiopathic dilated cardiomyopathy and coronary heart disease. Hum Mutat. 2000;16(6):534. Williams J, Wasserberger J.  Crack cocaine causing fatal vasoconstriction of the aorta. J Emerg Med. 2006;31(2):181–4. PubMed PMID:17044582 Wilson PD, Loffredo CA, Correa-Villaseñor A, Ferencz C.  Attributable fraction for cardiac malformations. Am J Epidemiol. 1998;148(5):414–23. PubMed PMID:9737553 Witsch T, Stephan A, Hederer P, Busch HJ, Witsch J. Aortic Dissection Presenting as “Hysteria”. J Emerg Med. 2015;49(5):627–9. https://doi.org/10.1016/j. jemermed.2015.05.039. PubMed PMID:26272546 Wright C.  Cardiac surgery 2002: staged repair of hypoplastic left heart syndrome. Crit Care Nurs Q. 2002;25(3):72–8. PubMed PMID:12450161 Yogasundaram H, Hung W, Paterson ID, Sergi C, Oudit GY.  Chloroquine-induced cardiomyopathy: a reversible cause of heart failure. ESC Heart Fail. 2018;5(3):372–5. https://doi.org/10.1002/ehf2.12276. PubMed PMID:29460476; PubMed Central PMCID: PMC5933951 Yogasundaram H, Paterson ID, Graham M, Sergi C, Oudit GY. Glycogen storage disease because of a PRKAG2 mutation causing severe biventricular hypertrophy and high-grade atrio-ventricular block. Circ Heart Fail. 2016;9(8) pii: e003367. https://doi.org/10.1161/ CIRCHEARTFAILURE.116.003367. PubMed PMID:27496753 Yuan SM, Jing H. Palliative procedures for congenital heart defects. Arch Cardiovasc Dis. 2009;102(6–7):549–57. https://doi.org/10.1016/j.acvd.2009.04.011. PMID 19664575. Retrieved 2010-02-27 Zeman M, Sepši M, Vojtíšek T, Sindler M.  Suddenly deceased young individuals autopsied at the Department of forensic medicine, Brno  – analysis, Soud Lek. 2012;57(3):44–7. PubMed PMID:23057440

2

Lower Respiratory Tract

Contents 2.1

Development and Genetics

 141

2.2 2.2.1 2.2.2 2.2.3 2.2.4 2.2.5

 ysmorphology and Perinatal Congenital Airway Diseases D Foregut Cysts of Bronchogenic Type Agenesis, Aplasia, and Hypoplasia Pulmonis (Pulmonary Hypoplasia) CPAM and Congenital Lobar Emphysema Tracheal and Bronchial Anomalies Sequestrations and Vascular Anomalies

 145  146  148  148  151  152

2.3 2.3.1 2.3.2 2.3.3 2.3.4

Infantile and Pediatric NILD Neonatal Respiratory Distress Syndrome “Old” and “New” Bronchopulmonary Dysplasia (OBPD and NBPD) Atelectasis Cystic Fibrosis

 155  157  157  158  158

2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6 2.4.7

Infantile and Pediatric ILD Diffuse Lung Development-Associated ILD Trisomy 21 (Down Syndrome)-Associated ILD ILD Related to Other Chromosomal/Genomic Microdeletion Disorders Neuroendocrine Hyperplasia of Infancy (NEHI) Pulmonary Interstitial Glycogenosis (PIG) Surfactant Dysfunction Disorders Pulmonary Alveolar Proteinosis

 159  159  161  163  163  164  164  166

2.5 2.5.1 2.5.2 2.5.3 2.5.4 2.5.5 2.5.6 2.5.7 2.5.8 2.5.9 2.5.10 2.5.11

“ Adult” ILD of the Youth Diffuse Alveolar Damage (DAD) Cryptogenic Organizing Pneumonia (COP) Usual Interstitial Pneumonia/Pneumonitis (UIP) Nonspecific Interstitial Pneumonia/Pneumonitis (NSIP) Desquamative Interstitial Pneumonia/Pneumonitis Respiratory Bronchiolitis ILD Pulmonary Langerhans Cell Histiocytosis Lymphoid Interstitial Pneumonia/Pneumonitis (LIP) Hypersensitivity Pneumonia/Pneumonitis (HSP) Acute Eosinophilic Pneumonia/Pneumonitis Progressive Massive Fibrosis

 167  167  170  173  175  176  177  179  180  181  182  184

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_2

139

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140 2.6 2.6.1 2.6.2 2.6.3 2.6.4 2.6.5 2.6.6

Inflammation: Tracheobronchial Laryngotracheitis Acute Bronchitis Bronchial Asthma Pulmonary Hyperinflation Bronchiectasis Neoplasms

 184  184  184  184  188  189  189

2.7 2.7.1 2.7.2 2.7.3 2.7.4

I nflammation: Infectious (Pneumonia/Pneumonitis) Lobar Pneumonia Bronchopneumonia Interstitial Pneumonia Primary Atypical Inflammation (Pneumonia)

 190  190  191  193  193

2.8 2.8.1 2.8.2 2.8.3

I nflammation: Non-­infectious (Pneumonia vs. Pneumonitis) Aspiration and Chemical Pneumonitis Lipoid Pneumonia Diffuse Pulmonary Hemorrhagic Syndromes

 193  193  195  196

2.9

I nflammation: Infectious/Non-infectious Granulomatous/ Nongranulomatous Primary Pulmonary Tuberculosis Sarcoidosis Aspergillosis Others

 197  197  200  201  202

2.9.1 2.9.2 2.9.3 2.9.4

2.10  hronic Obstructive Pulmonary Disease of the Youth C 2.10.1 Chronic Bronchitis 2.10.2 Emphysema

 202  203  203

2.11 2.11.1 2.11.2 2.11.3

“ Adult” Pneumoconiosis of the Youth Silicosis Asbestosis Non-silico Asbestosis-Related Pneumoconiosis

 204  205  206  207

2.12 2.12.1 2.12.2 2.12.3

Pulmonary Vascular Disorders Pulmonary Congestion and Edema Pulmonary Embolism/Infarction Pulmonary Arterial Hypertension (PAH)

 207  208  208  210

2.13  ransplantation-Related Disorders T 2.13.1 A  cute Rejection 2.13.2 C  hronic Rejection 2.14 2.14.1 2.14.2 2.14.3 2.14.4 2.14.5 2.14.6 2.14.7 2.14.8 2.14.9

Pediatric Tumors and Pseudotumors Pulmonary Teratoma Inflammatory Myofibroblastic Tumor Pulmonary Hamartoma Pulmonary Sclerosing Hemangioma Pulmonary Carcinoid Lymphangioma-(Leo)-Myomatosis (LAM) Kaposiform Lymphangiomatosis Pleuropulmonary Blastoma Metastatic Tumors

2.15 “ Adult”-Type Neoplasms in Childhood/Youth 2.15.1 “Adult”-Type Preneoplastic Lesions 2.16 2.16.1 2.16.2 2.16.3

Pleural Diseases Pleural Effusions and Pleuritis Pneumothorax Neoplastic Pleural Diseases

 212  212  212  215  215  215  217  217  217  217  219  220  222  222  226  230  230  234  235

2.1 Development and Genetics

2.1

141

2.17

Posttransplant Lymphoproliferative Disorders (PTLD)

 237

2.18 2.18.1 2.18.2 2.18.3

 on-thymic Mediastinal Pathology N Anterior Mediastinal Pathology Middle Mediastinal Pathology Posterior Mediastinal Pathology

 240  241  242  242

Multiple Choice Questions and Answers

 242

References and Recommended Readings

 244

Development and Genetics

Lung development as endodermal derivate is central in the pathology of children and youth because the lung maturation is completed only after birth and precisely runs all through infancy until the age of 8 years. The acinus is the terminal respiratory unit. Parameters of lung maturity are the Wigglesworth coefficient and the radial alveolar count (Box 2.1). To study the lung maturity in open lung biopsies or babies who died during the pregnancy may be challenging. The collapsed lung specimen may jeopardize the proper evaluation. Moreover, many parameters may not be in line with the somatic growth. Effective and efficient criteria for the diagnosis of hypoplastic lungs have been searched for a long time. Wigglesworth proposed a coefficient considering his tremendous previous work in perinatal pathology. Wigglesworth focused on the ratio of lung weight to body weight and stated that this procedure is the most practical means of overcoming the intrauterine challenges. An LW/BW ratio (“lung weight/body weight”) ratio of ≤0.012 is generally associated with a reduction in alveolar number as indicated by the radial alveolar count (RAC) (vide infra). Wigglesworth and Desai considered appropriate to define lung hypoplasia in infants or fetuses with a gestational age CNS>skin>liver>kidney, but adolescents and youth may also been affected. It is debated how much is the lymphoproliferative process active in LYG. However, the current WHO criteria indicate that LYG is a distinct form of T-cell-­rich large B-cell lymphoma. Diagnostic criteria include (1) mixed mononuclear cell infiltrate composed of an angiocentric and angio-destructive formation of large and small lymphoid cells with often plasma cells and histiocytes and the fate to replace the lung parenchyma implementing a clearcut vascular infiltration and (2) variable cell population of T-cell-rich B-cell infiltration, which are CD20-(+) large B cells in a background of CD-3– (+) small lymphocytes. There are optional findings, although supportive, not often seen. They include necrosis of the cellular infiltrate with positivity for EBER (in situ hybridization for Epstein Barr virus or EBV RNA), multiple lung nodularity, skin involvement and CNS involvement. The WHO recommendation is that LYG is graded as 1, 2, or 3, according to the number of EBV-positive large B cells, being grade 1 containing  50 EBV+/HPF, while grade 2 between 5 and 50 EBV (+)/HPF. Treatment of LYG includes IFN α-2b for both classes 1 and 2, while DLBCL therapy is indicated for class 3 LYG.

2.5.9 Hypersensitivity Pneumonia/ Pneumonitis (HSP) • DEF: ILD with a specific immunologic reaction to inhaled agents (e.g., fungus, mold, ani-

182

• •

• •

mal proteins), often labeled according to the job of affected people (e.g., farmer’s lung, maple bark stripper’s disease, pigeon breeder’s disease), or to the etiologic agent (e.g., byssinosis, actinomycosis). SYN: Extrinsic allergic alveolitis. EPG: Combination of type III (immune complex)-associated hypersensitivity responsible for the acute inflammation features and type IV (cell-mediated)-driven hypersensitivity reactions accountable for the formation of granulomas. CLI: Essentially, two forms. Acute (substantial exposure): Severe dyspnea, cough, fever about 6 h after exposure and usually resolving in 12–18  h (self-limited), although continued exposure can lead to permanent damage (chronic ⇒ DILD  – chronic hypersensitivity pneumonia/itis). Chronic: Prolonged exposure to small doses and insidious onset of dyspnea and dry cough (restrictive lung disease) and characterized by “BIG”: 1. Bronchiolo-centric Interstitial pneumonia/ pneumonitis 2. (patchy, peribronchiolar, temporally syn chronized, with uninvolved lung parenchyma in between, with CD4  3  weeks lasting coughing, bloody expectorate, chest pain, or pain with breathing or coughing, failure to thrive, weight loss, fatigue, fever, night sweats, and chills. • GRO: Consolidation of the focus at the pulmonary areas where there is the most significant volume of air flow. • CLM: Slightly wavy or beaded bacteria, which are Gram+, ZN+, SS+, and AFB+ and located in the caseating granuloma, which is the hallmark lesion of tuberculosis (“soft tubercle”). The “hard tubercle” represents granulomas with a cellular center. Ghon focus: 1–1.5  cm gray-­ white inflammatory nodule seen at the periphery of the upper part of a lower lobe or lower part of upper lobe which becomes granulomatous and then centrally necrotic by the 2nd week and usually clinically silent. Conversely, the Ghon complex is a combination of primary lung lesion, draining lymphatics, and ipsilateral lymph node involvement. Occasionally, the primary focus may enlarge, erode into bronchi, giving rise to the satellite with bloodstream (miliary tuberculosis). The term “miliary” arises from the similarity to innumerable “millet seeds” observed on CXR in cases of tuberculosis dissemination. The term Ranke complex is reserved to a Ghon complex undergoing fibrosis and calcification. • DDX: Other granulomatous infections of the lung. • TRT: The most common medications used to treat tuberculosis include isoniazid, rifampin, ethambutol, and pyrazinamide. • PGN: Although rare in high-income countries, miliary dissemination may become a reality,

199

particularly in immunodeficient children. The increasing burden of pediatric TB in both foreign-­ born children and North America-­ born children of foreign-born parents suggests for more timely diagnosis of source cases. More effective and efficient screening of latent TB infection should be one of the primary tasks of the future. Typical mycobacteria (e.g., M. tuberculosis, M. bovis, M. leprae) are 3–5-μm-long bacteria, which may be slightly wavy or beaded. Conversely, atypical mycobacteria (e.g., Mycobacterium avium intracellulare) are somewhat longer and thicker. The identification of mycobacteria can be very time-consuming. It has been advised to use thick sections, screen for 20 min at 40× and focusing up and down. Secondary TB usually arises from reactivation of old primary lesions creating progressive pulmonary TB, tuberculous empyema, intestinal TB, in case of swallowing of aspirated material, or miliary seeding. Isolated distant organ involvement includes extrathoracic lymph nodes, meninges, kidneys, adrenal glands, bones, fallopian tubes, testis, and epididymis. Secondary TB is usually accompanied by fever, night sweats, weakness, failure to thrive, fatigability, and loss of appetite. As historical notes, Heinrich Hermann Robert Koch (1843–1910) was a German physician and microbiologist. He is at the basis not only of the tuberculosis, but he is still recognized for paving the basis of clinical microbiology using his four postulates, including 1) the need of the microorganism to be always present in every case of the disease; 2) the need of the isolation of the microorganism from a host containing the disease and ability to grow in pure culture; 3) the need to prove a causative role for the microorganism taken from pure culture ro induce disease after inoculation into a healthy animal; 4) the need to have the same disease and same microorganism in the inoculated animal as first isolated from the primary diseased host. The date of March 24, 1882 is recorded as a milestone in clinical microbiology because that day Robert Koch announced to the Society of Physiology in Berlin Physiological Society that he had discovered the cause of tuberculosis. His presentation

2  Lower Respiratory Tract

200

was followed by a scientific paper a few weeks later. His name is behind tuberculosis, cholera, and anthrax and received the Nobel Prize in Physiology or Medicine in 1905 for his research on tuberculosis.

Box 2.16 Sarcoidosis: Clinical Presentation and Tissue/Organ Involvement

1. 2. 3. 4.

2.9.2 Sarcoidosis • DEF: Multisystem-involving disease of unknown etiology (probably or possibly infectious) characterized by a frequent involvement of the lower respiratory tract with non-­ necrotizing granulomatous inflammation showing numerous clusters of epithelioid histiocytes, ↑ of B lymphocytes, polyclonal hypergammaglobulinemia, and CD4  >  CD8 rates. • SYN: Besnier-Boeck-Schaumann disease. • EPI: Children and youth (15–35 years), ♂  CD8 (5:1/15:1) on flow cytometry (BAL, bronchoalveolar lavage; FC, flow cytometry). • CLI: Several and different organs and tissues may be involved. Lungs are frequently involved. The involvement of the lower respiratory system may be the only manifestation in >1/2 of cases, CXR+ (interstitial infiltrates with hilar adenopathy), and TBB+ (non-necrotizing granulomatous inflammation) (Box 2.16) (TBB, transbronchial biopsy). The term “potato nodes” is sometimes used in this

5. 6. 7. 8. 9.

Cardio involvement Renal involvement Intestinal involvement Lung involvement (bilateral coalescent granulomatous areas with ↑ hilar LNs) Liver/spleen involvement LN involvement (non-necrotizing granulomatous lymphadenitis) Eyes involvement: uveitis Skin involvement: erythema nodosum Skeletal involvement: sarcoid arthritis

Notes: The mnemonic word CRI-LESS is useful to remember the various organs involved in this multisystem disease

•

•

• •

•

setting because of the striking enlargement of the lymph nodes observed on CXR or CT scans. LAB: ↓ T-cell-mediated immunity (CD8), ↑ T-cell activity of helper class (CD4), ↑ humoral immunity (↑ B cells, ↑ Ig-polyclonal) ⇒ BAL showing CD4 > CD8 (5:1/15:1) on FC. Serum: ↑ACE, hypercalcemia, hypercalciuria, (+) Kveim test. The Kveim test, NickersonKveim or aka Kveim-Siltzbach test is not usually performed because of the risk that certain infections, such as bovine spongiform encephalopathy, could be transferred during this test. GRO: Consolidation without caseous necrosis. CLM: Non-necrotizing granulomatous inflammation composed of tight clusters of epithelioid histiocytes, MNGC of Langerhans type, few lymphocytes, and tendency to locate in interstitium vs. airspaces, along lymphatics, ± granulomatous vasculitis, and tendency to progressively hyalinize but no caseous necrosis, which is typically seen in tuberculosis. Nodular sarcoidosis: Coalescence of large areas of hyalinized granulomas. DDX: Infection (special stains and culture for fungi), TB (special stains and culture),

2.9 Inflammation: Infectious/Non-infectious Granulomatous/Nongranulomatous

Mycobacterium avium intracellulare (special stains and culture), reactions to metals/minerals (clinical history, polarization field), hypersensitivity pneumonitis (loose granulomas with more cellular inflation), local sarcoid-­ like responses (as seen adjacent to neoplasms and in draining lymph nodes), Wegener granulomatosis (suppurative “dirty” necrosis with neutrophils and necrosis surrounded by palisaded histiocytes). • TRT: In Nathan’s study patient data were analyzed after a follow-up of 18  months and 4–5 years. In the   1  cm), inter 2.11.1. Silicosis stitial type (air penetration into the connective 2.11.2. Asbestosis tissue stroma of the lung, mediastinum, or sub 2.11.3. Non-silico-Asbestosis-Related cutaneous tissue), and the compensatory type Pneumoconiosis (pseudo-emphysematous dilatation of alveoli

2.11 “Adult” Pneumoconiosis of the Youth

and production occupations where silica exposure occurs. The 17 deceased adolescents and young people had an underlying or a contributing cause of death listed that indicated multiple drug use or drug overdose, but it does not seem that their talc-­related death was occupational because none was working or was exposed in talc exposure-­ associated jobs. Mesothelioma is rare cancer most commonly diagnosed in people in their 60s and 70s, but over 300 cases of mesothelioma have been reported worldwide in young adults, children, and even infants. There is plenty of literature that in most cases of mesothelioma diagnosed in childhood and youth, there is no clear-cut family or personal history of exposure to asbestos differently from the adult cohorts, but the publications are often missing a proper environmental incidental report. In fact, most exposures to asbestos

205

may come from the environment or exposure from fathers or mothers working in asbestos exposurerelated job companies and bringing the working dress home. Secondhand exposure from a parent who worked with asbestos is a very critical cause in mesotheliomas of childhood and youth. Moreover, asbestos is still present in schools, and environmental asbestos is still a significant burden today because children can breathe the air or play in or eat contaminated soil. Asbestos in toys such as chalk, crayons, and modeling clay may be an additional factor (Fig. 2.32).

2.11.1 Silicosis • Silica associated lung disease: SiO2 (e.g., quartz).

a

b

c

d

Fig. 2.32  Pneumoconiosis showing a schema of the silica involved pathogenesis (a) and microphotographs of silicosis of the youth, which is similar to the pneumoconiosis of advanced age. There is fibrous collagenous silicosis with hemosiderin-laden macrophages (b: Perls’ Prussian Blue stain, 40×; c: H&E, 20×; d: Periodic acid Schiff stain, 100×). The main steps of the iterative cycle of pneumoconiosis include direct cellular toxicity, production of reactive oxygen species (ROS), reactive nitrogen species (RNS), and inducible nitric oxide synthase, secretion of inflammatory and fibrotic mediators, lung remodeling through collagen and elastin deposition, and programmed cell death with release of indigestible silica. Freshly fractured elements of silica stimulate mitogen-activated protein kinase (MAPK) family members, as was proved by Ding et al. (1999) evidencing the phosphorylation of p38 MAPK and extracellular signalregulated protein kinases

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• Acute silicosis (“accelerated silicosis”): Heavy exposure over 1–3  years with a pulmonary alveolar proteinosis-like appearance with variable amounts of interstitial fibrosis. • Chronic silicosis: Pneumoconiosis following 20–40 years exposure to dust containing up to 30% quartz. Activities with mining, sandblasting, metal grinding, tunneling, and ceramics are at risk. There is a highly debated frame of progression with regards to the years after exposure and subsequent proliferation of hyalinized nodules and the reality is that there are individual and environmental factors that may play an important role. Chronic silicosis usually prefers the peripheral areas at the upper lobes. There may be variable amounts of black pigment (concomitant exposure to coal dust), well-delimited, concentric lamellated hyaline, with rare MNGC or granulomas and rare fields with necrosis. Finally, an expansion of the nodules with obliteration of the small airways does eventually occur. • CLM: Whorled laminar collagen with doubly birefringent refractile round particles (1–2 μm) and peripheral plasma cells ⇒ silicotic nodules ⇒ conglomeration (obliteration of the small airways), which is often responsible for the final lung insufficiency. • PGN: Complications  – TB (in average 20× increased risk to contract this infection; 10–30× relative risk as a common range in numerous institutions involving individuals of different age). In childhood, silicosis due to secondary exposure can occur and particularly among the children of mining communities in India. Unfortunately, malnourishment, tuberculosis, and silicosis are co-morbid conditions, especially in vulnerable populations like children who live close to stone mines. Important works of the American Academy of Pediatrics (AAP), Section on International Child Health (SOICH), in advocating more heath for children worldwide are key. Children are especially susceptible to silicosis from nonoccupational exposure in stone-mining areas where (a) communities are impoverished and have little access to modern medical facilities, (b) families live close to the workplace, and

casual child labor is common, and (c) mine owners do not take preventive measures. Although mine owners do not comply with legislation to protect the health and safety of workers, particularly in some geographical areas, the state continues ignoring this situation as the stone-mining industry generates much foreign exchange, and there is limited legislative protection for families from subsequent exposure.

2.11.2 Asbestosis Clinicopathologic diagnosis requiring histological confirmation with (1) diffuse interstitial fibrosis of the asbestosis type and (2) evidence of asbestos as the etiology (asbestos bodies). 1. Interstitial fibrosis of at least grade 3 or grades 1–2 with a typical distribution. Asbestosis typically manifests in the lower lobes with irregular “reticular” markings on CXR toward the lung periphery and involves the costophrenic angles with subpleural accentuation. 2. Asbestos bodies (AsBds): –– Identifiable when ferruginated as golden foreign bodies using PPB (Pearls Prussian Blue histochemical special stain) –– Located in the walls of the respiratory bronchioles and associated with intra-­ alveolar Mф –– Significance level when >1 AsBd in ≥1–5-μm-thick PPB-stained lung tissue section from ≥1 several FFPE lung tissue blocks (standard: 1 AsBd/100 sections; FFPE, formalin-fixed and paraffin-embedded) (it ­ has been proposed to have 30-μm-thick sections to reduce the time to find asbestos bodies, but it is not feasible at all times) –– Quantification also in BAL and TEM –– TEM evaluation: The reference values are roughly 1–2  ×  106 fibers·g−1 dry lung for total amphibole fibers and 0.1  ×  106 fibers·g−1 for amphibole fibers longer than 5 μm. –– Asbestos-related pleural plaques (macronodular and microscopic “basket-weave” collagen)

2.12 Pulmonary Vascular Disorders

–– Compensation is foreseen for asbestosis, diffuse pleural fibrosis, or asbestos-related neoplasm (malignant mesothelioma and any lung carcinoma). • DDX of asbestos-related pleural fibrosis include: –– Sarcomatoid mesothelioma –– Tuberculosis –– Connective tissue disorders –– Lung adenocarcinoma Interstitial fibrosis similar to UIP, beginning as peribronchiolar fibrosis, preferentially lower lobes, with pleural fibrosis/calcification, parietal pleural plaques. The grading of the severity is related to the fibrosis. • PGN: Progressive massive fibrosis and “new” Caplan syndrome. There is a ↑ risk of bronchogenic carcinoma  – risk relative to unexposed is 5× (relative risk for smokers, 11×; relative risk for smokers exposed to asbestos, 55×). Asbestos exposure increases unavoidably the risk for mesothelioma (both pleural and peritoneal), although the non-bronchogenic mesothelioma is still more rare than bronchogenic mesothelioma.

2.11.3 Non-silico Asbestosis-Related Pneumoconiosis Coal Workers Pneumoconiosis (CWP) Simple CWP does present after years of exposure to coal. Two definitions are useful. Dust macule is defined as interstitial dust-filled MΦ surrounding dilated respiratory bronchioles and in the interlobular septa, usually affecting the upper portions of lobes, with minimal fibrosis, while coal nodule is defined as discrete palpable  5 cm • Lack of pedicle (“non-pedunculated SFT”) • Hypercellularity accompanied by cellular pleomorphism and/or giant cells • Hyperdivision of the cells (high mitotic index with MI > 4/10 HPF) • Necrosis Notes: MI, mitotic index.

ers of cuboidal mesothelial cells without atypia histologically. It is important to emphasize here that the amphiboles are more carcinogenic than chrysotile asbestos properly in consideration of the next paragraph.

2.16.3.3 Malignant Mesothelioma • DEF: Malignant pleural mesothelial tumor (MPM). • EPI: Rare, diffusely infiltrating wall with thickening, rigidity, and luminal narrowing. • CLM: Conventional squamous cell carcinoma (SqCC): tumor cells showing cytological or tissue architectural features of squamous cell differentiation (e.g., keratin, tonofilament bundles, or desmosomes). The differentiation of the tumor toward squamous epithelium could be difficult to ascertain on routine histologic sections, and sensitive, specific markers of squamous differentiation may be required: p63 (nuclear) and CK5/6! • PGN: Extensive circumferential and/or longitudinal spread common due to rich lymphatic supply, but the prognosis is not bad if it is confined to the wall and 1/2 of the cases are prone to surgical excision. 5-YSR: 5–10% (overall). The high prevalence of Barrett metaplasia and esophageal SqCC in patients who underwent esophageal repair because of atresia has impor-

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a

b

c

d

e

f

Fig. 3.7  An extremely rare occurrence of an esophageal carcinoma in a young male is shown with the histologic features of poorly squamoid differentiation. All microphotographs are stained with H&E and have 40×, 100×, 100×,

200×, 200×, and 400× in (a–f), respectively, as original magnification. There is a high prevalence of Barrett esophagus (Barrett metaplasia) and esophageal squamous cell carcinoma after repair of esophageal atresia (see text)

tant implications for transition of youth from pediatric care to adult gastroenterology departments. These patients need to receive life-long endoscopic follow-up evaluation to pinpoint early diagnosis of preneoplastic lesions.

rare type of carcinoma, which rarely metastasizes. Spindle cell carcinoma (aka epidermoid carcinoma with spindle cells, pseudosarcoma, carcinosarcoma) is another variant with large ­ size, polypoid aspect, and relatively better prognosis than traditional SqCC and constituted by a predominant spindle cell stroma with similarity to MFH with possible heterologous differentiation (e.g., cartilage, bone, or skeletal muscle differentiation) and minimal epithelial component. IHC markers, including p63 and CK5/6 as well as pan-CK, are handy, particularly in children, to rule out regional soft tissue sarcoma, such as

Four major variants of squamous cell carcinoma of the esophagus are known. Verrucous carcinoma is a predominantly exophytic growth with spires of well-differentiated epithelium with minimal cytologic atypia, inconspicuous kerato-­hyaline granules, and chronic inflammation, pushing margins and slow growth. It is a

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mesenchymal chondrosarcoma, osteogenic sarcoma, or rhabdomyosarcoma, which are more often observed. Basaloid squamous cell carcinoma is a variant with highly aggressive behavior. Histologic sections show solid nests of large, hyperchromatic pleomorphic nuclei with scant cytoplasm and nuclear palisading at the periphery and central necrosis. Small cell carcinoma is a highly malignant variant, which is characteristically fungating in its gross appearance. Microscopically, there are solid sheets, nests, or ribbons of small round-oval hyperchromatic cells with speckled chromatin, indistinct nucleoli, nuclear molding, scant cytoplasm, and a diffuse infiltrative growth pattern. Adenocarcinoma Approximately 10% of esophageal carcinomas, mostly in white ethnics, ♂:♀ = 5:1, young-middle aged adults, 2/3 lower esophagus. Most of the cases arise in the setting of Barrett metaplasia and present as mass or nodule in the otherwise intact mucosa. Histologically, three types are recognized and the acronym “IDA” may be used for mnemonic purposes:

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3.3

Box 3.6 lists the categories of disorders we are going to deal in this chapter.

Box 3.6 Disorders of the Stomach

3 .3.1. Defects (Congenital and Acquired) 3.3.2. Vascular Changes 3.3.3. Inflammation 3.3.4. Metabolic and Degenerative Diseases 3.3.5. Tumors

3.3.1 Gastric Anomalies Box 3.7 summarizes the innate and acquired anomalies of the stomach (Figs. 3.8 and 3.9).

Box 3.7 Congenital and Acquired Anomalies of the Stomach

• Intestinal: as seen in the stomach or small/ large bowel • Diffuse: diffuse infiltration of mucin-­ producing cells (signet ring cell-like) • Adenosquamous: a mixture of squamous cell and adeno-Ca portions Esophagectomy indications in children and youth are Barrett esophagus with high-grade dysplasia, caustic-related stenosis/occlusion, and esophageal carcinoma. In some scientific literature HGD is a very controversial indication and a vivid debate exists. Other Tumors of the Esophagus Other malignant tumors include adenosquamous carcinoma, mucoepidermoid carcinoma, leiomyosarcoma, malignant melanoma, malignant lymphoma, and plasmacytoma. All of them have not been reported in detail or represent a rarity in childhood, although their occurrence in young adults has been occasionally observed.

Stomach

3 .3.3.1. Agenesis and Dystopias 3.3.3.2. Duplications (Cysts, Diverticula, Tubular Malformation) 3.3.3.3. Ectopia/Heterotopia (Gastric, Pancreatic, Salivary Gland) 3.3.3.4. Obstructive Disorders (Congenital and Acquired Hypertrophic Pyloric Stenosis) 3.3.3.5. Gastric Antral Vascular Ectasia 3.3.3.6. Acquired Anomalies with Dysmotility

3.3.1.1 Gastric Agenesis and Dystopias Gastric agenesis or gastric atresia (often antrum atresia) is an interruption of the continuity of the upper gastrointestinal tract that is extremely rare. Developmental defects with final obstruction or disruption of the continuity of the upper digestive tract include congenital pyloric stenosis, acquired pyloric stenosis, antral web, and pancreas heterotopia in the differential diagnosis.

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278 Celom / peritoneal cavity

a

Somatopleuric mesoderm

Dorsal mesentery Primitive gut tube

Retroperitoneal space

b

Splanchnopleuric mesoderm

c

d

e

f

Fig. 3.8  In (a) is a cartoon showing the elements that combined will form the diaphragma and the primitive gut. In (b) a cyst lining is shown (H&E stain, ×400), which is

CK7 positive (c) (×200), CK20 negative (d) (×50), low proliferative (Ki67) (e) (×50), and TTF, a marker of lung epithelium, positive (f) (×200)

3.3.1.2 Gastric Duplications Gastric duplications account for about 7% of gastrointestinal tract duplications. In a comprehensive review, most of the gastric duplications have been characterized as noncommunicating, spheric, or ovoid closed cysts. In the majority of cases, the most common site is the greater curvature. About the mucosal lining, this is usually gastric mucosa. However, both pseudostratified respiratory epithelium and pancreatic tissue have been reported. Bremer theory (1944) focuses on persistent vacuoles within the primitive foregut epithelium to explain the small gastric cysts, but McLetchie et  al. (1954) may be right indicating that large

duplications may be the result of faulty endoderm and notochord separation early in the human development. Clinically, most duplications present within early childhood with symptoms, including vomiting and abdominal pain. However, infants are frequently asymptomatic and are discovered to harbor such disease later in life.

3.3.1.3 Ectopia/Heterotopia Ectopic/heterotopic tissue may mean gastric antral mucosa in other regions of the stomach, which do not usually have antral mucosa (e.g., body), pancreatic tissue, and salivary gland tissue. Heterotopic pancreas is quite common and observed in 1–2%

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a

b

c

d

e

f

Fig. 3.9  In (a) is shown two trichobezoars, which are intraluminal accretions of ingested hair. While trichobezoars are a rare entity, they occur in children and psychiatric patients. They may present with significant complications, such as obstructions and perforations. In consideration of the infection risk and considerable size of many of these bezoars, an open removal is a safe proce-

dure. In (b) is shown a biopsy with Menetrier disease (H&E stain, ×100). In (c) (H&E stain, ×100) hyperemia is seen with intact mucosa and no necrosis, which conversely present in (e, f) showing hemorrhagic necrosis (H&E stain, ×100). In (d) is a singular case of pancreas heterotopia in a stomach (H&E stain, ×40). Pancreas heterotopia is a rare cause of gastrointestinal bleeding in children

of the general population. Grossly, there is a domeshaped mass (Ø: 1–2 cm), nipple-like projection, or symmetric cone. Microscopically, the heterotopic pancreatic tissue is found in 75–85% of the cases in the submucosa and 15–25% in the muscu-

laris propria with about 2/3 located in the antrum and about 1/4 of cases in the pylorus. It is constituted by exocrine tissue only in about 2/3 of cases, while endocrine pancreas (islets) are present in the remaining 1/3 of cases.

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3.3.1.4 Obstructive Disorders Obstructive disorders include both congenital and acquired hypertrophic pyloric stenosis. Congenital hypertrophic pyloric stenosis (CHPS) is a familial malformation, which is seen in 1/300–900 live births with a male preponderance (♂:♀  =  4:1) and most commonly observed in firstborn infants. CHPS is characterized by hypertrophy and hyperplasia of the circular muscle of the muscularis propria of the pylorus region. Infants with CHPS present with regurgitation and vomiting in the 2nd or 3rd week of life. In contrast, acquired pyloric stenosis is a longterm complication of chronic antral gastritis and/ or peptic ulcer disease and may be seen in subjects with disabilities and abnormal development of the nervous system. The acquired form of pyloric stenosis can also be seen in carcinomas of the pylorus, head of the pancreas, or malignant lymphomas, particularly Burkitt lymphoma. An unusual situation is a condition determined by bezoars, trichobezoar, and Rapunzel syndrome. Infants and children may acquire the practice of ­swallowing foreign material, which if it persists may lead to bezoars in the gastrointestinal tract, usually the stomach and rarely small intestine. This habit may mainly be present in infants and children with the psychosocial delay or mentally disturbed. The syndrome was named after the maiden in the Grimm brothers’ fairy tale of 1812. Rapunzel’s long hair allowed her to flee out of prison being rescued by her prince. The underlying psychiatric disorder in young females is trichophagia and is more frequent than in children or infants (Gr. θρίξ “hair” and -φαγία from φαγεῖν “to eat”). There is often a history of trichotillomania, which is characterized by recurrent pulling out of their hair, increasing sense of tension before pulling out, and relief or pleasure following the action (obsessive-compulsive behavioral disorder). The site is usually scalp, but also eyelashes, eyebrows, pubic area, or other parts of the body. Trichobezoars make up to 55% of all bezoars, but the foreign material may be vegetable or any other substance. In all situations of trichobezoars, strands of swallowed hair extend as a tail through the duodenum beyond the stomach. The typical presentation is an obstruction of the gastrointesti-

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nal tract with nausea and vomiting, gut perforation, acute pancreatitis with potentially life-threatening necrosis of the pancreatic parenchyma, obstructive jaundice, hypochromic anemia, vitamin B12 deficiency, weight loss, or an abdominal mass causing pain or discomfort. The abdominal mass is usually well defined and exquisitely mobile; in the majority of cases, it may calcify at the edges and may be indented (“Lamerton sign”). Laparoscopic removals are adequate for small bezoars, but open surgery is the first choice for the removal of large trichobezoars. Psychological support may be productive. Some patients may respond well to fluoxetine or other serotonin reuptake inhibitors, and the prognosis remains excellent if trichophagia can be controlled.

3.3.1.5 Acquired Anomalies with Dysmotility Dysmotility may be the primary symptom of acquired anomalies, and studies of physiology should be carried out promptly to address the patient correctly.

3.3.2 Gastric Vascular Changes Vascular processes include a short number of conditions that are summarized below (Box 3.8).

Box 3.8 Abnormal Vascular Conditions of the Stomach

3.3.2.1. Hyperemia 3.3.2.2. Gastric Antral Vascular Ectasia

3.3.2.1 Hyperemia It refers to the passive or active congestion of the blood vessels of the stomach, and one of the most frequent conditions is passive congestion due to backflow from the supragastric organs. 3.3.2.2 Gastric Antral Vascular Ectasia Gastric antral vascular ectasia is very rare in youth, but genetic syndromes may be a predisposing factor.

3.3 Stomach

• DEF: Distinctive pattern of gastric changes with an associate distinctive endoscopic appearance. • SYN: Watermelon stomach (from the endoscopic appearance). • CLI: >40  years, but younger patients have been reported, ♂ 2/3 pits) ◦◦ Metaplasia (present/absent) ◦◦ Atrophy (present/absent) ◦◦ Helicobacter pylori (Hp) (present/absent) and density (+/++/+++)

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a

b

c

d

e

f

g

h

Fig. 3.10  In (a) is shown septic shock erosive gastritis. In (b) is shown a stress-ulcerative gastroduodenitis in a 1-year-old patient affected with hypoplastic left heart syndrome who underwent a series of palliative cardiac surgical procedures. In (c, d), there is evidence of a chronic, active Helicobacter pylori gastritis with lymphofollicular hyperplasia (c, H&E stain, ×200; d, H&E stain, ×100)

with identification of the bacteria using Giemsa stain (e) and Warthin-Starry stain (f) at ×630 as original magnification. In (g, h) are two microphotographs of a C (chemical)gastritis with impressive edema of the interstitium and retronuclear vacuoles in a young patient with NSAID exposure (g, H&E stain, ×100; h, H&E stain, ×400)

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a

b

c

d

e

f

g

h

Fig. 3.11  In (a) is a focally enhanced gastritis (FEG) in a patient with Crohn disease, while (b) shows a erosive Crohn gastritis. FEG is more frequently found in patients with Crohn disease than patients with ulcerative colitis. In (c) is shown a granulomatous gastritis in a patient with Crohn disease. In (d) is shown a lymphocytic gastritis. In

(e) is shown an autoimmune gastritis with CD8 attack of the glandular epithelium (f) (Anti-CD8 immunohistochemistry). In (g) is shown an eosinophilic gastritis, while in (h) there is a gastric ulcer with regenerative hyperplasia (H&E stain for all apart f, ×200, ×200, ×200, ×100, ×100, ×400, ×200, ×200 as original magnification)

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Box 3.10 Classification of Chronic Gastritis

Type A, aka autoimmune gastritis, which involves mainly fundic mucosa with usually sparing of the antrum and patients harboring circulating antibodies to parietal cells and/or intrinsic factor, common hypo-/achlorhydria, loss of parietal cells due to the autoimmune destruction, and hypergastrinemia. In 10% of adults, it may develop pernicious anemia after several years. A-Gastritis is associated with other autoimmune disorders (Hashimoto thyroiditis, Addison disease). Type B, aka nonimmune gastritis, which is associated with Helicobacter pylori infection and does not have associated parietal cell antibodies or pernicious anemia. Intestinal metaplasia may be present but does not show any bacterium on the surface epithelium.

•

• •

• Hypersecretory subtype: Antrum-­ • restricted, minimal fundic atrophy, hyperacidity with often duodenal ulcers, and normal gastrin levels. • Environmental subtype: Fundus and antrum-involving inflammation with a strong association with atrophy, metaplasia, and carcinoma. Type C, aka chemical gastritis, caused by bile reflux has a characteristic appearance like NSAIDs or alcohol-related gastritis. Bile reflux should be probably considered a promoter of gastric carcinogenesis in the postsurgical stomach and an appropriate follow-up is required.

3.3.3.3 Specific Gastritides Lymphocytic Gastritis • DEF: Morphologic endpoint of gastritis with several and different etiologies characterized by an increase of IELs  >  25/100 epithelial cells in the surface and upper foveolar epithelium (consecutive fields read using a 400× magnification: ocular ×10 and objective ×40)

without taking into consideration any increase of inflammatory cells of the lamina propria, which should be assessed as nonspecific. CLI: Endoscopically, the stomach may exhibit varioliform appearance, nodularity, hypertrophic folds, and aphthous erosions. EPG: Infection (e.g., Hp), celiac disease, autoimmune. CLM: IELs are not difficult to count because their nuclei are smaller than the nuclei of the epithelial cells and scant cytoplasm is seen. The inflammatory glandular involvement, i.e., glands containing inflammatory cells, should also be counted of a fixed total number of superficial glands and calculated as percent rate of the involved glands (optional). Moreover, the distribution and number of lymphoid aggregates differentiating between the presence and not germinal centers in the antrum should be provided in the final pathologic report. IHC: Monoclonal antibodies against CD8 (T lymphocytes, mostly suppressor/cytotoxic) and CD20 (B lymphocytes) are useful to evaluate the cellular and humoral immune response, respectively. CD8+ cells are characteristically higher in GSE-associated LG than Hp gastritis. Additional optional staining may include monoclonal antibodies against CD4 (T lymphocytes, mostly helper). CD57 (NK lymphocytes) and CNA42 (follicular dendritic cells), although they are not particularly useful, because NK activity is negligible in both Hpand GSE-associated gastritis and the process of antigen presentation occurs in the lymph node.

It is essential to remind in this setting some pearls and pitfalls. In particular, the dominant cytokine response to Hp and GSE has a T-helper 1 (Th-1)-type profile. The pathogenetic relationship between three conditions associated with inflammation of the stomach, including Hp gastritis, the gastric involvement of celiac disease, and lymphocytic gastritis, is still not completely clarified. Gastric Hp presence does attenuate duodenal lesions of celiac disease patients. In pediatric patients, LG has CD3, CD7, and CD8 (+) IELs, while Hp gastritis has CD3, CD4 (+)

3.3 Stomach

IEL, and prominent lymphoid aggregates with an increased number of mononuclear cells (B and T lymphocytes, plasma cells, MΦ, and mast cells) in the lamina propria. B-cell proliferation is driven by activated T lymphocytes (CD4+) that progressively activate mononuclear phagocytes. In young patients with detection of Hp and suspicion of atypical celiac disease (negative serology with increased IELs and normal villous-to-crypt ratio – Marsh I) with a differential between gastric involvement of celiac disease and Hp-caused gastritis, two factors may play a significant role, including the number of CD8+ IELs in the antrum and the number of lymphoid follicles. The first would point to a gluten-sensitive enteropathy with gastric involvement, while the latter would direct toward the infective etiology. Granulomatous Gastritis Gastritis with granulomas is usually observed in Crohn disease but also in sarcoidosis or as an isolated disorder or following an infectious disease, such as TB and mycosis. The inflammatory involvement may extend beyond the borders of the muscularis mucosae. Eosinophilic Gastritis Gastritis with infiltration of the mucosa and sometimes submucosa by numerous eosinophils usually targeting the distal stomach and proximal duodenum with or without necrotizing vasculitis and probably allergic reaction to the ingested material. Currently, an average density of ≥127 eosinophils/ mm2 in ≥5 separate fields (≥30 peak eosinophils/400× HPF) in gastric biopsies with no known causes of eosinophilia has been proposed for the definition of histological eosinophilic gastritis. In case of small biopsies, three separate fields may suffice to the diagnosis of eosinophilic gastritis. Also, an abnormal eosinophil localization in the surface or foveolar epithelium, muscularis mucosae, or submucosa in the presence of (1) mucosal damage (e.g., foveolar hyperplasia), (2) architectural distortion, and (3) significant chronic ­(lymphocytic/lympho-­plasmacellular) or active (neutrophilic) inflammation has also been advocated as essential clues for the diagnosis of eosinophilic gastritis (Caldwell et al. 2014).

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Helicobacter heilmannii Gastritis It is a rare form of bacterial gastritis caused by H. heilmannii (previously known as Gastrospirillium hominis), which can be found in primates, cats, pigs, and carnivorous mammals. A transmission to humans usually occurs from domestic animals (Box 3.11).

Box 3.11 Helicobacter heilmannii Versus Helicobacter pylori

H. heilmannii: long and straight (4–10 μm × 0.5–0.9 μm) bacterium with a corkscrew morphology usually not attached to the surface epithelium H. pylori: short and narrow (3.5 μm × 0.5– 1.0  μm) bacterium with a curvilinear, “seagull” morphology, usually attached to the surface epithelium

• EPI: Rare in children (0.3–0.4 of children undergoing esophago-gastro-duodenoscopy (EGD) ≠ H. pylori gastritis, which is up to 9% using such procedure). • CLI: Symptoms are similar to those of H. pylori gastritis and include epigastric abdominal pain, with or without nausea and vomiting, heartburn, dysphagia, and acute upper GI bleeding. Endoscopy shows antral erythema, thickened folds, gastric erosions, gastric and duodenal ulcers, esophagitis, and micronodular transformation of the antrum. • CLM: Mild chronic gastritis, conversely from H. pylori, only occasionally causes peptic ulceration, gastric carcinoma, or MALT lymphoma. There is chronic gastritis with lymphoplasmacytic infiltrate, foveolar hyperplasia, vasodilation, edema of the lamina propria, an increase of the intracytoplasmic mucin of the epithelium, and occasionally foci of active inflammation with neutrophils. The microorganism may be detected by histochemical special stains (HSS) other than the routine hematoxylin and eosin (H&E) staining.  HSS include Giemsa (for bacteria), Warthin-Starry or other silver stains, and cresyl violet stains. Immunohistochemistry can also be used and

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several centers use the same polyclonal antibody used to detect H. pylori (cross-reactivity), which is linked to a rapid urease test (+). Finally, sub-specific characterization using FISH and partial 16S ribosomal DNA sequencing has been used. • TRT: H2 blockers or PPI and two antibiotics of choice (clarithromycin, amoxicillin, and metronidazole) or bismuth compounds.

• •

•

3.3.4 T  issue Continuity Damage-­ Related Gastric Degenerations The lesions recognized under the umbrella of the degenerations related to the tissue continuity damage are described in Box 3.12.

3.3.4.1 Gastric Ulcers Stress Ulcers • DEF: Multiple small lesions, mainly gastric (sometimes duodenum) with shedding of the superficial epithelium to full-thickness ulceration occurring in the setting of “severe stress,” e.g., shock, sepsis, severe trauma, etc. • ETP: There are three typical ulcers, including: –– Cushing ulcers: ↑ intracranial pressure with ↑ vagal tone and ensuing ↑ acid secretion –– Steroid ulcer: following steroid use –– Curling ulcers: following extensive burns Peptic Ulcers • DEF: Chronic, usually solitary lesion (80%) occurring at any level of GI tract exposed to acid-peptic juices with preferred sites: first

Box 3.12 Tissue Continuity Damage-Related Degeneration

3.3.4.1. 3.3.4.2. 3.3.4.3. 3.3.4.4.

Ulceration Hyperplasias Metaplasias Metabolic/Degenerative (Amyloi­ dosis, Hemochromatosis) 3 .3.4.5. Dysplasias

•

portion duodenum (~80%), antrum of the stomach (~20%), but also Barrett metaplasia and Meckel diverticulum. EPI: ♂:♀ = 3:1 (duodenal); 1.5–2:1 (gastric). CLI: Nearly all patients experience pain after eating, concurrent chronic antral gastritis (e.g., Helicobacter pylori gastritis), ↑ of both the basal and stimulated level of acid secretion, and fast gastric emptying. GRO: Oval, sharply delimited defect with a tendency for overhanging mucosal margins with minimal if any heaping up of margins (≠ in carcinoma) with gastric folds radiating out from an ulcer. PGN: Remitting and relapsing course. Fatal in 5% (e.g., perforation → bleeding → hemorrhagic shock → death). 1–3% will develop gastric cancer (adenocarcinoma).

3.3.4.2 Gastric Hyperplasia It is a condition, which is neither hypertrophic nor inflammatory but hyperplastic. It corresponds to giant, cerebriform enlargement of the rugal folds, and radiographically, it can be easily confused with malignant lymphoma. Menetrier Disease • DEF: Hyperplasia of the surface mucous (foveolar) cells with tortuous, corkscrew cystic dilatation extending to the base of the glands with two different gastric patterns, including: 1. Polyadenomes polypeux (probably equivalent to multiple hyperplastic polyps) 2. Polyadenomes en nappe, which genuinely corresponds to Menetrier disease • SYN: Hypertrophic/hyperplastic gastropathy, giant hypertrophic gastritis, giant hypertrophy of gastric rugae. • ETP: Unknown, idiopathic. • CLI: Hypochlorhydria (chronic and severe) and chronic protein loss ⇒ hypoproteinemia. It is usually progressive with gastric antrum typically uninvolved and presenting with nausea, anorexia, epigastric pain, and diarrhea. • GRO: Marked proliferative change with zenith along the greater curvature and characterized by markedly hypertrophic, gyri-like rugae

3.3 Stomach

with almost pathognomonic lack of antral involvement. • CLM: Histological triad including: 1. Foveolar hyperplasia, with tortuous pits, some degree of cystic dilatation, and extension into the base of the glands or occasionally even beyond the muscularis mucosae 2. Atrophy of the underlying secretory (glandular) component (mild to moderate) 3. Edema and inflammation of the surrounding stroma • DDX: Malignant lymphoma, carcinoma. • PGN: It harbors a slightly increased risk of carcinoma. Zollinger-Ellison Syndrome • DEF: Hyperplasia of the glandular cells with parietal cells tending to overwhelm the chief cells and potential proliferation of the enterochromaffin-­ like cells secondary to gastrin-­secreting tumor due to MEN-I (1/5 of cases) (gland lumen size is average; no cyst formation). • SYN: Hypertrophic hypersecretory gastropathy. • CLI: Hyperchlorhydria ± hypergastrinemia with two variants (“protein-losing” mimicking Menetrier disease and n­ on-protein-­losing with a more characteristic histology pattern as described above).

3.3.4.3 Metaplasias • Pyloric Metaplasia: Age-dependent fundic gland mass ↓ and replacement by pyloric glands. • Ciliated Cell Metaplasia: Replacement by mucosa with ciliated columnar cells. • Intestinal Metaplasia: Replacement by mucosa with goblet cells, absorptive cells, Paneth cells, etc. Both may be either complete or incomplete: –– Complete (type I): Sialomucin predominates (goblet cells). –– Incomplete (type II): No absorptive cells, but gastric foveolar cells retained. • Type IIA: Foveolar cells contain neutral mucins.

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• Type IIB: Foveolar cells contain sulfomucins. • If IM is of incomplete type, special stains are needed to detect the different staining properties of the mucins (e.g., Alcian PAS and Alcian 2.5).

3.3.5 Gastric Tumors Gastrointestinal (GI) tract malignancies are an infrequent diagnosis in childhood, and less than 5% of pediatric cancers account for this kind of malignancy in the USA and Canada as well as in the most industrialized countries (Box 3.13) (Figs. 3.12, 3.13, 3.14, and 3.15).

3.3.5.1 Benign Epithelial Neoplasms Polyp: Any lesion that projects into the gastric lumen above the plane of the mucosa. Gastric polyps are identified in ~5% of upper endoscopies of combined children and adults, although the finding of gastric polyps in children is relatively low. Gastric polyps can be classified histogenetically according to the cell of origin in epithelial, mesenchymal, lymphoid, and miscellaneous. Epithelial polyps may be subclassified in fundic gland polyp, hyperplastic polyp, adenoma, neuroendocrine tumor, polyp or polypoid carcinoma, and polyp or polypoid metastatic carcinoma. Some tumors are increasingly identified in children and young adults, because of the screening due to genetic or familial diseases to detect dysplasia at an early stage. From the statistical point of view, hyperplastic polyps are the

Box 3.13 Gastric Tumors

3 .3.5.1. Benign Epithelial Neoplasms 3.3.5.2. Malignant Epithelial Neoplasms 3.3.5.3. Neuroendocrine Tumors 3.3.5.4. Lymphoepithelial Lesions 3.3.5.5. Stroma Tumors and Smooth Muscle Differentiating 3.3.5.6. Nonstroma/Smooth Muscle Dif ferentiating Mesenchymal Tumors 3.3.5.7. Secondary Tumors

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a

b

c

d

e

f

g

h

Fig. 3.12  In (a) is shown a fundic gland polyp. In (b) is shown a hamartomatous polyp. In (c, d) are shown two microphotographs of a hyperplasiogenic polyp of the stomach, while (e–g) show low-grade dysplasia of a tubu-

lar adenoma of the stomach with hyperchromasia of the nuclei, pseudostratification of the nuclei, and decrease of mucus cells. In (h) is shown an inflammatory cardia polyp of the stomach

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a

289

b

c

d

e

f

g

h

Fig. 3.13  This panel illustrates a gastric teratoma with the presence of neuroblastic tissue (a, imaging; b, gross photograph). In (c) is shown a site of membranous ossification, while (d) shows neuroepithelium of a primitive tube (immature teratoma). Pseudostratified ciliary epithe-

lium and choroidal plexus are shown in (e, f). The microphotographs in (g, h) show neuroectodermal tissue portend to a diagnosis of neuroblastoma, which was synaptophysin positive and chromogranin A positive other than S100 and other neural markers (not shown)

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a

b

c

d

e

f

Fig. 3.14  In (a, b) are shown microphotographs of an intestinal-type gastric carcinoma, while in (c, d) are shown microphotographs of a diffuse-type gastric carcinoma using the Lauren classification. In the gastric carcinoma of intestinal type, detectable glands that range from well-differentiated to moderately differentiated tumors are seen, while in the diffuse type, poorly cohesive cells

diffusely infiltrating the gastric wall with no or little glandular formation are seen. The signet ring cell type of the WHO classification corresponds to the diffuse type. In (e,  f) are shown microphotographs of a carcinoid of the stomach with chromogranin A immunostain (f) and synaptophysin immunostain (not shown)

most often recognized polyp followed by the adenomatous polyp and others. Hyperplastic (85%) (aka inflammatory, regenerative) polyps represent an exaggerated regenerative response to injury and are often multiple, sessile, 50% extracellular mucin pools), and signet ring cell type (>50% signet ring tumor or SMAD4/BMPR1A gene-mutated polyps. Finally, further consideration should be paid to cells). In hereditary diffuse gastric carcinoma the condition called polypoid mucosal prolapse, (HDGC), multiple foci of intramural signet ring which may occur at the gastroenterostomy stoma cell carcinoma show a preference for the body/ and has similar histologic features as hyperplastic antral transition zone, which needs to be carepolyps. Box 3.14 shows a recapitulating classifi- fully sampled. The overall incidence in most industrialized countries has been steadily dropcation of nonepithelial gastric polyps.

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ping over past several years, but the rate of carcinoma in the cardia region of the stomach is conversely increasing with about half of gastric cancers in white men being localized in the cardia. In 1993, McGills et al. reported 17 cases of primary gastric adenocarcinoma in patients under 21  years of age and mainly single case reports had been published since. In children, the majority of gastric carcinomas occur in the antrum, the esophagogastric junction, and the greater or lesser curve. Overall, the histological diagnosis is adenocarcinoma, linitis plastica, or poorly differentiated signet ring cell carcinoma. Ataxiatelangiectasia, IgA deficiency, and thymic dysplasia (lack of Hassal bodies) ± cerebellar atrophy are the pathologies that can occur in combination with pediatric gastric carcinoma. Adenocarcinoma • DEF: Malignant epithelial tumor-forming autonomous atypical glandular proliferations associated or not to some relevant genes/syndromes (Box 3.15) (Haller JA (1987), Lauren (1965), Asherson (1979), Lyle HH. VIII (1911), Agnes (2017), CEBM, Centre for Evidence-Based Medicine). • EPI: In general terms, it represents 85–90% of gastric malignancies with increased incidence unusually high in Japan, Chile, Scotland, and Finland, while it is lower in the USA, the UK, Canada, and Greece. RF: dietary/environmental factors (e.g., nitrogen compounds), chronic active gastritis with intestinal metaplasia, pernicious anemia, gastric adenomatous polyps, post-gastrectomy, gastro-stump, Menetrier disease, and Epstein-Barr Virus (EBV) (cardiac carcinoma).

Box 3.15 Most Relevant Genes/Syndromes Associated with Gastric Cancer

Intestinal-type adenocarcinoma: HNPCC and FAP Diffuse-type adenocarcinoma: CDH1 and BRCA2 Note: HNPCC, hereditary non-­polyposis colon carcinoma; FAP, familial adenomatous polyposis; CDH1, E-cadherin gene; BRCA2, Breast Cancer 2

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• CLI: Hypochlorhydria accompanies gastric adenocarcinoma in 85–90% cases, and chronic atrophic gastritis is usually present, and the lesser curvature is involved three times more frequently than greater curvature. • CLM: Lauren Classification –– Intestinal Type (aka expanding carcinoma): Relatively cohesive nodular, polypoid, or ulcerated, well-circumscribed mass of tumor cells with characteristic pushing margins. Microscopically, tumor cells may arise from metaplastic epithelium and show foveolar cells, intestinal columnar cells, and/or goblet cells. Its incidence is relatively decreasing when compared to the diffuse type. It is more prone to give liver metastases than diffuse type. –– Diffuse Type (aka infiltrative carcinoma): Diffuse infiltration, which offers a hard aspect to the stomach (linitis plastica) and may be challenging to recognize grossly. Microscopically, the individual infiltrating tumor cells show intracellular mucin vacuoles, often forming signet ring cells with a stroma characterized by severe inflammation and desmoplasia. Its incidence is slightly increased due to screening programs for families harboring genetic defects. The term “linitis plastica” was coined by William Brinton (1823–1867) in 1854 and derives from two Latin words (linitis recalling the similar visual aspect of the hypertrophic submucosa resembling fibers of linen., while plastica meaning inelastic). Metastases are often into the peritoneum, lung, adrenal gland, and ovary (Krukenberg tumor). –– Mixed Type: A combination of intestinal and diffuse type. • PGN: Often present in advanced stage, gastric adenocarcinoma may present with metastases with only about half the tumors easy to resect at diagnosis, although it depends on the age, being youth most frequently harboring a worrisome prognosis. In about 80–90%, there are local LN metastases at the time of diagnosis. Peculiarly, Virchow node is the isolated metastasis to left

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supraclavicular LN (also called Trousseau sign). The overall 5-YSR is still 5–15%, although several approaches have been established. The early form of gastric adenocarcinoma (superficial spreading carcinoma) represents 10–35% of gastric carcinomas and is limited to mucosa and submucosa with less than 1/5 harboring LN metastases and with 5-YSR of 80–95%. Some features may help in identifying good and bad behavior in gastric tumors (Box 3.16). In addition to the four mentioned poor prognostic features described in Box 3.16, some authorities also suggest other characteristics, including young age, deep invasion, positive margins, LN invasion, and vascular invasion. Other Carcinomas Another histologic type of carcinomas is infrequent and seems to not play any role in childhood. They are also rare in adults constituting less than 1% of gastric cancer and include adenosquamous carcinoma, squamous cell carcinoma, mucinous carcinoma, hepatoid adenocarcinoma, and parietal gland carcinoma. The mucinous gastric carcinoma (MGC) seems to have a worse prognosis at first glance. The prediction of MGC patients is worse compared to that of non-­ mucinous gastric carcinoma (NMGC) patients, as the former group consists of more advanced-­ stage cases. When patients with similar stages of disease are compared, the incidence of peritoneal metastasis is significantly higher among MGC

Box 3.16 Behavior Characteristics of Gastric Tumors

Characteristics outcome

that

portend

a

good

• Small size, distal gastric involvement, pushing margin, and intestinal type Characteristics outcome

that

portend

a

poor

• Large size, proximal gastric involvement, infiltrative margin, and diffuse type

patients, but hepatic metastasis is significantly more often observed in NMGC patients. Although MGC is rarer and mostly detected at an advanced stage, the diagnosis of the mucinous histological subtype is not an independent prognostic factor. Another subtype which is gastric carcinoma with neuroendocrine differentiation is described in the next paragraph. Medullary carcinoma is a lymphoepithelial-­like carcinoma, poorly differentiated with prominent lymphoid stroma, and pushing borders and composed of cells arranged in a syncytial fashion with vesicular nuclei, EBV (+), and harboring a better outcome than other subtypes. It is usually identified as a neoplasm of the older individuals, of intestinal type, and is characterized by an expanding growth pattern and low TNM at the time of oncological staging.

3.3.5.3 Neuroendocrine Tumors This term replaces the term carcinoid tumor, which has repeatedly been criticized in the scientific literature. The term carcinoid should not be included in the pathology report as diagnosis, but apparently can be inserted in the “comment.” Neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NEC) can arise in many organs of the body, but most of the research and studies have been conducted on neoplasms of the gastrointestinal tract, pancreas, and lung. In this chapter, NETs and NECs, as well as neoplasms, may be interchangeable terms, being mostly used by different corporation bodies or institutions across Europe and worldwide. However, the WHO classification of the tumors of the digestive tract (2010) reserves the term NET for the first two grades only and NEC for the highest grade. Although originally thought tumors are derived from the embryonic neural crest, it has been proved that NETs recapitulate cells of endodermal origin and have been classified as endocrine. However, the simultaneous expression of neural markers and epithelial markers let retain the term neuroendocrine, which has been emphasized in the WHO classification of the digestive system (2010). In the case of metastasis of unknown origin, the organ of derivation may be identified using specific markers, such as TTF1 for lung, CDX2 for intestines or pancreas, and PDX1 or

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ISL1 for the pancreas. The term differentiation indicates how the neoplastic cells look like their non-neoplastic counterparts. In well-differentiated NETs, there is an organoid arrangement of the tumor cells with characteristic patterns, including nests, trabecular, or gyriform. The neoplastic cells are characterized by relative uniformity with the production of neurosecretory granules, which can be visualized as membranebound granules with a dense core and peripheral halo on TEM and expressing chromogranin A and synaptophysin by immunohistochemistry. Poorly differentiated NETs show less similarity to the cells of origin, and the growth pattern is less organoid but more sheetlike or d­ iffuse. Both TEM and IHC would probably work hard in some cases to demonstrate neuroendocrine differentiation. The differentiation between argyrophilia and argentaffinity is paramount in the study of neuroendocrine tumors (Box 3.17).

Box 3.17 Argyro-philic vs. Argent-affinic

• Argyro-philic: Tumor able to take silver (Ag) up, but unable to reduce it. • Argent-affinic: Tumor able to take silver (Ag) up and reduce it. • Argyro-philic stain: Grimelius. • Argent-affinic stain: Fontana-Masson. • Foregut NETs are argyrophilic-­positive, but argentaffin-negative. • Midgut NETs are argyrophilic-positive and argentaffin-positive. • Hindgut NETs are often argyrophilic-­ positive, but argentaffin-negative. • Foregut: (+) NSE, CGA, low 5-HT, multihormonal, ± carcinoid syndrome, + bony MTX. • Midgut: (+) NSE, CGA, high 5-HT, multihormonal, ++ carcinoid syndrome, ± bony MTX. • Hindgut: (+) NSE, CGA, (±) 5-HT, multihormonal, ± carcinoid syndrome, + bony MTX. Note: NETs, neuroendocrine tumors; NSE, neuron-specific enolase; CGA, chromogranin A; 5-HT, 5-hydroxytryptamine

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The chromogranins (A, B, and C) are acidic polypeptides that are the primary component of the secretory granules, and neuron-specific enolase (NSE) is a γ-γ dimer of the glycolytic enzyme enolase, while synaptophysin (SYN) is a calcium-binding vesicle membrane glycoprotein that is singularly expressed independently of other neuroendocrine proteins. In foregut NETs, cytoplasmic granules are 180-nm (Ø) round and variable density. In midgut NETs, cytoplasmic granules are 230  nm (Ø), are pleomorphic, but have uniform thickness. In hindgut NETs, there are cytoplasmic granules with 190 nm in Ø, and they are round and show variable density. The diagnosis of NET needs to be formulated using grade and differentiation, which are essential parameters to address the therapy correctly. The use of a Minimum Pathology DataSet or CAP (College of American Pathologists) Tumor Checklist is paramount information to be entirely included in pathology reports on NETs. Conversely, the term grade is linked to the biologic aggressiveness of the neoplasm, i.e., lowgrade NETs have an indolent course, and high-grade NETs show a more aggressive outcome. As a general measure of understanding, well-differentiated NETs may be of low or intermediate grade, while poorly differentiated NETs are usually of high rank. The current WHO classification identifies four categories for NETs with slightly different terminology in different medical journals. Grade: Low (G1) means neuroendocrine tumor (NET) I G1 and corresponds to the traditional entity known as “carcinoid”; Intermediate meaning NET II G2 corresponds to “atypical carcinoid tumor”; and neuro-intestinal carcinomas (NEC) or G3 are subdivided into a small cell and large cell carcinomas. Mitotic count and Ki67/MIB1 index are used to classify the grade of a NET and should be included in the pathology report supporting the diagnosis. In particular, the number of mitoses per 10 HPF or 2 mm2 should be determined using manual or computer-based counting in 50 HPF of the most mitotically active areas or the highest labeling Ki67/MIB1 density. The mostly used grading system for the NET of the GIT is as follows. According to the WHO NET categories,

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grading is low if MI 20% Ki67 index. NET G1, NET G2, and NEC of the stomach correspond to what was formerly called carcinoid tumor (also named well-­ differentiated endocrine tumor), atypical carcinoid tumor, and endocrine cell carcinoma (also named small cell carcinoma), respectively. Slightly different grading systems exist for the pancreas and lung and will be highlighted in the respective chapters. In the Minimum Pathology DataSet or CAP Tumor Checklist for resection of primary tumors, some data need to be collected in the synoptic pathology report: –– Anatomic site of cancer, diagnosis, and size (three dimensions); –– Multicentricity; –– Histologic and cellular features (e.g., oncocytic, clear cell, gland-forming); –– Grade with mitotic count value (per 10 HPF in ≥50 HPF) or mean percentage of the highest labeling density (ki67/MIB1) as % on 500– 2000 cells (optional immunostaining is that proposed by Volante et al. (2007) using somatostatin receptor type 2A (SSTR2A) score); –– Nonischemic tumor necrosis or other pathologies (e.g., non-neuroendocrine components); –– The extent of the depth of invasion; –– Vascular invasion; –– Perineural invasion; –– Immunohistochemical findings (CGA, SYN, MIB1); –– Lymph node metastases (positive nodes/total number of nodes examined); –– TNM staging; –– Resection margins indicating positivity, negativity, and proximity and proliferation changes or other abnormalities in non-neoplastic neuroendocrine cells. The use of immunohistochemistry tools including chromogranin A (CGA) and synaptophysin (SYN) helps both to verify neuroendocrine differentiation and to classify endocrine neoplasms as hypergastrinemia-related or as spo-

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radic gastrinoma. Adjacent mucosa in hypergastrinemia-­ related carcinomas can show changes of linear hyperplasia (≥5 endocrine cells in a linear arrangement), nodular hyperplasia (cluster of ≥5 endocrine cells with Ø ♀, with weight loss, fatigue, diarrhea, rituximab/early autologous stem cell transabdominal pain, and often Fe deficiency. Most plant (ASCT) in suitable candidates represent cases have sIgM, and 50% of patients have the mainstay of therapy for MCL. sIgD and are characterized by an aggressive • PGN: Median survival of 3–4 years is characclinical course. teristic for MCL. The blastoid and pleomor• CLM: Naked benign germinal centers surphic variants have a more aggressive clinical rounded by malignant cells is the major histocourse, and the Ki67/MIB1 index has PGN logic distinguishing feature with the absence association and should be part of the patholof neoplastically transformed cells (centroogy report. blasts), para-immunoblasts, and proliferation centers. “Cancerous” lymphoid cells usually Follicular Lymphoma straddle the muscularis mucosae, without Germinal center (GC) neoplasm with extranodal involving the mucosa. There are neither lym- GI involvement of the small intestine, particuphoepithelial lesion nor neoplastic germinal larly the duodenum, usually in individuals of the centers, which are two important features for fifth to sixth decade (rarely younger patients), the differential diagnosis with other ♂=♀, may occur as multiple small polyps to lymlymphomas. phomatoid polyposis with usually a grade 1 mor• DDX: MALT lymphoma and other GC neo- phology-based (centrocytic) without residual plasms, such as follicular lymphoma, which germinal centers, unlike MCL. Distinction from may also present as lymphomatoid polyposis reactive follicular hyperplasia is paramount and

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includes effacement of the architecture, minimal variation in size/shape and even distribution of the follicles, poorly defined follicle borders, no polarization (CC-­ CB), no mantle, monomorphism, no TBM (tingible body macrophages), minimal phagocytosis, and atypical cells in interfollicular regions. TBMs are a type of macrophages often found in germinal centers, containing several to numerous phagocytized, apoptotic cells in various states of degradation, which are referred to as tingible bodies. • IHC phenotype: –– (+) CD19, CD20, CD22, CD79a (B cells) and (−) CD5, CD43 (T-cell markers) and (−) Cyclin D1 –– (+) CD10 and Bcl6 and CD23 ± –– t(14;18)(q32;q21) ⇒ IGH/BCL2 ⇒ Upreg­ ulation of BCL2 oncogene The extranodal follicular lymphoma differs from the nodal type, because of the expression IgA as well as α4β7 mucosal homing receptor suggesting an origin from local B cells, expression of VH4 gene, and no activation-induced cytidine deaminase expression. • PGN: Indolent course with a low stage and 5-YSR ~65% with a usual “watch and wait” approach, because they do not develop extraintestinal spread. In rare cases with advanced disease or grade 3B, chemotherapy + rituximab or involved field radiotherapy (IFRT) to localized disease has been suggested. Maintenance with rituximab following first- or second-­line treatment has also been indicated. Burkitt Lymphoma • DEF: GC B-cell neoplasm, mostly EBV associated with the aggressive clinical course and three presenting subtypes, including endemic (EBV+: 95%), sporadic (EBV+: 20%), and HIV-associated (EBV+: 30%). • CLI/EPI: The endemic BL occurs mostly in the jaw, orbit, kidney, with highly adrenal gland, and ovaries (JAKOO as mnemonic word for sites) of children with a mean age of 10  years in equatorial Africa, while the sporadic BL occurs in the ileum at an age rela-

• •

•

•

tively older. The HIV-associated BL does usually not belong to childhood and youth. GRO: Bulky, fleshy tumors with or without necrosis. CLM: Monotonous small round cells with a high mitotic rate approaching 100% (Very Important Point!!!) and several prominent basophilic nucleoli and scant cytoplasm with numerous intracytoplasmic fat vacuoles with ORO positivity on touch preparation giving rise to the classic “starry-­sky pattern” of the classic hematology books. IHC phenotype: –– (+) CD19, CD20 (Pan-B markers) and (+) EBER (EBV) and (−) Cyclin D1 –– (+) CD10 and Bcl6, and CD23−, CD43+ –– t(8;14)  ⇒  c-myc from 8q24 and Ig loci from 14q32 –– Other translocations t(8;2) and t(8;22). TRT: Resection and chemotherapy.

Diffuse Large B-Cell Lymphoma • DEF: Heterogeneous B-NHL with GC and post-GC (activated B-cell) subtypes with highly prognostic relevance. • CLM: There is a diffuse growth of cells lacking cohesiveness and showing cells with approximately double the size of normal small lymphocytes. It is important to recall that small lymphocytes are 7 to 10 µm in diameter, while large lymphocytes are 14 to 20 µm in diameter. These cells show open vesicular chromatin pattern with nucleoli adjacent to the cell membrane (in the case of centroblasts) or centrally located. Nucleoli can be eosinophilic in the case of immunoblasts. • DDX: Poorly differentiated carcinoma, which is positive for mucin and keratin staining, negative B-cell markers, the presence of syncytial cell aggregates or malignant acinar formation, malignant melanoma, and myeloid sarcoma. • IHC phenotype: –– (+) CD19, CD20 (Pan-B markers) and (+) EBER (EBV in the case of PTLD) and (−) Cyclin D1 –– (+) CD10 and Bcl6, and CD23 (−), CD43 (−) –– T(14;18) ⇒ IGH/BCL2

3.3 Stomach

–– Heterogeneity: B cells (50–60%), T cells (5–15%), histiocytic (5%), no cell markers (30–40%) • TRT: Chemotherapy. • PGN: Rapid progression and poor PGN, if untreated, but good results with aggressive therapy. Extranodal Marginal Zone B-Cell Lymphoma of MALT (ENMZL/MALT) • DEF: Postgerminal center B-cell NHL (aka MALT-oma) strongly associated with H. pylori infection and autoimmune disorders and composed of morphologically heterogeneous small B cells with an indolent course harboring the tendency to remain localized for long periods before progressing. It can also transform into a large cell lymphoma, which behaves much more aggressively. Most common EN sites are salivary glands and GI tract. • CLM: Early lesions are Ag-driven (e.g., H. pylori in the stomach), while later, the neoplastic process is Ag-independent. • IHC phenotype: –– (+) CD19, CD20 (Pan-B markers) and (−) EBER and (−) CD5 and Cyclin D1 –– (−) CD10 and Bcl6, and CD23− but CD43± –– (±) EMA • t(1;14)(p22;q32) ⇒ BCL10/IGH • t(14;18)(q32;q21) ⇒ IGH/MALT1 • t(11;18)(q21;q21) ⇒ API2/MALT1

• DDX: Gastric MALT lymphoma ≠ gastritis. Distinguishing features are lymphoepithelial lesions and reactive follicles with germinal centers. There are diffuse and nodular forms, where neoplastic cells have initially a perifollicular distribution and then may infiltrate as lymphocytic cuff (mantle zone pattern) or colonize germinal centers (follicular colonization). Plasma cellular differentiation with Ig light chain restriction and plasma cellular overgrowth characteristically located in the tips of the lamina propria of the mucosa by ascending CD20 (+) tumor cells may also help to delineate the differential diagnosis.

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• PGN: Two scoring systems are needed to be mentioned here. They include the Wotherspoon scoring of the lymphocytic infiltrates and the Copie-Bergman scoring for post-­therapy grading. The prognosis is variable. On univariate analysis, the longer event-­free survival (EFS) and overall survival (OS) times were observed in single MALT site involvement (OS), no nodal disease (EFS and OS), skin and orbit lymphoma (OS), localized disease (EFS and OS), and stage IV disease without bone marrow involvement (OS). However, both bone marrow and nodal involvement have been indelibly associated with the shorter OS on multivariate analysis. Immunoproliferative Small Intestine Disease (IPSID) • DEF: B-NHL (aka Mediterranean lymphoma or α heavy chain disease), which is uncommon and included under the MALT lymphoma in the current WHO classification. It is a form of MALT lymphoma developing in MALT areas of the small intestine and a there is a more or less frank correlation with C. jejuni infection. It arises in the intestinal mucosa as a morphologically benign-appearing infiltrate with a dense plasma cell proliferation (either lymphoplasmacytic or large cell, immunoblastic plasmacytic with IgA heavy chain restriction). • CLI: Youth up to 40–45 years, malabsorption, duodenum/proximal jejunum involvement, villous atrophy (Marsh classification!), and plasma cell infiltration of the adjacent intestine with > serum IgA. • TRT: Antibiotics (early) and DLBCL chemotherapy (late), when IPSID evolves to large cell lymphoma. Gastrointestinal T-NHL Gastrointestinal T-NHL includes the enteropathy-­ associated T-cell lymphoma (EATL) essentially. Enteropathy-Associated T-Cell Lymphoma (EATL) T-NHL arising as clonal transformation of inflammatory intestinal intraepithelial T cells and

302

occurring with wide age range (20–70 years) and a wide interval of history of malabsorption (2  months to >5  years), mostly celiac disease (even in the setting of a strict compliance to gluten-­free diet) and harboring a highly aggressive course with poor outcome (5-YSR: 8–20%). Of note, only 2–5% of patients with celiac disease develop NHL. The refractory celiac disease is defined as “persistent clinical enteropathy and histological features of villous atrophy with intraepithelial lymphocytosis, despite strict adherence to a gluten-free diet for at least 12 months following a prior resolution.” EATL usually involves the proximal small bowel (jejunum) presenting as an ulcerating mucosal mass that circumferentially invades the wall but may also be multifocal with multiple ulcers (“ulcerative jejunitis”). The presentation includes abdominal pain, diarrhea, weight loss, and anemia, which may portend to a diagnostic workup for recurrent or refractory celiac disease. • EATL-I: Medium- to large-sized cells with vesicular nuclei and prominent nucleoli and large pale-staining cytoplasm and accompanied by inflammatory cells (often eosinophils). • EATL-II: Small- to medium-sized monomorphic cells with hyperchromatic nuclei and a scant rim of cytoplasm. IHC panel is useful in distinguishing two types of EATL: EATL-I is typically associated with refractory celiac disease, but the refractory celiac disease may also precede (not always occasionally) EATL-II.

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• TRT: Initially surgery is the first choice where possible. Aggressive chemotherapy may be an option, while radiotherapy has no role due to the frequent dissemination of the neoplasm. Nonnasal NK/T-Cell NHL NK/T-cell lymphoma of East Asian and Hispanic population (fourth to sixth decade, but younger patients have been reported, ♂>♀), EBV associated with poor PGN (median survival: 10  months, reduced to 4 months in advanced disease), and targeting multiple locations. Its occurrence in the bowel is accompanied by the usual broad cytologic spectrum of the nasal type, ranging from small to intermediate size to large cells with marked nuclear pleomorphism. There is no villous atrophy of the adjacent mucosa (Marsh classification), but the lymphoma shows ulceration, angiocentricity, and angioinvasion with both fibrinoid and coagulative necrosis. IHC pattern includes cytoplasmic, but not surface CD3 expression and (+) TIA1 and (+) CD56 like EATL-II. Moreover, NK/T-cell NHL is EBV (+), but CD8(−) and βF1(−), unlike EATL-II, which is EBV (−) and CD8(+) and βF1(+). The βF1 or β Framework 1 antibody is key. The βF1 recognizes a common epitope on the β chain of the TCR for antigen which is expressed by thymocytes and peripheral T lymphocytes following the treatment of lymphoid cells with permeabilization reagents. The βF1 does not react with γδ TCRbearing T cells.

• IHC phenotype: –– EATL-I: CD3+, CD5−, CD8−, CD4+, CD56−, TCR− β ±, HLA-DQ2/-DQ8 (>90%) –– EATL-II: CD3+, CD5−, CD8+, CD4−, CD56+, TCR-β+, HLA-DQ2/-DQ8 (40%)

• CMB: del(6)(q21:q25), i(6)(p10), TCR rearrangement have been identified. • TRT: Chemotherapy and radiation are the mainstay. In advanced or relapsed disease, it has been suggested combination chemotherapy containing L-asparaginase, such as the SMILE regimen. (Steroid/dexamethasone-Methotrexate with leucovorin-Ifosfamide with mesna-L- asparaginaseEtoposide).

Both types are CD30+, which is present in large, bizarre multinucleated cells mimicking HL. CD5 helps to distinguish this entity from ALK lymphoma, which may share a similar morphology with EATL-I.  Moreover, both types express the cytolytic granule-associated proteins. Molecular biology studies evidence TCR gene rearrangement.

Peripheral T-NHL NOS can also involve the GI tract but is a rare occurrence in childhood or youth. The Ann Arbor staging system is quite well validated for nodal involvement, and some modifications are present in the literature for extranodal involvement. There are some staging systems for primary gastrointestinal lymphomas, but the

3.3 Stomach

“Lugano Staging System” seems to be commonly accepted and used (Rohatiner et al. 1994). Another option is that according to Mussoff (1977), which seems quite often used in some countries. Later, an international prognostic index was proposed and accepted. Please consult the current classification and staging of tumors of the gastrointestinal lymphatic and hematopoietic system in the “blue books” of the World Health Organization. Pseudolymphoma It is a localized lymphoid hyperplasia, which may be observed, for instance, in the stomach, intestines, and rectum. Lymphoid proliferation may be follicular (nodular) in the terminal ileum and appendix or diffuse, such as in the stomach, proximal small intestine, and rectum. Distinguishing features are polymorphous infiltrate, well-formed reactive lymphoid follicles, the proliferation of blood vessels, dense collagenous fibrosis, and ulceration, although this latter (Caveat!) may be a malignant feature as well.

3.3.5.5 Stromal Tumors and Smooth Muscle-Differentiating Tumors GIST: Gastrointestinal Stromal Tumor • DEF: It is the most common mesenchymal neoplasm of the GIT arising from the interstitial cells of Cajal harboring-activating mutations of c-Kit or PDGFRA (CD117), which is tyrosine kinase receptor involved in mitogenic signals and quite resistant to standard chemotherapy and radiation. • EPI: In pediatric patients, the GIST median age is 12 years, ♂:♀ = 1:3, although it remains a rare occurrence in childhood (6.8–15/106). • ETP: Genetic syndromes: Carney triad (GIST, paraganglioma, pulmonary chondroma), germline KIT or PDGFRA gene mutations, and NF-1. Gain-of-function mutation  ⇒  constitutive activation! PDGFRα type III tyrosine kinase and DOG1 are ion trafficking involving transmembrane proteins. ~80% C-Kit (tyrosine kinase): oncogenic, gain-of-function mutations.

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~10% PDGFRA (a related tyrosine kinase), c-Kit being the receptor for stem cell factor. • CLI: Abdominal pain, bloating, melena, anemia, or bowel obstruction, which may occasionally be dramatic and discovered in the emergency departments. • GRO: Mass with tan-white, fleshy cut surface and potential foci of cystic degeneration, hemorrhage, or necrosis. • CLM: Three main histologic subtypes: spindle cell type, epithelioid type, and mixed type. Histologically, there is a uniform, monotonous appearance with minimal cytologic atypia, occasional cellular pleomorphism, and low mitotic activity. Compared with the adult GIST, which is mostly spindle cell type, the pediatric GIST is epithelioid primarily with a more indolent natural history than the adult counterpart (median survival: 20 months!). CD117 is also expressed in MZ and other hematopoietic precursor cells and neoplasms, such as melanoma, renal cell carcinoma, and seminoma. Thus, many words of caution should be expressed. GIST with “dot-like” IHC pattern is probably extraintestinal or exhibiting an epithelioid morphology. • DDX: GIST, which is (+) c-kit, PDGFRα, DOG1, (±) CD34 (2/3), SMA (1/3), S-100 (1/20), DES (rare), Leiomyosarcoma (LMS), which is (+) SMA (~3/4), (±) DES, CK, (±) CD34 (1/10), (−) CD117/c-kit, (±) S-100 (rare), Schwannoma, which is (±) CD34, (−) CD117/c-kit, Desmoid-type Fibromatosis, which is (+) β-CatN, and Solitary Fibrous Tumor (SFT), which is (+) CD34, (−) CD117/ c-kit, (±) β-CatN. • PGN: Following resection, which is the first option for treatment, the outcome depends on staging. Smooth muscle actin (SMA) indicates smooth muscle differentiation but also identifies myofibroblasts and myoepithelial cells, while desmin suggests myogenic differentiation (cardiac, smooth, and striated muscle cells), but also myo-

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3.4.1.1 Infantile Colic Most of the conditions involving an infant crying during the first few months of life are not organic in nature. It is estimated that up to 1/3 of the infants experience colicky pain and in Smooth Muscle Tumors 95% of cases this pain should be considered Most smooth muscle tumors are benign and have functional. However, an excessive crying baby unusual characteristics (extreme cellularity, infre- can be dangerous for both parents and physiquent large cells with eccentric hyperchromatic cians. Infantile colic is still defined according nuclei, marked diffuse vascularity, palisading of to Wessel et al. (1954) as a crying infant >3 h/ nuclei, clear cytoplasm) but still benign. MI is day, >3 days/week, and >3 consecutive weeks. low. Finally, the solitary fibrous tumor (SFT) can Typical aspects of a developing child during the occur and is distinct by (1) “patternless pattern” of first 3 months of life usually comprise fussing growth, (2) thick collagen bands, and (3) heman- and crying, and during this time, babies cry an giopericytomatous/staghorn-like blood vessels. average of 2.2 h per day, peaking at 6 weeks of age and then gradually showing a decreasing 3.3.5.6 Nonstroma/Smooth Muscle-­ tendency. Colicky infants have attacks of Differentiating Tumors screaming in the evening associated with abnorThese tumors include glomus tumor, lipoma, mal motor behavior, including facial flush, furgranular cell tumor, neurofibroma, and schwan- rowed brow, and clenched fists, pulling up of noma, but they are rarities in pediatrics and youth. the legs to the abdomen, and emission of a ­piercing, formidably high-pitched scream. The 3.3.5.7 Secondary Tumors etiology is variable and there are most and less Metastases to the stomach may occur in child- common conditions. Most common conditions hood or youth, but they may be restricted to small include alimentary disorders, constipation, round blue cell tumors almost exclusively. anal/rectal fissure, gastroesophageal reflux, cow’s milk protein intolerance, otitis media, urinary tract infections, and viral illness. Less 3.4 Small Intestine common conditions, of which organic causes are underlying disorders in ♀, 50% with ectopic gastric mucosa (± peptic ulceration) ± pancreas, usually in the adjacent intestinal mucosa. Complications include perforation, ulceration, bleeding, and intussusception, which is the invagination of one portion of a tubular anatomical (in our case, the gastro-intestinal tract) structure within the next (Latin intus “within” and susceptio “catching, lifting up”, vide infra).

3.4.4.2 Segmental Dilatation (Congenital) Limited dilatation of the intestine with an abrupt transition between normal and dilated intestinal segments without intrinsic or extrinsic barrier distally to the dilatation.

3.4.5 Small Intestinal Dystopias Dystopias or abnormal location of the intestines include intussusception, volvulus, and nonrotation or malrotation of the bowel.

3.4.5.1 Intussusception It is generated by a telescoping phenomenon of some intestinal loops with one segment of small intestine (the intussusceptum) becoming “telescoped” into the immediately distal segment (the intussuscipiens). This situation promotes continuous propulsion of the proximal portion further inward by peristalsis, taking the mesentery (including blood vessels) with it. The consequence of involving blood vessels is an infarction. In older children, lymphoid hyperplasia may become the leading point of traction, while in adolescents or adults, i­ntussusception may occur in the setting of a mass lesion, such as Burkitt lymphoma, which forms the leading edge. 3.4.5.2 Volvulus Condition when a loop of the bowel twists around itself and the mesentery that supports it, resulting in a bowel obstruction or discontinuity of the lumen. Clinically, there are abdominal pain,

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abdominal bloating, vomiting, progressive bowel obstruction, constipation, and bloody stool.

3.4.5.3 Nonrotation and Malrotation Intestinal nonrotation or malrotation does occur if there is no mesenteric fixation of the intestine. No fixation means an increased risk of displacement and subsequent ischemia of the abdominal segments involved because of twisting of mesenteric blood vessels. Nonrotation and malrotation can occur both in fetal and postnatal life. Acute midgut volvulus with bilious emesis and classic “corkscrew” imaging is a typical presentation of infants with malrotation.

3.4.6 Composition Abnormalities of the Intestinal Wall Heterotopias or abnormal intestinal wall composition may include tissue that belongs to a part of the primitive stage of the primordial gut. This tissue is differentiated in a wrong location, but it is still primordially gut-linked. Thus, a heterotopia is usually a hamartia (Gr. ἁμαρτία, or errore). Choristiae are defined as heterotopic tissue parts that do not belong to the primordial gut embryologically. Hamartomas and choristomas may arise from these parts. In his Poetics, Aristotle first used this term to refer to the protagonist’s error of a tragedy.

3.4.6.1 Pancreas Heterotopia 1–2 cm mucosal elevation, ducts, and acini, usually without islets, variable location in the small intestine, but most commonly in the periampullary region of the duodenum. It may serve as a lead point for intussusception. 3.4.6.2 Gastric Heterotopia Discrete small nodules or sessile polyps in the duodenum or Meckel’s diverticulum. It is composed of fundic-type mucosa with the chief and parietal cells. 3.4.6.3 Endometrial Heterotopia (Endometriosis) Müllerianosis is an organoid structure of embryonic origin, i.e., a choristoma composed of

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Müllerian rests  – normal endometrium, normal endosalpinx, and normal endocervix – singly or in combination, incorporated within other normal organs during organogenesis. Sampson then divided “misplaced endometrial or Müllerian tissue” into “four or possibly five groups, according to the manner in which this tissue reached its ectopic location” (1925). Sampson’s classification of heterotopic or misplaced endometrial tissue is essentially based on pathogenesis. Sampson recognizes (1) “direct/ primary endometriosis” [adenomyosis] (similar to the condition, which occurs in the wall of the tube [endosalpingiosis]), (2) “peritoneal or implantation endometriosis,” (3) “transplantation endometriosis,” (4) “metastatic endometriosis,” and (5) “developmentally misplaced endometrial tissue.”

3.4.7 Small Intestinal Vascular Changes 3.4.7.1 Non-NEC Vascular Necrosis In the neonatal period, thromboemboli secondary to the use of intravascular catheters may represent an important etiology for bowel infarction. This entity is, however, different from neonatal necrotizing enterocolitis (NEC), a multifactorial syndrome of acute necrotizing inflammation of the small and large intestine. NEC is not linked to thromboembolic and needs to be kept nosologically distinct from vascular changes (infarction) of older children. Both NEC and infarction have coagulative necrosis as a crucial morphological feature, but NEC is an inflammatory process, and the initiating site has been repeatedly identified in a venule, although some controversy does exist. Conversely, bowel infarction may also have an accompanying inflammatory process, but the initiating site is an artery. Indeed intestinal pneumatosis, a characteristic finding of NEC, is not seen in infarctions. Other causes of bowel infarctions are rare and include abnormalities of intestinal blood vascular supply. It is quite convenient to classify bowel necrosis secondary to infarction according to the extent of the wall involvement (mucosal-mural-transmural).

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Acute Intestinal Ischemia EPG: Occlusive (arterial thrombosis and embolism, atherosclerosis, arteritis, small-vessel disease, and mesenteric venous thrombosis), nonocclusive (vasoconstriction-related due to decreased cardiac output, hypotension, hypovolemia, dehydration, or drugs, such as digitalis and cocaine), or dissecting aneurysm involving SMA (superior mesenteric artery), arteriopathy with intimal hypertrophy in systemic hypertension, radiation injury, or fibroelastosis adjacent to neuroendocrine tumors. SMA is much more involved than IMA (inferior mesenteric artery) because the IMA has a more oblique take-off from the aorta. Occlusive causes of arteritis may include PAN, RA, SLE, and Takayasu disease, whereas occlusive causes of small-vessel disease may consist of HSP, leukocytoclastic vasculitis, and DIC. Grossly hemorrhagic, whether arterial or venous in origin, arterial occlusions tend to have sharper margins, while venous occlusions tend to fade gradually into regular bowel segments. There is severe congestion, subserosal and submucosal hemorrhages, edema, and later blood in the lumen. Mesenteric venous thrombosis is associated with portal hypertension, hypercoagulable status (e.g., polycythemia), abdominal surgery or trauma, intra-abdominal sepsis, and presence of a mass (“tumor quia tumet”). The term “hemorrhagic gastro-enteropathy” is also used for nonocclusive, vasoconstriction-­related hypovolemic conditions. Chronic Intestinal Ischemia It is the outcome of either acute mural infarction or chronic mesenteric insufficiency, e.g., HSP, RA, and SLE.  PAN usually involves the small intestine, while phlebitis characteristically engages the colon. The ischemic bowel disease may have a gross picture that can mimic Crohn disease. There may be solitary or multiple ulcers with mucosal or transmural necrosis. The obstruction of the main branch of the mesenteric artery determines an extensive infarction, while secondary branches usually do not affect, because of numerous collaterals. Terminal branch obstruction causes a localized infarction. Fibrosis is

3.4 Small Intestine

most pronounced in the mucosa, and a fibrotic narrowing can also occur (intestinal stricture or strictura intestinalis). In scleroderma, visceral involvement may precede or occur in the absence of skin changes. The GIT is rigid, fibrotic, and often dilated, and there is atrophy of the tunica muscularis propria with the disappearance and fibrous replacement of inner circular muscular layer, concentric intimal thickening, medial fibrosis, and fibrin deposition in medium- and small-sized arteries, as well as some nonspecific mucosal chronic or active inflammation.

3.4.8 Inflammation and Malabsorption Inflammation and malabsorption are in most cases strictly interconnected, and treatment of all of these conditions in one chapter seems a good option. We can also differentiate infective and noninfective disorders and disorders where both etiologies may play a role, but an underlying immunological problem may worsen the clinical scenario, such as inflammatory bowel diseases and specifically Crohn disease. Thus, inflammation and malabsorption are very intertwined. Malabsorption is the abnormal absorption of fat, fat-soluble vitamins, or other vitamins, proteins, carbohydrates, and minerals, usually with abnormal fecal excretion of fat (steatorrhea: >6 g/day) and due to a long list of possible conditions. Pathogenesis relies on defective intraluminal hydrolysis, mucosal abnormality, lymphatic obstruction, infection, by selecting only some of the numerous conditions associated with this disturbance. Malabsorption is also associated with inflammation, and inflammation can be the first condition seen in premature babies. Malabsorption may be due to impaired digestion (due to liver, pancreas, gastric surgery), small bowel mucosal damage (due to celiac disease, tropical sprue, Whipple disease, parasitic disease, radiotherapy/ chemotherapy, lymphoma), small bowel flora alteration (e.g., blind loop syndrome), biochemical dysregulation (e.g., disaccharidase deficiency), endocrinopathies (e.g., carcinoid syndrome, Zollinger-Ellison syndrome), and

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c­ irculatory disorders (e.g., mesenteric ischemia, low-output syndrome/shock, sepsis). The pathology named necrotizing enterocolitis seems to be the first condition to start with because of the infantile age and involving both inflammation (and necrosis) and malabsorption.

3.4.8.1 Necrotizing Enterocolitis • DEF: Etiologically multifactorial-based, homogeneous syndrome of acute necrotizing inflammation of small (enteritis) and large intestine (colitis) (TI, cecum, ascending colon, i.e., a “watershed” area) with quite uniform morphology (1/2 of cases: small and large bowel with continuous and discontinuous involvement) and occurring mostly in premature babies on 2nd to 3rd day of oral feeding (formula fed-risk > breastfed-risk). NEC has specific risk groups, including ~10% of all premature (4/5 of cases) newborn babies or VLBW infants ( Altered health of enterocytes (4) Impairment of intestinal barrier (mucosal) repair evidenced by ↓TTF1 and TTF2 mRNA expression due to ROS-dependent cell toxicity, which induces DNA damage, PUFA oxidation (lipid peroxidation), oxidations of amino acids in proteins, and inactivation of specific enzymes by oxidation of cofactors ⇒ (5) Vasoconstriction-related Maladaptation through an ongoing I/R-I ⇒ NECROSIS! Notes: I/R-I, ischemia/reperfusion – injury; ROS, reactive O2 species; RhoA GTPase is a key intracellular regulator of actomyosin cellular dynamics as well as other functions, including adhesion, proliferation, and survival; COX-2 or cyclooxygenase-2 is an enzyme responsible for inflammation and pain; PUFA or polyunsaturated fatty acids are fatty acids that contain more than one double bond in their backbone and play a major role in inflammation. However, PUFA in culinary oils undergo oxidative deterioration at temperatures of 150 °C (302 °F) with a free radical chain reaction, able to oxidize the PUFAs into hydroperoxide and several secondary products.

3.4 Small Intestine

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surgical procedure, and the mortality rate remains still substantial with values of 25–30%). Medical imaging may show the diagnostic pneumatosis intestinalis (air in bowel wall) (Gr. πνευματικός “relating to wind or air” arises from πνεῦμα “air, breath, spirit, wind” and πνέω or “I breath, blow”). NEC clinical stages include Stage I (“Suspected”) characterized by abdominal distension, ↑ pregavage residual, blood in stool, lethargy, apnea, and bradycardia; Stage II (“Definite”), which is the same as that for I + pneumatosis intestinalis or portal vein gas;

and Stage III (“Advanced”), which is I/II + shock, DIC, ↑ pH blood, ↓ platelets, and intestinal perforation. • GRO: Distended, lusterless, and gray-­greenish bowel loop or segment, which is incredibly soft and fragile and potentially prone to perforation, if the process is transmural. • CLM: Mucosal coagulative/ischemic necrosis with a prominent acute inflammatory infiltrate, fibrinous exudate ± pseudomembrane formation, and pneumatosis intestinalis are observed. Tips and pitfalls of NEC diagnostics are provided in Box 3.21.

Box 3.21 NEC Pearls and Pitfalls

• Up to 1/2 of NEC will develop an “advanced” stage, which will require surgical treatment. Surgery indications include clinical deterioration, ileus, perforation, and intestinal stricture. –– Perforation: single or multiple, usually at necrotic areas or necrotic healthy boundaries. –– Intestinal strictures: fibrosis of “NEC intestine”, which occurs after 2–3 weeks to months/years after recovery. • SBS (aka intestinal failure) occurs when small intestine (1 PMN defines focal acute inflammation in the lamina propria or epithelium and more than >1 focus in a tissue biopsy. Acute duodenitis (focal) is not a sensitive feature in Crohn disease but has high specificity (92%) and high predictive value (93–95%). The interobserver rate of interpreting duodenal biopsies may show different κ-factors depending on the institution but also from the gastrointestinal histopathological education of the pathologist. Lymphocyte spreading seems to be decidedly sensitive, but it may require additional training in the correct interpretation of the histology of the upper GI tract. The diagnosis of GSE may remain challenging because no single test shows 100% sensitivity and 100% specificity in every patient. The most common GSE mimickers are Helicobacter pylori (H. pylori) infection; drugs, especially NSAIDs or protonpump inhibitors (PPIs); and inflammatory bowel disease (IBD). H. pylori infection is linked to chronic active gastritis, ulcer disease, and chronic active duodenitis-bulbitis. Nonspecific duodenitis and peptic duodenitis are situations with an acid injury. H. pylori infection is classically associated with duodenal gastric metaplasia, which is characterized by gastric-type mucus-secreting cells (foci) interspersed between duodenal enterocytes, which may be easily recognized by the PAS (+) staining of the cells having neutral mucin and no brush border. NSAIDs have been associated in a few cases of duodenal IEL.  Brunner gland hyperplasia does not seem to be relevant. Other drugs include colchicine, mycophenolate mofetil, ipilimumab, and several chemotherapy agents or radio-/chemotherapy protocols. These drugs can produce villous architectural changes. Both Crohn disease and ulcerative colitis may have IELs in the duodenum. Duodenal granulomas are a useful finding in confirming the diagnosis of Crohn disease, but they are seen in 6  months of a strict GFD.  Moreover, Catassi-Fasano five-­ point scoring system has been proposed for patients who have signs and symptoms of GSE but have borderline histology or who refuse an endoscopy. The presence of four out of the five criteria (or three out of four, if gene testing is not performed) would meet diagnostic criteria for GSE.  Failure to respond to GFD may be due to some clinical settings, including no GSE, pancreatic insufficiency, bacterial overgrowth, microscopic colitis, irritable bowel syndrome, anal sphincter incompetence, dietary intolerance (lactose, fructose, soy, and milk protein), collagenous sprue, ulcerative jejunoileitis (UJI), and EATL. A misdiagnosis should also be considered. The differential diagnosis of villous atrophy includes acute viral enteritis, cow’s milk or soy protein intolerance, lambliasis (G. lamblia) and other parasites, acquired immunodeficiency syndrome, hypogammaglobulinemia, Whipple disease, connective tissue disorders, radiation or drug enteritis, and tropical sprue. There are a few different etiologic factors of malabsorption with a lesion-like GSE, including refractory sprue, tropical sprue, infectious gastroenteritis, stasis syndrome, and kwashiorkor. Tropical sprue responds to folic acid and broad-spectrum antibiotics, but not to GFD, while in the stasis syndrome, lesions are usually patchy and rarely severe, and there is a response to antibiotics. Finally, kwashiorkor is a severe

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diffuse lesion due to protein deficiency and is not related to gluten. In celiac disease, the involvement of the gastric mucosa is often described, mainly in the form of chronic superficial gastritis and lymphocytic gastritis. Nenna et al. (2012) emphasized that mucosal participation is not only confined to the duodenum. In their series of children affected with GSE, about 1 in 5 and about 1 in 20 patients showed chronic superficial gastritis and lymphocytic gastritis, respectively. Although Helicobacter pylori (Hp) infection was also found in very few patients, this accompanying infection is quite debated in the literature. Gastric lesions are classified according to the Updated Sydney System that comprises several groups of diseases grouped in three categories (acute, chronic, and unique or distinctive) and inflammation degree in three grades (grade 1 for mild lesions, 2 for moderate injuries, and 3 for severe injuries) and rapid urease testing and histology diagnose Hp infection. An association has occasionally been observed in childhood and youth of celiac disease with sarcoidosis and a recent systematic review and meta-analysis found a significantly higher risk of sarcoidosis among patients with celiac disease (Wijarnpreecha et al. 2019). In patients with sarcoidosis, there is an altered gastrointestinal mucosal immune response, which is accompanied in about 40% of patients by specific sensitization to wheat protein. Gastrointestinal symptoms of GSE may appear at the same time or precede those of sarcoidosis. GSE complications occur usually in the adult age. They include EATL-I/II (see lymphoproliferative processes); chronic ulcerative jejunoileitis, which shows recurrent episodes of small intestinal ulcerations and formation of strictures; gastrointestinal adenocarcinoma of the usual jejunum; collagenous disease with collagen just under the surface epithelium with a poor prognosis; and metabolic disorders (lactose intolerance, ↓ [Ca] level, osteoporosis, and short stature). • DDX: The differential diagnosis of GSE may be quite broad and include some differentials that may not occur in childhood (Box 3.22).

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Box 3.22 Most Common Differential Diagnoses with Pathology of Malabsorption

• Abetalipoproteinemia: Normal villous morphology with surface epithelium showing vacuolated enterocytes filled by lipid particles (ORO+ on frozen section). • Eosinophilic gastroenteritis: Villous abnormality with disproportionate eosinophils (the pathological diagnostic criteria of an eosinophilic gastrointestinal disorder are as follows: esophagus, eosinophil count ≥ 15/HPF; stomach and duodenum, eosinophil count ≥ 25/HPF; colon and rectum, eosinophil count ≥ 30/HPF according to Lucendo and Arias 2012). • Giardiasis (lambliasis): Villous abnormality of variable severity, usually mild and few to numerous parasites on the surface coat of the surface epithelium (Leung et al. 2019). • Intestinal lymphoma: Villous abnormality of variable severity and atypical lymphoid infiltrate localized in the lamina propria (IHC is crucial). • Lymphangiectasis: Villous abnormality of variable severity that is determined by the patchy or diffuse presence of dilated lymphatics (D2-40/podoplanin + by IHC). • Strongyloidiasis: Villous abnormality of variable severity with intracryptic worms and larvae (Egg: 55 x 30 μm and oval; adult: parasitic or free-living male ~ 0.7 mm in length, while parasitic female ~ 2.2 mm in length, and free living female ~ 1 mm in length) (Beknazarova et al. 2016). • Whipple disease: Villous abnormality and lamina propria filled with PAS+ macrophages with Tropheryma whippelii (detectable on TEM/0.5–1  μm semithin sections during active disease). Note: IHC, immunohistochemistry; TEM, transmission electron microscopy

3.4 Small Intestine

The small intestinal abnormalities in addition to pathognomonic lesions in other organs are summarized in Box 3.23. Here, we show diseases with impaired epithelial replacement, which can be patchy. The proximal small bowel is more damaged than the distal portions because there is significant mucosal exposure of the proximal regions to the highest concentration of gluten if we consider the untreated patient. Remarkable results came out from several experimental studies. When the distal portion is exposed to a high concentration of gluten, this portion of the small bowel will become like the proximal parts.

Box 3.23 Small Intestine and Pathognomonic Lesions in Other Organs

•

•

•

•

•

•

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In case the patient does not respond to a GFD, some causes need to be taken into account, including poor compliance, T-cell lymphoma, carcinoma, and collagenous sprue. Box 3.24 provides some tips in the diagnostics of GSE. The ESPGHAN and NASPGHAN combined criteria are illustrated in Box 3.25. The ESPGHAN targets children exclusively, while ACG and WGO target both children and adults. The report of GSE should contain paramount and clinically-relevant data as reported in Box 3.26. Box 3.27 provides some pitfalls in the diagnostics of GSE.

• Gastrinoma (ZES): Patchy acute inflammation with microulceration that disapAcrodermatitis enteropathica (Danbolt-­ pears after gastrectomy and diagnosis Closs syndrome, Brandt syndrome): based on excessive gastric acid secretion AR-inherited metabolic disorder affecting and ↑serum gastrin level. the Zn uptake through the mucosa of the • Histoplasmosis: Villous morphology showbowel and characterized by periorificial ing club-shaped villi with lamina propria and acral dermatitis, alopecia, and stuffed with macrophages containing characdiarrhea. teristic encapsulated fungi (H. capsulatum). Amyloidosis: Amyloid in blood vessels • Lipid storage disorders: Vacuolated macrodetected in rectal biopsy using Congo red phages and ganglion cells in autonomous and apple-green birefringence with polarplexus using semithin sections, histochemized light. istry, IHC (anti-CD68 monoclonal antiCapillariasis: Parasitic infection caused by body), and TEM. two species of nematodes, Capillaria • Macroglobulinemia: Plasma cell dyscrasia hepatica, which induces hepatic capillariawith increased levels of macroglobulins in sis, and C. philippinensis, which causes the circulating blood showing extracellular intestinal capillariasis. amorphous hyaline in lamina propria. Chronic granulomatous disease: Clumps • Schistosomiasis: Ova of S. mansoni or S. of vacuolated pigmented macrophages in japonicum in the stool on a simple smear lamina propria and normal villous (1–2 mg of fecal material) using the Katomorphology. Katz technique (20–50  mg of fecal mateCMV: Variable and patchy intestinal lesions rial) or the Ritchie technique. with enlarged cells with typical large intra- • Soy protein reaction: Lesions severe, nonnuclear oval inclusions surrounded by a halo. specific, soy protein related, but very rare. Crohn disease: Transmural inflammation, Note: AR, autosomal recessive; CMV, cytoulcerations, lymphoid aggregates, and nonmegalovirus; ZES, Zollinger-Ellison syndrome; caseating granulomas with or without giant TEM, transmission-electron microscopy cells.

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Box 3.24 GSE Pearls and Pitfalls

• Gluten-sensitive enteropathy (GSE) should be considered as a continuum with findings ranging from early mucosal changes through overt disease with total villous atrophy. • The grade of Marsh classification is indicated by the most severe change in a duodenal biopsy at one time, although this grading has been controversially discussed and most authors report IIIA as partial villous blunting in a mixture of normal and subtotal villous blunting. • Small bowel mucosal IELs without atrophy and crypt hyperplasia (Marsh I) or with crypt hyperplasia (Marsh II) and lab-based positive endomysial antibodies belong to the spectrum of genetic gluten intolerance, and patients benefit absolutely from a GFD. • CD3+ IELs may be stained with monoclonal antibody Leu-4, αβ+ IELs with the monoclonal antibody BetaF1 antibody, and γδ+ IELs with the TCR-γ antibody. • Villous height/crypt depth ratio (Vh/CrD) should be measured as a mean of at least five well-oriented villous-crypt pairs, and a ratio of 10/HPF). GRO: Friable mucosa with mucosal ulceration (often rectum) and bleeding. CLM: Variable degrees of villous atrophy, edema of the lamina propria, crypt abscesses, and an inflammatory cell infiltration with ↑lymphocytes, eosinophils, and mast cells as well as plasma cells displaying IgM and IgA by IHC. DGN: Consistent clinical features with improvement following the withdrawal of the suspected causal protein. An OFC is sometimes performed to confirm the diagnosis or to determine the resolution of the food allergy. DDX: Allergic food disorders, infectious diseases, intestinal obstruction due to anatomic or functional etiologies, severe GERD, and metabolic, neurologic, and cardiac conditions should be kept in the differential diagnosis. Apart from other forms of malabsorption, NEC should also be considered in the acute form of FPIES.  GSE should be excluded explicitly by antibody testing (IgA-TTG) and histologic features (villous blunting, intraepithelial lymphocytes, and crypt hyperplasia), which are typically less severe of the GSE. TRT: Elimination of the food trigger(s) from the diet with symptoms resolution 2–4 h with standard management (e.g., intravenous fluids with or without intravenous glucocorticoids). PGN: Cow’s milk and soy FPIES resolve in a majority of patients by the age of 3  years, although infants with solid-food FPIES and/or those with concomitant detectable food-­ specific IgE may show a more protracted course. Oral food challenges (OFCs) may be proposed every 18–24 months.

3.4.8.5 Crohn Disease • DEF: Idiopathic, chronic, and recurrent Th1/ Th17-driven CIBD (regional ileitis) with vari-

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able distribution in the GI tract and possible related extra-GI lesions (skin, bone, muscle, lung) showing the involvement of bowel at any level characterized by: 1. 2. 3. 4.

Transmural inflammation Ulceration of the mucosa/submucosa Lymphoid aggregates Granulomas of the noncaseating type as well as IL-12 and IL-23 production

• EPI: Onset approximately 2nd-3rd decades, +++ in the USA, the UK, and Scandinavia, white>blacks, ♂6 weeks or >90 days). SBS is common in VLBW babies, and almost all of them follow NEC. In SBS, the absorptive capacity of the intestine is inadequate to meet nutrition, hydration, electrolyte balance, and growth requirements. There are three categories: traditional SBS, resulting from the loss of enough intestine to create IF; malabsorptive states, such as MVID; and motility disorders, such as intestinal pseudo-obstruction.

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3.4.10 Small Intestinal Transplantation Small intestinal transplantation (SITx) and multivisceral transplantation (MVTx) represent indeed today a reality. The hope became real. In the 1960s and 1970s the first experimental investigations were put in place. SITx and MVTx are a viable alternative to parenteral feeding for treatment of pediatric and adult intractable failure of the gastrointestinal tract. This situation has been possible because numerous factors came to the place, such as improvement of the transplant medical management and posttransplant monitoring, suitable animal models, superior immunosuppression therapies, enhanced surgical techniques, and the growth of knowledge in gut physiology and mucosal immunology among others. Several national insurance programs have approved SITx worldwide, although not in all countries this option is available. In children, the most frequent current indications for SITx are short gut following surgical resection for gastroschisis, volvulus, NEC, Hirschsprung disease, pseudo-obstruction, intestinal atresia, microvillous inclusion disease, and tufting enteropathy. In adolescents and youth, the most frequent current indications for SITx are ischemia, Crohn disease, dysmotility, trauma, volvulus, mesenteric neoplastic processes (e.g., desmoid), and intestinal graft failure. Mostly, there are three types of SITx, including the isolated small intestinal allograft (ITx), with or without colon; the composite liver-SI-allograft (LITx) with transplantation of the liver, duodenum, pancreas, and of course, small intestine, with or without colon; and the multivisceral graft (MVTx) with transplantation of the liver in addition to the same organs seen in the liver-small intestine allograft. The colon is considered optional but is frequently used to increase absorptive capacity in specific settings (e.g., Hirschsprung disease). Once the transplantation takes place, the gastrointestinal allograft (graft) presents the recipient (host) with a sizable alloantigen hematological and parenchymal cellular load harboring the ability to initiate and maintain a forceful and diverse host effector immune response. This response under-

3.4 Small Intestine

lies the immune-based complications that are under continuous monitoring from the medical management team including acute and chronic rejection (host versus graft) as well as direct toxicity from continual immunosuppressive therapy (e.g., renal and neurological) and complications associated with a sustained state of immunosuppression (e.g., multisystemic infections and posttransplant malignancies). The hematolymphoid cell population introduced with the graft is also capable of initiating a graft immune response against the host (i.e., graft-versus-host disease). These immune-based and the numerous nonimmune-­ based complications may also be influenced by several variables such as host innate immunogenetic polymorphisms, immune subpopulations, and the amount of alloantigen disparity between the host and donor. The transplant pathologist uses biopsies and other ancillary markers to identify acute and chronic rejections as well as infections, GVHD, and malignancies. The pathologist plays a significant and/or critical role in the evaluation of patients following SITx, and intense communication with the gastroenterologist and surgeon is vital. The pathologist should know the patient’s history and endoscopic findings, including the location of biopsies, native organ versus graft, and appearance of the mucosa (erosions, ulcers, and irregular mucosa). Protocol allograft biopsies are 2–3 times/week for the 1st  month and 1–2 times/ week for the following 2 months. At least three biopsies per location are needed, because rejection may be focal. The pathologist should also evaluate the adequacy of the biopsies. Each biopsy should include surface epithelium, muscularis mucosae, and superficial submucosa to allow the evaluation of a substantial number of crypts. Inadequate biopsies include biopsies close to the stoma (reactive changes) among others. Routine H&E sections should contain 6 levels per tissue slides to allow the contiguous evaluation of the crypts. If antibody-mediated rejection (AMR) is in the differential, a separate biopsy should be sent fresh or frozen and analyzed by immunofluorescence for C4d. In several laboratories, an immunohistochemical protocol to identify C4d in formalin-fixed and paraffin-

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embedded tissue sections has been established. However, C4d immunohistochemistry on formalin-fixed and paraffin-embedded tissue is, however, challenging and some laboratories still prefer to run the immunofluorescence protocols on fresh tissue. Immunostaining and in situ hybridization should also be performed for cytomegalovirus (CMV) and Epstein-­ Barr virusencoded RNA (EBER), respectively. Adenovirus may be evaluated either by immunostaining or electron microscopy demonstrating the classic crystalline lattice of 72–82  nm viral particles. Early fibrosis is also assessed, and trichrome staining is performed as well. Of course, native tissues (e.g., esophagus, rectum, and skin) and biopsies from allografts (e.g., stomach, small bowel, and large bowel) are often simultaneous procured and often necessary for a complete approach. Native and allograft tissue-based approaches help to distinguish whether changes are exclusive to alloimmune response (i.e., rejection), global and indiscriminate disorders (e.g., infections, PTLD), or graft-originated modifications (e.g., GvHD). Pathologic findings in intestinal grafts include preservation injury, acute cellular rejection, antibody-­ mediated rejection, chronic rejection, infections, and posttransplant lymphoproliferative disorders (PTLDs). Preservation injuries are seen during the first few days following TX and resolve within a week and include mild ischemic-type injury of the superficial mucosa with congestion and superficial wound or drop out of the surface epithelium, partial villous atrophy with regenerative changes in crypts, and minimal or no usually neutrophilic-­ driven inflammation. Acute cellular rejection (ACR) is the leading cause of graft failure in the first 2 months following TX and occurs between 1 and 9 weeks postTX.  Clinically, patients may experience fever, ­ nausea, vomiting, diarrhea, abdominal pain, and abdominal distension with an increase of the stomal effluxion. ACR is based on the apoptotic body count (ABC), which is defined as the ratio between the numbers of apoptotic bodies per ten consecutive crypt cross sections. There have been some techniques to pick up apoptosis in the tissue slides,

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but morphology using a conventional H&E remains the gold standard. Apoptotic bodies are fragments of nuclei and cytoplasm with variable morphology from classic “exploding crypt cells” to “intraepithelial clusters of basophilic material.” ACR is a complication that can occur in GI allografts at any time post-Tx and can be related to factors of new onset (e.g., viral infections), loss of compliance with immunosuppressive therapy, but may also have no identifiable inducing factor. The Lee et al. grading system seems to be the current evaluation method (Lee et al. 1996) with some updates according to Ruiz et al. (2004). An indeterminate grade is inserted between 0 and 1 if ABC 2.5 cm), LN involvement, stage, LVI, perineural invasion, Oddi’s sphincter muscular invasion (staging), signet ring histology (typing), G3 (grading), and positive margins (R-classification). Histologic follow-up of ampullary adenomas in patients with Familial Adenomatous Polyposis (FAP) or other polyposis syndromes is needed because villous adenoma of the papilla of young children with FAP can transform in a malignancy later in life and genetic counseling may be appropriate. Neuroendocrine Neoplasm See the previous section “Neuroendocrine Tumors of the Stomach.” It is one of the most common tumors of the small bowel with ~1/3 of

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patients presenting with concurrent malignancies (intestinal or extraintestinal). Other carcinomas include adenosquamous carcinoma and anaplastic (sarcomatoid) carcinoma that is practically inexistent in childhood and youth.

3.4.12.4 Gangliocytic Paraganglioma • DEF: Rare neuroendocrine tumor (aka nonchromaffin paraganglioma, para-­ ganglioneuroma), usually benign tumor of the second portion of the duodenum (almost exclusively and near ampulla of Vater), and wide age range with no gender preference (♂=♀). • CLI: They can present with abdominal pain, gastrointestinal bleeding, or obstruction and may be an incidental finding at endoscopy or autopsy. • GRO/CLM: Small, submucosal, pedunculated, frequently ulcerated nodule with a tendency to bleed (nonfunctional) and made up of a combination of three cell types: endocrine cells, ganglion cells, and spindle-shaped S-100-­ positive Schwann-like cells. • PGN: Rare metastases and careful assessment before local excision are necessary with pancreaticoduodenectomy if the lesion is large. 3.4.12.5 Other Tumors Other tumors include smooth muscle tumors, which are much more likely to be malignant than esophageal or gastric type, and malignant lymphoma (EATL, IPSID, and de novo lymphomas). Also, other tumors include lipoma, hemangioma, neurofibroma, and granulocytic sarcoma. The most common tumor in the small bowel is by far the metastasis that can often present as multiple polypoid lesions. Pediatric primaries include myofibroblastic tumor foremostly. Metastatic tumors are the most common neoplastic processes in the small intestine. It can often be involved as numerous polypoid lesions. Most common primaries in childhood and youth include rhabdomyosarcoma, malignant melanoma, and germ cell tumors. There are some diseases and conditions that need a Whipple surgical operation, including ampullary carcinoma, cholangiocellular carcinoma, and complications post-Whipple surgery include pancreatic fistula and gastroparesis (early) and malabsorption, alteration in diet and

3.5 Appendix

loss of weight (late), malignancy of the duodenum, malignancy of the head of the pancreas, and nonmalignant conditions (e.g., hyperinsulinism).

3.5

Appendix

The appendix vermiformis of the intestine is found in the cecum between the small and large bowel. It is tremendously rich in lymphoid tissue in young individuals but undergoes atrophy ­during a lifetime. The appendix may also result in early fibrous obliteration, and immunostaining against nerve fibers reveals hypertrophy suggesting that appendix may show a schwannoma-like degeneration during lifetime, at least in some individuals (Box 3.31) (Figs.  3.30, 3.31, 3.32, 3.33, 3.34, and 3.35).

3.5.1 Appendiceal Anomalies The primordium of the cecum and appendix appears in the 6th  week as a swelling on the antimesenteric border of the caudal side of the midgut loop. A tube-shaped cecum is seen more during the fetal period, while a saccule-shaped asymmetric-type cecum is seen in adults more at the end of the fetal period. Congenital anomalies of the appendix anatomy are rare, but it is imperative to be aware of them. There is the possible confusion with other acquired entities, and they may be the basis for an additional pathology. Congenital anomalies of the appendix include agenesis, hypoplasia, duplication, and diverticula. In some genetic syndromes, congenital defects of the appendix can occur, and the pediatric pathologist should know them, in the case of surgical resection or autopsy. Appendix duplication is an extremely rare anomaly (0.004–0.009%

Box 3.31 Appendix

I. Congenital Anomalies II. Vascular Changes III. Inflammation IV. Metabolic and Degenerative Diseases V. Tumors (Treacherous Entities)

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of appendectomy specimens) that was first classified in 1936 according to their anatomic location by Cave and later modified by Wallbridge in 1963. Agenesis of the appendix is a rare anatomic finding; Morgagni reported the first case in 1719. Collins found 1 example in 104,066 appendectomies or an incidence of 0.0009%. The cause of a missing appendix is assumed to be secondary to an intrauterine vascular accident. An arrest of development may occur at any stage and give rise to the absence of cecum and appendix (type 1), blunt conical cecum without appendix (type 2), longitudinal symmetrical cecum with longitudinal muscle bands converging toward its apex but without appendix (type 3), and asymmetric cecum without appendix (type 4). The diagnosis of agenesis should not be made except the ileocecal area, and retrocecal space is methodically explored. Associated mesenteric lymphadenitis is noted during laparoscopy or laparotomy for congenital absence of appendix. However, an autoamputated appendix may also be the focus for inflammation. In other cases, no apparent cause for the patient’s symptoms is found. Congenital absence of the appendix should be a diagnosis of exclusion at laparotomy. Congenital diverticula of the appendix are to be found on the antimesenteric border. It is important to remember that agenesis, duplication, and congenital diverticula may occur in the setting of other congenital anomalies, such as either associations or genetic syndromes. Acquired diverticula of the appendix are not uncommon and consist of an extension or protrusion of the mucosa through the muscularis propria and may differentiate from congenital diverticula because the natural ones have the typical layers of the appendix.

3.5.2 Appendiceal Vascular Changes Hyperemia is a classic feature in the case of “normal”-appearing appendix without evidence of inflammation. Appendiceal necrosis is rarely seen. In newborns, a systemic hypoxic state, including extracorporeal membrane oxygenation (ECMO) and non-ECMO-related CHD or ischemia following NEC or postsurgical procedures, may be the underlying conditions.

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a

b

c

d

e

f

g

h

Fig. 3.30  Congenital anomalies of the appendix are shown in this panel illustrating a congenital diverticulum (a) in a not inflamed appendix and ectopic liver (b, c). The immunostains for Hep-Par1 (d), pan-keratins (e), CK7 (f),

CK19 (g), and CEA (h) confirm the histologic diagnosis of hepatic tissue. CK7 and Ck19 highlight the interlobular bile ducts, while CEA detects the bile canaliculi

3.5 Appendix

345

a

b

c

d

e

f

g

h

Fig. 3.31 Appendicitis with prominent inflammatory myofibroblastic component (a). In (b) is shown an appendicitis with histologic proof of a perforation. In (c, d) are shown microphotographs of a gangrenous appendicitis. In

(e–g) are shown microphotographs of interval appendicitis with foreign body giant cells, while (h) represents a Crohn appendicitis with non-caseous granulomas

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346

a

b

c

d

e

f

g

h

Fig. 3.32  Enterobius vermicularis (a) (H&E stain, x50) highlighted in a particularly suggestive panel with different special stains, including mucin (b), Alcian blue pH2.5

(c), Alcian blue/PAS (d), PAS (e), PASD (f), Giemsa (g), and Grocott Methenamine silver (h) (b–h, x100)

3.5 Appendix

347

a

b

c

d

e

f

g

h

Fig. 3.33  Carcinoid in a gross photograph (a) and several H&E-stained histological sections (b–h)

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348

a

b

c

d

e

f

g

h

Fig. 3.34  Immunohistochemistry of an appendix carcinoid showing positive stains for chromogranin A (CGA), neuron-specific enolase (NSE), CGA, CGA, NSE, synap-

tophysin, AE1-3, and Ki67 proliferation antigen in (a–h), respectively

3.5 Appendix

349

a

b

c

d

Fig. 3.35  Langerhans cell histiocytosis of the appendix is a very rare condition with very few case reports. Here is the H&E of one pediatric case (a–b) confirmed by S100- (c) and CD1a-positive (d) immunostains

3.5.3 Appendicitis • DEF: Inflammation (acute/subacute/chronic) of the appendix. • EPI: 10–30  years, ♂ black; ♂50% crypt involvement, 3 for more than 50 neutrophils/HPF with crypt abscesses, and 4 for acute inflammation and ulceration. • DDX: CD and infectious colitis need to remain on the top of the differential diagnoses. Although at least once a year has been suggested to perform a lower GI endoscopy, it is often performed when the patient is symptomatic or does not respond well to therapy. The endoscope also has the goal to identify early lesions that may be able to transform into malignancy. • PGN: Complications are subdivided in non-­ neoplastic (intestinal and extraintestinal) and neoplastic. Intestinal (bleeding, toxic or ful-

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minant colitis, toxic megacolon, stricture, dysplasia, and neoplasia) and extraintestinal (musculoskeletal system-related peripheral and axial arthritis; osteoporosis, osteopenia, and osteonecrosis; and bony fractures; skin-­ related erythema nodosum, pyoderma gangrenosum, oral ulcers; hepatobiliary PSC (25% are P-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies) positive: more likely to develop primary sclerosing cholangitis or PSC), steatosis hepatis, autoimmune live disease; ocular episcleritis, scleritis, uveitis, iritis, conjunctivitis; hematopoietic-­ related anemia, clotting abnormalities abnormal fibrinolysis, thrombocytosis, endothelial abnormalities, and thromboembolism). Carcinoma: 1% at 10 years, 3.5% at 15 years, 10–15% at 20  years, and 30% at 30  years duration (the incidence is directly proportional to the extension of the inflammatory involvement). Colon-Rectal Dysplasia = Intraepithelial Neoplasia According to Riddell et al. (1983), it is “unequivocal neoplastic alteration of the intestinal epithelium that remains restricted within the basal membrane within which it originated.” Thus, we have three aspects to define IEN, including nuclear abnormalities (atypia), cytoplasmic abnormalities, and growth pattern abnormalities. 1. Nuclear Abnormalities: nucleomegaly (↑N/C), crowding (↑ICD), hyperchromasia 2. Cytoplasmic Abnormalities: altered differentiation (goblet cell depletion) and clonality 3. Growth Pattern Abnormalities: faulty control of cellular proliferation, including glandular crowding, tubular or villous architectural change, and lack of standard of epithelial base-surface maturation “Dysplasia” definitions include negative for dysplasia (NFD), indefinite for dysplasia (IFD), low-grade dysplasia (LGD), high-grade dysplasia (HGD). Dysplasia-Associated Lesion on Mucosa (DALM) is subtyped in (a) Adenoma-­like, which may be indistinguishable from sporadic adenoma, and (b) Non-Adenoma-like, which may present as sessile irregular masses/nodules/strictures.

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Surroundings about dysplasia may be necessary to report as well. Normal or colitis may be found in NFD and sporadic adenoma; otherwise, in all other events, colitis is found. In DALM, an increased architectural disarray, abnormal villous architecture, and inflammation are often seen. Polyps with “top-down” dysplasia have a better outcome (favorable histology) than polyps with “bottom-up” dysplasia or full-­thickness dysplasia. LGD needs to be carefully separated from HGD. LGD are single columnar/cuboidal epithelia with nuclei, which are visible crowded, of elliptical shape, hyperchromatic, but with smooth, delicate nuclear membranes, containing inconspicuous nucleoli, and typical mitotic figures. HGD are single, stratified, or cribriform epithelia with nuclei, which are visibly stratified haphazardly or skewed, enlarged (nucleomegaly), pleomorphic, hyperchromatic, or vesicular, containing prominent nucleoli, and atypical mitotic figures. The deceitful features of IFD are inflammation and regeneration of severe degrees, the technical inadequacy of specimen (i.e., very small, very superficial, misoriented, fragmented, poorly fixed), reactive crypts harboring unusual stratification or hyper-basophilia of nuclei, reactive crypts sheltering superficially villiform mucosa with an inadequate sampling of the basal crypts, and hyperserrated dilated crypts. The relevant immunohistochemistry-supported key features of dysplasia are as follows. 1. Flat dysplasia may be at the base of the polyp stalk or surrounding mucosa. 2. DALM has an irregular architecture and is (+)np53, (+)mβ-Cat, and (−)cBcl2. 3. Adenoma has a regular architecture and is (−)np53, (+)n/mβ-Cat, and (+)cBcl2. 4. Past or present histology (+) for chronic idiopathic IBD is required for DALM. 5. DALM does not require proctocolectomy, but endoscopic mucosal resection is feasible. The rationale for these key features is that APC gene mutations are rare in DALM, which do not show any nuclear staining for β-catenin. Conversely, APC gene mutations are often seen in sporadic adenomas, which leads to loss or a reduction of the protein. APC is a protein that forms part

3.6 Large Intestine

of a complex, which degrades some proteins, including phosphorylated β-catenin. If APC function is lost, there is a reduced breakdown of β-catenin, which accumulates and migrates to the nucleus. Here, it upregulates the transcription of several cell proliferation genes. This situation is demonstrated by IHC with strong nuclear staining for β-catenin in adenomas in addition to the usual membranous staining as seen in DALM. Also, P53 gene mutations are common in DALM with an accumulation of the protein p53 in the nucleus, which can be demonstrated by IHC. Conversely, P53 gene mutations are rare in sporadic adenomas with no avidly collection of P53 protein into the nucleus. Consequently, BCL-2 anti-apoptotic protein is typically overexpressed by epithelial cells in sporadic adenomas as a downstream effect of mutation of the K-ras gene as observed by IHC. Conversely, K-ras gene mutations are rare in DALM, and no (or very faint) BCL-2 staining is seen. Risk and clinical management of dysplasia in UC are also paramount. In sporadic adenoma, the absence of surrounding colitis should be confirmed microscopically, and caution should be used for the pedicle, because it may be dysplastic. Caution should also be spent if the patient is younger than 40 years or lesion recurs after polypectomy. In adenoma-like dysplastic polyp, no flat dysplasia in the adjacent mucosa or elsewhere in colon and caution should be spent if the patient is younger than 40 years or lesion recurs after polypectomy. In adenoma-like dysplastic polyp, it seems that the presence of HGD should not change management. In DALM, flat LGD, and flat HGD, the confirmation of the diagnosis by a second pathologist is mandatory. In flat LGD, it seems that unifocal LGD has a similar risk as well as multifocal LGD (Box 3.44). Box 3.44 Simple Features Favoring Dysplastic vs. Reactive Epithelium

• Diffuse nuclear changes (e.g., hyperchromatic nuclei, macronucleoli, atypical mitoses) • Intraluminal necrosis (“dirty necrosis”) • Lack of base-to-surface epithelial maturation gradient • Loss of cellular polarity

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Most recent literature has highlighted that the molecular pathogeneses of colon-rectal dysplasia and cancer in IBD have some common signals (e.g., TNF-α, IL-6, IL-23), some mediators (e.g., TLR4, NF-κB, cytosine deaminase), and numerous targets (e.g., P53, KRAS, APC, p16/p14, DCC, src) and mechanisms include oxidative damage, chromosomal instability, microsatellite instability, aberrant methylation, TSG mutational silencing, telomere shortening, clonal expansion, growth factors, epithelial-stromal interactions, and epithelial-inflammatory cell interactions. Gene targets associated with CRC in IBD include APC (5q21), DCC/DPC4 (18q21), TP53 (17p13), CDKN2A (9p21), CDKN1B (12p13), E-cadherin, K-RAS, C-SRC, TGFBR2 RII, MSH2, and MLH1. The first six are tumor suppressor genes, the subsequent two are oncogenes, and the last two are DNA mismatch repair genes, while TGFBR2 RII is a TGF-β1 receptor gene. Preoperative IFX use has been associated with more postoperative complications than without IFX use, and colectomy with end ileostomy should probably use within 8 weeks of colectomy in consideration that by 8  weeks, the minimal amount of this anti-­TNF agent remains in the body. Backwash Ileitis The term “Backwash Ileitis” in UC was used initially in 1936 from Crohn and Rosenak to describe the pathologic features and clinical course of 9 patients with a combination of ileitis and colitis, although White first described ileal involvement in 5 of 11 UC patients in 1988 at the Guy Hospital in London. Haskell et  al. (2005) have reviewed the pathologic features and clinical significance of backwash ileitis in UC. Ileal changes showed a variable phenotype, including villous atrophy, crypt regeneration without increased inflammation, increased neutrophilic and mononuclear inflammation in the lamina propria, patchy cryptitis, and crypt abscesses, and focal superficial surface erosions, some with pyloric metaplasia. They also emphasized that the inflammation at this location does not affect the prevalence of pouch complications, alternatively the occurrence of dysplasia or carcinoma.

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3.6.3.2 Infectious Colitides • DEF: Acute self-limited colitis, whose etiology is one or more of the following etiologic agents with edema, inflammation, hyperemia, and hemorrhage. • ETP: Most commonly, Campylobacter, Salmonella, Shigella, and E. coli can cause acute hemorrhagic colitis. Other infectious colitides are amebic with a preference for cecum and ascending colon and flask-shaped ulceration with minimal inflammation. The tubercular disease is most commonly ileocecal, but a tubercular mass (tuberculoma) may be found in ~1/2 of cases. CMV is most widely ileocecal with extensive ulceration, and inclusion bodies are prominent. Cryptosporidiosis represents the most common cause of severe watery diarrhea in patients who have AIDS. 3.6.3.3 “Microscopic Colitis” Microscopic colitis is defined as a chronic or episodic watery diarrhea with radiographically and endoscopically normal bowel and “microscopic” inflammation of the colon. Patients are often >30  years of age, but children and adolescents have been reported; ♂:♀ = 1:6; patients may have an autoimmune disease. Surface epithelium is somewhat flattened with loss of mucin and cytoplasmic vacuolization and is infiltrated by lymphocytes, neutrophils, and eosinophils. Collagenous colitis: Lymphocytic colitis with deposition of ≥10-μm-thick hypocellular collagenous band beneath surface epithelium. Matta et al. (2018) reviewed 12 pediatric patients affected with collagenous gastritis, of which three had associated collagenous colitis. They found that the most common clinical presentation was iron deficiency anemia and a histologic improvement was only identified in one patient who had received oral corticosteroids and azathioprine. 3.6.3.4 Others This group includes Crohn colitis, indeterminate colitis, diversion colitis, radiation colitis, colitis cystica profunda, and (pseudo-)melanosis coli and the reader should be referred to specific textbooks of gastrointestinal pathology.

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3.6.4 Colon-Rectum Neoplasms Pseudopolyps are seen in ulcerative colitis. Lymphoid polyps are localized but may also be diffuse. Juvenile polyps show standard components, but they have arranged abnormally cystic glands with normal or inflamed epithelium, usually in the rectum of young children; Peutz-Jeghers polyps have an arborizing structure and may occur throughout the gastrointestinal tract, adenomas are all dysplastic, but pre-malignant. The malignant potential is proportional to size, villosity, and degree of dysplasia and may be associated with abundant mucus and hypokalemia (Box 3.45).

3.6.4.1 Adenomatous and Serrated Polyps Adenomatous and serrated polyps need to be differentiated, because of the clinical implication and therapy. Adenomatous polyps are subclassified as tubular, tubulovillous, and villous adenoma according to the morphology (villous component). Conventional adenomas have at least low-grade dysplasia, because it is inside of the definition of adenomatous change, including hyperchromasia of the nuclei of the neoplastic enterocytes, depletion of goblet cells, and initial pseudostratification of the nuclei without loss of nuclear polarity or vesicular nuclei with prominent nucleoli among other features, which identify high-grade dysplasia (vide infra). In the pathological report, it is important to emphasize this two-­tiered grading system indicating the absence of high-grade dysplastic or atypical proliferating epithelium with invasion  – invasive adenocarcinoma (“negative for high-grade dysplasia and malignancy”) to avoid over therapy, in addition to the amount of villosity (villous morphology),

Box 3.45 Polyps: Classification

1. Inflammatory (pseudopolyp, benign lymphoid polyp) 2. Hamartomatous (juvenile polyp, Peutz-Jeghers) 3. Neoplastic (adenoma, adenocarcinoma) 4. Others (hyperplastic, lipoma, leiomyoma)

3.6 Large Intestine

and status of the polyp margins. High-risk adenomas is a term used in screening programs for tubulovillous or villous adenomas or any adenomas with high-grade dysplasia or ≥1 cm on the size and need short surveillance intervals. The terms “carcinoma in situ” and “intraepithelial carcinoma” are synonymous with high-grade dysplasia and should be avoided to avoid confusion. Sessile serrated polyps or lesions have been suggested mimicking other polyps characterized by crypt serration with or without low-/highgrade dysplasia (Torlakovic et al. 2008). Serrated polyps may be subclassified as sessile serrated adenomas (SSA); traditional serrated adenoma (TSA); serrated polyp, unclassified (USP); and hyperplastic polyp (HP). It should also be reported by the pathologist, if dysplasia is present or not, because SSA with dysplasia should be considered a lesion with an increased tendency to transform to malignancy and complete removal should be part of the standard of care, including either short-term re-endoscopy and excisional biopsy or surgical resection (Snover 2011). Villosity: if 75– 80% ⇒ Villous adenoma. The term “at least tubulovillous” is recommended, if the polyp is known to be large and at least one villus is observed in a biopsy that results to be small or fragmented. Villi have been classified as classic, palmate, or foreshortened. Classic villi are long, slender upgrowths showing minimal branching and thin stromal cores. However, it may be encountered broader, branching structures, which characterize palmate villi, and leaf-­like upgrowths. In addition, foreshortened villi are slender outgrowths with no branching and thin stromal core. On the other hand, villosity should be distinguished from pseudovillous morphology, such as axially sectioned crypts. High-grade dysplasia is defined on both architectural AND cytologic features, including cribriform pattern with “back-to-back” glands, prominent glandular budding, and intraluminal papillary tufting as well as loss of cell polarity; nuclear stratification through the entire height of the surface epithelium; nuclei with open, vesicular chromatin pattern and prominent nucleoli; atypical mitoses; dystrophic (if any) goblet cells; and prominent

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karyorrhexis (apoptosis). As stated above, an adenoma with lamina propria invasion should be reported as high-grade dysplasia rather than intramucosal carcinoma. Since there are no lymphatics in the lamina propria, there is a negligible risk of a spread to regional lymph nodes. Intramucosal atypical glandular proliferations are not typically accompanied by stromal desmoplasia. Invasive adenocarcinoma is defined as atypical glandular proliferation through the muscularis mucosae into the submucosa (pT1) with usually stromal desmoplasia. The pathologic report should also state if any amount of poorly differentiated (G3) portions, any vascular invasion (blood vessels and lymphatic channels), as well as any positivity (distance in micrometers) of the marginal status are present. It has also been recommended that a distance of the invasive component ≤1000  μm should be reported as a positive margin. Additional optional features may be important and could be part of a requirement in the next future. They include tumor budding (presence of single infiltrating tumor cells or small clusters of tumor cells at the invasive front of the tumor). The Haggitt levels and Kikuchi levels are often difficult to assess, because they require correctly oriented specimens and the muscularis propria, respectively. Serration is defined by the sawtooth luminal aspect of the crypts and identifies four kinds of polyps, including sessile serrated adenomas (SSA); traditional serrated adenoma (TSA); serrated polyp, unclassified (USP); and hyperplastic polyp (HP). Hyperplastic polyp (HP) is characterized by prominent serrations in the luminal halves of crypts with straight and narrow crypt bases and is usually found in the distal colon and rectum. HPs can be further subclassified as microvesicular (mucin), goblet cell-rich, and mucin-poor types. Microvesicular HPs are often found throughout the colon, while the goblet cell-­rich type is predominantly seen in the left colon and rectum. Sessile serrated adenoma (SSA) is characterized by a frequently right colon-sided, flat, ill-defined outgrowth on the crests of mucosal folds with architectural and cytologic abnormalities. These features include deep crypt serrations (serrated architecture is observed throughout the full length of the glands) made up of abnormally located, dif-

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ferentiated cells (goblet or gastric-type) with horizontal spreading and crypt dilation (“boot- or anchor-shaped” crypt bases) and may present dysplasia with identical features as seen in adenomatous polyps. Traditional serrated adenoma (TSA) is characterized by a tubulovillous or villous-like outgrowth with prominent and rigid serrations and ectopic budding crypts, which appear to sprout into the underlying lamina propria. The cells are slender with thin, elongated “penicillate” nuclei and large eosinophilic cytoplasm. LGD/HGD with identical features as seen in adenomatous polyps may be present. Serrated polyp, unclassified (USP) is a lesion with aspects that are felt indeterminate between one type and another (e.g., hyperplastic polyp and SSA or SSA and TSA). Specimen handling and processing are vital for the patient, clinician, and pathologist. Each polyp arising from a different area of the GI tract should be sent to the pathologist in a separate container with adequate fixative and correctly labeled. If multiple outgrowths are from the same area, a unique container can be used, and the electronic or paper-based requisition form should state if the specimen is polyp biopsy (incisional biopsy) or a polypectomy specimen (excisional biopsy). In the pathology laboratory, the following information should be recorded and inserted in the grossing description: number and size of polyps or tissue fragments, as well as the presence of stalks in intact polyps and their length and diameters. Polyps or tissue fragments should be grossed once they are properly fixed, and it depends on the size of the tissue specimen. Formaldehyde penetration and fixation is a slow process, requiring at least 15  h for routine processing of pathology samples, different from monolayers of cultured cells that can typically be adequately fixed in 15–30 min. It is important to remember that a fixative labeled as 10% buffered formalin is only a 4% solution of formaldehyde because 10% buffered formalin is made from a stock bottle of 37–40% formaldehyde or more accurately a 3.7–4% solution of formaldehyde. The penetration rate of formaldehyde is mostly irrelevant to tissue up to 1.5 cm thick, although it is not 2 mm per hour, it is variable. Considering the Fick law and the solid state chemistry the depth of penetration of a specified concentration

3  Gastrointestinal Tract

is proportional to the square root of the time of diffusion. In our context the coefficient of diffusibility is about 3.6. Thus, it has been determined that a 4 mm tissue block is thoroughly penetrated in less than 1 h. Although this is useful for standard H&E tissue slides, additional studies need appropriate binding time. A minimal binding time is 24 h at 22°C and 18 h at 37°C. Thus, an overnight fixation has been suggested to be appropriate in most of the cases. In the follow-up: (a) Re-recto-colonoscopy (RCS) if >3 hyperplastic polyps proximal to the RSC or any hyperplastic polyp >1 cm (b) 5-YSR-Re-RCS for conventional tubular adenomas 5 juvenile polyps of the colorectum, 3.6.4.4 Familial vs. Sporadic Colorectal Neoplasia multiple juvenile polyps throughout the GI tract, and any number of juvenile polyps + family his- Familial Adenomatous Polyposis (FAP), APC/ WNT-related (~2/3) tory of juvenile polyposis. Familial Adenomatous Polyposis (FAP), MMRrelated (~2/3) Peutz-Jeghers Syndrome (PJS) AD inherited, polyposis with multiple character- Hereditary Nonpolyposis Colorectal Cancer istic hamartomatous (arborizing fashion with (HNPCC) glands supported by broad bands of smooth mus- Sporadic Colorectal Cancer (SCRC), APC/ cle) polyps in the colon (30%), small bowel WNT-related (~4/5) (100%), and stomach (25%); mucocutaneous Sporadic Colorectal Cancer (SCRC), MMRmelanotic pigmentation around the lips, mouth, related (  L colon, CRC (SSA, Muc-ACA) • SCRC, APC/WNT-rel.: None, APC, R  L, CRC (SSA, Muc-ACA) Note: HNPCC is also called Lynch syndrome; AD, autosomal recessive pattern of inheritance; AR, autosomal recessive pattern of inheritance

and PMS2, or methylation of the MLH1 promoter. Microsatellites are defined as recurring nucleotide sequences that are distributed throughout the genome. Microsatellites consist of mono-, di-, or higher-order nucleotide repeats, which are more frequently copied incorrectly when DNA polymerases cannot bind them efficiently. Interestingly, nature has ideated a reparative mechanism, which is indeed the MMR system that is responsible for the surveillance and correction of these replication errors. MSI may be detected by either PCR comparing the length of nucleotide repeats in tumor cells and healthy cells (+MSI if the length of repeat sequences from tumor vs. normal cells differs in >30%) or immunohistochemistry. MMR defects may result from a germline mutation in one of the MMR genes followed by a variation on the second allele of that gene (somatic inactivation of the wild-­type allele) or methylation of the promoter of an MMR gene (usually MLH-1). Consequently, there are a loss of protein function and lack of detection by immunohistochemistry. MMR status is critical to assess for prognosis

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(MSI-­associated tumors have a more favorable outcome and less nodal and distant metastases), response to 5-FU, and irinotecan therapy. Irinotecan is a semisynthetic derivative of camptothecin, which is a cytotoxic alkaloid extracted from some plants (e.g., Camptotheca acuminata). Irinotecan and its active metabolite (SN38) target the DNA replication enzyme topoisomerase I, which determines reversible single-strand breaks in DNA during its replication. It seems that stage II MSI tumors do not benefit and might be harmed by 5-FU therapy whereas may be more responsive to irinotecan than microsatellite-­ stable (MSS) tumors and detection of HNPCC or Lynch syndrome. In adult CRC, the mechanisms of tumorigenesis include three pathways: (1) chromosomal instability neoplasia (CIN), (2) CpG island methylator phenotype (CIMP), and (3) microsatellite instability (MSI). The most common pathway is the CIN pathway, which occurs in 70–80% of CRC, whereas the CIMP pathway is the second common pathway to CRC and accounts for about 15% of CRC. Both CIN and CIMP pathways are typically used for the oncogenesis of sporadic CRC in adults. It has been determined that probably approximately 5% of CRC (i.e., 1 in 20 cancers of colon-rectum) develops via the MSI pathway in adults. In childhood CRC, the mechanism of tumorigenesis is not well investigated compared to adult CRC, and a suggested mechanism is the inheritance of biallelic germline mutations of the MMR genes. MSI test and/or IHC are recommended when: 1 . CRC is diagnosed in a patient ≤50 years. 2. Syn-metachronous CRC (or another HNPCC-­ related neoplasm) is found. 3. CRC in a patient ≤60 years exhibiting tumor-­ infiltrating lymphocytes, Crohn disease-like lymphocytic reaction, mucinous/signet ring differentiation, or medullary growth pattern. 4. (+) FH according to the revised Bethesda guidelines. If the tumor shows MSI-high and protein loss by IHC, MMR genetic testing is recommended according to the IHC patterns.

3  Gastrointestinal Tract

386

Box 3.48 Interpretation of IHC Stains for DNA MMR in MSI-H Tumors IHC MLH1

IHC PMS2

IHC MSH2

IHC MSH6

MLH1 Mut

–

–

+

+

MSH2 Mut

+

+

–

–

MSH6 Mut

+

+

+

–

PMS2 Mut

+

–

+

+

N.B.  The red box is “loss” and green boxes are “maintained” nuclear staining. This box has been gathered from Sepulveda Recommendations and Table.

IHC principle: Pathogenic mutations in an MMR gene lead to the absence of any detectable nuclear staining of the gene product by IHC. In CRC with MSI and absent MLH1 expression, BRAF analysis and/or MLH1 promoter methylation studies are recommended (Box 3.48). HNPCC: Virtually 100% negative for BRAF mutation! SCRC: 40–80% positive for BRAF mutation! When a mutation occurs in an MMR gene complex, the ability to repair other random mutations is compromised, and this results in an accumulation of mutations (MSI). The occurrence of these mutations leads to inactivation TSGs and subsequent penetrance of CRC.  Both IHC and mutational analysis for point mutations and large genomic arrangements (duplications and deletions) are instrumental. HNPCC – Lynch Syndrome is defined as mutations in one of the four MMR genes, AD, ~5% of CRC with other tumors at Breast, Ovary, Urinary tract, GI and liver, Endometrium, Skin (“Chateau de BOUGES” mnemonics). The Amsterdam Criteria II include three cases of Lynch-­ associated cancer AND ≥2 successive generations affected of which first-degree relatives of the other two, AND ≥1 with diagnosis  2 cm, deep depth of invasion, N+, M+), mucosa or with condyloma acuminatum or in nonmarginal location, ploidy, grade, and hishemorrhoid specimens. HPV is commonly tology. Anal margin tumors harbor a better detected in these lesions (usually HPV 16, 18) outcome. The cloacogenic carcinoma has and particularly in HIV patients. The risk of both been considered a carcinoma with a slightly prevalence and incidence of high-grade AIN better PGN, but this term is now obsolete. increases as CD4 counting falls. Cytology thin-­ Worse PGN is found in nonkeratinizing basapreps and smears may be helpful for detection. loid and small cell carcinoma. The sensitivity of the cytology is around 85% and Tumors that arise from the columnar epithethe specificity practically half of this figure when lium of proximal zone of the anal canal are considcompared with histology. Anal cytology by the Palefsky method is simple to perform, has a sen- ered rectal tumors because they are usually CK7−/ sitivity and specificity comparable with cervical CK20+ as found in colorectal carcinomas, but

3.7 Anus

mucinous adenocarcinoma may also arise from anal glands or congenital anorectal duplications. • IHC: (+) CK, EMA, CEA, p53, (−) ER, PR. Anal Carcinoma Histologic Variants • Squamous Cell Carcinoma: Nodular, ulcerated, invading deeply and spreading both proximally and distally showing squamous cell differentiation similar to tumors of the skin or upper aerodigestive tract (keratinizing/ well-­differentiated) ± basaloid (worse PGN) and mucoepidermoid differentiation. • Verrucous Carcinoma: Condyloma-like carcinoma with very well-differentiated squamous epithelium with minimal atypia and pushing borders that invade stroma similarly to upper respiratory tract and lower female genital tract lesions (better PGN). • Basal Cell Carcinoma: Mostly of nodular type, this tumor is about 0.2% among all anorectal cancers and etiopathogenetic factors include chronic trauma, chronic dermatitis, nevoid BCC syndrome, TP53 mutation, immunodeficiency, sexually transmitted disease, and arsenic exposure. • Adenocarcinoma: Ulcerated mass with gelatinous consistency showing mucinous epithelium with atypical ductal proliferation and dilated, mucin-filled cysts containing free-­ floating tumor cells (colloid adenocarcinoma) ± granulomatous reaction to mucin. There is Hx. of perianal fistulae and/or vaginal cysts, and the course is indolent with gradual progression. • Clear Cell Carcinoma: Clear cell-dominant anal carcinoma. • Small Cell Carcinoma: Very aggressive variant showing solid nests of small cells with little or minimal cytoplasm, hyperchromatic nuclei with molding, and central necrosis with IHC phenotype (+) CGA, SYN, NSE, CD57). • DDX: Basal cell carcinoma of the anal region needs to be distinguished from basaloid SqCC because of the therapeutic and prognostic implications. Basal cell carcinoma is usually located in the perianal area, while basaloid

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SqCC originates from the anal canal/anorectum. Basal cell carcinoma is distinguished from the basaloid SqCC, because the former shows a particular retraction artifact, uncommon atypical mitoses, no in situ component, and IHC expression of Ber-EP4 and BCL2. SqCC usually has no retraction artifact, common atypical mitoses, in situ component, and IHC expression of CDKN2A and SOX2.

3.7.4.3 Paget Disease • DEF: Erythematous, ulcerated, or eczematous perianal lesion, which may be associated with an underlying local malignancy showing single, occasionally nests or gland-like formations of large, pale-staining to clear intraepidermal carcinoma cells with abundant mucin. Other associations of PD include squamous hyperplasia, fibroepithelioma-like hyperplasia, and papillomatous hyperplasia. • IHC: Mucin (mucicarmine, PAS), CK7, CEA, EMA; ± CK20. • DDX: Gross cystic disease fluid protein 15 (GCDFP-15) is key. PD associated with the primary cutaneous tumor with sweat gland differentiation are GCDFP-15+ and CK20−, while PD associated with an underlying rectal ACA are GCDFP-15−, CK20+, and MUC2+. GCDFP-15 is regulated by the androgen receptor (AR) and is a crucial diagnostic marker for mammary differentiation in anatomic pathology. Animal studies have been performed in mice, in whom anal carcinoma may be induced by chemical carcinogens that can be potentiated using growth factors. 1,2-Dimethylhydrazine (DMH) or symmetrical DMH is one of the two isomers of DMH acting as a DNA alkylating agent whose action may be potentiated using EGF (Zaafar et al. 2014).  Moreover, in preserving the anal continence, the surgeon reflects on two essential components, including the internal and external sphincters. If patients need excision of both muscles of not more than half of the circumference of the anus, anal continence is preserved. Finally, in case an extensive surgery is required, an abdominoperineal resection (APR) is performed.

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3.7.4.4 Nonanal Carcinoma Neoplasms Carcinoid tumor (1/3 have a second tumor, often CRC) Embryonal rhabdomyosarcoma (infants and children, botryoid/diffuse growth pattern, IHC, and TEM evidence of muscle differentiation) GIST (small asymptomatic intramural nodules to large painful masses with + CD117, CD34, DOG1 highly cellular spindle cells and occasional epithelioid morphology; poor PGN if Ø > 5 cm with five mitotic figures/50 HPF) Histiocytic sarcoma (extremely rare in childhood and adolescence) Leiomyosarcoma (most common stromal tumor of the anus, forming a polypoid intraluminal mass and showing – CD117, +SMA spindle cells with oval to moderately elongated, often blunt-ended nuclei and distinct eosinophilic cytoplasm and numerous mitoses) Lymphoma (AIDS and AIDS-associated, EBV ±) Melanoma (Tumor with relatively rare occurrence being as 1/10 as common as squamous cell carcinoma. It is possibly mistaken as hemorrhoid with ~10% 5-YSR. Grossly, there is a single or multiple, polypoid mass(es), which are pigmented and exhibit a growth near the dentate line with histologic similarities to other mucosal melanomas with nests of pigmented epithelioid or spindle cells ± junctional component with lentiginous appearance, crypts invasion, and potential DSR. IHC: (+) S100, HMB-45, MART-1/ Melan-A. PGN is related to tumor size and depth of invasion (≤2 mm: better outcome). 3.7.4.5 Secondary Tumors Metastases to the anus or perianal region are rarities, but rectal carcinomas are most common. Rare cases have been reported from other sites (lung, breast, and kidney). In childhood and youth, embryonal rhabdomyosarcoma and m ­ alignant lymphoma may probably be the most frequent types. 3.7.4.6 TNM Staging and CAP Guidelines The following staging is valid for anal canal tumors; however, perianal tumors, melanoma, carcinoid tumors, and sarcoma need to be

3  Gastrointestinal Tract

excluded. Moreover, stage tumors overlapping the anorectal junction should be considered as anal tumors, if epicenter (not hypocenter) is distal to ≤2 cm proximal from dentate line, and as rectal tumors, if epicenter (not hypocenter) is >2  cm proximal to the dentate line. CIS, carcinoma in situ (Bowen disease, HSIL, AIN II-III); the adjacent organs are vagina, urethra, and urinary bladder, but the direct invasion of the rectal wall, perirectal skin, subcutaneous tissue, or sphincter muscle is not classified as pT4. Moreover, TX, NX, and MX refer to as primary site, lymph node, or distant sites cannot be assessed, respectively. Regional lymph nodes (LNs) are perirectal (anorectal, perirectal, lateral sacral), internal iliac (hypogastric), and inguinal (superficial). An important aspect emphasized in some reports, although not part of TNM, is the identification of single cells or small clusters of cells ≤0.2  mm (i.e., ≤200 μm), so-called “isolated tumor cells” (ITC), found by routine H&E, IHC, PCR, or another method. LNs or distant sites with ITC are classified as pN0 or pM0. In a pathology report, it is mandatory to report the following features: polyp size (at least one dimension), typing or histologic type (squamous cell carcinoma, adenocarcinoma, mucinous adenocarcinoma, small cell carcinoma, undifferentiated carcinoma, other, or undetermined carcinoma), grading or histologic grade (well, moderately, or poorly differentiated, undifferentiated, undetermined grade), depth/extent of invasion (no invasion, indeterminate, lamina propria, muscularis mucosa, submucosa), resection margin (not assessable, positive/negative for tumor, and if negative, closest tumor to mucosal margin is mm as well as information on carcinoma in situ absent/present at mucosal margin), and angiolymphatic invasion (absent, present for large/ small vessels, or indeterminate), perineural invasion, pTNM, and stage. Moreover, the diagnosis of adenocarcinoma is based on % of tumor that forms glands: well, >95%; moderate, 50–95%; poor, 5–49%; and undifferentiated, 2  mg/dL), and persistent (>2  weeks), further investigation to determine the basis for the elevated bilirubin levels and prompt management are indicated. The protracted conjugated hyperbilirubinemia or neonatal cholestasis is a

4.4 Infantile/Pediatric/Youth Cholangiopathies

Box 4.6 Etiology and Clinical-RadiologicBiochemical Investigations for Neonatal/ Infantile Cholestasis (10 Major Categories)

1. Obstructive cholangiopathies (BA and NBAIOC) • Biliary atresia (GGT, ultrasound, HIDA scan, ERCP, liver biopsy) • Choledochal cyst (GGT, ultrasound, HIDA scan, ERCP, liver biopsy) • Caroli disease and syndrome (GGT, ultrasound, HIDA scan, ERCP, liver biopsy) • Neonatal sclerosing cholangitis (GGT, ultrasound, HIDA scan, ERCP, liver biopsy) • Idiopathic biliary system perforation (GGT, ultrasound, HIDA scan, ERCP, liver biopsy) 2. The paucity of intrahepatic biliary ducts (syndromic/non-syndromic Alagille syndrome) (Extrahepatic anomalies, hypercholesterolemia, genetics) 3. Defects of the intracellular transport of conjugated bilirubin • Progressive familial intrahepatic cholestasis (PFIC) (GGT, IHC, genetics) • Cystic fibrosis (CF) (GGT, sweat test, genetics) 4. Infections (TORCH) (TORCH screen, HA/B/CV, and HIV) • Viruses/parasites: CMV, rubella, Reo3, Parvovirus B19, coxsackie, HHV-6, HSV, T. gondii • Bacteria: Sepsis, UTI, L. monocytogenes, late-onset Streptococcus infection, TB, and T. pallidum 5. Metabolic dysregulations • Alpha-1-Antitrypsin Deficiency (AATD) (AAT, IEF, genetics) • Carbohydrate-related disorders (galactosemia, hereditary fructosemia, CGD) • Bile acid synthesis disorders (BASD) • Amino acid metabolism disorders (e.g., tyrosinemia) (succinylacetone, urinary organic acids) • Urea cycle disorders (UCD) (e.g., arginase deficiency) • Mitochondrial hepatopathies

441

• Lipid metabolism disorders and lipoprotein defects (mass spectrometry, liver biopsy) • Total parenteral nutrition (TPN) (chart review, GGT, MDT meetings/rounds) • Peroxisomal disorders 6. Toxin-related disorders • Fetal alcohol syndrome (FAS) (chart review, MDT meetings/rounds) • Breast milk-related cholestasis (chart review, MDT meetings/rounds) 7. Immunological disorders • Neonatal lupus • Neonatal hemochromatosis (congenital alloimmune hepatitis) • ABO blood group incompatibilitylinked inspissated bile syndrome • Autoimmune hemolytic anemia 8. Endocrine gland dysfunctions and • Hypothyroidism hypoparathyroidism • Hypopituitarism and diabetes insipidus • Hypoadrenalism 9. Chromosomal abnormalities (chart review, MDT meetings/rounds, karyotype) • Trisomy 13, 18, 21 syndromes • Non-trisomic chromosomal abnormalities (Turner syndrome, cat’s eye syndrome) 10. Miscellaneous/idiopathic • Non-biliary atresia – “high GGT intrahepatic cholestasis” and idiopathic • Hemophagocytic lymphohistiocytosis (HLH) (ferritin, BMB) • ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) Notes: BMB, bone marrow biopsy; CMV, cytomegalovirus; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma-glutamyl transpeptidase; HHV-, human herpesvirus 6; HSV, herpessimplex virus; HIDA, hepatobiliary iminodiacetic acid; IEF, isoelectrofocusing; MDT, multidisciplinary team; TB, tuberculosis; TORCH, Toxoplasma gondii, other viruses (HIV, measles, etc.), rubella (German measles), cytomegalovirus, and herpes simplex; UTI, urinary tract infections

4  Parenchymal GI Glands: Liver

442

a

b

c

d

e

f

g

h

Fig. 4.8  In (a) is demonstrated a cartoon showing the development of the intrahepatic biliary system in a schematic way to evaluate the number of abnormal structures in infantile cholangiopathies. Using antibodies against CK7 the microphotographs (b) through (h) show the

abnormalities encountered in case of biliary atresia at different days of liver biopsy. It has been stressed in the literature that a Kasai porto-enterostomy may not be efficacious, but actually deleterious in the advanced stages of biliary atresia

4.4 Infantile/Pediatric/Youth Cholangiopathies

heterogeneous group of diseases characterized clinically by an increase of bile acids and alkaline phosphatase other than an increased serum concentration of conjugated bilirubin and pathologically by stasis of bile pigment or feathery degeneration of hepatocytes resulting from stagnation of bile acids (cholatostasis). Neonatal cholestasis represents a challenge for the pathologist in evaluating liver tissue biopsies from affected infants because the list of potential causes of neonatal cholestasis is very extensive. Different categories have been identified, including infectious agents, metabolic disorders, toxins or drugs, genetic or chromosomal diseases, anatomic abnormalities, and different conditions with either mechanical obstruction to bile flow or functional impairment of the hepatic excretory function. Substantially, it is essential to divide neonates with cholestasis into two major categories, i.e., “correctable” and “non-correctable forms.” Conceptually, it is critical to keep separate the class including newborns with primary intrahepatic disease (e.g., an inborn error of bile acid metabolism, syndromic and nonsyndromic form of the paucity of the intrahepatic bile ducts) from the category including newborns with primary extrahepatic disease (e.g., obliterative cholangiopathy of the common bile duct). However, there are practically multiple areas of potential overlap on the clinical, histogical, or biochemical basis. The role of the pathologist and the diagnostic accuracy of percutaneous (needle) liver biopsy in the diagnosis of surgery-correctable forms has been an argument of intense discussion, but remains crucial in the 21st century. Although first studies emphasized the usefulness to perform a liver biopsy in picking up features characteristic of surgerycorrectable cholestatic forms, later studies objected the reliability of the histopathologic diagnosis because divergent opinions arose from several authorities with a failure rate of 33%. Subsequently, a percutaneous liver biopsy was re-evaluated and was seen to correlate reasonably well with open surgery liver biopsy. More recently, the diagnostic accuracy of percutaneous liver biopsy has been reported to be up to 95%. Probably, the problem resides in the impact the multi-etiology of many surgery-correctable

443

cholestatic forms and their diverse morphology have on the developing perinatal liver. In analyzing the changes observed in the hepatocytes and intrahepatic bile ducts in both surgery correctable and non-correctable forms of neonatal cholestasis, overlap situations can still occur. Liver of infants showing extrahepatic bile duct obstruction and the paucity of intrahepatic bile ducts (replacing the previous misnomer of intrahepatic biliary atresia) has been described. Similarly, extrahepatic bile duct obstruction has been found associated with hyperplasia of intrahepatic bile ducts or congenital hepatic fibrosis. To complicate the categorization of the liver histology of infants with neonatal cholestasis, Schweizer postulated the existence of (at least) two forms of biliary atresia with or without associated malformations (e.g., situs inversus, malrotation, polysplenia). The Han ethnics of Chinese population is particularly useful for Genomic-Wide Association Studies. (GWAS) because of the large size and homogeneity of this ethnics. Recently, GWAS found a potential susceptibility locus for BA between the genes ADD3 and XPNPEP1 located with the chromosomal localization of 10q25.1 with replication in independent Chinese and Thai specimens and in a Zebrafish model (Tang et al. 2016). Adducins are heteromeric proteins constituted of different subunits, which are involved in the assembly of the spectrin-actin network in red blood cells and at sites of cell-cell contact in epithelial tissues.

4.4.2  N  on-BA Infantile Obstructive Cholangiopathies (NBAIOC) This spectrum of disorders includes the agenesis and the aplasia of the extrahepatic biliary system and the intrinsic and the extrinsic obstruction of the extrahepatic biliary system. Inherent etiology consists of inflammation with edema of the wall of the extrahepatic biliary tree, the presence of obstruction due to stone or abnormal bile composition. The extrinsic obstructive cholangiopathies include inflammatory or a neoplastic process compressing the extrahepatic biliary system. At neonatal age, one of the most common neoplasms is the neuroblastoma IVS with the presence of neuro-

444

blastoma localized in the liver. Neuroblastoma IVS is able to compress the extrahepatic biliary tree extrinsically.

4.4.3  T  he Paucity of the Intrahepatic Biliary Ducts (PIBD) It is the lack of the scarcity of interlobular bile ducts per portal tract in the liver. PIBD can be divided in a syndromic and a non-syndromic form. The syndromic form also called Alagille syndrome or arterio-hepatic dysplasia reveals hepatic ductopenia, accompanied by cardiac, ocular, facial, and skeletal anomalies. It is an autosomal dominant inherited disease with its gene locus on 20p12 (jagged-1) (JAG1). It can also be associated with other congenital disorders like α1-antitrypsin deficiency, Turner syndrome (Monosomy X0), and Down syndrome (trisomy 21 syndrome). Major hepatic features are chronic cholestasis, portal fibrosis, and progressive decrease or lacking bile ducts in the portal tracts. The bile duct to portal area ratio lies between 0 and 0.4 in comparison with 0.9 and 1.8 in healthy children, according to Alagille definition. Cardiac and renal complications may have severe consequences on the patients’ health, too. A non-syndromic form of bile ducts paucity has not shown a definite association with any genetic, congenital, or metabolic disorders but could be observed in relation with Byler disease, Zellweger syndrome, NiemannPick disease, cytomegalovirus infection, or Alpers disease, to cite just a few of diseases. Bruguera et al. (1992) have also suggested a relationship to idiopathic adulthood ductopenia. Moreover, Ishak (2002), Witzleben (1982), as well as other studies have been pillar for the investigation of this very complex and complicated topic. Alagille syndrome is a genetic disorder involving the correct development of the intrahepatic biliary system which includes first the condition named Alagille syndrome or syndromic paucity of intrahepatic interlobular bile ducts, which is due to either human jagged-1 (JAG1) gene (ALGS1 disease) or Notch homolog 2 (NOTCH2) gene (ALGS2 disease). Some illnesses that not resemble Alagille are grouped under the umbrella of “non-syn-

4  Parenchymal GI Glands: Liver

dromic paucity of interlobular bile ducts” and include several syndromes (Fig. 4.9).

4.4.4  N  eonatal Hepatitis Group (NAG) NH is an intrahepatic cholestatic nonobstructive disorder of viral (HSV, CMV, rubella virus, etc.), metabolic (α1-antitrypsin deficiency, CFTR, galactosemia, etc.), or idiopathic nature (more than 50%) (Box 4.7). Besides cholestasis, lobular inflammation, focal fibrosis and a hepatocellular transformation such as giant-cell -transformation are current main findings. Progressive forms may result in massive fibrosis and liver cirrhosis (Figs. 4.10, 4.11, and 4.12).

Box 4.7 Neonatal Hepatitis Group (NAG)

4.4.4. Neonatal Hepatitis Group (NAG) 4.4.4.1. Bile Acid Synthesis Disorders (BASD) 4.4.4.2. Defects of the Intracellular Transport of Conjugated Bilirubin –– Progressive Familial Intrahepatic Cholestasis Types I–III –– Cystic Fibrosis 4.4.4.3. Infection-Related Neonatal Hepatitis 4.4.4.4. Non-BASD Metabolic Dysregulation-Related Neonatal Hepatitis 4.4.4.5. Toxin-Related Neonatal Hepatitis 4.4.4.6. Immunology-Based Neonatal Hepatitis 4.4.4.7. Endocrine Gland Dysregulation-Based Neonatal Hepatitis 4.4.4.8. Multi-etiologic Chromosomal Abnormality-Associated Cholangiopathy 4.4.4.9. Miscellaneous/Idiopathic NAG

4.4 Infantile/Pediatric/Youth Cholangiopathies

445

a

b

c

d

Fig. 4.9  PIBD CK7 patterns highlight the very few reactive biliary structures located at the periphery with virtual absence of any interlobular bile duct. The microphotographs (a–d) show these different patterns in different

children with PIBD. It is important to remember that an interlobular bile duct should be usually present within three diameters of the adjacent portal artery (anti-CK7 immunostaining)

4.4.4.1  B  ile Acid Synthesis Disorders (BASD) When “neonatal hepatitis” (“giant cell transformation of the lobular hepatocytes”) is prominent, and bile canaliculi show an immunoreactivity using the anti-BSEP and anti-GGT antibodies, bile acid synthesis defects (BASD) become highly likely. In particular, if average or low serum bile acid concentrations, normal or minimally elevated GGT, and absence of pruritus occur in a patient with jaundice and conjugated hyperbilirubinemia, the suspicion for BASD should be high and a clinical-pathological conference or multidisciplinary team meeting should be promptly called. Bile acid synthesis defects are crucial for not only the pediatrician (and pediatric pathologist) but also for the internist and neurologist. It is now demonstrated that BAS defects may present as cerebrotendinous xanthomatosis, myocardial infarction of the young/ middle-aged individual, spastic paraparesis, and early dementia, other than cholestasis/liver dis-

ease at infancy. Synthesis of bile acids from cholesterol requires modifications to the nucleus of the cholesterol molecule and oxidation of the cholesterol side chain. There are two pathways used by the human organism to produce bile acids. They are called “neutral” pathway, which is confined to the liver and usually responsible for the symptomatology in children and adults, and the “acidic” or alternative pathway, which is responsible for the remotion of cholesterol and production of bile acids in extrahepatic organs, mostly the brain and organs rich in macrophages, other than the liver. This latter seems to be usually responsible for the symptomatology in neonates and infants. Bile acids are needed as detergents in the intestinal lumen for the digestion and absorption of fat, and the pumping of bile acids drives fat-soluble vitamins and the secretion of bile by the liver into the canalicular system. Failure to synthesize the standard bile acids leads to inadequate bile flow, which determines the clinical and histologic pictures of cholestasis by retention of compounds generally

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a

b

c

d

e

f

g

h

Fig. 4.10  In this panel are shown microphotographs of neonatal hepatitis (a–c) with numerous giant cell transformation of the hepatocytes, abnormal expression of the polyclonal antibody against carcinoembryonic antigen (CEA) for bile canaliculus (d), and abnormalities of biliary tract (e–h) with numerous biliary duct proliferation units, pseudoacinar transformation of the hepatocytes (“pseudorosettes”), and immunohistochemical phenotype change with acquisition of the biliary phenotype by some

hepatocytes. The microphotographs (a–c) are Periodic acid Schiff with diastase digestion (PASD), x100; PASD, x100; and H&E, x200. The microphotographs (d) through (h) are pCEA, x200; anti-CK7, x50, x100, x100, respectively. The immunohistochemical slides have been performed using either an antibody against the carcinoembryonic antigen (CEA, polyclonal) or against the (cyto-)keratin 7 (CK7, monoclonal) and AvidinBiotin-Complex (ABC)

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a

b

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d

e

f

Fig. 4.11  Several patterns of CK7 expression in infantile cholangiopathies. In (a) is shown a ductopenia not otherwise specified (NOS) (paucity of interlobular bile ducts) in an infant without congenital defects or metabolic storage disorder (anti-CK7 immunostaining, ABC method, x200 original magnification); in (b) is shown some abnormal reaction patterns identified in a patient with Langerhans cell histiocytosis and hepatic involvement (S-100, CD1a positive, not shown) (anti-CK7 immunostaining, ABC method, x200 original magnification); and in microphotograph (c) the same patient with Langerhans cell histiocytosis-associated liver cirrhosis with nodules and pseudonodules (anti-CK7 immunostaining, ABC method, x100 original magnification). In the (d) microphotograph is shown the liver with abnormal reaction patterns, cholestasis, and hyperbilirubinemia in a newborn with necrotizing enterocolitis with hepatic disease (antiCK7 immunostaining, ABC method, x100 original magnification); in the (e) microphotograph is shown the liver

histology of an infant affected with Wissler-Fanconi allergic subsepsis syndrome (WFASS) with cholestasis and hyperbilirubinemia (anti-CK7 immunostaining, ABC method, x160 original magnification). WFASS is a rare rheumatic syndrome that was first described by Wissler in 1944 and Fanconi in 1946 with similar presentation to sepsis and is characterized by polymorphous exanthemas, recurrent high fever, leukocytosis, and arthralgia. In the (f) microphotograph is shown the liver histology of a patient with cholestasis and hyperbilirubinemia and fatty change NOS (anti-CK7 immunostaining, ABC method, x200 original magnification). In the (g) microphotograph is shown the histology of an infant with hereditary fructose intolerance (HFI) (anti-CK7 immunostaining, ABC method, x320 original magnification); while the (h) microphotograph exhibits the liver histology of a patient with glycogenosis 1b (anti-CK7 immunostaining, ABC method, x320 original magnification)

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g

h

Fig. 4.11 (continued)

a

b

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Fig. 4.12  Several patterns of CK7 expression in infantile cholangiopathies. In the (a) microphotograph is shown the liver of an infant with neonatal cholestasis, not otherwise specified (NOS) (anti-CK7 immunostaining, Avidin-Biotin-Complex [ABC] method, x100 original magnification); in the (b) microphotograph is shown the histology of a patient with neonatal cholestasis and congenital lung disease with pulmonary hypertension not otherwise specified (anti-CK7 immunostaining, ABC method, x320 original magnification); in the (c) microphotograph is shown the liver of an infant with cholestasis and Alpers disease (anti-CK7 immunostaining, ABC method, x100 original magnification) (Alpers disease/syndrome is a progressive neurologic disorder that begins during infancy/childhood and is complicated

by serious liver disease and is due to mutations of the POLG gene); in the (d) microphotograph is shown the liver histology of a newborn with neonatal cholestasis and gestation affected with HELLP syndrome (a complication of pregnancy characterized by hemolysis, elevated liver enzymes, and a low platelet count) (anti-CK7 immunostaining, ABC method, x200 original magnification). In the microphotograph (e) is shown the liver histology of an infant with sepsis-related liver disease with diffuse pseudo-acinar transformation (anti-CK7 immunostaining, ABC method, x320 original magnification); in the microphotograph (f) is shown the liver histology of a newborn with biliary atresia (extrahepatic type) (anti-CK7 immunostaining, ABC method, x62.5 original magnification)

4.4 Infantile/Pediatric/Youth Cholangiopathies

e

449

f

Fig. 4.12 (continued)

excreted in bile such as conjugated bilirubin. The deficiency of bile acid synthesis is also responsible for the lack of elevation of GGT, unlike other forms of cholestasis. This situation is due to the deficient detachment of GGT from the canalicular membrane, which is mediated by bile acids. This feature is essential for early recognition of this condition in the setting of neonatal/ infantile cholestasis, although amidation defects do show GGT increase. Bile acids are the final products of cholesterol utilization and represent the major pathway of cholesterol catabolism in mammals. Four primary physiologic functions have been identified, including (1) elimination of excess cholesterol, (2) anti-crystallization of cholesterol in the gallbladder, (3) facilitation of the digestion of dietary triacylglycerols (triglycerides) by emulsifying them and making them accessible to pancreatic lipases, and (4) facilitation of the absorption of fat-soluble vitamins. The liver is the one organ where their full synthesis can occur, although some of the enzymes involved in the biogenesis may be expressed in several cell types. Bile acids are essential for the solubilization of dietary cholesterol, lipids, fatsoluble vitamins (A, D, E, K), and some other important nutrients. Bile acid synthesis needs the interaction of 17 enzymes occurring in multiple intracellular compartments, including endoplasmic reticulum, mitochondria, peroxisomes, and cytosol. In human bile, the most abundant bile acids are chenodeoxycholic acid or CDCA (45%) and cholic acid or CA (31%), which are referred to as the primary bile acids. There are two pathways for the biosynthesis of the bile

acids, including the classic or neutral and the alternative or acidic pathway. In rodents, the acidic pathway can account for up to 1/4 of total bile acid synthesis, while in humans it accounts for about 1/20 of total bile acid synthesis. The reaction catalyzed by the 7-α-hydroxylase (CYP7A1) is the rate-limiting step of the total bile acid synthesis hydroxylating the molecule of cholesterol at the position 7. The 7-hydroxycholesterol is changed into CDCA and CA using several steps. Another important limiting step is due to the action of 3β-hydroxy-Δ5-C27-steroid oxidoreductase, which is encoded by HSD3B7 gene. It initiates the epimerization (a stereochemistry process where an epimer is produced to transform into its chiral counterpart) of the cholesterol molecule at the three positions when the hydroxyl group in the β-orientation is converted in α-orientation. CA is distinct from CDCA because CA derives from intermediates of the HSD3B7 gene product on molecules where CYP8B1 can act, while CDCA escapes the action of CYP8B1. The enzymatic activity of CYP8B1 is crucial in determining the CA/CDCA ratio. CYP8B1 is regulated by the end products (CA and CDCA) using their regulation of the nuclear receptor FXR.  The mitochondrial enzyme sterol 27-hydroxylase (CYP27A1) generates bile acid intermediates, which are subsequently hydroxylated on the position seven by oxysterol 7α-hydroxylase (CYP7B1) (alternative pathway). The alternative or acidic pathway appears to play a major role in infancy and as a means to control cholesterol levels in extrahepatic tissues, mainly the nervous system. The

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secretion of the bile acids may occur following their conjugation via an amide bond at the terminal carboxyl group using either glycine or taurine, which are two amino acids. The glycol- and tauro-conjugates are essential to increase the amphipathic nature of these molecules making them more able to be secreted. The conjugated bile acids are the major solutes in human bile which are converted to salts in the presence of sodium (bile salts). Bile salts are, then, secreted from hepatocytes into the bile canaliculi using a bile salt export protein (BSEP; an ATP-binding cassette B11, ABCB11). MDR3, aka ABCB4, is necessary for the transport of phospholipids into the bile canaliculi. MDR3 deficiency is a very confusing topic because the terminology is a difficult topic. In fact, MDR3 deficiency applies to several disorders including not only progressive familial intrahepatic cholestasis (PFIC) type 3, benign recurrent intrahepatic cholestasis (BRIC), low phospholipid associated cholelithiasis (LPAC) syndrome, transient neonatal cholestasis (TNC), but also adult biliary fibrosis/cirrhosis, and some cases of intrahepatic cholestasis of pregnancy (ICP) and drug induced cholestasis (DIC). All these disorders are determined by mutations of the ABCB4 gene. Bile salts, phospholipids, and cholesterol are transported from the bile canalicular system into the interlobular bile ducts, segmental ducts into the gallbladder, where they are concentrated to form bile. In addition to these compounds, electrolytes, minerals, some proteins, bilirubin, and biliverdin pigments account to complete the mixture of bile. The bile salts primary role is to solubilize cholesterol preventing cholesterol crystallization and subsequent gallstone formation (Admirand and Small, 1968). Lipid consumption induces the secretion of cholecystokinin (CCK) from duodenal enteroendocrine I cells. CCK binds to an epithelial receptor of the gallbladder. This process promotes the contraction of smooth muscle cells of the gallbladder and, subsequently, the relaxation of the sphincter of Oddi. The gallbladder-arising intraduodenal micelles promote the absorption of fat-soluble vitamins as well as the digestion of lipids by pancreatic enzymes. The enterohepatic cycle is complete

4  Parenchymal GI Glands: Liver

when bile salts are reabsorbed using an apical Na+-dependent bile transporter (ASBT). ASBT is located in the brush border of the intestinal surface cell or enterocyte. About 95% of bile salts are reabsorbed into the distal ileum. The intra-enterocytic transport from the cytosol of the basolateral membrane occurs using the ileal bile acid-binding protein (IBABP, aka fatty acidbinding protein subclass 6 or FABP6). The transfer from the basolateral membrane into the bloodstream occurs via a heterodimeric transporter of organic solutes (OSTα/OSTβ). Some small percentage of bile salts stay intraluminal and undergo deconjugation by intestinal bacteria before being either adsorbed or converted into secondary bile acids. These secondary deconjugation products are deoxycholate (DCA) and ursodeoxycholate (UDCA) from CA and lithocholate (LCA) from CDCA.  These compounds are either excreted in the stools or passively adsorbed from the colon. Both primary and secondary bile acids are transported back to the hepatocytes via the bloodstream using a Na-Na (Na+)-taurocholate cotransporting polypeptide (NTCP/SCL10A1) and organic anion transporters (OATP) like OAT1B2. Regulation of bile acid homeostasis occurs through the action of some important receptors, the farnesoid X receptors (FXRs) , which belong to the superfamily of nuclear receptors including the steroid/thyroid hormone receptor family, liver X receptors (LXRs), retinoid X receptors (RXRs), and the peroxisome proliferator-activated receptors (PPARs). Bile acids are physiologic FXR ligands, being CDA the most potent activator of human FXR. FXR targets mostly the small heterodimer protein (SHP) gene, which represses the expression of CYP7A1, but also SREBP-1c or sterol 12α-hydroxylase, and solute carrier family 10 (or sodium/bile acid cotransporter family), member 1, which is identified as the Na+taurocholate cotransporting polypeptide (NTCP). FXR also interacts with BSEP, MDR3, and MRP2. Interestingly, gene mutations altering the steric structure of BSEP and MDR3 are associated with PFIC types 2 and 3, respectively, while gene mutations affecting MRP2 are associated with Dubin-Johnson syndrome.

4.4 Infantile/Pediatric/Youth Cholangiopathies

Inborn Errors of Bile Acid Synthesis The combined use of mass spectroscopy and gas chromatography on blood, urine, or bile has been able to identify nine defects in the synthetic pathway. The ESI-MS or electrospray-ionization tandem mass spectrometry is used to screen BASD analyzing urinary cholanoids (bile acids and bile alcohols). The infants usually present with a neonatal hepatitis-like syndrome (lobular involvement > portal tract involvement) and absent or low bile acids and direct hyperbilirubinemia. An essential biochemical clue may be the average serum level of gamma-glutamyl transferase (GGT) found in patients affected with BASD, as seen in PFIC-1 and PFIC-2. GGT is an enzyme synthesized in the hepatocytes and secreted into the bile and then reabsorbed by damaged bile duct epithelial layer. Bile acids promote the detachment of GGT from the canalicular membrane. Thus, in the absence or low bile acids, there is no plasmatic elevation of GGT. The liver is damaged in BASD due to the lack of usual choleretic influence of CA and DCA and due to the intrahepatocytic accumulation of metabolic intermediates. Metabolic intermediates are constituted by hydrophobic bile acids, which are hepatocytic- and cholangiocytetoxic. In comparing classic NH with BASD, some histologic clues may point to BASD, although clinical presentation and course may be quite variable with the life-threatening infantile cholestatic liver disease to pediatric/adult progressive neurological disease with signs of upper motor neuron damage (spastic paraparesis). Histologic clues of BASD are more common giant cell necrosis than NH and cytotoxic interface hepatitis with cholate stasis (swollen and necrotic cholangiocytes in the smallest Herring ductules) accompanied by normal interlobular bile ducts. CYP7A1 (Cholesterol 7α-hydroxylase) Marked elevation of total cholesterol and LDL, cholelithiasis, premature coronary and peripheral vascular disease, statin-resistant hypercholesterolemia, no liver dysfunction are the features.

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CYP27A1 (Sterol 27-hydroxylase) or Cerebrotendinous Xanthomatosis • LAB: ↑ bile alcohol glucuronides in serum and ↑ of plasma cholestanol: cholesterol ratio in the urine. 1. Life-threatening neonatal cholestasis 2. Infantile chronic diarrhea with develop mental delay/regression and accompanied by bilateral cataracts (progressive neurological dysfunction) 3. Adult upper motor neuron disease with spastic paraparesis, IQ fall/early dementia, ataxia, and dysarthria with seizures and/or peripheral neuropathy, xanthomata, premature atherosclerosis with myocardial infarction in the 4th decade, and osteoporosis leading to pathological skeletal fractures. CYP7B1 (Oxysterol 7α-Hydroxylase) Neonatal cholestasis, hepatosplenomegaly, cirrhosis, liver failure, marked an increase of serum ALT and AST with or without associated neurologic co-morbidity (AR-inherited spastic paraplegia 5A or SPG5A), being these patients more prone to have mutations of the gene encoding for CYP7B1. • LAB: Marked increase of serum BA, mainly 3β-Δ5-mono-hydroxy bile acids and an increase of sulfate and glycosulfate conjugates of 3β-Δ5-mono-hydroxy bile acids and no primary bile acids in the urine. • CLM: Giant cell hepatitis, marked fibrosis/cirrhosis, and steatosis of micro- and macrovesicular type. HSD3B7 (3β-δ5-C27-steroid Oxidoreductase) • CLI: Hepatomegaly with jaundice, pruritis, steatorrhea, and fat-soluble vitamin deficiency (e.g., “nutritional” rickets). • LAB: Decrease or absent primary bile acids in serum and increase of dihydroxy- and trihydroxy cholenoic acids as well as a decrease of or missing primary bile acids in the urine.

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• CLM: Giant cell change of the hepatocytes and hepatocyte disarray with cholestasis and cholatestasis as well as bridging fibrosis and late-onset liver disease with malabsorption. • PGN: Good response to bile acid replacement therapy. AKR1D1 (or SRD5B1) (Δ4-3-Oxosteroid-5β-reductase) HSD3B7 deficiency like presentation, but earlier with the more severe liver disease, neonatal cholestatic jaundice, evidence of fat-soluble vitamin malabsorption, prolonged prothrombin, and progressive cirrhosis. • LAB: ↑ 3-oxo-Δ4 bile acids, increase of all bile acids and a decrease of primary bile acids in serum and increase 3-oxo-Δ4 bile acids, an increase of all bile acids, and a reduction of primary bile acids in the urine. • CLM: Giant cell hepatitis with steatosis and extramedullary hematopoiesis of the liver as well as “neonatal hemochromatosis”-type iron accumulation in several tissues. • PGN: Bile acid supplementation is efficient, but treatment should be started before the liver is irreversibly damaged. AMACR (2-Methyl acyl-CoA Racemase) Neonatal cholestatic liver disease with severe fatsoluble vitamin deficiencies, hematochezia, as well as adult-onset peripheral motor neuropathy of sensory type. • LAB: ↑ C27 trihydroxycholestanoic and pristanic acid, ↓ primary bile acids with normal LCFA and phytanic acid in serum, and ↓ primary bile acids in the urine. Bile Acid Conjugation Defects • CLI: Transient neonatal cholestasis and fat soluble vitamin deficiencies. • LAB: Increase of unconjugated CA and DCA and absence of CDCA in serum and absence of glycine and taurine conjugates and presence of cholic glucuronidated and sulfates and unconjugated cholic acid in the urine.

4  Parenchymal GI Glands: Liver

4.4.4.2  Defects of the Intracellular Transport of Conjugated Bilirubin Substantially, progressive familial intrahepatic cholestasis I, II, and III types and cystic fibrosis (mucoviscidosis) play a significant role in this subgroup. Progressive Familial Intrahepatic Cholestasis (PFIC-1-3) The hepatic uptake of bile salts, organic anions, and cations are regulated by the sodium-dependent taurocholate cotransporter protein (NTCP), organic anion transporters (OATP1–2), and organic cation transporter (OCT1) at the basolateral membrane of the hepatocyte. These transporters are not directly ATP-dependent for their function. ATP-dependent function is mostly vital for transporters mediating the secretion from the liver to bile drainage system (ATP-binding cassette proteins or ABC) with several members including the P-glycoprotein (MDR), the multidrug resistance proteins (MRPs), the cystic fibrosis transmembrane regulator, the transporter associated with antigen presentation (TAP) proteins, and a peroxisomal long-chain fatty acid transporter. Three proteins are at the basis of PFIC-1-3. It is important to remember that phospholipids are required in bile for the protection of the canalicular membrane and of the cholangiocytes from the toxic effects of high concentrations of bile salts, and this protection is achieved by using mixed micellar formation. Translocases and Transporters of the Hepatocyte Membrane ATP8B1 (18q21-22) encodes for FIC1 located in the canalicular membrane of hepatocytes, cholangiocytes, enterocytes, pancreas, among other tissues/organs (P-type ATP-dependent aminophospholipid flippase translocating phosphatidylserine from outer to inner leaflet of bile canalicular membrane). Gene mutations, inherited in an AR fashion, can cause PFIC-1 (Byler disease), ICP, and BRIC according to the presence of modifier and modulator genes. Clinically there is a serum increase of bile salts, normal GGT, decrease bile acid secretion, and conse-

4.4 Infantile/Pediatric/Youth Cholangiopathies

quent pruritus, jaundice, and diarrhea. Therapy includes partial external biliary diversion, rifampicin, and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR) inhibitors, such as simvastatin. In the case of milder functional defects, BRIC is diagnosed, which manifests with recurrent cholestatic/icteric attacks but no progression toward liver cirrhosis. Greenland familial cholestasis (GFC) also is associated with PFIC-1 gene mutations. This gene, which is on chromosome 18, is also mutated in the milder phenotype, benign recurrent intrahepatic cholestasis type 1 (BRIC1). Byler disease (BD), also called progressive familial intrahepatic cholestasis (PFIC), is of autosomal recessive inheritance. Two specific gene defects could be identified: PFIC-1 located on 18q21.22 and PFIC-2 situated at band 2q24. Low serum levels of GGT activity are linked to these defects. Progressive cholestasis is accompanied by histomorphology changes including the lack of the intrahepatic bile ducts, giant cell transformation of the hepatocytes, and intensifying fibrosis. Final cirrhosis leads to death in late infancy or early childhood. ABCB11 (2q24) encodes for BSEP located in the canalicular membrane of hepatocytes (ATPdependent bile salt exporter protein toward the lumen of the bile canaliculus), and gene mutations (AR inheritance) can cause PFIC-2, ICP, and BRIC as well as mixed cholelithiasis. ABCB4 (7q21) encodes for multidrug resistance protein 3 or MDR3 located in the canalicular membrane of hepatocytes, macrophages, cerebral vascular endothelial cells, among other tissues/organs (ATP-dependent phospholipid floppase translocating phosphatidylcholine from inner to outer leaflet of bile canalicular membrane), and gene mutations (AR inheritance) can cause PFIC-3, ICP, drug-induced cholestasis, cholesterol cholelithiasis, and “cryptogenic” cholangiopathic cirrhosis. In PFIC-3 jaundice and pruritus are associated with hepatosplenomegaly and portal hypertension. Therapy: ± UDCA.  Even though ICP is a limited disease, which resolves after delivery, it may be related to stillbirth, premature births, or other complications of the fetus (Dixon et al. 2017). In summary, clinically and biochemically, PFIC-3 is

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differentiated from PFIC1-2 due to high GGT, while PFIC-1 is differentiated from PFIC-2 by the occurrence of extrahepatic symptoms, such as diarrhea or pancreatic insufficiency, which are characteristics of PFIC-1, but not of PFIC-2. Histologically, PFIC-2 can be diagnosed by the absence of BSEP-2 immunohistochemical reactivity from the canaliculi using BSEP-specific antibodies (Box 4.8). A rabbit polyclonal and a mouse monoclonal antibody are commercially available. Most often, the immunogen is the recombinant fragment corresponding to human ABCB11/BSEP between the amino acids at position 474 and 745 (internal sequence).

Box 4.8 PFIC Group of the “Three Musketeers”

PFIC-1: ATP8B1 on 18q21-22  ⇒  ¬ FIC1 ⇒ ↓ Bile secretion into bile with normal GGT PFIC-2: ABCB11 on 2q24 ⇒ ¬ BSEP ⇒ ↓ Bile secretion into bile with normal GGT PFIC-3: ABC B4 on 7q21 ⇒ ¬ MDR3 ⇒ No secretion of PC into bile with ↑ GGT Notes: The use of the term three musketeers is linked to the close liaison that all three diseases may have in the dysregulation of the hepatocytic bile flow. GGT gamma-glutamyl transpeptidase, PC phosphatidylcholine, ¬ abnormal

Cystic Fibrosis An AR-inherited disease characterized by the accumulation of thick, sticky mucus that can damage several organs. The most affected organ is the lung, but other organs are also affected, among them the pancreas and liver. The features of CF and its severity vary among affected individuals. Mutations in the CFTR (cystic fibrosis transmembrane conductance regulator, an ATPbinding cassette subfamily C, member 7) gene on 7q31.2 cause cystic fibrosis. The gene product is a protein making a channel that transports negatively charged chloride

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ions into and out of cells. Mutations in the CFTR gene interrupt the correct functioning of the chloride channels, preventing them from regulating the flow of chloride ions and, of course, water across cell membranes. At the cholangiocellular level, CFTR gene mutations may determine cholestasis in the liver, and hepatobiliary complications may occur with evolution to secondary biliary cirrhosis. CF diagnosis relies on >1 characteristic phenotypic feature and one out of three laboratory findings: an elevated sweat chloride concentration on two occasions, one of the two most frequent CFTR gene mutations (ΔF508, i.e., deletion of the three nucleotides that comprise the codon for phenylalanine at position 508), and the demonstration of abnormal nasal epithelial ion transport (Box 4.9).

Box 4.9 CF Liver Patterns Pattern Rate “Transaminitis” 10– 35% Neonatal 100  μg/day. Primary tumor infiltration may be an embryonal sarcoma, hepatoblastoma, hepatocellular carcinoma, rhabdomyosarcoma, teratoma, and hemangioendothelioma. Secondarily, the liver may be infiltrated by neoplasms of adjacent organs such as the adrenal glands/paraganglia (neuroblastoma), kidney (Wilms tumor), and lymph nodes (Hodgkin lymphoma and NHL). These neoplastic processes interfere with the complex metabolic processes that run in the liver determining a dysregulation at different time of the neoplastic infiltration. A standard feature of many metabolic disorders is represented by pericellular fibrosis that may exquisitely help to distinguish these disorders from other more common causes of fibrosis, such as chronic active hepatitis. Chronic active hepatitis is usually characterized by a more confluent portal fibrosis. On the other hand, prominent microvesicular steatosis in the liver of a child with hepatomegaly and with or without subsequent portal hypertension does not necessarily point to a primary dysregulation of the lipid utilization pathway. Hepatic fatty change may coexist as a confounding variable in several and different metabolic defects, either of poor metastasis intake or because the primary deficiency intrinsically interferes with lipid processing or lipid utilization.

4.5 Genetic and Metabolic Liver Disease

Acute liver disease etiologies include viral hepatitis A and B viruses, Reye syndrome, and cystic liver diseases. Systemic diseases involving the liver include cystic fibrosis, sickle cell disease, obesity, TPN, celiac disease (AIH, PSC, PBC, “transaminitis” an increase of liver enzymes), PSC, IBD, Langerhans cell histiocytosis (LCH), hemophagocytic lymphohistiocytosis (HLH), muscular dystrophies, and inborn errors of glycosylation (carbohydrate-deficient glycoprotein syndromes).

4.5.1  Endoplasmic Reticulum Storage Diseases (ERSDs) Endoplasmic reticulum storage diseases are a group of metabolic disorders with an accumulation of undigested material or inappropriately stored content in the endoplasmic reticulum of a cell (Box 4.11). Box 4.11 ERSD(s)

4.5.1.1. Alpha-1-antitrypsin deficiency (AATD) 4.5.1.2. Non-AATD endoplasmic reticu lum storage diseases

4.5.1.1  Alpha-1-antitrypsin Deficiency (AATD) Alpha-1-antitrypsin (AAT) is a serum acute phase protein with essential roles in the inflammation and other processes of the body and is synthesized in the ER and glycosylated in the Golgi complex. AAT deficiency (AATD) is probably doubtless the prototype for an ERSD along with diseases such as Alzheimer disease and Parkinson disease. AATD may also be considered a disorder of protein structure and degradation affecting a selected group of proteins called “serine proteases.” This group of diseases has also been collected together under the name of serpinopathies, and the gene encoding AAT is on 14q31-32.3 and has labeled SERPINA1. The gene comprises four expressing regions or coding exons (II, III, IV, V) and three additional exons (IA, IB, IC) on 5′.

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Promoters, responsible for the steady state of the protein, and enhancers, accountable for expression during inflammatory states, are distinct. They are specifically regulated through different mechanisms in hepatocytes and monocytes, which are the two critical cells that produce AAT.  In hepatocytes, there are discrete binding sites that provide well distinct pathways able to regulate the acute phase response through different cytokines interaction (Fregonese and Stolk, 2008). Among others, the control of the local transcription is associated with sites located upstream of HNF-1a and HNF-4, which are two binding sites. Probably, the humoral regulation is mostly mediated by IL-6 and oncostatin-M.  In monocytes and other cell types, the promoter for SERPINA1 is regulated by a distinct group of transcription factors aka “SP1 family.” Alternative transcripts and stability of the gene product are also physiologically significant. RNA stability explicitly influences gene expression, and some gene transcripts seem to be quite more stable than others. This situation may be particularly relevant for therapy purposes as well. A defective gene in a cell type, e.g., monocyte, may be corrected by transfection of small DNA fragments of the unaffected gene to result in increased protein secretion. More than 100 genetic variants of SERPINA1 are known, although the most common and clinically essential alleles leading to AATD are the Z and S alleles, while the normal allele is M. The Z allele is higher in Scandinavian countries, while the S allele is highest in Spain and Portugal. Alphabet letters are derived from the migration of the protein through a 5% polyacrylamide gel electrophoresis (PAGE) (pH 4–5) with isoelectric focusing (IEF) usually performed at 1400 volts or 40–50  mA for 1.5  h on an electrophoresis unit. Each protease inhibitor (Pi) type shows a characteristic set of bands from top to bottom on PAGE and is reported as Pi phenotype. Each chromosome is responsible for its gene transcription. Thus, AATD is an autosomal co-dominant inherited disease. • EPI: The Z allele frequency varies in different geographic regions, being the highest in Northern Europe with a value of 0.0140

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among Caucasians. In North America, the Z allele is 0.0092 and in Australia and New Zealand is 0.0151, whereas values of 0.0002 and 0.0061 have been reported in Japan and South Korea. In the remaining parts of Asia, Z allele varies from 0.0036 in Southeast Asia to 0.0056 in the Middle East. • CLI: Clinically significant disease states occur mainly with PiZZ, PiSZ, and PiNull (or PiQ0), the latter defined as no protein is produced due to a stop codon. Clinically, individuals affected with AATD may have a widely variable spectrum of disease, ranging from asymptomatic individuals to patients with fatal liver or lung disease. PiZZ and PiSZ are well-known risk factors for the development of respiratory symptoms, such as dyspnea, coughing, earlyonset emphysema, and airflow obstruction in youth. The 52 kDa AAT protects in the pulmonary parenchyma the healthy and fragile alveolar tissue from proteolytic damage by enzymes like elastase released by neutrophils during inflammatory states. Neonatal hepatic syndrome with prolonged jaundice after birth with conjugated hyperbilirubinemia and abnormal liver enzymes can also be seen. In about 10% of neonates, however, there is frank jaundice. • In AATD, the Z allele is the most important genetic defect. It corresponds to Glu → Lys at position 342 of DNA. The Z allele-derived protein has an abnormal polymerization in the hepatocytes with aggregation in the ER and consequently reduced secretion and naturally decreased serum AAT concentration. The Glu to Lys amino acid substitution disrupts a crucial salt bridge in a beta-pleated sheet region of AAT. It allows the reactive loop from one molecule to insert itself into the beta sheet of an adjacent molecule. The PiS phenotype corresponds to Glu264Val, which has no dramatic consequences as observed in the PiZ phenotype. • CLM: AATD liver disease is due to continuous polymerization and consequent accumulation of the protein and formation of light microscopically identifiable cytoplasmic inclusions, which are more evident in chronic inflammatory states in childhood or more often at adult

4  Parenchymal GI Glands: Liver

age. AATD neonatal type shows, histologically, the characteristic triad of cholestasis, the giant-cell transformation of the hepatocytes, and PIBD, in the absence of the above mentioned cytoplasmic inclusions (Fig.  4.15). Thus, a pitfall may be to diagnose AATD by the simple identification of inclusions. The fate of AATD liver disease is liver cirrhosis with or without neoplastic transformation (HCC and CCA). In AATD, the inclusions are PAS+ and diastase resistant, round to oval cytoplasmic globules and located in the periportal regions of the liver. Small AAT globules may be difficult to distinguish from lipofuscin, iron, or fibrinogen or even giant mitochondria. Thus, the wise use of special stains and immunohistochemistry using an antibody against the AAT molecule or, also, the Glu-Lys protein (or protein from Z allele) is of enormous help (Callea et al. 1991). Moreover, nonspecific inclusions are associated with congestion and mostly centrilobular rather than periportal. Giant mitochondria are usually not periportal and are PAS negative. Mallory hyalin is irregular in shape rather than round and located more often in the centrilobular areas rather than periportal regions with the exception of the Mallory hyalin occurring in cholate stasis. On the other hand (“unwise use”), immunohistochemistry may lead to false-positive results, because a diffuse granular cytoplasmic staining without granulopoiesis may be detected in several disease states, including various regeneration and degenerate conditions. Finally, PiMM phenotype may occasionally be observed also with an accumulation of AAT. Genotyping of these patients characterizes a special group, called “M-like” AAT molecules. These AAT molecules harbor peculiar mutation leading to normal Pi phenotype on usual IEF but are detectable with IEF using a restricted range of isoelectric pH or molecular techniques, such as DNA sequencing. A few AAT molecules have been characterized and include M-Duarte, M-Malton, or M-Cagliari. Electron microscopy investigation shows a characteristic accumulation of finely granular material, which is located in dilated

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a

b

c

d

e

f

g

h

Fig. 4.15  Alpha-1-antitrypsin deficiency is associated with fibrosis and cirrhosis and the presence of eosinophilic, PAS-positive, and diastase-resistant periportal globules that are expression of an accumulation of alpha1-antitrypin (a–e). Some patients may show an impressive and fast developing perihepatocytic (peri-sinusoidal) collagen fiber deposition that may points to a rapid deterioration of the liver with need for the patient to be considered for liver transplantation in the near future. In

fact, the liver is unable to excrete this protein because a mutation alters the 3D structure allowing the protein to keep stacked in the endoplasmic reticulum. As expression of the endoplasmic reticulum storage disorder, there is accumulation of granular material in the endoplasmic reticulum of the hepatocytes as observed in the transmission electron microscopy (h). Cholestasis is present (f) and proliferating biliary structures (g) are seen at the periportal areas

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cisterns of the rough endoplasmic reticulum and is moderately electron-dense. The ultrastructural evidence is particularly useful in the evaluation of neonatal or infantile cholestasis with AATD, because of the infrequent histologic evidence of periportal globules. AATD lung disease develops in some individuals harboring AATD deficiency. In the lung, AAT that is released into the serum by the hepatocytes enters by diffusion, where it inhibits neutrophil elastase. The inhibition of neutrophil elastase is fascinating because of the proteolytic cleavage of the reactive loop of AAT by elastase. The division of this peptide bond determines the N-terminal portion of the circle to insert into the main beta sheet structure of the AAT molecule. Thus, the elastase becomes trapped against the inhibitor, which leads to its internalization and following degradation of the protease/inhibitor complex by lysosomes. Interestingly, AAT plays a role of competition/inhibition with leukocytic elastase. Reaction kinetics favors elastase complexing with AAT rather than with the elastin molecule, which is its substrate. If transplantation of a liver from a donor with M-type genotype is useful for reverse AATD, treatment of lung disease includes intravenous AAT augmentation therapy, annual flu vaccination, and a pneumococcal vaccine every 5 years. Non-hepatic/non-pulmonary AATD-related diseases include panniculitis and glomerulonephritis among other complications. In the UK study, four categories are recognized, which are listed in Box 4.12.

Box 4.12 AATD Liver Disease Categories

1. Gradual improvement and normal liver by the age of 3–10 years 2. “Transaminitis” (e.g., persistent, abnormal serum AST) 3. Cirrhosis with liver transplantation by the age of 17 years 4. Hepatomegaly and portal hypertension with serum AST increase, but no jaundice

4  Parenchymal GI Glands: Liver

Pediatricians who have neonates in the ward with bleeding disorders or unexplained jaundice have a long list of differential diagnosis, such as virus infection. Unlikely to be associated with AATD would be Wilson disease, which usually occurs after 6 years of age, and AIH, which is also characteristic of older children. Hemochromatosis of neonatal type is a heterogeneous disorder and needs to be taken into consideration. Phenotyping by IEF and genotyping by molecular biology techniques should be performed in case of a serum level of AAT 2.5 mmol/L and persistently increased; (2) molar ratio of plasma lactate/pyruvate, >20.1 mol/ mol; (3) molar ketone body ratio arterial 3-hydroxybutyrate/acetoacetate, >2.1  mol/mol;

(4) postprandial plasma ketone bodies or lactate, paradoxical increase; (5) OGTT (2 g/kg) assessing plasma lactate/pyruvate ratio every 15 min six times for 90 min, elevated lactate/pyruvate ratio; and (6) urinary levels of lactate, succinate, fumarate, malate, 3-methylglutaconic, and 3-methyl glutaric by gas chromatography-mass spectroscopy. The oral glucose tolerance test (OGTT) is usually used to diagnose an intolerance to glucose/glycids. It involves the oral administration of a glucose drink to challenge the insulin-glucose response. All pregnant women not known to have

4.5 Genetic and Metabolic Liver Disease

gestational diabetes should be screened for glucose intolerance at 24th–28th weeks’ gestation if they are at low or medium risk (an early screening is performed if the risk of gestational diabetes is higher). The original OGTT is performed assessing the glucose level 2 h after a 75 g glucose drink for nonpregnant women/adults and three blood samples (fasting or before the drink, 1 h, 2 h) after a 75 g glucose drink.

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•

Neonatal Liver Failure (NLF) • DEF: Complex I-, III-, and/or IV-related NLF with acute onset in the early newborn age with major clinical features, including transient hypoglycemia, neurologic involvement with severe hypotonia, apnea, lethargy, myoclonus epilepsy, psychomotor retardation, ↑ plasma lactate/pyruvate ratio, and β-hydroxybutyrate and arterial ketone body ratio of β-hydroxybutyrate to acetoacetate and rapid fatal downhill. Associated features may be low birth weight (about 1/4 of cases), polyhydramnios, hypertrophic cardiomyopathy, ventricular septal defects, cardiac arrhythmias, and hydronephrosis. The intersections between cardiac pathology and liver pathology are astonishing when investigating pediatric patients. Mitochondrial DNA Depletion Syndrome (mtDNA-DS) • DEF: Congenital multisystemic acute/chronic reduction in mtDNA copy number leading to insufficient synthesis of complexes I, III, IV, and V of mtDNA as compared to nuclear DNA, nDNA ( liver symptoms. • CLM: Portal fibrosis with extension to micronodular cirrhosis, steatosis of microand macrovesicular type, pseudoacinar formation, MNGC formations, cholestasis, and periportal inflammation.

• CLI: Reye syndrome-like symptoms and liver disease occur in defects in carnitine handling (uptake) involving OCTN2, carnitine palmitoyltransferase (CPT1, CPT2) defects, medium chain acyl-CoA dehydrogenase (MCAD) deficiency, and LCHAD deficiency. Some FAO defects, including MCAD deficiency, LCACD deficiency, carnitine transporter defect, and carnitine translocase defect, have been indicated as etiologic factors in some SUDI and SUD in childhood (Bove KE, Histologic Pattern of Metabolic Disease, chapter 10). At autopsy, urine collection for acyl and acylcarnitine compounds, skin/tendon biopsy to establish a fibroblast culture, and freezing of six tissue samples should be considered essential. Clinical presentation is also variable with the metabolic crisis with non-ketotic hypoglycemia in the immediate neonatal period to progressive liver fibrosis with or without cardiomyopathy. FAOD determine the accumulation of neutral lipid in FAOdependent organs such as the liver, heart, proximal renal tubule, and type 1 skeletal muscle fibers. The neutral lipid accumulation mani-

(renal tubular disease or Fanconi’s syndrome), small intestine (partial villous atrophy), skin (patchy erythematous lesions and photosensitivity), eyes (visual impairment and pigmentary retinopathy), and hydrops fetalis.

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fests histologically as microvesicular steatosis, which may be transitory as seen in MCAD when homeostasis is restricted. • TEM: Generic mitochondrial findings, which are not distinctive compared with abnormalities of the mitochondria seen in primary disorders of electron transport, mtDNA depletion syndrome, and RS.  Thus, the diagnosis is practically based on FAB-MS measurement of plasma acylcarnitine profile utilizing Guthrie card blood spots and of urinary acyl-carnitine and organic acid profiles as well as investigations carried out on cultured fibroblasts.

Urea cycle defects (UCD) include the deficiency of the respective enzymes:

Carnitine Deficiency • DEF: It is a genetic disorder condition in which the individuum does not have the carnitine shuttle, and this deficit prevents the body from using some fats for energy. • CLI: 1. Reye’s syndrome-like form. 2. Severe liver involvement form (hepato megaly, hypoglycemia, hyperammonemia, and CNS dysfunction). • CLM: Variable phenotype from normal or slight “portitis” to steatosis of microvesicular and macrovesicular types. • TEM: Intracellular lipids. • DDX: Reye’s syndrome among other metabolic defects presenting with steatosis.

ORNT1 or ornithine transporter is a carrier protein that allows the transfer of ornithine from the cytosol to the mitochondrion, and CITRIN is a hepatic mitochondrial aspartate glutamate carrier protein, and NAGS is N-acetyl glutamate synthetase which adds acetyl CoA to glutamate to form NAG that with NH3 and HCO3− is transformed to carbamyl phosphate that enters the urea cycle. Deficiency of NAGS, CPS, and OTC in the mitochondrial matrix impairs the subsequent synthesis of CO(NH2)2 or carbamide (urea) by reducing the production of the mitochondrial citrulline. Most of the urea cycle metabolic capacity is located in the liver, and the genes for the respective enzymes are well known. CPS has a gene located on 2q35, OTC on Xp21.1, ASS on 9q34, ASL on 7cen-q11.2, and arginase on 6q23. In case of a defect of a urea cycle enzyme, there are two consequences, including:

4.5.5.3  Urea Cycle Enzyme Defects The urea cycle has two aims, which are the (1) de novo biosynthesis and degradation of arginine and (2) serves to incorporate the surplus of nitrogen into urea that is considered a waste nitrogen product. The urea cycle consists of well-delineated and orchestrated enzymatic steps, in which the nitrogen arising from ammonia and aspartate is transferred to urea, which is found in the urine of mammals, amphibians, and fishes. The urea cycle enzymes are partly localized in the mitochondria and partially localized within the cytosol. Carbamyl phosphate synthetase (CPS) and ornithine transcarbamylase (OTC) are within the mitochondria, whereas argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), and arginase (ARG) are in the cytosol.

1. Carbamyl phosphate synthetase deficiency (CPSD) 2. Ornithine transcarbamylase deficiency (OTCD) 3. Argininosuccinate synthetase deficiency (ASSD), aka citrullinemia 4. Argininosuccinate lyase deficiency (ASLD), aka argininosuccinic aciduria 5. Arginase deficiency also called hyperargininemia

1. The transformation of the amino acid arginine from non-essential to essential (except hyperargininemia only) 2. The progressive accumulation of nitrogen in several molecules, particularly ammonia Hyperammonemia is a toxic state for the brain because it interferes with the metabolism of neurotransmitters influencing the glutamine-glutamate-GABA balance and with energy production. However, differently from liver failure where ammonia is one of the multiple toxins, in UCD ammonia is the only toxin except hyperarginin-

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emia, where a synergistic effect may also play a role. Remarkably, the brain MRI of patients affected with UCD demonstrates asymmetric focal lesions, while brain MRI of patients with liver failure generalized and symmetric lesions are typically seen. • EPI: 1:8200 (prevalence, USA), but the overall incidence of defects presenting is ~ 1:45,000 live births. • CLI: Two typical presentations: neonatal and pediatric. • A lethargic and hypotonic baby characterizes the neonatal form with the progressive development of vomiting, seizures, hypothermia, and hyperventilation and signs of increased intracranial pressure with bulging fontanel and macrocephaly and death within a few days. • The pediatric form (older child) is characterized by either chronic and episodic course with lethargy, headache irritability, agitation, confusion, hallucinations, vomiting, hypotonia, ataxia, dysarthria, or stroke-like episodes with focal dysfunction of the brain. Coarse and friable hair, also called trichorrhexis nodosa, is seen in ASLD. Other organ involvements are ocular (scotomas), circulatory (shock), renal (renal failure), the lung (hemorrhage), and the liver (hepatomegaly). All UCD except hyperargininemia is similar. In hyperargininemia, there is a slow progression of growth failure, psychomotor retardation, progressive spastic tetraplegia, tremor, ataxia, choreoathetosis, epilepsy, and hyperactivity with or without episodes of lethargy, vomiting, and, finally, coma. • CLM: 1. Carbamyl phosphate synthetase deficiency (CPSD): Neuropathology 2. Ornithine transcarbamylase deficiency (OTCD): Neuropathology ± liver pathology (occasional mitochondrial and peroxisomal changes) 3. Citrullinemia: Neuropathology 4. Argininosuccinic aciduria (ASLD): Neuropathology and hepatomegaly with ALT increase and macrovesicular steatosis to severe fibrosis on LM and dilation of

4  Parenchymal GI Glands: Liver

rough and smooth endoplasmic retuculum, megamitochondria, mitochondrial polymorphism with shortened cristae and paracrystalline matrix inclusions admixed to normal mitochondria, and excess of glycogen on TEM • PGN: Regarding outcome and genetic counseling of hyperargininemia, the lifespan of this disorder is longer than in other UCDs. Prenatal diagnosis can carry out on the amniotic fluid by measuring abnormal metabolites, on chorionic villi or amniocytes for DNA analysis, or on cultured amniocytes or in utero liver biopsy samples. The detection of the carrier in OTCD is performed using protein loading, alanine loading, and allopurinol challenge to induce orotic aciduria. However, a negative test does not typically rule out the carrier status. Importantly, DNA techniques can be successfully used for carrier detection if the mutation in the affected patient and parents are known. Citrin deficiency is due to an abnormal or absent mitochondrial aspartate-glutamate carrier protein in the hepatocytes owing to gene mutations causing type II citrullinemia in adults and cholestasis in infants, mostly of ethnic East Asian origin. Microscopically, neonatal citrin deficiency manifests with NH features with macrovesicular steatosis, accompanied by lobular cholestasis, the prominent acinar transformation of the hepatocytes (pseudorosettes of cholestatic origin), and progressive pericellular/perisinusoidal fibrosis, which is unusual in NH of newborns with the ethnic European-American background. The control of the metabolism of glutamate, glutamine, and ammonia within the CNS is referred to as the glutamate-glutamine cycle. Synaptic glutamate is removed using three distinct mechanisms: 1. Absorption from the postsynaptic glutamatergic neuron 2. Reuptake into the presynaptic neuron 3. Uptake from astrocytes, which is mediated by Na+-independent and Na+-dependent systems, the later having a high affinity for gluta-

4.5 Genetic and Metabolic Liver Disease

mate and subdivided into excitatory amino acid transporter 1 (EAAT1, aka GLAST) and excitatory amino acid transporter 2 (EAAT2, aka GLT1). The glutamate is then converted back to glutamine within the astrocytes.

4.5.5.4  Secondary Mitochondrial Hepatopathies Secondary mitochondrial hepatopathies are hepatopathies with the involvement of the mitochondrial cytologic subunit secondary to several and different etiologies. We include mostly Reye syndrome, hepatic copper overload (Wilson disease, Indian childhood cirrhosis, idiopathic infantile copper toxicosis, cholestasis), hepatic iron overload (genetic hemochromatosis, juvenile hemochromatosis, GALD/ neonatal hemochromatosis, tyrosinemia, type I, Zellweger syndrome), drug administration (amiodarone, barbiturates, chloramphenicol, nucleoside analogs, salicylic acid, tetracycline), bacterial toxins (cereulide, Bacillus cereus emetic toxin), ekiri, chemical toxins (Fe, ethanol, cyanide, antimycin A, rotenone), mitochondrial lipid peroxidation (cholestasis, hydrophobic bile acid toxicity, non-alcoholic steatohepatitis (NASH), total parenteral nutrition (TPN), bacterial contamination of small bowel, jejunoileal bypass, or idiopathic), and liver cirrhosis. Some of these disorders are found in other paragraphs of this chapter as well as other sections of this book.

Box 4.20 Groups and Subgroups of Peroxisomal Disorders

Peroxisomal Biogenesis Disorders (PBDs) Zellweger Spectrum Disorders (ZSDs) Zellweger Syndrome (ZS) Neonatal Adrenoleukodystrophy (NALD) Infantile Refsum Disease (IRD) Rhizomelic Chondrodysplasia Punctata Type 1 (RCDP1) Single Peroxisomal Enzyme Deficiencies (SPEDs) Acyl-CoA Oxidase 1 (ACOX1) Deficiency D-Bifunctional Protein (DBP) Deficiency

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4.5.6  Peroxisomal Disorders Peroxisomes are organelles that starting their life in an individual sub-compartment of the ER are essential for the metabolism of ether-phospholipids, fatty acid beta-oxidation, and fatty acid alpha-oxidation. Peroxin 3 (PEX3) with different peroxisomal membrane proteins (PMPs) plays significant roles for the initial formation of the peroxisomes and PEX5 and PEX 7 being responsible for targeting the peroxisomal matrix proteins into the peroxisomes. Ether-phospholipids are different from the diacyl-phospholipids because they have an alkyl or alkenyl group instead of an acyl group at the sn-1 of the glycerol molecule. Ether-phospholipid biosynthesis begins in the peroxisomal environment, because the first two enzymes, i.e., dihydroxyacetone phosphate acyl-transferase (DHAPAT) and alkylDHAP synthase (ADHAPS), encoded by GNPAT gene and AGPS, respectively, are located in the peroxisomes, while the other enzymes are located in the endoplasmic reticulum. Peroxisomal disorders are a genetic disease that can be identified by an impairment in 1 or 1+ functions of peroxisomes and are classified into three subgroups with several subgroups (Box 4.20). Like mitochondria, peroxisomes contain a fatty acid β-oxidation system, which harbors four enzymatic reactions and targets the chain shortening of some fatty acid substrates, of which three most important are C26:0, pristanic acid, and di-/

2-methyl Acyl-CoA Racemase Deficiency Sterol Carrier Protein X Deficiency (SCPX) Phytanoyl-CoA Hydroxylase (Adult Refsum Disease) Deficiency Acyl-CoA-Dihydroxyacetonephosphate Acyltransferase (RCDP2) Deficiency A l ky l - D i hy d r o x y a c e t o n e p h o s p h a t e Synthase (RDCP3) Deficiency Single Peroxisomal Substrate Transport Deficiency (SPSTD) X-Linked Adrenoleukodystrophy (X-ALD)

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trihydroxycholestanoic acid. To the success of the four subsequent enzymatic reactions, there are two distinct acyl-CoA oxidases (ACOX1 and ACOX2), two bi-functional proteins (LBP and DBP), and two different thiolases (pTH1 and pTH2), of which one (aka SCPX) is important for the last step. ACOX1, DBP, and SCPX deficiencies have been identified in humans. A fourth defect of the SPED group is constituted by the deficit of phytanoyl-CoA hydroxylase (adult Refsum disease). This enzyme is essential for fatty acids with a methyl group at the 3-position, such as phytanic acid or 3,7,11,15-tetramethyl hexadecanoic acid, which needs to undergo α-oxidation before being β-oxidized. Peroxisome biogenesis disorders consist of heterogeneous groups and can be subdivided into 13 complementation groups. Complementation group 8 contains three clinical phenotypes: Zellweger syndrome, infantile Refsum disease, and neonatal adrenoleukodystrophy. PEX26, the pathogenic gene for this group of peroxisomal biogenesis disorders, has recently been identified. Zellweger Syndrome and PEX Disorders • DEF: ZS is the severe form of peroxisomal disorders and expresses itself through craniofacial dysmorphism and neurological, ocular, renal, and hepatic anomalies and usually leads to death within the 1st year of life. • SYN: Cerebro-hepato-renal syndrome. Zellweger syndrome is named after Hans Zellweger (1909–1990). Dr. Zellweger was a Swiss-American pediatrician, professor of Pediatrics and Genetics at the University of Iowa who identified and researched on this disorder. • EPI: 1:105 births • EPG: It is an AR-inherited disease due to mutations of several and different genes involved in peroxisomal biogenesis and characterized by multiple enzymatic defects affecting β-oxidation, plasmalogen synthesis, and phytanic acid oxidation. Mutations in PEX1, PEX2, PEX3, PEX5, PEX6, PEX10, PEX12, PEX13, PEX14, PEX16, PEX19, and PEX26 genes, which encode peroxins and are responsible for the normal assembly of per-

4  Parenchymal GI Glands: Liver

oxisomes, are at the basis of this genetic disease. • CLI  – Cerebro-hepato-renal syndrome, including: –– Severe and generalized hypotonia and psychomotor retardation (brain involvement) –– Hepatomegaly ± icterus (liver involvement) –– Renal cortical cysts (kidney involvement) Patients harboring this syndrome evidence an abnormal shape of the head and unusual facial characteristics. The face is characterized by a high forehead, large anterior fontanel, hypoplastic supraorbital ridges, bilateral epicanthus, and abnormal ears. The CNS examination shows a severe truncal and peripheral hypotonia, lack of visual and auditory responses, seizures, glaucoma, and retinitis pigmentosa. Moreover, cortical dysplasia with polymicrogyria and pachygyria in the perisylvian area, neuronal heterotopia, migration defects of Purkinje cells, and discontinuation in the principal nucleus of the inferior olivary complex as well as dysmyelination of the cerebral white matter have been described. • LAB: ↑ Pipecolicacidemia, ↑ trihydroxycoprostanic acidemia (THCA), ↑ [VLCFA]urine (>C22). • PGN: Poor outcome with death within 6–12 months of life. X-ALD is an X-linked genetic disease due to ABCD1 gene mutations without genotype-phenotype correlation. The ABCD1 gene encodes ABCD1 (or ALDP), which is a peroxisomal transmembrane protein with the structure of an ATP-binding cassette transporter. There is a rate of 1:42000 (or 1:20000 males) and is the most frequent monogenetically demyelinating disease as well as the most frequent peroxisomal disorder. Clinically, there are two distinct phenotypes, including (1) adreno-myeloneuropathy (AMN) with the involvement of the adrenal gland (adrenal insufficiency or Addison disease) and spinal cord involvement with progressive stiffness, weakness of the legs, impairment of the vibration

4.5 Genetic and Metabolic Liver Disease

sense, sphincter disturbances, and impotence, and (2) X-ALD of cerebral demyelinating type (CDA), showing cerebral demyelination. There is an increase of VLCFAs. In NALD, there is a severe truncal peripheral hypotonia, lack of visual and auditory responses, and seizures as well as retinitis pigmentosa. Moreover, hepatomegaly is seen, and the CNS shows polymicrogyria only ± dysmyelination for infants older than 2  years. In IRD, there are some ZS-like external features but no neuronal migration disorders and no progressive white matter involvement. Psychomotor retardation, retinitis pigmentosa, and peripheral deafness are seen in surviving children. In RDCP1, the inheritance is AR, and there is rhizomelic dwarfism with growth retardation, microcephaly, characteristic face (prominent forehead and midface hypoplasia with anteverted nares and long philtrum), congenital cataracts, and neurological features, including truncal hypertonia, spastic tetraplegia, and epilepsy. X-ray shows rhizomelic dwarfism with severe shortening of humeral bones and femora, metaphyseal cupping or splaying punctate calcifications, and malformations of the spine with characteristic coronal clefts of the vertebral bodies. Acyl-CoA Oxidase 1 (ACOX1) deficiency is an AR-inherited disease with severe neonatal hypotonia, inadequate response to visual and auditory stimuli, retinitis pigmentosa, hepatomegaly, and seizures but no facial dysmorphism. X-ray is mute, but brain imaging shows progressive white matter demyelination with Blood-Brain Barrier (BBB) disruption like X-ALD. D-Bifunctional Protein (DBP) deficiency is an AR-inherited genetic disease with ZS-like facial dysmorphism, neonatal hypotonia, seizures, failure of the visual system (nystagmus, strabismus, inability to properly fixate objects, retinitis pigmentosa) and thermoregulatory system, and peripheral neuropathy. Brain imaging delay of maturation of the white mater and demyelination of cerebral hemispheres and progressive cerebral atrophy. Sterol Carrier Protein X (SCPX) deficiency is an AR genetic disease with a stutter in childhood accompanied later by dystonic head tremor and spasmodic torticollis with respective hyperintense signals in the thalamus

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using magnetic resonance imaging, so-called butterfly-like lesions in the pons, and injuries in the occipital areas. Other diseases include the Adult Refsum Disease (ARD), deficiency of acyl-CoA-dihydroxyacetone phosphate acyltransferase (DHAP-AT), and scarcity of alkyldihydroxyacetone phosphate (ADHAPS).

4.5.7  Iron Metabolism Dysregulation Hepcidin and Regulation of Fe Metabolism Liver cells have the HAMP gene, which encodes for hepcidin, a master regulator of iron metabolism. In response to infection and iron overload states, hepcidin is upregulated, and this upregulation is also supported by hemojuvelin (50%), HFE protein (25%), and TFR2 (25%), which increase hepcidin production. The TFR2 gene provides instructions for building the protein called transferrin receptor 2. The release of hepcidin by hepatocytes slows down the passage of Fe3+ ions through the intestinal enterocytes and, simultaneously, the release of Fe2+ from macrophages at various locations determining a decrease of iron in serum. In MΦ, Fe2+ comes from the degradation of RBC, and it seems that hepcidin acts on MΦ by internalizing ferroportin (FP-1) in these cells (Figs. 4.18, 4.19, and 4.20). Box 4.21 lists the disorders of the regulation of the iron metabolism that will be part of this section. Neonatal hemochromatosis has been a mystery for a long while, and it seems that recently some aspects of neonatal iron accumulation have clarified. As early as 1865, Trousseau described a collection of disorders including the association of diabetes, cirrhosis of the liver, fibrosis of the pan-

Box 4.21 Iron Metabolism Dysregulation

• Neonatal hemochromatosis • Genetic hemochromatosis, adult type • Hereditary hemochromatosis, juvenile type

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a

b

c

d

e

f

Fig. 4.18  Hereditary hemochromatosis (HFE) is a disorder that causes the body to hyperabsorb iron from the diet and store the excess iron in the body’s tissues and organs, particularly the skin, heart, liver, pancreas, and joints leading to early failure of several organs and deaths of these patients. Most patients are homozygous for a C282Y mutation in the HFE gene, which is frequent in northern Europe,

where 1:5–10 individuals are carriers. In (a) liver cirrhosis of homozygous HFE young male is seen. The accumulation is massively represented in the trabecular hepatocytes (a). Multiple organs are involved by iron accumulation (b–f), such as pancreas (b), adrenal gland (c), thyroid gland (d), and heart (e–f). The Pearls’ special stain highlights the iron deposition identifying the iron as blue granules

creas, and pigmentation of the skin. Twenty-four years later, on the Versammlung Deutscher Ärzte at Heidelberg, Germany, von Recklinghausen labeling the disease Haemochromatosis reported 12 more similar cases with brown pigmentation in almost all the organs. Noteworthy, Straeter was the first author to state tissue siderosis at infancy. He described two infants, one of them probably affected by an infection showing iron accumulation in the spleen, liver, pancreas, and lymph

nodes at autopsy, the other one apparently concerned with a severe hemolytic anemia showing iron accumulation in the endothelial layer of the vessels, liver, spleen, lymph nodes, lungs, thymus, kidney, and pancreas. Strictly related to the prominent role of the organ at fetal age, some liver iron storage is physiologic in the term infant. The diagnosis of neonatal iron storage disease relies on multi-organ iron accumulation with sparing of the reticuloendothelial system. Cottier

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a

b

c

d

e

f

Fig. 4.19  Gestational alloimmune liver disease (GALD) is a maternofetal alloimmune disorder directed at the fetal liver, often manifesting as neonatal liver failure and neonatal iron storage disease of various extrahepatic tissues. The mechanism of iron overload in GALD relates to severe depressed hepatic expression of hepcidin (HAMP) in the injured fetal liver, which leads to dysregulation of placental iron flux. In (a) is shown the first demonstration

of a neonatal hemochromatosis in the German literature. In (b) is shown the neonatal liver failure with cirrhotic nodules full or iron (b). Early features of iron accumulation can be discovered in infants before liver failure (c, e). The iron accumulation is often seen in the biliary proliferation, a common marker of inherited Fe storage disorders (f)

was the first author to recognize in infants the phenotype of advanced liver disease together with extrahepatic parenchymal siderosis as mimicking late-stage hemochromatosis in adults. The tissue distribution of hemochromatosis-type iron is different from the secondary siderosis, e.g., transfusional siderosis. The hemochromatosis siderosis involves, in approximate order of severity, periportal hepatocytes (the first site of iron

deposition following adsorption into the portal venous plasma from chyme), the remaining hepatic lobule, exocrine pancreas, myocardium, and some endocrine epithelia. Conversely, the reticuloendothelial elements in the spleen, lymph nodes, and bone marrow and along hepatic sinusoids represent the primitive iron deposition sites in secondary siderosis. Excess iron storage in tissues led to organ dysfunction. Both in hemochro-

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a

b

c

d

Fig. 4.20  In (a, b) are shown the microphotographs of a unique young patient harboring HFE and Caroli disease showing dilated segmental ducts and iron accumulation

(a, H&E; b, Pearls’ Prussian Blue stain). In (c) and (d) the gross photograph and the histopathology of liver failure of a young patient with Wilson disease are presented

matosis siderosis and in secondary siderosis, the failure of the myocardial and endocrine systems results in the death of the affected individuals. Almost certainly, neonatal iron storage disease is not one specific entity but a clinicopathologic phenotype. Currently, neonatal iron storage disorder is considered a GALD, i.e., gestational alloimmune liver disease, which is a maternofetal alloimmune disorder directed at the fetal liver, often producing neonatal liver failure with the most common presentation being the neonatal hemochromatosis. GALD is the result of neonatal complement-mediated severe liver injury. The hepatic damage is mediated by maternal allo-antibodies, which are detected by immunohistochemistry staining using the complement C5b-9 complex (Melin-Aldana et al. 2015). The initiation of antenatal therapy with high-dose intravenous immunoglobulin (IVIG) in women with an affected offspring to prevent the reappearance of the disease in subsequent pregnancies has given excellent results demonstrating the effectiveness of this approach. Newborns affected with neona-

tal hemochromatosis present clinically with liver disease-related complications: hypoglycemia (reduced capacity to store glycogen and release glucose), hypoalbuminemia (reduced synthesis of albumin), hemorrhagic diathesis (reduced synthesis of clotting factors and thrombocytopenia), and icterus (impaired hepatic synthesis and excretion of bilirubin). Although transaminase activities and blood concentrations of alpha-1-antitrypsin, ceruloplasmin, and transferrin are low, alphafetoprotein may be high reflecting the attempted liver regeneration due to reduced hepatocellular mass. Abnormal bile acid metabolism may represent a subgroup of this disorder. The increase in ferritinemia may be nonspecific and not diagnostic of neonatal hemochromatosis. Hypotransferrinemia reflects severe liver disease with reduction of the synthesis function of the hepatocytes, and transferrin saturation should be determined when neonatal hemochromatosis is being considered. Although liver biopsy is a procedure to diagnose neonatal iron accumulation, it is difficult to carry out safely. This situation is due

4.5 Genetic and Metabolic Liver Disease

to the hemorrhagic diathesis associated with this disorder. MRI can provide evidence of siderosis of the pancreas and myocardium and exclude splenic siderosis. However, anesthesia or sedation may worsen the clinical situation of an ill infant. A 3-mm punch biopsy specimen of the lower lip mucosa may be more feasible. The lower lip mucosa biopsy has been used to demonstrate extrahepatic parenchymal siderosis and to support the diagnosis of neonatal iron accumulation. Formalin-fixed and paraffin-embedded tissue obtained from the mucosa lower lip a few millimeters above the more inferior oro-alveolar sulcus generally suffices to prove siderosis without examining repeated frozen sections. Salivary gland biopsies have allowed the diagnosis to be made quite early. During the clinical approach, some conditions can be mistaken for neonatal hemochromatosis, including liver-predominant mitochondriopathies, hepatic infarction, hemophagocytic lymphohistiocytosis, and Finnish lethal neonatal metabolic syndrome. In the case of poor prognosis, orthotopic liver transplantation (OLT) is mandatory. In a 10-year retrospective analysis, Sigurdsson et al. (1998) found 14 infants with neonatal hemochromatosis, 8 patients of whom had been diagnosed after 1993 and had received the antioxidant-chelation cocktail (including deferoxamine, vitamin E, N-acetylcysteine, selenium, and prostaglandin-E1). Genetic (or hereditary) hemochromatosis is a relatively common, AR-inherited inborn error of metabolism leading to massive iron deposits in hepatic and extrahepatic (the pancreas and other endocrine organs, heart, kidney, and salivary glands, are the first organs irrorated with a conspicuous amount of blood) tissues (often up to 100 times the average level). Mutations in five genes, including HFE, HAMP, HJV, SLC40A1, and TFR2, can cause genetic or hereditary hemochromatosis. HFE gene mutations cause type 1 hemochromatosis, while type 2 hemochromatosis results from mutations in either the HAMP or HJV gene. Mutations in the TFR2 gene cause the type 3 of genetic hemochromatosis, while mutations in the SLC40A1 gene are responsible for the type 4 hemochromatosis. HFE gene is on 6p22.2 with some rela-

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tionships to HLA-A3, HLA-B7, and HLA-B14. HFE homozygosity is 1:400 to 1:200 individuals in the general population, although about 1/5 of the homozygous individuals are progressing to symptomatic disease. Heterozygosity is 1/10. The most frequent gene mutation is C282Y leading to the substitution of tyrosine for cysteine at amino acid 282 in the HFE protein. Pathogenetically, there is an impairment of the enterocytes to regulate iron absorption, which leads to a saturation of circulating transferrin with iron. Saturated transferrin reaches hepatic and extrahepatic tissues, where it is first as ferritin and then as hemosiderin. Fe toxicity is due to the generation of free radicals that cause peroxidation of organelle membranes and cell death-leading intracellular changes. Simultaneously, there is a paracrine stimulation of collagen-producing cells leading to tissue fibrosis. Clinically, the classic triad which is cirrhosis, skin pigmentation, and diabetes mellitus (“bronze disease”) is rarely seen, if adequate treatment is started. Biochemically, hepatic iron index (HII) is mole Fe/grams dry weight liver/age. The HII is a quite useful parameter, although the use of clinical judgment to discern severity is paramount. Healthy subjects have HII of 0.1–1, while homozygotes and heterozygotes have >2 and 0.2–2, respectively. GH needs to be differentiated from other states with iron tissue deposition, such as multiple transfusions, Porphyria Cutanea Tarda (PCT), and chronic dietary Fe overload. In secondary siderosis, iron overload is without associated tissue damage, and iron preferentially accumulates in the Kupffer cells. Brown discoloration of most of the organs is seen during grossing (gross morphology). This aspect corresponds to the increased hemosiderin storage in most of the organs.

4.5.8  Copper Metabolism Dysregulation Wilson disease and Menkes syndrome are metabolic conditions with altered copper metabolism (Box 4.22).

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Box 4.22 Copper Metabolism Dysregulation

4.5.8.1. Wilson Disease (Hepato-Lenticular Degeneration) 4.5.8.2. Menkes Syndrome

4.5.8.1  Wilson Disease • DEF: AR-inherited metabolic disorder of the copper metabolism due to mutations of ATP7B on 13q14 leading to a ↓ Cu-transporting ATPase 2 and inability to excrete Cu into the bile. • SYN: Hepato-lenticular degeneration. • EPG: The gene product of ATP7B is a P-type ATPase that is exclusively found in the liver (intracellular trans-Golgi site) and is required for both copper incorporation into ceruloplasmin and biliary excretion. • EPI: 33/106 births. • LAB: Cu level measured by atomic absorption spectroscopy (AAS) is useful for the initial differentiation of the homozygous patients. There is Cu > 250μg/1 g dry weight of liver in patients affected with Wilson disease. • CLI: Clinically liver disease (fulminant hepatitis, fatty change or liver cirrhosis) may be associated with degeneration of the basal ganglia (= hepato-lenticular degeneration as is also known Wilson disease in the older literature) and Cu accumulation in the Descemet membrane of ocular limbus (Kayser-Fleischer rings on the cornea). • GRO: Diffuse areas of necrosis in the case of fulminant hepatitis with massive hepatic necrosis, yellow hepatomegaly in case of steatosis, and no gross changes (CAH) are the grossing milestones to remember. • CLM – It includes three features: 1. Acute/chronic hepatitis (CAH) 2. Fulminant hepatic failure (FHF) 3. Cirrhosis In (1) there is steatosis (micro- and macrovesicular type) and an increase of glycogen-rich nuclei in the acute phase, and the addition of a portal infiltrate characterizes the prolonged period. In (2) there is massive hepatic necrosis with a pat-

4  Parenchymal GI Glands: Liver

tern indistinct from other causes of FHF, although the preexistence of fibrosis or cirrhosis at the time of onset of FHF is quite indicative of Wilson disease. Also, Mallory hyaline, Cu, and lipofuscin are seen. Mallory hyalin is periportal, does not attract neutrophils, and is not associated with other histologic features of different diseases showing Mallory hyalin such as alcoholic liver disease. Finally, in (3) there is cirrhosis with Mallory hyaline, Cu, and lipofuscin with location variability, (+) orcein staining, and Victoria blue staining for Cu-associated proteins and (+) rhodanine staining and rubeanic acid staining for elementary Cu, which is initially intracytoplasmic rather than lysosomal giving rise to a diffuse light staining of the cytoplasm.

• TEM: It includes abnormalities of peroxisomes and mitochondria. Peroxisomes show an enlargement and matrix flocculency, while mitochondria exhibit increased matrix density, separation of inner and outer layers of the mitochondrial limiting membrane, and bulbous dilatation of the tips of the cristae. • DDX  – Cu accumulation states (other than Wilson disease) include: –– Primary biliary cirrhosis –– Primary sclerosing cholangitis –– Long-standing extrahepatic biliary obstruction –– Indian childhood cirrhosis • PGN: Poor outcome if the patient does not receive some treatment.

4.5.8.2  Menkes Syndrome It is a disorder that affects Cu levels in the body and shows several findings, including sparse, kinky hair, failure to thrive, and deterioration of the CNS. Patients with Menkes syndrome usually begin to develop symptoms during infancy and survival is minimal after 3 years of age. A milder form starts in early to middle childhood (occipital horn syndrome). Mutations in the ATP7A gene cause Menkes syndrome. Cu accumulates mainly in the small intestine and kidneys. The decreased Cu supply can induce a decrease of the activity of numerous copper-containing enzymes that are

4.5 Genetic and Metabolic Liver Disease

crucial for the structure and function of the skeletal system, other than skin, the nervous system, and the vascular system. For more details, please refer to genetic books.

4.5.9  Porphyria-Related Hepatopathies Both porphyria cutanea tarda (PCT) and erythropoietic protoporphyria (EPP) affect the liver showing characteristic histologic and ultrastructural changes. In PCT, there are intrahepatocytic needle-shaped inclusions, which are autofluorescent, birefringent, and hydrosoluble. There are also focal hepatocellular necrosis, portal lymphocytic infiltrate, Fe deposition, and fatty change. A regeneration (thickened liver cell plates) can also be appreciated. The ultrastructural study of PCT reveals intrahepatocytic, elongated crystalline electron-lucent bodies surrounded by electrondense material revealing alternating areas of differing electron density using transmission electron microscopy (TEM). In EPP, there is centrilobular canalicular cholestasis with dark brown bile with red “Maltese cross” configuration when polarized → ductal cholestasis with pericellular and portal fibrosis/cirrhosis. The ultrastructural study of EPP reveals “starburst” crystalline material in hepatocytes ductal epithelium and Kupffer cells. PCT evolution comprises liver fibrosis, cirrhosis, and neoplastic degeneration (HCC), while the outcome of EPP includes liver fibrosis and cirrhosis (Box 4.23).

Box 4.23 Liver “Highlights” of Porphyria Cutanea Tarda (PCT)

1 . Focal hepatocellular necrosis 2. Portal lymphocytic infiltration 3. Fe deposition 4. Diffuse fatty change Note: 4 “F’s” to recall these findings include “Foci” of necrosis, “Fullness” of lymphocytes in the portal tracts, “Fe” deposition, and “Fatty” change of diffuse type.

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4.5.10  Shwachman-Diamond Syndrome (SDS) • DEF: AR-inherited disease, determined by mutation of the SBDS gene on 7q11 and characterized by pancreatic exocrine insufficiency, BM hypoplasia (fat replacement of myeloid lineages and myeloid maturation arrest), and bony abnormalities (metaphyseal dysostosis) as well as hepatomegaly with a variable pattern from steatosis to cirrhosis. • CLI: Failure to thrive and hematological abnormalities, including anemia, neutropenia, and thrombocytopenia, are seen in infancy and childhood of affected individuals. • PGN: ↑ risk to develop myelodysplastic syndrome and leukemia. Other than SDS, there is a growing list of possible metabolic defects or genetic syndromes showing NASH or early cirrhosis in life, and OMIM or other search engines may be able to create an updated list. However, some conditions should be kept in mind, because patients may be seen either under the lens or at autopsy. It is essential to remember partial or congenital lipodystrophy, Bardet-Biedl syndrome, Alstrom syndrome, Bloom syndrome, Dorfman-Chanarin syndrome, Aarskog syndrome, Donohue syndrome, or leprechaunism with fatty change associated or not with hepatocellular and reticuloendothelial siderosis.

4.5.11  Chronic Granulomatous Disease (CGD) • DEF: Eclectic group of X-linked diseases in which individual cells of the immune system have difficulty forming the ROS compounds (e.g., superoxide radical due to defective phagocyte NADPH oxidase) used to kill certain pathogens following phagocytosis by the MΦ. • SYN: Bridges-Good syndrome, chronic granulomatous disorder, and Quie syndrome. • EPI: 1:200,000 people in the USA, with about 20 new patients/year. • EPG: Deletions, frameshift, nonsense, and missense mutations in the CYBA, CYBB, NCF1, NCF2, or NCF4 genes can cause CGD.

4  Parenchymal GI Glands: Liver

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• CLM: Granulomatous inflammation and diffuse accumulation of lipofuscin pigment, Fontana (+) in RES cells. Confluent granulomas (DDX, Sarcoidosis!) may progress to necrosis and suppuration of some areas. Pigmented histiocytes are light tan in color and are PAS+ and argentophilic. On frozen section, pigmented histiocytes are sudanophilic and autofluorescent. This lobular activity is associated with portal inflammation by lymphocytes, and plasma cells with mildmoderate periportal or perisinusoidal fibrosis and occasionally steatosis are seen.

Box 4.24 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection

4.6.1. 4.6.2. 4.6.3. 4.6.4. 4.6.5. 4.6.6. 4.6.7. 4.6.8.

Acute Viral Hepatitis Chronic Viral Hepatitis Autoimmune Hepatitis Drug-/Toxic-Induced Liver Disease (DILD/TILD, chemical injury) Granulomatous Liver Disease Alcoholic Liver Disease Non-alcoholic Steatohepatitis (NASH) Liver Allograft Rejection

4.5.12  Albinism-Related Liver Diseases Chediak-Higashi syndrome (CHS) and Hermansky-Pudlak syndrome (HPS) are two albinism-related liver diseases. Thus, in ACHS, hepatosplenomegaly with hemophagocytosis associate with fever, lymphadenopathy, and recurrent infections, due to pancytopenia, progressive neuropathy mostly of the cranial and peripheral nerves, and hyperlipidemia. Conversely, in AHPS (or oculo-cutaneous albinism), widespread deposition of ceroid pigment (granules intermingled with lipid and delimitated by a single membrane, ultrastructurally) in RES cells is associated with mild bleeding diathesis due to a storage pool of defects of platelets. Individuals affected with AHPS may develop lung fibrosis, cardiomyopathy, renal failure, and granulomatous colitis.

4.6

 iral and AI Hepatitis, V Chemical Injury, and Allograft Rejection

Either viruses or autoimmune as well as drugs or toxins may start an inflammation of the liver, which may be in different areas and may suggest some etiologies more than others. Box 4.24 summarizes the topics that are going to be the target of this subchapter. The clinic-pathological syndromes following a viral exposure are listed in Box 4.25.

Box 4.25 Clinicopathologic Syndromes Following Viral Exposure

1. Acute asymptomatic infection with subsequent recovery 2. Acute symptomatic infection (hepatitis of anicteric/icteric type) with subsequent recovery 3. Chronic hepatitis (>6  months) with potential progression to liver cirrhosis 4. Fulminant hepatitis with submassive to massive parenchymal necrosis

4.6.1  Acute Viral Hepatitis Hepatitis A  Nonenveloped ssRNA, icosahedral, 27  nm, picornavirus without direct cytopathic effect (incubation period, about 1 month, antibodies 2  weeks later), but with portal inflammation (“portitis”) with periportal involvement (conversely, Hep B and Hep C are mostly pan-lobular) and abundant plasma cells (like AIH). • LAB: IgM → acute infection; IgG → previous HAV exposure. • PGN: No chronic carrier state, no chronic hepatitis, no HCC, death   L) PT inflammation with interphase activity and lobulitis ± mild fibrosis (L/PC, lymphocytes/plasma cell ratio). • PGN: Cirrhosis (40% for type I and 80% for type II), although a good response to prednisone ± azathioprine is critical. 10-YSR (post-LTX): 75% and recurrence post-LTX: up to 40%.

4  Parenchymal GI Glands: Liver

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In Box 4.29 are summarized some pearls and pitfalls during the diagnostic procedure of AIH. Box 4.27 AIH in Childhood and Youth Type Type I Type II

Age Infancy∗

Lab ASMA, ANA, pANCA ↑↑↑ HGG 2–14 years LKM-1, ↑ HGG

Associations AIT, GD, UC

4.6.4  D  rug-Induced Liver Disease (Chemical Injury) and TPN A broad range of different chemical agents, e.g., drugs, industrial toxins, and anesthetics, can produce a restricted number of patterns of liver cell

Box 4.28 AIH – Biochemistry

AIH I: (+) ANA, SMA, AAA, anti-SLA/ LP, HLA-DR3 AIH II: (+) ALKM-1, ACL1 Notes: AAA anti-actin autoantibodies, ANA antinuclear antibodies, SMA smooth muscle antibodies, anti-SLA/LP antibodies against soluble liver antigen/liver-pancreas, ALKM anti-liver-kidney microsome antibodies; ACL1 is the ATP-citrate synthase subunit 1 (ATP-citrate (pro-S-)-lyase 1), which catalyzes the formation of cytosolic acetyl-CoA, which is mainly used for the biosynthesis of fatty acids and sterols.

DM, AIT, APECED

Notes: ∗Type I is also seen in elderly. AIT, autoimmune thyroiditis; APECED, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy; ASMA, antismooth muscle antibodies; DM, diabetes mellitus; GD, Graves disease; HGG, hyper-γglobulinemia; LKM-1, antiliver-kidney microsome type 1; pANCA, Perinuclear antineutrophil cytoplasmic antibodies; UC, ulcerative colitis.

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Fig. 4.22  Autoimmune hepatopathy shows marked lymphoplasmacellular infiltration with interface hepatitis (a– d). The immunohistochemistry (e–h) shows positive CD3

(e), CD20 (f), CD68 (g), and CD138 (h). CD138 is high specific for plasma cells

4.6 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection

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Fig. 4.22 (continued)

Box 4.29 Pearls and Pitfalls

• In AIH, AMA is not seen in high titers, unless there is a condition also known with the term “overlap syndrome,” which combines AIH and PBC (AIH/ PBC). • “Overlap syndrome” shows liver histology of both AIH and PBC other than combined positivity for both AMA and ANA, with a picture of lobular hepatitis, interface hepatitis, and plasma cell infiltration more than the usual degree expected for a PBC!

damage, when ingested, inhaled, or administered parenterally. The range of liver disease varies from fatty change with an accumulation of triglycerides within the hepatocytes through cholestasis and hepatitis to extensive hepatic necrosis requiring liver transplantation. Chemical-induced damage is the etiology in about ¼ of cases of fulminant hepatic failure (FHF) and is a significant healthcare problem worldwide because of the

limited number of available allografts (Figs. 4.23 and 4.24). Hepatotoxicity may be subdivided in predictable (intrinsic) and unpredictable (idiosyncratic) forms. The predictable or inherent hepatotoxicity results from the exposure of liver to chemical agents that are intrinsically hepatotoxic injuring probably everyone having contact with it. The degree of cell damage is dose-dependent and is experimentally reproducible and is usually zonal necrosis (e.g., inorganic phosphorus targeting zone 1, whereas acetaminophen, carbon tetrachloride, and halothane determining damage in zone 3). Predictable or intrinsic hepatotoxins may be subclassified as direct or indirect toxinsrelated. Direct hepatotoxins or their metabolic products act on liver cells and their organelles by an immediate, nonselective effect of either physical or chemical nature distorting and destroying the basilar framework of the liver cells. The cellular injury is usually mediated by peroxidation of lipids of the membranes and leads to metabolic defects with resulting steatosis and tissue necrosis. Direct hepatoxicity due to yellow phosphorus determines steatosis and zone 1 necrosis, whereas

4  Parenchymal GI Glands: Liver

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Fig. 4.23  Drug-induced liver disease can assume several histopathology patterns with steatosis, inflammation, cholestasis, eosinophilic recruitment, and ground glass-like change of the hepatocytes (a–h)

direct hepatotoxicity by CCl4 is steatosis and centrilobular (zone 3) necrosis acting on cytochrome P450. Indirect hepatotoxicity is due to a selective interference with a specific metabolic pathway or structural process. The consequence of the cell damage is some tissue changes, including steatosis, cholestasis, and necrosis. A few characteristic examples are targeting peculiar

systems of the cell framework. Tetracycline, IV administered, can lead to microvesicular steatosis; acetaminophen determines the production of large amounts of toxic metabolites by the mixedfunction oxidase (MFO) system outpacing the detoxifying abilities of thiol-rich glutathione. Thus, the substance may covalently bind to tissue macromolecules (e.g., N-acetyl-p-benzoquinone)

4.6 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection

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Fig. 4.24  Total parenteral nutrition hepatopathy is shown grossly (a–b) and histologically (c–h)

and determines zone 1 necrosis of liver tissue. Outpacing the detoxifying properties of the MFO system may also be seen with a limited amount of the drug in a setting of chronic alcoholism and MFO system stimulants (e.g., phenobarbital).

Amanita phalloides may lead to steatosis and zone 1 necrosis. Erythromycin and anabolic or contraceptive steroids are able, instead, to induce cholestasis. Chronic alcoholism is also part of ethanol toxicity, which is linked to acetaldehyde

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production (vide infra). Unpredictable (idiosyncratic) hepatotoxic agents may act either through a hypersensitivity-related injury or an aberration of metabolic pathways. In unpredictable hepatotoxicity, liver cell damage is observed in only a very few or few individuals exposed to this agent. There is no dose-dependency, and most of the hepatotoxic drug reactions are of an idiosyncratic type. Liver tissue damage includes nonzonal necrosis to massive hepatic necrosis. In hypersensitivity-related injuries, such as the following phenytoin, chlorpromazine, sulfonamide, and halothane, the exposure to the chemical agent occurred 1–5 weeks earlier than the diagnosis of liver tissue damage. There is a recurrence of the liver tissue damage by re-exposure. Liver tissue eosinophilia and/or granulomas are seen, and systemic symptoms (fever, rash, peripheral eosinophilia) are present. In dysregulated metabolism injury, such as the following isoniazid, the hepatotoxic reaction is the consequence of an aberrant metabolic pathway due to an accumulation of toxic metabolites (weeks to several months) in a particularly susceptible patient. No systemic symptoms are seen, but a liver biopsy may be a challenge in sorting out other etiologies, such as acute viral hepatitis. Clinically, chemical hepatitis of affected individuals may show jaundice, fever, arthralgia, nausea, vomiting, dark urine, and abdominal pain. CCl4 intoxication may also determine a headache, drowsiness, and dizziness. The CIOMS (Council for International Organization of Medical Sciences) criteria for DILD are as follows. It is designated hepatocellular injury, if ↑ ALT is >2 than normal (isolated) OR ALT/ALP ≥ 5 is seen, cholestatic injury if ↑ ALP >2 than normal (isolated) OR ALT/ALP ≤ 2, mixed injury if ↑ ALT + ALP and 2  2:1 and possible hepatic encephalopathy (e.g., confusion, lethargy, hallucination, asterixis, and coma) in late stages. • CLM: There is a zone 3 (perivenular)-starting macrovesicular prevalent steatosis with focal lipogranulomas and retrograde restructuring of the liver following 2–4 of ethanol abstinence. Moreover, there are ASH showing a zone 3-starting steatosis with liver cell damage (ballooning degeneration, Mallory hyaline, and neutrophil-rich inflammatory infiltrate ± L/PC infiltrates) and perivenular fibrosis (phlebosclerosis) to chicken wire-like fibrosis along the spaces of Disse to central hyaline sclerosis leading ultimately to liver cirrhosis (vide infra). Other microscopic features are not specific and may be present in other forms of hepatitis and include siderosis, cholangiolitis, cholestasis, portal fibrosis, and interface hepatitis. Hepatocellular steatosis (fatty change) results from three mechanisms that may act simultaneously or in tandem/subsequently like in the “National Football League.”

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1. NADH+H+ in excess due to the action of two significant enzymes of CH3CH2OH metabolism, ADH, and acetaldehyde dehydrogenase inducing shunting of standard substrates away from catabolism and toward lipid biosynthesis 2. Increased Fat catabolism at the periphery 3. Impairment of Lipoprotein assembly and secretion Notes: N=NADH+H+ in excess, fat catabolism increased, and lipoprotein malfunction • PGN: COD (cause of death) in ALD is due to hepatic coma, more frequently seen in teenagers. Other COD include hepatorenal syndrome developing to multi-organ failure, intercurrent infection evolving to sepsis, massive GI bleeding, and neoplastic transformation (HCC) with metastasis. In a study from Leipzig (Germany), Schoeberl et  al. (2008) identified that during the years 1998– 2004, the rate of alcohol-intoxicated teenagers increased at about 171.4%. A total number of 173 patients with an average age of 14.5  years was admitted to the university children hospital. They found severe symptoms in many of them, including 62 were unconscious, 2 were in a coma, and at least 3 patients had to be ventilated. Hepatic coma and death are impressively increasing in the adolescence and youth.

4.6.7  Non-alcoholic Steatohepatitis Hyperlipidemic diet is quite typical in the Western world, but it became a problem in some other regions as well, such as the Mediterranean areas. Obesity is a reality in our countries. Dietary intake, particularly items such as juice and sugar-sweetened beverages, decreased physical activity, and sedentary behaviors, such as screen time, are quite diffuse. The body mass index (BMI) is used to determine whether a child is obese and is calculated as body weight (kg) divided by length or height (m2). World Health Organization (WHO) growth curves are avail-

4  Parenchymal GI Glands: Liver

able and allow to determine the progression of children (Fig. 4.25). Obesity is influenced by primary genetic or endocrine factors and nongenetic endocrine ones, including the environment, family, and social. Primary genetic or endocrine etiologies are rare but need to be taken into consideration, if the child has dysmorphism, severe hyperphagia, developmental delay, clinical signs of Cushing impressively increasing in or Cushingoid syndromes, and hypothyroidism. Risk factors for obesity also need to be considered and include a family history of obesity, substantial pregnancy weight gain, and gestational diabetes mellitus. Health risks for the child include hyperlipidemia, hypertension, insulin resistance, low quality of life (quoad valetudinem), and sleep-disordered breathing and poor school performance. The identification of acanthosis nigricans, a sign of insulin resistance, has been proposed by some authorities. AAP guidelines recommend a fasting lipid profile for children older than 2  year of age affected with obesity, and the Canadian Diabetes Association 2013 recommends screening prepubertal children for T2DM every 2 years, if some factors are met, including obesity, high-risk ethnic group, family history of type 2 diabetes mellitus, in utero exposure to hyperglycemia, and signs of insulin resistance. NASH grading has been indicated to harbor an extreme prognostic value. There is a growing list of possible metabolic defects or genetic syndromes showing NASH or early cirrhosis in life, and OMIM or other search engines may be able to create an updated list. Box 4.33 shows some tips and pitfalls in diagnosing of NASH/ASH.

4.6.8  A  cute and Chronic Rejection Post-Liver Transplantation Acute rejection in liver transplant recipients is an important clinical event, which may be lifethreatening. Despite improvements in immunosuppressive therapy, hepatic allograft rejection remains an important cause of morbidity. Moreover, it is a critical etiology for late graft loss in patients undergoing liver transplantation.

4.6 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection

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Fig. 4.25  Alcoholic steatohepatitis and NASH can be recognized by multiple vacuolation of the hepatocytes with fibrosis and neutrophilic damage (a–h, H&E, Masson’s trichromic, periodic acid Shiff, and Oil Red O stains)

In about 5–10% of liver recipients who develop acute cellular rejection, there is a progression to severe ductopenic rejection despite antirejection therapy. Histologic features portend a terrible

outcome include arteritis, ductopenia (PIBD), and/or simultaneous hepatocellular ballooning and hepatocellular dropout and necrosis. Bile duct damage in the diagnosis of acute rejection

500

should include a predominantly lymphocytic infiltrate and a damaged bile duct. Useful features of bile duct damage include variation in biliary epithelial nuclear size, vacuolation of the cytoplasm, missing nuclei, and, naturally, intraepithelial lymphocytes. The importance of ductopenia depends mainly on the degree and

Box 4.33 NASH/ASH Pearls and Pitfalls! (Fig. 4.25)

• NASH is Non-ASH and includes a series of several etiologies, including obesity, DM, drug toxicity (e.g., amiodarone, perhexiline maleate, estrogens), or post-jejunoileal bypass surgery or gastropexy for adiposity. The differential diagnosis requires a clinicopathologic correlation! • Mallory hyaline (aka Mallory-Denk body) can be highlighted by histochemistry and immunohistochemistry. Masson trichrome

Box 4.34 Pearls and Pitfalls on Liver TX-DDX

• If you see spotty necrosis with neutrophilic microabscesses, then think of CMV! • If you see spotty necrosis with portal mononuclear infiltrates ± lobular mononuclear infiltrates, then think of HBV and HCV. • If you see spotty necrosis only, then think of hepatitis NOS. • If you see focal lobular mononuclear clusters only, then think of a nonspecific finding! • If you see the biliary ductular reaction with bile plugs, then think of sepsis or preservation injury (time and lab notes are essential)! • If you see biliary ductular reaction without bile plugs, then think of severe early tissue preservation injury, ACR, LDO and severe viral hepatitis, and the list may not be complete (time and lab notes are essential)! • If you see a mixed inflammatory infiltrate of the portal tracts with bile duct damage and/or inflammation (mononuclear, eosinophils, neutrophils), then think of ACR!

4  Parenchymal GI Glands: Liver

persistence of the scarcity (Figs. 4.26, 4.27, and 4.28). See Box 4.34 for pearls and pitfalls on liver TX and the DDX. Posttransplantation lymphoproliferative disorders may be a complication of the immunosuppression used in patients to avoid rejection or GvHD.

stain is useful to detect the Mallory-Denk bodies (MDBs). Immunohistochemistry for p62, ubiquitin, or CK8/CK18 may also be positive in MDBs. • Mallory hyaline is also seen in Wilson disease, Indian childhood cirrhosis, some liver neoplasms, and some disorders associated with chronic cholestasis (e.g., PBC). Notes: CK8 cytokeratin 8, CK18 cytokeratin 18

• If you see periductal neutrophilic infiltrates and duct damage, then resolving rejection or LDO are on the top of the list (clinicopathologic correlation is essential!). • If you see cholestasis only, then tissue preservation injury, LDO, or chronic rejection should be considered (crucial is the interlobular bile ducts/portal tract ratio)! • If you see diffuse hepatocyte ballooning, then think of ischemia and/or hepatitis. • If you see centrilobular hepatocyte necrosis and/or swelling, minimal inflammation with or without congestion and/or fibrosis, then think of tissue preservation injury, ischemia, or vascular rejection. • If you see parenchymal necrosis, then think of local ischemia/another injury. Notes: ACR acute cellular rejection, LDO large duct obstruction

4.6 Viral and AI Hepatitis, Chemical Injury, and Allograft Rejection

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Fig. 4.26  TX hepatopathy shows hemorrhages (a) as well as acute rejection with endothelialitis and inflammatory infiltrate of the portal tract (b–h)

4  Parenchymal GI Glands: Liver

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Fig. 4.27  In this panel a quite unique panel of progressive sclerosing cholangitis (de novo)-related transplant hepatopathy is shown (a–h)

4.7 Hepatic Vascular Disorders

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Fig. 4.28  In this panel is shown chronic graft-versushost disease with paucity of the interlobular bile ducts in an adolescent. Note the biliary proliferation of peripher-

4.7

Hepatic Vascular Disorders

Hepatic vascular disorders are a common coming in the pathology practice (Boxes 4.35 and 4.36).

4.7.1  A  cute and Chronic Passive Liver Congestion Cholestasis, as well as liver cell damage, may also be encountered in ischemic or hemorrhagic processes involving the structure of the liver.

ally located bile ductules, some of them showing lumina with inspissated bile (a–c: H&E stain; d–f: anti-CK7 immunostain)

Box 4.35 Circulatory Disorders

1. ↓ blood flow into the liver 2. ↓ blood flow through the liver 3. ↓ blood flow out of the liver

Acute and Chronic Passive Liver Congestion Clinical (hepatomegaly) and pathologic (gross and histologic passive congestion) are observed in right-sided heart failure and, often, seen with children with congenital heart defects affecting

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4  Parenchymal GI Glands: Liver

Box 4.36 Hepatic Vascular Disorders

Box 4.37 Liver Circulatory/Vascular Changes

4.7.1. Acute and Chronic Passive Liver Congestion 4.7.2. Ischemic Hepatocellular Necrosis 4.7.3. Shock-Related Cholestasis

• BCS: Partial/sub-occlusive/occlusive thrombosis and/or fibrous obliteration of the major hepatic veins or inferior vena cava ± membranous webs • CLN: prolonged congestive heart failure • CPC: Right heart failure (nutmeg appearance with centrilobular congested areas and relative pallor of the periportal areas with distension of central veins and perivenular sinusoids of the zone 3 of Rappaport) • Infarction: Thrombus • PVT: Abdominal malignancies, peritoneal sepsis, pancreatitis, post-surgery, cirrhosis, metastatic carcinoma; clinically, abdominal pain and ascites • VOD: Pyrrolizidine alkaloids, azathioprine, thioguanine, hepatic radiation, BMT with GvHD; sclerosis-related occlusion of the central veins with associated sinusoidal congestion of all three zones Notes: BCS Budd-Chiari syndrome, CLN centrilobular necrosis, CPC chronic passive congestion PVT portal vein thrombosis, VOD veno-occlusive disease

the functionality of the right heart. The etiology of hepatic congestion is increased pressure within hepatic venules and sinusoids due to severe rightsided heart failure and constrictive pericarditis, thrombosis of large hepatic veins (Budd-Chiari syndrome), and veno-occlusive disease (VOD). Budd-Chiari syndrome may be observed in neoplastic or non-neoplastic myeloproliferative states, hypercoagulability, malignancies of the liver, kidney, and adrenal gland, postradiation exposure, and following contraceptive use administered orally. VOD has been associated with herbal teas-containing pyrrolizidine alkaloids, radiotherapy, and chemotherapy (azathioprine and cytotoxic agents in bone marrow transplant (BMT) and kidney transplant (KTX) recipients). Clinically, hepatomegaly with or without dysregulation of liver enzymes is seen. Grossly, the classic nutmeg liver with diffuse parenchymal mottling with reddish-purple perivenular areas surrounded by paler regions is observed. Microscopically, a variable range of changes is seen, including sinusoidal congestion, atrophy and disappearance of the hepatocyte plates with the collapse of the reticulin framework and fatty change of zone 2, and reverse lobulation with pericentral fibrosis and portocentral septa. Budd-Chiari syndrome may also show fibrin thrombi, while VOD is a fibro-obliteration of the terminal venulae. Overall, ischemia is the consequence of shock or other systemic hypotensive states or other states leading to congestion (e.g., some cirrhotic nodules in patients with hypodynamic heart function). Grossly, there are no right ischemic infarcts due to the liver’s dual blood supply. Zahn infarct is a wedge-shaped area due to sinusoidal dilation due to an occlusion of intrahepatic portal vein branches. Liver changes due to either obstruction of blood inflow (hepatic artery or portal vein) or

blood outflow (central vein or hepatic vein/s). In infarction, there is a sudden obstruction of the hepatic artery. Liver circulatory changes are summarized in Box 4.37. The etiology of BuddChiari syndrome includes polycythemia vera, pregnancy, oral contraceptives, hepatocellular carcinoma, and intra-abdominal malignancies. Peliosis Hepatis Rochalimaea henselae/Rochalimaea quintanarelated vascular change of the liver with cystic pools of blood lined by hepatocytes (CD31-, no endothelial cells) due to the progressive death of infected hepatocytes (skin→ bacillary angiomatosis) with non-infective mimickers, including anabolic steroid use, exposure to vinyl chloride, post renal TX, and hematologic disorders.

4.8 Liver Failure and Liver Cirrhosis

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4.7.2  Ischemic Hepatocellular Necrosis

4.8

The patterns of hepatic injury with necrosis and apoptosis can be subdivided according to the distribution and degree of involvement. According to the distribution, we may have centrilobular necrosis, which is most common and is immediately around the terminal hepatic vein. According to the degree of involvement, we can have focal or spotty necrosis (only scattered cells within the hepatic lobulus), interface hepatitis (between periportal parenchyma and inflamed portal tracts), bridging necrosis, spanning adjacent hepatic lobules, submassive necrosis involving entire lobules, and massive necrosis, comprising most of the hepatic parenchyma.

Liver failure is referred to an acute liver illness associated with encephalopathy and subdivided according to the onset of brain involvement (vide infra) (Box 4.38) (Figs. 4.29 and 4.30).

4.7.3  Shock-Related Cholestasis • DEF: Shock-related bilirubinostasis due to some etiologies that may act singly or in combination, as shown below: 1. Inhibition of the hepatocellular Na+-K+ ATPase at the basolateral membrane due to endotoxin, hypoxia-related damage, and/or DILD 2. Hyperthermia/fever, and dehydration 3. Bile ductular proliferation with some obstruction 4. Bacterial β-glucuronidase-related production of bile concretion 5. Effect(s) of inflammatory substances (e.g., leukotrienes) on interlobular bile ducts and/or bile ductules. • CLM: Perivenular necrosis of hepatocytes with cholestasis is due to the reduction of the O2 supply to the liver, particularly to hepatocytes located in the acinar zone 3, which are the peripheral territory of the hepatic acini. • DDX: Necrotizing hepatitis, TPN, BA, decompensated liver cirrhosis.

 iver Failure and Liver L Cirrhosis

Box 4.38 Liver Failure

–– Acute liver failure (ALF) –– Chronic liver disease (CLD). –– Hepatic metabolic dysfunction (HMD) without overt necrosis (e.g., tetracycline toxicity)

Acute liver illness is associated with encephalopathy and subdivided according to the onset of brain involvement: –– Fulminant, if  NH4+ ⇒ edema 2. Hepato-renal syndrome: Renal failure in CLD (intrinsic morphologic/functional injury) 3. Hepato-pulmonary syndrome: Hypoxemia and IPVD (intrapulmonary vascular dilatation) in CLD Liver cirrhosis refers to the end stage of several and different progressive and chronic diseases leading to diffuse and irreversible parenchymal damage. Three processes of regeneration are described in the original German

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a

b

c

d

e

f

g

Fig. 4.29  Neonatal HSV-liver failure is life-threatening and shows liver failure both grossly (a–c) and histologically (d–f). The microphotograph (g) shows the detection

of HSV in the hepatocytes of this infants who suffered from HSV-induced liver failure

literature of pathology schools: “Abbau-AufbauUmbau.” In liver cirrhosis, there is simultaneous presence of all three processes, which include dismantlement of the normal liver architecture with portal triads and centrolubar zones (Abbau),

increase of collagen and collagen-producing cells through paracrine activity (Aufbau), and conversion of the normal hepatic architecture into structurally abnormal nodules (Umbau). These three events, although simultaneous, may be incon-

4.8 Liver Failure and Liver Cirrhosis

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a

b

c

d

e

f

g

h

Fig. 4.30  In this panel are shown the species of the Amanita genus mushroom that each summer is culprit of some deaths worldwide and the mechanism of damage due to amatoxin and phallotoxin (a–b). In (c) and (d) are two gross photographs of common mushroom poisoning liver failure. The histopathology of liver failure can be different, because the etiology of fulminant liver failure is

variable (e–h). In (g) adenovirus-related liver disease is seen (H&E stain). The microphotograph in (h) shows the biliary proliferation encountered in cases of subacute liver failure when the liver has some time to regenerate and rebuild some excretory biliary ways to drain the bile (antiCK7 immunostain)

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spicuous in the early stages (at least one or two out of three) and become more prominent as the disease progresses leading to the abnormal vascular relationship (AV shunts) and portal hypertension with obvious consequences for the affected individuals (Box 4.39).

Box 4.39 Chronic Liver Disease (CLD) End Stage

Cirrhosis – End stage of CLD is characterized by: –– Loss of hepatocytes (Abbau of the German literature) –– ECM deposition (Anbau of the German literature) –– Vascular reorganization (Umbau of the German literature) with sinusoidal capillarization in Disse space Evolving to: –– Bridging fibrous septs –– New parenchymal nodules –– Liver architecture disruption

Some stimuli can bring forth the activation of stellate cells, which are at the basis of the liver fibrosis. They are cyto-/chemokine release by KC, endothelial cells, hepatocytes, and biliary cells. ECM disruption, inflammation of chronic type (⇒ inflammatory cytokines, such as tumor necrosis factor (TNF), lymphotoxin, IL1-β, and lipid peroxidation products), and toxin-/drugrelated direct stimulation of stellate cells (stellate cells → myofibroblasts (MFB) ⇒ collagen I and III through the expression of platelets growth factor receptor beta (PDGFR-β), transforming growth factor beta (TGF-β) , matrix metalloproteinases (MMP2), and tissue inhibitor of metalloproteinases (TIMP1-2)) are important key factors in liver cirrhosis. The easiest way to classify the liver cirrhosis is according to the size of the nodules, i.e., micronodular or macronodular or mixed. Classifications

based on etiology may also be used, but the size of the nodules will direct the pathologist to the most critical criterion and then to some etiology list. The cutoff for micro- or macronodular cirrhosis is 3 mm. If more than 3 mm, the cirrhosis is macronodular, while if less or equal to 3 mm, the cirrhosis is classified as micronodular. However, in many cases the liver may show a combination of features of both macro- and micronodules. The micronodular is classically the Laennec or portal cirrhosis, while the macronodular is usually the post-necrotic or post-hepatic liver cirrhosis. Causes of death (COD) of patients with liver cirrhosis are (1) progressive liver failure, (2) portal hypertension-related complications, and (3) hepatocellular carcinoma.

4.9

Portal Hypertension

Portal venous pressure in physiological conditions is 0–10  mm Hg and is slightly above the venous pressure of the inferior vena cava. However, the hepatic venous pressure (HVP) gradient is usually ~ 5mmHg. If it rises over 6mmHg portal hypertension is considered to be present, but if it is over over 10mmHg clinical features of portal hypertension can develop and a HVP gradient greater than 12 mmHg is accompanied by varices and other complications. The gradient between the two pressure venous systems is low because: –– High compliance of the portal vein and sinusoids –– The low resistance of the portal vein and sinusoids –– The outflow of the large suprahepatic veins Also, there is an adverse pump effect resulting from direct drainage into the right atrium and the perfect location at the thoraco-abdominal interface. Portal hypertension: It is defined by a pressure that is higher than typical values. The etiology is dual. Portal hypertension may be due to (1) either an increased resistance to portal flow at the level of the sinusoids (2) or a partial venous blood flow produced from a hyperdynamic circulation.

4.10 Bacterial and Parasitic Liver Infections

There are four consequences of portal hypertension, including (1) ascites (sinusoidal hypertension, hepatic lymph percolation, splanchnic circulation vasodilation, and hyperdynamic circulation), (2) portal system venous shunts, (3) congestive splenomegaly and hypersplenism, and (4) hepatic encephalopathy. A common classification of portal hypertension includes a prehepatic (e.g., thrombosis of the portal vein and “cavernomatous” change, splenic vein thrombosis, splenic arteriovenous fistula, and idiopathic tropical splenomegaly), hepatic (pre-sinusoidal, e.g., hepatic fibrosis due to, for instance, schistosomiasis, but also hepatic neoplasms, viral hepatitis, and infiltrative disease such as tuberculosis, sarcoidosis, hemochromatosis, and rarely amyloidosis; sinusoidal, cirrhosis, for instance, in biliary atresia, but also acute viral hepatitis, NASH/ASH, and fatty liver of pregnancy; and post-sinusoidal for instance of veno-occlusive disease and in case of hyaline sclerosis of central veins), and post-hepatic (e.g., Budd-Chiar syndrome, but also inflammatory and/or neoplastic infiltration, caval inferior occlusion due to thrombus or neoplasm, right ventricular failure, tricuspid regurgitation, and constrictive pericarditis). Arterio-Portal Hypertension It is an excessive and constrained arterial blood inflow into the portal venous system, which is typically a closed vascular system that is limited by volume with a single outflow. Typical underlying condition: arterio-portal fistula from a vascular malformation located in the liver or the splanchnic area. The arterio-portal fistula is defined as simple or complex according to single or multiple arteries ending in a common venous channel or an aneurysm. Management of portal hypertension may be very challenging, especially in childhood (De Ville de Goyet et al. 2012). Surgical management may depend not only on parenchymal damage and hepatic dysfunction but also about the secondary injury and fibrosis occurring in patients with post-sinusoidal portal hypertension. Surgical intervention was rarely a common practice in the past assuming that blood vessels may become more stable with age and the chance of success increase. However, several

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studies have evidenced excellent technical outcomes even in early childhood, and the management is changing worldwide. This information is relevant to liaise correctly with the pediatric surgical team at multidisciplinary team meetings or clinical rounds and to evaluate precisely failed procedures associated with death at the time of postmortem investigations or the court for medicolegal cases. Complications following shunt and bypass may occur even in best centers. The incidence of complications is variable because some factors should be taken into consideration, mostly the underlying clinical condition(s) of the patient.

4.10 B  acterial and Parasitic Liver Infections 4.10.1  Pyogenic Abscess It is defined as a collection of pus (purulent abscess) that has built up within the liver in a newly formed cavity (the condition in which pus and fluid from infected tissue accumulates in a pre-existing body cavity is called empyema, e.g. pleural empyema). Both abscess and empyema have Latin and Greek origin (Abscessus from abscēdō “depart” and ἐμπύημα “suppuration”). There are four significant ways in which pyogenic microorganisms invade the liver. 1. The microorganisms may travel through the portal vein from regions drained by it, such as acute suppurative appendicitis, pyophlebitis, gastric and intestinal ulcers, as well as infectious (pyogenic) diseases of the rectum, spleen, and pancreas. 2. The microorganism belongs to blood-borne infection and is transmitted through the hepatic artery. Etiologies include osteomyelitis, acute infections of the urinary tract, or pyemia from any source. 3. The microorganism gets access to the liver through a direct extension from a contiguous infection (e.g., subphrenic abscess, empyema, nephritic abscess, perinephritic abscess). 4. The microorganisms can invade the liver directly through trauma, and this may be a

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penetrating injury (accidental, criminal, iatrogenic) or a subcutaneous injury (mostly, random).

4.10.2  Helminthiasis Helminthiasis group includes echinococcosis, schistosomiasis, and ascariasis. Worldwide, helminths remain probably the primary cause of wildlife diseases and, unfortunately, represent a significant burden for the patients, healthcare, and the often-economic crisis in the livestock industry. Human socioeconomic problems are a considerable task in developing countries as well and added to the burden. Helminths often live in the gastrointestinal tract of their hosts with the option to burrow into other organs inducing relevant damages. Liver disease is derived from any macroparasitic illness of humans and animals in which the liver is infected with parasitic worms, called helminths (Greek: ἕλμινς, ἕλμινθος “intestinal worm”).

4.11 Liver Tumors 4.11.1  Benign Tumors (Figs. 4.31, 4.32, and 4.33) Benign tumors are essential to differentiate from malignant, but benign tumors also have a quite complicate or variable list of names that may confounder either the pathologist or the clinician. It is essential to differentiate between reactive (or regenerative) changes and true neoplasm (benign or malignant). In the liver, it is useful first to distinguish a nodular regenerative group from liver cell adenoma. The concept of hepatocellular dysplasia is presented, although is controversially discussed in the scientific literature. Benign bile duct tumors (i.e., non-hepatocytic but biliary cell-differentiated benign tumors) are listed in Box 4.40. Finally, the remaining benign tumors include non-hepatocytic, non-biliary cell-differentiated tumors, which are a cavernous hemangioma, infantile hemangioendothelioma, peliosis hepa-

Box 4.40 Benign Bile Duct Tumors

• • • •

Bile duct hamartoma Bile duct adenoma Biliary cystadenoma Biliary papillomatosis

tis, and hepatic mesenchymal hamartoma. The most common genetic syndromes associated with pediatric liver tumors are illustrated in Box 4.41. The entities collected in the group of regenerative nodularity are particularly important for the differential diagnosis of hepatocellular tumors.

4.11.1.1  Nodular Regenerative Hyperplasia (NRH) Nodular regenerative hyperplasia (aka nodular transformation) is constituted by the formation of cirrhosis-like nodules (“compensatory hyperplasia”) separated by the compressed atrophic liver with atrophic features without intervening fibrosis and associated with myelo-proliferative disorders, RA, chronic venous congestion, and drugs (e.g., steroids, chemotherapy protocols). Ischemia or chemical insults may determine the hyperplasia of the hepatic muralium (two-cell thick indicating regeneration) and generally involving the entire liver. 4.11.1.2  Partial Nodular Transformation (PNH) The early stage of NRH with similar changes but confined to the area of the hilum. 4.11.1.3  F  ocal Nodular Hyperplasia (FNH) Well-circumscribed, hyperplastic and hypervascular, asymptomatic lesion (4/5 single, 1/5 multiple) due probably to a pre-existing arterial malfunction with specific arteriographic finding (hypervascularity with centrifugal filling and a particular blush of dense capillarity). Grossly, solid, gray-white, unencapsulated (usually Ø    1  cm, occurring in the setting of cirrhosis with a thin fibrous rim, similar to surrounding smaller nodules. DDX: LCA, dysplasia. It is paramount to mention the definitions and aspects of nodular regenerative hyperplasia (NRH) and partial nodular transformation (PNT). In NRH, there are regenerating hepatocytes with thickened cell plates and compression of adjacent areas, which present with thinning or atrophy of the cell plates in the absence of fibrosis (≠ cirrhosis) separating the several nodules. In PNT, there is an NRH morphology but limited to the perihilar region of the liver and caused by a vascular insult. Thus, location is crucial (diffuse vs. focal-perihilar) and then evaluate the presence of fibrosis. If no fibrosis, it is NRH/PNT, while in a state of fibrosis, the diagnosis portends to cirrhosis and Masson trichrome stain may be crucial. The trichromic stain is essential in differentiating NRH/PNT from cirrhosis. 4.11.1.5  Liver Cell Adenoma (LCA) • DEF: A benign epithelial tumor of hepatocellular origin, which may be associated with oral contraceptives, anabolic steroids, antiestrogen therapy, Klinefelter syndrome, GSD Ia/ III, Fanconi anemia, FAP, DM, mucopolysaccharidosis Type IH (MPS-IH or Hurler syndrome), tyrosinemia and classified in four types with the acronym “FAT” to remember the three most important types (Box 4.42) and presenting as a well-circumscribed, hyperplastic but hypovascular, often symptomatic (bleeding ¼ of cases) lesion with a specific arteriographic finding (hypovascularity). • EPI: Worldwide, 2nd–4th decades, 2–4% liver tumors in childhood, ♂:♀ = 1:9. • CLI: Mostly solitary, right lobe, usually >10 at presentation (in case of liver cell adenomatosis, Flejou et al. 1985), and symptomatic (hemorrhage 1/4 of cases) and hypovascular-

Box 4.42 Typing of Liver Cell Adenomas (Four Types) Type Fatty LCA Atypia/ adenomatous LCA Telangiectatic LCA LCA, NOS

Etiology HNF1α CTNNB1 GP130

Histology/IHC LFABP (−) Inflammation, β-cat (+)n/c SAA (+), CRP (+)

Unknown

Notes: CRP C-reactive protein, CTNNB1 beta-catenin gene, GP130 glycoprotein 130, HNF1α hepatocyte nuclear factor 1 alpha, SAA serum amyloid-A

ity on arteriography (imaging). Flejou et al. (1985) definition of liver cell adenomatosis include the following criteria (a) arbitrarily >10 hepatic nodules, (b) equal sex distribution, (c) no association with oral contraceptives, (d) ↑ levels of serum ALP and GGT. Chiche et al. (2000) distinguish two patterns of liver cell adenomatosis, including the massive type presenting with hepatomegaly, a deformation of the liver contour, with nodules of 2–10 cm (Ø), and the multifocal type containing many adenomas up to 4 cm (Ø) but lacking a deformation of the liver contour. A rapidly progressive course is usually restricted to the massive type. • GRO: Partially or unencapsulated, mostly round, yellow-tan, subcapsular and without necrosis. • CLM: Well-differentiated hepatocytes with abundant cytoplasm and growing in two-cell thick trabeculae with solitary arterial blood vessels without evidence of portal triads, central veins, fibrosis, bile ducts or connection with the biliary system (“unpaired arteriae,” NTBV  – non-triadic blood vessels), intact reticulin framework, no mitoses, and no invasiveness. The acronym “MAGIC” is useful to remember some important criteria (MI = 0, Atypia = 0, Growth = two cell thick with unpaired AA and no BD, Invasiveness = 0, C = Clinical History, often +). The blood vessels tend to be localized at the periphery of the

4.11 Liver Tumors

•

•

• •

tumor showing intimal thickening and smooth muscle proliferation. HSS/IHC: Ret (+), GPC-3 (−), CD34 (±) + subtyping markers (LFABP, β-cat, SAA, CRP) and E/PR (+), p53 (−). DDX: Hepatocellular nodular lesions, including FNH, NRH (even a large regenerative nodule), PNT, FLC, and HCC. The normal liver always has portal tracts, and nontriadal blood vessels are never seen in other lesions other than LCA. TNT: Resection. PGN: In case of oral contraceptive/anabolic steroid-induced LCA, the tumor often regresses when these drugs/supplements discontinued. The condition “multiple hepatocellular adenomatosis” represents an incredible challenge may be a very well-differentiated HCC and expert pathology consultation is strongly recommended.

Box 4.42 highlights the distinctive phenotyping of liver cell adenomas as we know from the most current classification.

4.11.1.6  Hepatocellular Dysplasia The concept of HCD is controversially debated. It has been suggested that even when correctly diagnosed, no clear indications for therapy exist. Large cell dysplasia refers to isolated large cells with enlarged nuclei but standard N/C ratio and normal nuclear contours. It seems to be often seen in some livers with cirrhosis. There is no clear-cut evidence to assign this condition a level of premalignant condition. Small cell dysplasia refers to clusters of normal-sized hepatocytes with visible larger nuclei and distinct increased N/C ratio as well as irregular nuclear contours. The architecture seems, however, unaffected. Flow cytometry studies evidence an increase in the number of peaks, mostly 2n and 4n. MIB1/Ki67 and PCNA are increased, although not so high as much we can detect in an HCC. There is a broad platform of consensus, although not univocal, that “small cell dysplasia” may be considered a premalignant condition.

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4.11.1.7  Bile Duct Hamartoma (BDH) BDH is a ductal plate malformation or anomaly and is aka von Meyenburg complex or Moschowitz complex. Typically, there are multiple small white nodules scattered throughout the liver showing, microscopically, a mostly periportal anarchic collection of biliary structures, some of them with dilation and bile pigment in lumens embedded in an abundant fibrous stroma. There is an ischemic origin raised from some authors, although some of them are, apparently, of malformative origin and associated with ADPKD. 4.11.1.8  Bile Duct Adenoma (BDA) Subcapsular, firm, white, small (  ♀ (especially if +cirrhosis). • CLI: Abdominal pain, ascites, hepatomegaly, and ↑ AFP in serum. • RFs: Liver cirrhosis, HBV and HCV infections, xenobiotics, thorotrast (thorium dioxide), steroids (anabolic or progestational steroids), alcohol, radiation, metabolic diseases (PFIC-2, AATD, tyrosinemia, GH), aflatoxins (Aspergillus flavus), schistosomiasis, and ataxia-telangiectasia syndrome (Knisely et al. 2006). A xenobiotic (Greek ξένος  =  foreigner, stranger, and βίος = life, plus the Greek suffix for adjectives -τικός, -ή, -ό) is a chemical molecule that is found in an organism, although it is not usually produced or expected to be present in it. Examples of xenobiotics may be dioxins and polychlorinated biphenyls that may alter our metabolism and initiate the cascade of cancer, either as initiators or as promoters. Our food may become contaminated by the direct use of artificial hormones on animals or plants or involuntarily by using animals or plants living downstream of sewage treatment plant outfalls or other plants where pesticides or other harmful chemical substances are used. The International Agency for Research on Cancer, an Agency of the World Health Organization, is leading in the classification of carcinogenic substances, such as glyphosate (Guyton et al. 2015; Portier et al. 2016). • GRO: Typically, single large mass or multiple discrete nodules or, unusually, numerous small nodules diffusely scattered throughout the liver. The tumor can be encapsulated and pedunculated and may show necrosis or hemorrhage.

4.11 Liver Tumors

• CLM: Trabecular, solid, acinar (pseudoglandular), pelioid, giant cell, sarcomatoid, and clear cell are the histologic growth patterns. A network of sinusoidal blood vessels surrounds the neoplastic liver cells, and there is usually scant stroma. Hepatocytes may show a welldifferentiated to very bizarre phenotype. Angioinvasion is a standard feature, and portal vein thrombosis is often found. Other standard features include intranuclear pseudoinclusions, Mallory hyaline, bile pigment, and clear cell change (Figs. 4.37 and 4.38). • IHC: (+) AAT, transferrin, CAM 5.2, but (−) for CEA, AE1 and EMA and (+) HepPar1, GPC-3, and AFP (all three highly relevant!). CAM 5.2 is a monoclonal antibody often cited to be reacting with keratins 8, 18, and 19, although it seems to be specific for keratin 8 only (Makin et al. 1984; Smedts et al. 1990). • PGN – Poor with 5-YSR: 10%, but a better outcome may be observed, if low stage, encapsulation, single lesion, no cirrhosis, and OCP-Hx are (+). No effect on outcome is seen about tumor size, age, sex, and HBV status. The sclerosing variant of HCC that needs to be differentiated from HCC, fibrolamellar type, represents 3% of all primary hepatic tumors with ♂  =  ♀, usually in middle-aged individuals, and 2/3 of patients show hypercalcemia and hypophosphatemia without bony metastatic disease and half of the patients have liver cirrhosis. • CLM: Histologically, there are cords of tumor cells in a dense fibrotic stroma, and in most cases, they show characteristic hepatocellular histology. • PGN: Poor with the survival of 6 months only. Staging criteria for HCC include the direct invasion of adjacent organs other than gallbladder, the involvement of the principal division of the portal vein or hepatic veins, the presence or not of the involvement of visceral epithelium, the size (Ø) less or more than 5  cm, the number (solitary or multiple), and the vascular invasion at microscopic level.

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Additional pathologic findings that may be relevant for the oncologist are fibrosis score (none to moderate fibrosis or Ishak score 0–4 versus severe fibrosis/cirrhosis or Ishak score 5–6), the presence or not of hepatocellular dysplasia (low-grade versus high-grade dysplastic nodule), steatosis, iron overload, and chronic hepatitis. In North America, about 2/3 of the primary malignant liver tumors are hepatocellular carcinomas. Histologically, multiple architectural growth patterns can be encountered. Numerous growth patterns may be found in the same tumor. It seems that only the fibrolamellar variant has prognostic significance. It has, however, argued that the longer survival might relate to the age of the affected patients (young) and the absence of cirrhosis. The correct labeling as fibrolamellar carcinoma (FLC) of the neoplastic formation found in the liver requires the lack of any other usual growth patterns of hepatocellular carcinoma. The occurrence of only one additional pattern makes the diagnosis of FLC incompatible. Histologic grading of a hepatocellular carcinoma follows the original grading system of Edmondston and Steiner (1954). However, it has been observed that this grading is easily underestimated in liver core biopsies, and interrater disagreement between pathologists can be astonishingly significant unless consensus meetings are regularly held (Pirisi et al. 2010). Briefly, grade I includes minor differentiation between tumor cells and hyperplastic liver cells and the diagnosis of malignancy is made by more aggressive tumor growth patterns elsewhere in the neoformation. Grade II includes tumor cells with close likeness to normal liver cells but nuclei are larger than those observed in hepatocytes and exhibit more hyperchromasia. Sharp, clear-cut borders and abundant and acidophilic cytoplasm are characteristics of the tumor cells and acini can be found and have variable size. Moreover, protein precipitate or bile are commonly seen filling the lumina of neoplastic acini. Grade III is characterized by larger tumor cells harboring more hyperchromatic nuclei with a higher N/C ratio. The cytoplasm of the tumor cells is granular and acidophilic. Acini are less frequently encountered than Grade II. Similarly, protein or bile precipitates are less commonly seen. A single cell growth in vas-

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cular channels is more often seen than Grade II. Finally, grade 4 is characterized by a very large cell volume and nuclei are intensely hyperchromatic. Cytoplasmic granularity is mild or minimal and acini are rarely seen. Medullary growth pattern and tumor cell scattering in vascular channels without cohesion are also seen. Intriguingly, some spindle cell areas or short, plump cell forms similar to lung carcinoma, small-cell variant, may be encountered. Attention in childhood and youth should be reserved for the HCC, fibrolamellar variant. The fibrolamellar variant of HCC is peculiarly distinct from other malignant tumors. It is paramount to separate the FL-HCC or FLC from HCC by its unique clinicopathologic features. Edmondson initially described this tumor in 1956 as eosinophilic hepatocellular carcinoma with lamellar fibrosis. Its distinction from HCC took a long time. Although the World Health Organization (WHO) Classification of Tumors recognized FLC as having a unique histological pattern, only in 2010, FLC acquired its own WHO classification number (Bosman 2010). Clinically, FLC occurs in adolescents and young adults (no sex preference) with unknown etiology and is unrelated to liver cirrhosis, HBV infection, or metabolic abnormalities but symptomatology similar to classic HCC and tendency to metastasize to the abdominal lymph nodes, peritoneum, and lung. X-ray shows a central scar raising the differential diagnosis with FNH, although FLC shows some calcification, which is uncommon in FNH.  Interestingly, an increased serum AFP is present in only 1/10 of the patients, as compared with more than half of the patients with HCC showing this as an important distinguishing tumor marker clue. Epidemiologically, FLC is quite rare in East Asia, which shows a high incidence of conventional HCC. • GRO: Large, hard, scirrhous, well-circumscribed, bulging, brown or white-brown tumor with a central stellate scar and numerous fibrous bands throughout and preference for the left lobe. • CLM: FLC architecture exhibits nests, sheets, and cords of large oncocytic polygonal hepatoid

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•

•

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cells with low N/C ratio embedded in a background of dense, paucicellular collagen bundles arranged in a parallel fashion. At high power, the cells show well-defined cell borders, copious granular and eosinophilic cytoplasm with pale bodies or PAS+ hyaline globules, vesicular nuclei, and prominent nucleoli. There may be necrosis, angioinvasion, and often calcification with FBGC reaction. The surrounding liver is unremarkable. Rare patterns include trabecular, adenoid, and pelioid patterns. HSS/IHC: (+) HepPar, CK7, fibrinogen (pale bodies), Cu, Cu-binding protein, bile, AAT, pCEA and CAM5/2; (−) mucin, AFP. CMB: Diploid (2n) tumor with fewer chromosomal aberrations as compared with conventional HCC (vide supra). TEM: Mitochondria-rich (→ oncocytic) and RER-rich cell with fibrinogen (→ pale bodies), intracytoplasmic luminal/bile canaliculi (→ bile) without neurosecretory granules. FNA: Air-dried, Diff-Quick-stained slides, and alcohol-fixed smears stained with Papanicolau show mild-to-moderate cellular smears (dishesive cells) with occasional aggregates of fibrous tissue (collagen strands) and individual large cells with low N/C ratios, abundant granular cytoplasm, sharply outlined pale cytoplasmic vacuoles, as well as intracytoplasmic bile pigment. The nuclei are large and have prominent nucleoli, and naked nuclei with prominent nucleoli are often seen. Features associated with conventional HCC, such as vessels traversing groups of hepatocytes and “basket” pattern of endothelial cells surrounding clusters of hepatocytes, are useful for the differential diagnosis with the most frequent type of HCC. In case of a mediastinal mass showing the above-described features, some more common lesions need to be included in the differential diagnosis, such as thymic carcinoma, paraganglioma, ganglioneuroma, germ cell tumor, and metastatic melanoma. DDX: Adenosquamous carcinoma with sclerosis, CCA, FNH, HCC, sclerosing variant, metastatic carcinoma with sclerotic stroma, paraganglioma, and NE tumors.

4.11 Liver Tumors

• TRT: Management of HCC remains challenging since complete surgical resection is crucial for a cure. Nevertheless, in pediatric HCC,   ♀, 6th–7th decades (adults) and 2–7 years (children) • EPG: Vinyl chloride is a colorless organ-chloride gas with the formula H2C=CHCl with a sweet odor (aka vinyl chloride monomer, VCM or chloroethene), which is used to make the polymer polyvinyl chloride and vinyl products (e.g., plastic industry). Vinyl chloride is part of numerous products used in building and construction, industrial and household equipment, automotive industry,

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Box 4.44 Pearls and Pitfalls!

• Clusters of small acini (aka periluminal sacculi of Beale) may be quite often encountered in the extrahepatic biliary system and could represent a pitfall for CCA.  They should not be considered invasive CCA! • Perineural invasion in CCA is particularly useful in the intraoperative frozen section! • Precursor lesions for CCA are two, including biliary intraepithelial neoplasia, which is analog to PanIN (see below), and papillary intraepithelial neoplasm of the biliary tract, which is analog to IPMN of the pancreas (vide infra). • CCA shows no bile production, while bile production is seen in HCC! • The pseudoglandular or acinar variant of HCC contains colloid-like material or bile but no mucin, unlike CCC! • CCA glandular differentiation: (+) mCEA, mucin, and DPAS, different from HCC that is (−) mCEA, mucin, and DPAS (apart the combined HCCCCA or mixed type)! • (+) EMA, (−) HepPar1, GPC-3, AFP (CCA) ≠ (−) EMA, (+) HepPar1, GPC3, AFP (HCC)! • (+) CK7, CK19 (CCA) ≠ (±) CK7, (−) CK19 (HCC) • (±) CDX2 (CCA)  ≠  (+) (colon-rectum carcinoma)

electrical wire insulation and cables, piping, and medical supplies. • CLI: In children, there are three possible presentations: 1. Therapy refractory “infantile multinodular hemangioma” 2. Relapse of an infantile multinodular hemangioma, the following regression in the

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early infancy either spontaneously or after conventional therapy 3. Single/multiple liver mass in a patient older than 1 year of age In youth and adults, but also in younger patients, the most classical presentation is, thus, an abdominal mass. A number of signs and symptoms can occur and include jaundice, abdominal pain, vomiting, fever tachyand dyspnea, and anemia as well as high-output cardiac failure, hemorrhagic ascites, DIC, intraperitoneal bleeding, and Kasabach-Merritt syndrome (hemangiomathrombocytopenia syndrome or vascular tumor-thrombocytopenia syndrome). CLM: Mixed histology with some growth patterns such as sinusoidal, solid, papillary, and cavernous. In most cases, sinusoidal and solid are the encountered patterns. In the sinusoidal model, there are flat or hobnailed atypical cells sitting on both sides of the cell plate in a “scaffold-like” distribution, while spindle cells constitute the solid pattern. Atrophy and disruption of the cell plate are found among intermixed hepatocytes, although pseudoacinar formation can occur and should be considered a pitfall (see DDX). In the papillary pattern, the endothelial cell lining becomes multilayered and form papillary-like projections, while in the cavernous type areas of hemorrhage and necrosis are seen. HSS/IHC: (+) CD31, CD34, FVIIIa, Ulex europaeus agglutinin I, and VEGF (at least one of the first three should be positive). TEM: Weibel-Palade bodies. DDX: The rare occurrence of this neoplasm in children and adolescents makes, however, the diagnosis of angiosarcoma in a patient younger than 21 years a quite difficult topic at pediatric tumor boards. In Box 4.45 are summarized the diagnoses that need to be taken into consideration. Other less common differential diagnoses may include hepatic mesenchymal hamartoma and undifferentiated

4  Parenchymal GI Glands: Liver

Box 4.45 HAS Differential Diagnosis

1. Epithelioid hemangioendothelioma (EHE): Epithelioid cytology (potential pitfall, epithelioid variant of angiosarcoma, although in this latter more spindled areas are seen), less destructive pattern (less necrosis, low MI, less atypia) 2. Kaposi sarcoma (KS): HIV(+), HHV-8(+) 3. Infantile multinodular hemangioma (IMNH): No aggressive feature imaging, no tumor necrosis, no mitoses or very low MI, no atypia 4. Hepatocellular carcinoma (HCC): Hx(+) risk factors (vide supra), hepatocytic morphology of tumor cells (grade IV may be challenging), (+) Hepar1, GPC-3, pCEA/CD10, AFP, AE1–AE3, CD34, and (−) Ret 5. Cholangiocarcinoma (CCA): Hx(+) PSC, choledochal cysts, lithiasis, worm infestations

embryonal sarcoma, which may be seen at pediatric age. In differentiating vascular tumors of the breast, c-MYC amplification has been used, but no current data are present for vascular tumors of the liver. • TNT: Treatment may be quite challenging, and the prognosis is dismal in most of the cases. Liver TX is contraindicated in both children and adults, because of the high incidence of metastases, but this topic has no full consensus. Non-TX treatment strategies include vascular ablation, chemotherapy, and surgical exploration to perform right or left hepatectomy according to the location of the tumor. • PGN: Dismal outcome and liver TX is controversially discussed, even no metastases are found. Most patients die within 6–12 months of diagnosis and two significant COD are liver

4.11 Liver Tumors

failure and peritoneal hemorrhage. In the literature, the mean survival noted is 10 months to 2 years.

4.11.2.5  Undifferentiated Embryonal Liver Sarcoma (UELS) • DEF: It is a malignant mesenchymal tumor of the liver showing no lines of differentiation (apart from some focally postulated angiodifferentiated areas) that may occur with hepatic mesenchymal hamartoma or vaginal embryonal rhabdomyosarcoma. • SYN: Malignant mesenchymoma, mesenchymal sarcoma. • EPI: Worldwide, children>adults, ♂ = ♀. • CLI: Abdominal mass, abdominal pain, fever, and normal serum AFP. • GRO: Solitary, well-delimitated tumor with a soft consistency showing at places an appearance of cystic, gelatinous, hemorrhagic, and partly necrotic aspects. • CLM: Anaplastic spindle/oval cells with intracytoplasmic hyaline globules embedded in a myxoid stroma with many thin-walled blood vessels and accompanied by foci of extramedullary hematopoiesis and margination of trapped hepatocytes and biliary structures at the periphery (Fig. 4.40). • HSS/IHC: DPAS+ hyaline globules, (+) VIM, high MI as well as (+) GPC-3, CD56, paranuclear dot-like CKs, Bcl-2, AAT, AACT, and some myo-markers, but (−) AFP and myogenin. • TEM: Hyaline globules → lysosomes?/apoptotic bodies? • DDX: It includes echinococcosis (endemic areas, different imaging, but sometimes confusing), ERMS of the biliary system (myxoid mass, rhabdomyoblastic differentiation, cambium layer, no hyaline globules, no diffuse anaplasia, (+) DES, myogenin, and MYF4(+). GIST: Adults, (+) CD34, CD117, DOG1; HCC, sarcomatoid variant (rare in children, but not in youth); HCC,

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sclerosing variant (rare in children, intracellular bile, Mallory bodies, (+) HepPar1); Hepatoblastoma, mixed form (β-Cat+); and hepatic mesenchymal hamartoma, bland cystic tumor with DPM-like structures showing irregular branching biliary structures and no anaplasia. • TNT: In sano surgical resection (negative margins) + CHT. Alternative TNT → LTX. • PGN: Good outcome, although size may be a life-threatening factor.

4.11.2.6  Hepatic Leiomyosarcoma (HLMS) and Hepatic Rhabdomyosarcoma (HRMS) Hepatic Leiomyosarcoma (HLMS) and Hepatic Rhabdomyosarcoma (HRMS) are rare and need to be kept in mind, although hepatic rhabdomyosarcoma needs to be differentiated from a rhabdoid tumor of the liver and from the undifferentiated pleomorphic sarcoma, which may require different chemotherapy protocols. 4.11.2.7  Rhabdoid Tumor of the Liver • DEF: Very aggressive mesenchymal tumor with merging features of epithelioid sarcoma, intra-abdominal desmoplastic round cell tumor, rhabdomyosarcoma, melanoma, and carcinoma with new metastatic potential and inadequate response to therapy. • EPG: SMARCB1 loss. • CLI: History of intermittent fever, abdominal pain, and an enlarged abdomen. • IMG: Heterogeneously solid mass (CT) with prominent lobulation (MRI). • GRO: Solid mass. • CLM: Solid sheets of medium-sized cells with eosinophilic to the deep eosinophilic cytoplasm, nucleus displacement, and prominence of single nucleoli admixed with myxoid, hyalinized, and pseudoalveolar areas. The tumor infiltrates and replaces the hepatic parenchyma, sparing interlobular and segmental bile ducts, and growing into hepatic veins (Fig. 4.41).

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• IHC: (+) AE1/AE3, VIM, WT1, (±) EMA, but (−) INI1, DES, CDS (Caldesm.), S100, GFAP. • TEM: Prominent intermediate filaments of the cytoskeleton. • CMB: SMARCB1 gene loss. • PGN: High rate of death within 6 months of the diagnosis. • TRT: Three cycles of chemotherapy at 3-week intervals. The first member of an ATPase chromatin remodeling complex to be involved in carcinogenesis was, indeed, SMARCB1, which is the abbreviation for SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1, although it is also known as INI1 and BAF47. SMARCB1 provides instructions for making a protein that builds a part of several different SWI/SNF protein complexes, which regulate the gene expression by chromatin remodeling. SWI/SNF complexes are crucial in development because they are involved in many processes, including repairing damaged DNA, replicating DNA strands, and controlling the growth, division, and differentiation of cells. Both SMARCB1 protein and other SWI/SNF subunits are considered tumor suppressors. The loss of SMARCB1 causes cell cycle progression partially through the downregulation of p16INK4a and upregulation of E2Fs and Cyclin D1. Also, SMARCB1 loss triggers cell cycle checkpoints causing arrest and apoptosis. Overall, there is a histologic pattern characterized by numerous mitotic and apoptotic figures. The oncogenic synergy seems to be a result, at least partially, of the disruption of checkpoints via inactivation of TP53 in vivo with cancer formation. Moreover, there is an involvement of the cytoskeleton because of the role of SMARCB1 in

4  Parenchymal GI Glands: Liver

controlling the actin cytoskeleton network. Transcriptionally, SMARCB1 loss enhances RhoA signaling conferring boosted migratory potential upon several cell lines. The electron microscopy of a rhabdoid cell with SMARCB1 loss is particularly in syntonic clang with this finding showing prominent intermediate filaments. The cytoskeleton (microfilaments, microtubules, and intermediate filaments), unique to eukaryotic cells, acts as both muscle and skeleton, for movement and stability. Alteration of the cytoskeleton is considered necessary for the metastatic potential of tumor cells.

4.11.3  Metastatic Tumors Liver metastases are exceptionally rare in children as compared with the adult. However, exceptions do exist. An example is the presence of neuroblastoma in the liver, which might be considered abnormal localization rather than metastasis. The neuroblastoma IVS refers to a special group of neuroblastomas. The infant is younger than 1 year old, and the malignancy is on one side (unilateral) of the body. It might have spread to lymph nodes on the same side of the body (ipsilateral or homolateral) but not to contralateral nodes. The neuroblastoma has spread to the skin, liver, and/or the bone marrow, but ≤10% of marrow cells are malignant, and bone is not involved as investigated by imaging tests such as an aralkylguanidine, such as MIBG or lobenguane. An MIBG scan is a nuclear medicine imaging test, which combines a small amount of radioactive material with meta-iodobenzylguanidine (MIBG) to find certain types of tumors (e.g., pheochromocytoma and neuroblastoma) in the body (Figs. 4.42, 4.43, 4.44, and 4.45).

4.11 Liver Tumors

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Fig. 4.42  Histological panel with several examples of neuroblastoma characterized by small round blue cells infiltrating the liver (a, hematoxylin and eosin staining, ×50 original magnification; b, hematoxylin and eosin staining, ×200 original magnification; c, hematoxylin and eosin staining, ×200 original magnification; d hematoxylin and eosin staining,

×100 original magnification; e, hematoxylin and eosin staining, ×100 original magnification; f, hematoxylin and eosin staining, ×20 original magnification; g, hematoxylin and eosin staining, ×200 original magnification; h, hematoxylin and eosin staining, ×200 original magnification). Figures (g) and (h) show post-chemotherapy regressive changes

4  Parenchymal GI Glands: Liver

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Fig. 4.43  Immunohistochemical panel of neuroblastoma showing a positivity for synaptophysin (a, anti-synaptophysin immunostaining, ×100 original magnification), neuron-specific enolase (NSE) (b, anti-NSE immunostaining, ×100 original magnification), CD56 (c, antiCD56 immunostaining, ×200 original magnification), CD57 (d, anti-CD57 immunostaining, ×100 original magnification), chromogranin A (CGA) (e, anti-CGA immu-

nostaining, ×200 original magnification), neurofilaments (f, anti-neurofilaments immunostaining, ×100 original magnification), … ??? (g, anti-??? immunostaining, x??? original magnification), and lack of expression for CD99 (h, anti-CD99 immunostaining, ×100 original magnification). In CD99, the internal positive control is constituted by the intratumoral blood vessels

4.11 Liver Tumors

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Fig. 4.44  Histologic and immunohistochemical panel of a metastatic rhabdomyosarcoma to the liver with infiltration of small round blue cell tumors at low and high power magnification (a, hematoxylin and eosin staining, ×100 original magnification; b–d, hematoxylin and eosin staining, ×400 original magnification) and positivity for desmin, MyoD1, and myogenin (f, anti-desmin immunostaining, ×400 original magnification; g, anti-

MyoD1 immunostaining, ×400 original magnification; h, anti-myogenin immunostaining, ×200 original magnification). All immunostaining were performed using the avidin-biotin complex. Figure (e) shows the absence of glycogen in the tumor cells, a useful characteristic feature to distinguish from other small round blue cell tumors that may have intracytoplasmic glycogen (e, periodic acidSchiff special stain, ×400 original magnification)

4  Parenchymal GI Glands: Liver

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Fig. 4.45  Figures (a–c) show a metastatic neuroendocrine tumor of the pancreas (a, hematoxylin and eosin staining, ×100 original magnification; b, hematoxylin and eosin staining, ×400 original magnification; c, anti-synaptophysin immunostaining, ×100 original magnification). Figures (d–f) show a metastatic inflammatory myofibro-

 ultiple Choice Questions M and Answers • HEP-1 Cytoskeleton is made up of microtubules, actin filaments, and intermediate filaments and plays a significant role in the cell. These structures frame the cell shape and help organize the cell compartments as well as provide a basis for cellular movement and cell division. Cytokeratins are an essential component

blastic tumor (d, hematoxylin and eosin staining, ×50 original magnification; e, hematoxylin and eosin staining, ×200 original magnification; f, anti-anaplastic lymphoma kinase 1 immunostaining, ×200 original magnification). All immunostaining have been carried out using the avidin-biotin complex method

of intermediate filaments of epithelial tissue. Which of the following statement is TRUE? (a) Epithelial cells forming bile ducts express CK-8 and CK-18 in addition to CK-7 and CK-20, the latter two being also positive in normal adult hepatocytes. (b) Epithelial cells forming bile ducts express CK-7 and CK-20 in addition to CK-8 and CK-18, the latter two being also positive in normal adult hepatocytes.

Multiple Choice Questions and Answers

(c) Epithelial cells forming bile ducts express CK-7 and CK-19 in addition to CK-8 and CK-18, the latter two being also positive in normal adult hepatocytes. (d) Epithelial cells forming bile ducts express CK-7 and CK-20 in addition to CK-5 and CK-6, the latter two being also positive in normal adult hepatocytes. • HEP-2 Which of the following statements regarding fibrocystin is NOT correct? (a) The PKHD1 gene provides a protein called fibrocystin (aka polyductin). (b) More than 270 mutations in the PKHD1 gene have been identified in individuals with polycystic kidney disease, which is autosomal dominant inherited. (c) The PKHD1 gene is located on 6p12.3-p12.2. (d) PKHD1 is present in fetal and adult kidney cells, the liver, and the pancreas. (e) Fibrocystin may act as a receptor, interacting with extracellular molecules. (f) Fibrocystin is also found in primary cilia. • HEP-3 The paucity of the interlobular bile ducts (PIBD) can be part of a familial syndrome of cholestasis named Alagille syndrome (AGS) or occurs as non-syndromic PIBD.  Which of the following conditions is NOT presenting as PIBD, non-syndromic type? (a) Kartagener syndrome (b) Progressive intrahepatic familial cholestasis (PFIC) (c) Maternal use of progesterone during pregnancy (d) Hemophagocytic lymphohistiocytosis (e) Congenital pancreatic hypoplasia • HEP-4 Which material is NOT required in the pediatric pathologist’s liver biopsy cart? (a) Upright light microscope (b) Inverted light microscope (c) Containers of 10% buffered formalin, EM grade 2.5% glutaraldehyde in 0.1M buffer glutaraldehyde, and Hank’s Balanced Salt Solution with a sterile urine specimen cup containing two drops of Hank’s medium

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(d) Sterile scalpel blades, aluminum foil, the plastic mold containing OCT (optimal cutting temperature) compound, and Dewar flask of liquid nitrogen (e) Glass slides, Coplin jars of Diff-Quik staining solutions, and large-caliber squeeze-bulb soft plastic pipettes HEP-5 What is the most common cause of neonatal cholestasis? (a) Neonatal sclerosing cholangitis (b) The paucity of the interlobular bile ducts (c) Biliary atresia (d) Progressive familial intrahepatic cholestasis (e) Cystic fibrosis-related hepatopathy HEP-6 Which of the following etiologies of conjugated hyperbilirubinemia is NOT correct? (a) Cholelithiasis (b) Primary biliary cirrhosis (c) Hepatitis B Virus (HBV) hepatitis (d) Rotor syndrome (e) Crigler-Najjar syndrome type I HEP-7 Autoimmune hepatitis (AIH) is a relapsing and remitting immune-mediated liver disease that most commonly affects females in their 20s and 40s, but it may be seen in children and adolescents as well. It should be diagnosed following exclusion of other etiologies (e.g., viral hepatitis, drug reaction). What are the histologic hallmarks of AIH? (a) Hepatitis dominated by plasma cells and interface activity potentially accompanied by emperipolesis and pseudorosettes (b) Hepatitis with pericellular fibrosis and lobular disarray (c) The paucity of interlobular bile ducts with spotty necrosis in the liver lobules (d) Hepatitis with bile duct proliferation with emperipolesis and pseudorosettes HEP-8 Computed tomography scan of the abdomen in a young patient with a liver neoplasm shows a central scar inside of the mass. In addition to a fibrolamellar carcinoma of the liver, which condition should be considered in the differential diagnosis?

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(a) Mesenchymal hamartoma of the liver (b) Focal nodular hyperplasia (c) Nodular regenerative hyperplasia (d) Scirrhous variant of conventional hepatocellular carcinoma (e) Metastatic rhabdomyosarcoma • HEP-9 Aflatoxins are a family of toxins produced by certain fungi, mostly Aspergillus flavus and Aspergillus parasiticus, that are found on farming crops such as maize (corn), peanuts, cottonseed, and tree nuts. Which neoplasm is associated with exposure to aflatoxins? (a) Mesenchymal hamartoma of the liver (b) Cholangiocellular carcinoma (c) Hepatocellular carcinoma (d) Embryonal sarcoma of the liver (e) Hepatoblastoma • HEP-10 Which molecular biological abnormality is associated with the fibrolamellar carcinoma of the liver? (a) MYCN amplification (b) DNAJB1–PRKACA fusion transcript (c) BRCA2 amplification (d) t(2;5)(p23;q35) (e) NPM-ALK fusion protein

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547 Syrian male infant. Am J Perinatol. 1999a;16(3):133– 41. PubMed PMID: 10438195. Sergi C, Beedgen B, Linderkamp O, Hofmann WJ. Fatal course of veno-occlusive disease of the liver (endophlebitis hepatica obliterans) in a preterm infant. Pathol Res Pract. 1999b;195(12):847–51. PubMed PMID: 10631721. Sergi C, Kahl P, Otto HF. Contribution of apoptosis and apoptosis-related proteins to the malformation of the primitive intrahepatic biliary system in Meckel syndrome. Am J Pathol. 2000a;156:1589–98. Sergi C, Adam S, Kahl P, Otto HF.  The remodeling of the primitive human biliary system. Early Hum Dev. 2000b;58:167–78. Sergi C, Adam S, Kahl P, Otto HF. Study of the malformation of ductal plate of the liver in Meckel syndrome and review of other syndromes presenting with this anomaly. Pediatr Dev Pathol. 2000c;3:568–83. Sergi C, Mornet E, Troeger J, Voigtlaender T.  Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Am J Med Genet. 2001a;103(3):235– 40. PubMed PMID: 11745997. Sergi C, Penzel R, Uhl J, Zoubaa S, Dietrich H, Decker N, Rieger P, Kopitz J, Otto HF, Kiessling M, Cantz M. Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene. Hum Genet. 2001b;109(4):421–8. PubMed PMID: 11702224. Sergi C, Himbert U, Weinhardt F, Heilmann W, Meyer P, Beedgen B, Zilow E, Hofmann WJ, Linderkamp O, Otto HF. Hepatic failure with neonatal tissue siderosis of hemochromatotic type in an infant presenting with meconium ileus. Case report and differential diagnosis of the perinatal iron storage disorders. Pathol Res Pract. 2001c;197(10):699–709; discussion 711–3. PubMed PMID: 11700892. Sergi C, Arnold JC, Rau W, Otto HF, Hofmann WJ. Single nucleotide insertion in the 5′-untranslated region of hepatitis C virus with clearance of the viral RNA in a liver transplant recipient during acute hepatitis B virus superinfection. Liver. 2002;22(1):79–82. PubMed PMID: 11906622. Sergi C, Gross W, Mory M, Schaefer M, Gebhard MM. Biliary-type cytokeratin pattern in a canine isolated perfused liver transplantation model. J Surg Res. 2008a;146(2):164–71. Epub 2007 Jul 13. PubMed PMID: 17631899. Sergi C, Benstz J, Feist D, Nutzenadel W, Otto HF, Hofmann WJ. Bile duct to portal space ratio and ductal plate remnants in liver disease of infants aged less than 1 year. Pathology. 2008b;40(3):260–7. https:// doi.org/10.1080/00313020801911538. Sergi C, Abdualmjid R, Abuetabh Y.  Canine liver transplantation model and the intermediate filaments of the cytoskeleton of the hepatocytes. J Biomed Biotechnol. 2012;2012:131324. https://

548 doi.org/10.1155/2012/131324. Epub 2012 Mar 28. Review. PubMed PMID: 22536013; PubMed Central PMCID: PMC3321507. Sergi C, Shen F, Lim DW, Liu W, Zhang M, Chiu B, Anand V, Sun Z. Cardiovascular dysfunction in sepsis at the dawn of emerging mediators. Biomed Pharmacother. 2017;95:153–60. https://doi.org/10.1016/j.biopha.2017.08.066. Epub 2017 Sep 12. Review. PubMed PMID: 28841455. Shneider BL, Setchell KD, Whitington PF, Neilson KA, Suchy FJ. Delta 4-3-oxosteroid 5 beta-reductase deficiency causing neonatal liver failure and hemochromatosis. J Pediatr. 1994;124:234–8. Siafakas CG, Jonas MM, Perez-Atayde AR.  Abnormal bile acid metabolism and neonatal hemochromatosis: a subset with poor prognosis. J Pediatr Gastroenterol Nutr. 1997;25:321–6. Sigurdsson L, Reyes J, Kocoshis SA, Hansen TW, Rosh J, Knisely AS. Neonatal hemochromatosis: outcomes of pharmacologic and surgical therapies. J Pediatr Gastroenterol Nutr. 1998;26:85–9. Silver MM, Valberg LS, Cutz E, Lines LD, Phillips MJ. Hepatic morphology and iron quantitation in perinatal hemochromatosis. Comparison with a large perinatal control population, including cases with chronic liver disease. Am J Pathol. 1993;143:1312–25. Smedts F, Ramaekers F, Robben H, Pruszczynski M, van Muijen G, Lane B, Leigh I, Vooijs P.  Changing patterns of keratin expression during progression of cervical intraepithelial neoplasia. Am J Pathol. 1990;136(3):657–68. PubMed PMID: 1690513; PubMed Central PMCID: PMC1877502 Snover DC, Freese DK, Sharp HL, Bloomer JR, Najarian JS, Ascher NL. Liver allograft rejection. An analysis of the use of biopsy in determining outcome of rejection. Am J Surg Pathol. 1987;11(1):1–10. PubMed PMID: 3538917 Sohn DS, Kim KY, Lee WB, Kim DC.  Eosinophilic granulopoiesis in human fetal liver. Anat Rec. 1993;235(3):453–60. PubMed PMID: 8430915 Sokol RJ, Treem WR. Mitochondria and childhood liver diseases. J Pediatr Gastroenterol Nutr. 1999;28(1):4– 16. Review. PubMed PMID: 9890461 Stocker JT.  Hepatic tumors in children. Clin Liver Dis. 2001;5(1):259–81, viii–ix. Review. PubMed PMID: 11218918. Sträter R.  Beiträge zur Lehre von der Hämochromatose und ihren Beziehungen zur allgemeinen Hämosiderose. Virchows Arch. 1914;218:1–301. Sundaram SS, Sokol RJ. The multiple facets of ABCB4 (MDR3) deficiency. Curr Treat Options Gastroenterol. 2007;10(6):495–503. https://doi.org/10.1007/ s11938-007-0049-4. PMID: 18221610; PMCID: PMC3888315 Sundaram SS, Bove KE, Lovell MA, Sokol RJ.  Mechanisms of disease: inborn errors of bile acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5(8):456–68. https://doi.org/10.1038/ncpgasthep1179. Epub 2008 Jun 24. Review. PubMed PMID: 18577977; PubMed Central PMCID: PMC3888787

4  Parenchymal GI Glands: Liver Tang V, Cofer ZC, Cui S, Sapp V, Loomes KM, Matthews RP.  Loss of a candidate biliary atresia susceptibility gene, add3a, causes biliary developmental defects in zebrafish. J Pediatr Gastroenterol Nutr. 2016;63(5):524–30. https://doi.org/10.1097/ MPG.0000000000001375. Taylor SA, Kelly S, Alonso EM, Whitington PF.  The effects of gestational Alloimmune liver disease on fetal and infant morbidity and mortality. J Pediatr. 2018;196:123–128.e1. https://doi.org/10.1016/j. jpeds.2017.12.054. Epub 2018 Feb 27. PubMed PMID: 29499991. Tõnisson M, Tillmann V, Kuudeberg A, Lepik D, Väli M. Acute alcohol intoxication characteristics in children. Alcohol Alcohol. 2013;48(4):390–5. https:// doi.org/10.1093/alcalc/agt036. Epub 2013 Apr 30. PubMed PMID: 23632804 Tsai EA, Grochowski CM, Loomes KM, Bessho K, Hakonarson H, Bezerra JA, et  al. Replication of a GWAS signal in a Caucasian population implicates ADD3  in susceptibility to biliary atresia. Hum Genet. 2014;133(2):235–43. https://doi.org/10.1007/ s00439-013-1368-2. Turner JM, Wales PW, Nation PN, Wizzard P, Pendlebury C, Sergi C, Ball RO, Pencharz PB.  Novel neonatal piglet models of surgical short bowel syndrome with intestinal failure. J Pediatr Gastroenterol Nutr. 2011;52(1):9–16. https://doi.org/10.1097/ MPG.0b013e3181f18ca0. van den Brand M, Flucke UE, Bult P, Weemaes CM, van Deuren M.  Angiosarcoma in a patient with immunodeficiency, centromeric region instability, facial anomalies (ICF) syndrome. Am J Med Genet A. 2011;155A(3):622–5. https://doi.org/10.1002/ ajmg.a.33831. Epub 2011 Feb 18. PubMed PMID: 21337690 Van Hoof F, Hageman-Bal M. Progressive familial myoclonic epilepsy with Lafora bodies. Electron microscopic and histochemical study of a cerebral biopsy. Acta Neuropathol. 1967;7(4):315–36. PubMed PMID: 4166286 Verloes A, Lombet J, Lambert Y, Hubert AF, Deprez M, Fridman V, Gosseye S, Rigo J, Sokal E.  Trichohepato-enteric syndrome: further delineation of a distinct syndrome with neonatal hemochromatosis phenotype, intractable diarrhea, and hair anomalies. Am J Med Genet. 1997;68:391–5. Vitola BE, Balistreri WF.  Liver disease in systemic disorders. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson’s textbook of pediatrics. 21st ed. Philadelphia: Elsevier. Vohra P, Haller C, Emre S, Magid M, Holzman I, Ye MQ, Iofel E, Shneider BL.  Neonatal hemochromatosis: the importance of early recognition of liver failure. J Pediatr. 2000;136:537–41. Voigt M, Schneider KT, Jahrig K.  Analyse des Geburtsgutes des Jahrgangs 1992 der Bundesrepublik Deutschland. Teil 1: Neue Perzentilwerte für die Körpermaße von Neugeborenen. Geburtshilfe Frauenheilkd. 1996;56:550–8.

References and Recommended Readings Vokuhl C, Oyen F, Häberle B, von Schweinitz D, Schneppenheim R, Leuschner I.  Small cell undifferentiated (SCUD) hepatoblastomas: all malignant rhabdoid tumors? Genes Chromosomes Cancer. 2016;55(12):925–31. https://doi.org/10.1002/ gcc.22390. Epub 2016 Jul 29. PubMed PMID: 27356182. Von Recklinghausen FD. Über Haemochromatose. Tageblatt der 62. Versammlung deutscher Naturforscher und Aerzte in Heidelberg. 1889; 324–5. Vyberg M, Poulsen H. Virchows Arch. 1984. Wiedemann HR. Hans-Ulrich Zellweger (1909–1990). Eur J Pediatr. 1991;150(7):451. https://doi.org/10.1007/ BF01958418. PMID 1915492 Witzleben CL. Bile duct paucity (“intrahepatic atresia”). Perspect Pediatr Pathol. 1982;7:185–201. PubMed PMID: 6981794 Witzleben CL, Uri A. Perinatal hemochromatosis: entity or end result? Hum Pathol. 1989;20:335–40.

549 Wu X, Dagar V, Algar E, Muscat A, Bandopadhayay P, Ashley D, Wo Chow C. Rhabdoid tumour: a malignancy of early childhood with variable primary site, histology and clinical behaviour. Pathology. 2008;40(7):664– 70. https://doi.org/10.1080/00313020802436451. PubMed PMID: 18985520. Wu JF, Chang HH, Lu MY, Jou ST, Chang KC, Ni YH, Chang MH.  Prognostic roles of pathology markers immunoexpression and clinical parameters in Hepatoblastoma. J Biomed Sci. 2017;24(1):62. https://doi.org/10.1186/s12929-017-0369-1. PMID: 28851352; PMCID: PMC5574230 Zeman MV, Hirschfield GM.  Autoantibodies and liver disease: uses and abuses. Can J Gastroenterol. 2010;24(4):225–31. https://doi. org/10.1155/2010/431913. PMID: 20431809; PMCID: PMC2864616 Ziegler MM.  Meconium Ileus. Curr Probl Surg. 1994;31:731–77.

5

Parenchymal GI Glands (Gallbladder, Biliary Tract, and Pancreas)

Contents

5.1

5.1

Development and Genetics 

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5.2 5.2.1 5.2.2 5.2.3

 iliary and Pancreatic Structural Anomalies B Choledochal Cysts Gallbladder Congenital Abnormalities Pancreas Congenital Anomalies

 553  553  553  553

5.3 5.3.1 5.3.2 5.3.3 5.3.4

 allbladder and Extrahepatic Biliary Tract G Cholesterolosis and Cholelithiasis Acute and Chronic Cholecystitis Gallbladder Proliferative Processes and Neoplasms Extrahepatic Bile Duct Tumors and Cholangiocellular Carcinoma

 556  556  557  558  561

5.4 5.4.1 5.4.2 5.4.3 5.4.4 5.4.5 5.4.6 5.4.7

Pancreas Pathology Congenital Hyperinsulinism and Nesidioblastosis Acute and Chronic Pancreatitis Pancreatoblastoma and Acinar Cell Carcinoma in Childhood and Youth Cysts and Cystic Neoplastic Processes of the Pancreas PanIN and Solid Pancreas Ductal Carcinoma Other Tumors Degenerative Changes and Transplant Pathology

 561  561  563  566  567  571  571  571

Multiple Choice Questions and Answers

 574

References and Recommended Readings

 575

Development and Genetics

Before starting to list the congenital anomalies of the pancreatic gland, it is essential to recall four critical steps and times in its embryologic development. 1. Derivation from two diverticula (dorsal first and ventral later) of the primitive foregut just distally to the stomach at the 3rd–4th week of

gestation, following the development of the hepatic primordium. 2. Dorsal and ventral buds develop out as body-­ tail and the head-uncinate process of the pancreas, respectively. 3. The rapid growth of the dorsal primordium extending into the dorsal mesentery and simultaneous elongation of the hepatic primordium (the future common bile duct) with

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_5

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5  Parenchymal GI Glands (Gallbladder, Biliary Tract, and Pancreas)

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rotation along the ventral diverticulum to a more dorsal position. 4. At the end of the 6th week, there is the fusion of the two primordial and their ductal systems with the formation of the Wirsung duct from the ventral bud and distal portions of the dorsal ductular structure and the Santorini duct from the proximal portion of the dorsal lumen. Sinusoids are intercordal/between the acinar cords and lined by discontinuous, fenestrated endothelium. Lymphatics are embedded in the portal tract, but lymphatic flow starts from perisinusoidal space (Disse space) through periportal space (Mall area), portal tract lymphatics, and up to larger lymphatic ducts. The bile flow is as follows: hepatocytic bile canaliculi → canals of Hering → portal bile ducts → left and right hepatic ducts → common hepatic bile duct → joining with the cystic duct of the gallbladder → ductus choledochus → ampulla of Vater draining in the duodenum. Notes: Iron accumulation is mainly periportal, while lipofuscin is mostly pericentral. The canals of Hering are among cells intermediate between hepatocytes and biliary cells. Bile flow is energy dependent with active transport. Kupffer cells belong to the monocyte/phagocyte

system in sinusoids and are highlighted by the CAM5.6 stain. Perisinusoidal Ito cells are fat-­ containing mesenchymal cells located in the space of Disse with the function to store vitamin A. Immunohistochemical markers that are useful to characterize the phenotype of the biliary and hepatic epithelium are CK7 (late fetal biliary cell marker and permanent cholangiocyte marker of child and adult), CK19 (early fetal biliary cell marker and permanent cholangiocyte marker of child and adult), CK8 (hepatocyte marker of fetal, child and adult), CK18 (hepatocyte marker of fetal, child and adult), CD68 (KP-1, Kupffer cells), CAM5.2 (LMW-CK, interlobular bile ducts), and pCEA/CD10 (bile canaliculi of the hepatocytes) are useful markers in pediatric pathology. CAM5.2 reacts against cytokeratins 7 and 8, but not keratins 18 and 19. In several textbooks, and also in this book, CK (cytokeratin) is interchangeable with K (keratin). Intravital biliary excretion evaluation of the liver may be carried out using noninvasive techniques such as ultrasound, computed tomography, or magnetic resonance imaging or invasive procedures such as biopsy. The innervation of the pancreas is intimately linked to the development of the endocrine component (Fig. 5.1). Amella et al. (2008) studied the

a

b

c

d

Fig. 5.1  The ductulo-insular complexes highlighted by a study performed on fetal pancreas using an antibody against S-100 are shown in (a–c) (anti-S100 immunohistochemistry, Avidin-Biotin-Complex, ×20 original magnification for a, ×400 original magnification for b, ×100 original magni-

fication for c) with ductulo-insular complexes in the pancreas as a whole (a), in the parenchyma (b) and in proximity of the papilla Vateri (c), while (d) shows the 3-D representation at the level of the ramification of the post-ganglionic nerve bundles in the dorsal part of the pancreas

5.2  Biliary and Pancreatic Structural Anomalies

nerve structures by automatic immunostaining techniques using a polyclonal antibody against two S-100 proteins. The antibody reacts strongly with human S100A and S100B that are detected in Schwann cells. These authors found characteristic immunoreactivity patterns in the parenchyma of the head, body, and tail of the pancreas. The relative density was decreasing from head to tail. Also, they reconstruct some nerves associated with the superior mesenteric plexus. They found that the perimeter and the width of the nerve fibers seem to increase at a continuous rate up to term in all three regions of the pancreas. The study performed using spatial and temporal co-analysis identified that the head of the pancreas had a two-peak growth increase at the 14th and 22nd week of gestation about the area, perimeter, and width of the nerve structures. The body and tail regions showed a single peak at 20 weeks of pregnancy. Understanding the factors that may alter the pancreas nerve innervation can be of significance for the development of therapies in pancreatic disorders of a child and adulthood.

5.2

Biliary and Pancreatic Structural Anomalies

Hepatobiliary and pancreatic aberrations are central in the dysontogenesis of the human body, and the identification of some animal models and the progress of molecular biology techniques allowed us to understand the dysregulation of these processes better.

5.2.1 Choledochal Cysts • DEF: Cystic dilations of the choledochus, including cystic dilation of the entire extrahepatic duct (Alonso-Lej A), partial saccular dilation of the duct (Alonso-Lej B), and cystic dilation of the intraduodenal portion of the duct (Alonso-Lej C or choledococele) (Alonso-Lej F). Choledochal cysts need to be distinguished by Caroli disease, which is the intrahepatic dilation of the segmental ducts. The Todani modification of the Alonso-Lej classification is the most used classification. Type III often shows a classic presentation of

553

choledococele with the dilatation of the extrahepatic bile duct limited to the wall of the duodenum. In type III the intramural component is apparently in the duodenum. Imaging classically evidences type IVB by the “string of beads” aspect. Type V of congenital biliary cysts is represented by multiple sites of saccular or cystic dilatation of only intrahepatic biliary tree and is also known as Caroli disease or “communicating cavernous ectasias.” • CLI: Abnormalities of the choledochal system may present with pain, jaundice, and abdominal mass, symptoms of biliary obstruction, cholangitis-associated sepsis, or peritonitis linked to a rupture of the cyst.

5.2.2 Gallbladder Congenital Abnormalities Gallbladder and biliary tract abnormalities may become part of the spectrum of the fetal type of biliary atresia (vide infra) (Fig. 5.2).

5.2.3 Pancreas Congenital Anomalies Pancreas anomalies include agenesis/aplasia/ hypoplasia, restricted exocrine hypoplasia, ductal abnormalities, choledochal cysts (vide supra), heterotopia, annular pancreas, cystic dysplasia, and congenital cysts of the pancreas (Fig. 5.2).

5.2.3.1 Agenesis/Aplasia/Hypoplasia (Both Exocrine and Endocrine Components) Rare events detectable in nonviable fetuses and infants are due probably to the absent or low fetal insulin necessary for the pancreas development in the setting of fetal growth restriction. It may be linked with the lack of gallbladder. 5.2.3.2 Restricted Exocrine Hypoplasia (aka “lipomatous pseudohypertrophy of the pancreas”) Enlarged gland with a standard shape and fibrofatty replacement of the acinar tissue, presumably associated to intrauterine or genetic

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5  Parenchymal GI Glands (Gallbladder, Biliary Tract, and Pancreas)

a

c

b

f

d

e

Fig. 5.2 Development and congenital anomalies of the pancreas and extrahepatic biliary tract. In (a) is shown a pancreatic tissue heterotopia in the gallbladder (hematoxylin and eosin staining, ×50 as original magnification). In (b) is shown a quite fibrotic gallbladder in an infant with biliary atresia (hematoxylin and eosin staining, ×20 as original

magnification). Note the fibrosis with almost obliteration which may resemble a chronic cholecystitis of the adult. In (c) through (f) there are different phenotypic aspects of cholesterolosis, which may also assume the form of a polyp (c–f, hematoxylin and eosin staining, ×100, ×400, ×400, ×40 as original magnification, respectively)

5.2  Biliary and Pancreatic Structural Anomalies

or idiopathic infection, and similar to the ARVCM of the heart of young adults or to diffuse lipomatosis cordis of the elderly. REH (or LPP) may occur from infants to adults and may be associated with Johanson-Blizzard syndrome, which is recognized by the abnormal development of the pancreas, nose, and scalp. This syndrome, which is accompanied by mental retardation, hearing loss, and growth failure, may be life-threatening.

5.2.3.3 Ductal Abnormalities Frequent (up to 30% of healthy individuals) anomalies of the interaction between the ventral anlage, which is responsible for the Wirsung or main duct, and the dorsal anlage, which is responsible for the Santorini or accessory duct. Ductal communication variations are many. 1. A joint ventral duct and common bile at the ampulla of Vater are seen with complete regression of the dorsal duct. 2. A crossroads of ventral and common bile ducts at ampulla and persistence of the dorsal duct. 3. Persistence of both dorsal and ventral ducts without evidence of communication (pancreas divisum). 4. Common channel with ventral duct communicating with the common bile duct about 5–15 mm from the ampulla. 5. Separate communication of ventral duct into the duodenum with persistence of dorsal duct. Junction of the pancreaticobiliary system and ampulla of Vater are also seen and include a complete separation of the openings of both the common bile duct and the Wirsung duct or joint opening of the two ducts surrounded by some muscular bundles (“sphincter of Oddi”). The pathogenesis of choledochal cysts has been associated with a small entrance of the CBD into the main pancreatic duct less than 2 cm proximal to the duodenal wall. Since 1945 a long common channel (up to 1/5 of healthy individuals) has been formerly since associated to pancreatitis, as well as stenosis of the common distal duct and proximal strictures of the conduit. In pancreas divisum, which is a quite frequent anomaly (up to 1/4 of patients with “idiopathic” pancreatitis) of the 3rd–4th decades, but also identified in

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children, there is a separation of both ventral and dorsal pancreatic ducts. It may present as epigastric pain radiating to the back following fatty food ingestion.

5.2.3.4 Heterotopia Pancreatitis (Gr. ἕτερος or “Other, Different” and τόπος “Place”) Aberrant presence of pancreatic tissue located outside both intra- and extra-abdominal (stomach, duodenum, jejunum, liver, gallbladder, small intestine, colon, appendix, omentum, Meckel diverticulum, bronchogenic cyst, pulmonary sequestration, umbilicus) of the standard anatomic site (up to 15% of autopsy specimens). • GRO: The heterotopic pancreatic tissue is usually recognized as a discrete, firm, yellow, submucosal nodule and microscopically as pancreatic tissue with acini, islets, and ducts. Several theories have been proposed, including irregular sequestration during migration, abnormal differentiation of Brunner glands, abnormal adhesion of normal developing primordia with nearby structures, and abnormal differentiation of multipotent endodermal stem cells. A broad spectrum of symptoms may occur, and occasionally neoplastic transformation has been reported.

5.2.3.5 Annular Pancreas Abnormality constituted by usually a flat band of pancreatic tissue completely encircling the 2nd portion of the duodenum with or without duodenal atresia or stenosis and presenting from newborns to adults. AP may usually occur in two critical clinical settings, including trisomy 21 syndrome and intestinal malrotation. In neonates, it is a surgical emergency (duodenal atresia) with persistent bilious vomiting and failure to thrive, upper abdominal pain or epigastric pain with the “double bubble” radiologic sign. However, the presentation in older children and teenagers, it is different and characterized by nausea, vomiting, postprandial fullness, bloating, upper GI bleeding, and weight loss. Three theories have been proposed and include 1) hypertrophy of both ventral and dorsal ducts resulting in a ring adherence of the ventral primordium to the duodenum before

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rotating and 2) overgrowth or 3) adhesion of the left diverticulum of the primitive foregut of a paired ventral primordium. Prognosis may be uncertain in the early neonatal period if a surgical bypass is not promptly performed.

5.2.3.6 Cystic Dysplasia It is not a properly congenital anomaly but usually the consequence of inflammation and obstruction with retention in the setting of cystic fibrosis, although few “true” dysplastic cases of cystic dysplasia have been reported in some genetic syndromes. 5.2.3.7 Congenital Cysts of the Pancreas In contract to pseudocysts (no epithelial lining), true cysts are characterized by a cuboidal or stratified squamous epithelial lining and may be classified as solitary or multiple. Single cysts are rare and sometimes are associated with some additional anomalies and may present with polyhydramnios to gastroduodenal compression. Multiple cysts are a relatively more frequent event and occur in the setting of von Hippel-­ Lindau syndrome, Ivemark syndrome, and Meckel-Gruber syndrome.

5.3

Gallbladder and Extrahepatic Biliary Tract

The gallbladder has not frequently been a topic of discussion in many pediatric pathology meetings, although extrahepatic BA is the most common cause of obstructive cholangiopathy in a newborn with prolonged jaundice. In this section, we will target our discussion on congenital abnormalities, inflammatory conditions, degenerative changes, as well as neoplasms of the gallbladder and extrahepatic biliary tract (Box 5.1).

5.3.1 Cholesterolosis and Cholelithiasis In 2/3 of individuals, there is a common channel with common bile duct joining the primary pancreatic duct and emptying into the lumen of the

Box 5.1 Gallbladder and Extrahepatic Biliary Tract Pathology

5 .3.1. Cholesterolosis and Cholelithiasis 5.3.2. Acute and Chronic Cholecystitis 5.3.3. Gallbladder Proliferative Processes and Neoplasms 5.3.4. Extrahepatic Bile Duct Tumors and Cholangiocellular Carcinoma

duodenum at a single site, while in 1/3 of individuals, there are separate orifices. The gallbladder has neither muscularis mucosae nor submucosa but exclusively mucosa, lamina ­propria, muscularis propria, and connective tissue. This particular structure is specific for this bile receptacle.

5.3.1.1 Cholelithiasis • 10% Pure • 90% Mixed –– Pure cholesterol stones: pale yellow, round/ ovoid, granular surface, crystalline core –– Pure Ca bilirubinate stones (hemoglobinopathies, hemolysis, cirrhosis, pigment stones): black oval, smooth surface Most stones of mixed type are constituted by a variable combination of cholesterol Ca bilirubinate and Ca carbonate and appear to be multiple and laminated. Some authors classify stone as cholesterol stones if cholesterol is >70% and pigment stones if cholesterol is 75% of all cystic lesions in the pancreas with ♂ > ♀ preference in the setting of pancreatitis (a complication of chronic pancreatitis),

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5  Parenchymal GI Glands (Gallbladder, Biliary Tract, and Pancreas)

a

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Fig. 5.7 Pancreatoblastoma. A small round blue cell tumor with pseudorosettes is seen in the event of a pancreatoblastoma (a–c, hematoxylin and eosin staining, (d) periodic acid Schiff staining; ×12.5, ×200, ×100, ×100 as original magnification, respectively). The immunohistochemistry (e–h) with pankeratins, carcinoembryonic antigen (CEA), neuron specific enolase (NSE), and β-catenin

confirms the diagnosis of pancreatoblastoma (e) anti-pankeratin immunostaining, Avidin-Biotin complex, ×100 original magnification; (f) anti-CEA immunostaining, Avidin-Biotin complex, ×100 original magnification; (g) anti-NSE immunostaining, Avidin-Biotin complex, ×100 original magnification; (h) anti-β-catenin immunostaining, ×200 original magnification)

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trauma, and occasionally neoplastic duct obstruction (Box 5.4). • EPI: Childhood and youth. • EPG: Two phases: 1. Intraluminal necrotic debris, precipitated acinar secretions, and granulation tissue 2. Stroma proliferation with cellular fibrosis (the cellularity may be quite intense and be a challenge at frozen section, and cellularity may also mimic ovarian-type stroma) Pseudocystic fluid is necrotic but also rich in amylase. ± Extra-pancreatic extension (pancreatic pseudocysts may have an extra-pancreatic extension with peripancreatic hemorrhagic fat necrosis). • PGN: Rupture, erosion (→ spleen), bleeding, shock. As stated above, both mucinous cystic neoplasms (MCN) and intraductal papillary mucinous neoplasm (IPMN) are adult neoplasms, but occasionally they can be found in adolescent individuals and youth. Linings are serous, mucinous, squa-

Box 5.4 The Distinctiveness of Some Cystic Neoplasms of the Pancreas Age Gender Site U/M DC CLI MIC

IPMN >50 ♂ ≥ ♀ Head U/M + ACA L→HGD

MCN 18–95 ♂   High-grade dysplasia, CLI clinical features, MIC microscopy, U/M unifocal/ multifocal, OC/PC oligocystic/polycystic, Gly-­ Cyto glycogen-rich clear cell cytology with distinct cytoplasmic borders, and round, uniform nuclei with dense homogenous chromatin

mous, acinar, endothelial, and degenerated. Pseudocysts are localized collections of pancreatic secretions, lack of an epithelial lining evidencing a lining of macrophages or fibrosis, arise practically after one or more episodes of acute or chronic pancreatitis, measure up to several centimeters, harbor no risk for malignant degeneration, but are critical mimickers of pancreatic neoplasms. Ductal Lineage Markers include mucin, mucin-related glycoproteins and oncoproteins, MUCs, CA19-9, CEA, B72.3, and DUPAN-2. PanIn1a/b-2-3 may be considered precancerous lesions for invasive ductal carcinoma and should be defined as tiny (Ø ≤ 0.5 cm) epithelial proliferations within the smaller pancreatic ductal system with short and stubby papillae showing lobocentric atrophy and scarring in the lobular units, which are located downstream of PanIN lesions due to obstruction and lack of (forward)flow (DDX: ACA, which shows desmoplastic tissue reaction). If there is a loss of DPC4 (SMAD4), there is a high probability of ACA! IPMN has two primary variants identified as branch duct type and as main duct type. Useful criteria to distinguish between MCN and IPMN are illustrated in Box 5.5. Polycystic disease and VHL are different from serous cystadenoma in VHL. Individual cysts are practically indistinguishable from serous tumors. They are more widely spread in the pancreas; they are often multifocal; and there is an apparent association with cysts in other organs.

Box 5.5 Useful Criteria for the Distinction of MCN from IPMN Features Gender Endoscopy

MCN ♂  ♀, worldwide. • EPG: Bacteria (nephritogenic type group A β-hemolytic Streptococcus, Salmonella, Enterococcus, Staphylococcus, spirochetes), viruses (HBV, EBV), protozoa (malaria, T. gondii) as triggering factors and Type III hypersensitivity (immune complex mediated) as pathogenesis. ASO is a toxic enzyme produced by group A Streptococcus bacteria. • CLI: Abrupt onset of acute nephritic syndrome with darkening of urine, malaise, oliguria, edema, proteinuria, ↓ GFR with salt and H2O retention ± ↑ BUN, FENa IgA, granular staining for C3, fibrinogen within glomerular capillary loops; ± linear staining of tubular BM for Ig.

TEM: Fibrin associated with GBM breaks, but no deposits

Type II or post-infectious GN (severe form/ progression of PIGN but better PGN than other types)

IFM: Granular IgG-C3 IC (type III hypersensitivity)

TEM: Subepithelial “humps,” mesangial deposits, and fibrin deposition with GBM breaks

Type III or pauci-immune GN: ± vasculitis, + ANCA

6.4 Primary Glomerular Diseases

603

a

b

c

d

e

f

Fig. 6.10 The rapid progressive glomerulonephritis (RPGN) is a renal syndrome that is characterized by a rapid loss of renal function approaching typically a 50% decline in the glomerular filtration rate (GFR) within 3  months and glomerular crescent formation seen in 50–75% of glomeruli observed on kidney biopsies. In half

of cases, RPGN is associated with an underlying disease such as Goodpasture syndrome, systemic lupus erythematosus, or granulomatosis with polyangiitis; the other half of cases are idiopathic. Histologically, there is hypercellularity of the glomerulus with crescents as seen in figures (a–f) using both light and electron microscopy

p-ANCA, MPO-ANCA, MPA (MPA, Microscopic Poly-Angitis)

TEM: Fibrin associated with GBM breaks, but no deposits

c-ANCA, PR3-ANCA, WG (WG, Wegener Granulomatosis)

IFM: No Ig staining, ± C, and fibrinogen with crescents

Acute Nephrotic Syndrome-Associated Glomerulopathies A multi-etiologic clinical entity with increased glomerular permeability and presentation as massive proteinuria and lipiduria with edema, hypo-

604

albuminemia, and hyperlipidemia. Proteinuria >40  mg/m2/h (or  >  3.5  g/day/1.73  m2 BSA or > 50 mg/kg/24 h). Non-nephrotic range of proteinuria: 4–40 mg/m2/h. Since clinical and pathologic overlap exists, minimal change disease, diffuse mesangial proliferative, and focal and segmental glomerulosclerosis may be part of a spectrum of the same disease process. • PGN: Rapid, generally irreversible course and therapy (steroids, cyclophosphamide, plasmapheresis) usually do not help.

6.4.4 Minimal Change Disease • DEF: Multi-etiologic GN occurring as an acute nephrotic syndrome in 2–6-year-old children with phenotypically intact glomeruli on light microscopy but fusion of foot processes on electron microscopy. • SYN: Lipoid nephrosis, nil disease, foot process disease. • EPG: Idiopathic (primary) nephrotic syndrome (with atopy and HLA B12 or without atopy, often with Asian-Arabian ethnics) and secondary to HL, NHL, and solid tumors such as RCC in youth compared to pancreatic carcinoma, mesothelioma, colon carcinoma, prostate carcinoma, and syphilis of older adults. Immune-mediated T-cell dysregulation-­ related process with selective proteinuria usually without hematuria, HTN, or loss of renal function. • CLI: Proteinuria-related symptoms and signs. • CLM: Unremarkable, although occasionally tubules may show hyaline droplets. • IFM: Negative (occasionally, complement and fibrinogen in peripheral capillary walls). • TEM: Foot process “fusion” (polyanion content change → juxtaposition of the foot processes of visceral epithelial cells and obliteration of the slit pore), microvillus change of epithelial cells. • TRT: Good response to steroids, but, rarely, immunosuppression is required (e.g., cyclosporine). • PGN: Relapsing/polycyclic course; 70–80% full remission; 1–2% death.

6  Kidney, Pelvis, and Ureter

6.4.5 (Diffuse) Mesangial Proliferative GN • DEF: Glomerulonephritis with diffuse cellular proliferation of the mesangium and some increase in mesangial matrix with usually IgA or IgM deposits and variable outcome. –– With predominant IgA mesangial deposits (IgA nephropathy or Berger disease) = > hematuria –– With predominant IgM and/or C3 deposits = > variable (~) presentation –– With other patterns of Ig and C3 deposits –– No Ig or C3 deposits • EPG: Secondary to underlying disease, including resolving PIGN, SLE, RA, HSP, Alport syndrome, Goodpasture syndrome, Kimura disease, D-penicillamine. Penicillamine is an anti-rheumatic drug used to treat the active phases of rheumatoid arthritis. Penicillamine is also used for chelation of Cu (copper) in Wilson disease. • CLM: Variable degree of increase in mesangial cellularity (diffuse and global) without capillary wall changes (Figs. 6.11 and 6.12). • IFM: ± IgA, IgM, C3 mesangial deposits (IgG in PIGN) (vide supra). • TEM: ± Finely granular or homogeneous mesangial deposits.

6.4.6 Focal and Segmental Glomerulosclerosis • DEF: Multi-etiologic GN presenting as an acute nephrotic syndrome (nonselective proteinuria) and considered in most cases (at least with secondary causes) a pattern of response rather than a specific disease with hyalinosis and sclerosis representing entrapment of plasmatic proteins in extremely permeable ­ glomeruli and reactive mesangial contribution. • EPI: ~10% of childhood and ~15% of the adult nephrotic syndrome • EPG: Primary and secondary (DISH), including Drugs (heroin), Infections (HIV, VUR-­ associated), Soft tissue (obesity, obstruction, radiation, sarcoidosis, solid tumors, nephron ablation including partial nephrectomy, bilateral cortical necrosis, segmental hypoplasia,

6.4 Primary Glomerular Diseases

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a

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e

f

Fig. 6.11  Mesangial proliferative glomerulonephritis is a hypocomplementemic (C3) glomerulonephritis due to subendothelial and mesangial deposition of complement from dysregulation of alternative pathway. MesPGN includes dense deposit disease (membranoproliferative glomerulonephritis type 2) and proliferative glomerulonephritis with C3 deposits. There are large glomeruli with accentuation of lobules, irregular thickening of glomerular basement membrane by interposition of mesangial

cells between basement membrane and endothelium (a-c). There is crescent formation (d). Ig M and IgG depositions are shown in figures (e) and (f), respectively. Both figures (e) and (f) have been performed using antibodies against IgM and IgG by immunohistochemistry (avidin-biotin complex, ×400 original magnification). In MesPGN genetic mutations or the development of autoantibodies to complement may be encountered

and unilateral agenesis), and Hematologic gression to RF and characterized by (sickle cell disease, aging). hyperplasia of glomerular epithelial cells, • Primary causes include mutations in five genes tubular hyaline casts, and interstitial nephritis that encode slit diaphragm proteins: NPHS1on CLM and tubular-reticular structures in nephrin, NPHS2-podocin, Actinin-4, TRCP6 endothelial cells on TEM. (transient receptor potential channel 6), and • CLM: (1) FS-SCLEROSIS of glomeruli CD2AP (CD2-associated protein). (more common juxtamedullary) with hya• HIV-associated (AIDS) FSGS (IVDA): FSGS-­ line subendothelial material ± lipid inclucollapsing glomerulopathy with rapid prosions, synechiae, and foamy histiocytes; (2)

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a

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Fig. 6.12  lgA nephropathy is a type of diffuse mesangioproliferative glomerulonephritis (a-c) with elevated serum IgA and IgA present in mesangium (d-f; antibody against IgA, avidin-biotin complex, ×400 original magnification). All microphotographs have been taken at x400 as original

magnification. The microphotographs (a) and (b) are from H&E stained slides, while (c) is from a periodic acid Schiff-stained slide. The poor eosin staining in (a) and (b) is due to a low exposure to eosin or prolonged exposure to hematoxylin

epithelial cell detachment from GBM (clear zone or halo) (early) and hypertrophy and hyperplasia (late); (3) TBM thickening, tubular atrophy, and interstitial fibrosis (Fig. 6.13). • IFM: IgM and C3 in sclerotic segments (nonspecific and seldom seen). • TEM: Collapse of glomerular capillary loops with foot process fusion and ↑ of mesangial matrix and sclerosis. • TRT: Steroid-resistant PGN, 10-YSR, 50% (early presentation of FSGS has worse clinical course than the late presentation) as risk of recurrence in allografts.

6.4.7 Membranous Glomerulonephritis • DEF: Clinicopathologic insidious and indolent entity commonly associated with Nephrotic Syndrome and characterized by diffuse thickening of the glomerular capillary loops due to subepithelial IC deposits (type II and type III hypersensitivity). • EPI: MGN accounts for 1/20 and approximately half of nephrotic syndrome in children and adults, respectively. • EPG: Idiopathic or type II related (85%) and secondary or type III related with several etiolo-

6.4 Primary Glomerular Diseases

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Fig. 6.13  Focal segmental glomerulosclerosis shows a sclerosis, which is focal and segmental with mesangial sclerosis in lobules that appear to adhere to Bowman’s capsule, starting in corticomedullary region. Inframembranous hyaline deposits (periodic acid-Schiff positive, trichrome staining red, silver staining negative)

and endocapillary foam cells or lipoid droplets in focal glomeruli can be found. On the beginning there is mild mesangial hypercellularity, but in the advanced stage, the lesions become hypocellular as shown in the microphotographs (a–f) using light and electron microscopy

gies (“DISH”), including Drugs and toxic metals (e.g., D-penicillamine, captopril, heroin, gold, mercury), Infections (HBV, malaria, schistosomiasis, syphilis, leprosy, filariasis, hydatid disease), Soft tissue collagenopathies (SLE, RA, PSS, MCTD, dermatomyositis, sarcoidosis), and Hemato-vascular and neoplastic diseases (HL, NHL, renal vein thrombosis, SCD, Hashimoto thyroiditis, lung/colon/stomach carcinoma). Moreover, it may also occur as de novo in renal allografts, Gardner-Diamond syndrome, bullous pemphigoid, Fanconi syndrome, Kimura disease, and Weber-Christian syndrome. In prac-

tice, about ¾ of MGN is secondary to D-­penicillamine, gold, mercury, HBV, SLE, carcinoma, and de novo (1/4) in renal allografts.

• CLM: Uniform and diffuse capillary wall thickening (“stiff” glomerular loops) without any significant proliferation of endothelial, mesangial, or epithelial cells and spikes and domes of argyrophilic deposits (SS +) growing in the direction of the urinary space (Fig. 6.14).

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a

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g

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Fig. 6.14  Hereditary C4 deficiency (C4def) is a very rare inherited condition that predisposes to immune complex disease and end-stage renal failure with most of the patients suffering from systemic lupus erythematosus. Figures (a) through (e) show the normal appearance of the deposition of C1q, C3, HLA-DR, IgA, and IgM by immu-

nofluorescence. Figure (f) shows no or minimal C4 deposition. In figures (g) and (h), the microphotographs of Kaposi sarcoma are illustrated with infiltration of hyperchromatic spindle cells into the interstitium and slit-like lumina with entrapped erythrocytes (hematoxylin-eosin staining; g, ×20 and ×200 as original magnifications)

6.4 Primary Glomerular Diseases

• IFM: Diffuse granular subepithelial deposits (IgG > IgM > IgA; ±C3) • TEM: Four stages, including stage I with scattered subepithelial electron-dense deposits (domes), stage II with more deposits and projections of BM material deposited in between (spikes and domes), stage III with encircling of the deposits (chain-link), and stage IV with dissolution of deposits but irregular persistence of the thickening of GBM (swiss-cheese). • PGN: Excellent in children (10-YSR, 90%) but less benign in adults (10-YSR, 75%). MGN can lead to persistent proteinuria, mesangial cell proliferation, and slow ­progression to EDRF, but steroid therapy may help. In some cases, a transformation to anti-­GBM type is possible, and the progression to ESRF can become quite rapid. The outcome is tightly linked to the pres-

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ence of proliferating mesangial cells. If mesangial cell proliferation (+) → worse PGN.

6.4.8 Membranoproliferative (Membrane-Capillary) Glomerulonephritis • DEF: Multi-etiologic GN, presenting as an acute nephritic syndrome, acute nephrotic syndrome, and HTN in children and young adults. It is characterized by a slowly progressive and relentless course with intermittent remissions and gradual loss of renal function as well as a tendency to relapse in renal grafts. It has been described with cannabis use. • SYN: Hypocomplementemia (C3) or lobular GN.

a

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Fig. 6.15  Membranoproliferative glomerulonephritis (see text for detail). A cartoon is depicted in (a). All microphotographs (b-f) have been taken from H&E stained slides at x400 as original magnification

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Three subtypes: (1) classical/mesangiocapillary, (2) “dense deposits,” (3) mixed with monomorphic LM phenotype (mnemonic: ELMIC)

CLM: Enlargement and Lobular accentuation of the Glomeruli, Mesangial cell number and matrix increase, Irregular capillary wall thickening with interposition of mesangial cells between the BM and the endothelium giving rise to the double contour appearance or “tram track” or “reduplication of the GBM” pattern, and Crescents (1/5 of cases) (Fig. 6.15).

Type I  – Classical, “mesangiocapillary” (2/3): C-classical pathway activation (better PGN) • IFM: IgG, IgM  ±  IgA deposition and C3, C1q, and C4 deposition (“lumpy bumpy”) as well as granular fibrin deposition (in serum  ↓CH50) • TEM: Subendothelial and mesangial deposits with an increase of the mesangial matrix, which determines a “mesangialization” of the capillary loops, and foot process fusion

Type II  – Dense deposit GN (1/3): C-alternative pathway activation (worse PGN) • IFM: No Ig deposition, but extensive C3 deposition (normal C1q, C4, C2 because C3 NeF antibody stabilizes alternative pathway (C3 convertase)) and occasional fibrin deposition • TEM: Dense deposits in lamina densa of GBM with a long discontinuous ribbon of hazy material

Type III  – Mixed (rare). It may represent probably an advanced form of type I with subendothelial and subepithelial deposits.

• PGN: Severity of disease – renal function (FENa), kidney size  worst PGN! • TEM: “Fingerprint” subendothelial deposits and mesangial, subepithelial, and intramem-

branous deposits as well as tubular-reticular structures in endothelial cells WHO Class V (Membranous) Indolent progression. CLM/IFM/TEM: Identical to lesions of idiopathic membranous GN! WHO Class VI (Sclerosing). CLM: Global glomerulosclerosis with fibrous crescents, interstitial fibrosis, and tubular atrophy. TEM: Irregular thickening of capillary BM with intramembranous deposits. PGN: Young adult SLE  – renal involvement, 50–80% of patients with SLE and PGN is directly related to the extent of renal disease. Subendothelial deposits, the most hostile deposits, correlate well with RF ± lymphoplasmacytic tubulointerstitial infiltrate with eosinophils.

• • • • • •

6.5.2 Henoch-Schönlein Purpura • DEF: Systemic leukocytoclastic vasculitis of the 2nd-3rd infancy characterized by deposi-

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Fig. 6.17  Henoch-Schönlein purpura (HSP) is a systemic vasculitic disorder with nephropathy, including glomerular proliferation and cell infiltrates (a and b, hematoxylineosin staining, ×100 original magnification; (c) hematoxylin and eosin staining, ×400 original magnification) and

granular mesangial IgA (e), which is often accompanied by C3 (g), fibrinogen, and both light chains and less frequently by IgG (d) and/or IgM (f). Figure (h) shows the C1q deposition. All immunofluorescence microphotographs have been taken at ×400 as original magnification

tion of IgA-immune complexes linked often to infections, drugs, or idiopathic (~1/3) with mostly restitutio ad integrum. • CLI: HSP presents as Arthralgia (non-­migratory), Renal involvement (asymptomatic hematuria/ proteinuria to GN), Cutaneous palpable purpura

(subepidermal hemorrhages + necrotizing vasculitis involving the small BV of the dermis with IgA deposits), and Intestinal involvement (pain, vomiting, bleeding ± intussusception) (“ARCI”). • EPG: Infectious (e.g., β-hemolytic Streptococcus, Lancefield group A, HBV, HSV, PV-B19, cox-

6.5 Secondary Glomerular Diseases

sackievirus, adenovirus, Helicobacter pylori, measles, mumps, rubella, Mycoplasma spp.), drugs linked to HSP, usually as an idiosyncratic reaction, include the antibiotics vancomycin and cefuroxime, ACE inhibitors enalapril and captopril, anti-inflammatory agent diclofenac, as well as ranitidine and streptokinase. • CLM: Similar to IgA nephropathy but often crescentic GN when severe (Fig. 6.17). • PGN: Typically, HSP resolves within several weeks and requires no treatment apart from symptom control but may relapse in 1/3 of the patients with potentially irreversible kidney damage (~1/100).

6.5.3 Amyloidosis • DEF: Group of diseases having in common the deposition of a similar-appearing protein, the Amyloid, which is a pathologic proteinaceous substance, deposited in the extracellular space in various tissues and organs of the body in a wide array of clinical settings. Most common forms of Amyloid Proteins:

1. AL (A-light chain): Ig light chain (λ > κ) secreted by monoclonal PC (Bence-­ Jones protein). 2. AA (A-associated): Derived by proteolysis of SAA (Serum Amyloid Associated), a non-Ig protein synthesized by the liver in inflammation as part of the Acute Phase Response: Secondary Amyloidosis. 3. Aβ (β-protein): Derived by proteolysis of APP (amyloid precursor protein) and is the core of cerebral plaques in Alzheimer disease and cerebral BV as well as trisomy 21 syndrome. 4. Other biochemically distinct proteins include TTR, which is specifically involved in familial amyloid polyneuropathies and senile systemic amyloidosis, A-β2-microglobulin engaged in long-term hemodialysis, and misfolded prion proteins.

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• EPG: Misfolded proteins are unstable with an intrinsic tendency to self-associate = > deposition = > disruption of the normal function of tissues by alteration of the proteasome. The Ubiquitin Proteasome Pathway (UPP) is considered the main mechanism for protein catabolism in mammals. The UPP affects numerous cellular processes. Defects in the system can result in the pathogenesis of several human diseases. Its role in medicine and biology has been universally recognized in 2004 with the Nobel Prize for Chemistry which was awarded to Avram Hershko, Aaron Ciechanover and Irwin Rose. The proteasome is supposed to degrade IC misfolded proteins. Genetically determined structural abnormality in the SAA molecule renders it resistant to degradation of Mф. • Localized amyloidosis forms comprise senile cerebral (Alzheimer disease), which occurs early in individuals with trisomy 21 syndrome, medullary carcinoma of the thyroid, T2DM in the islets of the pancreas (AIAPP), and the isolated atrial amyloidosis (AAMI). • SAA-Conditions: TB, bronchiectasis, and chronic osteomyelitis in the pre-antibiotic era. RA, ankylosing spondylitis, IBD, heroin/“skinpopping” of narcotics, HL, RCC, and FMF in the post-antibiotic era. • GRO: Enlarged and firm organ with waxy appearance (iodine- > yellow +H2SO4 - > blue-­ violet), such as the kidney, spleen (“sago spleen” with tapioca-like granules and “lardaceous spleen” with map-like areas), liver, heart (restrictive CMP, congestive heart failure, arrhythmias), and tongue (macroglossia). In pediatrics, amyloidosis is AA-­type or reactive to chronic inflammatory diseases, and the most important causes are the Familial Mediterranean Fever (FMF) (> IL-1, pyrin, polyserositis, Middle East) and other autoinflammatory disorders (e.g., juvenile rheumatoid arthritis). Tuberculosis has practically disappeared or strongly decreased in pediatrics of developed countries but still present in underdeveloped countries.

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Amyloid: Hyaline, eosinophil, Congo-red+ and apple-green birefringence when polarized. Historically, the amyloid detection with the iodine-sulphuric acid reaction had been identified in the 19th century (Aterman 1976).

Amyloid protein A deposits (+Congo-­red/ AG-B) ⇒ massive proteinuria (12–20 g/24 h!).

CLM: Homogeneous deposits in glomeruli, tubular BM, and BV walls.

IFM: ±Ig, but nonspecific.

TEM: Amyloid fibrils, β-pleated sheet, 7–12 nm, randomly arranged, non-branching in mesangium and peripheral capillary BM (≠18–24  nm θ of fibrillary GN or 30–50 nm θ of immunotactoid GN).

6.5.4 Light Chain Disease 7–10% of patients with MM • CLM: Capillary wall thickening, nodular sclerosis, and AL-deposits (“AL Amyloid”). • IFM: Monoclonal κ or λ light chain  – linear deposition. • TEM: Granular deposits in glomerular and tubular BM.

6.5.5 Cryoglobulinemia 50% of patients (usually adults, rare in children) with lymphoproliferative disorders (MM, WM, CLL, B-cell NHL), infections (mainly HCV), AID, and essential. It usually presents as type I membranoproliferative (mesangiocapillary) GN.

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• Type I (monoclonal IgM): Waldenstrom macroglobulinemia (WM), multiple myeloma (MM) • Type II (monoclonal IgM  +  polyclonal IgG): WM, MM, CLL • Type III (polyclonal IgM and IgG): RA, SLE, PAN >90% of mixed cryoglobulinemia → (+) HCV and 50% of (+) HCV have cryoglobulinemia. • CLM: Glomerular enlargement with diffuse ↑ of mesangial matrix and # of mesangial cells accompanied by lobular accentuation, neutrophils, and intraluminal eosinophilic occlusive thrombi ± crescents. • IFM: IgG and IgM deposition in peripheral capillary deposits as well as C3, C1, and C4 in a granular fashion (mixed cryoglobulinemia type II or type III). • TEM: Subendothelial and mesangial deposits.

6.5.6 Diabetic Nephropathy Diabetes is one of the most common internal diseases globally and across ages. Dramatically, the worldwide incidence of type 1 diabetes mellitus (T1DM) is rising by 3% per year. Diabetic nephropathy may occur in children and adolescents as early tubulopathy and in many countries a growing number of children and adolescents are suffering from type 2 diabetes mellitus (T2DM) with or without obesity. This increase is not more restricted to Caucasian children, but rising rates have also been scored in Asian communities worldwide. The high-fructose corn syrup is the ingredient of several pop drinks and has been considered the culprit but probably increased sugar content in the diet of children and adolescents plays a major role in several communities and cultures. Recent advances in DM treatment have been successful in decreasing morbidity and mortality from diabetes-related retinopathy (DM-Ret), nephropathy (DM-Nep), and neuropathy (DM-Neu). T1DM-Nep/T2DM-­Nep is more

6.6 Hereditary/Familial Nephropathies

common in early onset or poorly controlled DM and presents with recurrent proteinuria, often nephrotic, with papillary necrosis of both kidneys and slow progression to CRF. Diffuse and Nodular Types → “ThIN” • CLM: Thickening, diffuse hyaline type of capillary wall, “insudative” glomerular lesions (fibrin cap, capsular drop), nodular (Kimmelstiel-­ Wilson) sclerosis, arteriolar nephrosclerosis, and duration-related global sclerosis. • IFM: Diffuse “thin” linear staining for IgG, C3, and albumin. • TEM: Diffuse GBM thickening (up to 5–10× normal), ↑ mesangial matrix and subendothelial granular deposits. • PGN: Diabetic children, even with normal levels of albuminuria, show ↑ urine neutrophil gelatinase-associated lipocalin (NGAL) supporting the hypothesis of a “tubular phase” of diabetic disease preceding overt diabetic nephropathy. Thus, the use of urine NGAL measurement for early evaluation of renal involvement may be beneficial.

6.6

Hereditary/Familial Nephropathies

6.6.1 Fabry Nephropathy Although arising in late adolescence and youth, Fabry disease may play a role for genetic counseling. Fabry nephropathy is X-linked recessive ­lysosomal storage disease, and there are several mutations of the GLA gene leading to a lack or deficiency of the lysosomal enzyme α-galactosidase A. It results in progressive glycotriaosylceramide accumulation in multiple organs, of which the kidney is primarily involved. Fabry nephropathy is characterized by vacuolization of the cells in the glomeruli, tubules, interstitium, and arteries. The TEM shows myelin bodies. Although the kidney biopsy is not necessary for diagnosis, it does have a critical role in the evaluation of disease evolution and treatment efficiency with the enzyme replacement therapy (Fig. 6.18).

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6.6.2 Alport Syndrome • DEF: Genetic disorder, mostly X-linked dominant (COL4A5 gene), which is characterized by glomerulosclerosis, tubular atrophy, and interstitial foam cells. There is a real chance to progress to ESRD, sensorineural hearing loss, abnormalities of the eyes, and male fertility disturbances. Ocular findings include anterior lenticonus, maculopathy (whitish or yellowish specks or granulations in the perimacular region), posterior polymorphous corneal dystrophy (PPMD, vesicles of the Descemet membrane and the corneal endothelium), and recurrent corneal erosion. Lenticonus anterior is an anterior bulging of the lens capsule and the underlying cortex diagnosed by biomicroscopic examination and is virtually pathognomonic of Alport syndrome. Conversely, the lenticonus posterior is not associated with systemic disease. • IFM: No specific staining and no reactivity using anti-GBM from patients with Goodpasture syndrome (linear fluorescence would be present in healthy individuals or patients with TBMN). By IHC, the α5 chain of collagen IV is expressed. • TEM: “Basket-weave” pattern of the lamina densa, which is split into multiple interwoven lamellae showing thinning, thickening, and splitting of GBM. • Subtypes of collagen IV-related nephropathies are X-linked Alport syndrome (XLAS), AR-­ Alport syndrome (ARAS), AD-Alport syndrome (ADAS), and TBMN (vide infra). Any of these genes harboring mutations determine proteins that prevent the proper production or assembly of the network of collagen IV, which plays an essential structural element of basement membranes in some organs such as the kidney, inner ear, and eye. COL4A5 (aka ASLN, ATS) is collagen IV, α5 and is located on Xq22. COL4A5 translates one of the six subunits of collagen IV. Collagen IV is the primary structural component of basement membranes. COL4A5 shares some similarities with other members of the collagen gene family. COL4A5 is organized in a head-to-head conformation with another collagen IV gene. The fate of this phenomenon is that each gene pair shares a common promoter.

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616 Lysosome

a

b Acroparesthesias Angiokeratomas Corneal opacity GI disease Renal disease CNS disease Cardiac disease Death

α-Gal

α-Gal Deficiency

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Y1 Yn 5 10 15 20 25 30 35 40 45 50 55 5 25 10 40 15 40 20 40 20 40 25 40 35 40 40 55

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GL-3

Integrin av 3

Plasminogen Podocyte contraction

uPAR

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Plasmin

Proteinuria

e

f

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Fig. 6.18 Fabry disease or Anderson-Fabry disease (AFD) is a lysosomal storage disorder caused by genetic deficiency of the enzyme encoded by the alpha-­ galactosidase A (a-Gal A) enzyme, which is located on the X chromosome (Xq22.1) with the lipids highlighted by special stains for the accumulation products (a). This causes progressive intracellular accumulation of globotriaosylceramide and other sphingolipids throughout the body with progressive life quality impairment (b). Renal histology (d–g) shows hypertrophic glomerular podocytes distended with foamy appearing vacuoles, mesangial wid-

ening, and varying degrees of glomerular obsolescence. Vacuolation is also observed in the capillary endothelium and distal tubular epithelial cells, including the epithelial cells of Henle’s loop and the collecting duct and less often in proximal tubular epithelial cells (d and e, hematoxylin and eosin staining, ×200 as original magnification; f and g, hematoxylin and eosin staining, ×400 as original magnification). Figure (h) shows the ultrastructural findings with enlarged secondary lysosomes, which are also known as myeloid or zebra bodies, packed with lamellated membrane structures (×1500, original magnification)

6.6 Hereditary/Familial Nephropathies

6.6.3 Nail-Patella Syndrome

617

compound heterozygous mutation in nephrin gene (NPHS1; 602716), which is located on • DEF: Classic clinical tetrad of a particular chromosome 19q13.1. The congenital nephrotic phenotype with AD inheritance involving syndrome is characterized by massive proteinuria changes of the ungueal apparatus (most con- at prenatal onset and enlarged placenta (1/3 body stant feature), knees, elbows, and iliac bones. weight of the newborn). At birth, there is a severe Nails may be absent, hypoplastic, or dystro- steroid-resistant nephrotic syndrome with rapid phic. They have been described with different progression to ESRD within 1–3  years. It is morphologies such as nails with longitudinal essential to remind to the genetic heterogeneity or horizontal ridges, pitted, discolored, or even of nephrotic syndrome and FSGS (vide supra). separated into two halves by a longitudinal Both disorders represent a spectrum of hereditary cleft or ridge of the skin. In the knees, the renal diseases. In fact, NPHS2 (600995) is caused patellae may be small. Occasionally, the patel- by mutation in the PODOCIN gene (604766), lae are irregularly shaped, or, even, absent. NPHS3 (610725) is linked to the PLCE1 gene Elbows may have the limitation of extension, (608414), NPHS4 (256370) is related to the WT1 pronation, and supination, cubitus valgus, and gene (607102), NPHS5 (614199) is associated antecubital pterygia. Iliac horns are bilateral, with LAMB2 gene (150325), and NPHS6 conical, bony protuberances that project pos- (614196) is connected to the PTPRO gene terolaterally from pelvic iliac bones. Renal (600579). FSGS1 (603278) is caused by a mutainvolvement may first manifest as proteinuria tion in the ACTN4 gene (604638), while FSGS2 with or without hematuria up to half of the (603965) is linked to the TRPC6 gene (603652). Moreover, FSGS3 (607832) is associated with patients, and ESRD occurs in 1:20 patients. • TEM shows thickening of GBM with collagen-­ genetic variation in the CD2AP (604241), FSGS4 like fibers within the GBM and electron-lucent (612551) is on chromosome 22q12. FSGS5 areas giving a mottled “moth-eaten” appear- (613237) is caused by a mutation in the INF2 ance. Additional complications include primary gene (610982). Renal histology of congenital open-angle glaucoma and ocular HTN (annual nephrotic syndrome shows immature glomeruli visual monitoring is advisable). Diagnosis is with sclerosis (mesangial → global sclerosis), based on clinical features and LMX1B gene tubular cyst formation (aka microcystic disease) screening. LMX1B (aka NPS1) is LIM homeo- and atrophy, interstitial fibrosis, and medial artebox transcription factor 1, β gene with protein riolar hypertrophy. TEM exhibits an increased product located on 9q33.3. This gene belongs to mesangial matrix and an obliteration of foot the homeoboxes or LIM class gene families. processes. There are two homologs in mouse and rat species (Lmx1b). This gene translates a member of LIM-­homeodomain family of proteins, which 6.6.5 Thin Glomerular Basement Membrane Nephropathy contains two N-terminal zinc-binding LIM (TBMN) domains, a homeodomain, and a C-terminal glutamine-rich domain. The protein works as a transcription factor, which plays an essential TBMN is an AD-inherited disorder with >50% role for the healthy development of dorsal limb of the patients having a family history of hemastructures, the GBM, the anterior segment of the turia. In about half of the families affected with eye, and for the development of dopaminergic TBMN, the condition co-segregates with heterozygous COL4A3/COL4A4 gene mutations. and serotonergic neurons. TBMN is characterized by diffuse thinning of the lamina densa and the GBM as a whole and 6.6.4 Congenital Nephrotic Syndrome manifests as persistent microscopic hematuria (persistent or intermittent) with onset in childNephrotic syndrome type 1 (NPHS1), aka Finnish hood, no uremia or renal insufficiency, with congenital nephrosis, is due to homozygous or rare extrarenal abnormalities. LM and IF are

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usually unremarkable, although small amounts of Ig and C3 deposited along GBM may be encountered. IF with anti-GBM antibodies from the serum of patients with Goodpasture syndrome is positive like in healthy individuals, a feature helping to differentiate from Alport syndrome. The intraglomerular variability in GBM width, observed in TEM, is small in individuals with TBMN. GBM is ~200 nm vs. 300– 400  nm of GBM in healthy individuals. The GBM of persons affected with TBMN remains attenuated over time, rather than undergoing the progressive thickening and multi-lamellation identified in renal biopsies of patients affected with Alport syndrome. Individuals with TBMN exhibit standard GBM staining for the collagen α3(IV) chain, α4(IV) chain, and α5(IV) chain.

6.7

Tubulointerstitial Diseases

6.7.1 Acute Tubulointerstitial Nephritis (ATIN) Acute inflammation of the interstitium with often involvement of the tubules – four diseases

6.7.1.1 Acute Pyelonephritis • DEF: Patchy, wedge-shaped mostly cortical suppurative inflammation with edema and neutrophils in tubular lumina and interstitium, as well as areas or necrosis/ abscess in the cortex, but sparing of glomeruli and BVs. • CLI: Flank pain, fever, malaise, dysuria, and pyuria with Gram-negative GIT bacilli (>85%), e.g., E. coli, Proteus spp., Klebsiella spp., and Enterobacter spp., occurring in the setting of obstruction of the lower urogenital tract (e.g., prostatic valves, pregnancy), hematogenous spread, ascending infection, and VUR (during micturition) (Figs.  6.19 and 6.20). 6.7.1.2 Pyonephrosis Purulent inflammation of the kidney with a filling of the pelvic system and kidney caused by near complete obstruction.

6.7.1.3 Acute Hypersensitivity Nephritis (AHN) • DEF: Hypersensitivity-based acute nephritis. • EPG: AHN may be associated to various etiologies, including allergic/drug-induced, infectious (Hantavirus, EBV, HSV, CMV, adenovirus, HIV), and autoimmune/systemic (SLE, Sjögren’s, RA); otherwise idiopathic forms of the disease also exist. Drugs constitute the most common etiology of AHN in roughly 2/3 of patients. Multiple agents from many different classes of drugs can be the underlying cause, and clinical presentation, as well as laboratory findings, may vary according to the class of drug involved. Most common drugs are aminoglycosides (e.g., gentamycin), rifampin, amphotericin, beta-­lactam antibiotics, NSAIDs, PPI, diuretics, and phenytoin. • CLM: Tubular and interstitial lymphoplasmacytic inflammation with macrophages and eosinophils as well as ± tubular damage and regeneration with interstitial fibrosis. There is sparing of glomeruli and BV. In NSAID-­linked AHN, there is also glomerular foot process fusion. Noninvasive tests, such as gallium-67 (67Ga) scintigraphy and eosinophiluria testing, have limited diagnostic utility, but a renal biopsy can establish a definitive diagnosis. • PGN: Good, if there is timely discontinuation of the causative agent and partial recovery of kidney function with or without steroids is customarily observed. Since patients can eventually develop ESRD and RF, early recognition is crucial. 6.7.1.4 Renal Papillary Necrosis • DEF: Necrosis of the renal papillae due to DM, acetaminophen intoxication (also phenacetin, aspirin, codeine, and EtOH), and vascular occlusion (e.g., SCD, leukemia) – related TIN, generally affecting the upper and lower pole renal papillae. • Synchronized lesions in DM and temporal heterogeneity in non-DM causes. • Analgesic nephropathy is dose-dependent ≠ nephrotoxic ATN due to NSAIDs and penicillins. Three stages (Fig. 6.21):

6.7 Tubulointerstitial Diseases

619

a

b

c

d

e

f

g

h

Fig. 6.19  Xanthogranulomatous pyelonephritis (XGPN) with bosselated surface of the kidney (a) and homogeneous gray-whitish/yellowish cut surface and hemorrhagic pelvis (b). Figures (c) and (d) show the histology with granulomatous mixed (lymphocytic-rich) inflammatory infiltrate with fibrosis, glomerular obsolescence, and thyroidization of the parenchyma with eosinophilic con-

cretions in the lumina of collecting ducts (c and d both hematoxylin and eosin staining taken at ×50 and ×100 as original magnification). Figures (e) through (h) show an interstitial pyelonephritis with immunohistochemical detection of antibodies against CD45, CD68, CD4, and CD8, respectively (avidin-biotin complex, ×200 original magnification)

6  Kidney, Pelvis, and Ureter

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a

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Fig. 6.20  This panel illustrates eight microphotographs (a-h) showing the variability seen in sepsis with bilirubin casts in case of hepatorenal failure (a-g). In some case, hemosiderin deposition is particularly prominent (h). If

(h) is Perls Prussian blue stained, (a) through (g) are H&E stained. All microphotographs are at x200 as original magnification, apart (a), (b), and (g), which are at x100 as original magnification

6.7 Tubulointerstitial Diseases

621

Tubular disorders: Tubule proteinuria (Urine protein/C ratio Cartilage > Bone > Extramedullary hematopiesis > Nerve > Nodular renal blastema

b

c

d

e

f

g

h

Fig. 6.39  In (a) are displayed the Ridson-Hill lesions of multicystic kidney dysplasia. The microphotographs (b) through (h) show the rare occurrence of a renal cell carcinoma arising on the ground of a multicystic kidney dysplasia

6.12 Non-embryonal Tumors of the Young

• Xp11 RCC: RCC of children and young adults defined by several different translocations involving Xp11 with fusion at different chromosomes and involving the TFE3 gene (MITF), being grossly, well-demarcated, but nonencapsulated ± irregular margins and perirenal and renal sinus extensions, yellow-tan CS  ±  H/N, and, microscopically, characterized by papillary/nested/alveolar patterns with psammoma bodies (often within hyaline nodules) composed of Fuhrman G3–G4 cells with clear or granular cytoplasm and uncertain PGN. • IHC:  −CK7, +AMACR, +CD10, − EMA, +TFE3 • DDX: CCRCC: −CK7, −AMACR, +CD10, +EMA, −TFE3 PRCC: +CK7, +AMACR, +CD10, −EMA, −TFE3

653

clearing making the cytoplasmic borders thick and distinct (“plant cell appearance”). No chicken-wire vasculature (more fibrovascular than vascular) and no PGN value of Fuhrman grading:

• Type 1: Small cells with slightly granular eosinophilic cytoplasm • Type 2: Medium-large cells with prominent perinuclear halo • Type 3: Large, polygonal cells with thick cell border and abundant cytoplasm

• HSS/IHC: (+) Hale’s colloidal iron (acid mucopolysaccharides in microvesicles), LMWCK, CK7 (diffuse and strong, compared to oncocytoma with scattered single cells), EMA/MUC1 (diffuse cytoplasmic), parvalbumin (calcium-binding protein), CD117/C-Kit The immunostaining using TFE3 is useful to (membranous), E-Cadherin, Claudin-7 (distal pick up PRCC-TFE3 renal carcinomas, ASPL-­ nephron marker), kidney-specific cadherin, ± TFE3 renal carcinomas, and PSF-TFE3 renal carRCC-Ma, CD10  – VIM (or weak), and cinomas, as well as ASPS. N-­ Cadherin, there is low Ki-67 expression (MIB1) indicating a low proliferation rate. • TEM: Microvesicles (Ø: 150–300 nm) and 6.12.2 Chromophobe Renal Cell optional abundant mitochondria in the eosinoCarcinoma philic variant of Ch-RCC. • PGN: Poor PGN factors  include specifically • DEF: Relatively favorable behavior (5-YSR: sarcomatoid change, necrosis, high stage, and ~90%)-accompanied RCC (1/20 adult renal vascular invasion epithelial tumors) of the intercalated cell of cortical collecting duct with distinctive cytology occurring in youth to middle-aged patients 6.12.3 Papillary Adenoma and Renal Cell Carcinoma with no gender preference (♂ = ♀) and ± BHDS (FLCN at 17p11.2). • GRO: Well-circumscribed, tan-brown with Papillary Adenoma geographic necrosis, micro cysts, ± multifocality/bilaterality, and no central scar (≠ renal • DEF: Most common renal tubular epithelial oncocytoma). tumor, usually occurring as an asymptomatic • CLM: Sheets or alveolar pattern with thickevent in 1/10 individuals 0.5  cm, red/brown tumor with thick capsule and reactive changes (hemor-

•

•

•

a

b

c

d

Fig. 6.40  Intraoperative photograph demonstrating exophytic lesion before (a) and after (b) resection. Imprints show very large cells with eccentric nuclei (c). The tumor infiltrated the tumor capsule invading the surrounding

rhage)  ±  multifocal (80%) and characteristically “pouring out” of the kidney. CLM: Papillary or tubulo-papillary tumor with foamy MΦ and intracellular Fe deposition as well as columnar or cuboidal cells with G1-G2 nuclei with longitudinal nuclear grooves and finely granular cytoplasm ± glassy hyaline globules, psammoma bodies, PMNs, and necrosis (Figs. 6.40 and 6.41). IHC: (+) CK7, AMACR, CD10, LMWCK (CK 8/18 and CK19), but also (+) m-EMA/ MUC1, RCC-Marker, CD117/C-Kit (cytoplasmic); (±) VIM; (−) HMWCK (34BE12: CK1, CK5/6, CK10, CK14), UEA, PVA, WT1 TEM: Variable size of microvilli, small amount of intracytoplasmic lipid, but no glycogen. DDX: Papillary adenoma (similar morphology, but  ♀, (+) developed RER, pre-melanosomes and numerclinical triad, mild response to RT/CHT and ous vesicles in the edge of the cytoplasm. poor PGN (even death within 15 weeks). There is no continuous basal lamina. • GRO: Solid ± H/N (no cyst!). Premelanosomes contain longitudinal fila• CLM: Solid/adenoid-cystic/reticular growth ments that may be cross-linked with one pattern with DPSR of G3–G4 cells with large another with an enveloping bilayered vesicular nuclei and prominent nucleoli and membrane. eosinophilic cytoplasm admixed with PMNs • Variant: Epithelioid AML (EAML), which has and bounded by lymphocytes (intense inflama locally infiltrative growth pattern and commatory response of the “host” at the interface posed of sheets of malignant-­appearing epibetween tumor and adjacent renal parenchyma. thelioid cells (DDX: sarcomatoid RCC). • HSS/IHC: (+) AE1/AE3, LMWCK, EMA, EAML seems to be less aggressive than VIM, HIF, VEGF, (±) CK7, CEA, (±) believed to be at the time of the original HMWCK, Ulex. description. • DDX: Uro-Ca (+CK20, adjacent CIS) and CDC (+HMWCK, Ulex). • “Sickle cell trait”  – 7 nephropathies: gross 6.12.7 Oncocytoma hematuria, papillary necrosis, nephrotic syndrome, renal infarction, hyposthenuria, pyelo- • DEF: 1/20 of all renal tumors, ♂ > ♀, III–VI nephritis, and RMC. decades, benign tumor of the intercalated cells

6.12 Non-embryonal Tumors of the Young

a

Epitheliogenesis Adipogenesis

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Myogenesis Angiogenesis PDFG VEGF Pericyte without TSC protein function

ATII

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ER stress

Unfolded protein response

MelanA HMB45 GPNMB

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Fig. 6.42  In (a) is shown the carcinogenetic pathways with differentiation of an angiomyolipoma. The microphotographs (b) through (h) show an angiomyolipoma with the characteristic triphasic morphology with myoid spindle cells, islands of mature adipose tissue (e), and

abnormally structured (“dysmorphic”) thick-walled blood vessels (g) (hematoxylin and eosin staining). All microphotographs (b-h) are H&E and the original magnification is x20, x100, x100, x200, x400, x200, and x200, respectively

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Fig. 6.43  The immunohistochemical panel of angiomyolipoma shows an expression of actin (a), caldesmon (b), HMB45 (c, d), and desmin (e), but no expression of AE1– AE3 (f), epithelial membrane antigen (g), and low prolif-

eration activity (h). Avidin-biotin complex immunostaining (a) at ×50, (b) at ×100, (c) at ×100, (d) at ×200, (e) at ×100, (f) through (h) at ×100 as original magnification

6.12 Non-embryonal Tumors of the Young

•

•

• •

•

•

of collecting duct, usually solitary (multiple, 1/20) either asymptomatic or with ­hematuria/ flank pain/mass, ± BHDS, and #Y-, #1-, #14-, 11q13~ = > CCDN1- > cyclin D1 (MCL). GRO: Mahogany-brown, large, and solid tumor with central stellate scar (focal ­hemorrhage in 1/5 of cases). CLM: “Archipelagineous” architecture with solid sheets or nests of cells with small, round, and regular nuclei (Fuhrman 1–2) and abundant granular acidophilic cytoplasm in a loose fibrous stroma. HSS/IHC: ±CK7, ±AMACR, ±CD10, +EMA, −VIM, +CD117, and + CK14. DDX: Ch-RCC  ±CK7, -AMACR, ±CD10, +EMA, −VIM, +CD117, and ±CK14, other than cytology, Hale, IHC, TEM. If Fuhrman 3–4 → degenerative change, but Fuhrman 3–4 and + MI and necrosis → RCC, oncocytic variant. TEM: Many mitochondria (≠ Ch-RCC that exhibits numerous cytoplasmic microvesicles of Ø: 150–300 nm). PGN: Good, but the invasion of the capsule or renal vein is possible, and debate still exists to call it as oncocytoma or regards it as RCC, oncocytic variant. Exclusion criteria: areas of clear cell carcinomas, sarcomatoid carcinoma, prominent/diffuse papillary architecture, gross/microscopic necrosis, ↑MI, and atypical mitoses.

6.12.8 Other Epithelial and Mesenchymal Tumors –– TUBULOCYSTIC CARCINOMA: LMP-RCC, an incidental and indolent tumor with an unknown cell of origin and occurring in a wide age range of mostly males (♂:♀ = 6:1), and no well established cytogenetics. –– GRO: Well-demarcated, spongy tumor with “bubbly wrap-like” CS. –– CLM: Small-to-intermediate-sized tubules admixed with cystically dilated tubules (“spider-­web” pattern) lined by a single layer of flat, “hobnail,” or cuboidal to columnar cells in a fibrotic intervening stroma (no clear cell aggregates!).

659

–– IHC: +CK7, +AMACR, +CD10 (DDX: MTS-­ RCC, PRCC, CDC). –– TEM: Many microvilli (like PRT) or sparse microvilli and cytoplasmic interdigitations (ICC of collecting duct-like). –– MUCINOUS TUBULAR AND SPINDLE CELL CARCINOMA (MTS-RCC): Very low-­ grade, incidental, and indolent tumor with epithelial and mesenchymal components, of the proximal nephron (+CK7 and AMACR), occurring in a wide range of age of mostly females (♂:♀  =  1:4), ± nephrolithiasis, and variable cytogenetics (losses of #1, 4, 6, 8, 13, and 14, and gains of #7, 11, 16, and 17). –– GRO: Cortical or central located, well-­ circumscribed occasionally encapsulated with gray-tan and glistening CS. –– CLM: Tightly packed elongated tubuli of G1 cytology in a bubbly myxoid stroma with abundant basophilic extracellular mucin and G1 spindle cells areas. –– IHC: +CK7, +AMACR, -CD10 (DDX: CCRCC and PRCC); +LMWCK and -HMWCK. –– TEM: Loop of Henle-like morphology. –– CYSTIC NEPHROMA (OF THE ADULT): Very low-grade, incidental, and indolent tumor with epithelial and mesenchymal components of mostly females (♂:♀  =  1:8) older than 30 years. –– GRO: Solitary, unilateral, encapsulated, and well-circumscribed tumor of the upper pole composed of numerous cysts of variable size with uneventful adjacent renal parenchyma. –– CLM: Multilocular cysts lined by a single layer of flat, “hobnail,” or cuboidal to columnar cells and separated by fibrous septa of variable thickness (no nephronic differentiation, no blastema, no clear cell aggregates!). –– MIXED EPITHELIAL AND STROMAL TUMOR: Very low-grade, incidental/symptomatic (triad), and indolent tumor with epithelial and mesenchymal components of mostly females (♂:♀ = 1:8) of the 4th decade. Grossly, centrally located, well-­circumscribed, and encapsulated tumor with protrusion into the renal pelvis and microscopically, consisting of highly complex epithelial cells lined

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papillae (true papillae) lined by a single layer wide age range from children to elderly (♂ < of flat, “hobnail,” or cuboidal to columnar ♀) originating from of the modified smooth cells and variable cellular stroma composed of muscle cells of the juxtaglomerular apparatus spindle cells with plump nuclei and copious and presenting with refractory HTN, hypercytoplasm ± myxoid change or collagen, ­ reninemia, secondary hyperaldosteronism, smooth muscle, or fatty tissue. and hypokalemia. Grossly, unilateral, solitary, –– IHC: (+) CK and VIM in the epithelial compocortical, solid, encapsulated, well-demarcated nent & (+) SMA and DES in the mesenchymal (Ø < 5  cm), gray-white/yellow-­tan tumor ± component. hemorrhage and, microscopically, composed –– RENOMEDULLARY INTERSTITIAL CELL of solid sheets of uniform, round to polygonal TUMOR (aka “medullary fibroma”): Mostly and spindle cells with round to oval nuclei, asymptomatic, incidental mesenchymal tumor low or nil MI, and copious granular with a wide age range from adolescents to ­eosinophilic cytoplasm as well as thin- and elderly originating from a prostaglandin-­ thick-walled prominent BVs with hemangioproducing interstitial cell in renal medulla pericytoma-like “antler vascular pattern” in involved in the regulation of the blood pressure. numerous fields. Grossly, pyramid-located, well-­circumscribed –– IHC: (+) VIM, SMA, CD34, Renin. (Ø < 0.5 cm), gray-white nodule and, micro- –– TEM: Rhomboid crystals → Renin-specific scopically, consisting of small stellate and spin(DDX: rhomboid crystals of ASPS!). dle cells embedded in a loose myxoid stroma. Finally, rhabdo- and leiomyosarcoma can also –– JUXTAGLOMERULAR CELL TUMOR: occur in the kidney (Fig. 6.44). In 2016 has been Benign renin-secreting (DDX: WT, RCC, renal oncocytoma) mesenchymal tumor with a published the new W.H.O. classification of the

a

> Smooth muscle differentiation > Fascicles of eosinophilic spindle cells with cigar-shaped nuclei > Differential diagnosis includes - Infantile Myofibromatosis - Leiomyoma - Monophasic synovial sarcoma - Spindle cell rhabdomyosarcoma

c

Fig. 6.44  In (a) are shown the characteristic features of a leiomyosarcoma that are displayed in the microphotographic panel (b) through (d). All three microphotographs

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(b-d) have been taken from H&E-stained slides and the magnification is x100, x100, and x400, respectively

6.13 Non-neoplastic Pathology of the Pelvis and Ureter

urinary system. Several familial forms of RCC have been linked to the corresponding histology, which can also arise sporadically. The multilocular cystic renal cell carcinoma or multilocular clear cell renal cell carcinoma is currently described as multilocular cystic renal neoplasm of low malignant potential. The size cutoff for papillary adenoma was increased from 0.5 cm to 1.5 cm. Two forms, pediatric and adult, are collected under the term “cystic nephroma” and, as indicated above, the adult form is included along a spectrum of mixed epithelial and stromal tumors. Similar to carcinoids of other systems, renal carcinoids are re-classified into well-differentiated neuroendocrine tumors of the kidney.

6.13 Non-neoplastic Pathology of the Pelvis and Ureter 6.13.1 Anatomy and Physiology Notes Ureter: ~30 cm in length and 0.5 cm in Ø. Three points of luminal narrowing, including the ureteropelvic junction, the crossing point with the iliac BV, and at entry into the urinary bladder, need to be kept in mind by the pediatric urologist and pathologist.

6.13.2 Congenital Pelvic-Ureteral Anomalies 1. Pelvic-Ureteral Junction (PUJ) Stenosis/ Obstruction (ab externo: PUJ stenosis is the most common cause of collecting duct system dilation in the fetal kidney and one of the most frequent anomalies occurring in the urinary tract in children. There is an association with anomalies of the contralateral kidney, including pelvicureteral junction obstruction, renal agenesis, renal dysplasia, multicystic dysplastic kidney (MCDK), and obstructive dysplasia (Potter type IV). PUJ obstruction ab externo may occur in compression or kinking of the excretory system by a neoplastic or inflammatory tumor of the abdomen or pelvis. In UPJ

661

stenosis, which usually occurs in males, there is an abnormal organization of and excess stromal deposition of collagenous tissue between smooth muscle bundles, and cells are derived from medullary interstitial cells. Surgical (urological) intervention is indicated if there is impairment of the kidney function, pyelonephritis, lithiasis, or pain. 2. Hydrocalyx/Hydrocalycosis: Dilation of a significant calyx may occur in the context of central obstruction, as described in infundibular stenosis, or by extrinsic obstruction by a blood vessel or non-neoplastic (e.g., parapelvic cyst) or neoplastic (e.g., desmoplastic small round blue cell tumor). This condition needs to be distinguished from megacalycosis, which is nonobstructive dysplastic lesion with dilated and over numeracy calyces with or without renal medullary hypoplasia. 3 . Calyceal Diverticula: Cystic structures connected to an adjacent minor calyx by a narrow ductule or channel. 4 . Partial Duplication of the Renal Pelvis and Ureter: Typically, unilateral and no clinical significance.

6.13.3 Congenital Ureteric Anomalies Ectopia of the ureters is usually associated with complete ureteric and renal duplication, and about 10% are bilateral. Interestingly, there is a dysplastic upper pole of a duplex kidney, which is drained by the ectopic ureter that is connected below the common ureterovesical junction into the lower trigone or the proximal urethra. Ectopia of the ureters is much more common in females, and the insertion occurs in either vagina or vulva, with subsequent urinary incontinence. Ectopia of the ureters may also be associated with ureteroceles, which is a cystic dilation of the terminal ureter. Clinically, there is UTI, obstruction of the bladder neck, blockage of the contralateral kidney, or nephrolithiasis. Megaureters may be differentiated in primary and secondary causes. Primary ureter results from a functional obstruction of the distal ureter, which is caused by a peri-

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staltic segment, while secondary megaureter is multi-etiologic with causes ranging from intrinsic ureteric obstruction (e.g., stone) to bladder outflow obstruction, vesicoureteral reflux (VUR), and compression ab externo of the distal ureter. With an incidence rate of 1–2% in children and diagnosed by a voiding cystourethrogram (VCUG) and an intravenous pyelogram (IVP), VUR is defined as a retrograde flow of urine from the urinary bladder into the ureters due to a deficiency of the functional valve-like mechanism at the ureterovesical junction. The competence of this valve depends on three factors, including the length of the intramural length of the ureter, the position of the ureteric orifice in the urinary bladder, and the integrity of the musculature of the bladder wall (tripodal competence or “competentia tripodalis”). Shortage of the intramural portion of the distal ureter and lateral ectopic position of the orifice are the most common causes of VUR in children. Genetic f­ actors may play a substantial role, owing to a 30- to the 50-fold ↑ risk of VUR if an immediate relative is also affected by this pathology. An important note to recall is that the intramural ureter lengthens with age and subsequently VUR is progressively rarer or disappears when the child grows up. VUR may also be an associated pathology to Prune Belly syndrome and posterior urethral valves. A dramatic complication related to primary and secondary VUR is reflux nephropathy. Reflux encourages more or less infected urine from the urinary bladder to be swept up into the kidneys. Subsequently, this phenomenon leads to recurrent pyelonephritis, tubulointerstitial nephritis with “thyroidization” of the renal parenchyma, and gross scarring at the renal poles. The glomeruli become sclerotic with consequent proteinuria, arterial HTN, and progressive loss of renal function. Antibiotic therapy (sulfamethoxazole and trimethoprim) reduces recurrent infections by about 40% in children with age 8.0 is suggestive of a urea-splitting organism (e.g., Proteus, Klebsiella, or Ureaplasma urealyticum). Alkaline (basic) pH suggests “struvite nephrolithiasis” or “infection” kidney stones. Hemorrhagic cystitis: Mucosal (lamina propria) hemorrhage-characterized cystitis due to chemotherapy (cyclophosphamide, busulfan, thiotepa), industrial products (aniline and toluidine derivatives present in dyes and insecticides), and viruses (adenovirus, type 11 and 21, polyomavirus, HSV-2).

7.3 Urinary Tract Inflammatory and Degenerative Conditions

a

b

c

d

e

f

g

h

Fig. 7.5  In (a) through (h) are shown the microphotographs of a neurogenic bladder of a patient with spinal muscular atrophy type 2 who underwent cystectomy (a–g; hematoxylin and eosin staining; ×40, ×100, ×40, ×100,

685

×200, ×400, ×200 as original magnifications, respectively; h, anti-S100 immunostaining, Avidin-BiotinComplex, ×200 original magnification)

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• Interstitial (Hunner’s) cystitis is a persistent, chronic inflammation of the urinary bladder presenting with painful hematuria, urinary frequency, urgency, clinically and edema, hemorrhage, granulation tissue, mononuclear inflammatory infiltrates (also perineural) with numerous mast cells, as well as fibrosis of all layers microscopically. A localized ulcer is often present, and mast cells are present beneath the ulcer, within the detrusor muscle, and in the bladder mucosa between the urothelial cells. The diagnosis is generally one of exclusion after the elimination of other causes (infection, malignancy). Mast cells can be highlighted by histochemistry (tryptase, Giemsa stain, Leder stain, toluidine / methylene blue) or IHC (e.g., CD117). • Radiation cystitis may present as polypoid cystitis, which is dome/posterior wall located inflammation with polypoid features simulating neoplasm and secondary to radiation, but also indwelling catheter, bladder lithiasis, and fistulas (DDX). Microscopically, there are stromal edema, congestion, and chronic inflammation with atypical mesenchymal cells and telangiectasia of the blood vessels with hyalinization and thrombosis as well as urothelium with karyorrhexis and nuclear and cytoplasmic vacuolation but standard N/C ratio. The IHC is crucial in distinguishing radiation cystitis (e.g., a child with leukemia receiving radiation) and CIS. The IHC profile of radiation cystitis is CD44 (+) CK20 (−) p53 (−), while CD44 (−) CK20 (+) p53 (+) suggests a CIS. Giant cell cystitis is the presence of giant cells in lamina propria due to chemotherapy toxicity or radiation but is not a distinct clinical entity. Eosinophilic cystitis is not a clinical entity and the term “eosinophilic cystitis” should be used as a descriptive term only. The inflammatory process has a polypoid aspect mimicking polypoid cystitis, rhabdomyosarcoma of botryoid type, and urothelial carcinoma. Eosinophilic cystitis is often seen in pediatric specimens from children with allergic gastroenteritis, asthma, or allergic disorders while in adults following prior transurethral biopsy, prostatic hyperplasia, and blad-

7  Lower Urinary and Male Genital System

der carcinoma. Rarely, parasitic infection is also a critical etiology that needs to be kept in the DDX in particular settings.

7.3.3 Malacoplakia of the Young Malakoplakia is a vesical lesion characterized by soft yellow 3–4  cm mucosal plaques or polyploidy bladder mass covered with intact mucosa clinically and constituted by accumulation of tightly packed, large, foamy histiocytes (von Hansemann cells, +CD68, +CD163) with characteristic cytoplasmic inclusions (Michaelis-­ Gutmann bodies, PAS+, Pearls Prussian Blue stain+, von Kossa+), occasional giant cells, and interspersed lymphocytes microscopically. Michaelis-Gutmann bodies are laminated mineralized concretions tightly located within and between histiocytes. However, in the early lesions (youth), Pearls and von Kossa stains may be negative, because mineralization occurs later in the disease process. Malakoplakia is an inadequate host response to bacterial infection (insufficient phagolysosomal activity), typically Gram-­ negative bacilli (E. coli, Proteus) and needs to be differentiated from granulomatous inflammation, Langerhans cell histiocytosis (LCH), small round blue cell tumors, urothelial carcinoma, and prostatic carcinoma. Obviously, granulomatous inflammation, small round blue cell tumors, and LCH play a major role in childhood and adolescence, while both urothelial carcinoma and prostatic carcinoma will play a major role later in life.

7.3.4 Urinary Tract Infections and Vesicoureteral Reflux Infections may spread from the urinary bladder to the urinary tract along an ascendant pathway to the ureter, pelvis, and ipsilateral and contralateral kidney (UTI, urinary tract infections). In patients with vesicoureteral reflux (VUR), infections are quite common. VUR refers to a medical condition in which urine flows in a retrograde way from the urinary bladder into the ureters/ kidneys. VUR grade 5 indicates UTI with or without bacteriuria/yeast urea and recurrent

7.3 Urinary Tract Inflammatory and Degenerative Conditions

pyelonephritis. DMSA scan, which is a radionuclide scan that uses dimercaptosuccinic acid, assesses the renal function carefully. To date, DMSA scan is considered the most reliable test for the diagnosis of acute pyelonephritis. The VUR grading system is as follows. Grade I means ureteral dilatation, but VUR does not reach the renal pelvis. Grade II means ureteral dilatation, and VUR reaches the pelvis without dilatation of the collecting system. Grade III means ureteral dilatation ± “kinking” and dilatation of the collecting system and healthy fornices, while grade IV indicates moderate ureteral dilatation ± “kinking” and dilatation of the collecting system and blunt fornices with still visible papillary impressions. Finally, grade V means severe dilatation with “kinking” of the ureter and collecting system with the disappearance of the papillary impressions and clear-cut intraparenchymal (renal) reflux.

7.3.5 Megacystis, Megaureter, Hydronephrosis, and Neurogenic Bladder The megacystis is relatively poorly defined and harbors a multi-etiologic spectrum. It is mostly defined as distended urinary bladder identified in utero. It may be diagnosed by ultrasound after the fetus starts producing urine at about the 10th week of gestation. If there is a megacystis, there may be a mechanical or functional bladder outlet obstruction, which can be either partial or complete. Occasionally, the urinary bladder is normal. Its etiology includes posterior urethral valves (PUV), prune belly syndrome (PBS), urethral atresia/stenosis, cloacal malformities, and megacystis-­microcolon-­intestinal hypoperistalsis syndrome (MMIHS). Megaureter is a dramatic condition that applies to the ureter showing a dilation out of proportion to the rest of the urinary tract due to a vast number of elastic fibers. The following classification seems the most accepted one by most of the pediatric urologists worldwide. It separates the obstructed megaureter from the reflux and nonobstructed and non-reflux megaureter. The obstructed megaureter is further classified as pri-

687

mary (e.g., intrinsic obstruction, stenosis, adynamic segment) and secondary (e.g., post-urethral obstruction, post-­ neuropathic bladder, postextrinsic obstruction, retroperitoneal tumor, benign or malignant). The reflux megaureter is also further classified as primary (e.g., primary reflux megaureter, prune belly syndrome) and secondary (e.g., post-­urethral obstruction, post-neuropathic bladder). The non-obstructed and non-reflux-linked megaureter is subdivided in primary and secondary (e.g., polyuria, infection). Hydronephrosis refers to a unilateral or bilateral swelling of a kidney due to a retrograde (backward) buildup of urine as consequence of a blockage or obstruction. Ureteral dilatation may essentially be caused by VUR, obstructive disease, high urine flow from non-concentrating kidneys, and maldevelopment of the ureteral muscular layers. The fibers of the renal pelvic muscle run obliquely, and connective tissue well separates the muscle bundles. The ureteropelvic junction is an ill-defined structure showing muscle bundles with different orientation lying side by side. Consequently, the ureter consists of braided bundles of muscle fibers arranged in interlacing spirals. The distal pelvic ureter shows an outer circular muscular orientation and an inner longitudinal muscular orientation. The Waldeyer spaces (or better “Ureterscheide”, separators) separate the loops of the outer spirals. Importantly, the muscle fibers of the roof of the intravesical ureter sweep laterally to intersect the floor, and then both continue distally at the superficial trigone (trigonum vesicae urinariae), which is specifically a structure separated from the detrusor muscle. In the examination of the congenital ureteral muscle abnormalities, either quantitative or qualitative or both changes may occur. Right hydronephrosis and hydroureter/megaloureter should be addressed by right ureterostomy and cystoscopy for detection of PUV, and if the diameter of the ureter is ≥1 cm, it has been advised to perform a closure ureterostomy and bilateral reimplant (new ureterostomy) after ureteral tapering. Prune belly syndrome (Eagle-Barrett syndrome) refers to a congenital disorder characterized by partial or complete lack of the abdominal muscles, failure of both testes to descend into the

688

scrotum (bilateral cryptorchidism), and urinary tract malformations (Fig. 7.4). Posterior urethral valves (PUV/PUVs) are obstructing membranes, which are in the posterior male urethra as a result of abnormal intrauterine development. The Woodart classification entails PUV I–III: category I (renal dysplasia, oligohydramnios, lung hypoplasia, Potter facies, urethral atresia), category II (full triad features, minimal/unilateral renal dysplasia, no lung hypoplasia, tendency to progress to renal failure), and category III (incomplete/mild trial features, mild to moderate uropathy, no renal dysplasia, stable renal function, and absence of any form of pulmonary hypoplasia). PUV is the most common cause of bladder outlet obstruction in male newborns and occurs in ~1/8000 newborns. There are a few prognostic markers in assessing PUVs in the amniotic fluid. These biological markers include Na+   A and 182A  >  G, QK650E) (Goriely et  al. 2009). The occurrence of these somatic mutations harbors an oncogenic value having been linked to other cancers such as urinary bladder malignancy. If these mutations are transmitted as germline mutations, severe/lethal skeletal osteochondrodysplasia occur such as thanatophoric dysplasia or Costello syndrome. Milder ligand-­dependent mutations in FGFR3 can give origin to achondroplasia. Spermatocytic seminoma is a definitive diagnosis of middle-aged adults, but the study of this neoplasm is particularly crucial for the relationship with genes expressed during spermatogenesis that can speed up research in pediatric urology. The differential diagnosis of seminoma is crucial for any treatment option (Box 7.5).

7.7.1.3 Embryonal Carcinoma (Testicular EC or TEC) • DEF: CD30 expressing non-seminomatous germ cell tumor (pure or mixed with other tumor components) with early tendency to ­metastasize and harboring a worse prognosis than seminoma (Fig. 7.25). • GRO: TEC is heterogeneous with a solid gray appearance and multiple foci of hemorrhage and necrosis. • CLM: Embryonal carcinoma may be quite polymorphic showing solid (sheets), glandular, tubular, and papillary areas or alveolar nests of undifferentiated cells with vesicular nuclei, prominent nucleoli, pleomorphism, and high MI (i.e., epithelioid features of carcinoma). • IHC: (+) CK & CD30, OCT4, D2–40, and PLAP as well as (+) SALL4 and SOX2, but (−) CD117 and EMA.  TEC occurs most often mixed with other histologic types, being pure in ~ 5% of the cases only. Thus, thorough sampling is paramount. When pure, AFP is negative.

711

Box 7.5 Outstanding Practical Differential Diagnosis of Seminoma

1. YST: (−) Lymphocytes, flatlining, AE1/3+, AFP+, Schiller-Duval bodies 2. SCT: Elongated cell islands with palisading nuclei at the periphery, (+) “VINCAP.” 3. ECA: Glands/papillae, nuclear pleomorphism, crowding and irregularity, cytoplasm hyperdensification, indistinct cell membranes, (+) CK, CD30, OCT4, D2–40, (−) PLAP 4. SSE: Three-cell type tumor, (−) ITGCN, (−) OCT4, (−) PLAP, (+) CD117 5. DLBCT: Interstitial/intertubular NOT intratubular involvement, (−) ITGCN, (+) CD45, CD20, CD79a, PAX5, and (−) CD117, OCT4, D2–4, PLAP Notes: YST yolk sac tumor, SCT Sertoli cell tumor, ECA embryonal carcinoma, SSE spermatocytic seminoma, DLBCL Diffuse large B-cell lymphoma

A note should be made for CD30  in metastatic disease after chemotherapy, because this marker, especially if investigated in LNs or other possible metastatic sites, is frequently lost giving false-negative results that may influence the outcome of the patients. Chemotherapy may indeed alter the immunological phenotype. The characteristic histologic appearance may be retained forming the basis to support and emphasize the importance of H&E slides. PLAP is always a marker that needs to be ordered in investigating a testicular tumor, because, in the DDX between TEC and immunoblastic lymphoma/Ki-1 lymphoma, PLAP is determining. • PGN: The cure rate for patients with TEC is excellent if the proper chemotherapeutic regimens are employed with a careful follow-up evaluation post-therapy, including radiographic evaluation and serial AFP and β-hCG determinations.

7  Lower Urinary and Male Genital System

712

a

b

c

d

e

f

g

h

Fig. 7.19  The microphotographs (a) through (h) show an exaggerated myofibroblastic proliferation in a patient with orchi-epididymitis. Alk1 immunostain, quite specific for inflammatory myofibroblastic tumor, was negative

(not shown) (a–h, hematoxylin and eosin staining; a, ×200; b, ×200; c, ×100; d, ×200; e, ×200; f, ×200; g, ×200; h, ×400, as original magnifications, respectively)

7.7 Testicular Tumors

713

a

Teratoma

b

Lifestyle

Environmental Toxins

Genetic Anomalies

Polymorphisms

Teratocarcinoma

Embryonal Carcinoma

Testicular Dysgenesis YES — Embryonic structures

Totipotential Cell Differentiation

Leydig Cell Dysfunction

Differentiation toward embryonic structures

Germ Cell

Sertoli Cell Dysfunction Alteration of Germ Cell Differentiation

↓ INSL3 & Androgens

NO — Extra-embryonic structures

Cryptorchidism Seminoma/ Dysgerminoma

Yolk Sac Tumor

Hypospadias

Choriocarcinoma

Congential

c

d

e

f

Hypotestosteronemia Infertility Adult

TIN / Testicular Cancer Childwood / Adulthood

Fig. 7.20  In (a) and (b) are schemas for germ cell tumor differentiation, while (c) through (f) show seminoma and testicular intraepithelial neoplasia (germ cell neoplasia in situ or GCNIS) microphotographs (c–d, hematoxylin and eosin staining, c, ×100; d, ×400; e–f, Avidin-Biotin Complex anti-PLAP or placental alkaline phosphatase immunostaining, ×200, as original magnifications).

Positive markers othern than PLAP include OCT3/4, SALL4, D2-40 (podoplanin), NANOG, SOX17, and CD117. Of note, PLAP is positive in infantile germ cells until age one and CD117 is displayed in spermatogonia as patchy membranous or cytoplasmic staining. Both PLAP and CD117 can constitute common pitfalls

7.7.1.4 Teratoma Testicular teratomas are biologically different from the mature cystic teratoma of the ovary or dermoid cyst, being the first with low malignant potential and the latter thoroughly benign. On the other hand, it is well known that teratomas occurring in prepubertal boys are invariably benign, regardless of the composition, whereas those occurring after puberty possess a malignant

potential, even when they look like histologically mature and benign Fig. 7.21 and Fig. 7.22). • GRO: Heterogeneous tumors with multiloculated cysts and cartilage. Teratoma is indeed a different tumor possibly presenting as monodermal or pluridermal form. The monodermal forms are subdivided in “carcinoid” and “Primitive Neuroectodermal Tumor (PNET).”

7  Lower Urinary and Male Genital System

714

a

b

c

d

e

f

g

h

Fig. 7.21  Teratoma of the testis with the presence of all three germ cell layers (ectoderm, mesoderm, endoderm) as well as primitive neuroectodermal tissue portend to a diagnosis of a neuroblastoma, poorly differentiated

(hematoxylin and eosin staining; a, ×40; b, ×40; c, ×40; d, ×40; e, ×40; f, ×100; g, ×200; h, ×400, as original magnifications, respectively)

7.7 Testicular Tumors

715

Box 7.6 IHC Staining Panel for Granulosa Cell Tumors INA CALR LMW-CK (CAM 5.2) EMA LCA CGA

Inhibin A Calretinin Low molecular weight keratins Epithelial membrane antigen Leucocyte common antigen (CD45) Chromogranin A

+c +n/c +a – – –

Notes: aThe LMW-CK staining of GrCT is dot-like or globoid perinuclear staining

Box 7.7 IHC Staining Panel for SLCT (VINCAP) VIM INA WT1 CALR CD99 EMA LCA CGA

Vimentin Inhibin A Nephroblastoma Ag -> WT1 Calretinin and CKs PNET Ag -> CD99 Epithelial membrane antigen Leucocyte common antigen (CD45) Chromogranin A

The pluridermal forms contain elements of >1 germ cell layer (ectoderm, mesoderm, endoderm). • CLM: Mature and immature forms of teratomas are identified. Immature tissue involves the presence of immature neural tissue, i.e., neuroepithelium. Practically, PNET has all immature neural tissue. Various foci resembling different forms of CNS tumors, such as medulloepithelioma, ependymal neoplasms, or neuroblastoma, may be encountered considering that the malignant component of monodermal germinal origin may have several histological mimickers in the CNS. Cancerous part of germinal origin may constitute mixed tumors with teratoma and embryonal carcinoma, YST, seminoma, and choriocarcinoma. The combination of embryonal carcinoma and teratoma is designated as a mixed tumor of teratocarcinoma type. YST

microfoci can also occur. The identification of microfoci of YST may be based on Heifetz et  al.’s data. Recently, microfoci have been reported when one or more microfoci were seen, each occupying not more than two adjacent HPF (40X). If YST foci bigger than two adjacent HPF are found, the tumor should be classified as a malignant teratoma. The presence of a malignancy, e.g., adenocarcinoma, arises in a mature component labeled cancer as teratoma with malignant transformation (a lethal part of somatic origin). Finally, teratomas in children have no ITGCN, while teratomas in adults may contain ITGCN.  The grading used in immature teratoma of the ovary may be applicable to teratomas of the testis, although there are some controversial issues in adopting this ovarian grading system according to O’Connor and Norris (immature tissue 3 LPF/slide = grade 3).

7.7.1.5 Yolk Sac Tumor (YST)/ Endodermal Sinus Tumor (EST) • DEF: Non-seminomatous germ cell tumor recognized as a monomorphic teratoma mimicking embryonal yolk sac (Fig. 7.23). • GRO: YST is homogeneous, soft, microcystic, yellow-white, and mucinous. • CLM: Various patterns can be encountered explaining the organoid intermingling of epithelial and mesenchymal elements that are frequently observed. The presence of multiple histologic patterns is, on the other hand, a considerable aid in diagnosis. The histologic patterns are microcystic, endodermal sinus, solid, pseudoglandular, macrocystic, trabecular, alveolar, myxoid, sarcomatoid, polyvesicularvitelline, hepatoid, and parietal. Two additional ­ characteristics are of support in diagnosis, i.e. (non-­glycogen-­harboring, diastase resistant) intracellular hyaline globules (PAS+, D-PAS+) and Schiller-Duval bodies, which are constituted by a central vessel intimately rimmed by loose connective tissue that in turn is outlined by dysplastic epithelium (epithelial cells with atypia and abnormal

7  Lower Urinary and Male Genital System

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a

b

c

d

Fig. 7.22  The neuroblastoma identified in the previous teratoma panel of the testis shows positivity for CD56, synaptophysin, neuroblastoma marker, and Ki67  in (a),

(b), (c), and (d), respectively. S100 was focal positive (not shown), while chromogranin A was quite diffusely positive (not shown)

a

b

c

d

Fig. 7.23  The testis may also show yolk sac tumor (a, b, c) with alpha-fetoprotein positivity (d) (a–c, hematoxylin and eosin staining; d, anti-alpha-feto-protein Avidin-

Biotin Complex immunostaining; a, ×50; b, ×200; c, ×200; d, ×50, as original magnifications, respectively)

7.7 Testicular Tumors

architecture), all within a cystic space. Schiller-Duval bodies are seen in endodermal sinus pattern. Pink extracellular bands of eosinophilic BM material may also be encountered between the tumor cells. • IHC: (+) CK, AFP, GPC-3, SALL4, and PLAP. GPC3 (Glypican-3) is a protein encoded by the GPC3 gene (Xq26) in humans. GPC3 gene mutations have been identified in Simpson-Golabi-Behmel syndrome, a multiple congenitaly anomaly syndrome characterized by craniofacial, skeletal, cardiac, and renal abnormalities. • PGN: Generally, the prognosis for YST of the testis is good in infants but poor in adolescents and adults. It and depends on the size of the tumor, the stage of the tumor, the overall health of the patient, the location in the testes of the tumor, and the number of tumor masses/ nodules present within the testes.

7.7.1.6 Polyembryoma Polyembryoma is a very rare, probably quite sporadic non-seminomatous germ cell tumor show-

717

ing multiple embryoid bodies, i.e., an amnion-like cavity with embryo-like cellular invagination, which overlies a yolk sac-­like structure. It is seen as a mixed tumor with YST or TEC.  Diffuse embryoma is termed a mixed tumor constituted by embryonal, yolk sac, and trophoblastic elements in the systematic arrangement.

7.7.1.7 Choriocarcinoma • DEF: Non-seminomatous germ cell tumor accounting for 5% of all testicular neoplasms with syncytio- and cytotrophoblastic differentiation (Fig. 7.24). • GRO: A small, hemorrhagic, and often partially necrotic tumor (tumor-related necrosis). • CLM: Syncytiotrophoblast AND cytotrophoblasts are seen in choriocarcinoma. Both components need to be recognized. It is a biphasic, plexiform pattern with giant syncytial trophoblasts with large atypical nuclei that is intermixed with cytotrophoblasts. If the primary tumor regresses, there is necrosis and hemosiderin pigments, because of the extensive hemorrhagic component present in this tumor.

a

b

c

d

Fig. 7.24  Testis with choriocarcinoma, pure and mixed with other teratoma portions. In (c), HCG immunostain confirms the diagnosis of choriocarcinoma (a–b and d–f,

hematoxylin and eosin staining; c, Avidin-Biotin Complex immunostaining; a, ×50, b, 200; c, ×100; d–f, ×100, as original magnifications, respectively)

7  Lower Urinary and Male Genital System

718

e

f

Fig. 7.24 (continued)

a

b

c

d

e

f

g

h

Fig. 7.25  In this panel is shown a mixed embryonal carcinoma and teratoma (a–h), and CD30 immunostaining characteristic for embryonal carcinoma is shown in (g) and (h) (a–f, hematoxylin and eosin staining; g–h, Avidin-

Biotin Complex immunostaining; a, ×50; b, 400; c, ×50; d, ×400; e, ×400; f, ×100; g, ×50; h, ×400, as original magnifications)

7.7 Testicular Tumors

719

a

b

c

d

e

f

Fig. 7.26  The panel presented here shows the characteristic morphology of a Sertoli cell tumor (see text for detail) (hematoxylin and eosin staining, a–f, ×200, as original magnifications)

a

b

c

d

Fig. 7.27  In this panel, a Leydig cell tumor is shown with the characteristic architecture and cell morphology (see text for details) (hematoxylin and eosin staining; a, ×40; b–d, 200, as original magnifications)

7  Lower Urinary and Male Genital System

720

• HSS/IHC: hCG (+) in syncytial cells; PPB (±) due to both iron deposition and the degree of regressive changes. • PGN: The outcome is unfortunate because it is often disseminated at presentation.

7.7.2 Tumors of Specialized Gonadal Stroma Sex cord-stromal tumors include Leydig cell tumor, Sertoli cell tumor, classic type and sclerosing variant, as well as large-cell calcifying Sertoli cell tumor and granulosa cell tumor of adult and juvenile type.

7.7.2.1 Leydig Cell Tumor (LeCT) • DEF: Tumor of the sex cord-stromal tumor group of testicular cancers arising from Leydig cells.

a

AMH/ BMP-R

TGF β Activin

Cytokine Rec.

• EPI: Leydig cell tumor (LeCT) accounts for up to 1/20 of testicular neoplasms. Epidemiological studies have revealed that this tumor in 4/5 of cases occurs in adults, while 1/5 of the patients in children (Fig. 7.27). • CLI: Testicular mass with or without gynecomastia in adults, while children harboring LeCTs can manifest with endocrine symptoms, including virilization and gynecomastia. • GRO: Small (~ 1–3 cm), solid, sharply demarcated, lobulated, yellow-tan, relatively soft, and mostly single nodule. • CLM: The histologic patterns include solid (or sheets), trabecular (or cords), and pseudoglandular (or acinar) growth patterns of tumor cells, which are medium-sized cells with well-­ defined cell borders, round to oval nucleus with single prominent nucleolus, and abundant eosinophilic or clear acidophilic cytoplasm. Intervening stroma may be either

b

SMAD 1/5/8 NICD s3 FoxoL2 cleavage

PI3K

Foxo 1/3

GATA4

SMAD 3

AKT 4

GATA

Bcl2

Cyclin2

Fo

xo

1/

Apoptosis

3

P27

Rb

on

ati

fer

oli

Pr

c

Fig. 7.28  In this panel is depicted the molecular pathogenesis of juvenile granulosa cell tumor (a) and shown the characteristic morphology of a juvenile granulosa cell tumor with macrocysts of the testis and granulosa cells

d

(hematoxylin and eosin staining; b, ×12.5; c, ×50; d, ×50; e, ×50; f, ×50; g, ×200; h, ×200, as original magnifications)

7.7 Testicular Tumors

721

e

f

g

h

Fig. 7.28 (continued)

a

b

c

d

Fig. 7.29  The immunohistochemistry of the previous JGCT shows a positivity for inhibin A, CAM5.2 (low MW cytokeratins), calretinin, and the Ki67 proliferation anti-

gen in (a, b, c, and d), respectively (Avidin-Biotin Complex immunostaining; a, ×100; b, ×100; c, ×200; d, ×200, as original magnifications)

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edematous or fibrous. TEM shows mitochondria with tubular cristae, SER, and Reinke crystalloids (moderately electron dense, elongated structures with tapered ends) as well as some lipochromes. Lipochrome (Greek λίπος “fat” and χρῶμα “color”) is a naturally occurring fat-soluble pigment, one of the which most known is lipofuscin, which is a fatbyproduct associated with the decomposition of cellular membranes. • DDX: Nodular Leydig cell hyperplasia (multiple, each Ø  5  cm), necrosis, invasion of surrounding structures, MI (>5/10HPF), and LVI (+).

7.7.2.2 Sertoli Cell Tumors, Pseudotumors, and Related Lesions • DEF: Sertoli cell tumors (SeCT) account for up to 1% of testicular neoplasms and in ~85% of cases occur in adults, while ~15% of the patients are typically children. Generally clinical presentation is characterized by a testicular mass with gynecomastia, which is present in 1/3 of cases, and associated with accompanying impotence. Both symptoms are due to estrogen production by the tumor cells (Fig. 7.26). • GRO: SeCT are well-delimitated solid, pale yellow, or gray-yellow nodule. • CLM: Solid (or sheets), trabecular (or cords), and pseudoglandular (or acinar) growth patterns of tumor cells, although most of the cases show “solid and hollow tubules” containing Sertoli cells in the paucicellular stroma. Tumor cells have a polygonal

•

• •

•

nucleus and clear to pale to eosinophilic cytoplasm. TEM: Studies evidentiate Charcot-Buettner filaments, which are perinuclear aggregates of intermediate filaments. IHC: The immunohistochemistry of the granulomas cell tumors is shown in Boxes 7.6 and 7.7. PGN: Studies indicate that 10% of SeCTs in adults are malignant, while all pediatric cases are usually benign. Similar to LeCTs destructive features include large size (>5  cm), ­necrosis, invasion of surrounding structures, MI (>5/10HPF), and LVI (+). DDX: Seminoma, androgen insensitivity syndrome (aka testicular feminization), Sertoli cell nodules, Sertoli cell hyperplasia (hypoplastic tubules with Sertoli cell prominence), Sertoli cell adenoma (elongated tubules lined by Sertoli-like cells and centralized BM deposits), and sex cord tumor with annular tubules (Sertoli cell adenomarelated and male counterpart of the ovarian SCTAT, usually seen only in patients with Peutz-Jeghers syndrome).

Two variants are significant to mention, because they may occur in children and adolescents and include sclerosing Sertoli cell tumor, which is characterized by solid and hollow tubules embedded in a hypo-/acellular abundant sclerotic stroma) and large-cell calcifying Sertoli cell tumor (LCCSCT), which shows sheets and cords of tumor cells with copious cytoplasm separated by abundant fibrous intervening stroma with calcifications. LCCSCT is seen in patients with Peutz-Jeghers syndrome, Carney Complex, adrenal cortical hyperplasia, Leydig cell tumors (Fig. 7.27), and pituitary tumors. Carney complex is AD-inherited genetic disorder due to mutations of PRKAR1A (Protein Kinase c-AMPDependent Type I Regulatory Subunit Alpha) on 17q23–24, which may function as a tumor suppressor gene. The protein is a critical component of type I protein kinase A (PKA), which is also the main mediator of cAMP signaling in mammals. It belongs to the class of type 1A regulatory subunits of protein kinase A. Inactivating germ-

7.7 Testicular Tumors

line mutations of PRKAR1A are seen in 2/3 of patients with Carney Complex, labeled as LAMB (lentiginosis, atrial myxoma, blue nevi) or NAME (nevi, atrial myxoma, myxoid neurofibromas, ephelides). Other sex cord-stromal tumors include granulosa cell tumor and counterparts of ovarian surface epithelial tumors (serous, mucinous, endometrioid, clear cell, and Brenner). Granulosa cell tumor is characterized by lobular arrangements of large follicles lined by polygonal cells in an arrangement fashion, diffuse or solid pattern, and microcystic foci ± intervening fibrous stroma (Figs. 7.28 and 7.29). Mixed germ cell and sex cord-stromal tumor include also the unique type of gonadoblastoma, which is characterized by multiple roundovoid clusters of seminoma-like cells with dark sex cord (Sertoli-like) cells, peripheral palisading of small hyperchromatic Sertoli-­like cells, and irregular deposits of eosinophilic BM material. The study of the BM material indicates that

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this structure is similar to that seen in Sertoli cell adenoma and Sertoli cell ­ nodule. The gonadoblastoma should be considered definitely as premalignant, because it can progress to an invasive germ cell tumor, typically seminoma. Other tumors include tumors of the adrenogenital syndrome, adenocarcinoma of the rete testis, and hematopoietic neoplasms (lymphoma, plasmacytoma, leukemia, and capillary hemangioma). Malignant lymphomas are rare in the youth, while they are more characteristic of the elderly. The differential diagnosis may incorporate them if the patient has been transplanted (PTLD, posttransplant lymphoproliferative disorder). Lymphomas are bilateral in 20% against 2% of bilateralism observed typically in seminomas. Malignant lymphomas are generally germinal center and post-germinal center neoplasms. Finally, about the hematopoietic malignancies, testes are a “sanctuary” site for leukemia, and half of the patients who die with leukemia have leuke-

a

b

c

d

Fig. 7.30  In this panel are shown the morphology with strap cells of a classic embryonal rhabdomyosarcoma (see text for details) (Hematoxylin and eosin staining; a,

×12.5; b, ×200; c, ×200; d, ×200; e, ×200; f–h, ×630 as original magnifications)

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e

f

g

h

Fig. 7.30 (continued)

a

b

c

d

Fig. 7.31  The immunohistochemistry of the previous rhabdomyosarcoma shows a positivity for CD56 (a), CD57 (b), desmin (c–f), and MYF4 (g). The Ki67 prolif-

eration antigen is moderately high in (h) (a, ×100; b, ×100; c, ×400; d, ×400; e, ×100; f, ×400; g, ×100; h, ×50)

7.7 Testicular Tumors

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e

f

g

h

Fig. 7.31 (continued)

a

b

c

d

Fig. 7.32 The microphotographs show a spindle-cell rhabdomyosarcoma with gross photograph (a), cytology (b), and histology (c–h) Microscopically, tumor cells are arranged in lobules, small nests, microalveoli and single

file arrays. They are embedded in a matrix, which may exhibit abundant hyalinization. Scattered rhabdomyoblasts can be encountered and show eccentric nuclei and copious eosinophilic cytoplasm. Mitotic figures are frequent

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e

f

g

h

Fig. 7.32 (continued)

a

b

c

d

e

f

Fig. 7.33  The microphotographs of the previous spindle-cell rhabdomyosarcoma show positivity for vimentin (a), CD56 (b), CD57 ©, desmin (d, e), and MYF4 (f)

7.8 Tumors of the Epididymis

mic cells in the testis at the time of the autopsy. However, a recent Chinese study identified genitourinary lymphomas in children and youth as 20% of the patients studied. In this study, DLBCL was found in about 2/3 of cases, followed by mucosa-associated lymphoid tissue (MALT) lymphoma, Burkitt lymphoma, peripheral T-cell lymphoma, and plasmacytoma. PNET is an infrequent diagnosis but can occur and needs to be differentiated from germ cell tumors. PNET has been considered a variant of teratoma. It is CD99+, and neuroendocrine markers (NSE, CGA, SYN) may also be positive.

Box 7.8 Prostatic Carcinoma Mimickers

Hyperplasiabased:  Adenosis, sclerosing, adenomatous hyperplasia,  basal cell hyperplasia, BNH/ PNH-small gland type,  clear cell cribriform hyperplasia Anatomybased:  Cowper’s glands, mesonephric gland remnants, paraganglion, seminal vesicles/ejaculatory ducts, verumontanum glands Atrophyrelated:  Simple, sclerotic, streaming, cystic, post-atrophic hyperplasia Atypia, Reactive: Inflammatory, ischemic, radiation-induced Inflammationassociated:  Usual and granulomatous prostatitis, xanthogranulomatous prostatitis, malakoplakia Metaplasiaassociated: Mucinous, nephrogenic (adenoma)

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7.7.3 Rhabdomyosarcoma and Rhabdoid Tumor of the Testis Rhabdomyosarcoma of the Testis The most common rhabdomyosarcoma that occurs in the scrotal region in children and youth is the paratesticular spindle-cell variant of embryonal RMS, which has a better outcome than classic RMS (Figs. 7.30 and 7.31), although metastases to retroperitoneal LNs are seen in 40% of cases (Figs. 7.32 and 7.33). Rhabdoid Tumor of the Testis The rhabdoid tumor of the testis is similar to an extrarenal rhabdoid tumor in morphology and immunohistochemical phenotype (Figs. 7.34 and 7.35).

7.7.4 Secondary Tumors Metastasis to testis is not a typical event in children or young individuals.

7.8

Tumors of the Epididymis

7.8.1 Adenomatoid Tumor Adenomatoid tumor is a D2-40 (podoplanin) expressing benign epididymal tumor of the youth that can manifest as a mass with or without pain. Grossly, the adenomatoid tumor is small, solid, firm and white and contains tiny cysts. Microscopically, the adenomatoid tumor is unencapsulated with cords of flattened to cuboidal epithelium lining dilated channels and prominent stroma with smooth muscle and elastic fibers. Lining cells have vacuolated cytoplasm, and hyaluronidase-sensitive mucin staining is observed. IHC shows (+) AE1/3, CK7, CAM5.2, CALR, VIM and D2–40, as well as WT1. The occurrence of D2–40 may represent a pitfall for germ cell tumors.

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7.8.2 Papillary Cystadenoma Papillary cystadenoma is seen in individuals of families with von Hippel-Lindau syndrome (VHLS) and is small, well-delimitated cystic or solid tumor grossly. Microscopically, papillary structures with infoldings lined by tumor cells with clear cytoplasm are seen. The malignant counterpart is rare. VHLS is highly suspected when an individual harbors 1) multiple hemangioblastomas of the brain, spinal cord, or eye, or 2) one hemangioblastoma and tumors including clear cell renal cell carcinoma, pancreatic cysts, pheochromocytoma, endolymphatic sac tumor, or a epididymal cyst, or, alternatively, 3) multiple bilateral clear cell renal cell carcinomas are diagnosed.

7.8.3 Rhabdomyosarcoma The rhabdomyosarcoma (RMS) of the epididymis is a rare tumor with rhabdomyosarcomatous ­differentiation that recapitulates the aspects of the RMS described in the soft tissue chapter (Figs. 7.32 and 7.33). Most of these tumors are of spindle-cell type and harbor a better prognosis than the more classical type (e.g., embryonal rhabdomyosarcoma, ERMS).

7.8.4 Mesothelioma The tunica vaginalis is lined by mesothelial cells and participates all but the posterior aspect of the testis. There is a visceral layer around the testis and a parietal layer against the scrotal wall. The visceral layer of the tunica vaginalis blends imperceptibly with the tunica albuginea. Mesothelioma is extremely rare in children or young people and arises from tunica vaginalis of the testis and is usually of fibrous type. DDX includes adenocarcinoma of the rete testis. In rare cases, the tunica vaginalis may be involved by mesothelioma. However, scrotal mesotheliomas are less common than those found in the pleural or peritoneal compartments. While the mean age of patients at presentation is 53  years, the age range is broad, with some patients presenting in

adolescence and youth. Asbestos exposure has been linked to mesothelioma, but less than half of patients have such a positive history. Benign and malignant mesotheliomas have been reported. Concomitant malignant pleural or peritoneal mesothelioma may be present.

7.9

Inflammatory Disorders of the Prostate Gland

7.9.1 Acute Prostatitis Bacterial infection of the prostate gland may represent a medical emergency. It should be distinguished from other forms of prostatitis such as chronic bacterial prostatitis and chronic pelvic pain syndrome (CPPS).

7.9.2 Chronic Prostatitis Chronic prostatitis is a syndrome of low-pelvic pain and urinary symptoms. It occurs either with recurrent bacterial infection (chronic bacterial prostatitis [CBP]) or as pain without evidence of bacterial infection (CPPS). Sporadically, there may be positive bacterial cultures from prostatic secretions in CPPS, but there is no evidence that these are causative of the symptomology. An inflammatory “tumor” was diagnosed in a 4.5-yearold boy. The child suffered from pollakiuria, dysuria, secondary urinary incontinence, and decreased urine stream. Although pollakiuria associated with other signs and/or symptoms may be indicative of urinary tract infections (UTI), the isolated finding of pollakiuria is not associated with an underlying pathological condition. Pollakiuria can be triggered by the child’s heightened awareness of the urinary bladder. The urinary bladder is constantly filled up with urine produced by the kidneys, which determines it to progressively expand. This feeling stimulates the recently toilet trained child and may alarm the parents. Ultrasonography, magnetic resonance imaging, and transrectal tumor biopsy confirmed the diagnosis of an inflammatory tumor of the prostate with a size of up to 5  cm. Under antibiotic therapy, the clinical symptoms disappeared within 6 weeks. Ultrasonography per-

7.10 Prostate Gland Overgrowths

formed 3 months later exposed a healthy prostate with a residual midline cyst of 3x4mm. The inflammatory tumor can be explained by the embryologic development of the prostatic gland and the persistence of an intraprostatic cyst.

7.9.3 Granulomatous Prostatitis Chronic granulomatous disease (CGD) is a rare hereditary disease in which phagocytes have small cytologic tools to generate the superoxide radical (O−2) required to kill specific pathogens. Patients affected with CGD are outstandingly susceptible to a particular set of infections and granulomatous lesions. A 15-year-old boy with X-linked CGD revealed a necrotizing granulomatous inflammation in the prostate with computed tomography showing a fluid collection in the prostatic fossa, later determined to be a prostatic abscess and granulomatous prostatitis (Agochukwu et al. 2012).

7.9.4 Prostatic Malakoplakia of the Youth Malakoplakia is a rare inflammatory condition that is considered to develop secondary to a

Box 7.9  IHC Markers for Prostatic Carcinoma Mimickers

Basal cell markers: 34βE12, CK5/6, p63 Secretory markers: PSA, PSAP, CD57 NE markers: CGA, SYN, NSE, CD56, S100 (sustentacular) WBC-macrophage markers: CD45, CD3, CD20, CD56, CD68, MPO Others: AMACR Notes: Alpha Methyl Acyl Coenzyme A Racemase (P504S) is a mitochondrial/ peroxisomal enzyme identified from PrCa involved in β-oxidation of dietary branched-chain fatty acids and fatty acid derivatives.

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macrophagic inadequacy to digest the bacteria of chronic E. coli infection. Typically, malakoplakia affects the genitourinary tract but may also be observed in the colon, stomach, liver, lungs, uterus, bones, and skin in both children and adults (Diapera et al. 2009). Malakoplakia of the genitourinary system usually involves the urinary bladder and the prostate glands. Although malakoplakia of the prostate is mostly exclusively seen in elderly, there are occasional case reports in adolescents and youth. Malakoplakia may be clinically mistaken for prostatic benign tumors and malignancies.

7.10 Prostate Gland Overgrowths 7.10.1 Benign Nodular Hyperplasia of the Young and Fibromatosis Benign nodular hyperplasia (BNH) or benign prostate hyperplasia (BPH) is stromal and glandular hyperplasia of the prostatic gland and usually seen in men older than 40 years. The stromal component has small blood vessels, and clinically relevant prostate cancer may be ­ encountered in ~1.5% of resections for BPH.  Occasionally, it may be observed in individuals younger than 40 years (Berry et al. 1984). The fibromatoses of the prostatic gland are rare. They constitute a group of nonmetastasizing fibrous growths with a tendency to invade surrounding tissues and ambiguous biological behavior, varying from spontaneous regression to aggressive and devastating local growth (Scholtmeijer et al. 1988) (Fig. 7.11).

7.10.2 Rhabdomyosarcoma, Leiomyosarcoma, and Other Sarcomas (e.g., Ewing Sarcoma) Rhabdomyosarcoma (RMS) is the most common sarcoma identified in the first two decades of life (Figs. 7.12, 7.13, 7.14). Urinary bladder/prostate (BP) RMS accounts for 5% of all cases. Through efforts from multiple cooperative study groups inside of the Children’s Oncology Group and the International Society for Paediatric Oncology, survival has improved significantly. Gross find-

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Box 7.10  PIN Main Histologic Patterns

(1) Tufted:

Nuclear enlargement, prominent nucleoli, and some residual basal cells (2) Micropapillary: Finger-like arrangement of the acinar epithelial cells (3) Flat: Pseudostratified and linear arrangement of the acinar epithelial cells (4) Cribriform: Interconnecting intraluminal bridges of the acinar epithelial cells (5) Small cell: Small cells (6) Hobnail: Polarization of enlarged nuclei of secretory cells toward the lumen

ings and histology are not dissimilar from other locations. Positron emission tomography–computed tomography (PET-CT) scanning remains superior to conventional metastatic workup. All cooperative oncology groups agree on surgical biopsy for diagnosis and staging of BP RMS. Patients are then grouped and risk classified before receiving chemotherapy. Other sarcomas in pediatrics include PNET or Ewing sarcoma. Leiomyosarcoma is not seen in children or youth but needs to be differentiated from the spindle-cell variant of the rhabdomyosarcoma.

7.10.3 Prostatic Carcinoma Mimickers

7  Lower Urinary and Male Genital System

containing cells (+DPAS, Alcian Blue, mucicarmine) with bland cytologic features (bland cytology: small nuclei and inconspicuous nucleoli), radiating from a central excretory duct lined by pseudostratified epithelium, typically located within skeletal muscle. IHC: (+) CK, HMWCK (only ductal cells), SMA (basal cells at the periphery of the acini), (−) S100, PSAP, but (±) PSA.  DDX: mucinous prostate carcinoma (lumens never almost occluded as in Cowper’s glands) and foamy gland carcinoma (large atypical glands, mucin-negative). Mesonephric Gland Remnants  Mesonephric ducts are primordia (organs or tissues in its earliest recognizable stage of embryological development) for ejaculatory ducts, and primordial ureters and remnants can pose an unembellished DDX with carcinoma. In fact, mesonephric gland remnants show a vaguely lobular and/or infiltrative proliferation of crowded, small atrophic tubules with a single cell of bland-appearing epithelial cells with scant cytoplasm with neither nuclear enlargement or prominent nucleoli, which contain dense eosinophilic colloid-like secretion (unlike loose granular eosinophilic secretion of acinar carcinoma), (±) HMWCK, (−) PSA and PSAP. Paraganglion  Solid, rounded structure with small, solid nests of cells with clear to amphophilic, finely granular cytoplasm, often with a “Zellballen” arrangement with a prominent/delicate background of the vascular capillary network, (+) CGA, SYN, S100 (sustentacular cells), (−) PSA, and PSAP. DDX: G3-Pr-Ca or grade 3 prostate carcinoma (vascular background, the granular cytoplasm of the cells, IHC).

Seminal Vesicles/Ejaculatory Ducts  Paired, coiled, and tubular sex accessory glands located Mimickers of the prostatic carcinoma are crucial posterolaterally to the urinary bladder and antepitfalls. The mnemonic word “Harim” (Head of rior to Denonvilliers’ fascia (rectoprostatic fasthe 3 of 24 priestly departments instituted by cia) and rectum with ejaculatory ducts arising King David) may be used (Box 7.8). from each seminal vesicle medially surrounded Cowper’s Glands  Well-circumscribed lob- by a band of loose fibrovascular connective tissue ules (lobular architecture) of small, compact and running through the base of the prostate to tubuloalveolar glands constituted by mucus-­ the urethra. Histologically, there is an adenosis-

7.10 Prostate Gland Overgrowths

like pattern with large dilated glands and peripherally small glands with nuclear hyperchromasia and pleomorphism, but no mitoses and the presence of prominent golden-brown lipofuscin granules. IHC: (+) HMWCK, p63, (−) PSA, PSAP.  DDX: Pr-Ca, benign prostate tissue, PIN-III. Verumontanum Mucosal Gland Hyperplasia (VMGH)  Suburethral (adjacent to the posterior prostatic urethra) small proliferation of uniform, closely packed, round small acini with an intact basal cell layer (+ HMWCK), bland-appearing cytology, and inconspicuous nucleoli and prominent intraluminal corpora amylacea and distinctive brown-orange secretions and intracytoplasmic lipofuscin pigment. DDX: G1-PrCa or grade 1 prostate carcinoma (infiltrative and haphazard arrangement of the atypical glands without the peculiar intraluminal concretions characteristic of VMGH). Atrophy  A common mimicker of the adenocarcinoma of the prostate with possible occurrence adjacent to any neoplastic proliferation with a wide age range (from second decade to elderly). The anatomic prostate zones are Central (CZ), Peripheral (PZ) and Transitional (TZ). Atrophy occurs in PZ > CZ > TZ without evidence of an increased risk of harboring or developing a prostate malignancy. There are four patterns, including simple, sclerotic, streaming, and cystic as well as post-atrophic hyperplasia. There are glands arranged in multiple lobules separated by fibrotic stroma with well-formed lumens and cells with hyperchromatic nuclei, small/inconspicuous nucleoli, scant cytoplasm, and fragmented basal layer (+HMWCK, p63). DDX: Atrophic variant of Pr-Ca (prostate carcinoma). In post-atrophic hyperplasia, there is a combination of atrophic acini and acini lined by cuboidal secretory cells with abundant clear/amphophilic cytoplasm and increased N/C ratio.

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Inflammation  Usual and granulomatous prostatitis, XGP (xanthoma/xanthogranulomatous prostatitis), and malakoplakia. Metaplasia Mucinous gland metaplasia: The lobular architecture of mucinous glands lined by tall columnar cells, small basal nuclei with inconspicuous nucleoli resembling Cowper’s glands (+DPAS, AB, MCM -PSA, PSAP). Nephrogenic adenoma/metaplasia: Small, solitary proliferation of gland-like structures mostly involving the urinary bladder associated with radiation, surgery, stones, instrumentation, intravesical thiotepa, BCG, and renal TX and grossly presenting as papillary, polypoid, friable, and velvety lesion and microscopically in four histologic patterns, including tubular, cystic, polypoid-­papillary, and diffuse. Microscopically, there are often small hollow tubules with low columnar cells ± hobnailing and reactive atypia, ± colloid-like secretions, and ± surrounded by a thickened hyaline sheath. IHC: ± PSA, PSAP (tubular secretions), + AMACR, + HMWCK. Thiotepa is an organophosphorus compound (“alkylating agen”) with the formula SP(NC2H4)3 and anti-cancer properties. There are several types of alkylating agents: Mustard gas derivatives (mechlorethamine, cyclophosphamide, chlorambucil, melphalan, and ifosfamide), Ethylenimines (thiotepa and hexamethylmelamine), Alkylsulfonates (busulfan), Hydrazines and Triazines (altretamine, procarbazine, dacarbazine, and temozolomide), Nitrosureas (carmustine, lomustine and streptozocin), and Metal salts (carboplatin, cisplatin, and oxaliplatin).

Hyperplasia Adenosis, sclerosing: Circumscribed nodular proliferation of small- to medium-sized acini (± poorly formed glands and single cells) with thick eosinophilic BM separated by a cellular spindle cell-/edematous stroma (lightly basophilic), mainly in the TZ, and constituted by clear cells Atypia  (Reactive), which includes inflammatory-­ with abundant cytoplasm and bland-appearing induced atypia, ischemic-induced atypia, and nuclei with inconspicuous nucleoli (±PSA, radiation-induced atypia. PSAP) and a fragmented basal cell layer

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(+HMWCK, p63, SMA, MSA, S100). TEM: Myoepithelial cell differentiation (abundant microfilaments with prominent dense bodies). DDX: WD-PrCA (lobular architecture and IHC cell markers). Adenomatous, hyperplasia: Circumscribed nodular proliferation of peripherally closely packed small acini with centrally elongated, larger glands with papillary infolding set in a paucicellular stroma, mainly in the TZ, periurethral area, and apex, and constituted by clear cells with abundant cytoplasm and bland-appearing nuclei with inconspicuous nucleoli (± PSA, PSAP) and a fragmented basal cell layer (+HMWCK, p63, SMA, MSA, S100). DDX: WD-PrCA (haphazard gland architecture, often at right angles to each other, enlarged nuclei, large nucleoli, the absence of basal cell layer). Basal cell hyperplasia: Nodular and diffuse expansion of uniform round (occasionally ­cribriform) glands set in acellular/paucicellular stroma is present. It is part of the spectrum of BPH, mainly in the TZ and PZ with inflammation, ranging from incomplete with still present residual small lumina lined by secretory cells (± PSA, PSAP) surrounded by multiple layers of basal cells (multilayering) (+HMWCK, p63) to complete forms with solid nests of cells with hyperchromatic nuclei and lack of luminal differentiation. BCH with prominent nucleoli is a BCH variant with prominent nucleoli and part of a continuum of BCH and adenoid basal cell tumor (+ HMWCK).Well-formed lamellar calcifications and intracytoplasmic eosinophilic globules may be found. DDX: Ca (nodular arrangement, +NH, cellular uniformity, ± prominent nucleoli, +34βE12-multilayering). BNH/PNH-small gland type: Very few cases of youth with benign nodular hyperplasia have been described. Clear cell cribriform hyperplasia: It is a peculiar form of nodular hyperplasia with the cribriform arrangement, but without atypia, mainly in the TZ and after androgen deprivation therapy, and constituted by the crowded proliferation of complex glands with clear cells, cribriform and uniform lumina, evident basal cells (+HMWCK), and small uniform nuclei with inconspicuous nucleoli.

7  Lower Urinary and Male Genital System

DDX: PIN-high grade (prominent nucleoli and no basal cell layer) and cribriform adenocarcinoma (lack of low-power nodularity and basal cells and the presence of significant cytologic atypia). The immunohistochemical markers for mimickers of the prostatic carcinoma are shown in Box 7.9. (Cyto-)keratins (CK or K) are intermediate filaments of the cytoskeleton, and each type I of acidic CK (Moll type I), CK 10, 15, 16, and 19, forms a pair with a type II of basic CK (Moll type II), CK 1–8. All epithelial cells contain at least two CK (exception is CK19, which is unpaired). AE1/3: AE1 reacts with acidic (Moll type I) CK 10, 15, 16, 19, whereas AE3 reacts with basic (Moll type II) CK 1–8. AE1/3 does not detect CK17 and CK18. 34βE12 (HMWCK): CK 1, 5/6, 10, 14 useful to stain basal cells in prostatic glands and to differentiate in situ neoplasm. CAM5.2 (LMWCK): CK 8, 18, 19, while PAN-CK entails high and low molecular weight cytokeratins. Other tumorlike conditions include sarcoma-­ like nodules; exuberant stromal reaction; melanosis; urethral polyps, which occur in children and youth; and amyloid nodule.

7.10.4 Prostatic Intraepithelial Neoplasia (PIN) Prostatic intraepithelial neoplasia (PIN) is a preinvasive form of prostatic adenocarcinoma and usually identifiable on low power by light microscopy. The glands have standard architecture but have the acronym “PNH”: 1 . Papillary projection into the lumen 2. Nuclear enlargement with overlapping and stratification 3. Hyperchromasia The PIN is almost exclusively confined to PZ, and the hallmark for HGPIN (high-grade PIN) is the presence of prominent nucleoli. The PIN main histological patterns are shown in Box 7.10.

7.10 Prostate Gland Overgrowths

Other patterns include apocrine, foamy gland; mucinous, Paneth cell-like, pleomorphic, signetring cell; and small cell neuroendocrine. The bubbly pattern is made of pale/foamy cells with voluminous xanthoma-like cytoplasm that can build solid and cribriform patterns. The desquamating apoptotic model shows desquamating acinar cells containing apoptotic nuclear material that coalesce in the luminal gland giving rise to basophilic intraluminal masses. The mucinous model shows mucinous distension of glands. There is flat epithelial lining. The intraluminal blue-stained mucinous secretions are +DPAS and AB (periodic acid Schiff reaction with diastase treatment and alcian blue stain). Grading: PIN I, II, or III or low (I) and high (II or III) grade with prominent nucleoli making at least PIN II. However, there is poor reproducibility for a PIN of low grade, which seems to be found in 70% of patients, classified as “normal.” Conversely, HG-PIN indicates up to a 70% chance that in this prostatic gland, there may be a coexisting adenocarcinoma elsewhere.

7.10.5 Prostate Cancer of the Young Prostate cancer in individuals with age 40 years or younger is sporadic. Reyes and Slutsky reported on two male patients on moderately ­differentiated prostatic adenocarcinoma aged 35 and 40  years that initially manifested as lymph node metastasis of an unknown origin and reviewed the topic in the oncologic community. A few more cases have been published in the scientific literature. It is probably unknown the actual incidence of prostatic carcinoma and PIN in this age group. However, some studies have tried to shed light on this controversial topic. In healthy men aged 20–30  years who died from trauma or homicide in Detroit, the incidence of some PIN was found 8%. PSA seems to be probably questionable in this age group. Searching in the SEER (Surveillance, Epidemiology, and End Results Program of the National Cancer Institute) database, an authoritative source for cancer statistics in the US., 1673 cases of prostate cancer in men aged 35–44 years out of 453,195 total cases

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have been identified, although most of them have low-grade neoplasms. Interestingly, the 10-YSR was equivalent to that of male individuals whose diagnosis was made at older ages. Only a subset of young men with high-grade malignancy behaves worse than older men with the high-­ grade disease. Thus, a natural consequence of it is to think that the outcome of these young men was better than older men indicating that young age group at diagnosis does not portend a poor prognosis as observed in breast cancer for young women. Overall, the approximate incidence of prostate cancer among men 40  years old or younger seems to be around 1% according to most relevant literature data, but the incidence seems to be lower if data from single hospitals or institutions are analyzed. In 1980, prostate cancer was reported in a young boy of 11 years age and summarized the clinicopathologic characteristics of prostatic carcinoma in infant and adolescents (Shimada et al. 1980). It was thought that the aggressive behavior of prostate cancer in young individuals could be related to the undifferentiated histology. In another retrospective analysis by Astigueta et al. (2010), a remarkable number of 41 patients of prostate cancer under 50 years of age were identified and carefully evaluated from 1952 to 2005. All patients had bone metastasis. Also, 20 patients had retroperitoneal metastasis, 3 patients had mediastinal lymph node metastasis, 4 had liver, 3 had lung, and 1 patient had testicular metastasis. All prostatic biopsies were reported as poorly differentiated or undifferentiated, and according to current classification, predominant Gleason score was 9. Patients received different kinds of palliative treatment like bilateral orchidectomy and adrenalectomy in the 1970s and oral or parenteral ADT (androgen deprivation therapy) in recent years. Additionally, patients received palliative radiotherapy and other symptomatic therapy. Median survival was 16.1 month, and all patients died of progressive disease. It has been controversially discussed that with every 10-years’ time, the PIN will progress further to become invasive eventually and will manifest in 4/5 of men later in life. About the genetics familial clusters of prostate cancer (defined as the presence in at least two family

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members) seem to be seen in about 15%–25% of cases and some hereditary form of prostate malignancy compatible with a Mendelian inheritance in up to 1/10 of patients. Genetic heterogeneity is explained on the basis that in some families with recurrent prostatic malignancy, aggregation of several tumors may suggest the involvement of common predisposing genes, while in other families, the genetic component appears to be polygenic. Some single nucleotide polymorphisms (SNPs) have been associated with an increased risk of developing a prostatic malignancy. A unique role of the pediatric pathologist is reserved for prostatic malignancy, which includes investigating PIN/cancer in the young at the autopsy, notably, if a promoter factor (e.g., inflammation for congenital GU anomalies) is added to an initiator factor (e.g., genetic alteration or abnormal SNPs). Moreover, he/she needs to provide tissue material for morphologic, epidemiological studies and NGS studies and the exclusion of the relatively most frequent tumor of the prostatic gland in childhood and adolescence (rhabdomyosarcoma). • DEF: 2nd most common malignancy in men (following skin cancer) in developed countries, blacks>white and rare in Asians and no carcinoma if prepubertal castration and low incidence with hyperestrogenism (liver cirrhosis) and no association with STD, smoking, occupational exposure, diet, and BNH. • EPG: Genetics: BRCA2, AR, PI3K/AKT, PTEN, ERG/TMPRSS. • CLI: DRE (digital rectal examination), TUUS (3D trans-urethral ultrasound), and elevated PSA (> 4 or increasing over time) are useful, and PrC secretes 10x the PSA of healthy tissue, but routine screening programs using PSA with or without DRE do not significantly affect mortality overall or from prostate cancer. Consequently, the value of routine screening has been challenged and is controversially debated in medical prevention. • DDX: BNH, granulomatous prostatitis, tuberculosis, infarct, and lithiasis other than prostatic carcinoma, and DDX of elevated PSA

7  Lower Urinary and Male Genital System

include BNH, prostatitis, infarct, trauma (biopsy, TURP), other tumors (e.g., salivary duct carcinoma). The diagnosis of prostatic adenocarcinoma is based on biopsy and evaluation using a specific score called “Gleason score” based on histologic patterns and considering several tips arising from years of practice of pathology colleagues working with the lower uro-genital system. 1. Transrectal biopsies have been found to be more accurate than transperineal biopsies. 2. “Six-pack” model: Six samples from selected portions of the prostate, using a spring-­ loaded 18-gauge biopsy, have a little false-­ negative rate of ~10% due to sampling error and is further reduced when using 12–18 samples as used in many centers. 3. Gleason score in biopsy mostly correlates with the Gleason score of the final report coming out from prostatectomy specimens (same: ~ 60%, ± 1 unit: ~90%). 4. More errors occur with Gleason scores 5 or 6, which tend to underestimate prostatectomy Gleason score. 5. In 2005 a new consensus was reached to change some assignments of histologic pattern to a specific Gleason pattern. Consequently, Gleason score of needle biopsies  3 are needed if atypical glands are encountered. 9. Pathology review of core biopsies is strongly recommended before radical prostatectomy is performed. 10. A needle biopsy is considered unsatisfactory if neither prostatic glands nor stroma are found. The presence of stroma only may indicate a hyperplastic stromal nodule and should be considered satisfactory. 11. A single histologic level misses approxi mately 1/4 of total length of a core, and pre-­ embedding cores techniques may be used (e.g., “stretch” method) to yield more tumor/ core, more cores with tumor, more cases with tumor, fewer atypical small acinar diagnoses, and fewer cases with 3 mm or less of Gleason 6 or less cancer. 12. The assessment of intraluminal, amorphous eosinophilic material should be carried out ruling out decapitation-like secretions or fractured corpora amylacea. Also, collagenous micronodules are considered accumulations of paucicellular, eosinophilic, fibrillar stroma impinging on acinar lumens. Moreover, glomerulations are defined as rounded epithelial tufts within glands reminiscent of renal glomeruli and are not observed in benign lesions. 13. In a core, features suggestive of malignancy include prominent nucleoli, marginated nucleoli, multiple nucleoli, blue-tinged mucinous secretions, intraluminal crystalloids, intraluminal amorphous eosinophilic

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material, collagenous micronodules, glomerulations, perineural invasion, and fatty tissue invasion. 14. HMWCK and p63 detect basal cells, which are lacking in prostatic adenocarcinoma. However, it is diagnostic of malignancy, if there is a high pretest suspicion of carcinoma, and positive control in benign glands should be demonstrated. Positive staining is useful in identifying benign mimickers of prostatic adenocarcinoma. 15. AMACR is sensitive and specific for prostate carcinoma on needle biopsies and has been recommended to use a combination of P504S and 34βE12 to diagnose limited prostatic adenocarcinoma, but negative staining with P504S in suspicious foci does not necessarily indicate a benign diagnosis. In fact, AMACR may stain hyperplastic nodules and benign glands close to TZ prostatic adenocarcinoma. 16. Minimal prostatic adenocarcinoma is a challenging diagnosis and should be reserved after careful consideration and probably approved by another urological pathologist. It relies on some common malignant features (nucleomegaly, infiltrative growth pattern, intraluminal secretions, prominent nucleoli, associated HG-PIN, amphophilic cytoplasm, hyperchromatic nuclei, and intraluminal crystalloids). 17. Uncommon features of minimal prostatic adenocarcinoma include perineural invasion, collagenous micronodules, and mitoses. 18. DDX should always include adenosis, atrophy, and high-­grade PIN primarily before a diagnosis of cancer is given. Tumor extension occurs locally through the seminal vesicles and bladder base, rarely via prostatic urethra, whereas rectal invasion is rare due to the Denonvilliers’ fascia (rectoprostatic fascia). Seminal vesicle invasion occurs by three modalities including (a) direct spread along ejaculatory duct complex; (b) spread outside the prostate, through the capsule, and then into a seminal vesicle; and (c) isolated deposits of tumor in the vesicle with no apparent contiguity to the primary lesion diagnosed in the prostate.

7  Lower Urinary and Male Genital System

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a

b

c

d

e

f

Fig. 7.34  The microphotographs of this rhabdoid tumor of the testis show a Diff-Quick cytology in (a) and characteristic morphology in (b) through (f). The tumor is characterized by solid sheets of large cells with eosinophilic

cytoplasm, laterally displaced nucleus, and prominent nucleoli. Myxoid, hyalinized, and/or pseudoalveolar areas are frequently encountered

PrAC that is incidentally detected is considered clinically significant if total tumor volume is ≥0.5  ml, Gleason grade 4 or 5, extraprostatic extension, seminal vesicle invasion, and lymph node metastasis present. In cystoprostatectomy specimens for bladder cancer, incidental prostatic adenocarcinoma is clinically significant in about 1/2 of cases. Metastases of PrAC involve usually skeletal system (osteoblastic, upward spread: from lumbar to cervical via Batson’s vertebral venous plexus (a complex valveless network of veins located near the vertebral column) and

accompanied by hypocalcemia, hypophosphatemia, and increased alkaline phosphatase), lung/ pleura, liver, adrenals and lymph nodes and testes (breast metastasis if estrogen therapy is performed, and the carcinoma may metastasize to male papillary breast cancer), and dura. Markers of prostatic origin include PSA, PAP, and NKX3.1 (NK3 Homeobox 1), which is recently identified marker of prostatic origin in metastatic tumors. NKX3-1 is a protein coding gene and genetic alteration shave been found in Chromosome 8p Deletion and Rete Testis

7.10 Prostate Gland Overgrowths

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a

b

c

d

e

f

g

h

Fig. 7.35  The immunostaining microphotographs highlight the positivity of the rhabdoid tumor for vimentin (a), EMA (b), AE1–3 (c), synaptophysin (d), calretinin (e, f),

WT1 (g), and Ki67 (h) (a, ×200; b, ×100; c, ×200; d, ×400; e, ×100; f, ×400; g, ×100; h, ×100 as original magnifications)

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Box 7.11 Penile Noninvasive Squamous Lesions (HPV and Non-HPV Related) Disease Condyloma acuminatum

Etiology HPV types 6 and 11

Gross Cauliflower-like nodule at urethral meatus, fossa navicularis, or corona of glans

Bowenoid papulosis

HPV types 16 and 18

Bowen disease

HPV types 16 and 18 HPV types 16 and 18 Chronic inflammation

Multiple shiny erythematous papulae that may coalesce at penis shaft and perineum Single scaly plaque at penis shaft or scrotum Shiny red erythematous plaque(s) at glans and foreskin White-gray plaque

Erythroplasia of Queyrat Pseudoepitheliomatous hyperplasia

Adenocarcinoma. Recurrence after radical prostatectomy of PrAC is 40 months as median interval, and often there are no visible histologic features of malignancy. Subsequently, lower threshold for diagnosis should be kept in mind because atypical glands should be absent. Prognostic factors include stage, Gleason score, surgical margins, preoperative PSA, perineurial invasion, ALVI, and size of LN metastasis. However, patients younger than 20  years usually have obstructive symptoms, advanced stage, high grade, inadequate response to treatment, and survival 3 μm is quite specific for malignancy, but also >1 μm is suggestive for neoplasm). An HG-PIN is generally observed in 4/5 of carcinomas. Mitoses are not usually present, apart from in high-grade tumors. Loss of basal cells accompanies the malignant transformation of acini, and the immunohistochemistry may play a significant role. The most common pattern is infiltrative medium-­ sized glands (Gleason 3), but Gleason 1–2 may be found in TZ or CZ.  The cribriform pattern may appear intraductal with preserved basal cell layer but is invasive, and correct grading assessment is vital for the management. Gleason 3 should be given if cribriform glands harbor smooth borders, while in Gleason 4 the cribriform glands should have uneven edges. In the experience of many urinary pathologists, this last statement regarding Gleason 4 is the most frequent occurrence in routine practice. A single cell infiltration (Gleason 5 pattern) may resemble lobular carcinoma of the breast.

7.11 Inflammatory and Neoplastic Disorders of the Penis

Box 7.12 Pearls and Pitfalls of Penile Malignancies

• In the report for both epithelial and mesenchymal malignancies, it is essential to specify the location (glans, foreskin mucosal surface, foreskin surface, coronal sulcus, the skin of the shaft, and penile urethra). • Surgical procedures that can be performed for penile lesions include incisional biopsy, excisional biopsy, partial penectomy, total penectomy, and circumcision. • There are three different foreskins. These types include the short type, in which the orifice of the preputium is located behind the coronal sulcus, the medium type, in which the hole is between the corona and the meatus, and the long foreskin, when the glans is covered in full, and there is no possibility to identify the meatus unless the foreskin is not retracted. • If >2 ipsilateral inguinal LN (+) ⇒ high probability for (+) in contralateral inguinal LN and ipsilateral pelvic LN. • Resection margins of a penectomy specimens are three and include (1) the margin involving the proximal urethra and the surrounding periurethral cylinder (epithelium, lamina propria, corpus spongiosum, and penile fascia), (2) the margin affecting the proximal shaft (corpora cavernosa, tunica albuginea, and Buck’s fascia), and (3) the cutaneous margin with underlying corporal dartos. • Resection margins of circumcision specimens need a full histologic examination of the coronal sulcus margin and cutaneous margin. • LVI subclassify T1 tumors in T1a and T1b.

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• TRT: It is variable and depends on contingent factors: → Radical prostatectomy (not warranted if positive pelvic nodes) → Brachytherapy (radioactive seeds) → External beam radiation therapy → Watchful waiting (for low-grade tumors, localized tumor, or limited life expectancy) → Chemotherapy or hormonal treatment (LHRH analogs or luteinizing hormonereleasing hormone agonists, antiandrogens, orchiectomy, because most tumors are androgen sensitive initially) for metastatic neoplastic disease

7.10.6 Hematological Malignancies Recurrence of acute lymphoblastic leukemia has been reported in adolescence and youth. However, leukemia can manifest or relapse in the prostate.

7.10.7 Secondary Tumors Secondary tumors are practically inexistent in pediatric age, apart from metastases from rhabdomyosarcoma of the epididymis.

7.11 Inflammatory and Neoplastic Disorders of the Penis 7.11.1 Infections Cystic anomalies need to be differentiated from inflammatory processes (Fig. 7.36). Infections can determine balanitis, posthitis, or balanoposthitis (Fig. 7.37).

7.11.1.1 Balanoposthitis Balanitis refers to inflammation of the glans, while posthitis is the inflammation of the prepuce, but most commonly both conditions are ­associated,

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and the term “balanoposthitis” is widely used. It affects about 1/10 of the uncircumcised male infants or children, possibly related to poor hygiene, aeration, irritation by smegma (Greek: σμῆγμα, “unguent, soap”). Balanoposthitis is usually a nonspecific inflammation of the glans and prepuce due to an infection with streptococci, staphylococci, N. gonorrhoeae, Gardnerella vaginalis, and Trichomonas particularly in uncircumcised infants and children. Balanoposthitis may be a mimicker or a form of presentation of penile cancer, which is typically a malignancy of the middle-age and elderly but can occur in patients as young as 30 years old.

7.11.1.2 Syphilis Treponema pallidum-induced infection with three stages at level of the penis, including primary syphilis (firm, erythematous papule ­ located on glans, which ulcerates aka “hard chancre” with a characteristic lymphocytic and plasmacytic infiltrate, endothelial cell proliferation, and capillaritis), secondary syphilis (flat, maculopapular, aka condylomata lata), and tertiary syphilis (penile syphilitic granulomas, aka “gummas”). 7.11.1.3 Lymphogranuloma Venereum Chlamydia trachomatis-induced short-lived painless papula or ulcer, which evolves into suppurative inflammation of the regional (inguinal) lymph nodes. 7.11.1.4 Others Other infections of the penis include granuloma inguinale or donovanosis, which is due to an infection with K. granulomatis (aka Calymmatobacterium granulomatis) affecting the skin and mucous membranes in the genital region and resulting in nodules that evolve into beefyred destructive ulcers, Herpes genitalis (HSV 1 and 2), and molluscum contagiosum (MCV, a DNA poxvirus). Moreover, pilonidal sinus of the penis is another possible but rare infection and reported to be recently caused by Actinomyces spp. In young individuals, granulomatous disease following intravesical BCG for urinary bladder

7  Lower Urinary and Male Genital System

carcinomas has also been described. A pilonidal cyst or sinus is an acquired pathology characterized by an abscess or a chronic draining sinus, which typically contains hairs and can manifest as a localized inflammation with pain, infection, and redness but also with chronic ulceration or a draining sinus or abscess formation. In the penis, it has been observed in the midline pits in the natal cleft. Dead or distorted hair pushed by mechanical forces into tiny abrasions or scars in the penile skin (coronal sulcus) form a one-ended tunnel where bacteria may collect and generate. A foreign-­body giant cell reaction with multi-nucleated giant cells of foreign body cell type is typical. The biological basis for HIV infection of the circumcision has also been recently discussed. However, the discussion of circumcision on young boys is not going to settle down so smooth and is controversially addressed by several medical panels.

7.11.2 Non-infectious Inflammatory Diseases Non-infectious inflammatory diseases include the most common balanitis xerotica obliterans, the quite obscure balanitis circumscripta plasmacellularis, and the Peyronie disease.

7.11.2.1 Balanitis Xerotica Obliterans Balanitis xerotica obliterans (BXO) (lichen sclerosus) is inflammation with a striking equivalent to lichen sclerosus (et atrophicus) of the vulva of elderly. Grossly, there is a gray-white area of partial atrophy, which shows under the lens thinning of the epidermis and loss of the lamina propria structures such as diffuse fibrosis or a subepithelial hyaline band delimitated in depth by a lymphocytic infiltrate. 7.11.2.2 Balanitis Circumscripta Plasmacellularis Balanitis circumscripta plasmacellularis (Zoon’s Balanitis, BCP) is the primary differential diagnosis with erythroplasia of Queyrat and is characterized by well-circumscribed lesions, which are orange-red with a shiny appearance and multiple

7.11 Inflammatory and Neoplastic Disorders of the Penis

pinpoint red spots (aka “cayenne pepper spots”) associated with pain, irritation, and discharge. Microscopically there are epidermal atrophy, loss of rete ridges, “lozenge keratinocytes,” and spongiosis as well as a plasmacytic infiltrate at the subepidermal location. The “lozenge keratinocytes” are rhomboidal elongated keratinocytes. The etiology is unknown, although some argue against a distinct entity, while some other physicians recall Mycobacterium smegmatis as the leading case.

7.11.2.3 Peyronie Disease Peyronie disease is a localized fibromatosis between the corpora cavernosa and tunica albuginea, which limits the movements of these structures past each other during an erection and is visualized with a curvature toward the side of the lesion. In 2/3 of cases, Peyronie disease is idiopathic, but either a blunt penile trauma or a trauma incurred during sexual intercourse has been identified in some cases, and some conditions are also associated with this fibromatosis such as diabetes mellitus, hypertension, d­yslipidemia, ischemic cardiomyopathy, smoking, excessive alcohol consumption, and radical prostatectomy. A study investigating the possible development of Peyronie disease in boys following radical prostatectomy for ERMS does not seem to have been performed. Peyronie disease is probably related to other conditions, including Dupuytren contractures, Ledderhose disease, and tympanosclerosis.

7.11.3 Penile Cysts and Noninvasive Squamous Cell Lesions Penile cysts may be distinct in congenital and acquired. The congenital cysts are usually epidermoid and typically originate from the median raphe. The site of origin is at any level from the urethral meatus to the base of the scrotum. It is thought that they occur from epithelial rest incidental inclusions to incomplete closure of urethral or genital folds. Alternatively, an epithelial split off growths after primary closure of the folds. The cysts can extend to the pelvis but have no urethral communication. Conversely, the acquired cysts are generally inclusion cysts after penile surgery

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(e.g., hypospadias repair or circumcision) (Fig.  7.36). STDs are the primary relationship with noninvasive squamous lesions of the penis, and HPV plays a significant role. Bowenoid papulosis occurs in patients younger than 35  years, unlike Bowen disease, which is more characteristic of patients older than 35 years. Both conditions need to be carefully discriminated against, because the malignant potential is entirely different, being the latter a squamous cell carcinoma in situ (CIS). On the other hand, Queyrat erythroplasia is a CIS of the elderly and should not be part of the central panel of differential diagnoses. Moreover, up to 1/3 of Bowen disease lesions will progress to invasive SqCC, and 1/3 of patients harboring this condition have some association with visceral malignancy (lung, GI tract, or urinary tract), unlike Queyrat erythroplasia, which needs to be differentiated by the Bowenoid papulosis. This entity is a skin lesion characterized by pigmented verrucous papules on the body of the penis. Bowenoid papulosis is associated with human papillomavirus, the etiologic agent of genital warts (Fig. 7.37). The penile noninvasive squamous lesions are listed in Box 7.11. Penile intraepithelial neoplasia (PeIN) refers to an intraepithelial neoplastic proliferation without invasion. PeIN is a lesion that can affect any part of the penile surface. There are different degrees of dysplasia. PeIN is classified into PeIN 1, 2, and 3, which is also known as CIS.

7.11.4 Penile Squamous Cell Carcinoma of the Youth Penile squamous cell carcinoma of the youth (PeSqCCY) is a rare event with few cases described in the literature, and the incidence seems to have some geographic characteristics being most often reported in Central Africa (Uganda) and Brazil, an area where STD, mainly HIV, is quite prevalent. In general terms, SqCC represents 1% of all male cancers in the USA, and the incidence is lower among circumcised populations. Patients are usually 40–70 years, and the central localization is on the glans. Young patients aged 18 years have been

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a

b

c

d

e

f

g

h

Fig. 7.36  In this panel are shown cysts of the penis with epithelial inclusion cyst (a and b) and median raphe cyst (c and d). The immunostaining of the median raphe cyst in (e) through (h) show positivity for CK7, EMA, CEA, but not for CK20 (f) (a–d, hematoxylin and eosin staining, ×12.5, ×100, ×200, ×200 as original magnifications,

respectively; e–h: Anti-CK7 immunostaining, anti-CK20 immunostaining, anti-EMA immunostaining, and antiCEA immunostaining, Avidin-Biotin Complex, respectively: ×200 as original magnification for all four immunohistochemical microphotographs)

7.11  Inflammatory and Neoplastic Disorders of the Penis

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a

b

c

d

e

f

Fig. 7.37  Overgrowth in the penis in childhood and youth is rare but needs to be kept differentiated from the infections. In (a), (b), and (c) are shown lichen sclerosus et atrophicus (balanitis xerotica obliterans), while in (d) is shown a verumontanum polyp. In (e) and (f) are shown

microphotographs of a Bowenoid papulosis (a–f; hematoxylin and eosin staining apart from the c) mictophotograph, which is stained with Movat pentachrome staining; ×100, ×100, ×50, ×12.5, ×40, ×200 as original magnifications, respectively)

reported (Coelho et al 2018). The risk factors for penile squamous cell carcinoma remain HPV infection (HPV types 16 and 18 but also types 11 and 30), hygiene (poor), lack of circumcision, and phimosis.

tasis at diagnosis. Nearly half of the penile carcinoma are squamous cell carcinomas NOS. The tumor basis at the infiltration may display two different patterns. There is an infiltrating invasion pattern, which is characterized by tumor cell invasion into the stroma with small solid strands and a pushing invasion pattern, which is characterized by tumor cell invasion into the stroma with large blocks with clear-cut tumor-stroma interface. SqCC grading is conventionally subdivided in grade 1, when prominent keratinization with mini-

• GRO: Two growth patterns, including the exophytic/papillary with characteristic extensive keratinization, and the flat/ulcerating, mostly on the glans and prepuce. • CLM: A slow-growing carcinoma but about 15% of penile carcinomas have already metas-

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mal deviation from the morphology of normal or hyperplastic epithelium is seen. Grade 2 occurs when moderate keratinization with relatively high N/C ratio, evident mitotic activity, and less prominent keratinization are encountered, while grade 3 are defined as tumors showing any proportion of anaplasia in neoplastic cells.

7  Lower Urinary and Male Genital System

 ultiple Choice Questions M and Answers

• LUS-1 What are the histopathologic features of a testicular torsion after 6 hours of the torsion? (a) Interstitial hemorrhage and apoptosis of germ cells (b) Intratubular hemorrhage, germ cell atypia, The depth of invasion is determined as a meaand Leydig cell hyperplasia surement (mm) from the epithelial-stromal junc (c) Interstitial hemorrhage and edema, germ tion of an adjacent non-neoplastic epithelium to cell desquamation, and/or necrosis of the deepest level of aggression if a non-­ germ cells verruciform neoplasm is examined and from a (d) Interstitial hemorrhage and germ cell superficial plane underneath the keratin layer to atypia the deepest level of invasion if a verruciform • LUS-2 Which features correspond to the tumor is under the lens. Mikuz score 2 of testicular torsion? (a) Diffuse infarction of testicular • PGN: Depends on the extension of the neoparenchyma plastic disease. If the penile carcinomas are (b) Diffuse interstitial hemorrhage, focal limited to the glans, there is more than 95% of necrosis of the germ cells survival, but survival drops to less than 50% in (c) Interstitial edema, desquamation of germ case of the involvement of shaft and regional cells LNs. Moreover, tumors invading ­corpora cav (d) Interstitial edema, limited blood extravaernosa have a higher risk of lymph nodal sation, desquamation of germ cells metastasis than tumor invading the corpus • LUS-3 Which one of the following histopathspongiosum only. Other factors influencing ologic features does NOT belong to acute the outcome include the percentage of the Mumps orchitis? poorly differentiated tumor, the depth of inva (a) Edema and perivascular lymphocytic sion, the size of the most extensive nodal exudate metastasis, the extranodal and extracapsular (b) Diffuse lymphocytic infiltration of the extension, and the HPV status. interstitial tissue with focal hemorrhage (c) Pronounced destruction of the germinal The tips and pitfalls of penile malignancies epithelium with plugging of the tubules are shown in Box 7.12. by epithelial debris, fibrin, polymorphonuclear leukocytes, and giant cells (d) Collagenization (e) Calcification 7.11.5 Non-squamous Cell Carcinoma Neoplasms • LUS-4 Gonadoblastoma is a rare lesion of that of the Penis consists of germ cells that resemble those of dysgerminoma and gonadal stroma cells that look like those of a granulosa or Sertoli tumor. Penile mesenchymal lesions are rare. However, These neoplasms usually arise in dysgenetic these lesions may occur more often than squagonads. Which of the following disorders is mous cell lesions in children and young adults. associated with the highest risk of gonadal The most critical mesenchymal lesion is doubtneoplasia? less rhabdomyosarcoma of the penis, which has (a) Turner syndrome been described a few times in the literature. (b) Pure gonadal dysgenesis Single reports include clear cell sarcoma and (c) Mixed gonadal dysgenesis leiomyosarcoma.

Multiple Choice Questions and Answers

(d) Klinefelter syndrome (e) WAGR (Wilms’ tumor, aniridia, genital anomalies, mental retardation) syndrome • LUS-5 A 21-year-old young man presents at his family doctor with a painless testicular mass. A testicular biopsy is performed. Histologic sections show relatively uniform polyhedral cells in sheets that are divided into poorly demarcated lobules by delicate fibrous septa. Lymphocytes and plasma cells are seen in the septa. Some granulomatous inflammation with Langhans-type multinucleated giant cells is seen at places. An immunohistochemical investigation shows the polyhedral cells to be positive for PLAP, OCT3/OCT4, CD117, D2-40, and SALL4 and negative for EMA, CD30, AFP, hCG, and glypican 3. Which is the most likely diagnosis? (a) Embryonal carcinoma (b) Yolk sac tumor (c) Foreign body orchitis with reactive changes (d) Seminoma, classic (e) Choriocarcinoma • LUS-6 Octamer-binding transcription factor 4 (OCT 4) is a critical embryonic stem cell regulating gene regulating self-renewal and differentiation of embryonic stem cells and is encoded by the POU5F1 gene at 6p21.3. Which neoplasm is not expressing OCT 4 by immunohistochemistry? (a) Non-small cell lung carcinoma (b) Neuroblastoma (c) Seminoma/dysgerminoma (d) Embryonal carcinoma (e) Intratubular germ cell neoplasia (f) Teratoma-immature neuroepithelium (g) Spermatocytic seminoma • LUS-7 A 15-year-old child presented with dysuria and pyuria for 2 weeks unresponsive to antibiotic treatment. She complained right flank pain and fever accompanied by hematuria for 4 days. Both past medical history and family history were unremarkable. On physical examination, lower abdominal tenderness and mild right costovertebral angle tenderness were noted. An ultrasound of the abdomen showed an ellipsoid mass located in the urinary bladder with inhomogeneous echo-

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genicity. Transurethral resection was performed. The tumor reveals a spindle cell proliferation and an inflammatory infiltrate. There is positive immunohistochemical staining for vimentin, smooth muscle actin, and anaplastic lymphoma kinase (ALK) and negative immunohistochemical staining for ­ desmin, myogenin, myoglobin, CD117, and S100. There is also a polyclonal kappa and lambda light chain Ig staining in plasma cells. Which of the following diagnosis corresponds to the tumor in this question? (a) Angiosarcoma (b) Synovial sarcoma (c) Rhabdomyosarcoma (d) Nodular fasciitis (e) Inflammatory pseudotumor • LUS-8 Which genes with germline mutations are associated with an increased risk of developing adenocarcinoma of the prostatic gland? (a) BRCA1, BRCA2, and HOXB13 (b) RET, WNT, and RB (c) TP53, WNT, and AAT (d) BRCA1, BRCA2, and HOXB16 (e) WNT, BRCA2, and RB • LUS-9 Which bacterium is a risk factor to develop adenocarcinoma of the prostate in youth? (a) Moraxella catarrhalis (b) Propionibacterium acnes (c) Mycobacterium avium intracellulare (d) Methicillin-resistant Staphylococcus aureus (e) Fusobacterium nucleatum • LUS-10 Which of the following statements does NOT correspond to prostatic intraepithelial neoplasia (PIN)? (a) The intratubular neoplasia shows acinar cells with the presence of prominent nucleoli visible at a 40x magnification or lower. (b) There is complete or partial retention of the basal cell layer. (c) The most common patterns are micropapillary/cribriform, flat, and tufted. (d) Often multicentric in prostatectomy specimens.

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References and Recommended Readings Acién P, Acién MI. The history of female genital tract malformation classifications and proposal of an updated system. Hum Reprod Update. 2011;17(5):693–705. https://doi.org/10.1093/humupd/dmr021. Epub 2011 Jul 4. Review. Acién P, Acién M, Sánchez-Ferrer M. Complex malformations of the female genital tract. New types and revision of classification. Hum Reprod. 2004;19(10):2377–84. Epub 2004 Aug 27. Agochukwu NQ, Rastinehad AR, Richter LA, Barak S, Zerbe CS, Holland SM, Pinto PA.  Prostatic abscess in a pediatric patient with chronic granulomatous disease: report of a unique case and review of the literature. J Pediatr Surg. 2012;47(2):400–3. https:// doi.org/10.1016/j.jpedsurg.2011.11.003. Review. PubMed PMID: 22325401; PubMed Central PMCID: PMC3282836. Agrons GA, Wagner BJ, Lonergan GJ, Dickey GE, Kaufman MS.  From the archives of the AFIP.  Genitourinary rhabdomyosarcoma in children: radiologic-pathologic correlation. Radiographics. 1997;17(4):919–37. AIRTUM Working Group. Italian cancer figures, report 2013: Multiple tumours. Epidemiol Prev. 2013;37(4–5 Suppl 1):1–152. English, Italian. Akiyama H, Kim JE, Nakashima K, Balmes G, Iwai N, Deng JM, Zhang Z, Martin JF, Behringer RR, Nakamura T, de Crombrugghe B.  Osteochondroprogenitor cells are derived from Sox9 expressing precursors. Proc Natl Acad Sci U S A. 2005;102(41):14665–70. Epub 2005 Oct 3. PubMed PMID: 16203988; PubMed Central PMCID: PMC1239942. Alam S, Goebel J, Pacheco MC, Sheldon C.  Papillary urothelial neoplasm of low malignant potential in a pediatric renal transplant recipient (PUNLMP): a case report. Pediatr Transplant. 2007;11(6):680–2. Alanee S, Shukla AR.  Bladder malignancies in children aged   10/10 HPF). It usually occurs in pregnant women with a wide age range from adolescence through 4th and 5th decades of life. It is probably hormone-induced hyperplasia of connective tissue or the end-stage of granulation tissue. IHC: (+) VIM, (−) DES, and (+) ACT (DDX: botryoid rhabdomyosarcoma, which would show cambium layer, epithelial invasion, rapid growth, cross striations, and (+) Myo-D1).

• Low-risk HPV types: 6 and 11 • High-risk HPV types: 16, 18, 31, 33, and 35

8.5.1.7  Endometriosis Vulvae Sive Vaginae Vel Vulvovagine Endometriosis is the presence of endometrial glands and stroma outside of the uterus.

Chlamydia trachomatis - induced cervicitis is one of the most common STD, and histological sections of the cervix show chronic nonspecific inflammation, reactive epithelial atypia, and occasional scattered prominent lymphoid follicles, which may raise the suspicion of a lymphomatous lesions at places.

8.5.2 Inflammation-Associated Cervical Lesions Inflammation-associated cervical lesions include infectious and noninfectious cervicitis, papillary endocervicitis, cervical lymphoma-like lesion, and cervical arteritis.

8.5.2.1  Infective Cervicitis HPV is the cause of condyloma acuminatum, flat condyloma, and papilloma with risk to progress to carcinoma/malignant lesion according to the typing of the virus.

HPV is a virus with a high oncogenic risk for some subtypes. High oncogenic risk lasts longer than infection with low oncogenic risk, although 50% of HPV infection are formally cleared within 8  months and 90% within 2  years. Susceptible cells are immature basal cells of the squamous epithelium areas of epithelial breaks and immature metaplastic cells of the squamous epithelium located at the squamocolumnar junction. Simple koilocytosis refers to a binucleate cell with surrounding halo and denser peripheral cytoplasm and specific nuclear change. There is no disruption or expansion of the basal cell layer, which would point to cervical dysplasia. Cervix operative procedures are (1) cold knife cone excision, (2) loop electrical excision procedure (LEEP), and (3) large loop excision of the transformation zone. Herpes simplex virus (HSV) 1 and 2 are two members of the human Herpesviridae family, a set of viruses that produce viral infections in the majority of humans. HSV-induced cervicitis can also occur. There is an intense nonspecific chronic and acute inflammation with ulceration. To remember are the characteristic features of multinucleated giant cells (MNGCs) and the molding of nuclei.

8.5.2.2  Non-infective Cervicitis Reactive (trauma)-related cervicitis. 8.5.2.3  Papillary Endocervicitis Papillary endocervicitis refers to papillae of several sizes which are filled with inflammatory cells. It represents a process that may be interpreted either as post-chronic inflammation or hamartomatous in origin, although most of the authors tend to consider it an inflammatory condition. Microscopically, there are edema, chronic

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inflammation in a fibrotic stroma, and dilated glands underneath of the epithelium. MNGCc may be scattered and present in the stroma. Other lesions of the cervix include the cervical lymphoma-like lesion and the cervical arteritis.

8.5.3 Reactive Changes of the Cervix Reactive changes of the cervix include repair atypia, radiation-induced atypia (e.g., post radiotherapy for urinary bladder neoplasms), POSN, inflammatory atypia, and atypia-accompanying atrophic lesions.

8.5.4 Cyst-Associated Cervical Lesions Cyst-associated cervical lesions include Nabothian cysts, tunnel clusters, microglandular hyperplasia, and mesonephric remnants or hyperplasia. Nabothian cysts refer to dilatation of endocervical glands due to blockage, which is usually secondary to inflammation. Microglandular hyperplasia (MGA) (aka microglandular adenosis) refers to a complex of histologic characteristics including (1) complex proliferation of tightly packed small glands with flat to cuboidal epithelial cells expressing substantially no atypia, (2) squamous metaplasia of some glands and subcolumnar reserve cell hyperplasia, and (3) stroma infiltration with acute and chronic inflammatory cells and intraluminal neutrophils. MGA is seen in young patients with history positive for oral contraceptive pills (OCP) pregnancy, and a history of single/multiple polypoid lesions resembling small cervical polyps. IHC: (−) CEA. DDX: mucinous endocervical adenocarcinoma. The DDX with clear cell carcinoma (CCC) is essential, and in this latter mucin is (+). Clear cell carcinoma, which is an adenocarcinoma, would show tubulocystic and papillary histologic patterns, an irregular infiltration of the stroma, and marked atypia with brisk mitotic figures (↑ MI). Vestigial elements of the mesonephric or Wolffian ducts usually regress during the development of the female genital tract. In the early development of the embryo, two pairs of genital ductular

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s­tructures form, which are the mesonephric or Wolffian ducts and the paramesonephric or Müllerian Ducts. These ducts parallel one another as they, during the early development of the female genital tract, run cranio-caudally from the mesonephros to the cloaca. Typically, mesonephric rests are located in the lateral wall of the cervix (or in utero) in 1/3 of females, deeply to the endocervical glands. Microscopically, there are a single cell layer, usually cuboidal forming tubules with characteristic - but not pathognomonic - intraluminal eosinophilic homogeneous PAS (+) secretions. Clear cells may be seen, but hobnailing is lacking. Immunohistochemically, the glandular epithelium is Bcl2 (+) and CD10 (+). In particular, both markers may be useful in the DDX with cervical adenocarcinoma, which is Bcl2 (−) and CD10 (−) as well as strongly positive for both p16 and Ki-67 (MIB-1). The latter two markers are usually weakly positive in mesonephric remnants.

8.5.5 Ectopia-Associated Cervical Lesions Ectopia-associated cervical lesions include endometriosis cervicis and ectopia prostatae (ectopic prostatic tissue).

8.5.6 Pregnancy-Associated Cervical Lesions Reactive changes of the cervix include Arias-­Stella change or reaction, decidual pseudopolyps, and decidualization as well as a mesodermal stromal polyp or fibroepithelial polyps. Arias-Stella change refers to endometrial and endocervical glandular change associated with the above considered presence of chorionic tissue seen during pregnancy. It is entirely benign, although in the past it has been mis-diagnosed with malignant transformation. Five types are identified, including minimal atypia; early secretory pattern; secretory or hypersecretory pattern; regenerative, proliferative, or nonsecretory pattern; and “monstrous” cell pattern. Microscopically, ASC often displays tortuous glands with clear and hobnailed cells with some cytologic atypia, but – very important – ASC

8.5 Inflammatory, Reactive Changes and Degenerative Conditions of Vulva, Vagina, Cervix, Uterus,…

is only focal and always associated with pregnancy, and the decidual reaction is seen in the cervical stroma. Decidual pseudopolyp or decidualization is a decidual reaction to pregnancy, and, grossly, there are multiple, red-­yellowish papulae, which may present with a friable aspect, which may represent a pitfall for malignancy.

8.5.7 Cervical Metaplasias Cervical metaplasia includes squamous metaplasia, tubal metaplasia, tubo-endometrial metaplasia, and transitional cell metaplasia. Two other conditions are part of this paragraph and are cervical ectropion and diffuse laminar endocervical hyperplasia. Squamous metaplasia is a benign change with the retreat of the transitional zone into endocervix, in which squamous cells acquire nucleoli and polygonal appearance on cytology and starts basally on histology. Since it may involve glands, a careful differentiation between pseudo-­ invasion and invasion is needed. Cervical ectropion refers to the presence of classic glandular epithelium in ectocervix. There is a strong correlation with in utero DES exposure, which also associated with cervical hyperplasia, VA, and CCC. Diffuse laminar endocervical hyperplasia (DLEH) refers to a benign proliferation of endocervical glands with usually an inflammatory infiltrate and a very welldelimitated lower extent of the lesion. Basal (reserve) cells are essential in dealing with MGA (Box 8.3). Basal cells have some characteristics, including residence in the endo-

Box 8.3 Emblematic Features Distinguishing Microglandular Adenosis from Clear-Cell Carcinoma of the Cervix

1 . Vacuoles at subnuclear location (+) 2. Mucin at intracytoplasmic location (mucin+, CEA−) 3. Lack of glycogen ⇒ PAS (−) glands 4. MI very low or nil 5. No/minimal cell atypia 6. (+) Reserve cell hyperplasia 7. (+) Squamous metaplasia Notes: MI, mitotic index

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cervical glands, squamocolumnar junction, and potential differentiation into either endocervical glandular cells or squamous cells.

8.5.8 Non-neoplastic and Preneoplastic Uterine Lesions It is important to correctly define the abnormal endometrial bleeding as dysfunctional (anovulatory) uterine bleeding due to an excessive loss of blood without demonstrable cause (e.g., estrogen breakthrough bleeding, estrogen withdrawal bleeding).

8.5.8.1  Dysfunctional Uterine Bleeding Dysfunctional (anovulatory) uterine bleeding (DUB) refers to excessive bleeding without evident cause. Examples of DUB may be due to estrogen breakthrough bleeding or estrogen withdrawal bleeding. Bleeding may be labeled as menorrhagia if bleeding is >7 days or > 80 ml flowing at the regular time in the cycle, metrorrhagia when bleeding occurs at irregular intervals, and menometrorrhagia when both menorrhagia and metrorrhagia characteristics do occur, i.e., the female patient is in a setting characterized by prolonged or excessive bleeding outside of regular periodic cycle. Dyssynchrony is also a term indicating a > 4-day variation between glands and stroma maturation. Typically, DUB causes may be grouped into four categories (mnemonic: COLE): 1. Contraceptive-induced DUB: Discordant appearance or dyssynchrony between glands and stroma showing inactive glands exquisitely intermixed to a mature stroma reminiscent of pregnancy-­related decidua. 2. Ovulation failure DUB: Dyssynchrony showing proliferative glands without secretory activity and stromal breakdown, which can be classified as unscheduled. 3. Luteal phase inadequacy: Inappropriate secretory endometrial activity for that determinate POD. 4. Endometrial disorders: This is a very comprehensive term, which may include several heterogeneous processes such as cystic atrophy.

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8.5.8.2  Endometritis Acute endometrial inflammation or acute endometritis refers to a critical inflammatory process of the endometrium, which may follow abortion (missed abortion or miscarriage and interruption of pregnancy), delivery, or instrumentation procedures performed in the usually inappropriate way. The main characteristic is tissue neutrophilia. DDX includes as first obviously menstruation, which may be identified from the active secretory glands broken and embedded in a stroma showing obvious decidual changes. To acquire training in this very delicate sector of public health, it may be essential to evaluate the endometrium in adolescent’s inquiries following gynecologic visits or during inappropriate post-delivery care. Chronic endometrial inflammation or chronic endometritis indicates an underlying constant inflammatory process of the endometrium, which may be due to chronic pelvic inflammatory disease (PID), post-delivery or post-abortion, intrauterine device (IUD) manipulation, or TB infection. Microscopic sections show an infiltration of lymphocytes and plasma cells in an edematous stroma. The presence of one plasma cell suffices for the diagnosis of a chronic inflammatory process of the endometrium because they are not present in usual conditions. Clinically, both vaginal bleeding and pelvic pain are present and may be complicated by extensive PID or mucopurulent cervicitis. Endometrial dating in endometritis is not feasible, because there is gland maturation variability. Therefore, tissue neutrophilia and chronic inflammatory infiltrate should direct the pathologist to liaise with the gynecologist to investigate the possible etiology. The complications reported by IUD manipulation are endometritis, acute and chronic, stroma hemorrhage, shortening of the secretory phase, squamous metaplasia, atrophy, fibrosis, and actinomycosis. In mentioning the important gynecologic genes and gene products relevant to diagnostic routine practice, it is essential to recall four members, including P16, TP53, P57, and P63.

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• P16 gene product is p16, which binds to cyclin-CDK 4/6 complex to intimately regulate the cell cycle at G1-S interphase (cyclin-­ kinase inhibitor) by preventing the phosphorylation of the retinoblastoma (RB) gene product (pRB or RB1). RB is a tumor suppressor gene, whose function is to prevent excessive cell growth by inhibiting cell cycle progression, other than to recruit several chromatin remodeling enzymes such as methylases and acetylases. In HPV-infected cells, there is overexpression of p16 and pRB, and the target of p16 inhibitory activity is inactivated by the E7 HPV oncoprotein. In practice, p16 is used as a surrogate for HPV infection. Diffuse nuclear and cytoplasmic staining is encountered in HSIL and adenocarcinoma in situ (AIS). • TP53 is a tumor-suppressor gene, whose mutational status cause conformational changes and stabilization of the gene product or p53 protein. The protein p53 is involved in regulating cell growth. Gene mutations allow the IHC detection of the protein. A complete absence of signal should point to gene deletion, which is a particularly significant event in some neoplasms. • P57 is a parental imprinted gene, which is expressed only when maternal DNA is present, and is a cell cycle inhibitor of cell proliferation. The p57 protein can be detected in decidua and extravillous trophoblast by immunohistochemistry. The marker p57 is particularly crucial in evaluating products of conception to rule out molar pregnancies at the microscopic level. • P63 is a transcription factor gene that belongs to the p53 family. The gene product or transcription factor p63 is reactive in both immature basal and reserve squamous cells of the cervix. It is a principal diagnosis for cells of squamoid differentiation that looks like entirely undifferentiated.

8.5.8.3  Endometrial Metaplasias Metaplasia in the endometrium is not an uncommon finding, although some metaplasia is not usually seen in childhood or youth (Box 8.4).

8.6 Tumors of the Ovary

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Box 8.4 Endometrial Metaplasias Type Squamous

Subtypes Adenoacanthosis Squamous morulae Ichthyosis uteri

Ciliated cell (tubal) Oxyphilic (eosinophilic) Mucinous Endocervical Intestinal Mesonephroid Secretory Stromal

Syncytial papillary

Morphology Acanthosis “Berry”-like clusters Keratinization Ciliated cells Oxyphilic epithelium Mucinous epithelium Hobnail and clear cell change Secretory changes Islands of foamy cells, smooth muscle, cartilage, and bone Papillary growth

Notes: Mnemonic: SCOMS, i.e. South Carolina Osteopathic Medical Society

8.5.8.4  Adenomyosis and Endometriosis Adenomyosis refers to endometrial cells and stroma growing into the uterine wall, while endometriosis is when endometrial cells and endometrial stroma are in a location outside of the uterus. They can occur together, and both can cause pain, but endometriosis does not always cause heavy bleeding. The non-neoplastic endometrial proliferative disorders include atrophy, disordered proliferative endometrium, endometrial hyperplasia, and endometrial polyp. The atrophy is defined as a flat epithelial lining with nuclear pyknosis and cystically dilated glands and spindled stroma.

8.5.9 Non-neoplastic Abnormalities of the Tuba Non-neoplastic abnormalities of the tuba include Walthard cell nests (benign cluster of epithelial cells, which are most frequently found in the connective tissue of the fallopian tubes but also seen

in the mesovarium, mesosalpinx, and hilus of the ovary), paratubal cysts, tubal endosalpingiosis, tubal endometriosis, and salpingitis isthmica nodosa. Also, an extrauterine pregnancy can occur (tubal pregnancy).

8.6

Tumors of the Ovary

Ovarian neoplasms constitute the fifth cause of cancer-related death in women, although 80% are benign with age range of 15–45 years. Nine out of ten ovarian malignancies are generally of epithelial origin (carcinoma). In 4/5 of cases, there is is spread beyond the ovary at diagnosis. • Risk factors: IDAHO mnemonic word including 1) intercourse without parity, nulliparity; 2) drugs (clomiphene and long-­ term estrogen replacement therapy) – dysgenesis, gonadal; 3) age (older); 4) heritage  – genetic background (BRCA1, BRCA2, HNPCC), 5) others (other factors). Pregnancy and OCD decrease the risk! • BRCA1/BRCA2: BRCA1/BRCA2 mutations cause 10% of ovarian carcinomas, of which 16% of women harbor the abnormal genetic background. These patients have ovarian neoplasms, generally serous cystadenocarcinomas, which are occult in 4.5% of prophylactic salpingo-oophorectomies. • BRCA1 gene mutation prevalence: 1–2% in US Ashkenazi Jews but ~2.5 per 1000 in other US whites. In 1–2% of patients, undergoing prophylactic oophorectomy, there is peritoneal adenocarcinoma with clinical and histologic similarities to papillary serous carcinoma of the ovary. Origin of Ovarian Neoplasms (a) The coelomic surface epithelium of various organs of Müllerian lineage, including the ovary, endometrium, fallopian tubes, peritoneum, and cervix ⇒ epithelial neoplasms (b) Germ cells migrating to ovary from yolk sac ⇒ germ cell tumors (c) “Specialized” stroma of ovary ⇒  sex-cord stromal tumors

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The stroma can synthesize hormones, unlike the nonspecific stroma of other epithelial tumors. Clinically, there may be localized pain at the lower abdominal quadrant (right or left or undefined), abdominal enlargement, obstruction signs on neighboring organs (intestinal or ureteral obstruction with hydronephrosis), ascites, or bilateral diffuse uveal melanocytic proliferation, which is considered a paraneoplastic syndrome constituted by an increase of uveal melanocytes. Uveal melanocytic proliferation can cause blindness. CA-125 (cancer antigen 125 or carbohydrate antigen 125, aka MUC16) is a protein that in humans is encoded by the MUC16 gene and a member of the mucin family glycoproteins. An elevation of serum levels of CA-125 is somewhat sensitive but not specific for ovarian carcinoma. Spread of the malignancy can occur toward the contralateral ovary, peritoneal cavity, pelvic and paraaortal LNs (Sister Joseph’s nodule: umbilical metastasis, maybe the first manifestation of disease), liver, lung, pleura, omentum, and diaphragm. 5-YSR: ~45%. However, according to the American Cancer Society an early detection (stage 1) typically results in a 5-YSR of 92%. Features to report in an ovarian tumor are specimen type, tumor site, specimen integrity (intact, ruptured, fragmented, or other), tumor size, typing (histologic type), grading (histologic grade, i.e., benign, borderline, malignant or poor, moderate, or well-differentiated), staging (invasion sites within the ovary, surface involvement, involvement of fallopian tube, opposite ovary, other tissues, implants: noninvasive epithelial, noninvasive desmoplastic, or invasive; vide infra for definitions), radicality of surgery (margins), and additional staging features including angiolymphatic space involvement, LNs positive/number of nodes examined, eventual extranodal extension, and the presence of endometriosis or other non-neoplastic findings. The risk of malignancy rises with the increase of solid areas. Accordingly, a generous sampling of the base of papillary formations, which are recognizable in the gross room, and areas adjacent to the ovarian surface is necessary. The designation epithelialstromal instead of epithelial only has been proposed because most of the epithelial tumors may

8  Female Genital System

show a stromal component as well. Ovarian epithelium may undergo metaplasia/neoplasia to bear a resemblance to the tubal, endometrial, or endocervical mucosa (the so-­ called Müllerian differentiation). Subtyping related to the pattern (cystic, solid, surface), amount of fibrous stroma, and invasiveness/atypia are probably essential factors for ovarian tumors in the youth. Grading of the surface epithelial-­stromal tumors is a matter of debate because clear-cut criteria seem to be incomplete or missing for some categories. According to most of the authorities, who are expert in gynecologic pathology, there may be several grading systems different for each tumor type. Tips and pitfalls of the ovarian oncology are presented in Box 8.5.

8.6.1 Germ Cell Tumors Germ cell tumors constitute about 1/3 of all ovarian tumors, and most entities are observed in children, adolescents, and young adults. Most cases are benign cystic teratomas, but 1/10 of germ cell tumors are of a mixed type, e.g., dysgerminoma with a yolk sac component (non-“seminomatous” component of the testis).

8.6.1.1  Dysgerminoma • DEF: Seminomatous germ cell tumor with uniform cells that resemble primordial germ cells and interpreted as the female counterpart of seminoma of the testis. • EPI: It accounts for less than 1% of all ovarian tumors. Approximately 80% of the patients harboring dysgerminoma are children, ­adolescents, and young adults (second to third decades of life). • CLI: There are associations with gonadal dysgenesis (Swyer syndrome), androgen insensitivity or pseudohermaphroditism, pregnancy, and hypercalcemia. • LAB: ± ↑ LDH, LDH1, and HCG. Lactate dehydrogenase (LDH) with four distinct enzyme classes catalyzes the interconversion of pyruvate and lactate with concomitant interconversion of NADH (reduced form of nicotinamide adenine dinucleotide) and

8.6 Tumors of the Ovary

Box 8.5 Pearls and Pitfalls

• IHC-implants/M1: (+) WT1, ER, PR, CA125; (−) GCDFP-15, CEA (apart from mucinous differentiation) (WT, Wilms tumor; ER, estrogen receptor; PR, progesterone receptor; CA125, cancer antigen 125 aka mucin 16 or MUC16; GCDFP-15, Gross cystic disease fluid protein 15; CEA, carcinoembryonic antigen). • Coexistence with uterine carcinoma may be a diagnostic challenge. It may reflect metastases from uterus or ovary (possibly also contralateral) or two single independent tumors. Some “pearls” pointing to metastasis from uterine origin (uterine carcinoma) are bilateralism, multinodularity, the small size of the ovarian tumor, the involvement of the tubal lumen, deep myometrial invasion, or angioinvasion of the myometrium. Overall, there is, obviously, a better prognosis in independent tumors than in metastatic tumors. • In childhood, most ovarian tumors are benign, and malignant tumors seem to have a favorable outcome with chemotherapy, even after recurrence. Pediatric ovarian tumors are usually unilateral without metastasis at presentation, and pediatric

NAD+ (oxidized form of nicotinamide adenine dinucleotide). Human chorionic gonadotropin (HCG) is a hormone produced by the placenta following uterine implantation. • GRO: Uni-(85%)/bilateral, encapsulated, smooth tumor with a tangled surface and graywhite solid cut surface with minimal/no hemorrhage or necrosis. • CLM: Well-defined nests of clear cells separated by fibrous stroma infiltrated by scattered T lymphocytes. Tumor cells have clear, glycogen-rich cytoplasm (PAS+ cytoplasm), oval, uniform, and mostly central nuclei with 1–2 prominent nucleoli. Scattered HCG+ syncytiotrophoblastic cells (no PGN significance) are seen. If MI ≥ 30/10 HPF is seen, there is an obvious early carcinomatous differentia-

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malignant tumors of the ovary are mostly of germ cell type, although sex cordstromal tumors and epithelial tumors also do occur. Among the benign tumors, mature cystic teratomas are common. In childhood, pediatric ovarian tumors need to be differentiated from other tumors, including neuroblastoma, Ewing sarcoma/PNET, adrenal gland carcinoma, rhabdomyosarcoma, and DSRCT (desmoplastic small round cell tumor). • Grading challenge: Serous carcinomas can be classified using a two-tier system that is related to the tumor biology (low-­grade vs. high-grade), although staging (FIGO/ WHO) has more weight than typing and grading. Endometrioid carcinoma can be graded using the same three-tier system as used in the uterus, while mucinous carcinomas have a classification according to nuclear atypia in expansile lesions and a three-tier system, comparable to that of the endometrioid type, for infiltrative lesions. Clear cell carcinomas are usually high grade, while transitional cell carcinomas are graded according to a three-tier system based on nuclear morphology.

tion of dysgerminoma (anaplastic dysgerminoma), which may potentially aggravate the outcome (Fig. 8.2). • IHC: (+) CD117, OCT 3/4, D2–40, PLAP, (−) CK7 and EMA, but (±) LMW-CK, (−) CK20 and HMW-CK, (−) CD30, and (±) VIM. OCT3/4 or now relabelled OCT-4 is a nuclear POU-domain octamer binding transcription factor specifically expressed in cells with pluripotent capacity. The word POU is derived from the names of three transcription factors in mammals, including the pituitary-specific Pit-1, the octamer-binding proteins Oct-1 and -2, and the neural Unc-86 from Caenorhabditis elegans. • CGB: 12p abnormalities in most cases (12p overrepresentation and isochromosome 12p).

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a

b

Fig. 8.2  In (a) is shown a table with germ cell tumor FNAC features, while (b) shows a classic ovarian dysgerminoma (H&E stain, x200 original magnification). The

Box 8.6 Germ Cell Tumors – Differential Diagnosis Endometrioid carcinoma ESS (endometrial stromal sarcoma) Fibroma/thecoma Gonadoblastoma Metastatic breast carcinoma Metastatic melanoma Multiple follicle cysts SCTAT (sex cord stromal tumor with annular tubules) Small-cell carcinoma Undifferentiated carcinoma

Histological growth patterns, INA (−), EMA (+) “Tongues,” estrogenism (−), arterioles (+), INA (−) Reticulin (+) Intersex, histological growth patterns INA (−), EMA (+), GCDFP-­15 (+) Intracytoplasmic melanin (+), INA (−), HMB45 (+) Histological features PJS, multiplicity, histological growth pattern

Histological features, hypercalcemia, estrogenism (−) INA (−), VIM (−), EMA+

Note: INA, inhibin A; EMA, epithelial membrane antigen; GCDFP-15, gross cystic disease fluid protein 15; HMB45, Human Melanoma Black; VIM, vimentin

• DDX: See Box 8.6. • TRT: Surgery + CHT, but no RT, although it may adequate for the male counterpart. • PGN: 5-YSR: 95%, if pure. But mixed germ cell tumor of dysgerminoma (10% of cases)

tumor is constituted by cells with clear cytoplasm, centrally located nuclei with coarsely granular chromatin and one or more nucleoli. Lymphocytes are also scattered seen

with choriocarcinoma, yolk sac tumor, or embryonal carcinoma have an influence to worse the prognosis. Also, anaplastic dysgerminoma (marked nuclear atypical changes and high MI) may have a worse outcome, but this finding has been disputed in the recent years.

8.6.1.2  Teratoma Teratoma accounts for 1/5 of all ovarian tumors and mostly in patients younger than 30  years. Most of the cases are benign (98%), unlike the testicular counterpart (Fig. 8.3). 8.6.1.3  Y  olk Sac Tumor (YST)/ Endodermal Sinus Tumor (EST) • DEF: Germ cell tumor of children and young adults with an increase of serum alpha-fetoprotein (AFP), which is encoded by the AFP gene located on the q arm of chromosome 4 in humans and representing a major plasma protein of the yolk sac and the fetal liver during early embryonic and fetal development. • GRO: There is a smooth and glistening surface. • CLM: A variety of pattern may be observed, including reticular, microcystic, papillary, solid, parietal and endodermal sinus as well as a polyvesicular vitelline pattern, hepatoid pattern, and a glandular pattern. Characteristic are SchillerDuval bodies, which are glomeruloid structures with bulbous pseudopapillary having a central blood vessel and intracytoplasmic PAS+ hyaline droplets of BM material (+ IV collagen and

8.6 Tumors of the Ovary

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a

b

c

d

e

f

g

h

Fig. 8.3  The microphotographs (H&E staining) of this panel show an ovarian teratoma with immature elements (neuroectodermal tube) in (e) (x50 original magnification). In (a) there is ectodermal differentiation with hair follicles of different age (x100 original magnification). In (b) there is also an ectodermal differentiation with dermoid cyst (x50 original magnification), while (c) shows

bone and a tooth with mesodermal differentiation (x12.5 original magnification). In (d) choroidal villi and glial tissue are evident (x100 original magnification). In (f–g) all three layers of differentiation seem to be represented (f, x50 original magnification; g, x50 original magnification). In (h) (x100 original magnification) the lymph nodal metastasis of teratoma is seen.

8  Female Genital System

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a

b

c

d

e

f

Fig. 8.4  The microphotographs of this panel are characteristic for yolk sac tumor with some different growth patterns of this yolk sac tumor. In (a) there is a reticular / microcystic pattern with anastomosizing channels and cysts of variable size (H&E stain, x50). In (b) is shown a Schiller-Duval body characterized by tubular structure with papillary accentuation including a vascular core centrally and cuboidal to

columnar epithelial cells as lining (H&E stain, x400). In (c) a microcystic pattern with aspects of polyvesicular pattern are encountered (H&E stain, x12.5), while a solid and a hepatoid pattern are observed in (d) and (e), respectively (H&E stain, x50 and x100, respectively). In (f) the AFP is positive in this gland with angulated features (anti-AFP immunostaining, ABC method, x100 original magnification)

laminin). In the polyvesicular vitelline pattern, small cystic structures with eccentric constrictions are seen. A dense spindle-cell stroma separates these. The hepatoid pattern looks like hepatoblastoma or HCC (Fig. 8.4). • IHC: (−) CD117, (−) OCT3/4, but (+) AE1– AE3, PLAP, AFP, and Hep par-1 (Hep par-1 recognizes a mitochondrial antigen of hepatocytes), and (−) CK7 and EMA. • PGN: 3-YSR: ~15%.

8.6.1.4  Embryonal Carcinoma The embryonal carcinoma (aka undifferentiated malignant teratoma) is rare in the ovary, and serum HCG and AFP levels are elevated, and it may present with isosexual precocious puberty or menstrual irregularities (Fig. 8.5). • IHC: (−) CD117, OCT 3/4, D2–40, and PLAP.

8.6 Tumors of the Ovary

a

Fig. 8.5  These two microphotographs (a, b) show an embryonal carcinoma of the ovary with an immunostaining positive for CD30 (a, H&E stain, x400 otiginal mag-

8.6.1.5  Polyembryoma It is a rarity in the family of the ovarian tumors and the germ cell tumor family. It is constituted by a predominance of embryoid bodies at various stages of differentiation, usually less or equal to 18. There may be malformed embryos or embryonic disc elements with an ectodermal layer of columnar cells and an endodermal layer of cuboidal cells. The embryoid body is considered to have an amniotic cavity-like structure, which is continuous with the intestinal duct, and rarely squamous cell nests, unlike the “yolk sac” which is continuous with the hepatic tissue. Embryoid body seems to be a product of divergent differentiation into the intestine and seems to be derived from the embryonic gut. 8.6.1.6  Choriocarcinoma Primary ovarian choriocarcinoma is rarer than metastases from uterine tumors. It can present with isosexual precocious puberty, i.e., with the appearance of phenotypically appropriate (girls) secondary sexual characteristics before the age of 8 years. If it is present in a gonad, like an ovary, choriocarcinoma is usually part of an MGCT (mixed germ cell tumor). It has to be differentiated from the scattered HCG+ syncytiotrophoblastic cells of dysgerminoma. In choriocarcinoma, there is a biphasic cell population with cytotrophoblast in addition to syncytiotrophoblasts (+ HPL and HCG). PGN: Poor, predominantly if the tumor is a pure choriocarcinoma.

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nification; b, anti-CD30 immunostaining, ABC method, x200 original magnification)

Box 8.7 Pearls and Pitfalls of Germ Cell Tumors

• Accurate, complete, and thorough sampling is of utmost importance in germ cell tumors. • Select sampling from various areas mostly from solid areas but without forgetting to sample the cystic changes. • Areas with calcification should suggest the pathologist assistant or resident the diagnosis of a gonadoblastoma and additional blocks may be appropriate.

Tips and pitfalls of germ cell tumors are presented in Box 8.7.

8.6.2 Surface Epithelial Tumors 8.6.2.1  Serous Tumors Serous tumors are ovarian neoplasms, which are often cystic and filled with typically clear serous fluid and characterized by both secretory and ciliated cell differentiation characteristic of the fallopian tube as well as psammoma bodies (concentric calcifications) in carcinomas (Figs. 8.6 and 8.7). In most of the tumor statistics, surface epithelial tumors represent one-fourth of all ovarian tumors (60% benign, 15% borderline, 25% malignant). Unlike an in situ subtype as seen in

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a

b

Fig. 8.6  These two microphotographs show a serous cystadenoma (a) and a mucinous cystadenoma (b) (a, H&E stain, x400; b, H&E stain, x200)

breast and other organs, surface epithelial tumors have been traditionally subdivided in benign, malignant and in a hybrid component, which is called “borderline”. This category harbors atypical features of cytology without invasion into the ovarian stroma. The site of origin for serous tumors of pelvic location is the ovarian surface (cortical endosalpingiosis, cortical inclusion cysts), the distal fallopian tube, or the Müllerian epithelial rests in the pelvis. In case neither lesion in the ovary nor the tuba is seen, the tumor is supposed to originate from the peritoneum. If cystic, the prefix “cysto-” is added, named as serous “cystadeno-”; if prominent fibrous component (“more than a few papillae having a broad fibrous stromal core”), the suffix “fibroma” is added as adenofibroma or adenocarcinofibroma. • IHC: (+) CK7, (−) CK 20; (+) CK8, CK18, CK19, EMA, B72.3, S100; (−) CAL and CEA (+) WT1 and ER and (−) HNF-1β and HER2. Apart from keratins, B72.3 is also a useful marker. There is a monoclonal antibody that is used in immunohistochemistry. This antibody recognizes a tumor-associated glyocoprotein 72 (TAG-72) located on the surface of numerous malignant cells. This antibody is largely used in differentiating lung adenocarcinoma (positive) from malignant mesothelioma (negative). HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family.

HER2 is aka receptor tyrosine-protein kinase erbB-2, CD340, proto-oncogene Neu, HER2/ neu, and ERBB2. ERBB is the abbreviation of the words “erythroblastic oncogene B”. HNF-1β is hepatocyte nuclear factor 1 homeobox B or transcription factor 2 (TCF2), a protein of the homeobox-containing basic helix-turn-helix family. Borderline (LMP, low malignant potential) tumors are more often in younger women, often pregnant, with unusual malignant behavior and bilateral in 1/3 if include microscopic tumors and their 5-YSR: 100% if confined to the ovary and 90% if the peritoneal surface is involved. Causes of death may be a bowel obstruction, ureteral obstruction, invasive carcinoma, sepsis, and treatment-related complications. Grading  Serous carcinomas can be graded using a two-tier system that is related to tumor biology (low-grade vs. high-grade), although staging (FIGO/WHO) has more weight than typing and grading according to several authors and cancer agencies. Serous Cystadenoma/Cystadenofibroma Grossly, these tumors show a smooth glistening cyst wall with or without papillary projections on the outer surface or protruding into the cystic cavity, and, microscopically, there are usually small, multilocular, simple papillary processes with a single layer (unstratified) of tall, columnar, and ciliated cells resembling normal tubal epithelium. The cells have scant eosinophilic cytoplasm

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Fig. 8.7  In this panel, (a) shows a table with positivity of several markers for different tumors of the ovary. Serous carcinoma from the fallopian tube is shown in (b, c) (H&E stains, x12.5 and x100, respectively). Serous carcinoma,

serous papillary, and clear cell carcinoma are shown in (d–e, f, and g–h, respectively (d, H&E stain, x50; e, H&E stain, x200; f, H&E stain, x50; g, H&E stain, x50; h, H&E stain, x200))

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and oval nuclei with bland appearance and small inconspicuous basophilic nucleoli without obvious nuclear/cellular atypia, architectural complexity, or invasion. Serous Borderline (Proliferative) Tumors (LMP) The diagnosis of borderline may be subjective, but it is usually based on more than a small focus with the hierarchical branching of the papillary structures with clear stratification of the epithelial cells and “budding” into the extrapapillary space. Grossly, borderline tumors are cystic with “cauliflower-like” papillary projections in the internal cavity wall. Following the diagnosis of borderline lesions, five features need to be assessed and reported in the final pathology report. These features are of utmost importance and may have clinical and prognostic relevance. 1. 2. 3. 4. 5.

Surface involvement Stromal microinvasion Nodal involvement Implants identification Salpingitis

1. Surface involvement refers to autoimplants, which are single cells or glands and aggregations of cells with eosinophilic cytoplasm (G1G2) within dominant fibroblastic stroma and associated with noninvasive peritoneal implants. Autoimplants have no apparent adverse prognostic value in stage I and should not be considered evidence of invasion. In consideration of autoimplants, ovarian clear cell carcinoma with papillary features (unilateral, nonhierarchical branching, monomorphic cells with classic features elsewhere, endometriosis, focal cytologic atypia) and low-grade serous carcinoma (clear-cut destructive stromal invasion) need to be taken into consideration. 2. Stromal microinvasion referred to microfoci, which are defined as dishesive cells “percolating” through the papillary stroma and categorized as 1 of the following “back-to-back” architecture (i.e., little or no stroma), (a) serpiginous shapes, (b) complex glands, (c) complex true papillary, (d) irregular glands with necrotic contents, and (e) cribriform histological growth pattern.

8.6.2.3  Endometrioid Tumors Endometrioid differentiated tumors account for up to 15% of all ovarian tumors, and about 1/5 of cases are bilateral, have concurrent endometriosis, and/or synchronous endometrial carcinoma of the uterus. The tumoral synchronism may be explained by either a single clonal tumor with concordant genetic alterations using identical LOH, PTEN mutation, or sporadic MSI patterns, or a single clonal tumor with genetic progression, or eventually (potentially) ≥  2 clonal tumors. There is also a possible association with YST. • GRO: Endometrioid tumors frequently show large to huge cysts with some solid, often hemorrhagic areas obviously devoid of papillary structures (grossly). • CLM: The histologic aspect is similar to endometrioid endometrial adenocarcinoma (tubular glands identical to endometrium) with areas of squamous metaplasia (“squamous morules”). Benign (no cytologic atypia, no architectural complexity) and borderline forms (cell clusters, glands, or cysts of endometrioid-­type epithelium with atypical features but lacking destructive stromal invasion, glandular confluence, or stromal disappearance) are extremely rare compared with

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the carcinoma. Ovarian endometrioid carcinoma (OEC) can be graded using the same three-tier system as used in the uterus. High-­ grade/grade 3 nuclei are large, pleomorphic with coarse chromatin, large irregular nucleoli, high MI, ±  villoglandular architecture (histological growth pattern), and microinvasion, which refers to areas of invasion ≤10 mm2. Variants include a granulosa cell tumor-like variant, Sertoliform variant, and spindle-cell variant of endometrioid carcinoma of the ovary. • IHC: (+) CK7, (−) WT1. • CGB: PTEN mutations in ~1/5 of cases. • PGN: OEC shows a better survival than serous or mucinous carcinomas. • DDX: OEC vs. OSC. • IHC: WT1 – β -Cat – p16 (p16INK4A): • OEC is usually WT1−, β-Catn−, p16−. • OSC is generally diffusely, and strongly WT1+, shows nuclear translocation of β-Cat (β-Catn+), and is diffusely and strongly p16+.

8.6.2.4  Clear Cell (Mesonephroid) Tumors • DEF: It is probably a variant of endometrioid carcinoma and indeed may occur with endometrioid carcinoma, and all are (almost) of the high grade. Ovarian clear cell (adeno-) carcinoma (OCCC), aka mesonephroid adenocarcinoma, is an epithelial-stromal tumor that may be associated with three clinical conditions, including: 1. Endometriosis (or endometrioid carcinoma of the ovary) 2. Hypercalcemia 3. Thromboembolism OCCC is typically characteristic of middle-aged women, but young females have been reported in the literature. Pediatric clear cell carcinoma of the ovary (PCCCO) is considered by some authors a separate entity. • GRO: OCCC has a spongy-cystic texture, which corresponds to histology. • CLM: Three histologic patterns are frequently encountered on low-power magnification:

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1. Tubular-cystic pattern 2. Papillary pattern with or without prominent hyalinization 3. Solid pattern On high-power magnification, the tumor is constituted by large cells, some with nuclei that protrude into lumina (hobnail cytologic feature), with clear cytoplasm (mostly glycogen ⇒ PAS+, mucin−, ORO−), and may resemble mucinous tumor cells on intraoperative frozen section. • IHC: (+) CK7 and (−) CK20, (+) EMA, (−) WT1 and ER, (+) HNF1β, but (±) CA-125, CD15, CEA, AFP and (±) PR and p53 (no expression of PR and TP53 gene product in ~90% of cases); CD15 (Leu-M1) is mostly positive in OCCC, but negative cases have been observed in the literature and personal experience. • DDX: It includes epithelial and mesenchymal tumors, although the “specific” immunophenotype with the H&E pattern may help to distinguish OCCC from some other similar tumors. 1. O-HGSC, as these tumors are usually WT1, ER, PR, p53, positive, and negative for HNF1β.  Immunohistochemically, OEC is typically WT1 (−), ER/PR +, and p53−. The same immunophenotype as O-HGSC, as described above, is seen in borderline serous tumors except for p53 overexpression. 2. YST/EST (+ AFP, + GPC) and (−) CK7, EMA, CD15. 3. Dysgerminoma (+CD117, OCT 4, D2–40, PLAP). 4. JGCT shows (+) INA, CALR, SF-1, WT-1, and CD 56; (+/-) CKs (dot-like pattern); (-) EMA. Differently from adult-type granulosa cell tumor (AGCT), they do not have FOXL2 gene mutations. Molecular genetic analysis of AGCT has evidenced that over 90% of AGCTs have a missense somatic point mutation in the FOXL2 gene. JGCT are indistinguishable from AGCT grossly, but histologically, these tumors have solid (diffuse or nodular) and follicular growth. The follicular

8.6 Tumors of the Ovary

growth pattern exhibits follicles of varying size and shape containing eosinophilic or basophilic secretions. Moreover, differently from AGCT, JGCT cells have ample eosinophilic to vacuolated cytoplasm and rounded nuclei without grooves. 5. Peritoneal malignant mesothelioma (PMM) and well-differentiated papillary mesothelioma (WDPM) need to be taken into account particularly in women of young age. In WDPM, there is a papillary proliferation with focally hyalinized or foamy macrophages. The fibrovascular cores are lined by a single layer of cuboidal cells and nuclear atypia is minimal with a very low mitotic index (MI) In WDPM, there are no destructive infiltration of the underlying stroma. Conversely, PMM may show focal well-differentiated papillary areas together with other growth patterns (solid, biphasic, sarcomatoid, deciduoid). Moreover, atypia is usually higher than mild or focal. The association of moderate or severe atypia, extensive pseudostratification, or high MI indicate PMM. 6. Lipid-rich Sertoli cell tumor shows (+) VIM, INA, MART-1, LMW-CK, CALR, AR, PR, and (−) CK7, WT1, and (±) CD99. SF-1 (adrenal four-binding protein) is a nuclear transcription factor regulating genes that are involved in the development of gonads and adrenal glands, sexual differentiation, steroidogenesis, reproduction, and metabolism. 7. Clear cell variant of struma ovarii, which shows no evidence of atypia, and other patterns are also present. 8. MTX from numerous sites including the kidney (−CK7, −CK20, ±EMA, +CD10, +RCC-Ag), adrenal, and the gastrointestinal tract. • PGN: 5-YSR is 40–50%.

8.6.2.5  B  renner (Transitional Cell) Tumors Brenner tumors or transitional cell-differentiated ovarian tumors account for up to 2% of all ovarian tumors and probably a variant of serous tumors, particularly when high-grade tumors are

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compared. In ¾ of cases, the presentation is 40+ years, but female adolescents with this kind of tumors have been reported. There is an association with hyperestrinism, mucinous cystadenoma, struma ovarii, and urothelial carcinoma of urinary bladder. Grossly, Brenner tumors are typically unilateral, firm, white, and solid, and, microscopically, there is quite a unique constellation of solid and cystic nests of cells similar to transitional epithelium of the urinary tract with cells (PAS+ histochemically) showing distinct cell borders, oval “coffee-bean” nuclei with small and distinct nucleolus, and longitudinal grooves. The solid and cystic nests of transitional cells are embedded in a dense, fibroma-like stroma. Benign Brenner tumor does not show atypia or invasion; borderline Brenner tumor has atypia, but no invasion. Malignant Brenner tumor, which needs to harbor a benign Brenner component, shows mucin-containing microscopic spaces, malignant cytology, and obvious stromal invasion. A three-­tier system based on nuclear morphology is used for grading. Transitional cell carcinoma of the ovary does not have a benign Brenner component. Differentiating malignant Brenner tumor from transitional cell carcinoma of the ovary is not irrelevant, because the latter has a more aggressive course. Moreover, the transitional cell carcinoma of the ovary may exhibit a better chemosensitivity than malignant Brenner tumor. • IHC: (+) WT1, ER, CK7, EMA, CEA, and CA125 and (±) CK20, URO-III, and CD141 Benign Brenner tumors show a line of some urothelial differentiation (either CK20, or URO-­ III, or CD141), which is absent in a peculiarly critical differential diagnosis such as transitional cell carcinoma, allowing the differentiation with urothelial carcinoma of the urinary bladder, which is (−) WT1 and (−) ER. Transitional cell carcinoma of the ovary is also (+) WT1 and ER. Variants: • Metaplastic Brenner tumor: Prominent cystic formations with clear-cut mucinous changes analogous to cystitis glandularis

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• Proliferating Brenner tumor: Papillary tumor with low-grade nuclear atypia similar to low-­ grade urothelial carcinoma of urinary bladder DDX includes four entities that need to be ruled out: (1) Granulosa cell tumor, (2) Carcinoid, (3) Mucinous ovarian tumor, and (4) Transitional cell carcinoma of the urinary tract, which shows (+) CK20, URO-III, and CD141. Transitional cell carcinoma of the ovary, which lacks a benign Brenner component, may be impossible to distinguish from metastatic urothelial carcinoma of the urinary tract if an appropriate patient history is not available. Other tumors include squamous cell tumors, mixed surface epithelial tumors, and undifferentiated surface epithelial tumors. In Box 8.8 there are some tips and pitfalls of the ovarian mucinous tumors.

8.6.3 Sex Cord-Stromal Tumors Sex cord-stromal tumors (SCSTs) are ovarian neoplastic proliferations derived from the ovarian stroma, which arises from sex cords of embryonic gonad and in turns considered a predecessor of Sertoli, Leydig, granulosa, and theca cells. Sex cord-stromal tumors account for 1/20 of all ovarian neoplasms, and about the same rate has been identified for malignant ovarian neoplasms. It is important to remember that typically estrogens are produced from theca cells, while androgens are produced from Leydig cells. Classification of SCSTs is based on morphology, although clinical and biochemical findings support it. Characteristic IHC markers useful for SCSTs are in Box 8.9. Negative IHC stains, useful for a combined immunohistochemical panel, are EMA, PLAP, CEA, CA19-9, CA125, as well as CD45 and CGA. PTPRC or protein tyrosine phosphatase, receptor type, C is an enzyme that is encoded by the PTPRC gene in humans. Most often, PTPRC is aka CD45 antigen and leukocyte common antigen (LCA). Typically, WT1 and CD99 are expressed in all SCSTs except steroid cell tumor and fibroma/

Box 8.8 Ovarian Mucinous Tumors: Pearls and Pitfalls

If mucin is (+), then think of primary mucinous carcinoma of the ovary (+CK7, ±CK20), most Krukenberg tumors (CRC-­ MTX: −CK, +CK20, +CEA, +B-CAT(N + C), +CDX-2), and mucinous carcinoid tumors (+CGA and SYN). If mucin is (−), then think of primary clear cell ACA of the ovary, signet ring stromal tumor, and sclerosing stromal cell tumor of the ovary. Be aware that ovarian mucinous tumors may be associated with teratomas in children! OEC needs to be sampled thoroughly, as serous or undifferentiated carcinoma component lowers 5-YSR from 2/3 to ~1/10. Also, a thorough sampling is of utmost importance because a YST component may be present, which makes the tumor’s behavior very aggressive.

Box 8.9 IHC Markers Useful for SCSTs (VINCAP/VIMCAP) IHC markers Vimentin Inihin A Nephroblastoma antigen Melanoma antigen recognized by T cells 1 Low-molecular weight Cytokeratins Cytokeratins 7/8 Calretinin Androgen receptor Progesterone receptor CD99

Abbreviation VIM INA WT1 MART-1 LMW-CK CAM 5.2 CALR AR PR PNET-Ag

fibrothecoma, respectively, while MART-1 is expressed in steroid cell tumor and Sertoli-­ Leydig cell tumor only. In the latter entity, MART-1 seems restricted to Leydig cell component only. Moreover, INA and CALR are less fre-

8.6 Tumors of the Ovary

quently expressed in fibroma/fibrothecoma/ thecoma group in comparison with the other type of SCST. Recently, SF-1 or adrenal four-binding protein, a nuclear transcription factor that regulates genes involved in steroidogenesis, gonadal and adrenal gland development, sexual differentiation, reproduction, and metabolism, seems to be the most sensitive marker for SCSTs followed by INA, being expressed in 100% of the cases in all types of tumors. Anti-Müllerian hormone staining is also a marker, which is specific for a percentage of granulosa or Sertoli tumor cells. Moreover, a potential pitfall could be some INA positivity that may also occur in luteinized cells from other tumors other than SCSTs.

8.6.3.1  Granulosa Cell Tumor • DEF: Granulosa cell-based SCST (GrCT) with clinical occurrence both pre- (60%) (meno-/metrorrhagia or amenorrhea) and postmenopausal (40%) (postmenopausal bleeding) and 1/20 of cases even prepubertal. Biochemically, there is hyperestrogenism in 3/4 of cases with subsequent estrogenicrelated disturbances, including isosexual pubertal precocity, endometrial hyperplasia/ carcinoma, meno-/metrorrhagia, and fibrocystic disease of the mammary gland. • GRO: GrCTs (also known as adult granulosa cell tumors or AGCT) are almost constantly unilateral, encapsulated, solid, and lobulated, gray with variegated cut surface with ± cysts with straw-­colored fluid. • CLM: Microscopically, there is a variable number of histological patterns, including microfollicular (Call-Exner bodies-rich), macrofollicular, trabecular, insular, solid, and “watered silk” (cell arranged in undulated rows). Call-Exner bodies are small “glands”-like follicles filled with acidophilic material. Tumor cells have “coffee-bean” nuclei with folds and grooves, and bizarre multinucleated cells may be occasionally encountered, which are a sign of degenerative cytologic change rather than malignancy. Theca cell component is often present (up to 90% of cases), and cells may luteinize showing central nuclei, abundant eosinophilic

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•

•

•

•

•

cytoplasm, and well-developed cell borders (Figs. 8.10 and 8.11). Remarkably, reticulin fibers (reticulin stain or silver stain) surround groups of cells, rather than single cells as seen in thecoma or fibroma. This distinguishing feature between GrCT and thecoma/ fibroma is particularly important in the evaluation of biopsies. FNAC study shows cells with little cytoplasm and nuclear indentation looking like mesothelial cells. IHC: (+) VIM, INA, WT1, CAM5.2, CALR, CD56, and (−) EMA but also (+) S100, SMA, DES, desmoplakin, and anti-Müllerian hormone. LMW-CK (CAM 5.2) is present but dot-like. EMA is an important negative marker to rule out possible similarities with ovarian surface tumors and we advise to order systematically for immunohistochemistry. TEM: Abundant intermediate filaments as common cytoskeletal structural components and desmosomes. CGB: Monosomy 22 and trisomy 12, although +14, monosomy X, and monosomy 17 have also been observed. Diploidy of the tumor cells is seen in 4/5 of tumors. Diploidy indicates that the tumor cells have the same number of chromosomes as normal, healthy cells (2X sets of 23 chromosomes). This data suggests that these tumors are slower-growing and probably less aggressive than aneuploid malignancies. DDX includes: 1. Ovarian, surface epithelial carcinoma, poorly differentiated (→ CK7, EMA) 2. Carcinoid tumor (CGA and search for neurosecretory granules on TEM) 3. Endometrial stromal sarcoma 4. Endometrioid carcinoma (+CK7, −WT1) 5. Small-cell carcinoma of hypercalcemic type 6. Pregnancy-related granulosa cell proliferation (multiple, microscopic foci, atretic follicles) PGN points to the relevance of tumor size and staging with 10-YSR of >90%; most deaths occur after 5 years (up to 20 years later!). In fact, as indicated, most of these tumors are diploid (vide supra).

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Fig. 8.10  In (a–d) are shown the microphotographs of a juvenile granulosa cell tumor with macrocysts (a-d, H&E stain, x40, x400, x400, x400, respectively)

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d

Fig. 8.11  The adult granulosa cell tumor shows small microcysts and Call-Exner bodies (a–d, H&E stain, x12.5, x200, x200, and x400 original magnification, respectively)

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• Variant: Juvenile granulosa cell tumor (JGCT), which occurs in 4/5 of cases in children and adolescents before the age of 20 years showing a multiloculated architecture with cysts and solid areas with or without hemorrhage and necrosis grossly. JGCT clinical associations are Ollier disease, Maffucci syndrome, Goldenhar syndrome, and ambiguous genitalia/karyotype aberrations. Microscopically, diffuse or macrofollicular patterns with rare or no Call-Exner bodies but mucin (+) in follicular secretions. Tumor cells are large, hyperchromatic round/ oval nuclei with few or no nuclear grooves and variable scant (non-luteinized) or large cytoplasm (luteinized). MI is high (~7/10 HPF) (Fig. 8.10). • DDX: 1. AGCT (microfollicular with intraluminal BM-material, Call-Exner bodies, nuclear grooves, and lack of hyperchromasia) 2. Thecoma (age > 40 years, no follicles, no atypia, nil or low MI, obvious ret stain pattern) 3. OCCC (diffuse hobnailing, lack of follicles or JGCT cells, (+) CK7 and EMA, and (−) WT1 and ER)

SCST has a relatively good prognosis (Figs. 8.12, 8.13, and 8.14). The Greek word άρρεν (male) is the root for the arrhenoblastoma, which links the ovarian neoplasm to the growth pattern of “testicular-like” tubules and the secretion of male sex hormone, inducing virilization in female individuals. Other names used for this kind of tumors are andreioma, andreoblastoma, androma, and arrhenoma, but they are rarely used. Robert Meyer introduced the term ‘arrhenoblastoma’ for most widely now as Sertoli–Leydig cell tumor and his subclassification of SLCTs into well-differentiated, intermediate, and poorly differentiated forms remains a milestone in gonadal oncology. Biochemically, androgens ⇒  erythrocytosis, although testosterone and estradiol are found in both cell types. Clinical associations: ± FHx (family history is crucial). It has been associated with sarcoma botryoides of the cervix and thyroid disease. The extended Meyer classification of SLCT includes WD-SLCT, MD-SLCT, PD-SLCT, SLCT with heterologous elements, retiform SLCT, and pure Sertoli cell tumor (WD, welldifferentiated; MD, moderately-differentiated; PD, poorly-differentiated).

8.6.3.2  Sertoli-Leydig Cell Tumor

1. WD-SLCT (Meyer type I) (~10%): Hollow/ solid tubules lined by Sertoli-like cells separated by cellular (fibrous) stroma with a variable number of Leydig-like cells. PGN: 5-YSR: 100%. 2. MD-SLCT (Meyer type II) (~55%): Clusters, cords, or sheets of Sertoli-like cells separated

The SCST has a young age group occurrence and mostly androgen-producing features (aka androblastoma, arrhenoblastoma formerly). It accounts for less than 0.2% of ovarian neoplasms. Although it depends from the degree of differentiation, a

b

Fig. 8.12  The two microphotographs (a–b) show a well-differentiated Sertoli-Leydig cell tumor (a-b; H&E stains, x50 and x200 as original magnifications, respectively)

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Fig. 8.13  In this panel are shown the microphotographs of a poorly differentiated Sertoli-Leydig cell tumor showing anaplasia and heterologous differentiation (a–h; H&E,

x100, x200, x400, x200, x200, x200, x200, x200 original magnification, respectively)

by cellular (fibrous) stroma with intermixed Leydig-like cells. PGN: 5-YSR: 90%. 3 . PD-SLCT (Meyer type III) (~10%): Diffuse growth of undifferentiated cells and/or

spindle cells arranged in a sarcomatoid fashion with very few or no Leydig-­like cells and mucus-filled epithelial cells. PGN: 5-YSR: 40%.

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Fig. 8.14  This panel shows some special stains and the positivity of the immunohistochemistry for several markers. We used PASD, AB2.5, VIM, DES, WT1, and CD10 (a–f; x100, x100, x100, x100, x100, x100 original magni-

fication, respectively). In (f) is also shown the focal positivity for inhibin A (inset, x400 original magnification). Avidin-Biotin Complex was used for immunohistochemical procedures.

4. SLCT with heterologous elements (~20%): Mucinous epithelium, hepatic tissue, skeletal muscle, and cartilage (aka “teratoid androblastoma” or “teratoid arrhenoblastoma”). 5. Retiform SLCT (~10%): Sertoli-Leydig histological elements growing as elongated, branching tubules with low cuboidal epithelium with or without blunted papillae resembling rete testis ± homologous or heterologous differentiation (DDX includes YST, metastatic ACA, carcinosarcoma, carcinoid tumor, serous tumors of borderline or malignant type, endometrioid carcinoma

with sex cord-like elements, Wilms’ tumor or nephroblastoma). 6 . Pure Sertoli cell tumor (very rare): ± Peutz– Jeghers syndrome (PJS) (a particularly lipid-rich variant of pure Sertoli cell tumor), premenopausal (precocious pseudopuberty with vaginal bleeding), and postmenopausal (irregular bleeding, solid and hollow tubules lined by Sertolilike cells with intracytoplasmic lipid (ORO+) identifiable by histochemistry without atypia, excellent prognosis). PJS is an AD medical condition characterized mainly by mucocutaneous pigmentation and intestinal polyposis.

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• IHC: (+) VIM, INA, Nephroblastoma-Ag/ WT1, CK [AE1–AE3, CAM5.2] and CALR, AR/T, and PR and PNET-Ag/CD99 (mnemonic word: VINCAP) as well as (−) EMA, PLAP, CEA, CA19-9, CA125, and, obviously, (−) CD45 and (−) CGA. • TEM: “Sertoli cell-like” ultrastructural features with elongated nuclei, deep indentation annulate lamellae, apical microvilli, and frequent desmosomes. • PGN: There are four unfavorable prognostic factors for SLCT, including (1) rupture, (2) extraovarian spread, (3) poor differentiation, and (4) heterologous elements. All four elements need to be reported in the pathological report and discussed at the multidisciplinary tumor board meeting.

8.6.3.3  Steroid/Lipid Cell-Rich Tumor Group It is a group of SCST of the ovary with steroid/ lipid-rich features and includes a few similar entities with different names but that show quite identical clinical and microscopic characteristics, e.g., virilization (amenorrhea or postmenopausal bleeding) and MART-1 (Melanoma-associated Antigen Recognized by T cells - 1) expression (only in steroid cell tumor and restricted to Leydig cell component of Sertoli-Leydig cell tumors). 1. Stromal luteoma. 2. Leydig/hilus cell tumor: Leydig cell tumor, if Reinke crystals (“rod-like” cytoplasmic inclu-

a

Fig. 8.15  The fibroma (a) – fibrosarcoma (b) or spectrum  – group is shown in this two-microphotograph panel (a-b; H&E stains, x100 original magnification

sions) are visible, while in hilus cell tumor, the location of the tumor is at the hilus of the ovary. 3. Steroid cell tumor. Grossly, unilateral, yellow or yellow-brownish solid mass with vague nodularity is separated by fibrous trabeculae. Microscopically, S/LCRT (Steroid/Lipid Cell-Rich Tumor) shows clusters of large rounded or polyhedral cells with exquisitely identifiable features of steroid hormone secretion (abundant eosinophilic or vacuolated cytoplasm) ± Reinke crystals. • IHC: (+) VIM, CAM 5.2, AE1–3, (±) EMA, and S100. • TEM: SER (smooth endoplasmic reticulum) prominence and tubulovesicular cristae in mitochondria. • DDX: neoplasms with the secondary proliferation of steroid hormone-­ producing cells, including stromal luteoma, luteinized GrCT, fibroma/thecoma, s­tromal Leydig cell tumor, and focal spread at the periphery of other ovarian tumors. • PGN: Favorable, but unfavorable PGN factors include size, high MI, and nuclear atypia.

8.6.3.4  Fibroma/Thecoma Group Spindle-cell-based SCSTs with similar gross, histologic, and molecular/chromosomal (12+ by fluorescence in situ hybridization - FISH) features (Fig. 8.15). b

for both microphotographs) (see text for details about definition of both entities)

8.6 Tumors of the Ovary

• Fibroma: age    40  years, ± dysfunctional uterine bleeding, pelvic/abdominal pain, or distension and sclerosing peritonitis. Estrogenic-­ related individualized risk of endometrial hyperplasia/carcinoma • Fibrothecoma: Generalized term for the combination of both fibroma and thecoma in the same neoplasm • Fibroma: Unilateral, solid, lobulated, firm, and white, grossly • Thecoma: Unilateral, solid, lobulated, firm, and yellow, grossly • Fibroma: Closely packed spindle cells in “feather-stitched” or storiform histological growth pattern, ORO (−), ± hyaline bands/ edema, and no atypia • Thecoma: Spindle cells with pale cytoplasm with reticulin fibers surrounding individual cells, ORO (+), ± hyaline bands/calcification, and no atypia • Fibroma: (+) WT1, (+) ER-β, (+) PR • DDX includes: 1. Cellular fibroma (MI ≤ 3/10 HPF) 2. Fibrosarcoma (large Ø, hypercellularity, MI > 3/10 HPF, severe nuclear atypia) 3. Fibromatosis 4. Sclerosing stromal tumor

8.6.3.5  Sclerosing Stromal Tumor Fibroma/thecoma group-related SCST of the younger age group (15–30  years) with similar gross, histologic, and molecular (+12 by FISH) features. Grossly, SST is a unilateral, small, gray-white, and hormonally inactive neoplasm with the variegated cut surface. Microscopically, SST shows a hypercellular pseudo-lobular architectural pattern with dual cell population (collagen-producing spindle cells  =  fibroblasts + round/ovoidal cells with clear, lipid-rich cytoplasm = luteinized stromal cells) with accompanying prominent,

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“staghorn”-­shaped, ectatic BVs AND intervening, hypocellular edematous zones. • TEM: Variable cytological configuration of fibroblasts, luteinized theca-like cells, and primitive mesenchymal cells. • Variant: Signet-ring cell stromal tumor.

8.6.3.6  S  ex Cord Tumor with Annular Tubules • DEF: Sex cord tumor with peculiar histologic annular tubules. It is generally associated with PJS in 1/3 of events (benign fashion: “small and bilateral SCTAT”) and ­hyperestrinism in 1/2 of events (isosexual precocious puberty or menstrual irregularities). • GRO: Solid mass with distinctive yelloworange diacritic nuances. • CLM: There are simple and complex rings (“annular tubules”) with basal nuclei-­ containing cells (antipodal nuclear diacritical arrangement) around a hyalinized luminal “body” of BM material. • HSS/IHC: (+) PAS, CD10, and INA. • TEM: Granulosa and Sertoli cell ultrastructural distinctiveness including nuclear indentation, an interdigitating plasmatic membrane with joined desmosomes as well as intracytoplasmic Charcot-Bottcher filaments, which are spindle crystalloids of 10-25 µm in length. • DDX: Pure Sertoli cell tumor, GrCTs, and gonadoblastoma. • PGN: Malignant behavior in 1/4 of SCTAT not associated with PJP. Genetic counseling is appropriate and needs to be suggested in the comments section of the pathological report. 8.6.3.7  Gynandroblastoma SCST showing a mixture of similar amounts of granulosa-thecal elements (GYN component) and Sertoli-Leydig elements (ANDRO component). The distinction between fibroma, fibrothecoma, and thecoma remains in many centers quite vague and indeed subjective. It has been suggested that thecoma should be designated “fibromatous tumors with large vacuolated or luteinized cytoplasm content and evident band-like hyaline

8  Female Genital System

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plaques between tumor cell clusters” probably imparting a vague nodularity to the intriguing neoplasm. Incomplete development of thecoma features may suggest the use of fibrothecoma, in which this designation should qualify tumors intermediate between fibroma and thecoma. Gorlin syndrome is an AD-inherited disease characterized by multiple skin carcinomas of basal cell type, odontogenic keratocysts, palmoplantar pits, congenital bony abnormalities, and ectopic calcifications due to mutational inactivation of PTCH. The Drosophila-homologue specifies polarity. The human PTCH1 gene, which has been mapped to 9q22.3-31, consists of 23 coding exons (~74 kylobases) encoding a 1447-amino-acid transmembrane glycoprotein. PTCH1 is involved in the Hedgehog (Hh) signaling pathway, which plays a major role in body patterning and organ development during embryogenesis.

• IHC: (+) SALL4 and SF1 and anti-Müllerian hormone focally. SALL4, i.e., Sal-like protein 4 is a transcription factor encoded by a member of the Spalt-like (SALL) gene family. SALL4 participates in the Wnt/β-Catenin signaling pathway and regulation of pluripotent stem cells. SALL4 gene is altered in DuaneRadial Ray Syndrome and Ivic Syndrome. • DDX: It includes SCTAT and MMGCT.

8.6.4 O  ther Primary Ovarian and Secondary Tumors

8.7.1 Benign Neoplasms

8.6.4.1  Gonadoblastoma Gonadoblastoma (aka dysgenetic gonadoma) is an expansion of an SCST with a germ cell component and occurs typically in 80% of cases with female phenotype of the patients and 20% with phenotypic males with undescended testes and female internal secondary organs, and in 1/2 of cases, there is a coexistent dysgerminoma (thorough sampling!) and bilaterality in 1/3 of cases. Patient karyotype: gonadal dysgenesis with a Y chromosome, i.e., XV gonadal dysgenesis, XO-XY mosaicism, but not XX gonadal dysgenesis. Gonadal dysgenesis with Y chromosome harbors a neoplastic risk of 25%. Clinical associations: Ataxia-telangiectasia, which is a rare inherited disorder involving early (childhood) difficulty with coordinating movements (ataxia) associated with chorea, myoclonus, neuropathies, and telangiectases of eyes and skin.

Other entities not described here include the female adnexal tumor of Wolffian origin (FATWO), the microcystic stromal tumor, the ovarian endometrioid stromal sarcoma (OESS), the small-cell carcinoma of hypercalcemic type, the small-cell carcinoma of pulmonary type, the hepatoid adenocarcinoma, and fibromatosis.

8.7

Tumors of the Tuba

There are mostly two entities that play a role as benign tumors in the salpinx. These are an adenomatoid tumor and papillary cystadenoma. Leiomyoma and teratomas are rarities.

8.7.2 Malignant Neoplasms The malignancies that may occur in the salpinx are carcinoma of the fallopian tube, MMMT (Malignant Mixed Müllerian Tumor) or carcinosarcoma, and choriocarcinoma as primary tumors. Moreover, the serous tubal intraepithelial neoplasia (STIC) and secondary tumors need to be taken into account.

8.8

Tumors of the Uterus

Malignant epithelial neoplasm of the endometrial lining with only 1/5 of cases occurring in pre• GRO: Small solid tumor. menopausal women. Endometrial carcinomas • CLM: Tumor cell nests containing Call-­Exner-­ have been identified in the pediatric age group. In like hyaline “blobs” surrounded by fibrous particular, children with Turner syndrome receivbands and ± hyalinization and calcification. ing unopposed estrogens as well as rarely some

8.8  Tumors of the Uterus

genetic syndromes such as Turcot syndrome and Leprechaunism (Donohue syndrome) (Figs. 8.16, 8.17, 8.18, and 8.19) may be affected with this kind of neoplasms. Risk factors: Mnemonic “IDAHO” acronym word for infertility, diabetes, age  >  35  years, hypertension, and obesity.

8.8.1 Type I/Type II EC 1. Type I or endometrioid endometrial carci noma (EC) 2. Type II or clear cell/serous-papillary EC 3. Non-type I/non-type II EC

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8.8.3 U  terine Leiomyoma (ULM) and Variants Uterine leiomyoma is a quite frequent finding in the uterus from puberty through middle age. Variants of leiomyoma include cellular, mitotically active, symplastic, and myxoid. The following sections are going to focus on uterine lymphangiomyomatosis, uterine stroma tumors, as well as hematological and secondary malignancies.

8.8.4 Uterine Leiomyosarcoma (ULMS)

It is the malignant counterpart of the uterine leiomyoma. Thus, it is important to assess correctly and carefully mitotic figures as well as cellular atypia. Mitosis criteria include (1) “hairy” extension of chromatin distribution pattern, (2) no nuclear membrane, and (3) exclusion of mitosis mimickers (e.g., lymphocytes, mast cells, stripped nuclei, degenerated cells, and peculiar precipitations of hematoxylin). All three criteria MUST be checked out before the term mitosis is applied! Atypia criteria include an assessment which is based on nuclear pleomor8.8.2 Non-type I/Non-type II EC phism, nuclear size, nuclear plasma membrane Non-type I/non-type II endometrial carcinomas irregularities, chromatin density, and size and are a heterogeneous group including mucinous, prominence of nucleoli. G1-G2-G3 refers to squamous cell, transitional cell, mixed, small degrees of differentiation of a tumor (well, modcell, and undifferentiated. Mucinous endome- erately, and poorly differentiated, respectively) trial carcinoma refers to carcinoma with >50% but may refer – under certain circumstances – to of neoplastic cells showing intracellular mucin. the degree of atypia of the cell type. G1 refers to Squamous cell carcinoma or epidermoid carci- the uniformity of nuclei ± enlargement, smooth noma shows squamous differentiated neoplastic contours of the nuclear membrane, evenly districells, and its diagnosis is made only in the bution of chromatin pattern, and minimal variaabsence of squamous cell carcinoma of the cer- tion in size and shape. G2 refers to mild vix. Transitional cell carcinoma requires >90% dis-uniformity of nuclei (pleomorphism) with of neoplastic cells showing urothelial differen- enlargement, plumpness, and irregularities, tiation. Mixed endometrial carcinomas have ≥2 coarse distribution of chromatin, and occasional cell types with ≥10% each type. Small-cell car- enlarged abnormal mitoses. G3 refers to marked cinoma of the endometrium shows both pan-­ dis-uniformity of nuclei (nuclear pleomorphism) keratin (AE1–AE3) and neuroendocrine markers with enlarged bizarre nuclei, dense chromatin, (CGA, SYN) expression. Undifferentiated and atypical prominent nucleoli. Tumor cell necrosis of coagulative type, endometrial carcinoma displays no i.e., tumor cell necrosis intrinsic to the tumor differentiation.

Apart from type I or endometrioid endometrial carcinoma (EC) and type II or clear c­ ell/serouspapillary EC, there is a non-type I/non-type II EC. The type I shows closely packed irregular glands lined by atypical columnar epithelium with scant stroma and occurs in women younger than 40 years in less than 5% of cases. Type II is characterized by a clear cell and serous papillary growth pattern, but is inexistent in youth.

8  Female Genital System

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Fig. 8.16  This panel shows benign noninvasive neoplasias of the uterus. In (a) and (b) the microphotographs show an endometrial polyp with complex atypical hyperplasia progesterone-treated (H&E stains, x12.5 and x100 original magnification, respectively). In (c) and (d) are shown a high grade superficial intraepithelial lesion with microglandular hyperplasia (H&E stain, x100 and P16

immunostain, ABC method, x100, respectively). In (e) is shown an atypical endometrial hyperplasia with morular metaplasia (H&E stain, x50 original magnification). In (f–g) is shown a symplastic leiommyoma (H&E stain, x50 and x200 original magnification, respectively). In (h) is shown an adenomatoid tumor of the uterus (H&E stain, x50 original magnification).

8.8 Tumors of the Uterus

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Fig. 8.17  This panel of rare uterine neoplasms include an endometrioid endometrial carcinoma (a, b), a choriocarcinoma (c), a poorly differentiated carcinoma with clear cell areas (d, e), and a leiomyosarcoma (f). All of these tumors occurred in youth. The serous papillary endometrial carci-

noma is, conversely, practically inexistent in childhood or youth and reported here for comparison from an older patient (a-f; H&E stains, x100, x200, x100, x100, x100, x200 original magnification, respectively).

and not of ischemic type, needs to be differentiated from hyalinizing patterns of necrosis that may occur for several necrobiotic processes. Once criteria for mitotic figures, atypia, and necrosis type are set and retained with confidence by the gynecologic, pediatric, and general surgical pathologist, the “If…, then…” rules to differentiate leiomyoma from atypical leiomyoma and leiomyosarcoma may be applied (Box 8.10).

The concept of STUMP is a controversy. STUMP is an acronym defined as smooth muscle tumor of uncertain malignant potential. Its diagnosis can be applied if all criteria are met in a very rigorous way. The requirements are minimally atypical SM neoplasms with low MI but with uncertain histology AND combination of standard SM differentiation, G3-atypia, low MI, but uncertain necrosis, AND G2-G3 atypia, but with unclear MI.

8  Female Genital System

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Fig. 8.18  A very rare occurrence of neuroblastoma of the uterine wall with characteristic features infiltrating the wall of the uterus in all the microphotographs presented. In this child, there was no evidence of neuroblastoma in either adrenal gland or paraganglia. It may have arisen from ectopic neuroblasts or choristiae located in the uterus. Extrarenal Wilms’ tumor is

another rare entity in the uterus with blastemal cells that may share similar pathogenesis. The various locations of extrarenal Wilms’ tumor include the retroperitoneum, skin, and thorax, other than uterus (a–h; H&E stains, x200, x100, x100, x100, x 50, x 100, x100, x100 original magnification, respectively)

8.8 Tumors of the Uterus

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Fig. 8.19  This panel illustrates the immunohistochemistry of the neuroblastoma shown in the previous panel. The immunostaining Avidin-Biotin Complex) of this panel is for CD56, chromogranin A, S100, NSE, neurofilaments,

CD99, desmin, and Ki67 (MIB1)  in (a–h), respectively (a-h; x200, x400, x400, x200, x400, x200, x100, x50 original magnification, respectively)

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Box 8.10 LM/LMS “If…, then…” Criteria

IF “no/mild (G1) atypia”  – “tumor cell necrosis,” then LM. IF “G2-G3 atypia” – “tumor cell necrosis,” then assess MI. –– If MI   5  cm, infiltrative borders, marked pleomorphism, tumor-related necrosis, and high MI (man: mitoses, atypia, necrosis). PGN investigations point to recurrence after lung TX.

8.8.7 Uterine Stroma Tumors Uterine stroma tumors include stromal nodule, endometrial stromal sarcoma (ESS, formerly endometrial stromal sarcoma of low grade), and undifferentiated stromal sarcoma (USS), formerly endometrial stromal sarcoma of high-grade type (Box 8.11).

8.8.8 Hematological Malignancies and Secondary Tumors Lynch syndrome (hereditary nonpolyposis colon cancer (HNPCC)) is an essential diagnosis because endometrial carcinomas develop before colon malignancy in more than half of females and HNPCC should always be considered if the patient is younger than 50  years and/or with a family history of colon carcinoma. In these cases, DNA mismatch repair can be performed by IHC using the commercially available kit to MLH1, MLH2, MLH6, and PMS2. The correlation is between loss MLH2 and MLH6. PCR can assess high levels of MSI for defective DNA mismatch repair. Lynch syndrome individuals demonstrate endometrial carcinomas with a wide variety of histologic types, being non-endometrioid endo-

8.9  Tumors of the Cervix

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Box 8.11 Stroma Nodule vs. ESS vs. USS Stromal nodule On LPM Invasion

(−)a

LVI

(−)

ESS

USS

(+) “tongues” (+) “wormlike” (+/−)

(+++) (+)

Extrauterine (−) (+) extension On HPM Cellularity Uniformity Uniformity Pleomor­ phism MI 1%) in the population. The 1% cutoff is arbitrary, although it seems to function in many biological systems. TP53 gene has 14 polymorphisms, of which p53 Arg72Pro variant (TP53 rs1042522), i.e., Arg  →  Pro involving guanine (CGC) to cytosine (CCC) nucleotide exchange on exon four at codon 72, is mostly associated with some cancers, although this data is controversially debated. According to a recent meta-­analysis TP53 rs1042522, it is unlikely to be associated with breast, colorectal, or endometrial cancer. A weak association with lung cancer has been suggested. The use of genetic investigation obtained from tumor tissue for genotyping can still represent a bias in estimating some genetic effect on cancer. Future investigation should avoid the use of tumor tissue as the primary source of genetic material, precisely when the genetic loci of interest are known to demonstrate LOH.  About cervical cancer, it seems that p53 Arg72Pro variant is associated

8  Female Genital System

with progression of HSIL to cervical carcinoma only in the presence of HPV positivity where the abnormal p53 is more susceptible to be degraded by E6 protein. However, it seems that there is no association of p53 Arg72Pro variant with overall risk or initiation of carcinoma in either HPV-(+) or HPV-(−) women. In the malignant transformation, the viral oncogenes E6 and E7 (E stands for early expression) are the key players. Loss of the transcriptional control system leads to high levels of expression of the viral oncogenes throughout the epithelium favoring the malignant progression. E6 has a ubiquitin ligase activity that acts to ubiquitinate p53 leading to its proteasomal degradation. The introduction of viral DNA in the host genome would prevent cell death apoptosis and, finally, cancer progression. E7 acts differently by competing for pRB binding acting on the transcription factor E2F to transactivate its targets. This E7-mediated transactivation of E2F pushes the cell cycle forward leading to p16 protein accumulation. The detection of p16 in HSIL may be interpreted as a surrogate of the HPV test. Koilocytic changes are nuclear changes (enlargement and variation of size and shape, hyperchromasia, coarse chromatin granules) and perinuclear halo.

8.9.2.2  Cervical Epidermoid Carcinoma Cervical epidermoid carcinoma or squamous cell carcinoma of the cervix (C-SqCC) is the most common malignancy of the female genital tract and epidemiologically the second most common cause of cancer death in North America and most of the Western countries. The distinguishing features between invasion and non-invasion are listed in Box 8.12. The risk factors to develop a cervical squamous cell carcinoma are listed in Box 8.13. • GRO: C-SqCC may be infiltrative or bulky (exophytic) or both. • CLM: Significant subtypes include large cell nonkeratinizing (~2/3 of cases), keratinizing (~ ¼ of cases), small cell, basaloid, and verrucous histological subtype (microscopic architecture).

8.9 Tumors of the Cervix

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Box 8.12 Distinguishing Features Between Invasion and Non-invasion 1. (+) Paradoxic Matur. 2. Irregular contour of the invading nest (+) 3. (+) DSR (+) with metachromatic stain 4. (±) LVI 5. (±) µ-inv.

(−) Paradoxic Matur. Irregular contour of the invading nest (−) (−) DSR (+) with metachromatic stain (−) LVI (−) µ-inv.

Notes: Matur., maturation; DSR, desmoplastic stroma reaction; LVI, lympho-vascular invasion; µ-inv., microinvasion ( 10/10 HPF Fracture lines with absence of cell polarity and nuclear molding

WD-NEC = carcinoid

MD-NEC = atypical carcinoid

PD-NEC, large cell type

PD-NEC, small cell type

Note: Nuclear/cytoplasmic ratio (N/C); HGP, histological growth pattern; CDP, chromatin distribution pattern; HPF, high-power field; NEC, neuroendocrine carcinoma

8.10 Tumors of the Vagina

• DDX: Adenocarcinoma, small cell nonkeratinizing SqCC (well-defined nests similar to large cell nonkeratinizing SqCC, p63+, and CGA−), basaloid carcinoma (p63+, CGA−), PNET (CD99 is probably not useful, and FLI and/or t(11;22) detection is necessary), lymphoma (CD45 and B-/ T-cell markers), granulocytic/myeloid sarcoma (+lysozyme, chloroacetate esterase, CD34, CD68, MPO, − CD3, − CD20), melanoma (+S100, HMB45, Mel-A), embryonal rhabdomyosarcoma /RMS (+DES, MYD-1, MYF4), and metastatic carcinoma (lung or other sites). In particular, the expression of myelomonocytic antigens (CD34) and myeloid-associated enzymes (myeloperoxidase) is of enormous help in differentiating GS from malignant lymphoma and acute lymphocytic leukemia (ALL). Both markers can help recognize early myeloid cells. The absence of CD20 and CD3 markers is also necessary to rule out B-cell and T-cell lymphomas, respectively. Some histologic features that are commonly identified in poorly differentiated NEC vs. SqCC include (1) vascular invasion, (2) evident lack of coexisting inflammation, and (3) broad geographic areas of necrosis. Importantly, amphicrine carcinoma are defined tumors with small cell NEC component combined with squamous cell carcinoma or adenocarcinoma and may require caution in the differential diagnosis of this kind of tumors. • TRT: Radical hysterectomy with bilateral lymphadenectomy, radiation therapy, and chemotherapy for poorly differentiated NEC, but PGN remains poor. Other tumors include cervical mesenchymal neoplasms and hematological malignancies, as well as cervical secondary tumors.

8.10 Tumors of the Vagina 8.10.1 Benign Tumors The Müllerian and mesonephric structures may be characterized by histochemical stains and are seen in Box 8.16 (Fig. 8.20).

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Box 8.16 Müllerian vs. Mesonephric Roots

Müllerian Structures: Mucin (+), PAS (−), DPAS (−). Mesonephric Structures: Mucin (−), PAS (+), DPAS (−).

8.10.1.1  (Müllerian) Papilloma Arborizing connective tissue fronds constitute Müllerian papillomas with an overlying superficial epithelium consisting of flat cuboidal or mucinous epithelium. 8.10.1.2  Vaginal Fibroepithelial Polyp It is a polypoid rubbery lesion covered by classic vaginal mucosa and may protrude, grossly, from the introitus vaginae as multiple fingerlike projections, which particularly in infants and children may raise the principal differential diagnosis of embryonal RMS of botryoides subtype (vide infra). Microscopically, there is acanthotic squamous epithelium overlying a fibrovascular core consisting of fibrous connective tissue with dilated capillaries and occasional large bizarre cells. DDX: Botryoid RMS angiomyofibroblastoma, aggressive angiomyxoma, superficial angiomyxoma, condyloma acuminatum, neurofibroma (particularly in patients affected with NF1, if histology is spindle and the histological pattern recall neurofibroma and is supported by S100+), and leiomyoma. 8.10.1.3  Vaginal Postoperative Spindle (Cell) Nodule (POSN) Characteristics of the POSN are Hx. (+) recent surgery, bland cytology, and a prominent delicate network of BVs. 8.10.1.4  Other Vaginal Benign Tumors Other rare tumors include tubulovillous adenomas (arising from cloacal remnants), leiomyoma, rhabdomyoma (interweaving and haphazardly oriented bundles of spindle- to strap-shaped cells, some with cross striations with focal atypia but rare mitotic figures and no cambium layer),

8  Female Genital System

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Fig. 8.20  In (a) are septum heterotopic endocervical glands (hematoxylin and eosin staining, ×100 original magnification), in (b) is a vagina section with progestin-­ treated endometrial hyperplasia with extensively decidualized stroma in a peri-pubertal child (H&E, 50×), and in (c, d) are microphotographs of an angiomyofibroblastoma (H&E stain, ×12.5 and ×100 original magnification, respectively). The microphotographs (e–g) show a

botryoid rhabdomyosarcoma with cambium layer and positivity for actin, desmin, and myosin, respectively Avidin-Biotin Complex; ×100 original magnification for all three immunostains). Myogenin was also positive (not shown). In (h) is the microphotograph of a very rare melanoma of the vagina (hematoxylin and eosin staining, ×400 original magnification)

8.10 Tumors of the Vagina

superficial myofibroblastoma, Brenner tumor, and benign mixed tumor (aka spindle-cell epithelioma) (DDX: Teratoma). Other rarer tumors are hymenal polyp and polyposis vaginalis.

8.10.2 Precancerous Conditions and Malignant Tumors Precancerous conditions of the vagina are collected under the acronym of VAIN (I-II-III), which will be examined in detail in the next paragraph.

8.10.2.1  Vaginal Intraepithelial Neoplasia (VAIN I–III) VAIN and squamous cell (or epidermoid) carcinoma of the vagina are usually considered rare entities in childhood, but they may indeed occur in women aged less than 25  years. In the Automated Central Tumor Registry (ACTUR), the cancer registry for the US Department of Defense was used by You et al. (2005) to identify children to young adults diagnosed with malignancies of the female genital tract. ACTUR data between 1990 and 2002 were then compared with data obtained from the national Surveillance, Epidemiology, and End Report (SEER) program database, which demonstrated a similar distribution and incidence patterns. Squamous cell carcinoma of the vagina/vulva was about 1/3 of the most common histologic types, and the 21- to 25-year-old age group had the most number of cases for the entire group. Pediatric pathologists should be aware of these rare entities, because of the most efficient and productive application of health maintenance programs for patients in this age group (e.g., pelvic exams and Pap test screening). Unlike in the cervix, the intraepithelial neoplasia of the vagina arise from native squamous epithelium and not from metaplastic epithelium as in cervix. Approximately half of the cases are multifocal and often associated with other neoplasms of the lower genital tract. VAIN is usually located in upper 1/3 of the vagina and may show some tendency to the confluence with similar

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lesions in the cervix. DDX: urothelial (transitional) metaplasia. VAIN may range from mild dysplasia to carcinoma in situ and is amenable to local treatment, including local excision, partial vaginectomy, CO2, laser therapy, and 5-FU (Fluorouracil). Risk factors for VAIN or vaginal SqCC are (1) age at first sexual intercourse, (2) # of sexual partners (promiscuity), (3) conditions associated with immunosuppression, (4) tobacco use, (5) HPV status, and (6) malignancy of squamous cell differentiation elsewhere in the female genital tract.

8.10.2.2  Vaginal Epidermoid Carcinoma Approximately 95% of primary vaginal carcinomas are squamous cell-based but with different degree of squamous differentiation, occurring in the upper posterior vagina of elderly and maybe ± for HPV and/or postradiation locally. A cervical SqCC needs to be ruled out, before making the diagnosis of a primary vaginal SqCC. PGN: 5-YSR, ~40% and related to histology and staging (N1, M1). Therapy includes radiation (external, intracavitary), local excision, or radical surgery for upper 1/3 or posterior wall. If tumor recurs  5 cm, infiltrative markers, MI  >  5/10 HPF, and moderate/severe cytologic atypia. Ultimately, the diagnosis of leiomyoma should be made if only one of these criteria is reached, atypical leiomyoma in case of two definite criteria, and leiomyosarcoma, in

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Fig. 8.21  The microphotographs in (a, b) show a condyloma with cytopathic changes (H&E stains, x12.5 and x200 original magnification, respectively); the microphotographs in (c, d) show vulvar intraepithelial neoplasia (VIN) III differentiated (H&E stain; x12.5 and x100 original magnifica-

tions), while the microphotographs in (e, f) show an extramammary Paget of the vulva (H&E stain, x100 and x400 original magnification, respectively). Vulvar lichen sclerosus starts as early as the child is 8 years old as recently identified. Vulvar lichen sclerosus can progress to VIN

case of three. Finally, pseudosarcomatous fibroepithelial stromal polyp (pregnancy) or POSNs should be differentiated from malignant mesenchymal tumors (Figs. 8.21 and 8.22).

lesions in this age group. In 95% malignancies are of squamous cell carcinoma and in 9 out 10 cases are HPV16 or HPV18 positive. Malignant lesions can be multicentric and associated with vulvar intraepithelial neoplasia (VIN) III (CIS or Bowen disease). Progression of malignancy is commonly seen when the patient is older and/or immunosuppression is present. The metastatic burden is linked to size (Ø  2 cm), depth of invasion (θ), and/or ALVI.

8.11.2 Malignant Tumors In childhood, adolescence and youth benign neoplasms of the vulva may occur and need to be taken into account in the DDX of vulvar

8.11 Tumors of the Vulva

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Fig. 8.22  This panel shows another botryoid rhabdomyosarcoma (a-d), here located at the vulva with a characteristic cambium layer (H&E stain; x20, x100, x400, x400 original magnification, respectively)

8.11.2.1  Precancerous Malignant Conditions Precancerous lesions may occur in the youth and particularly important is to remember if the patient is immunocompetent or immunosuppressed or harbors some genetic disease like xeroderma pigmentosum.

classic VIN lesions. VIN3 features include traditional nuclear enlargement, hyperchromasia, and multinucleation in the lower epithelial layers with or without abnormal mitoses and apoptosis with “corps rounds”. On the surface, there is atypical parakeratosis with or without koilocytotic atypia. Classic VINs has also been subclassified into warty and basaloid types. Vulvar Intraepithelial Neoplasia (VIN) Bowenoid papulosis or Bowenoid dysplasia is Premalignant uni-/multifocal lesion, whose inci- a type of VIN with multiple small papules, often dence has markedly increased recently due to pigmented, in the vulva of young women, which most diffuse screening programs, has become looks like many warts. Bowenoid papulosis does more often diagnosed in young women (20– not typically progress to invasive carcinoma but 35 years). Its association with HPV and the early may recur and needs to be distinguished from presentation should be a stimulus for pediatric Bowen disease or CIS. Microscopically, there are pathologists to investigate these lesions. atypical cells in a background of orderly epitheVIN-1 is still not correctly defined. VIN-1 lium with sparing of acrotrichium, which the includes flat condylomas and acanthotic lesions uppermost distal part of the infundibular epiderwith mild atypia that are not incorporated into mis that traverses the epidermis (Greek ἄκρος, either the condyloma or classic VIN categories. It “highest”, τρίχωμα, “hair”, and -ium). is often used the classification LSIL/HSIL with Bowen disease is CIS (squamous cell carcilow-grade squamous intraepithelial lesion (VIN-­ noma in situ), i.e., a type of VIN, with full-thick1) for condyloma and high-grade squamous ness disorganization of the squamous epithelium intraepithelial lesion (HSIL; VIN-2/VIN-3) for with hyperkeratosis, parakeratosis, acanthosis,

820

multinucleated dyskeratotic cells, and abnormal mitoses throughout total thickness with intercellular bridges ± intraepidermal involvement of hair follicle (acrotrichium) but sparing of the sweat gland counterpart (acrosyringium) (HPV+, p16+). John T. Bowen, an American dermatologist, described this lesion in 1912. Differentiated (simplex) VIN should be considered a form of the preinvasive vulvar disease characterized by maturation, variable hyperplasia, keratinization, and parabasal atypia. Interestingly, nuclear atypia remains confined to the cells at the epithelial-stromal interface, and the atypia is not observed in the upper epithelial layers. This situation is different from other HSIL associated with HPV, and it has been suggested that the genetically altered cells retain the capacity to mature. Conservative excision and careful follow-up are part of the management of this lesion. Differentiated (simplex) VIN is not a diagnosis of young and middle-aged women, being more common in older women that share the clinical manifestations with vulvar lichen sclerosus and lichen simplex chronicus. Patterns of differentiated VIN include lichen sclerosus with basal atypia, prominent basal atypia with a strong lichenoid inflammatory presence, limited basal hyperchromasia with abnormal keratinocyte maturation, and differentiated VIN with variable keratinocyte maturation, hyperkeratosis, and basal atypia, and finally, discrete keratinocytes with dyskeratosis. DDX includes mainly psoriasis, spongiotic dermatitis, Candida vulvitis, which are all conditions that may be present in young females. Atypia in vulvar lesions needs to be carefully ruled out. It occurs as (1) squamous cell hyperplasia, (2) lichen sclerosus, (3) intraepithelial neoplasia, VIN I (mild dysplasia), (4) intraepithelial neoplasia, VIN II (moderate dysplasia), (5) intraepithelial neoplasia, VIN III (severe dysplasia)  =  CIS, (6) vulvar extramammary Paget disease, and (7) melanoma in situ.

8.11.2.2  Vulvar Epidermoid Carcinoma Vulvar epidermoid carcinoma (VEC) accounts for 95% of vulvar carcinomas and is more often seen in the sixth to seventh decades, although

8  Female Genital System

rarely may be encountered in female individuals younger than 30  years. Locations are usually labia majora, but it may be also found on labia minora and clitoris. RF include cervical carcinoma, genital granulomatous disease, immunodeficiency, promiscuity, and a tobacco smoking habit. • CLM: VEC is usually well-differentiated, but tumors on the clitoris may be more anaplastic, and VIN may be found at margins of the neoplasm. High-grade lesions may show focal glandular differentiation, although it is correct not to overcall adenosquamous subtype when you found yourself in this kind of settings. Depth of invasion characterizes the microinvasive squamous cell carcinoma (θ  stroma and the glandular configuration seem overall maintained).

9.3 Pathology of the Female and Young Adult

Microscopically, FA is circumscribed and composed of both proliferating glandular and stromal elements. The epithelial (glandular) component shows always a myoepithelium (ME) cell layer and no atypia, whereas the stromal c­ omponent, which should be not very cellular (DDX: phyllodes tumor), may contain cartilage and smooth muscle (hamartoma/choristoma). FCD may also be present, and the simultaneous occurrence is called fibroadenomatosis when FA merges specifically and undoubtedly with surrounding FCD.  SA, apocrine metaplasia, and squamous metaplasia may also occur (Fig. 9.3). Variants: 1. Juvenile: Afro-American adolescents, often bilateral and may be very large and have highly cellular stroma and glands (DDX: phyllodes tumor). 2. Myxoid: FA with prominent myxoid change ± Carney complex (cardiac and cutaneous myxomas, spotty pigmentation, and endocrine overactivity) ⇒ ↑ risk of recurrence. 3. Degenerative change-accompanied FA: FA ± stromal hyalinization, epithelial atrophy, calcification, and ossification. 4. Fibroadenomatoid change: Multiple adjacent TDLU with FA-like changes without forming a well-defined nodule or mass. 5. Complex FA: It is designated an FA with cysts with Ø > 3 mm, SA, non-SA epithelial hyperplasia, or papillary apocrine metaplasia. 6. Malignancy-arising FA: FA with a malignancy arising in a setting of an FA with >50% of lobular type. In most half of the investigated female patients, there is an obvious invasive carcinoma elsewhere in the mammary gland. Malignant transformation: 0.1%  →  LCIS (good PGN). A sarcomatous transformation still remains a rare event. Fine needle aspiration cytology (FNAC) plays a major role in breast pathology, and the quality improved enormously in the last two decades. Excellent textbooks of cytopathology can help the non-experienced and experienced pediatric pathologist in dealing with FNAC specimens.

841

9.3.4 Adenoma DEF: Any focal primary hyperplastic/adenomatous process of the epithelial (glandular) component of the breast, ± associated with pregnancy (lactating adenoma), characterized by a focal increase in the number of acini per lobule. It includes several histologic phenotypes:

9.3.4.1 Tubular Adenoma Circumscribed (no obviously right or straightforward capsule) firm tan-yellow mass composed of tightly packed regular small tubules with possible luminal secretion, but no cytoplasmic vacuoles. It may be part of a physiologic spectrum including lactating adenoma under different physiology (Fig. 9.3). 9.3.4.2 Lactating Adenoma Circumscribed gray-tan mass (no obvious and straightforward capsule) of densely packed regular round bilayered tubules with prominent secretory change (cytoplasmic vacuoles and luminal eosinophilic secretion) and scant stroma (no ductal compression), ± ↑ MI, no atypia. DDX: Tubular adenoma (luminal secretion may be present but lack of cytoplasmic vacuoles vs. noticeable lactational change), focal pregnancy-like change (focal changes vs. circumscribed mass or nodule), secretory carcinoma (sheetlike growth with focal infiltration and no myoepithelial cell (ME) layer vs. circumscribed mass of normal round tubules with ME cell layer). 9.3.4.3 Nipple Duct Adenoma (NDA) Periareolar compact (nodular) proliferation of small bilayered tubules lined by epithelial and myoepithelial cells featuring papillary pattern (intraductal hyperplasia) replacing/destroying the nipple. Fibrosis of adjacent stroma loose and no dense or desmoplastic stroma as seen in syringoadenomatous adenoma or SAN and tubular carcinoma, which shows neither basement membrane (BM) nor ME layer is an important feature of NDA. Other features of NDA include, continuity with the squamous epithelium of epidermis, peripheral clefting, oval nuclei, streaming, epithelial hyperplasia, and sclerosing adenosis foci. Keratin cysts or focal necrosis within proliferating ducts and bland cells in the epidermis that are

9 Breast

842

a

b

c

d

e

f

g

h

Fig. 9.3  In (a) is shown an FNAC of a fibroadenoma (Diff-Quik stain, 400×), in (b) an uninodular fibroadenoma (H&E stain, 20×), and in (c) a multinodular fibroadenoma (H&E stain, 12.5×) showing intralobular stroma enclosing partly open luminar spaces (pericanalicular) in (b) and compressed glandular spaces due to the stroma proliferation in (c). In (d, e) are microphotographs of a mixture of tubular adenoma (d) and fibroadenoma (e), both H&E stained and taken at 200× and 50× as original magnification. The collision tumor “tubular adenoma-fibroadenoma” is quite rare in childhood and youth. It shows the combined

pictures of a tubular adenoma with tightly packed tubules lined by epithelial and myoepithelial cells with little intervening stroma and those of a pericanalicular fibroadenoma showing intralobular stroma (fibrotic) enclosing glandular spaces, mostly with open lumina. The microphotographs (f, g, h) show immunohistochemical findings of the epithelial and stromal components highlighted by actin ((f) antiactin antibody, 100×), CAM 5.2 ((g) CAM 5.2, 12.5×), and muscle-specific actin ((g) anti-MSA, 100×). CAM 5.2 is a low molecular weight cytokeratin marker that identifies cytokeratins 7 and 8, but not to cytokeratin 18 or 19

9.3 Pathology of the Female and Young Adult

scattered or in small aggregates which are CAM5.2+, CK7+, CEA-, and HER2-, no atypia, and no cribriform component are also some additional features of NDA. DDX includes SAN and subareolar sclerosing duct hyperplasia, which is characterized by central sclerosis entrapping and distorting ducts with a pattern similar to radial scar (RS).

9.3.4.4 Syringomatous Adenoma of the Nipple (SAN) Haphazard proliferation of irregular, angulated, and comma-shaped tubules with compressed and open lumina, which may be widely separated by fibrous stroma, similar to the cutaneous syringoma, with permeative character (not destructive, unlike NDA), ME cell layer, small basophilic cells without intraductal hyperplasia, atypia or ±  ↑ MI, and ± squamous metaplasia (unlike tubular carcinoma that lacks squamous metaplasia). DDX: SAN vs. nipple adenoma (SAN permeates the nipple stroma, while NDA replaces the nipple stroma). DDX: Tubular Ca. (single-­cell layer, ME markers (−), apical “snouting”, no squamous metaplasia). 9.3.4.5 Intraductal Papilloma, Papillomatosis, and “Encysted Intraductal Papillary Carcinoma” The intraductal papilloma can arise in large or small ducts and is not rare in young females. Typically, intraductal papilloma presents with bloody nipple discharge and is solitary in the majority of the cases. However, sometimes more than 2–3 papillomas are found, and the term papillomatosis is used. Microscopically, there is an intricate, cellular, “arborescent” pattern which is a feature of all papillomas. Benignancy criteria include small size (75% tubules, 2 points if 10–75% tubules, 3 points if 95%, but 1/10 prone to metastasize). IHC: (+) ER, EMA, but (−) Her2. DDX: Sclerosing adenosis (SA), radial scar, microglandular adenosis, and micropapillary adenosis. • Cribriform: Tightly linked to a tubular variant, harboring an excellent prognosis and showing infiltrating tubular structures with a prominent cribriform pattern. • Mucinous (aka mucoid, colloid – but only if the non-mucinous component is 75% of tumor) with no glandular differentiation, indistinct cell borders, cytologically high-grade, large pleomorphic cells, large nucleoli, and high MI, (2) pushing borders, and (3) prominent lymphoplasmacytic cellular infiltrate at periphery (T cell-markers positive; IgA+), often with germinal centers. PGN: Slightly better survival than classic ductal (~80 vs. ~60% in 10-YSR). Papillary: “Frond”-forming architecture with in situ component, pushing growth pattern, and excellent prognosis. Micropapillary: Malignant epithelial tufts exhibiting “reverse polarity” portend a poor prognosis. Apocrine: Large cells with abundant acidophilic, granular PAS+ cytoplasm and decapitation secretion and basally located nuclei. Neuroendocrine: Invasive ductal carcinoma with quite specific neuroendocrine differentiation (+CGA, SYN, CD56) lacking carcinoid syndrome clinically. Microscopically, there is an organoid pattern with solid nests of cells, ribbons, rosettes, and fibrous stroma. TEM: Dense core neurosecretory granules. PGN: Same as IDC. Metaplastic: Tumor belonging to the group of triple-negative (ER-, PR-, HER2-) mammary carcinomas. Metaplastic carcinomas are well-

9 Breast

circumscribed grossly. Microscopically, there is a mainly sarcomatoid look and there is an incontrovertible VIM (+) mesenchymal immunohistochemical staining. Epithelial markers may be demonstrated using single cytokeratins (CK7, CK19, and CK20) or panels (34BE12 or HMWCK, CAM5.2 or LMWCK, and MNF116, which react with keratins 5, 6, 8, 17 and probably also 19). PGN: 1/4 metastasize thus portend a more aggressive than the classic pattern. Subtypes include monophasic sarcomatoid, which is also known as spindle cell carcinoma and biphasic sarcomatoid carcinoma (aka carcinosarcoma or malignant mixed tumor) (Fig. 9.5). • Inflammatory: Clinically, red and warm breast with edema of skin showing a tumor, which is, microscopically, a carcinoma with extensive dermal lymphatic invasion. PGN: Ominous (pT4d).

9.3.9 Sweat Gland-Type Tumors and Myoepithelial Tumors Since the mammary gland is a particular sweat gland, some tumors usually occurring in the salivary glands and bronchial system may also be seen in the mammary gland as well. Salivary gland-type tumors of the breast are traditionally pleomorphic adenoma, adenoid cystic carcinoma, acinic cell carcinoma, and mucoepidermoid carcinoma. Pleomorphic adenoma of the breast (PAB, aka benign mixed tumor) has been reported in the breast but also in other, less common, sites such as the paranasal sinuses, larynx, palate, and nasal septum other than the usual major and minor salivary glands. In the skin, it is known as chondroid syringoma. PAB is a circumscribed lesion grossly that is characterized microscopically by a mixture of epithelial and myoepithelial cells embedded in abundant stroma with ≥1 of the following matrices: (1) myxoid, (2) chondroid, or (3) osseous. The youngest patient that has been reported in the biomedical literature was 23 years old, but a wide age range has been observed according to my records and consultations.

9.3 Pathology of the Female and Young Adult

Adenoid cystic carcinoma: Carcinoma with two types of cavity formations, right glands and eosinophilic “cylinders” containing PAS+BM material (collagen IV). It needs to be differentiated from the much more common intraductal cribriform carcinoma. PGN: Poor (LN MTX in 6%; lung MTX in 12%). Acinic cell carcinoma and mucoepidermoid carcinoma are rare entities and similar to the counterparts seen in the salivary glands and bronchial system. Other tumors include eccrine spiradenoma (sharply circumscribed lobules with small lumina and basaloid cells) and papillary clear cell hidradenoma (a pedunculated tumor with intracystic and papillary architecture and clear and granular bi-epithelial cell types). A myoepithelial tumor that should be considered in the differential diagnosis is the so-called adenomyoepithelioma, which is one of the most common myoepithelial tumors and shares similar features with its counterpart of the salivary glands and bronchial system.

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(from the homologous avian virus, myelocytomatosis, or v-myc and its homologous human gene overexpressed in several cancers or C-MYC), EGFR, IGF1R (insulin growth factor 1 receptor), and TERT  and PDZ (for PSD95, discs large, and ZO-1) (gene-related) domains are conserved protein-­protein interaction modules. PDZ domains comprised of ∼80 to 100 amino acids and recognize specific carboxy-terminal sequences. Typically, they exist in proteins as tandem repeats and act as molecular scaffolds to facilitate the assembly of macromolecular complexes. • GRO: The tumor is somewhat round, quite firm, well-­circumscribed, with the solid graywhite cut surface containing cleft-like spaces with or without hemorrhage and necrosis. • CLM: Phyllodes tumors have benign glandular elements with hypercellular, CD34+ stroma (“stroma overgrowth”) harboring progesterone receptors (PR) but lacking ER. PR is NR3C3 or nuclear receptor subfamily 3, group C, member 3 as indicated in the official name and is activated by the steroid hormone progesterone. The neoplasm forms cellular 9.3.10 Phyllodes Tumor leaflike processes protruding into cystic spaces lined by epithelial and myoepithelial • DEF: Phyllodes tumor (an early name was cells. The hypercellular stroma may range “cystosarcoma phyllodes”) is considered the from a predominantly periductal fibroblastic “malignant” counterpart of fibroadenoma with appearance with foci of mature adipose tissue low- or high-malignancy potential. It is a mesto marked nuclear atypia and mitoses as well enchymal neoplasm with biphasic components. as metaplastic tissue (cartilage, bone, and • EPG: The tumorigenesis of a phyllodes tumor skeletal muscle). Metaplasia implies the transwith the involvement of three genes, including formation of one type of tissue into another, TERT1, MED12, and EGFR. There is a critii.e., to mold into a new form (Greek: μετάcal role of TERT (telomerase reverse tranand πλάσσειν, which is the present active scriptase) promoter mutations, located in infinitive of πλάσσω). Cambium layer is also 5p15.33, in cooperation with MED12 (mediaoften present with s­ubepithelial stroma contor complex subunit 12 genes) mutations, also densation (Box 9.5) (Fig.  9.6). If FA has no of epithelial growth factor receptor (EGFR), infiltration into the surrounding tissue, no in the development of phyllodes tumors. The cambium layer, no atypia, and low MI, the most commonly reported chromosomal copy biphasic neoplasms of low and high grade number alterations in phyllodes tumors are 1q have a different story. gain and 13q, 6q, and 9p losses, and gene • PGN: It is usually benign with locally aggresamplifications involve MDM2 (mouse double sive behavior. Although rare in adolescence it minute 2 homolog), MDM4, RAF1 (virus-­ is present in young females (female youth). induced rapidly accelerated fibrosarcoma), Low grade →  tendency for local recurrence, PDZD2 (PDZ domain containing 2), MYC but high grade harbors an increased potential to

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852

Box 9.5 Distinguishing Features of Biphasic Neoplasms Size Stroma Cambium layer Architecture Atypia Margins MI

LG-PT ~ small Moderate (+)

HG-PT ~ large High (+)

Leaflike, cystic G1-G2 “Pushing” 3/10HPF

Notes: FA, fibroadenoma; LG-PT, low-­grade phyllodes tumor; HG-PT, high-grade phyllodes tumor; ~ variable; G1-G2, mild to moderate grade of atypia (G1, well differentiated = mild atypia, G2, moderately differentiated  =  moderate atypia); G3, poorly differentiated  =  severe atypia. In botany, cambium layer is identified in plants and considered a meristematic tissue (Greek: μεριστός: “divided”) between the inner bark or phloem and the wood or xylem. Cambium layer is responsible for the growth of stems and roots by producing new phloem on the outside and new xylem on the inside in stems. CD10 and CD117 are expressed with increased frequency in HG-PT.  HG-PT (benign epithelial component, spindle cell component HMWCK/p63-, and no squamous differentiation) needs to be differentiated from metaplastic carcinoma (malignant epithelial component, spindle cell component HMWCK/p63+, and ± squamous differentiation). EGFR gene amplification is seen in HG-PT.

metastasize (3–12% incidence of metastases, usually lung or bones – rarely axillary nodes).

9.4

Cancer Mimickers

9.4.1 Hyperplasia, Ductal and Lobular Summarizing the degenerative and premalignant disorders, nonproliferative breast changes

are, indeed, constituted by three elements that may participate variably to the formation of the pathology. The three elements are cysts, adenosis, and fibrosis. Proliferative breast disease without atypia includes epithelial hyperplasia (mild/moderate), SA, radial scar/complex sclerosing lesion, and papilloma. Proliferative disorders with atypia include atypical ductal hyperplasia and atypical lobular hyperplasia. Hyperplasia, ductal and lobular, is defined as an epithelial proliferation or “epitheliosis” (according to some other authors) of the TDLU at ductal or lobular level with a slightly increased risk for invasive carcinoma. Relative Risk of Infiltrating Carcinoma according to Grading I Mild hyperplasia 1 II Moderate or florid hyperplasia 1.5 4.5 III Atypical ductal or lobular hyperplasia (ADH/ALH) (aka DIN1b) (DIN, ductal intraepithelial neoplasia) IV In situ ductal/lobular carcinoma (DCIS/ 9 LCIS) (aka DIN1c-DIN2-DIN3)

Usual ductal hyperplasia (UDH), aka “low-­ risk ductal intraepithelial neoplasia or DIN” (partly not encompassing with the lesion “flat DIN 1a” or “flat epithelial atypia”), is also classified as: –– Mild Hyperplasia, if ≤4 cells thick extending upward from the BM –– Moderate Hyperplasia, if >4 cells thick extending upward from the BM and potential some bridging in the lumen –– Florid (Flourishing) Hyperplasia, if the lumen is distended and potentially obliterated (a flower may be used to remember this structure with a core and some petals as distending lumens) However, there is no natural necessity to distinguish moderate from florid hyperplasia, because they are usually grouped to form a single category for risk assessment according to numerous authors. Most probably, it is not only an academic distinction, but it will be important in the future. However, it is imperative to remember that in UDH the luminal spaces observed histologically show preservation of a peripheral par-

9.4 Cancer Mimickers

853

a

b Specialized breast stromal cell

MED12 (exon 2)

Fibroadenoma Benign phyllodes Tumor cell

TERT +/– EGFR +/– other oncogenes/TSG (MED12 independent)

TERT +/– other oncogenes/TSG Borderline/malignant Phyllodes tumor cell

d

c

e Pathology feature

Benign

Borderline

Malignant

Atypia (stromal) Hyperplasia (interstitial) Mitotic index Tumor borders

Mild Mild 10/10 HPF (d) Size > 4cm (e) Eosinophilic globules • BRS-8 Which of the following statements is NOT correct? (a) Mammography represents an investigation of assessing breast masses effectively in a pediatric patient. (b) Over 50% of fibroadenomas resolve spontaneously over 5–10 years. (c) Juvenile fibroadenomas are more common in girls of African American ethnics.

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(d) Malignant phyllodes tumor is the most common primary pediatric malignancy of the breast.

References and Recommended Readings 1. Abou-Zamzam A, Somers S, Cora C, Pairawan S, Lum S. Percutaneous needle biopsies of the breast in women younger than 35 years: minimally or excessively invasive? Am Surg. 2017;83(10):1019–23. PubMed PMID: 29391087. 2. Al Jishi T, Sergi C.  Current perspective of diethylstilbestrol (DES) exposure in mothers and offspring. Reprod Toxicol. 2017;71:71–7. https://doi. org/10.1016/j.reprotox.2017.04.009. Epub 2017 Apr 28. Review. PubMed PMID: 28461243. 3. Bacchi CE, Silva TR, Zambrano E, Plaza J, Suster S, Luzar B, Lamovec J, Pizzolitto S, Falconieri G.  Epithelioid angiosarcoma of the skin: a study of 18 cases with emphasis on its clinicopathologic spectrum and unusual morphologic features. Am J Surg Pathol. 2010;34(9):1334–43. https://doi.org/10.1097/ PAS.0b013e3181ee4eaf. PubMed PMID: 20697249. 4. Berkey CS, Willett WC, Frazier AL, Rosner B, Tamimi RM, Rockett HR, Colditz GA.  Prospective study of adolescent alcohol consumption and risk of benign breast disease in young women. Pediatrics. 2010;125(5):e1081–7. https://doi.org/10.1542/ peds.2009-2347. Epub 2010 Apr 12. PubMed PMID: 20385629; PubMed Central PMCID: PMC3075610. 5. Bezić J, Karaman I, Šundov D.  Combined fibroadenoma and tubular adenoma of the breast: rare presentation that confirms common histogenesis. Breast J. 2015;21(3):309–11. https://doi.org/10.1111/ tbj.12400. Epub 2015 Mar 17. PubMed PMID: 25775939. 6. Boettger MB, Sergi C, Meyer P. BRCA1/2 mutation screening and LOH analysis of lung adenocarcinoma tissue in a multiple-cancer patient with a strong family history of breast cancer. J Carcinog. 2003 Oct 2;2(1):5. PubMed PMID: 14583096; PubMed Central PMCID: PMC239936. 7. Colditz GA, Bohlke K, Berkey CS. Breast cancer risk accumulation starts early: prevention must also. Breast Cancer Res Treat. 2014;145(3):567–79. https://doi. org/10.1007/s10549-014-2993-8. Epub 2014 May 13. Review. PubMed PMID: 24820413; PubMed Central PMCID: PMC4079839. 8. Connor AE, Baumgartner RN, Pinkston C, Baumgartner KB.  Obesity and risk of breast cancer mortality in Hispanic and Non-Hispanic white women: the New Mexico Women’s Health Study. J Womens Health (Larchmt). 2013;22(4):368–77. https://doi.org/10.1089/jwh.2012.4191. Epub 2013

858 Mar 26. PubMed PMID: 23531051; PubMed Central PMCID: PMC3627406. 9. D’Angelo P, Carli M, Ferrari A, Manzitti C, Mura R, Miglionico L, Di Cataldo A, Grigoli A, Cecchetto G, Bisogno G, AIEOP Soft Tissue Sarcoma Committee. Breast metastases in children and adolescents with rhabdomyosarcoma: experience of the Italian Soft Tissue Sarcoma Committee. Pediatr Blood Cancer. 2010;55(7):1306–9. https://doi.org/10.1002/pbc.22729. Epub 2010 Aug 20. PubMed PMID: 20730885. 10. Danner-Koptik KE, Majhail NS, Brazauskas R, Wang Z, Buchbinder D, Cahn JY, Dilley KJ, Frangoul HA, Gross TG, Hale GA, Hayashi RJ, Hijiya N, Kamble RT, Lazarus HM, Marks DI, Reddy V, Savani BN, Warwick AB, Wingard JR, Wood WA, Sorror ML, Jacobsohn DA.  Second malignancies after autologous hematopoietic cell transplantation in children. Bone Marrow Transplant. 2013;48(3):363–8. https:// doi.org/10.1038/bmt.2012.166. Epub 2012 Sep 10. PubMed PMID: 22964594; PubMed Central PMCID: PMC3525761. 11. Djakovic A, Engel JB, Geisinger E, Honig A, Tschammler A, Dietl J.  Pleomorphic adenoma of the breast initially misdiagnosed as metaplastic carcinoma in preoperative stereotactic biopsy: a case report and review of the literature. Eur J Gynaecol Oncol. 2011;32(4):427–30. Review. PubMed PMID: 21941969. 12. East EG, Zhao L, Pang JC, Jorns JM. Characteristics of a breast pathology consultation practice. Arch Pathol Lab Med. 2017;141(4):578–84. https://doi. org/10.5858/arpa.2016-0371-OA. PubMed PMID: 28353380. 13. Fallon SC, Hatef DA, McKnight AJ, Izaddoost SA, Brandt ML.  Congenital synmastia with concurrent fibroadenomas in a pediatric patient. J Pediatr Surg. 2013;48(1):255–7. https://doi.org/10.1016/j.jpedsurg.2012.10.053. PubMed PMID: 23331826. 14. Farley-Loftus R, Bossenbroek NM, Rosenman K, Schaffer JV. Clear cell papulosis. Dermatol Online J. 2008;14(10):19. PubMed PMID: 19061618. 15. Ferrari A, Casanova M, Massimino M, Sultan I.  Peculiar features and tailored management of adult cancers occurring in pediatric age. Expert Rev Anticancer Ther. 2010;10(11):1837–51. https://doi. org/10.1586/era.10.105. Review. PubMed PMID: 21080807. 16. Ferreira CG, de Melo AC, Nogueira-Rodrigues A. The adolescent and young adult with cancer: state of the art--epithelial cancer. Curr Oncol Rep. 2013;15(4):287–95. https://doi.org/10.1007/s11912013-0322-8. Review. PubMed PMID: 23754487. 17. Forsman CL, Ng BC, Heinze RK, Kuo C, Sergi C, Gopalakrishnan R, Yee D, Graf D, Schwertfeger KL, Petryk A.  BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. Dev Biol. 2013;373(1):95–106. https://doi. org/10.1016/j.ydbio.2012.10.007. Epub 2012 Oct 24. PubMed PMID: 23103586; PubMed Central PMCID: PMC3508155.

9 Breast 18. Frank B, Meyer P, Boettger MB, Hemminki K, Stapelmann H, Gast A, Schmitt C, Kumar R, Sergi C, Burwinkel B.  ARLTS1 variants and melanoma risk. Int J Cancer. 2006;119(7):1736–7. PubMed PMID: 16646072. 19. Frazier AL, Rosenberg SM.  Preadolescent and adolescent risk factors for benign breast disease. J Adolesc Health. 2013;52(5 Suppl):S36–40. https:// doi.org/10.1016/j.jadohealth.2013.01.007. PubMed PMID: 23601609. 20. Ghilli M, Mariniello DM, Fanelli G, Cascione F, Fontana A, Cristaudo A, Cilotti A, Caligo AM, Manca G, Colizzi L, Naccarato AG, Roncella M.  Carcinosarcoma of the breast: an aggressive subtype of metaplastic cancer. Report of a rare case in a young BRCA-1 mutated woman. Clin Breast Cancer. 2017;17(1):e31–5. https://doi.org/10.1016/j. clbc.2016.08.002. Epub 2016 Aug 30. PubMed PMID: 27697421. 21. Gilleard O, Goodman A, Cooper M, Davies M, Dunn J. The significance of the Van Nuys prognostic index in the management of ductal carcinoma in situ. World J Surg Oncol. 2008;6:61. https://doi.org/10.1186/14777819-6-61. PubMed PMID: 18564426; PubMed Central PMCID: PMC2459183. 22. Gupta SS, Singh O. Cystic lymphangioma of the breast in an 8-year-old boy: report of a case with a review of the literature. Surg Today. 2011;41(9):1314–8. https:// doi.org/10.1007/s00595-010-4382-1. Epub 2011 Aug 26. Review. PubMed PMID: 21874439. 23. Henderson TO, Amsterdam A, Bhatia S, Hudson MM, Meadows AT, Neglia JP, Diller LR, Constine LS, Smith RA, Mahoney MC, Morris EA, Montgomery LL, Landier W, Smith SM, Robison LL, Oeffinger KC.  Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med. 2010;152(7):444–55; W144-54. https://doi. org/10.7326/0003-4819-152-7-201004060-00009. Review. PubMed PMID: 20368650; PubMed Central PMCID: PMC2857928. 24. Herman JD, Appelbaum H.  Hereditary breast and ovarian cancer syndrome and issues in pediatric and adolescent practice. J Pediatr Adolesc Gynecol. 2010;23(4):253–8. PubMed PMID: 20632459. 25. John K, Becker K, Mattejat F.  Impact of family-­ oriented rehabilitation and prevention: an inpatient program for mothers with breast cancer and their children. Psychooncology. 2013; https://doi.org/10.1002/ pon.3329. [Epub ahead of print] PubMed PMID: 23760766. 26. Kapila K, Pathan SK, Al-Mosawy FA, George SS, Haji BE, Al-Ayadhy B. Fine needle aspiration cytology of breast masses in children and adolescents: experience with 1404 aspirates. Acta Cytol. 2008;52(6):681–6. PubMed PMID: 19068671. 27. Karadeniz E, Arslan S, Akcay MN, Subaşi ID, Demirci E.  Papillary lesions of breast. Chirurgia (Bucur). 2016;111(3):225–9. PubMed PMID: 27452933. 28. Kim SW, Roh J, Park CS.  Clear cell papulosis: a case report. J Pathol Transl Med. 2016;50(5):401–3.

References and Recommended Readings https://doi.org/10.4132/jptm.2016.02.16. Epub 2016 May 29. PubMed PMID: 27237133; PubMed Central PMCID: PMC5042892. 29. Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998;18(2):184– 7. https://doi.org/10.1038/ng0298-184. PMID 9462753. 30. Kuijper A, Mommers EC, van der Wall E, van Diest PJ. Histopathology of fibroadenoma of the breast. Am J Clin Pathol. 2001;115(5):736–42. PubMed PMID: 11345838. 31. Kulkarni D, Dixon JM.  Congenital abnormali ties of the breast. Women’s Health (Lond Engl) 2012;8(1):75–86; quiz 87–8. https://doi.org/10.2217/ whe.11.84. Review. PubMed PMID: 22171777. 32. La Rocca G, Anzalone R, Corrao S, Magno F, Rappa F, Marasà S, Czarnecka AM, Marasà L, Sergi C, Zummo G, Cappello F.  CD1a down-regulation in primary invasive ductal breast carcinoma may predict regional lymph node invasion and patient outcome. Histopathology. 2008;52(2):203–12. https:// doi.org/10.1111/j.1365-2559.2007.02919.x. PubMed PMID: 18184269. 33. Laé M, Gardrat S, Rondeau S, Richardot C, Caly M, Chemlali W, Vacher S, Couturier J, Mariani O, Terrier P, Bièche I.  MED12 mutations in breast phyllodes tumors: evidence of temporal tumoral heterogeneity and identification of associated critical signaling pathways. Oncotarget. 2016;7(51): 84428–38. https://doi.org/10.18632/oncotarget.12991. PubMed PMID: 27806318; PubMed Central PMCID: PMC5356671. 34. Lee JY, Chao SC. Clear cell papulosis of the skin. Br J Dermatol. 1998;138(4):678–83. PubMed PMID: 9640379. 35. Lemoine C, Mayer SK, Beaunoyer M, Mongeau C, Ouimet A. Incidental finding of synchronous bilateral ductal carcinoma in situ associated with gynecomastia in a 15-year-old obese boy: case report and review of the literature. J Pediatr Surg. 2011;46(9):e17–20. https://doi.org/10.1016/j.jpedsurg.2011.06.010. Review. PubMed PMID: 21929970. 36. Mizutani L, Tanaka Y, Kondo Y, Bando H, Hara H.  Glomus tumor of a female breast: a case report and review of the literature. J Med Ultrason (2001). 2014;41(3):385–8. https://doi.org/10.1007/s10396013-0517-5. Epub 2014 Jan 14. Review. PubMed PMID: 27277916. 37. Mosavel M, Genderson MW. From adolescent daughter to mother: exploring message design strategies for breast and cervical cancer prevention and screening. J Cancer Educ. 2013; 28(3):558–64. https://doi. org/10.1007/s13187-013-0503-z. PubMed PMID: 23813491; PubMed Central PMCID: PMC4046862. 38. Page DL, Rogers LW. Combined histologic and cytologic criteria for the diagnosis of mammary atypical ductal hyperplasia. Hum Pathol. 1992;23(10):1095–7. PubMed PMID: 1328030. 39. Richards MK, Goldin AB, Beierle EA, Doski JJ, Goldfarb M, Langer M, Nuchtern JG, Vasudevan S,

859 Gow KW, Javid SH. Breast malignancies in children: presentation, management, and survival. Ann Surg Oncol. 2017;24(6):1482–91. https://doi.org/10.1245/ s10434-016-5747-5. Epub 2017 Jan 5. PubMed PMID: 28058544. 40. Rodríguez Ogando A, Fernández López T, Rodríguez Castaño MJ, Mata Fernández C, Alvarez Bernardi J, Cebollero Presmanes M. Cystosarcoma phyllodes of the breast: a case report in a 12-year-old girl. Clin Transl Oncol. 2010;12(10):704–6. PubMed PMID: 20947486. 41. Sanchez R, Ladino-Torres MF, Bernat JA, Joe A, DiPietro MA.  Breast fibroadenomas in the pediatric population: common and uncommon sonographic findings. Pediatr Radiol. 2010;40(10):1681–9. https:// doi.org/10.1007/s00247-010-1678-7. Epub 2010 May 7. PubMed PMID: 20449731. 42. Sergi C, Dhiman A, Gray JA. Fine needle aspiration cytology for neck masses in childhood. An illustrative approach. Diagnostics (Basel). 2018;8(2):E28. https://doi.org/10.3390/diagnostics8020028. Review. PubMed PMID: 29690556. 43. Sillesen NH, Hölmich LR, Siersen HE, Bonde C.  Congenital symmastia revisited. J Plast Reconstr Aesthet Surg. 2012;65(12):1607–13. https://doi. org/10.1016/j.bjps.2012.08.008. Epub 2012 Sep 29. Review. PubMed PMID: 23026472. 44. Stasik CJ, Davis M, Kimler BF, Fan F, Damjanov I, Thomas P, Tawfik OW.  Grading ductal carcinoma in situ of the breast using an automated proliferation index. Ann Clin Lab Sci. 2011;41(2):122–30. PubMed PMID: 21844569. 45. Tang H, Liu F, Li H, Huang X, Zhao T. Pleomorphic carcinoma of breast: a case report and review of literature. Int J Clin Exp Pathol. 2014;7(8):5215–20. eCollection 2014. Review. PubMed PMID: 25197400; PubMed Central PMCID: PMC4152090. 46. Terenziani M, Casalini P, Scaperrotta G, Gandola L, Trecate G, Catania S, Cefalo G, Conti A, Massimino M, Meazza C, Podda M, Spreafico F, Suman L, Gennaro M.  Occurrence of breast cancer after chest wall irradiation for pediatric cancer, as detected by a multimodal screening program. Int J Radiat Oncol Biol Phys. 2013;85(1):35–9. https://doi.org/10.1016/j. ijrobp.2012.03.043. Epub 2012 Jun 5. PubMed PMID: 22677366. 47. Testa JR, Malkin D, Schiffman JD. Connecting molecular pathways to hereditary cancer risk syndromes. Am Soc Clin Oncol Educ Book. 2013;2013:81–90. https://doi.org/10.1200/EdBook_AM.2013.33.81. PubMed PMID: 23714463. 48. Tognon C, Knezevich SR, Huntsman D, Roskelley CD, Melnyk N, Mathers JA, Becker L, Carneiro F, MacPherson N, Horsman D, Poremba C, Sorensen PH.  Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002;2(5):367–76. https:// doi.org/10.1016/S1535-6108(02)00180-0. PMID 12450792. 49. Tse GM, Ni YB, Tsang JY, Shao MM, Huang YH, Luo MH, Lacambra MD, Yamaguchi R, Tan

860 PH.  Immunohistochemistry in the diagnosis of papillary lesions of the breast. Histopathology. 2014;65(6):839–53. https://doi.org/10.1111/ his.12453. Epub 2014 Oct 30. PubMed PMID: 24804569. 50. Wai DH, Knezevich SR, Lucas T, Jansen B, Kay RJ, Sorensen PH. The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene. 2000;19(7):906–15. https:// doi.org/10.1038/sj.onc.1203396. PMID 10702799. 51. Wang Y, Zhu JF, Liu YY, Han GP.  An analysis of cyclin D1, cytokeratin 5/6 and cytokeratin 8/18

9 Breast expression in breast papillomas and papillary carcinomas. Diagn Pathol. 2013;8:8. https://doi. org/10.1186/1746-1596-8-8. PubMed PMID: 23327593; PubMed Central PMCID: PMC3571902. 52. Zils K, Ebner F, Ott M, Müller J, Baumhoer D, Greulich M, Rehnitz D, Rempen A, Schaetzle S, Wilhelm M, Bielack S.  Extraskeletal osteosarcoma of the breast in an adolescent girl. J Pediatr Hematol Oncol. 2012;34(6):e261–3. https://doi.org/10.1097/ MPH.0b013e31823366b4. PubMed PMID: 22246152.

Hematolymphoid System

10

Contents 10.1

Development and Genetics

 862

10.2 10.2.1 10.2.2

Red Blood Cell Disorders  nemia A Polycythemia

 864  864  867

10.3 10.3.1 10.3.2 10.3.3

Coagulation and Hemostasis Disorders  oagulation and Hemostasis C Coagulation Disorders Platelet Disorders

 869  869  869  870

10.4 10.4.1 10.4.2 10.4.3 10.4.4 10.4.5 10.4.6 10.4.7 10.4.8 10.4.9 10.4.10 10.4.11 10.4.12 10.4.13 10.4.14 10.4.15 10.4.16 10.4.17 10.4.18 10.4.19

White Blood Cell Disorders  eukocytopenias and Leukocyte Dysfunctionalities L Non-neoplastic Leukocytosis Leukemia (Neoplastic Leukocytosis) or Virchow’s “Weisses Blut” Myelodysplastic Syndromes Hodgkin Lymphoma Non-Hodgkin Lymphomas Follicular Lymphoma Small Lymphocytic Lymphoma Mantle Cell Lymphoma (MCL) Marginal Cell Lymphoma Diffuse Large B-Cell Lymphoma (DLBCL) Lymphoblastic Lymphoma Burkitt Lymphoma Peripheral T-Cell Lymphoma Anaplastic Large Cell Lymphoma Adult T-Cell Leukemia/Lymphoma Cutaneous T-Cell Lymphoma (CTCL) Angiocentric Immunoproliferative Lesions Extranodal NK-/T-Cell Lymphoma

 871  871  871  872  878  878  887  888  890  891  891  892  894  896  902  903  903  904  905  906

10.5 10.5.1 10.5.2

Disorders of the Monocyte-­Macrophage System and Mast Cells  emophagocytic Syndrome H Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-­Dorfman Disease) Langerhans Cell Histiocytosis Histiocytic Medullary Reticulosis

 907  907

10.5.3 10.5.4

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_10

 908  908  909

861

10  Hematolymphoid System

862 10.5.5 10.5.6

True Histiocytic Lymphoma Systemic Mastocytosis

 910  910

10.6 10.6.1 10.6.2 10.6.3 10.6.4 10.6.5 10.6.6

Plasma Cell Disorders  ultiple Myeloma M Solitary Myeloma Plasma Cell Leukemia Waldenstrom’s Macroglobulinemia Heavy Chain Disease Monoclonal Gammopathy of Undetermined Significance (MGUS)

 910  911  912  912  912  912  913

10.7 10.7.1 10.7.2 10.7.3 10.7.4 10.7.5 10.7.6

Benign Lymphadenopathies  ollicular Hyperplasia F Diffuse (Paracortical) Hyperplasia Sinus Pattern Predominant Granulomatous Pattern Other Myxoid Patterns Angioimmunoblastic Lymphadenopathy with Dysproteinemia (AILD)

 913  914  918  919  920  921  921

10.8 10.8.1 10.8.2

Disorders of the Spleen  hite Pulp Disorders of the Spleen W Red Pulp Disorders of the Spleen

 921  922  922

10.9 10.9.1 10.9.2 10.9.3 10.9.4

Disorders of the Thymus  hymic Cysts and Thymolipoma T True Thymic Hyperplasia and Thymic Follicular Hyperplasia HIV Changes Thymoma

 924  924  924  925  925

Multiple Choice Questions and Answers

 927

References and Recommended Readings

 930

10.1 Development and Genetics The spleen (adult organ weight, 150 g, 12 cm as adult size in its largest dimension) is a hematopoietic and immunologic paramedian and single organ. It is aimed to filter cells and toxins, act in the immunological system, produce lymphoreticular or hematopoietic cells, and is considered the platelet storage organ for excellence. The cortex consists of red and white pulp. The red pulp has venous sinuses, which seem to be unique in the human body being surrounded by reticulin (Ret) annular rings (“Ret Rings”), and lining cells, called “littoral cells,” which show a specific phenotype CD8+, CD31+, FVIIIRA+, but CD34-. These sinuses are separated by pulp cords of Billroth and terminal branches of the arterial system. The white pulp is made of periarteriolar T cells, Malpighian corpuscles including germinal center cells (GCC) (IgD−, BCL2−), mantle small B cells (IgD+, BCL2+), and marginal zone monocytoid B cells (IgD−, BCL2+). Thus, using two antibodies against IgD and BCL2, we may able to differentiate the three zones. In fact,

the pulp cord is a meshwork of macrophages, T cells, and B cells. The thymus is a median lymphoepithelial organ essential for the immunocompetency of the organism. –– Anterior mediastinum, pyramid-shape, thin fibrous capsule, lobular with cortex (dark staining) and medulla (light staining) with interconnecting component of epithelial cells that form the scaffolding for the maturing immune cells (perivascular spaces or PVS are devoid of CK+ epithelial cells but packed with small lymphocytes) and characteristic Hassal’s corpuscles with onion-skin layered keratinization. –– It originates from third and fourth pharyngeal pouches, a finding that is essential to correlate for neck remnants. –– Organ weight is steadily increasing after birth until 30–40 g at puberty, and then there is a gradual fatty tissue replacement with weight change. –– Function: T-cell maturation with a selection of cells able to form the repertoire of mature T

10.1 Development and Genetics

cells and deletion of cells that bind with high affinity to self-peptide antigens (Box 10.1).

Box 10.1 Immunophenotype of Thymus Cell Population

1. Cortical thymocytes, immature T cells: (+) TdT, CD1a, CD99a AND (+) cCD3 and (−) sCD3 2. Medullary thymocytes, mature T cells: (−) TdT, CD1a, CD99a AND (+) s/ cCD3 3. B cells: (+) CD19, CD20, CD22, CD23; (−) CD5, CD21, CD32, CD35a; (+) cIgD, IgM, IgG Note: s, surface; c, cytoplasmic; CD, cluster differentiation

TdT may be a quite tricky antigen to be detected, and there are a few positive and negative situations and pitfalls that should be taken into account in the routine of a surgical and clinical pathologist. In fact, TdT usually is positive immunohistochemically in hematogones (B- and T-cell precursors) and cortical thymocytes as well as focally in benign pediatric lymph nodes and pediatric tonsils and needs to be taken into account by the pathologist. This situation may cause possible confusion in patients with acute lymphoblastic leukemia. Pathologic positive staining, i.e., staining that indicates a pathological result and has influence for the proper management of the patient, is seen in acute lymphoblastic leukemia, acute myelogenous leukemia, myeloid sarcoma, plasmacytoid dendritic cell neoplasm (blastic phase), and thymoma (lymphocyte predominant). Another condition, i.e., Merkel cell carcinoma, is also positive, but it is practically inexistent in children and youth. Negative staining should be detected in myeloid cells and developed leukemias and lymphomas (e.g., Burkitt lymphoma, diffuse large B-cell lymphoma, MALT lymphoma, mantle cell lymphoma, and T-cell prolymphocytic leukemia). Moreover, negative staining is seen in sarcomas and lung cell carcinoma, small cell type.

863

The bone marrow is the central hematopoietic organ of the body and produces a number of approximately 200 billion new erythrocytes every day, along with leukocytes and platelets. Bone marrow also contains mesenchymal and hematopoietic stem cells. Hematopoietic stem cells located in the bone marrow give origin to two main types of cells: myeloid and lymphoid lineages. These include monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, dendritic cells, and megakaryocytes or platelets, as well as T cells, B cells, and natural killer cells. Polymorphonuclear leukocytes (PMN) are usually equivalent to the term of polymorphonuclear neutrophils or granulocytes. There are different types of hematopoietic stem cells, which vary in their regenerative capacity and potency. Some stem cells are multipotent, oligopotent, or unipotent as determined by how many types of cell they can generate. The advent of techniques (e.g., CRISPR-Cas9 of gene editing) and new methods of targeting cancer stem cells have been pillars in new protocols in oncology. The pluripotent hematopoietic stem cells have the properties of both renewal and differentiation. In regeneration, these cells can reproduce another cell identical to themselves, while in differentiation, these cells can generate ≥1 subsets of more mature cells. Multipotent hematopoietic stem cells emerge within the delicate environment of human embryonic arteries. This process seems to be, at least partially, independent from the primitive vitelline hematopoiesis and uses a “bed” vascular endothelial cell intermediate. At 24–26  days of early development, the aortic-genital-mesonephric (AGM) primitive zone, i.e., the embryonic region comprising the aorta, genital ridges, and mesonephros, starts to be hemogenic in vitro. This event happens before the appearance of aortic clusters of hematopoietic stem cells. Cell sorting and culture experiments have, indeed, revealed that bloodforming potential in the AGM is strictly confined to the CD34-negative, i.e., non-endothelial, cell fraction. It specifically points to either that ventral aortic endothelial cells switch suddenly to hematopoiesis at day 27 of the embryogenetic development or that more primitive, CD34-angiohematopoietic progenitors migrate through the periaortic mesenchyme and colonize the floor of the aorta at this embryonic age. A body of know-

10  Hematolymphoid System

864

eldge arising from recent studies seems to support that the second hypothesis the second hypothesis as “more” correct. This situation is based on the expression of Fetal Liver Kinase 1 or Flk-1, or its human ortholog vascular endothelial growth factor receptor 2 (VEGF-R2), in the early human embryo. Some studies of developmental biology have revealed that a population of Flk-1+  CD34 cells migrate from the splanchnopleure into the subaortic mesoderm during the 4th week of embryonic development. Of note, kinase insert domain receptor (KDR), which is a type IV receptor tyrosine kinase and is aka VEGFR-2 is essentially a VEGF receptor. KDR is the human gene encoding it. KDR has also received a CD label or number (CD309).

10.2 Red Blood Cell Disorders 10.2.1  Anemia • DEF: It is defined as a reduction in the amount of circulating hemoglobin (Hb), red blood cells (RBC), or both. There is an imbalance between one or both the components and there is inability from the body to replace one or both parts through two usually mutually exclusive but possibly combining mechanisms, including: 1. Excessive blood turnover showing an increased reticulocyte count (↑ Rets). 2. Failure of blood production showing a decreased reticulocyte count (↓ Rets) (Fig. 10.1). According to RBC size, anemia is subclassified into microcytic, normocytic, and macrocytic. According to Hb content, anemia is subclassified in hypochromic and normochromic. Microcytic hypochromic anemia characterizes the well-known condition of sideropenia or iron deficiency. • CLI: It may be remembered clinically as Pallor cutis et albor membranorum internorum, a Latin sentence recalling the signs and symptoms of anemia that also accompany tachysphygmia and tachycardia, shortness of breath, palpitations, dizziness, and fatigue. There may be heart failure in case of moder-

ate and severe anemia and fatigue with very few other symptoms, if anemia develops slowly and compensation occurs.

10.2.1.1 Anemia Due to Excessive Blood Turnover 1. Excessive blood turnover is due to bleeding (outside of the vascular system) or hemolysis (inside the vascular system) ⇒ Bone marrow (BM) erythroid hyperplasia with increased Rets in the peripheral blood • If haptoglobin is +, then bleeding is the cause of the excessive blood turnover. • If haptoglobin is −, then acute hemolysis is the cause of the excessive blood turnover. This situation is because haptoglobin (Hg) [not to be confused with the symbol of mercury] is a plasma protein able to keep the Fe elaborated from the small amount of Hb, which is usually in the plasma. Thus, Hb released in events of acute hemolysis, binds to Hg within a few hours, and serum Hg is unmeasurable because the complex Hb-Hg is cleared from the circulation by the reticulo-endothelial system (RES).  In constant excessive blood turnover, the absence of Fe in the BM aspirate or biopsy indicates blood loss to the outside, whereas Fe deposits are seen in any other type of anemia. –– Hemorrhage: Hemorrhage-Associated Anemias • If acute: Normochromic normocytic anemia (⇒ hypovolemic shock with tachycardia, which can progress to death) • If chronic: Hypochromic anemia (variable etiology: GI, e.g., ulcer, cancer, polyp; GU, e.g., cancer or lithiasis; and GYN, e.g., meno-/ metrorrhagia) –– Hemolysis: Congenital Hemolytic Anemias with Defects in (a) Hb structure ⇒ hemoglobinopathies, e.g., sickle cell anemia (Glu→Val at position 6 in the β-chain of Hb ⇒ HbS). This anemia is

10.2 Red Blood Cell Disorders

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a

Aplastic Anemia (severe)

 NS-CHL > LR-CHL). The worse ent from NHL owing to: prognosis, and high rate of RSC seem to follow LD-CHL. In the vast majority of CHL, the neo 1. The manner of spread (contiguous vs. simul- plastic cells are derived from mature B cells at taneous nodal involvement), i.e., lymph nodal the germinal center stage of differentiation and, regions are usually involved in HL using a rarely, from peripheral (post-thymic) T cells. step-by-step fashion from the neck to mediasTo remember is that EBV detection may be tinum to celiac tripod and extranodal regions, relevant for the diagnosis of IM, PTLD or other while coincident lymph nodal regions are immunodeficiency states, Burkitt lymphoma, involved and are usually seen in NHL. NK-cell neoplasm (aggressive NK-cell leukemia 2. Histology (polymorphic vs. monomorphic), and extranodal NK-/T-cell lymphoma, nasal i.e., the cell population is in HL polymorphic type), and immunoblastic/plasmablastic lymwith many reactive cells, including small lym- phoma other than HL. Viral-encoded proteins are phocytes, plasma cells, eosinophils, and LMP and EBNA-2 that may be detected by IHC,

10.4 White Blood Cell Disorders

while EBV-encoded RNA needs to be assessed by in situ hybridizations (ISH). Thus, both IHC and ISH are essential tools in the diagnostic workup of lymphomatous processes. NLPHL derives from a germinal center B cell at the centroblastic stage of differentiation and is characterized by total or partial replacement of the lymph nodal architecture by a nodular or a nodular and diffuse infiltrate, mainly consisting of small lymphocytes and intermingled LP or popcorn cells. The diffuse areas are usually composed of small lymphocytes with admixed histiocytes that may be single or in clusters. The presence of a single nodule is sufficient to rule out the diagnosis of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). At the margins of the nodules of NLPHL, histiocytes and some polyclonal plasma cells can be detected. Reactive follicular hyperplasia accompanied by a progressive transformation of germinal centers (PTGC) adjacent to NLPHL can occasionally be found, and this transformation may either precede or follow a diagnosis of NLPHL. This finding may be significant because PTGC may develop to HL and oncologic surveillance may be advisable. Sclerosis is rarely seen, compared to CHL, and the presence of remnants of small germinal centers may help in the lowpower differential diagnosis with LR-CHL. Genetic Abnormalities and Oncogenes in NLPHL and CHL NLPHL: Clonal rearrangement of Ig genes (VH region of the IG) harboring a high load of somatic mutations as well as IGH/BCL6 translocation and BCL6 rearrangements (involving IG, IKAROS, ABR, etc.). Somatic hypermutations of the wrong type have also been found and most often in PAX5, PIM1, RhoH/TTF, and MYC. CHL: Recurrent gains of the chromosomal subregions on 2p, 9p, and 12q and high-level amplifications on 4p16, 4q23-q24, and 9p23-p24 may be detectable by comparative genomic hybridization. In CHL arising in follicular lymphoma, t(14;18) and t(2;5) may be found. Breakpoints in the IGH locus have been observed using interphase cytogenetics. Accurate diagnosis and staging are critical for the best management of cancer patients. About

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the treatment effect in HL and NHL, the Deauville 5-point scale or Deauville 5PS plays a significant role. This score is an internationally recommended scale for clinical routine and clinical trials in the initial staging and assessment of treatment response in both HL and some types of NHL.  The Deauville score is based on FDG-­ PET/CT, which is positron emission tomography with 2-deoxy-2-[fluorine-18]F-D-glucose integrated with computed tomography (18F-FDG-­ PET/CT). FDG-PET/CT has emerged as a powerful imaging tool for the detection of various cancers.

10.4.6  Non-Hodgkin Lymphomas Non-Hodgkin lymphoma (NHL) is a broad category comprising lymphomas of B- and T-cell type and represents clonal expansions of lymphocytic elements blocked explicitly at particular stages of B-cell and T-cell differentiation. NHLs are common neoplasms in both childhood and adulthood and are second only to acute leukemia as the most common form of tumor in children and youth. In the small bowel, lymphomas constitute 30–50% of all malignant tumors in a range of age comprising from children to adults. Thus, a solid presentation of NHL may not be uncommon and needs to be taken into consideration. Fine needle aspiration (FNA) may be very useful, but some contraindications are bleeding diathesis, suspicion of Echinococcus granulosus or liver abscess, carotid body tumor, and pheochromocytoma. NHL Etiology Directions and Trends Some factors have been associated or ascribed to be causative in NHL. These factors include alterations in immunoregulatory control mechanisms (congenital and acquired immunodeficiencies), infections, chemicals, and chromosomal changes. A number of molecular compounds have been reviewed by the International Agency for research on Cancer - World Health Organization in the last two decades and associated with NHL in both experimental animals and humans and results of these revisions are published in monographs (https://monographs.iarc.fr/). Congenital immuno-

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deficiencies such as ataxia-­ telangiectasia and Wiskott-Aldrich syndrome have an up to 50 times increased incidence of NHL than healthy people. Ataxia-telangiectasia (or Louis-Bar syndrome, OMIM 208900) is a rare inherited multisystem disorder that affects mainly the nervous and immune systems. There is progressive difficulty with coordinating movements (ataxia) beginning in early childhood with associated involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The gene underlying this disorder is called ATM and is located on 11q22-q23. ATM mutations prevent repair of broken DNA, increasing the risk of cancer. Wiskott-Aldrich syndrome is characterized by an X-linked congenital immune deficiency and a reduced ability to form blood clots. There are microthrombocytopenia, eczema, and abnormal white blood cells leading to an increased risk of several immune and inflammatory disorders as well as an increased susceptibility to infection and NHL.  Mutations in the WAS (Wiskott-Aldrich syndrome) gene located on Xp11.4-p11.21, forming a protein called WASp or WASP, cause Wiskott-Aldrich syndrome. WASP is involved in communicating signals from the surface of blood cells to the actin cytoskeleton, and its signaling activates cell adhesion. Acquired immunodeficiencies are also conditions predisposing to NHL.  An acquired immunodeficiency may develop in SLE, RA, Sjögren syndrome, and Hashimoto thyroiditis, following immunosuppression by transplantation (see posttransplant lymphoproliferative disorders or PTLDs) and aging. Infections such as HIV, EBV, and HHV8 among viruses are some known examples. EBV is a potent polyclonal stimulator for B-cell proliferation and has been implicated in Burkitt lymphoma as well as some immunoblastic lymphomas. HHV8 may escape HLA-class-I-restricted antigen presentation to cytotoxic T lymphocytes by increasing endocytosis of MHC class I chains from the cell surface. The consequence of this event is the possibility to enable latent infection and immune escape in primary and chronic infection. Both multicentric Castleman disease, a rare lymphoproliferative disorder of the plasma cell type in both HIV-­ seropositive and HIV-seronegative patients, and

10  Hematolymphoid System

pleural effusion lymphoma, or body cavity-based lymphoma, a NHL of B-cell lineage characterized by pleural, pericardial, or peritoneal lymphomatous effusions in the absence of a solid tumor mass, belong to the diseases associated with HHV8 infection. Chemicals such as phenytoin altering the surface membrane of some lymphocytes interfere with the immunoregulation and promote cellular proliferation, while chromosomal translocations such as t(8;14) involving protooncogenes such as c-myc and the heavy chain gene may encourage the development of NHL. Clinically, the immunoregulatory alterations predispose patients harboring NHL to develop infectious diseases. B-NHL usually predisposes patients to bacterial illness because there is increased catabolism of immunoglobulins and suppression of all B-cell functions, and T-NHL predisposes to viral, mycobacterial, or fungal infections.

10.4.7  Follicular Lymphoma • DEF: Germinal center NHL lymphoma with a nodular histologic pattern of growth, which and a “bitonal” taxonomy in the Working Formulation (WF) classification being split with the predominantly small cleaved and mixed cell types of low grade and the primary large cell type of intermediate grade (Fig. 10.10). • EPG: The cell of origin is the follicular center cell (FCC) with B immunophenotype (CD19+, CD20+) and exhibiting the expression of CD10+ and BCL6+ as well as BCL2+ but no expression of CD5 and CD43. • EPI: 1/2 of adult NHL, but pediatric follicular lymphoma has been delineated in the last decade and seem to be better recognized currently. Patients are usually with a median age of 55–65, although this kind of NHLs are not unusual in individuals 15 CB/10 HPF (HPF, high-power field).  However, there is an additional subdivision of high grade with 3A if CCs are present and 3B if solid sheets of CBs are present. Any area of DLBCL in an FL should be reported, according to the WHO recommendations, as the primary diagnosis and should also be reported an estimate of the proportion of DLBCL and FL present in all histologic tissue sections. • Variants: Signet ring lymphoma (prominent intracellular Ig, usually IgG of LCs vs. IgM of Russell bodies in lymphoplasmacytic malignancies) (Of note, Russell bodies are homogeneous Ig-containing inclusions representing distended endoplasmic reticulum and showing histochemical positivity for PAS stain and immunohistochemical positivity for both CD38 and CD138 stains)

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• BM: Paratrabecular lymphoid aggregates showing cellular monomorphism and increase in reticulin. Interestingly, FCC-NHL tends to be paratrabecular, differently from the nonparatrabecular location of large cell NHL. • PB: ± involvement (“buttock” cells): • Splenic involvement: 50% • Hepatic involvement: 50% (portal triads, involving and crossing the limiting plate) • CGB: t(14;18)(q32;q21) involving BCL2 on Chr. 18 and IGH on Chr. 14 (~80%). • PGN: Progression (SC→MC→LC) variable. Rarely, there may be a blastic transformation with conversion to leukemic phase, in which case the median survival is reduced to 2 months. • FLIPI (Follicular Lymphoma International Prognostic Index): Remarkably useful index constituted by histologic grade (1–2 vs. 3), ≥6 chromosomal breaks and complex karyotype, TP53 gene mutations, and proliferation of cell fractions (Ki67 immunohistochemistry with internal validation) • Pediatric FLL: a localized form of FCC-NHL, BCL2-, t(14;18) (−), and grade 3!

10.4.8  Small Lymphocytic Lymphoma • DEF: Well-differentiated lymphocytic lymphoma of B-cell type with an expression of CD5, CD23, and CD43, although CD23 may also be lacking and 1% of cases are T-cell NHL (immunophenotype-based). • SYN: WD-lymphocytic lymphoma. • EPI: Middle-aged to elderly. • CGB: 12+ (trisomy 12) and 13q−, being trisomy 12 a bad and 13q- a good PGN marker. • CLM: Effacement of the architecture by diffuse monotonous infiltration of lymphocytes with clumped chromatin pattern, no or inconspicuous nucleoli, few or rare mitoses, PAS+ inclusions either nuclear or cytoplasmic, and capsular invasion. The finding of (+) proliferation centers is crucial (proliferation centers: clusters of blasts and pro-lymphoblasts deter-

10  Hematolymphoid System

Box 10.9 Pseudofollicles vs. Follicles

• Round nuclei vs. ovoidal nuclei • Poor demarcation vs. well demarcation • No compression of surrounding Ret fibers vs. compression of surrounding Ret fibers

mining a pseudofollicular appearance with less basophilia) (Box 10.9). In patients with hepatomegaly (~1/10), there are portal triads, typically, which are infiltrated, but sinusoidal involvement is seen in CLL. In patients with splenomegaly (~1/4), the white pulp shows some extension into red pulp with asymmetric, coalescing nodules. In this context and in an appropriate epidemiological background, the DDX with splenic MZL is crucial. • PGN: “Poor outcome”-indicating markers include the evaluation of ZAP-70 and CD38. Del11q suggests a worse outcome, while del 13q a better result. Tumors with mutated Ig genes behave aggressively. Richter’s transformation: Transformation of a low-grade NHL to a higher-grade NHL (large cell lymphoma) occurring in 1/10 of cases. Another conversion may be prolymphocytic leukemia with BM involvement, usually not paratrabecular. Variant: plasmacytoid (immunocytoma), which is generally associated with monoclonal gammopathy, and up to half of the cases have BM involvement, typically paratrabecular. If most plasma cells are observed, the diagnosis of plasmacytoma (multiple myeloma) should be considered. The difference between light and heavy chain producers is essential. IgM or heavy chain producers tend to be lymphomas, while IgG or light chain producers tend to be myelomas. If IgM dysproteinemia is present the diagnosis of Waldenstrom’s macroglobulinemia should be given. Waldenstrom’s macroglobulinemia, is characterized by hyperviscosity, cryoglobulinemia, and Coombs-­ positive hemolytic anemia. The distinction between Russell and Dutcher bodies is also important. Russell bodies are “cytoplasmic” Ig inclusions, while Dutcher bodies are “nuclear”-located cytoplasmic Ig inclu-

10.4 White Blood Cell Disorders

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sions. Frankly speaking, Dutcher inclusions are inclusions of the cytoplasm that are either invaginated into or are covering the nucleus.

• IHC: (+) CD19, CD20, CD22, and CCND1 (aka cyclin D1, bcl1, PRAD1), but also CD43, CD79a, FMC7, sIgM or IgD, κ/λ, bcl2. • (−) CD10, bcl6 (unlike FL, which is also CD5-), (−) CD23 (unlike SLL/CLL), 10.4.9  Mantle Cell Lymphoma (MCL) CD11c, TdT (unlike lymphoblastic lymphoma), T-cell antigens (unlike many cuta• DEF: Intermediate grade B-cell non-Hodgkin neous T-cell NHL), p27(kip1) (unlike lymphoma characterized by overexpression of B-CLL, FL, MZBCL, and HCL). cyclin D1 and the t(11;14)(q13;q32) chromo- • MZBCL is (−) CD5, CD10, CCND1. somal translocation arising from naive pre-­ • CCND1 regulates the G1→S cell transition germinal center B lymphocytes present in which is not balanced by RB1 and p27Kip1 leading to the development of mantle cells and primary lymphoid follicles and mantle zones (+) also in HCL (possible in children and of secondary follicles with non-mutated young adults) and myeloma (not typically human immunoglobulin heavy-chain-variable observed in childhood and youth). region genes. Clinically heterogeneous, MCL frequently disseminates to extranodal areas • In situ MCL: CCND1 ISH/IHC restricted to the inner mantle zones only with a quite poor overall outcome. MCL shows a monomorphous neoplastic infiltration • CGB: t(11;14)(q13;q32) with IGH/CCND1 gene fusion transcript of small B lymphocytes (formerly MCL was also called centrocytic lymphoma) with CD5+, • Also, breakpoints at 8q24, 9p22–9p24, and 16q24 CD23−, CyclinD1+, and t(11;14)(q13;q32) as well as B symptoms (1/3), including fevers, • PGN: MCL may have variable survival rates but is, in general, more aggressive than SLL/ night sweats, and weight loss. CLL or MZBCL and tends to relapse, but not • EPI: Middle age, ♂  >  ♀, 3–10% of NHL to transform to DLBCL. Nodular or mantle (Western). zone patterns have more extended survival • CLI: Lymphadenopathy, BM involvement in rates (5 years), while blastic variant, high MI, 2/3 of cases (paratrabecular lymphoid aggrehigh Ki67/MIB1 index, PB involvement (leugates), ~ PB involvement (leukemic phase, 4 kemic phase), and trisomy 12, 3q+, 9q−, p53 usually 20 years), 1/3 of diffuse aggressive lymphomas in the USA and Canada, but it is more diffuse in East Asia and Africa. EPG: The increased incidence of T-/NK-cell lymphomas in East Asia and Africa is probably related to the frequency of endemic human T-leukemia virus 1 (HTLV-1) and EBV infections. CLI: Generalized lymphadenopathy (~ stage IV) with common B symptoms. CLM: Small cells (size slightly larger than normal lymphocytes) with highly condensed chromatin, irregular nuclei, small nucleoli ± abundant pale cytoplasm, AND large cells with vesicular nuclei and prominent eosinophilic nucleoli with the presence of nuclear pleomorphism, lobulation, ± multinucleation in both cell size types, AND inflammatory background with PMN, eosinophils, MΦ, and plasma cells. In the cutaneous form, dermis only is typically involved, and PB involvement occurs after skin involvement. IHC: ≥1 PAN-T-MARKER (CD2,3,4,7), (−) CD1a AND TdT (both markers of immature T cells).

Subtyping: CD4+, CD8+, CD4+  CD8+, CD4− CD8−; in most cases there are α/β T-cell receptors. There is a γ/δ variant, which is an aggressive form with marked hepatosplenomegaly and minimal lymphadenopathy. This variant involves mostly youth and shows common relapses. It is usually fatal. • IHC: CD3+, CD2+, and CD16+, but usually CD4- and CD8−. • DDX: In a partial list of non-cutaneous T-cell NHLs, we should count the T-cell prolymphocytic leukemia/lymphoma. Also, T-cell large granular lymphocytic leukemia/lymphoma, chronic lymphoproliferative disorder of NK cells, aggressive NK-cell leukemia, systemic EBV+ T-cell lymphoproliferative disease of childhood, adult T-cell leukemia/lymphoma,

10.4 White Blood Cell Disorders

extranodal NK-/T-cell lymphoma (nasal type), enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma (ALCL) (ALK+), and anaplastic large cell lymphoma (ALCL) (ALK–) are counted. Clinical features and age need to be taken into account when reading the immunophenotype or the flow cytometry data.

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• IHC: (+) CD2, CD5, CD45, CD30, ALK1, and EMA, but (−) CD15 and (±) CD4 and CD3. (+) Cytotoxic-associated antigens (T-cell intracellular antigen 1/TIA1, granzyme B, and/or perforin) 1. Classic type: younger subjects, often involving the skin, with histology simulating carcinoma, sarcoma, or malignant histiocytosis with the classic immunophenotype, an unusual clinical course. 2. Primary cutaneous type: variant closely related to lymphomatoid papulosis that may be considered the benign counterpart and harboring an abnormal immunophenotype with (−) EMA and ALK1, and no t(2;5).

In primary T-cell lymphoma, NOS (not otherwise specified), two most commonly lost pan-Tcell antigens are CD5 and CD7, and this is important to keep in mind during the workup of the immunophenotype of a T-cell NHL. Primary cutaneous CD30+ T-cell lymphoproliferative disorder lymphomatoid papulosis presents spontaneously as regressing papules, which are usually isolated to the limbs. The CD4+CD25+regulatory T cells (Treg) are paramount in immunology. In • CGB: Three common translocations: fact, (1) Treg suppress the activation of self-­ 1 . t(2;5)(p23;q35) involving ALK and NPM reactive T cells and prevent autoimmunity, (2) genes. Treg may prevent cytotoxic T cells from operat2 . t(1;2)(q25;p23) involving TPM3 (encoding ing a killing procedure on tumor cells, and (3) a nonmuscular tropomyosin) and ALK1. Treg suppress immunologic cells that are reactive 3 . t(2;3). Variant translocations involving to host antigens and to avoid graft-versus-host ALK and other partner genes on chromodisease (GVHD). somes 1, 2, 3, 17, 19, 22, and X also may be found. The translocation partners of ALK include TPM3, TPM4, TFG, ATIC, 10.4.15  Anaplastic Large Cell MYH9, CLTC, MSN, and ALO17.

Lymphoma

• DEF: Aggressive T-cell (mostly) NHL derived from activated mature CTL that are usually large with abundant pale cytoplasm and pleomorphic nucleus (lobate, “packman nucleus”), showing often a “horseshoe” shape and harboring t(2;5) involving ALK and NPM genes with ALK1 expression in the nucleus and marked expression of CD30 on cell membrane and Golgi apparatus (Fig. 10.20). • SYN: ALK1 NHL, and Ki-1 Lymphoma. It is paramount to recall three aspects: 1. Activated CTL with horseshoe-shaped nuclei and large cytoplasm 2. CD30 expression (almost, but not all!) 3. ALK1 expression due to t(2;5)

10.4.16  Adult T-Cell Leukemia/ Lymphoma • DEF: HTLV-1-associated NHL (HTLV, human T-cell leukemia virus) with distinct T-cell NHL, ♂=♀, youth, acute to subacute course, and often seen in southwestern Japan and the southeastern states of the USA. • CLM: Pleomorphic with multilobated nuclei (“flower cells” or “cloverleaf cells”), medium-­ sized cell, and mixed large and small cells with large cell and small cell variants. • CLI: Generalized lymphadenopathy, hepatosplenomegaly, leukemia, CSF positive for malignant cells, activated osteoclast-related hypercalcemia and/or bony lesions, and epidermotropism with Pautrier microabscesses.

10  Hematolymphoid System

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a

b

c

d

e

f

Fig. 10.20  Histological panel with micrographs of a nodal anaplastic large T-cell lymphoma taken at lowand high-power magnification. The lymph node is infiltrated (interfollicular T zones and nodal sinuses) by an atypical lymphoid population constituted by large cells with abundant cytoplasm, wreath-like or multiple nuclei,

multiple nucleoli, and nuclear pseudoinclusions (c–f). There is a high rate of mitotic figures (a, hematoxylin and eosin staining, ×12.5 original magnification; b, hematoxylin and eosin staining, ×200 original magnification; c–f, hematoxylin and eosin staining, ×630 original magnification)

• IHC: CD4+, IL2R+ (CD25+). • PGN: Stage IV at presentation, thus the outcome is poor, independent of the histologic subtype, and the aggressive chemotherapy does not seem to change the prognosis in these patients, being the median survival less than 1 year.

mycosis fungoides/Sezary syndrome, DFS, and fibroadenoma of the mammary gland as DDX.

TEM may reveal some cerebriform nuclear irregularity that needs to be distinct from other neoplastic cells. The ultrastructural evidence of extreme cerebriform nuclear irregularity includes

10.4.17  Cutaneous T-Cell Lymphoma (CTCL) • DEF: T-NHL with mainly cutaneous involvement showing a characteristic skin morphology with exocytosis of epidermotropic atypical lymphocytes (“Lutzner cells”), Pautrier microabscesses, and unique immuno-

10.4 White Blood Cell Disorders

phenotype (+CD2, CD4, CD5 and −CD30, − cytotoxic molecules). • SYN: Mycosis fungoides, Sezary syndrome. • EPG: The cell of origin of CTCL is CD4+ T cell. CTLA-4 or cytotoxic T lymphocyte antigen 4 is a protein that downregulates the immune system. • CLI: Initially cutaneous involvement only and then progression to another organ involvement.

Skin Disease 0. “Premycotic” stage, erythema, and eczema with focal round-oval circumscribed flat red macules 1. Patch stage, macular coalescence into the formation of patches with scaling and intense pruritus with purple-brown spots with some spontaneous regression, at least partially and focally 2. Plaque stage, tumescence of the macular coalescence into palpable discrete, indurated papules with potential restitutio ad  integrum centrally and progression/extension peripherally (TNM staging: T1-T2) 3. Nodule stage, nodular tumescence with size increase >1 cm in diameter and inherent tendency to erosion/ulceration Sezary syndrome: Triad constituted by erythroderma, lymphadenopathy, and atypical ­lymphocytes in the peripheral blood (“Lutzner cells,” cells with cerebriform aspect characterized by marked infolding of nuclear membrane) • CLM: Mnemonic word “API,” which is an acronym for: –– Acanthosis or strophy with focal parakeratosis –– Pautrier microabscesses or single exocytosis of “Lutzner cells” (epidermotropism) –– Infiltration of atypical into the superficial dermis with increased Langerhans cells and follicular mucinosis (mucinous degeneration of outer hair shafts) • LN-3 patterns, including –– Reactive follicular hyperplasia –– Malignancy with partial/total effacement of the architecture by replacement of the LN structure by monomorphic infiltrates

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of atypical lymphocytes ± coagulative necrosis –– Dermatopathic lymphadenopathy, characterized by paracortical expansion of proliferating histiocytes (TEM: racket-shaped granules → Langerhans cells). Pitfall: Pautrier microabscesses, although considered almost pathognomonic, may also occur in benign conditions, such as cutaneous lymphoid hyperplasia, lymphomatoid papulosis, and Jessner’s lymphocytic infiltration of the skin. Clinical and hematological correlations are needed. • IHC: (+) CD2, CD4, CD5, and CD3, mostly being “helper” CD4 T lymphocytes with IL2R- (CD25-), but (+) TCR β and (−) CD7, CD8, CD30, and cytotoxic molecules (TIA1, granzyme B, and perforin). • DGN: Dense band-like infiltrate of atypical lymphocytes in the papillary dermis with epidermotropism and Pautrier microabscesses (aggregates of atypical lymphocytes with cerebriform nuclei). • PGN: About 1/5 of the patients die of CTCL or related complications. The survival of this neoplasm is associated with skin stage. It seems that the most important clinical predictive factors for survival remain patient age, T classification, and extracutaneous disease.

10.4.18  Angiocentric Immunoproliferative Lesions EBV is a widespread infection or cohabitation in the human population worldwide. Systemic infection with EBV causes infectious mononucleosis, while local EBV-­related conditions with EBV etiology may stay localized, such as hairy leukoplakia or EBV-­driven mucocutaneous ulcer of the oral mucosa. It is well known that there are some neoplasms associated with EBV, including African Burkitt lymphoma, nasopharyngeal carcinoma, Hodgkin lymphoma, gastric carcinoma, PTLD, and extranodal NK-/T-cell lymphoma. An angiocentric immunoproliferative lesion (AIL) is a lesion that should be subdivided into

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three degrees according to the vascular destruction, luminal compromise, or necrosis present. AIL grade I or benign lymphocytic vasculitis is an angiocentric mononuclear cellular (lymphocytes, plasma cells, and immunoblasts) that involve blood vessels in an angiocentric fashion, but without evidence of vascular destruction, luminal compromise, or necrosis. AIL-I involves lungs and skin commonly and has the potential to progress to more aggressive forms of AIL. AIL grade II or lymphomatoid granulomatosis (LYG, aka “polymorphic reticulosis”) is an angiocentric mononuclear cellular infiltrate that shows angiodestruction and necrosis. LYG is subdivided in I-II-III degrees according to the angiodestruction and number of EBV-positive cells. • LYG-I shows sparse atypical EBV+ cells, generally 50/HPF, and prominent necrosis. There is a natural potential to progression to large cell immunoblastic lymphoma. LYG is classified under B-cell proliferation of uncertain malignant potential by the WHO, and a spectrum of biologic behavior has been reported in the literature. AIL grade III corresponds to angiocentric lymphoma with apparent neoplastic nature of the angiocentric mononuclear cellular infiltrate showing atypia in both small and large cells with angioinvasion, destruction, and extensive necrosis and predominantly extranodal (e.g., the spleen with the characteristic periarterial arrangement). The hemophagocytic syndrome may be detected due to lymphokine production by atypical T cells. EBV may be a challenge in a laboratory, and some tests may be performed (Box 10.11). LMP1 regulates its expression and the expression of human genes, and its expression promotes many of the EBV

Box 10.11 EBV Infection and Lab Tools

LMP1: Latent membrane protein 1 EBER: In situ study for EBV-encoded RNA

10  Hematolymphoid System

infection-related changes and activation of primary B cells. A short cytoplasmic N-terminus tail, six transmembrane domains, and a long cytoplasmic C-terminus form the structure of LMP1. The C-terminus form contains three activating domains.

10.4.19  Extranodal NK-/T-Cell Lymphoma • DEF: EBV-driven, mainly extranodal, EN-­ NHL with NK-/T-cell cytotoxic immunophenotype, which is characterized by angiocentric infiltration AND angiocentric destruction, luminal compromise, and prominent coagulative necrosis. • EPI: Asian and Native American populations from Central and South America, with adult>children, ♂  >  ♀, EBV+, and immunosuppression ± (e.g., post-TX). • EN sites: Upper respiratory and GI tracts, skin, soft tissue, and testis. • Nodal: ± LN involvement. • CLI: Nasal obstruction, epistaxis, extensive midfacial destruction (aka “Lethal Midline Granuloma”). • CLM: Extensive ulceration with diffuse and characteristically permeative neoplastic infiltrate of atypical mononuclear cells (medium-­ sized cells with irregularly folded nuclei, granular chromatin, inconspicuous nucleoli, and pale to clear cytoplasm showing high MI)  +  coagulative necrosis + apoptotic bodies. • IHC: Characteristic pattern, including: –– (+) CD2, CD3+(in T-type)/-(in NK-type), CD56, and cytotoxic granules (TIA1, GRAB, perforin) –– (+) CD43, CD45RO, HLA-DR, CD25, FAS, and FASL –– (+) LMP1 and EBER • DDX: Lepra (M. leprae infection) and ozena (disease of the nose in which the bony ridges and mucous membranes are progressively destroyed). • TNT: Radiation therapy (external beam radiation therapy) and postradiation chemotherapy (L-asparaginase, etoposide, ifosfamide, cisplatin, and dexamethasone).

10.5 Disorders of the Monocyte-­Macrophage System and Mast Cells

• PGN: Poor outcome with poor PGN factors include stage (III/IV), bone/skin invasion, high levels of circulating EBV-­ DNA, and BM-EBER+.

10.5 Disorders of the Monocyte-­ Macrophage System and Mast Cells This group is quite heterogeneous but is of high relevance to the pediatric pathologist (Box 10.12).

Box 10.12 Disorders of the Monocyte-­ Macrophage System and Mast Cells

10.5.1. Hemophagocytic Syndrome 10.5.2. Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman Disease) 10.5.3. Langerhans Cell Histiocytosis 10.5.4. Histiocytic Medullary Reticulosis 10.5.5. True Histiocytic Lymphoma 10.5.6. Systemic Mastocytosis

10.5.1  Hemophagocytic Syndrome The hemophagocytic syndrome or hemophagocytic lymphohistiocytosis (HLH) is an unusual immunological disorder first recognized almost 80 years ago. The use of molecular genetics and experimental animals allowed to identify the familial form of HLH which is due to a deficiency of cytotoxic killing. Specific diagnostic criteria for HLH have been revised by the Histiocyte Society and described below. • DEF: An immunological disorder characterized by hyperimmunity, organ damage, and life-threatening cytopenia. • SYN: Hemophagocytic lymphohistiocytosis (HLH). • EPG: Genetic form (rare, infants/young children, rapidly fatal, AR with definite FH or parental consanguinity) or acquired (EBV+ immunocompromised patients), and the

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pathogenesis may involve defects in the perforin gene, at least for a group of HLH patients. • DGN: The diagnosis of HLH may be established by either a molecular diagnosis consistent with HLH (e.g., pathologic mutations of PRF1, UNC13D, or STX11 are identified) or the fulfillment of five out of the eight criteria listed below. Moreover, in the case of familial HLH, no evidence of malignancy should be present. The HLH criteria (adapted from Henter et  al. 2007) include (1) fever; (2) splenomegaly; (3) cytopenias (≥2/3 cell lineages of the PB) (RBC (Hb  ♀), but children/youth have been described with a commonly associated long-standing history of chronic infections (inefficient Ig production). • CLI: Anemia, proteinuria, and recurrent infections (impaired immunity) initially and bony pain, fractures, and renal failure subsequently ± POEMS syndrome (most myelomas associated with POEMS syndrome are osteosclerotic, while the classic non-POEMS myelomas are osteolytic). • LAB: 3 g Ig/100 ml serum OR 6 mg Ig/1000 ml urine. Ig secretion: IgG:IgA:IgM:IgD:IgE = 60%:15– 20%:10–15%:5%:5% Although IgD are rare, IgD secretors have more aggressive clinical course (see below PGN). Increased M protein ⇒ rouleaux ⇒ thrombosis The immunophenotype of normal and atypical plasma cells is slightly different. Normal plasma cells are (+) CD19, (+) CD38, and (+) CD138, while MM “atypical plasma cells” are (−) CD19, (+) CD38, and (+) CD138. Most atypical plasma

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cells of MM are CD19-, CD20-, but (+) CD38 and (+) CD138, as well as CD56(±), which is considered as aberrant expression (MM, multiple myeloma). In about 10% of patients, there is evidence of systemic amyloidosis, and X-ray shows clearcut multiple destructive bony lesions, starting in the medullary cavity and eroding progressively the cortex, forming sharply “punched-out” defects (size, 1–4 cm) with a characteristic of a “soap bubble” aspect, mostly involving the spine (2/3), ribs (~1/2), and skull (~1/2). Other bony lesions involve the pelvis, femur, shoulder girdle, and soft tissue lesions may also appear and affect the spleen, liver, kidneys, lungs, LNs, and stomach. A primary gastric plasmacytoma, as a rare cause of hypertrophic gastritis in an adolescent, has also been reported in the literature. In all soft tissue lesions, the aspect is quite similar with fleshy, red-brown masse, grossly. • CLM: Patchy or diffuse (10–90%) BM/soft tissue infiltration by a variable range of maturity of plasma cells from very immature to mature (“flame cells,” Mott cells, cells with inclusions); bi-/trinucleation; PAS+; Russell bodies, which is a form of intracellular accumulation of protein, e.g., alcoholic hyalin or reabsorption droplets; or Dutcher bodies, which are nuclear in  location. Other inclusions in the plasma cells include fibrils and crystalline rods. Bone destruction is due to MΦ inflammatory protein 1 α (MIP1α) ⇒ ↑ RANKL, which activates osteoclasts. BM impaired hematopoiesis ⇒ anemia, infections, thrombosis Other clinical features are also related to the effects of plasma cellular infiltrates to other nonBM tissues and rely on impaired immunity ­ (pneumonia, abscesses, osteomyelitis) and excess of abnormal Ig productions (myeloma nephrosis and systemic amyloidosis) Renal pathology in multiple myeloma includes (1) toxic effect of BJP on renal tubular cells, (2) luminal obstruction by Bence Jones proteins (BJP) casts, (3) amyloidosis, (4) light chain nephropathy, and (5) nephrocalci-

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nosis due to hypercalcemia (“C” of CRAB CRASH lesions). Abnormal interstitial infiltrates of plasma cells + casts into the distal tubules and collecting ducts characterize the myeloma nephrosis (“myeloma kidney”). It is due to mostly BJ protein accumulation, which forms aggregates of eosinophilic material in the lumina. • TNT: Chemotherapy. • PGN: The survival is limited to 1–2  years without treatment. Poor prognostic factors include amyloidosis, anaplastic conversion of plasma cellular infiltrates, extensive/diffuse BM involvement, high immaturity of plasma cellular infiltrate, hyperalbuminemia, hypercalcemia, plasma cell leukemia, serum β-2-­ microglobulin >4 ng/μl, and renal failure. • CGB: Somatic hypermutation and IGH rearrangements on chromosome 14 include CCND1, CCND3, FGFR3, and MAF genes. Good cytogenetics-based prognostic factors are CCND1/t(11;14) or CCND3/t(6;14) and hyperdiploidy, while poor cytogenetics-based prognostic factors are t(4;14), MAF, 17p-/, and TP53 alterations.

10.6.2  Solitary Myeloma • DEF: Bony or soft tissue-located myeloma with the potential involvement of single soft tissue lesions, such as the lungs, oropharynx, nasal sinuses, and stomach. • SYN: Solitary myeloma (aka solitary plasmacytoma). • EPI: 40 years with occasional cases in childhood (e.g., primary gastric plasmacytoma), ♂>♀. • CLI: >1/2 of patients monoclonal protein in urine and/or serum, but 20% or absolute plasma cell count >2000 and very rarely tissue involvement.

10.6.4  Waldenstrom’s Macroglobulinemia • DEF: Plasmacytoid lymphoma showing a monoclonal gammopathy (IgM  >>  IgG or IgA) typically occurring in a setting of a LPD. • EPI: Generally, >60 years, few youth cases. • CLI: General symptoms (weakness, fatigue, weight loss). • LAB: Serum proteins >6.5 g/100 ml with IgM 1–3 g and Ig >15% of all Ig (nl. 5%), BJP (1/3 of cases). • CLM: Diffuse BM infiltration by plasma cells, plasmacytoid lymphocytes, and lymphocytes (all of them monoclonal), although tumor masses or lytic lesions are not seen. Dutcher bodies may be viewed, and similar may be found in the liver, spleen, and LNs. • PGN: Survival 2–5 years.

10.6.5  Heavy Chain Disease Plasma cell dyscrasias with production only of heavy chains, hepatosplenomegaly, and soft tissue tumors. All ages of individuals may be affected, although young and middle-aged adults are more commonly involved. Some classification according to the location has also been proposed. • Subtype α (“Mediterranean Lymphoma”): Pediatric HCD with two patterns (pattern 1,

10.7 Benign Lymphadenopathies

massive infiltrate of lamina propria of the intestine by heavy chain-producing plasma cells, villous atrophy, malabsorption, diarrhea, AND abdominal LN involvement, and pattern 2, respiratory tract involvement). • Subtype γ: Adult HCD with associated TB, RA, and AI disorders and histopathologically more similar to malignant NHL than myeloma (lack of lytic lesions). • Subtype μ: HCD variant seen in patients affected with CLL. • PGN: The course is variable with months to years of survival. Several studies have been performed and several authors suggest that associated underlying disorders may contribute to the variability of the clinical course.

10.6.6  Monoclonal Gammopathy of Undetermined Significance (MGUS) It is defined as a: constellation of paraprotein or M protein diffuse involvement with ↑ reticulin in affected areas. • TNT: Steroids ± combination chemotherapy. • PGN: Death (3/4 of cases). Poor PGN factors: (+) Clones of tightly packed immunoblasts (→ progression to immunoblastic sarcoma, T-cell type).

10.8 Disorders of the Spleen Spleen disorders are shown in Box 10.16 and congenital anomalies are shown in Box 10.17.

Box 10.16 Disorders of the Spleen

10.8.1. Hypofunction 10.8.2. White Pulp Disorders 10.8.3. Red Pulp Disorders 10.8.4. Splenomegaly 10.8.5. Cysts and Tumors of the Spleen

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Box 10.17 Congenital Anomalies

–– –– –– –– ––

Asplenia Hyposplenia Abnormal lobulation Polysplenia Accessory spleens

Hypersplenism, which is defined as an overactive spleen, may result in (1) splenic enlargement; (2) sequestration/loss of circulating RBCs, WBCs, and/or platelets; and (3) resolution of the cellular sequestration/loss following splenectomy.

10.8.1  W  hite Pulp Disorders of the Spleen Essentially four categories may be delineated, including reactive follicular hyperplasia, reactive non-follicular lymphoid hyperplasia, chronic lymphocytic leukemia, and malignant lymphomas.

10.8.1.1 Reactive Follicular Hyperplasia • DEF: Hyperplasia of the follicles of the white pulp of reactive nature. • EPI: Worldwide, children, ♂=♀. • EPG: Acute infections, ITP, RA, acquired hemolytic anemia, chronic hemodialysis, and Castleman disease. • TNT: None, but it is essential to distinguish between the several and different underlying disorders. • PGN: Usually linked to the underlying disorder. 10.8.1.2 Reactive Non-follicular Lymphoid Hyperplasia • DEF: Hyperplasia of the lymphatic tissue (white pulp) of reactive origin without formation of germinal centers. • EPG: Viral infections, graft rejections, AILD. 10.8.1.3 Chronic Lymphocytic Anemia It is the sole leukemia, which consistently and selectively targets the white pulp, although the involvement may be quite irregular.

10.8.1.4 Malignant Lymphomas Involvement of the spleen by either lymphoma confined to the spleen or lymphomas involving other hematopoietic organs. Four gross patterns: 1. “Miliary small nodules” pattern, which may conceal FL, B-CLL/SLL, LPL, MCL, MZBCL 2. “Solitary or several small clustered nodules” pattern, which usually corresponds to HL 3. “Solitary or multiple large fleshy nodules” pattern, which may represent the gross pattern for DLBCL, FL grade 3, some peripheral TCL, various high-grade lymphomas or HL 4. “Beef-Red” pattern, which may mean leukemia (apart B-CLL/SLL), hepatosplenic TCL, some DLBCL and PTCL, agnogenic myeloid metaplasia, systemic mastocytosis, and LCH.

10.8.2  R  ed Pulp Disorders of the Spleen There may be some diseases involving the red pulp, including congestion, infection, leukemia, mastocytosis of systemic type, and histiocytic proliferations exclusively.

10.8.2.1 Congestion Congestion may occur in hemolytic anemias, such as the case of splenectomy performed in cases of children with spherocytosis. In case of congestion, it is usual to divide into acute and chronic congestions. In the setting of chronic congestion, there is thickening of the splenic capsule and occurrence of Gandy-Gamna bodies, which are organized, fibrosed old hemorrhages with hemosiderin and calcium aggregates. 10.8.2.2 Infection Two major infections involve the red pulp and are EBV-driven infectious mononucleosis and sepsis. In case of an infection of the red pulp, we consider the process an acute splenitis, which is acute septic splenitis in case of a patient, in almost all cases, at autopsy. No figure is provided with infectious mononucleosis because the patient is not usually undergoing a splenectomy unless the spleen causes major harms to the patient.

10.8 Disorders of the Spleen

10.8.2.3 Leukemia In case of red pulp involvement by leukemia, the red pulp is strikingly prominent making the white pulp barely discernible. Three conditions need to be kept in mind and are hairy cell leukemia (HCL), chronic myelocytic leukemia (CML), and myeloid metaplasia of idiopathic (agnogenic myeloid metaplasia) or secondary nature. In HCL, blood lakes are frequently found (see below, under leukemia), which makes this pattern quite distinctive. In CML, there is a polymorphous infiltrate with eosinophilic myelocytes, which is quite characteristic, and obviously, clinical history and special stains are essential to review before signing out the case. In myeloid metaplasia, all three cell lines are present in the idiopathic subtype, while the picture may be limited to a single cell line in myeloid metaplasia of secondary type. 10.8.2.4 Histiocytic Proliferations Some diseases may recruit histiocytes and give the impression of a histiocytosis. Histiocytosis: LCH, JXG of the spleen, and malignant histiocytosis. Non-histiocytosis or generic histiocytic proliferations need to be kept separated. In this last group, granulomatous inflammations of the spleen in the setting of several infections, ceroid histiocytosis, Gaucher disease, and Niemann-­Pick disease are to be recalled. In ceroid histiocytosis, there is an accumulation of foamy macrophages laden with the wavy material, mainly sphingomyelin, and it may be seen in ITP and CML.

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lary projections, and cystic spaces and detached endothelial cells into the lumina, but neither sclerosis nor atypia is present. • IHC: CD31(+), CD68(+), but CD34(−), CD21(±), and CD163(+). CD21 is the C3d complement receptor and also, very important to remember, the EBV receptor of B lymphocytes and seems to be exclusively positive in SLCA.  CD163 is the high-affinity scavenger receptor for the hemoglobin-haptoglobin complex and a marker of cells from the monocyte-­macrophage lineage.

Inflammatory Pseudotumor ALK1(+)-spindle cell proliferation with quite bland cytology mixed with an inflammatory component constituted by plasma cells, lymphocytes, eosinophils, and histiocytes with low malignant potential. ALK1 is, however, positive in about 50% of cases and most of the cases are pediatric. Hyaline Perisplenitis Collagenous thickening of the capsule (“Zuckergussmilz” of the German literature, spleen with “sugarcoating” or perisplenitis cartilaginea), which follows states of portal vein stasis/hypertension. Neither symptoms nor sequelae are documented, apart from the underlying disorder, if noted.

Spontaneous Rupture It happens exclusively due to underlying pathologies, such as IM, malaria, typhoid fever, CML, Littoral Cell Angioma and acute splenitis. To list other causes, we should include the littoral hemangioma, angio• DEF: Endothelial+histiocytic markers-­sarcoma, and hairy cell leukemia. Sequelae are expressing tumor, which seems to derive from hemorrhagic shock and death. In case of seeding the littoral cells lining the venous sinuses of of the peritoneal cavity with splenic tissue, the the spleen. condition of splenosis may occur. • CLI: ± (50%) Anemia, hypersplenism-­ associated thrombocytopenia, and splenomeg- Peliosis aly and  ±  Crohn disease, colon-rectal Widespread, blood-filled cystic spaces due to carcinoma (CRC), and pancreatic carcinoma. androgens or chronic wasting diseases (TB or • CLM: Anastomosing vascular channels of a cachexia in the setting of metastatic carcinoma). monotonous type resembling splenic sinuses, but lined by tall prominent endothelial cells • DDX: Littoral hemangioma, cavernous hemwith LM-identifiable variable hemophagocyangioma, hairy cell leukemia, and tosis, channels with irregular lumina, papilhemangiosarcoma.

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10.9 Disorders of the Thymus The diseases of the thymus are shown in Box 10.18.

Box 10.18 Disorders of the Thymus

10.9.1. Thymic Cysts and Thymolipoma 10.9.2. True Thymic Hyperplasia and Thymic Follicular Hyperplasia 10.9.3. Thymoma 10.9.4. Thymic Carcinoma 10.9.5. Thymic Neuroendocrine Carcinoma 10.9.6. Non-thymic Neoplasms with Primary Intrathymic Onset 10.9.6.1. Hematopoietic 10.9.6.2. Germ Cell Tumors 10.9.6.3. With Associated Somatic Type Malignancy 10.9.6.4. With Associated Hematologic Malignancy 10.9.7. Ectopic Thymic and Related Branchial Tumors 10.9.7.1. Ectopic Thymoma 10.9.7.2. Ectopic Hamartomatous Thymoma 10.9.7.3. Spindle Epithelial Tumor with Thymus-­ Like Elements (SETTLE) 10.9.7.4. Carcinoma Showing Thymus-Like Elements (CASTLE)

10.9.1  Thymic Cysts and Thymolipoma The thymic cyst may be unilocular (congenital) or multilocular (acquired). The congenital thymic cysts are a thin-walled cyst filled with serous, limpid fluid and lined by the flat/cuboidal lining. The acquired thymic cysts are a thick-walled cyst filled with torbid, hemorrhagic, dusky fluid and lined by the flat/cuboidal/squamous/columnar/ ciliated lining. The thymic cyst is recognizable as a hole cavity in continuity with thymic remnants

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in the wall containing lymphocytes and cholesterol clefts crystals. The thymic cysts are subdivided into (1) foregut cysts of the mediastinum (branchial or branchiogenic cysts, esophageal cysts, enteric cysts, and duplication cysts) and (2) mesothelial cysts. • DDX: It includes the parathyroid cyst (location, Ca levels, PTH levels), cystic hygroma (age, chromosomes, genetics, dysmorphism), esophageal cyst (radiology, surgical report, histology), bronchial cyst (radiology, surgical report, histology), cystic teratoma (1–3 dermal teratoma), cystic thymoma (age, history, histology, IHC), and cystic degeneration (age, clinical history).

Thymolipoma It is a rare, benign anterior mediastinal mass of thymic origin displaying both thymic and mature adipose tissue. It is about 5% of all thymic neoplasms and involves children and adults.

10.9.2  True Thymic Hyperplasia and Thymic Follicular Hyperplasia True thymic hyperplasia (TTH): Thymic enlargement with a specific increase of volume but normal weight. ± AI (e.g., hyperthyroidism, MG, etc.), affecting both children and youth after CHT for malignancy. • CLM: Conservation of the lobular architecture with a normal distribution of lymphocytes and epithelial cells and preservation of corticomedullary differentiation. • Thymic follicular hyperplasia: Thymus with conserved size and weight, but the presence of numerous follicles with GC in the setting of ± AI (MG, RA, SLE, etc.). TTH needs to be kept distinct from thymic follicular hyperplasia (TFH) and thymomas. A lobular architecture characterizes the first with a normal distribution of lymphocytes and epithelial

10.9 Disorders of the Thymus

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Fig. 10.23 Human immunodeficiency virus changes include regressive changes of the thymus with hypotrophic lymphoid tissue (Modified Periodic acid Schiff with diastase digestion to highlight Hassall’s corpuscles, x100 original magnification)

cells and CM differentiation preservation. TFH is characterized by well-formed lymphoid follicles with germinal centers and CD20+ B lymphocytes in the germinal centers, while thymomas show no normal lobulation and absence of corticomedullary differentiation. Moreover, it is useful to distinguish between neoplasms and thymus and non-neoplastic thymic lesions and conditions, which are atrophy, cysts, Castleman disease, dysplasia, and hyperplasia (B cell, GC-typed, rebound, true thymic).

10.9.3  HIV Changes HIV infects CD4+ T lymphocytes, and the disease is manifested by CD4+ T-cell paucity. Both the thymic epithelial space (TES) and the perivascular space (PVS) are involved in HIV-1infected children. TES is a lymphoid compartment where thymopoiesis is located, while PVS is a lymphoid compartment where T lymphocytes are pooled. The knowledge of autophagy and apoptosis of the last couple of decades seems to reveal that HIV infection per se is not responsible for dying CD4+ T lymphocytes and anti-retroviral therapy does not instantly reduce the high death rates of CD4+ T lymphocytes. Brunner et  al. (2011) found that CD4+ and CD8+ cells were more numerous in PVS than in TES.  Moreover, they showed that

CD4 + CD8+ cells (immature thymocytes) were 15.4% (age-related control: 80.5%) in thymus cell suspensions. Very few apoptotic CD4+ cells were seen in TES, but very low to absent proliferation activity was demonstrated in both TES and PVS. Brunner et al. (2011) suggest that (1) lymphocyte exhaustion in HIV-1 infection is more pronounced in TES than in PVS, (2) ­immature thymocytes are not enhanced, and (3) an anti-apoptotic effect appears to be a potential ART mechanism elucidating the CD4+ pool increase (Figs. 10.23 and 10.24).

10.9.4  Thymoma • DEF: Epithelial cell-derived thymic tumor with lymphocytic “innocent bystanders” as immature T cells, conversely from thymic carcinoma where lymphocytes are of B-cell type. • CLI: ± myasthenia gravis, hypogammaglobulinemia, pure red cell aplasia, and connective tissue disorders (RA, SLE, scleroderma, polymyositis). • GRO: Round-oval mass with an appreciable fibrous capsule of variable thickness with tan fleshy lobules delimitated by thin/coarse fibrous septa (smooth, bosselated surface) in the form of jigsaw puzzle-like shape ± cysts and H&C (hemorrhage and calcification).

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a

b

c

d

e

f

Fig. 10.24  A specific study of the thymus in pediatric acquired immunodeficiency syndrome caused by human immunodeficiency virus shows a depletion of CD4 with an involvement of apoptosis as mechanism of depletion (a, anti-CD3 immunostaining, ×100 original magnification; b,

• CLM: A-B1-B3-AB (classification parameters include the type of epithelial cell, organotypic morphology, the relative proportion of associated immature T cells, and degree of epithelial atypia). A thymoma B1 thymoma

Bland, spindle cells (at least focally) with paucity or absence of immature (TdT+) T cells throughout the neoplasm Copiousness of immature T cells, areas of medullary differentiation (the so-called “medullary islands”), scarcity of polygonal or dendritic epithelial cells without clearcut evidence of clustering

anti-CD4 immunostaining, ×100 original magnification; c, anti-CD8 immunostaining, ×100 original magnification; d, anti-CD68 immunostaining, ×100 original magnification; e, TUNEL technique of in situ apoptosis detection; f, combined TUNEL-CD3 staining, ×100 original magnification) B2 thymoma B3 thymoma AB thymoma

↑ single or clustered polygonal or dendritic epithelial cells intermixed with copious immature T cells Sheets of polygonal atypical epithelial cells with paucity or absence of intermixed immature (TdT+) T cells Bland, spindle cells (at least focally) with copious immature (TdT+) T cells focally or throughout the tumor

Thymic carcinoma is differentiated in low grade (well-differentiated squamous, basaloid, ACA, adenosquamous, mucoepidermoid) and high grade (lymphoepithelial-like, LC undiffer-

Multiple Choice Questions and Answers

entiated, clear cell, sarcomatoid, midline carcinoma with t(15;19) translocation). Thymic NEC is subdivided in well-differentiated or carcinoid and poorly differentiated of small cell/large cell NEC. • TEM: (+) EC features, including tonofilaments, tight intercellular junctions, desmosomes, elongated cytoplasmic processes, and basal lamina (Pitfall! Due to the heterogeneity of the thymic neoplasms and lesions, there is a high potential for sampling error: ergo, TEM interpretation needs to be done only in the context of a contiguous and consonant LM, including H&E and IHC).

Myasthenia Gravis It is a defect in nicotinic acetylcholine receptor (AChR) present in the subsynaptic membrane of the neuromuscular junction (at motor end plate), which is due to circulating autoantibodies to the receptor. The AChR is also present in normal thymus. Hyperplastic medullary thymic epithelial cells are involved in provoking infiltration, and thymic myoid cells with intact AChR are involved in germinal center formation. Approximately 12% of patients affected with myasthenia gravis have other AI diseases (e.g., Graves’ disease, rheumatoid arthritis), 65% thymic hyperplasia, 25% normal thymus, and 10% thymomas. Myasthenia gravis is present in up to 45% of patients with thymomas. Thymectomy is the treatment of choice regardless of the presence of thymoma. Acute Thymic Involution Stress (chronic debilitating disease), HIV or other infections, prolonged protein malnutrition and immunosuppressive or cytotoxic drugs, GVHD, infants with chorioamnionitis, and sepsis are subject to involution of the thymus. There is a preservation of lobular architecture and Hassall’s corpuscles, but marked lymphocyte depletion (particularly with HIV) and BVs are large compared to the size of lobules, plenty of plasma cells, and fibrohyaline changes of the basement membrane of vessels and thymic epithelium.

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The thymic/non-thymic tumors potentially arising in the thymic region are hematopoietic neoplasms (primary mediastinal LBCL, EN-MZL, T-lymphoblastic lymphoma/leukemia), germ cell-type neoplasms (seminoma and non-seminoma germ cell tumor, including embryonal carcinoma, yolk sac tumor, teratoma, choriocarcinoma, mixed germ cell tumor ± associated somatic-type malignancy, e.g., embryonal rhabdomyosarcoma and angiosarcoma, OR  ±  associated hematologic malignancy (e.g., AML, acute megakaryoblastic leukemia). The thymic neoplasms most commonly associated with cysts or cystic degeneration are a basaloid carcinoma, ENMZL, HL, seminoma, and thymoma. Finally, the ectopic thymic and related branchial tumors are listed as ectopic thymoma (e.g., pleura, p­ulmonary, pericardium (3Ps)), ectopic hamartomatous thymoma, spindle epithelial tumor with thymus-­like elements (SETTLE), and carcinoma showing thymus-like elements (CASTLE).

 ultiple Choice Questions M and Answers • HEM-1 A 12-year-old boy presents at the emergency department with pallor, low-grade fever, and enlargement of the spleen. The parents indicate that the child suffers from hereditary spherocytosis. His blood work shows a hemoglobin of 1.86 mmol/L (normal, 7.45–11.17 mmol/L or 12–18 g/dL), reticulocyte count of 2%, white blood cells at 6.0 x 109 cells per liter (6,000/mm3; normal range, 4.3–10.8 x 109 cells per liter), and platelet count of 200 x 109 cells per liter (200,000/ mm3; normal range, 150– 400 x 109 cells per liter or 150,000–400,000/ mm3). What is the most likely diagnosis? (a) Acute leukemia (b) Sepsis (c) Aplastic crisis (d) Acute splenic sequestration (e) Hemolytic crisis • HEM-2 Fanconi anemia (FA) is a rare inherited recessive disease, which is determined by mutations in one of fifteen genes. These genes

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are known to encode FA pathway components. In response to DNA damage, nuclear FA proteins associate into complexes of high ­ molecular weight through a cascade of posttranslational modifications and molecular interactions. This results in the repair of damaged DNA. Which of the following features is NOT characteristic of FA? (a) Chromosome fragility (b) Infantile hematologic abnormalities (c) Pancytopenia (d) Skeletal anomalies (e) Squamous cell carcinoma of the head and neck • HEM-3 Which of the following disorders is associated with a factor extrinsic to the red blood cell? (a) Sickle cell anemia (b) Autoimmune hemolytic anemia (c) Glucose-6-phosphate dehydrogenase (G6PD) deficiency (d) Hereditary spherocytosis (e) Hereditary elliptocytosis • HEM-4 Which of the following statement on hereditary spherocytosis does NOT match with the disease? (a) Mitochondrial DNA pattern of inheritance.

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(b) The defect compromises the scaffolding of the red blood cell leading to a loss of membrane fragments with the formation of microspherocytes. (c) The microsporocyte membrane is hugely permeable to sodium. (d) Cholelithiasis and cholecystitis may develop in teenagers. (e) Splenectomy is the definitive therapy. • HEM-5 A 12-year-old boy presents with an enlargement of a right-sided lymph node persisting for more than 12 months. The child did not complain about any pain. The lymphadenopathy did not rise in the setting of an infection. There was no history of clinical symptoms, such as fever, malaise, night sweats, or weight loss. On physical examination, the lymph node was mostly soft and mobile. The lymph node was about 5 cm × 3 cm in size without apparent overlying skin changes. Laboratory testing showed a normal white blood cell count with elevated lymphocytes and positivity for Epstein-Barr virus (early immunoglobulin G), while Bartonella and Cytomegalovirus testing were negative. A biopsy was performed, and the histology of the lymph node is shown here:

Multiple Choice Questions and Answers

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What is the most likely diagnosis? (a) Castleman disease (b) Viral lymphadenitis (c) Langerhans cell histiocytosis (d) Hodgkin lymphoma (e) Diffuse large B-cell lymphoma

• HEM-6 A 15-year-old boy develops an enlargement of a cervical lymph node for more than 6 months. Neither weight loss nor other B symptoms are noted. Microbiologically, all tuberculosis and sarcoidosis tests were negative. A biopsy was performed, and the histology of the lymph node is shown here:

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• What is the most likely diagnosis? (a) Hodgkin lymphoma, nodular sclerosis variant (b) Hodgkin lymphoma, depleted lympho cyte variant (c) Diffuse large B-cell lymphoma (d) Mantle cell lymphoma (e) Langerhans cell histiocytosis • HEM-7 What is the best combination of immunohistochemical markers to diagnose classical Hodgkin cells? (a) AE1–AE3, CD15, CD30, PAX5 (b) CD15, CD30, PAX5, MUM-1 (c) CD20, CD21, CD15, CD30 (d) BOB-1, PAX5, MUM-1 (e) CD15, CD30, CD56, CD138 • HEM-8 Which of the following statements about mantle cell lymphoma (MCL) is TRUE? (a) Cyclin D1 is essential for the diagnosis of MCLs. (b) SOX11 is a useful marker in the diagnosis of MCL. (c) The proliferative index recognized by the mouse monoclonal antibody against Ki-67 (MIB-1 immunostaining) has no prognostic relevance. (d) Splenic involvement is rarely encountered as a presentation of patients harboring MCL. (e) B symptoms are common at the presentation of MCL • HEM-9 A 25-year-old woman who is an intravenous drug user brings to the emergency department her afebrile infant showing severe oral thrush. Upon examination, the infant’s blood work shows hypocalcemia on two repeated measurements, but white cell count seems to be within normal limits. What is the most likely diagnosis in this infant of the following ones proposed below? (a) Child abuse by the mother’s partner (b) Severe combined immunodeficiency disease with mutations in the tyrosine phosphatase CD45 gene (c) Chronic granulomatous disease (d) DiGeorge syndrome • HEM-10 Which of the following are the two best antibodies to apply in detecting bone

10  Hematolymphoid System

marrow metastases and minimal residual disease of neuroblastoma? (a) PHOX2B and NB84 (b) CD56 and CD57 (c) NB84 and S100 (d) NSE and S100 (e) S100 and CD56

References and Recommended Readings Alinari L, Pant S, McNamara K, Kalmar JR, Marsh W, Allen CM, Baiocchi RA.  Lymphomatoid granulomatosis presenting with gingival involvement in an immune competent elderly male. Head Neck Pathol. 2012;6(4):496–501. https://doi.org/10.1007/s12105012-0378-z. Epub 2012 Jun 19. PubMed PMID: 22711054; PubMed Central PMCID: PMC3500898 Bechan GI, Egeler RM, Arceci RJ. Biology of Langerhans cells and Langerhans cell histiocytosis. Int Rev Cytol. 2006;254:1–43. Review. PubMed PMID: 17147996 Broadbent V, Gadner H, Komp DM, Ladisch S. Histiocytosis syndromes in children: II. Approach to the clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Clinical Writing Group of the Histiocyte Society. Med Pediatr Oncol. 1989;17(6):492–5. Brunner J, Boehler T, Ehemann V, Kassam S, Otto H, Sergi C.  Decreased apoptosis despite severe CD4 depletion in the thymus of a human immunodeficiency virus-1 infected child. Klin Padiatr. 2011;223(4):246– 8. https://doi.org/10.1055/s-0030-1270514. Epub 2011 Jan 26. PubMed PMID: 21271506 Chaurasia JK, Singh G, Sahoo B, Maheshwari V. RosaiDorfman disease: unusual presentation and diagnosis by fine-needle aspiration cytology. Diagn Cytopathol. 2015;43(9):716–8. https://doi.org/10.1002/dc.23232. Epub 2014 Oct 31. Demir HA, Bayhan T, Üner A, Kurtulan O, Karakuş E, Emir S, Özyörük D, Ceylaner S.  Chronic lymphocytic leukemia in a child: a challenging diagnosis in pediatric oncology practice. Pediatr Blood Cancer. 2014;61(5):933–5. https://doi.org/10.1002/pbc.24865. Epub 2013 Nov 19. PubMed PMID: 24249660. Drut R, Drut RM.  Angiocentric immunoproliferative lesion and angiocentric lymphoma of lymph node in children. A report of two cases. J Clin Pathol. 2005;58(5):550–2. PubMed PMID: 15858132; PubMed Central PMCID: PMC1770650 Gini Ehungu JL, Mufuta JP, Ngiyulu RM, Ekulu PM, Kadima BT, Aloni MN.  A rare occurrence of hairy cell leukemia in a congolese child: a presentation and challenge of diagnosis in low resource settings. J Pediatr Hematol Oncol. 2013;35(8):e350–2. https://

References and Recommended Readings doi.org/10.1097/MPH.0b013e318290b9c7. PubMed PMID: 23652869. Giona F, Teofili L, Moleti ML, Martini M, Palumbo G, Amendola A, Mazzucconi MG, Testi AM, Pignoloni P, Orlando SM, et al. Thrombocythemia and polycythemia in patients younger than 20 years at diagnosis: clinical and biologic features, treatment, and longterm outcome. Blood. 2012;119:2219–27. https://doi. org/10.1182/blood2011-08-371328. Grifo AH.  Langerhans cell histiocytosis in children. J Pediatr Oncol Nurs. 2009;26(1):41–7. https://doi. org/10.1177/1043454208323915. Epub 2008 Oct 20. PubMed PMID: 18936291 Hait E, Liang M, Degar B, Glickman J, Fox VL. Gastrointestinal tract involvement in Langerhans cell histiocytosis: case report and literature review. Pediatrics. 2006;118(5):e1593–9. Epub 2006 Oct 9. Review. PubMed PMID: 17030599 Henter JI, Horne A, Aricó M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31. PubMed PMID: 16937360. Histiocytosis Association of America. The importance of clinical trials in the fight against histiocytosis. 2008. Retrieved 22 Mar 2008, from http://wwww.histio.org Hofmann I.  Myeloproliferative neoplasms in children. J Hematop. 2015;8(3):143–57. Epub 2015 Aug 2. PubMed PMID: 26609329; PubMed Central PMCID: PMC4655194. Hoover KB, Rosenthal DI, Mankin H.  Langerhans cell histiocytosis. Skelet Radiol. 2007;36(2):95–104. Epub 2006 Oct 7. Review. PubMed PMID: 17028900 Hurford MT, Altman AJ, DiGiuseppe JA, Sherburne BJ, Rezuke WN.  Unique pattern of nuclear TdT immunofluorescence distinguishes normal precursor B cells (Hematogones) from lymphoblasts of precursor B-lymphoblastic leukemia. Am J Clin Pathol. 2008;129(5):700–5. https://doi.org/10.1309/ ANERT51H38TUEC45. PubMed PMID: 18426728 Jordan MB, Filipovich AH.  Hematopoietic cell transplantation for hemophagocytic lymphohistiocytosis: a journey of a thousand miles begins with a single (big) step. Bone Marrow Transplant. 2008;42(7):433–7. https://doi.org/10.1038/bmt.2008.232. Epub 2008 Aug 4. Review. PubMed PMID: 18679369. Kobayashi S, Iwasaki S. Adult T-cell leukemia/lymphoma (ATL): pathogenesis, treatment and prognosis, clinical epidemiology of acute lymphoblastic leukemia – from the molecules to the clinic, Juan Manuel MejiaArangure. IntechOpen. https://doi.org/10.5772/54776. Available from: https://www.intechopen.com/ books/clinical-epidemiology-of-acute-lymphoblastic-leukemia-from-the-molecules-to-the-clinic/

931 adult-t-cell-leukemia-lymphoma-atl-pathogenesistreatment-and-prognosis Kushwaha R, Ahluwalia C, Sipayya V. Diagnosis of sinus histiocytosis with massive lymphadenopathy (RosaiDorfman disease) by fine needle aspiration cytology. J Cytol. 2009;26(2):83–5. https://doi.org/10.4103/09709371.55229. PubMed PMID: 21938160; PubMed Central PMCID: PMC3168026. Makras P, Alexandraki KI, Chrousos GP, Grossman AB, Kaltsas GA.  Endocrine manifestations in Langerhans cell histiocytosis. Trends Endocrinol Metab. 2007;18(6):252–7. Epub 2007 Jun 27. Review. PubMed PMID: 17600725 Onciu M, Lorsbach RB, Henry EC, Behm FG. Terminal deoxynucleotidyl transferase-positive lymphoid cells in reactive lymph nodes from children with malignant tumors: incidence, distribution pattern, and immunophenotype in 26 patients. Am J Clin Pathol. 2002;118(2):248–54. PubMed PMID: 12162686 Sidiropoulos M, Hanna W, Raphael SJ, Ghorab Z.  Expression of TdT in Merkel cell carcinoma and small cell lung carcinoma. Am J Clin Pathol. 2011;135(6):831–8. https://doi.org/10.1309/ AJCPLCB2Q9QXDZAA. PubMed PMID: 21571955 Strauchen JA, Miller LK.  Terminal deoxynucleotidyl transferase-positive cells in human tonsils. Am J Clin Pathol. 2001;116(1):12–6. PubMed PMID: 11447741 Sur M, AlArdati H, Ross C, Alowami S.  TdT expression in Merkel cell carcinoma: potential diagnostic pitfall with blastic hematological malignancies and expanded immunohistochemical analysis. Mod Pathol. 2007;20(11):1113–20. Epub 2007 Sep 21. PubMed PMID: 17885674 Takeshita M, Akamatsu M, Ohshima K, Suzumiya J, Kikuchi M, Kimura N, Uike N, Okamura T.  Angiocentric immunoproliferative lesions of the lymph node. Am J Clin Pathol. 1996;106(1):69–77. PubMed PMID: 8701936 Tavian M, Péault B. Embryonic development of the human hematopoietic system. Int J Dev Biol. 2005a;49(2– 3):243–50. Review. PubMed PMID: 15906238. Tavian M, Péault B. The changing cellular environments of hematopoiesis in human development in utero. Exp Hematol. 2005b;33(9):1062–9. Review. PubMed PMID: 16140155. Valent P, Horny HP, Escribano L, Longley BJ, Li CY, Schwartz LB, Marone G, Nuñez R, Akin C, Sotlar K, Sperr WR, Wolff K, Brunning RD, Parwaresch RM, Austen KF, Lennert K, Metcalfe DD, Vardiman JW, Bennett JM.  Diagnostic criteria and classification of mastocytosis: a consensus proposal. Leuk Res. 2001;25(7):603–25. Review Writing Group of the Histiocyte Society. Histiocytosis syndromes in children. Lancet. 1987;1(8526):208–9.

Endocrine System

11

Contents 11.1

Development and Genetics

 934

11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.2.5 11.2.6 11.2.7

Pituitary Gland Pathology  ongenital Anomalies of the Pituitary Gland C Vascular and Degenerative Changes Pituitary Adenomas and Hyperpituitarism Genetic Syndromes Associated with Pituitary Adenomas Hypopituitarism (Simmonds Disease) Empty Sella Syndrome (ESS) Neurohypophysopathies (Disorders of the Posterior Pituitary Gland)

 938  939  939  939  941  942  943  943

11.3 11.3.1 11.3.2 11.3.3 11.3.4

Thyroid Gland Pathology  ongenital Anomalies, Hyperplasia, and Thyroiditis C Congenital Anomalies, Goiter, and Dysfunctional Thyroid Gland Inflammatory and Immunologic Thyroiditis Epithelial Neoplasms of the Thyroid Glands

 943  946  946  948  949

11.4 11.4.1 11.4.2 11.4.3 11.4.4

Parathyroid Gland Pathology  ongenital Anomalies of the Parathyroid Glands C Parathyroid Gland Hyperplasia Parathyroid Gland Adenoma Parathyroid Gland Carcinoma

 965  965  965  966  966

11.5 11.5.1 11.5.2 11.5.3 11.5.4 11.5.5

Adrenal Gland Pathology  ongenital Anomalies of the Adrenal Gland and Paraganglia C Dysfunctional Adrenal Gland Adrenalitis Neoplasms of the Adrenal Gland and Paraganglia Syndromes Associated with Adrenal Cortex Abnormalities

 967  967  969  969  974  996

Multiple Choice Questions and Answers

 997

References and Recommended Readings

 998

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_11

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11  Endocrine System

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11.1 Development and Genetics The pituitary gland, aka hypophysis, is a small endocrine bioanatomic structure, weighing 0.35– 0.9 g, and located in the sella turcica of the sphenoid bone (neurocranium). The pituitary gland is composed of two portions, which are classified on a sagittal plane, i.e., anterior pituitary gland and posterior pituitary gland, as well as a vestigial intermediate lobe. The anterior portion constitutes about 3/4 of the gland, while the posterior portion represents about 1/4 of the gland. The histology of the pituitary gland shows small nests and cords of round uniform cells finely demarcated by a rich vascular network. The different tinctorial characteristics of the cells of the pituitary gland gave the original name to these cells, using the terms of acidophilic cells, basophilic cells, or chromophobic cells; the latter was used if no staining was present. The use of immunohistochemistry allows the classification of these cells according to the specific hormones they produce. It has been scrutinized that ~1/5 of the cells of the anterior pituitary gland lacks any immunoreactivity. These cells are subclassified as nonsecretory cells. Conversely, the histology of the posterior portion of the pituitary gland reveals an intricate framework of nerve

fibers with the support of glial cells. These nerve fibers are the axons of hypothalamic neurons and are unmyelinated. The ultrastructural examination of these unmyelinated nerve fibers discloses membrane-bound secretory granules, which are composed of antidiuretic hormone (ADH) or oxytocin. Neurophysins, which are specific binding ­proteins, make some complexes with either ADH or oxytocin. The hypothalamus is central in neuroendocrinology and controls both the anterior and the posterior portions of the pituitary gland. The hypothalamic control is, however, different. The anterior portion receives releasing and inhibiting hormones by the hypothalamus using the portal venous system, while the posterior part of the pituitary gland is directly under hypothalamic control because neurons in the hypothalamic cells secrete ADH and oxytocin. These hormones migrate down the axons in the pituitary stalk for storage and then are blood-released by the posterior pituitary. The cytologic diversity of the pituitary gland is impressive and may look like a symphony orchestra, because the several instruments play a role for proper functionality of the organism. The abnormal performance of a single “instrument” may considerably jeopardize the final “sound” of the entire organism (Box 11.1).

Box 11.1 Pituitary Gland Cyto-diversity Cytologic phenotype Somatotroph

Hormone type GH

Corticotroph Lactotroph Thyrotroph Gonadotroph

ACTH Prolactin TSH FSH/LH/ICSH

Null Hypothalamic nuclei Hypothalamic nuclei

None ADH Oxytocin

Action Body growth Insulin-antagonist Adrenal gland stimulation Mammary gland proliferation and function Thyroid hormones synthesis and secretion FSH: pre-ovulatory phase, estrogen secretion, ovulation LH: corpus luteum, progesterone secretion, ovulation Distal nephron H2O resorption and arteriolar constriction Smooth muscle contraction in uterus and ducts of the mammary gland

Note: GH or growth hormone is also called somatotropin. During corticotropin synthesis, three additional peptidic hormones are split off, including beta-lipotropic hormone, beta-­endorphin, and alpha-melanocyte-stimulating hormone (alpha-MSH). Beta-lipotropic hormone functions. β-endorphin has endogenous opiate action, while alpha-MSH facilitates the dispersion of melanin in the skin. ACTH, adreno-­corticotropin hormone; the same gonadotroph cells produce both follicle-stimulating hormone (FSH) and luteinizing hormone (LH). In the male organism, the interstitial cell-stimulating hormone (ICSH) works as a male counterpart for LH. ICSH stimulates the Leydig cells of the testis to secrete androgens. ADH, antidiuretic hormone

11.1 Development and Genetics

The thyroid gland is an endocrine organ. It develops from a tubular pouch of the embryonic pharynx (foramen cecum of the tongue), the socalled thyroglossal duct that migrates downward into the neck. In this location, the duct is an important bio-anatomic structure in the development of the thyroid gland. Thyroid gland grows downward in front of trachea and thyroid cartilage. The distal end of this primordial organ becomes the adult gland, while the proximal portion regresses progressively by the 5th to 7th week of gestation. This primordium is also joined by tissue derived by the 4th and 5th pharyngeal pouches, which contribute to the parafollicular cells, while the hyoid bones forms from the 2nd branchial arch. Anatomic thyroid gland milestones are, thus, identified the thyroid diverticulum and the thyroglossal duct (stalk), which eventually disappears. In case of persistence of the thyroglossal duct, there will be an ectopic glandular tissue of thyroid. The fate of this tissue is variable. It can stay silent or become cystic, inflamed, as well as, more rarely, neoplastic. When there is the arrest of the downward migration of the thyroglossal duct, it happens that some ectopic thyroidal tissue is found along this migration (thyroid gland ectopia). Some forms are clinically recognized, including lingual thyroid and thyroglossal midline remnant. The former structure is characterized by the presence of thyroidal tissue at the root of the tongue. The latter structure is a remnant of the thyroglossal duct fund along its pathway of descent. The lingual thyroid is very rare, while thyroglossal duct remnants are more often recognized. The thyroglossal duct remnant may become cystic (thyroglossal duct cyst) when epithelial remnants are allowed to secrete with time (late childhood and youth). The lining of the thyroglossal duct cyst is constituted by either squamous or ciliated (respiratory) epithelium, and the wall of the cyst is made up of thyroid tissue. Most commonly, thyroglossal duct cysts are found between the hyoid bone and the isthmus of the orthotopic thyroid gland, and the pediatric surgeon wisely excises the hyoid bone as well to avoid missing ectopic thyroidal tissue. The persistence of a cyst may be prone to be infected and develop into an abscess (thyroglossal duct abscess) and the

935

patient can develop local signs of infection but also fever and, potentially, septicemia. Two lateral lobes constitute the thyroid gland, which are joined across the midline by a bridge called isthmus (isthmus glandulae thyroideae). Also, there is a small lobe or pyramidal lobe, which extends upward from the isthmus. The pyramidal lobe is the vestigial point of attachment of the thyroglossal duct embryologically digging. At examination, the normal thyroid gland is firm, red-brownish, and smooth with a fibrous capsule that merges with the deep cervical fascia. Histology is variable from the gestational age, but once the thyroid gland has reached the maturity at birth, it is almost indistinguishable from healthy young adult size. The hematoxylin-­eosin staining of thyroid gland tissue shows firmly packed follicles separated by a quite rich vascular supply with little intervening stroma. The rich vascular texture is key to the definition of an endocrine gland differently from the poor or normal vascular texture identified in exocrine glands. Endocrine glands secrete into blood, while exocrine gland secrete in a non-blood filled cavity. The follicles are distinctly lined by cuboidal epithelial cells, and their lumens are filled with colloid, which contains thyroglobulin and thyroid hormones in a proteinaceous matrix. Moreover, the parafollicular or C cells are dispersed between the thyroid follicles and secrete calcitonin. In the thyroid gland, follicles vary in size: ~ 200  μm, but this size should be considered only cautiously. A single layer of cuboidal-columnar cells is seen, but epithelium may look like quite flat at places. Hürthle or Askanazy cells are acidophilic thyrocytes with abundant mitochondria. Thyroid immunoreactivity displays T3, T4, LMWCKs, EMA, and VIM. Thyroglobulin (TGB or TG) is a 650 kD protein synthesized and stored extracellularly as “colloid” with or without the presence of calcium oxalate crystals (1/2 of individuals). Tyrosyl residues are iodinated to monoiodotyrosine (MIT) and diiodotyrosine (DIT) and MIT and DIT couple to build T3 and T4, and in response to TSH, T3 and T4 are collected in pinocytotic vesicles and released into the blood. Thyroxine-­ binding protein (TBP) binds both T3 and T4, although T4 binds tighter, which means, in endocrinological investigations and

936

d­ iscussions, is less available in plasma. Parafollicular C cells are neural crest-derived cells, which are located between and within follicles ( ♀ Extrathyroidal extension: ↑ TNM stage Size-S-phase-Structure: Ø>4  cm, Aneu­ ploidy, (1-4) variants

(7) variants have an excellent prognosis. Of final note, the oxyphilic variant should be included in the Hürthle cell tumors. The sclerosing variant is mainly restricted to children and young adults.

11.3.4.4 Medullary Thyroid Carcinoma • DEF: Neuroendocrine malignant epithelial tumor with strong RET mutations (somatic/germinal), which shows one of the most histologically various growth patterns among thyroid neoplasms. It arises mostly in the upper half of the gland (more C cells) occurring in either sporadic form (~80%, solitary cold nodule, ~45 years as mean age) or familial form (~20%, multiple/bilateral cold nodules, ~35 years, and C-cell hyperplasia (vide infra) in residual gland, MEN II and MEN III, VHL, NF). • EPI: 5–10 of thyroid carcinomas. • GRO: Solid, firm, well delimitated, nonencapsulated, and gray-white. • CLM: Variable cytologic appearance showing carcinoid-like nests of round (plasmacytoid) to polygonal cells with granular cytoplasm, trabeculae, glands, or pseudopapillary architecture embedded in highly vascular stroma containing hyalinized collagen and Congo red/crystal violet special stains (+) amyloid (amorphous hyaline material), coarse calcifications, ± psammoma bodies (Fig. 11.10). • IHC: TG (−), but (+) TTF-1 & (+) CGA, SYN, CALC, CEA (± ACTH, VIP). • DDX: PTC, Hürthle cell carcinoma, atypical laryngeal carcinoid, and neuroendocrine lung tumors (vide infra) (Box 11.15). • PGN: Hematogenous (lung, liver, bone) and lymphatic spread with neuroendocrine “AMES”.  AMES mnemonic collects the worse features of MTC outcome:

–– Age: >40  years vs. younger individuals, who have a better outcome –– Male gender: ♂ > ♀ vs. female gender, which has better PGN –– Extrathyroid extension, increasing TNM staging vs. confined to the gland (better PGN) –– Sporadic-Solid-Stage (TNM): sporadic occurrence, solid growth, high stage. C-Cell Hyperplasia • DEF: Precursor lesion of familial MTC (vide supra) occurring in MEN2, Hashimoto thyroiditis, hypergastrinemic, and hypercalcemic states and characterized by >50 C cells/follicle with C cells within follicles and between them and mostly located in central part of lateral lobes. • IHC: (+) CALC and CEA. Collagen IV is also useful to highlight the BM, which should be single, complete, continuous without foci of reduplication (DDX: MTC!). • DDX: MTC, cross section of any MTC tumor embolus, intrathyroidal metastasis, “palpation thyroiditis”, islands of squamous metaplasia, tangential shave of a healthy follicle, parathyroid gland, and thymic rests. These eight differential diagnoses should be kept in mind at all times and particularly before rendering the diagnosis of neoplasm. Multiple Endocrine Neoplasias • DEF: AD-inherited genetic syndromes with high degree of penetrance and various neoplasias of the endocrine system harboring from “indigenous” hyperplasias (C cell of the thyroid, adrenal medulla) through frank neoplasias linked to either MENIN, a tumor suppressor gene (MEN I), located on chromosome 11q, or RET, an oncogene (MEN IIA = MENII and MEN IIB  =  MEN III), located on chromosome 10q.

MEN Type I • DEF: MENIN-related genetic disease • SYN: Wermer syndrome

11.3 Thyroid Gland Pathology

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a

b

c

d

e

f

g

h

Fig. 11.10  This panel shows the characteristic features of a medullary thyroid carcinoma with gross findings (a) including a solid white-yellow nodule with infiltrative margins. The histological examination reveals round, plasmacytoid cells in nests, cords, or follicles (b, ×100; c, ×400). The tumor cells show round nuclei with finely stippled to, at places, coarsely clumped chromatin and indistinct nucleoli. No nuclear pseudoinclusions are seen, although they may be encountered occasionally. There is

a low mitotic index. The stroma has amyloid deposits (b), which is Congo red positive (d, ×100). The Figures (b) and (c) are microphotographs taken from histological slides stained with hematoxylin and eosin. In the panel, the four other microphotographs show the immunologic expression of thyroid transcription factor (e, ×100), calcitonin (f, ×100), CD56 (g, ×100), and chromogranin A (h, ×100). The immunostaining was performed using the avivin-biotin complex

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Box 11.15 MTC Differential Diagnosis

1. PTC: both are (+) TTF-1, but MTC is (−) TG and (+) CGA, SYN, CALC. 2. Hürthle cell carcinoma: both are (+), but MTC is (−) TG and (+) CGA, SYN, CALC. 3. Atypical laryngeal carcinoid (ALC): both are NE tumors and (−) TG and (+) CGA, SYN, CALC, but ALC is (−) TTF-1, while MTC is (+) TTF-1. 4. Neuroendocrine tumor of lung (NETL): both MTC and NETL are (+) CGA, SYN, TTF-1, K7, and CAM5.2, but NETL is (−) CALC (usually), and MTC is obviously (+) CALC. Notes: CALC, calcitonin; CAM 5.2, cell adhesion molecules 5.2; CGA, chromogranin A; K7, (cyto-) keratin7; MTC, medullary thyroid carcinoma; PTC, papillary thyroid carcinoma; SYN, synaptophysin, TTF1 thyroid transcription factor 1, TG, thyreoglobulin. • CLM: Pituitary adenoma, parathyroid hyperplasia/adenoma, pancreas endocrine tumor (three Ps as mnemonic help) Pituitary adenoma Parathyroid gland chief cell hyperplasia/parathyroid gland adenoma Pancreas endocrine tumor: G cell (50%), B cell (30%), VIP cell (10%), and others (10%) G cells (gastrinoma)  ⇒  Hypergastrinemia (Zollinger-Ellison syndrome with hypersecretion and peptic ulceration) B cells (insulinoma) ⇒ Hyperinsulinemia VIP cells (VIPoma)  ⇒  WDHA syndrome or watery diarrhea (pancreatic cholera), hypokalemia, achlorhydria Also, nodular hyperplasia of the thyroid gland, carcinoid tumors of lung, thymus, GI tract, lipomas, and Menetrier’s disease can be observed in patients harbiring MEN type I. The surgical treatment of congenital hyperinsulinism has been recently revised (Adzick 2020). MEN Type II (IIA) • SYN: Sipple syndrome

11  Endocrine System

• CLM: Catecholaminergic pheochromocytoma + MTC (two Cs)  +  1P: Parathyroid chief cell hyperplasia. Also, adrenal cortical tumors can be observed. MEN Type III (IIB) • SYN: Gorlin syndrome • CLM: Catecholaminergic pheochromocytoma + MTC (two Cs) + 1P: Parathyroid chief cell hyperplasia + Mucosal ganglioneuromas of corneal nerves, lips, and GI tract • CLI: ± Marfanoid habitus with skeletal abnormalities Also, adrenal cortical tumors and parathyroid tumors can be observed.

11.3.4.5 Hürthle Cell Tumors Among Hürthle cell neoplasms, a significant percentage may show malignant outcome or show destructive tendency locally (5-YSR: 20–40%) along the years as compared to non-Hürthle cell neoplasms. The diagnosis of Hürthle cell cancer is difficult and usually occurs most commonly in subjects above 50 years of age. However, rarely it may be encountered in childhood. Hürthle cell neoplasms are more often seen in females. It appears as a solid, tan, well-­vascularized, and usually encapsulated mass grossly. Histologically, they show follicular (more often), trabecular, solid, or papillary growth pattern. Hürthle cell cytology is characterized by cells with granular, acidophilic cytoplasm due to the numerous mitochondria. Malignancy of the Hürthle cell neoplasms is carried out using the same criteria used for follicular lesions (Fig. 11.11). 11.3.4.6 Poorly Differentiated Thyroid Carcinoma This type of tumor is practically inexistent in children and youth, being reserved to older age group. It exhibits a tremendous high mortality (60%). PDTC harbors TP53, RAS, and BRAF gene mutations. These neoplasms are grossly invasive, and show, histologically, nested (insular) growth pattern (other growth patterns: solid, trabecular) with small uniform cells with convoluted nuclei, necrosis, and high MI (≥3/10 HPF). IHC: (−) TG, CALC (DDX: MTC).

11.3 Thyroid Gland Pathology

963

a

b

c

d

e

f

g

h

Fig. 11.11  This panel illustrates the occurrence of a Hürthle cell nodule with characteristic oncocytic morphology of the tumor cells (a, ×12.5; b, ×50; c, ×50; d,

×100; e, ×200; f, ×50; g, ×400; h, ×400; hematoxylin-­ eosin staining). (See text for details)

11.3.4.7 Anaplastic Thyroid Carcinoma This type of tumor is also practically inexistent in children and youth, being reserved to older age group. It exhibits the highest mortality (100%)

among thyroid gland neoplasms. ATC arises from pre-existing, less aggressive, well-­differentiated thyroid carcinomas, specifically papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), through a process of dedifferentiation, where epi-

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thelial and thyroid differentiation markers are lost. This process of dedifferentiations may recall the dedifferentiated liposarcoma. ATC is a rapidly growing neoplasm causing dysphagia/dyspnea and shows grossly hemorrhagic/necrotic areas. Histologically, ATC has three significant growth patterns (squamoid, spindle cell, and giant cell). Immunohistochemically, ATC is (+) VIM, CAM5.2, and EMA but (−) TG and TTF-1. If CALC is (+), the tumor should be considered an anaplastic variant of MTC.

11.3.4.8 Other Epithelial Tumors Two recently added entities need to be taken into account. They are spindle epithelial tumor with thymus-like (elements of) differentiation (SETTLE) and carcinoma showing thymus-like differentiation (CASTLE), which need to be considered in the differential diagnosis of thymoma, arising from intrathyroid ectopic thymus tissue. Moreover, practically inexistent in childhood and youth are clear cell tumor or mucinous carcinoma (DPAS(+), mucicarmine (+)), squamous cell carcinoma, mucoepidermoid carcinoma, sclerosing mucoepidermoid carcinoma with eosinophilia, small cell carcinoma, and paraganglioma. The paraganglioma may arise from the carotid body (Zellballen and S100 (+) sustentacular cells). The small cell carcinoma, has been suggested to be a poorly differentiated medullary carcinoma. SETTLE occurs in youth and is indolent and may metastasize to the lung and kidney. SETTLE is characterized morphologically by a lobular growth pattern with thick sclerotic fibrous septs as well as spindle (fascicles/storiform) and epithelioid cells with bland cytology and low MI forming papillae, tubules, trabeculae, and solid sheets ± Hürthle cell-like corpuscles)  ±  cysts from mucinous/respiratory epithelium without immature lymphocytes (DDX: intrathyroidal thymoma, which shows immature lymphocytes). ­ Immunohistochemically, SETTLE exhibits (+) SMA, MSA, CD99 (spindle cells), and (+) keratins/AE1-3 (epithelioid cells) but (−) CD5, CALC, and TG. CASTLE may occur in youth but is more prevalent in the middle age group and has a sluggish growth with local complications and rare tendency to give metastases. Histologically, lobular and insular patterns with fibrous septs and extrathyroidal spread have been described.

11  Endocrine System

Immunohistochemically, CASTLE is (+) CD5 and Bcl2 and (−) CALC and TG. Substantially, CASTLE shows also thymic carcinoma markers, including HMW-CK (high molecular weight keratin), p63, CD117, MCL1 (apoptosis regulator), CEA (carcinoembryonic antigen), GLUT1 (glucose transporter 1), and PAX8 (paired box 8).

11.3.4.9 Non-epithelial Neoplasms Malignant lymphoma and teratoma do play an important role in childhood and youth. Plasmacytoma is extremely rare in childhood and adolescence and should be reserved for tumors exclusively composed of atypical plasma cells and may be local or a manifestation of the generalized neoplastic disease. Malignant lymphoma is more often in the middle age but may occurs in childhood. It should be taken into consideration of the differential diagnosis of thyroid gland neoplasms. This is especially important to consider in patients following exposure to radiation therapy. Malignant lymphomas also arise in the setting of lymphocytic and Hashimoto thyroiditis. Two most common types have been described, including the diffuse large B-cell lymphoma and the extranodular marginal zone B-cell lymphoma. Clinically, the malignant lymphoma presents as one or more cold nodules, and grossly they show a fish-flesh solid tumor mass white cut surface. Morphologically, there are confluent sheets of B cells and immunohistochemically are not different from the respective nodal profile. Prognosis is variable, but it may recur, and if it does, it may recur in the gastrointestinal tract. Teratoma may occur in infants/children. It is usually cystic and mature with benign, favorable course. Ruling out germ cell tumors and malignant SRBCTs is essential for the oncologist. Rare other non-epithelial neoplasms include benign and malignant vascular tumors (hemangioma/hemangioendothelioma/angiosarcoma), smooth muscle tumors (leiomyoma, leiomyosarcoma), peripheral nerve sheath tumors (schwannoma, malignant peripheral nerve sheath tumor), solitary fibrous tumor, follicular dendritic cell tumor, Rosai-Dorfman disease, and LCH. Mucin-­ containing tumors include mucinous carcinoma, mucoepidermoid carcinoma (MEC), sclerosing MEC with eosinophilia, adenosquamous carci-

11.4 Parathyroid Gland Pathology

noma, and an amphicrine variant of medullary thyroid carcinoma (mucin-secreting SR-like cells). The sclerosing MEC with eosinophilia has a background of Hashimoto thyroiditis, nests, and cords in both mucoid and epidermoid components, diffuse sclerotic stroma with eosinophils ((−) TG, DDX: Nodular Sclerosis-variant of HL, sclerosing Hashimoto thyroiditis, PTC with squamoid metaplasia, and squamous cell carcinoma).

11.3.4.10 Secondary (Metastatic) Tumors It is crucial to recall soft tissue tumors, particularly small round blue cell tumors (e.g., rhabdomyosarcoma, embryonal) in childhood, but in the youth, the skin (melanoma), breast, kidney, and lung play a significant role.

11.4 Parathyroid Gland Pathology Parathyroid gland pathology may manifest with hyper- or hypofunction of the parathyroid gland physiology. Two clinical syndromes may be encountered clinically. Hyperparathyroidism Primary hyperparathyroidism is characterized by an increase of PTH secretion due mostly to either adenoma or chief cell hyperplasia. Carcinoma is seen in about 1 out of 20 cases. It is usually encountered in adults but can be familial and seen in MEN-I and MEN-II (or IIa) and has been associated with neck radiation and sarcoidosis. Biochemically, hypercalcemia, hypophosphatemia, and duodenal peptic ulcers are seen. Clinically, Recklinghausen disease (osteitis fibrosa cystica) and nephropathic changes are found.

Box 11.16 Parathyroid Gland Pathology

11.4.1. Congenital Anomalies of the Parathyroid Glands 11.4.2. Parathyroid Gland Hyperplasia 11.4.3. Parathyroid Gland Adenoma 11.4.4. Parathyroid Gland Carcinoma

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1. Recklinghausen disease shows an expansile multilocular bony lesion, most of the jaw with alternating solid and cystic areas, hemosiderin deposition in MΦ (Fe+), and MNGC, which is following the reversible removal of the hyperfunctioning parathyroid glands. 2. Nephropathy includes nephrolithiasis and nephrocalcinosis. Secondary hyperparathyroidism is delineated by an increase of PTH secretion as a consequence of chronic renal disease (commonly vitamin D-resistant) or intestinal malabsorption. Biochemically, there are hypocalcemia and hyperphosphatasemia. Morphologically, chief cell hyperplasia is noted. Tertiary hyperparathyroidism is characterized by the autonomy of one or more parathyroid glands in patients with secondary hyperparathyroidism. Finally, ectopic hyperparathyroidism may originate in renal cell carcinoma and pulmonary small cell carcinoma and need to be considered particularly in young non-smoker females of Chinese origin that may develop lung cancer.

11.4.1 Congenital Anomalies of the Parathyroid Glands • DEF: Anomalies of the ontogenesis, mostly involving the parathyroid gland. • Parathyroid Gland Dystopia (dystopia glandularum parathyroidarum) is an unusual location of the parathyroid glands, which may involve one or more parathyroid glands. Anomalous locations include intrathyroidal, carotid sheath, retroesophageal, and anterior mediastinum.

11.4.2 Parathyroid Gland Hyperplasia • DEF: Chief cell hyperplasia or water-clear cell hyperplasia. Chief cell hyperplasia means hyperplasia of chief cells. Water-clear cell hyperplasia means hyperplasia of water-clear cells. • Chief Cell Hyperplasia.

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• SYN: Primary nodular hyperplasia. • GRO: Enlargement of all glands, usually with tan-reddish discoloration and superior glands larger than inferior glands. • CLM: Lobulated architecture (with enlargement of single lobules) AND intralobular scattered fat cells ± fibrous septs, giant nuclei (DDX secondary hyperparathyroidism – chief cell hyperplasia, characterized by more variability, fewer giant nuclei, and more oxyphil cells). • Water-Clear Cell Hyperplasia. • GRO: Extreme enlargement of all glands (superior glands are more abundant than inferior glands). • CLM: Cells with optically clear cytoplasm with numerous clear vacuoles and size variability without giant nuclei.

11.4.3 Parathyroid Gland Adenoma • DEF: It is a benign epithelial tumor of the parathyroid glands (an inferior gland in ~¾ of cases) with CYCLIN D1/PRAD1 gene rearrangement, MEN1 (menin), and, less frequently, HRPT2 (parafibromin) gene mutations. • EPI: ♂:♀ = 1:3, 2nd-3rd decades of life. • GRO: Encapsulated nodule. • CLM: There is a diffuse growth of predominant chief cells, although other cells may be seen, with marked variability in nuclear size and hyperchromasia favoring benign vs. malignant and rare mitoses or no mitoses = nil mitotic index. Different growth patterns include nesting, follicular, and papillary. Features favoring parathyroid gland adenoma include one gland enlarged over three normal glands, excess weight (>1 g), lack of adipocytes, thin capsule separating it from the uninvolved gland, “endocrine-type atypia” in oxyphil cells or adjacent to hemorrhage with nil MI. Some authors that just one of these criteria may favor the diagnosis of adenoma over hyperplasia, but other authors require the fulfillment of all criteria and probably the truth is in the middle (in medias res stat virtus).

11  Endocrine System

Variants: Oxyphil cell adenoma and lipoadenoma (variable number of adipocytes within a solitary, nonlobulated lesion). • TEM: Glycogen and secretory vacuoles.

11.4.4 Parathyroid Gland Carcinoma • DEF: It is a malignant epithelial tumor of the parathyroid gland with HRPT2 (parafibromin) gene mutations or, less frequently, CYCLIN D1/PRAD1 gene rearrangement, MEN1 gene changes, functioning/nonfunctioning (more aggressive). • CLM: Trabecular arrangement of tumor cells ± spindling AND features favoring carcinoma over adenoma: vascular invasion, capsular invasion (penetration with growth into adjacent tissue), perineural invasion, and/or metastasis. The absence of the above-described features may be suggested, if the following features are seen: 1. +/++ MI (evident mitotic activity) 2. Dense fibrous bands (vs. fibrous tissue ± hemosiderin and cysts as seen in adenoma) • IHC: (+) p105 (pRb) favors carcinoma vs. adenoma, but if (−) p105 → not conclusive! In some reports, the term atypical adenoma has been used to identify an adenoma with some features of carcinomas of the adrenal gland. They include adherence of the parathyroid gland neoformation to the neighboring structures, increased mitotic activity, fibrosis, trabecular growth pattern, and the presence of tumor cells inside of the capsule but without evidence of invasive growth, including invasion through the capsule, invasion of the blood vessels, and invasion of the perineural space. In carcinomas of the parathyroid gland, there is invasion of the neighboring structures, blood vessel invasion, and perineural infiltrates. A mimicker of the invasion and therefore a caveat may be the condition called parathyromatosis, i.e., the transfer of parts of parathyroid gland due to previous surgery. Thus, clinical history may be determining and the detailed revision of the medical notes is a very helpful clue for the pathologist dealing with an intraoperative frozen section from parathyroid gland.

11.5 Adrenal Gland Pathology

In parathyroid adenoma, large, pleomorphic, and hyperchromatic nuclei can be seen, but the mitotic index is rare or nil. If numerous mitoses are found, the pathologist should look for the presence of invasion and other parameters that can direct to the diagnosis of parathyroid carcinoma. Parathyroid carcinomas are, however, extremely rare. Pseudoadenomatous hyperplasia is when one gland looks like larger than others in the setting of parathyroid hyperplasia, while a rarer form is parathyromatosis, which is characterized by numerous microscopic foci of hyperplastic parathyroid gland tissue in the neck. Atypical Adenoma: Parathyroid gland tumor is lacking unequivocal evidence of invasion but showing some other features suspicious for malignancy, including broad fibrous bands with or without hemosiderin depots, conspicuous or accurate mitotic figures, and neoplastic cell groups delimitated by a thickened fibrous capsule (“non-penetrating capsular invasion”). This diagnosis is controversially accepted in the scientific literature. The features suggesting carcinoma include MI >5 or >10 HPF OR > 5%, metastasis (+), abnormal monotonous cells with prominent nucleoli, ↑ N/C, spindling, coagulative tumor cell necrosis, invasion (angio-/vascular, capsular, perineural, surrounding soft tissue), and a thick hyaline fibrous capsule with internal fibrous bands enclosing nodules. It is important to remember the pseudoinfiltrative pattern of parathyroid tissue implants that can arise from previous surgery or pseudoinfiltrative pattern of clear cells in the wall of a benign parathyroid cyst and about metastasis to rule out renal cell carcinoma and small-cell type of lung carcinoma. Normal/atrophic chief cells need to be distinguished from hyperplastic/neoplastic chief cells. Two essential differential diagnoses are oxyphil parathyroid adenoma vs. thyroid Hürthle cell neoplasm and microfollicular parathyroid adenoma vs. thyroid follicular neoplasm.

11.5 Adrenal Gland Pathology In Box 11.17 are listed the topics covered in the pathology of adrenal gland and paraganglia.

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Box 11.17 Pathology of the Adrenal Glands and Paraganglia

11.5.1. 11.5.2. 11.5.3. 11.5.4.

Congenital Anomalies Dysfunctional Adrenal Gland Adrenalitis Neoplasms of the Adrenal Gland and Paraganglia 11.5.4.1. Adrenal Cortical Adenoma 11.5.4.2. Adrenal Cortical Carcinoma 11.5.4.3. Neuroblastoma 11.5.4.4. Pheochromocytoma

11.5.1 Congenital Anomalies of the Adrenal Gland and Paraganglia • DEF: Anomalies of the ontogenesis, mostly involving the adrenal gland. Developmental Anomalies A-/Hypoplasia (formation): Complete absence or reduced presence of the adrenal gland as well as small mono- or bilateral adrenal glands. All these anomalies of development are rare events. Additional abnormalities include dystopias (abnormal localization of the adrenal gland or paraganglia) and dysnomia (an unusual number of the adrenal glands and paraganglia). A significant pitfall is the occurrence of paraganglion / paraganglia in the adrenal gland mimicking a carcinoma. Ectopy of the adrenal gland (so-called ectopic adrenal gland) may occur in some anatomic sites. Ectopy is usually observed in retroperitoneum, anywhere along the urogenital ridge from the diaphragm to the pelvis, and is generally composed only of the cortex. However, small rests have also been occasionally found subcapsularly in the kidney, in the hilar region of testis or ovary, or in the sac of a hernia. Two types are distinguished, including the anencephalic type and the cytomegalic one (Fig. 11.12). Another anomaly is the finding of heterotopic tissue in the adrenal gland. Such a condition may represent an amartia or a coristia, whereby amartiae are heterotopias with tissue homogeneous of the accepting organ, while coristiae are

11  Endocrine System

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a

b

c

d

e

f

g

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Fig. 11.12  The panel illustrates a normal adrenal gland (a, ×50) with loose medulla on postmortem examination (b, ×50). Medulla neuroblasts form clusters during the intrauterine life (c, ×200; d, ×200). Stress- or sepsis-­related

microcystic degeneration is displayed in Figure e (×50), Figure f (×50), and Figure g (×50). Figure (h) shows a hyperplastic nodule (×12.5). (All microphotographs are taken from hematoxylin-/eosin-stained histological slides)

heterotopias with tissue, which is heterogeneous to the accepting organ. In Fig.  11.12f is shown heterotopic pancreas in a fetal adrenal gland.

Embryologically, the heterotopic pancreas is defined as pancreatic tissue that has no contact with the orthotopic pancreas with its ductal drain-

11.5 Adrenal Gland Pathology

ing system and vascular blood supply. About the origin of this congenital anomaly, it is postulated that the pancreatic primordium adhered to the original intestine or penetrates the intestinal wall during the development of the embryo. Heterotopic pancreas is not unusual in the gastric wall, abdominal wall, intestinal wall, and mesenteric wall, because of the original bowel movements linked to the embryogenesis. There is only one additional case of heterotopic pancreas in the adrenal gland described in a 21-year-old woman who presented with chronic lower back pain for a week without urinary disturbance or gastrointestinal pain or discomforts. Ultrasound revealed a cyst in the left kidney, and computed CT scan showed a cyst in the area of the adrenal gland. Removal of the cyst was performed. Histopathologic examination of the removed cyst wall showed heterotopic pancreatic cyst with cystic degeneration. Despite the close anatomic relationship of the adrenal gland and the tail of the pancreas, these two organs have different embryologic origins, and an explanation is still controversially debated for pancreatic coristiae. Agenesis  Absence of the adrenal gland(s) for lack of the primordial anlage. Heterotopy  Accessory adrenal tissue can be found in areas of the celiac axis, kidney, broad ligament, adnexa of the testis, spermatic cord, placenta, and, even, liver and lung. Adrenal Cytomegaly  Incidental finding, 3% newborns, 6.5% premature stillbirths, and usually ≤2 months of age, fetal cortex-located large (up to 120 microns in diameter) cells with marked nucleomegaly with pleomorphism and hyperchromasia, containing >25% the normal amount of nuclear DNA, ± occasional nuclear pseudoinclusions due to nuclear indentation or folding with intranuclear protrusion of cell cytoplasm. Focal “Adrenalitis”  Small foci of lymphocytes and plasma cells at the cortico-medullary junction and perivenular may accompany retroperitoneal chronic inflammatory processes.

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Ovarian Thecal Metaplasia  Small, partially hyalinized, fibroblastic nodules, wedge-shaped, and capsule-attached. Adreno-Renal Fusion  The adrenal glands are united in the midline with some medial deviation of kidneys in most cases. This condition has been associated with Cornelia de Lange syndrome.

11.5.2 Dysfunctional Adrenal Gland • DEF: It is a complex of disorders in which the adrenal glands produce an abnormal amount of sex hormones and cortisol (e.g., Cushing syndrome and Addison disease) (Fig. 11.12).

11.5.3 Adrenalitis It is an inflammation of the adrenal gland, which is caused by autoimmunopathies or infective events leading to adrenal insufficiency. The most frequent etiology of Addison disease is indeed an autoimmune lymphocytic adrenalitis. In this form, there is lymphoplasmacytic inflammation of the gland leading to the increased destruction of adrenocortical tissue. Another form of adrenalitis is of TB origin with a typical granulomatous change of the gland harboring caseous necrosis. Both types are sporadic in childhood. In both childhood and youth, other bacterial and viral infections play a role. The bacteria β-Streptococcus, N. meningitis, Epstein-­ Barr virus (EBV), and cytomegalovirus (CMV) may affect the adrenal glands in patients, specifically with immunodeficiency disorders or at posttransplant time. Hypoadrenalism Acute Hypoadrenalism is differentiated in primary (→ prolonged or difficult delivery, sepsis or Waterhouse-­ Friderichsen syndrome, the stressrelated crisis in patients with Addison disease, or too rapid withdrawal of steroids) or secondary (any disorder of hypothalamus or pituitary resulting in decreased levels of ACTH).

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Chronic Hypoadrenalism or Addison disease is defined as any condition able to destroy >90% of the adrenal cortex. Etiologies include usually adrenalitis, AI-related atrophy, and tuberculosis, but also amyloidosis, hemochromatosis, and metastases have been described. Isolated Mineral-Corticoid Deficiency refers to a deficiency of aldosterone production due to impaired release of renin from kidney in patients with DM, AI disease, amyloidosis, sickle cell anemia, heparin administration, and neoplastic proliferations. An idiopathic form is due to an AR-inherited disorder associated with a deficiency in CYP11B2 enzyme able to convert an 18-hydroxyl group to aldehyde at the end of aldosterone biosynthesis, and infants have a failure to thrive, recurrent dehydration, salt wasting. Primary Chronic Adrenocortical Insufficiency (Addison Disease) Any conditions which destroy >90% of the adrenal cortex produce the clinical picture of Addison’s disease including insidious development of weakness, fatigability, anorexia, nausea, vomiting, weight loss, hypotension, and hyperpigmentation (from elevated proopiomelanocortin peptides). Two most common causes are idiopathic adrenalitis/atrophy (probably AI-related) and TB. Others include amyloidosis, hemochromatosis, and metastatic carcinoma. In general, the cortex is atrophic with variable amounts of chronic inflammatory cells. AI Addison disease is often divided into two types: type I, involving hypoparathyroidism, mucocutaneous candidiasis, and defect in suppresser T-cell function, and type II (Schmidt syndrome) involving AI thyroid disease, and insulin-­ dependent diabetes mellitus (IDDM), associated with HLA-A1 and B8. Primary Acute Adrenocortical Insufficiency It can develop as a crisis in patients with Addison disease (precipitated by stress), following the too rapid withdrawal of steroids (suppressed endogenous production recovers slowly), or result from massive hemorrhage. In neonates, it can present with an enormous bleeding following prolonged or difficult delivery, presumably secondary to hypoxia or trauma.

Waterhouse-Friderichsen syndrome (WFS): Hemorrhagic destruction of the adrenal glands related to a severe bacterial infection (N. meningitidis, S. pneumoniae, S. aureus, H. influenzae) with widespread petechiae, purpura, and hemorrhages throughout body, particularly involving the skin and mucosal surfaces. Adrenals are hemorrhagic and necrotic, and, occasionally, they present as merely sacs full of blood clot. Secondary Adrenocortical Insufficiency Any disorder of the hypothalamus or pituitary gland resulting in decreased levels of ACTH is the correct definition for secondary adrenocortical insufficiency. Since tropic hormones are low, we do not usually see any hyperpigmentation. Secondary adrenocortical insufficiency may also be seen in the setting of exogenous corticosteroids. Hypoadrenalism • Infants: Adrenal gland hypoplasia (e.g., anencephalic fetus), familial unresponsiveness to ACTH, adrenal hemorrhage, or overwhelming sepsis (WFS). • Children and youth: Autoimmune adrenal insufficiency (Addison disease) alone or in association with another AI endocrinopathy (e.g., thyroiditis, IDDM) and infection (TB, fungi). • Adrenoleukodystrophy is a group of X-linked recessive inherited congenital disorders of long-chain fatty acid metabolism with signs of progressive neurologic deterioration in association with adrenal insufficiency. • Secondary insufficiency due to chronic ACTH deficiency or after withdrawal of pharmacologic steroid therapy as a result of suppression of pituitary ACTH.

Hyperadrenalism Conn Syndrome → Z.G.-targeting syndrome → ↑ aldosterone levels in the absence of ↑ renin levels. There is no edema, unlike secondary hyperaldosteronism. The underlying cause of Conn s­ yndrome is almost invariably an adrenocortical adenoma with identifiable features,

11.5 Adrenal Gland Pathology

including Ø5 cm, ♂ < ♀. • GRO: Bulky mass with “coarseness” (coarse nodules), along with areas of confluent necrosis, hemorrhage, and occasionally cystic degeneration, yellow-­to-­yellow-orange or tanbrownish on the cut surface. • CLM: Three basic microscopic patterns (Fig.  11.13) include (1) trabecular (broad anastomosing epithelial cords or serpentine,

or ribbon-like columns of cells with delicate slit-like intervening sinusoids or vascular channels), (2) alveolar (nests of cells), and (3) diffuse (solid arrangement of cells). Cytologically, there are lipid-depleted cells with cytoplasm condensations mimicking hyaline globules. There is, apparently, a mixed microscopic pattern as well. Some more rare features described are a pattern showing free floating nests and a perithelial distribution with intervening zones of necrosis. Intracytoplasmic hyaline globules (round to oval, refractile, intensely eosinophilic, PAS+,

a

b

c

d

e

f

Fig. 11.13  An adrenocortical tumor is shown in this panel at low power (a, ×40) and high power magnification (b, 200). Both microphotographs are from hematoxylin-/ eosin-stained histological slides. The four immunohistochemical microphotographs show no expression of chro-

mogranin A (c, ×200), focal expression of pan-cytokeratins (d, ×200), no expression of synaptophysin (e, ×200), and strong expression of vimentin (f, ×200). Immunostaining was performed using the avidin-biotin complex

11.5 Adrenal Gland Pathology

PASD+) may be a feature of both benign and malignant tumors and not characteristic of malignant potential (Box 11.19). • TEM: RER stacks, abundant SER (“tangled skein”), mitochondria with tubulovesicular cristae or platelike cristae, variably sized lipid droplets with zonation (strong uniform density with or without an internal round clear zone), lysosomes, and primitive cell junctions, as well as focal dense-core granules constitute identifying ultrastructural elements. • PGN: The prognosis depends on the stage, and about 2/3 of adolescents and young adults present with ACC at stage III or IV disease at the time of the first diagnosis. 5-YSR is about

Box 11.19 Features Portend a Diagnosis of ACC

1. MI  >  20/50 HPF  ⇒  high-grade malignant potential (HMP). 2. ↑Ki67 (MIB1) and/or TP53 expression ⇒ malignant behavior. 3. Confluent Tu.-Necrosis with angioinvasion, and capsular/extra-adrenal invasion are worrisome. 4. CGA (−) (DDX: Pheochromocytoma), but SYN (+), other than (+) Melan-A, INA, Calretinin, VIM and CKs (∗); (−) EMA. Notes: ∗ CK5 may be just weakly positive after protease digestion. Of note, DNA ploidy is not a reliable predictor of malignancy, and FNAC (fine-needle aspiration cytology) harbors a high rate of false positivity. Thus, it is extremely important to not diagnose ACC on FNAC. Substantially, generous embedding (1 block/cm) remains a key and necessary factor to increase the accuracy for the diagnosis of malignancy. Chessboard-like embedding of tumors with printed or scanned photograph to assess the malignant potential accurately is a wise decision. MI, mitotic index; HPF, highpower field; CGA, chromogranin A; SYN, synaptophysin, INA, inhibin A/α; VIM, vimentin; CK, (cyto-)keratins; EMA, epithelial membrane antigen.

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65% (i.e., ~2/3 of the patients are alive 5 years after the primary diagnosis) if the tumor is strictly contained in the adrenal gland, but 10% in case of ACC with metastatic disease. From the pearls of the pathology practice, it is essential to mention the features commonly associated with ACC according to Medeiros and Weiss (1992), which include high nuclear grade (according to Fuhrman criteria, Furhman et al. 1982), MI >5/50 HPF, atypical mitoses, cytoplasmic eosinophilia >75% of tumor cells, and diffuse architectural growth pattern in over 33% of the tumor, necrosis, invasion (venous, sinusoidal, and capsular). According to Madeiros and Weiss, the presence of ≤2 features foretells tumor with low-metastaticpotential (LMP), while the presence of >2 elements portends high-metastatic-potential (HMP) and/or recurrence. Although attention should be paid to all nine features, it seems that the three most important criteria are MI (>5/50 HPF), atypical mitotic figures, and venous invasion. Identification of a Tumor (Usually Carcinoma) as Adrenal-Originating Adrenal tumors, usually carcinoma, need to be differentiated by mimics originating from the medulla (pheochromocytoma) and other sites, including the liver (hepatocellular carcinoma, HCC) and kidney (clear cell renal cell carcinoma, CCRCC). Melan-A/ Mart 1, Inhibin A/α, and Calretinin are positive in ACC and useful for differentiating with pheochromocytoma as well as metastatic carcinoma, which should be negative for the three markers and positive for chromogranin A. Immunoreactivity for the antibodies D11, SF-1, and DAX has been reported as useful in identifying adrenal cortical tumors but is not yet widely used in diagnostic practice and still under intense investigation. Hepatocellular carcinoma is positive for HepPar1 (Hepatocyte Paraffin 1), AFP (α-feto-protein), and AAT (α1-anti-trypsin), while CCRCC is usually positive for CD10. However, as indicated previously, although validated monoclonal or polyclonal antibodies are beneficial for the diagnosis of an adrenal tumor, there is still the necessity to order antibodies in a panel and not singly to avoid abnormal expression, which may lead to a wrong diagnosis and a fatal verdict for the patient. Endocrinologically active ACC may be defined “functional” and subclassified as “pure,” if

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there is Cushing syndrome only, and “mixed” if Cushing syndrome is accompanied by virilization or any biochemical evidence of excessive steroid production. BWS tumors (incidence): Nephroblastoma > ACC > hepatoblastoma Adrenocortical blastoma (of infancy): Mixture of immature epithelial and mesenchymal elements with recapitulating morphology of the developing fetal cortex and with focal vascular invasion, but no metastases. Overall, ACC is rare in infants and young children but may be encountered in the practice of a pediatric pathologist. Occasionally, a newborn can even present with a congenital metastasizing ACC (Sherman et al. 1958). PGN: Factors able to influence the outcome include age fibrous, +++ atypical nuclear changes, and intramyxoidal curvilinear BVs –– Desmoid fibromatosis: No myxoid areas, slit-like BVs, and (+) β-Catn –– Neurofibroma: Cells with wavy nuclei, thick collagen bundles, and (+) S100 –– IFS/AFS: “Herringbone” pattern, no myxoid component, not (7;16) or t(11;16)

12.5.8.4 Sclerosing Epithelioid Fibrosarcoma • DEF: Sclerosing epithelioid fibrosarcoma (SEFS) is a rare, slow-growing sarcoma of deep soft tissue with epithelioid tumor cells in nests and cords and hyalinized fibrous stroma located at the limb/limb girdle, head, and neck, back/chest wall, and the base of the penis of adolescents and young adults. • GRO: SEFS is a poorly circumscribed tumor with firm, gray-white cut surface and may invade the surrounding bone without necrosis. • CLM: Hypo- and hypercellular areas with nests or cords of small-to-medium-sized, round to ovoid, relatively uniform and bland epithelioid cells with clear cytoplasm embedded in a hyalinized fibrous stroma and peculiar infiltrating single rows of cells (“Indian file pattern”) resembling carcinoma (grade I vs. grade III showing firmly packed tumor cells with dense chromatin, no/minimal collagenous stroma, and numerous mitotic figures) (Fig. 12.8). • HSS/IHC: (+) VIM, BCL-2, p53, ± EMA, CKs, S100 and (−) CD34 (DDX→SFT), CD45 (DDX→lymphoma), HMB-45, MART-1/Melan-A, Tyrosinase, and MITF (DDX→melanoma), DES, SMA. • TEM: Fibroblastic features with networks of IF that may form perinuclear whorls (epithelioid).

12.5 Fibroblastic/Myofibroblastic Tumors

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Fig. 12.8  Sclerosing Epithelioid Fibrosarcoma (SEFS). There are hypo- and hypercellular areas with nests or cords of small-to-medium-sized, round to ovoid,

relatively uniform and bland epithelioid cells with clear cytoplasm embedded in a hyalinized fibrous stroma and peculiar single-cell file pattern resembling carcinoma

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• CMB: The majority of LGFMS cases are characterized by a FUS-CREB3L1 fusion, but both FUS-CREB3L2 and EWSR1-CREB3L1 fusions may be encountered in a small number of LGFMS and SEFS/LGFMS hybrid tumors. Thus, generally this tumor is characterized by ± t(7;16)(q32–34;p11) ⇒FUS-CREB3L2. • DDX: –– LGFMS: M onotonous hypocellular with alternating myxoid/collagenous stroma, (+) CD99 –– SS: No extensive sclerosing areas as seen in SEFS, (+) CD99, TLE1, EMA, AE1–3, CK7 –– Sclerosing lymphoma: No extensive sclerosing areas as seen in SEFS and (+) CD45 –– Poorly differentiated carcinoma: (+) EMA, AE1–3, CK7 –– Lobular breast carcinoma: (+) EMA, AE1– 3, CK-7 and (+) ER, PR • TRT: It consists of intralesional excision, attempted wide local excision, and amputation with either adjuvant radiation therapy or chemotherapy. • PGN: About half of the patients suffer from a persistent disease or local recurrence, while the other half develops distant metastases. Follow-up of at least 12 months reveals persistent disease or local recurrence in half of the patients and distant metastasis in approximately 90% of the patients.

12.6 Fibrohistiocytic Tumors Benign entities of this group include the group of the benign fibrous histiocytoma (BFH), including deep BFH (counterpart of the superficial BFH or dermatofibroma), giant cell tumor of tendon sheath or BFH of the tendon sheath, and the diffuse-­type giant cell tumor or pigmented villonodular synovitis. Intermediate entities include plexiform fibrohistiocytic tumor and giant cell tumor of soft tissues. Malignant fibrohistiocytic tumors include malignant fibrous histiocytoma with pleomorphic, giant cell, and inflammatory subtypes (Box 12.11).

Box 12.11 Fibrohistiocytic Tumors

12.6.1 Histiocytoma 12.6.1.1 Juvenile Xanthogranuloma (JXG) 12.6.1.2 Reticulohistiocytoma 12.6.2 Benign Fibrous Histiocytoma (BFH) 12.6.2.1 Dermatofibroma 12.6.2.2 Giant Cell Tumor of Tendon Sheath (GCTTS, TSGCT) 12.6.2.3 Pigmented Villonodular Synovitis (PVNS) 12.6.2.4 Cellular Fibrous Histiocytoma 12.6.3 “Borderline” Fibrous Histiocytoma 12.6.3.1 Dermato-fibrosarcoma Protuberans (DFSP) 12.6.3.2 Pigmented Dermatofibrosarcoma (Bednar Juvenile Tumor) 12.6.3.3 Atypical Fibroxanthoma 12.6.4 Malignant Fibrous Histiocytoma (MFH) 12.6.4.1 Storiform-Pleomorphic MFH 12.6.4.2 Myxoid MFH/Myxoid Fibrosarcoma (Myxofibrosarcoma) 12.6.4.3 Giant Cell MFH 12.6.4.4 Inflammatory (Malignant Xanthogranuloma) 12.6.4.5 Angiomatoid MFH

12.6.1  Histiocytoma Histiocytoma refers polygonal cells tightly packed with minimal stroma, often inflammatory cells and development of fibrosis in older lesions. Two entities will be discussed here, i.e., juvenile xanthogranuloma (JXG) and reticulohistiocytoma.

12.6.1.1 Juvenile Xanthogranuloma Juvenile xanthogranuloma (JXG) is a benign, self-healing, non-Langerhans cell histiocytosis

12.6 Fibrohistiocytic Tumors

(LCH). It is often seen in children of the first infancy (first 2 years of life) and is rarely seen in children older than 3 years of age. Sites are frequently H&N and limbs and in 1/10 of cases are located deeply. Grossly, JXG is papular or nodular in the skin (yellowish asymptomatic papules/ nodules) and in extracutaneous location (eyes, lungs, liver, bones, kidneys, pericardium, gastrointestinal tract, testes, ovaries, and central nervous system). Microscopically, there is an ovoid to spindle-cell proliferation of bland histiocytes with some fibrosis and numerous Touton giant cells, foam cells, lymphocytes, and eosinophils. JXG is (+) VIM, CD68, FXIIIa, but (−) CD1a. Prognosis is good without recurrence.

12.6.1.2 Reticulohistiocytoma Reticulohistiocytoma is a slow-growing non-­ LCH. Sites are H&N and upper body, and there may be a positive Hx. for arthritis. Grossly, reticulohistiocytoma is characterized by cutaneous or mucosal papulae, which may be associated with severe polyarthritis and arthralgias. Microscopically, there is a uniform cellular population of multinucleated, DPAS+ histiocytes with abundant, “ground glass” cytoplasm and peripherally located nuclei with admixed histiocytes, epithelioid cells, and inflammatory cells (DPAS, diastase resistant periodic acid Schiff histochemical reaction). Reticulohistiocytoma needs to be kept separated from the histiocytic diseases that typically lack the characteristic “ground glass” cytoplasm. Also, CD1a and S100 immunohistochemical studies can be used to exclude LCH and Rosai-Dorfman disease, respectively. JXG shows classic “Touton” giant cells accompanying the lipid-rich histiocytes.

12.6.2  Benign Fibrous Histiocytoma Benign fibrous histiocytoma (BFH), aka dermatofibroma, is a common finding in the routine practice of pathology. BFH may also include three additional related entities, i.e., giant cell tumor of tendon sheath or BFH of the tendon sheath, and diffuse-type giant cell tumor or pigmented villonodular synovitis, as well as the cellular (or deep) fibrous histiocytoma.

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12.6.2.1 Dermatofibroma Dermatofibroma is a BFH that develops exclusively in the subcutaneous tissue. It is a benign superficial cutaneous, red-brown, painless, and slowly growing nodule. Microscopically, it is constituted by interlacing fascicles of slender spindle cells (storiform pattern) intermingled with foamy histiocytes (xanthoma cells), Touton giant cells, delicate branching vessels, and chronic inflammatory cells with accompanying pseudoepitheliomatous hyperplasia of overlying epidermis, which is useful for the differentiation from DFSP, which bears a deeper localization. No microcysts are seen. DDX includes: • Fibromatosis (larger size, infiltration into surrounding soft tissue of the lesion site or neighboring organs, abundant collagen separating spindle cells, and no tissue culture-like appearance) • Inflammatory MFH (larger size, slower growth, cellular pleomorphism, neutrophils, plasma cells, foam cells and atypical mitoses, no RBC extravasation, no keloid-type collagen) • IMFT (larger size, no rapid growth, no zonation, no prominent myxoid stroma, and mixed inflammatory infiltrate) • Myositis ossificans (myocentric reversed zonation with the distinctive zonal pattern showing fasciitis-like features, immature osteoid, or woven bone rimmed by osteoblasts in the center and bone formation at the periphery, initially with woven bone and, subsequently, lamellar bone and calcification, no nuclear atypia) • Myxofibrosarcoma (hypo-/hypercellular lobularity, curvilinear, regularly arborizing BV, atypia, and cellular pleomorphism) • Sarcoma NOS (high cellularity, atypia, and cellular pleomorphism) • Postoperative spindle-cell nodule (positive medico-surgical history, brisk mitotic activity, but no atypia)

12.6.2.2 G  iant Cell Tumor of Tendon Sheath (GCTTS) • DEF: BFH that develops in the tendinous tissue of fingers (interphalangeal joints), knees, and hips. GCTTS aka TSGCT, nodular tenosynovitis.

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• GRO/CLM: Circumscribed (fibrous pseudocapsule) solitary, lobulated, small (0.5–4 cm) slowly growing, painless tumor characterized by a proliferation of synovial-like mononuclear cells growing in sheets and accompanied by MNGCs with bland cytology, lipid-laden MΦ with cholesterol clefts, hemosiderinladen macrophages, and inflammatory cells of the 3th–6th decades of life with rare occurrence in children (♂ 5 cm), brown-yellow spongy tissue lesion, which is firm and nodular. Microscopically, it consists of diffuse expansive sheets of cells with infiltrative borders and variable cellularity and hyperplastic synovium with papillary projections composed of foamy histiocytes and hemosiderin-laden macrophages, large clefts, pseudoglandular or alveolar spaces lined by synovial cells, osteoclast-like MNGC with numerous nuclei (10–70), and epithelioid cells. Moreover, there are abundant collagen, giant hemosiderotic granules (2–3× diameter

•

• • •

•

of RBC), and brisk mitotic activity (MI > 5/10 HPF). Malignant features include nodular and solid invasive growth, large cells with macronuclei, prominent nucleoli, necrosis, and atypical mitoses. IHC: (+) CD68 (stromal and giant cells), (±) CD31, CALR, DES, CD14, HAM56, CD45, and LYS (lysozyme); (−) S100, CD45/LCA, EMA, CKs, HMB45, CD34, SMA. TEM: Ultrastructural features of histiocytes and fibroblasts. CMB: CSF1 overexpression or 1p13 (CSF1) rearrangements ± COL6A3 at 2q35. DDX: Hemosiderotic synovitis (intraarticular bleeding, no mononuclear or giant cell nodular proliferation, hemosiderin primarily in synovial lining cells). In the scientific literature, a malignant giant cell tumor of tendon sheath-diffuse type has been described. This lesion seems to be a rare occurrence of tumor showing coexisting prior benign giant cell tumor plus sarcomatous areas, but it is not a WHO-approved diagnosis.

12.6.2.4 Cellular Fibrous Histiocytoma Plexiform Fibrohistiocytic Tumor Dermal or subcutaneous, the proliferation of fibrohistiocytic cells growing in small nodules and elongated fascicles with multiple interconnections forming a characteristic plexiform pattern and accompanied by osteoclast-like MNGC and chronic inflammatory infiltrate of the upper extremities (mostly hands and wrists) of children and young adults. Giant Cell Tumor of Soft Tissues • DEF: Soft tissue (dermis or subcutis) counterpart of giant cell tumor of bone (aka soft tissue giant cell tumor of low-malignant potential) usually found in the extremities but also in the breast, mediastinum, groin, and surgical scars. • GRO: The tumor is a painless growing fleshy, red-brown-gray nodule, which is gritty at periphery due to calcification. Microscopically, it is characterized by fibrous tissue containing siderophages (vascularized

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stroma with blood lakes) separating nodules 12.6.4  Malignant Fibrous Histiocytoma containing round/oval mononuclear cells and osteoclast-like MNGCs, prominent osteoclast-like giant cells and mononuclear cells, • DEF: High-grade pleomorphic sarcoma with but no or mild atypia. different subtypes that usually occurs in late • IHC: (+) VIM, SMA, CD68 (MNGC), but adulthood (50–70 yrs) representing the second also (+) ALP, OPG, RANKL, TRAIL, and most common sarcoma of retroperitoneum but TRAP. OPG (Osteoprotegerin, aka osteoclasalso occurs in the extremities and the bone togenesis inhibitory factor or OCIF or tumour (grade III). Apart from myxoid and hyalinized necrosis factor receptor superfamily member forms, the cells show evidence of histiocytoid 11B - TNFRSF11B), is a cytokine receptor of differentiation: LYS, FXIIIa, AAT by IHC, the TNF receptor superfamily encoded by the and histiocyte-like cells with prominent lysoTNFRSF11B gene. somes, Golgi, and “surface ruffles” by TEM. • TEM: Apart from foamy cells, histiocyte-like Storiform-Pleomorphic (70%): Swirling, cartcells, fibroblast-like cells, and MNGCs are wheel, storiform pattern of polygonal hisencountered. tiocytoid cells, often with bizarre prominent • CMB: Guo et al. (2005) have described a oval nuclei, giant cells with pleomorphism, 12-year-old girl with GCTST of the right leg spindled fibroblasts, myofibroblasts and that metastasized to the lung. G-banded chrosmall undifferentiated mesenchymal cells mosomal analysis from direct and short-term as well as slit-like vascular spaces. PGN: cultures of the primary neoplasm disclosed common metastases at diagnosis in half of numerous telomeric associations involving the cases. multiple chromosomes. Myxoid (Myxofibrosarcoma) (15%): Lose • DDX includes: myxoid stroma for more than 50% of the –– GCTST-localized: peritendineous, hyalinized tumor mass with interspersed cellular stroma, foamy histiocytes, hemosiderin-­laden areas, extensive plexiform vascular netmacrophages, but rare bony metaplasia work, giant cells focally (DDX: MLPS). –– Plexiform fibrohistiocytic tumor: pediatric PGN: 5-YSR, >50%. tumor with plexiform growth pattern and Giant Cell (10%): Spindled cell morphology characteristic complex “tentacle-like with plenty of osteoclast-like giant cells extensions” arranged with polygonal cells in vague –– MFH-giant cell type: infiltrative, moderate-­ nodules. severe atypia, necrosis, and atypical Inflammatory (5%): Intense inflammatory mitoses infiltrate accompanying classic MFH with • TRT: It consists of complete excision with neutrophils-phagy and aggressive course negative margins, but in 10% recurs (incom(DDX: sarcomatoid RCC, malakoplakia). plete resection) and, occasionally, Angiomatoid ( 5 cm).

ring in young adults (multiple glomus tumors arise 10–15  years earlier than single neoplasms). In the anterior compartment the superficial muscles include the flexor carpi ulnaris, palmaris longus, flexor carpi radialis, and pronator teres. • Glomangioma: Glomus tumor with characteristics of a cavernous hemangioma. • Glomangiomatosis: Benign diffuse angiomatosis is resembling angiomatosis with excess glomus cells and needs to be differentiated from angiomatosis with some infiltrative features. Familial glomangiomas have been observed in families with individuals harboring a variety of deletions in the GLMN gene on chromosome 1p22.1 and responsible for the Glomulin protein, an FKBP associated protein. FKBP (aka FK506 binding protein) is a group of proteins that have prolyl isomerase activity and are related to the cyclophilins in function. These diseases have an AD inheritance pattern with incomplete penetrance. Glomalin a phosphorylated protein that is a member of a Skp1-Cullin-F-box-like complex and its gene has shown interactions with FKBP52, C-Met, and FKBP1A. There is an association of subungual glomus tumor and NF1 syndrome. • GRO: Ø   5/50 HPF and superficial location OR Ø  >  2  cm only OR deep position only).

12.8.2  Glomangiosarcoma Glomangiosarcoma is a malignant glomus tumor presenting with ONE of the three following features: 1. Tumor Ø  >  2  cm AND subfascial/visceral location 2. Atypical mitotic figures 3. Marked nuclear atypia (G2-G3) AND MI > 5/50 HPF A subdivision of the malignant glomus tumors into three categories based on their histology has been proposed: 1. Locally infiltrative glomus tumors (LIGHT)

2. Glomangiosarcomas arising in benign glomus tumors (GABG) 3. Glomangiosarcomas arising de novo (GADN)

12.8.3  Myopericytoma • DEF: The myopericytoma (MPC) is a benign perivascular myoid tumor occurring in young to middle-­ aged adults, although pediatric cases have been recorded. It usually affects dermis, subcutis, or soft tissue of the distal extremities and is constituted of “thin-walled BVs” with prominent “gaping” and multilayered concentric, perivascular array of the plump spindle to round cells with quite characteristic eosinophilic cytoplasm (“myoid features”). • CLM: Morphologically, MPC may be similar to infantile myofibroma/myofibromatosis and infantile hemangiopericytoma (Fig. 12.10). • IHC: (+) SMA, h-Cald; but (±) DES, and (−) S100 and CKs. • DDX: An important differential diagnosis is between myopericytoma vs. hemangiopericytoma or other allied lesions. First described by Zimmermann in 1923, pericytes are perivascular cells that are immediately adjacent to capillaries in many tissues. They are continuous with vascular smooth muscle cells of the media. About a half-century later, myopericytes have been identified as transitional cell forms between pericytes and vascular smooth myofibers (Attwell et al. 2016). Histogenetically, perivascular myomas are probably a continuum, including infantile myofibroma/myofibromatosis (MF/MF), glomangiopericytoma (GPC), and myopericytoma (MPC). However, MF/MF is characterized by a biphasic pattern with a mature zone of fascicles of spindle cells resembling smooth myofibers and immature zones with a hemangiopericytic pattern. GPC is distinguished by a biphasic pattern with prominent large dilated blood vessels but lack of myoid nodules. Finally, MPC shows a concentric proliferation of perivascular myoid cells. MPC should also be kept distinct from angioleiomyoma, which is constituted by mature smooth myofiber bundles with abundant vascular channels. MPC is considered a subgroup of

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Fig. 12.10  Myopericytoma. Myopericytes are the proliferating cells of this tumor (a, H&E stain 50× original magnification), which are better highlighted at higher magnification (H&E stain and 200× as original magnification for both (b) and (c) microphotographs). In (d) there is a characteristic feature of the myopericytoma, which is

the myoid nodules (H&E stain, 630× original magnification). The immunohistochemistry (e) through (h) confirms the histologic diagnosis of myopericytoma using anti-caldesmon (e, 100× original magnification; f, 630× original magnification) and anti-­CD31 (g, 50× original magnification; h, 630× original magnification)

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perivascular neoplasms with myoid differentiation expressing myogenic markers, i.e., SMA, SMM-HC, and h-Cald, and focally DES.  Therefore, MPC shares features of both smooth muscle cells and glomus cells. Progenitor cells of the myopericytes are either myofibroblasts or pericytes. Myofibroblasts are spindleshaped cells with an elongated nucleus and pale eosinophilic cytoplasm and are SMA+ and DES ± (weakly), while pericytes are contractile arborizing cells with multiple extensions encircling the vasculature and have a particular orientation to BV walls. TEM studies of myopericytes show a cell with a folded nucleus, prominence of RER, thin cytoplasmic filaments with dense focal bodies (myofilaments), subplasmalemmal densities, pinocytotic vesicles, and elongated elongation of cell processes; all features suggestive of differentiation toward myoid subtype. Pinocytosis (Gr. πίνειν ‘to drink’) is a crucial way of endocytosis. In this process, small particles suspended in extracellular fluid are transferred into the cell through an infolding of the cell membrane. It results in a suspension of the particles within a very small vesicle, which is located within the cell cytoplasm. Subsequently, these vesicles fuse with endosomes to hydrolyze the infolded particles. It is both a key constitutive process and a receptor-mediated process. Four categories of macropinocytosis, caveolae-mediated, clathrin-dependent, and dynamin/clathrinindependent pinocytosis have been delineated (Seto et al. 2002). A major task may differentiate MPC from MF because it depends on the predominant growth pattern. The tumor is considered MPC if the concentric perivascular grouping of plump spindle cells is seen, while the diagnosis of MF relies exquisitely on a zonation/biphasic appearance. MPC/MF spectrum needs to be extended to malignancies composed of small round cells arranged in hemangiopericytomalike vascular pattern, including Ewing sarcoma (CD99+), poorly differentiated SS (biphasic, EMA+, AE1–3+, bcl-2+, CD99+), mesenchymal chondrosarcoma (cartilaginous islands and S100 (+)), phosphaturic mesenchymal tumor (variable histology, calcification, osteoclast-like giant cells), and angiomatoid MFH. • PGN: Benign, because excision is usually curative.

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Box 12.12 Skeletal Muscle Tumors

12.9.1 Rhabdomyomatous Mesenchymal Hamartoma 12.9.2 Rhabdomyoma 12.9.3 Rhabdomyosarcoma (RMS) 12.9.3.1 Embryonal RMS 12.9.3.2 Botryoid RMS 12.9.3.3 Spindle-Cell RMS 12.9.3.4 Alveolar RMS 12.9.3.5 Pleomorphic RMS

12.9 Skeletal Muscle Tumors Soft tissue with skeletal muscle differentiation or skeletal muscle tumors includes rhabdomyoma and variants as benign entities as well as rhabdomyosarcoma (and subtypes) as malignant c­ ounterparts. The malignant tumor with skeletal muscle differentiation or rhabdomyosarcoma is one of the most frequent and differential diagnoses in pediatric oncology and is one of the small blue round cell tumors (Box 12.12).

12.9.1  Rhabdomyomatous Mesenchymal Hamartoma (RMH) • DEF: Rare benign overgrowth (not correctly tumor) of the skeletal muscle fibers of the skin potentially associated with disorders such as Goldenhar syndrome, amniotic band syndrome, and Delleman syndrome and harboring an excellent prognosis. • SYN: Congenital midline hamartoma of the skin, cutaneous striated muscle hamartoma. • EPI: Infants and children, ♂:♀  =  2:1, all ethnics. • CLI: Painless and solitary and generally present on the midline of the head and neck region including on the nose or chin. • GRO: Cupola-shaped or polyp-shaped lesion. • CLM: It is a disordered and variegated collection of mature adipose tissue, mature skeletal muscle, mature adnexal elements, collagen, and nerve bundles (Fig. 12.11).

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Fig. 12.11  Rhabdomyomatous Mesenchymal Hamartoma (RMH) & Rhabdomyoma. The first two upper microphotographs (a–b) show a RMH with its characteristic morphology (disordered and variegated collection of mature adipose tissue, mature skeletal muscle, mature adnexal elements, collagen and nerve bundles) (a, hematoxylin and eosin staining, x12.5 original magnification; b, hematoxylin

and eosin staining, ×50 original magnification). The other six microphotographs (c–h) show a classic rhabdomyoma (see text for details) (c-e, hematoxylin and eosin staining; f-h, immunohistochemitry with antibodies against desmin (DES), S100, myogenin (MYF4); c-d, ×100 original magnification; e-h, ×200 original magnification)

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• DDX: Fibroepithelial polyp, nevus lipomatosus, embryonal rhabdomyosarcoma, fibrous hamartoma of infancy, benign triton tumor, and fetal rhabdomyoma. • PGN: Excellent, although cosmetic issues have been reported. Moreover, the presence of other genetic disorders should be kept in mind. • TRT: Surgery if necessary from the cosmetic point of view, although other authors suggest a “watchful waiting” approach.

12.9.2  Rhabdomyoma There is some controversy in considering this lesion a real tumor or a hamartoma. However, it is regarded as a benign tumor in the W.H.O. classification and is presented in this way in this chapter. Several authorities consider cardiac rhabdomyomas and, possibly, also the extracardiac types, hamartomatous lesions, but it may be tissue or organ-based. Cardiac rhabdomyomas have indeed a more hamartomatous character rather than neoplastic because do not show an autonomous growth. Extracardiac types are probably true neoplasms and are divided into two types, fetal-type rhabdomyoma and adult-type rhabdomyoma (Box 12.13) (Fig.  12.11). The fetal-type rhabdomyoma is also subclassified as classic and intermediate, and the genital location of the fetal-type is almost exclusively seen in middle-aged women. DDX: It includes benign entities, such as ectopia, fibroepithelial polyp, papilloma (mesonephric or Müllerian), hibernoma, and granular cell tumor (S100+) as well as malignant neoplasms, such as rhabdomyosarcoma, leiomyosarcoma, lymphoma, and melanoma. These neoplasms are most easily identified by the infiltrative growth pattern in addition to the distinguishing and characteristic immunohistochemical phenotypes.

12.9.3  Rhabdomyosarcoma • DEF: Malignant soft tissue tumor with skeletal muscle differentiation. There are several

Box 12.13 Rhabdomyoma Fetal-type rhabdomyoma Age Young children and middle-aged adults (♀) Location H&N, genital areas CLM Bundles of immature skeletal myofibers intersecting randomly and quite sharply separated by strands of collagen with scattered primitive mesenchymal cells. MI = 0, (–) necrosis, cambium layer, and/or infiltrative growth pattern

Adult-type rhabdomyoma Young- and middle-aged adults H&N Large, well-­ differentiated, plump cells with cytoplasmic acidophilia (± focal cross-­ striations) and cytoplasmic clearing (glycogen and/or lipid)

Notes: H&N, head and neck; MI, mitotic index

classifications, including Horn and Enterline’s classification, Intergroup Rhabdomyosarcoma (RMS) Studies I and II, Societe International pour l’Oncologie Pediatrique/International Society for Pediatric Oncology (SIOP), National Cancer Institute, and International Classification of Rhabdomyosarcoma. All of them partly overlap. The International Classification of Rhabdomyosarcoma (ICR) seems to be the most recent and the most reproducible way to classify RMS. This classification has been partly modified and introduced in the CAP protocols, which are diffusely used by pathologists not only in North America but worldwide. It includes the following entities: –– Embryonal, Botryoid – B-RMS –– Embryonal, not otherwise specified (NOS) – E-RMS (NOS) –– Alveolar – A-RMS –– Mixed embryonal and alveolar rhabdomyosarcoma (E-RMS/A-RMS) –– Rhabdoid rhabdomyosarcoma –– Sclerosing rhabdomyosarcoma –– Undifferentiated sarcoma –– Ectomesenchymoma –– Rhabdomyosarcoma, subtype indeterminate

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• EPI: It is the most common soft tissue sar- out in a tissue specimen received for diagnocoma in children younger than 15 years of age sis and tumors with any degree of the alveolar with an incidence of 8% among all cancers. It ­pattern on histology or cytology portend an unfais one of the most common soft tissue sarco- vorable prognosis, regardless of extent. Botryoid mas in the adolescence and youth. In fact, and spindle-cell variants of embryonal RMS have, according to several epidemiological studies, conversely, a better outcome. Pleomorphic areas more than half of these neoplasms occur dur- with focal anaplasia may be found in any subtype ing the first decade of life, while the second of RMS but are more common in E-RMS. Two peak is located at 15–20  years of age. The subtypes need to be considered, although rare in early presenting RMS is often of embryonal children and youth. These include the pleomortype, the most common subtype among oth- phic RMS, which was not included from the ICR ers. ♂:♀  =  1.3:1.0, although male predomi- given its extreme rarity in children, and the ananance almost extinguishes toward adolescence plastic variant of RMS, which has a controversial and youth. Caucasians ethnic groups are more history and is also rare in children and youth. affected than Afro-­American ethnic groups. • EPG: RMS usually occurs at sites of embry- • CLI: It seems that each subtype often has a site onic tissue fusion (H&N, midline), but the preference. Thus, H&N region (parameninpostulated cell of origin is the subject of congeal, orbit, nasal cavity, nasopharynx, ear, siderable debate for almost a century. It has paranasal sinuses, tongue, palate, lips, and been argued that there is little to suggest that soft tissues), which is the most common site RMS arises from skeletal muscle cells. RMS harbors mostly ERMS.  The genitourinary is, indeed, found in tissues and organs in tract, the second most common site, also which striated muscle tissue is not present shows often ERMS, apart from the paratestic(e.g., common bile duct of the extrahepatic ular region with the spindle-cell subtype, biliary system, urinary bladder) or in topobeing the most frequent RMS subtype in this graphic regions in which striated muscle is particular area. Other most common sites are scant (e.g., nasal cavity, middle ear, and the retroperitoneum and pelvis with mostly vagina). However, the developing muscular ERMS.  The botryoid variant of ERMS that tissue at 5–8 weeks’ gestation of the embryo has a Greek etymology (Gr. βότρυς ‘grapes’) appears to be similar to the poorly differentihas the peculiar gross appearance of multiple ated embryonal type of RMS (E-RMS) shownodules of soft, myxoid tissue growing into ing small, round-ovoid cells with the lumen of a hollow viscus (vide infra). The hyperchromatic nuclei and indistinct or scant botryoid RMS is found mainly in the urinary cytoplasm and absent or very few d­ ifferentiated bladder, prostate, vulva, vagina, cervix, uterus, rhabdomyoblasts. The developing muscle at fallopian tube, perineal region, and common 9–15 weeks’ gestation would seem the mirrorbile duct of the hepatobiliary tree. Finally, ing embryologic image of the well-­ extremities are involved less commonly than differentiated E-RMS. It appears that genetic adult soft tissue sarcomas, and in this localizafactors and familial cancer syndromes may tion, the alveolar RMS (ARMS) is the most play a key role, but further investigations are common architectural pattern. warranted. Congenital retinoblastoma, FAP, • GRO: RMS reflect some intrinsic features, multiple lentigines syndrome, NF type I, including the degree of cellularity, the amount Costello syndrome, BWS, and a spectrum of of collagenous or myxoid stroma, and the other congenital anomalies have been presence and/or extent of secondary changes described in conjunction with RMS. (e.g., bleeding, necrosis, and ulceration) mostly. It is probably imperative to keep in mind that • CLM: RMS may show both on light and elecalveolar RMS is the most critical subtype to rule tron microscopy features of skeletal muscle

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differentiation. Both techniques are usually instrumental in identifying the rhabdomyoblasts. By light microscopy, the elements of striated muscle differentiation show bright cytoplasmic eosinophilia (myoblastic differentiation) with or without cross-striations. Some authorities indicate cross-striations to be a sine qua non feature for the diagnosis of RMS, but they are found in about 1/3 of cases. Most importantly, it is the identification of “tadpole cells,” i.e., cells with elongated tails of bright eosinophilic cytoplasm, and “strap cells,” i.e., cells with cytoplasm in the shape of a ribbon or “strap” (Figs. 12.12, 12.13, 12.14, and 12.15) that play a major role in the diagnosis.

12.9.3.1 Embryonal RMS Embryonal RMS (E-RMS) shows variable cellularity with pericellular reticulin staining and cells ranging from primitive stellate shape to elongated forms differently showing light or electron microscopy features of striated muscle differentiation. Optional features include myotube-like clusters, “smooth muscle-like spindle forms, myxoid areas and focal anaplasia (singly or clonal clusters). Anaplasia is defined using the Wilms tumor definition of simultaneous occurrence of cellular (nuclear) hyperchromasia, size enlargement (≥3 times the size of neighboring nuclei), and atypia (multipolar, polylobated or obvious atypical shape compared with the neighboring cells). Anaplasia may be found in any histologic subtype of RMS and up to 13% of all RMS and is subclassified as focal (group I) or diffuse (group II) anaplasia according to the extension. In patients with tumors in favorable sites, anaplasia seems to be more common, while is less common in younger children and patients with stage or clinical group II or III of disease. The presence of anaplasia, either focal or diffuse, negatively influences the failure-free survival rate and overall survival rates in patients with E-RMS. In contrast to Wilms tumor, anaplasia is not currently used in the stratification of patients. DDX of E-RMS NOS includes the botryoid and spindle cell variants, the solid variant of A-RMS, ectomesenchymoma, undifferentiated embryonal

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sarcoma of the liver, pleuro-pulmonary blastoma, Wilms tumor with skeletal muscle differentiation, fetal rhabdomyoma, giant cell tumor of tendon sheath (CD68+, Myogenin-), and pseudosarcomatous fibroepithelial polyps of the lower female genital tract. High MI (>15/50 HPF), marked hypercellularity, “cambium layer,” and IHC phenotype play a crucial role in addressing the diagnosis correctly. CMB: Chromosomal gains, including 2, 8, 11, 12, 13, and 20, but the most consistent finding is LOH for multiple closely linked loci at 11p15.5 resulting in activation of tumor suppressor genes. In the 11p15.5, there is imprinting of numerous genes. The allelic loss involves the maternal alleles in the 11p15.5 region. Some important genes involved are IGF2 (growth factor), H19 (noncoding RNA), and CDKN1C (kinase inhibitor). Other genes implicated are FGFR1, FOXO1, PAX3, and YBX1. FOXO1 (Forkhead Box O1) is a transcription factor and is the main target of insulin signaling. FOXO1 regulates metabolic homeostasis in response to oxidative stress. There is substantial evidence that FOXO1 plays important roles in the decision for a preadipocyte to commit to adipogenesis and is linked to fat mass and obesity-associated protein (FTO) (Yang et al. 2019; Peng et al. 2020). ERMS variants are the botryoid and the spindle-­cell variant.

12.9.3.2 Botryoid RMS Botryoid RMS (B-RMS) is a favorable prognosis subtype characterized by grape-like, polypoid nodules located in sites next an epithelial surface and growing into the lumen of a hollow viscus (e.g., urinary bladder or vagina) and needs to be differentiated from clear cell adenocarcinoma associated or not with DES (Di-EthylStilbestrol) exposure (Al Jishi & Sergi, 2017). The diagnosis of B-RMS relies on the identification of ≥1 microscopic field (any magnification) showing a “cambium layer,” which is a condensed layer of rhabdomyoblasts underlying a non-neoplastic epithelium. B-RMS seems to account for about 1–20 cases submitted to the Intergroup Rhabdomyosarcoma Study Group (IRSG).

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Rhabdomyosarcoma-associated Germline Mutations BeckwittWiedemann Li-Fraumeni

Gorlin

p53

IGF2 HRAS

Costello

Noonan PTCH1 DICER1

DICER1-PPB

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Fig. 12.12  Embryonal Rhabdomyosarcoma. Embryonal rhabdomyosarcoma-associated germline mutations are described in the cartoon in (a). The microphotographs (b) through (h) show an embryonal rhabdomyosarcoma with elements of striated muscle

differentiation show bright cytoplasmic eosinophilia (myoblastic differentiation) with or without cross striations (b–h, hematoxylin and eosin staining, ×200, ×200, ×200, ×200, ×200, ×200, ×200 as original magnification, respectively)

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Fig. 12.13  Embryonal Rhabdomyosarcoma. Gross, histology, immunohistochemistry, and ultrastructure of an embryonal rhabdomyosarcoma with features identified in the previous microphotographs. The gross photograph (a) show a solid nodule not sharply delimited. The microphotographs (b–f) show the characteristic histology of this skeletal muscle differentiating tumor. The microphotograph (g) highlights the positivity of this tumor for dermin (anti-desmin immunohistochemistry, avidin-biotin com-

plex). The electron microphotograph (h) shows actomyosin filaments, Z-bands, glycogen, and subcellular organelles, including mitochondria (b–f, hematoxylin and eosin staining, g, immunostaining with an antibody against desmin (DES), h, transmission electron microscopy; b, ×0.5 original magnification; c, ×12.5 original magnification; ×12.5 original magnification; ×100 original magnification; ×400 original magnification; g, ×100 original magnification; h, ×18000 original magnification)

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Fig. 12.14  Embryonal Rhabdomyosarcoma. Immunohistochemical panel for the diagnosis of rhabdomyosarcoma with the positivity for myogenic markers (a, b). The specific antibody used is apparent as abbreviation in the right lower corner of each microphotograph (a, anti-desmin immunostaining; b, anti-myogenin (MYF4) immunostaining). CD56, NSE, and beta-catenin may also be used, although their value is disputable (c–e) (c, antiCD56 immunostaining; d, anti-neuron specific enolase

(NSE) immunostaining; e, anti-Beta catenin immunostaining). The proliferation rate of these tumors is quite high (f) (f, anti-Ki67 (MIB1) immunostaining). All immuniistochemistry procedures have been performed using the Avidin-Biotin Complex (a-f, x200 as original magnification). The microphotographs (g) and (h) are transmission electron microscopy photographs and the scale bar in h) corresponds to 500 nanometers

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a

b

c

d

e

f

g

h

Fig. 12.15  Anaplastic Rhabdomyosarcoma. In this variant of rhabdomyosarcoma necrosis, fibrosis, and anaplasia of the tumor cells are presented (a–h). Tumor cells show multipolar mitotic figures, which are particularly

evident in the microphotographs e) and f) (a–h, hematoxylin and eosin staining; ×100, ×200, ×100, ×200, ×200, ×200, ×400, ×400 as original magnifications)

12.9 Skeletal Muscle Tumors

12.9.3.3 Spindle-Cell RMS Spindle-cell RMS (S-RMS) is a favorable prognosis subtype characterized by fascicles of spindled cells with eosinophilic, fibrillar cytoplasm showing a storiform arrangement pattern with a favorite site in the testicular/scrotal region. Spindled cells may be associated with variable collagen deposition, and two recognizable patterns are distinguished. The collagen-rich pattern of S-RMS shows spindle cells with variable myogenic differentiation embedded in a dense collagenous stroma, while the collagen-poor pattern of S-RMS shows spindle cells without significant collagen deposition and having a histologic similarity to a smooth muscle tumor. S-RMS is diagnosed when ≥80% of the neoplasm has elongated spindle cells in at least one of the two architectural patterns. DDX includes E-RMS NOS, fibrosarcoma, MFH, rhabdomyoma, leiomyoma, LMS, and nodular fasciitis. Leiomyoma and LMS are practically reserved to the middle-aged patients as well as MFH.  Fibrosarcoma has a quite distinctive herringbone pattern and nodular fasciitis features a classic cell culture-like histology. Both IHC phenotype and ultrastructural features may be pivotal to avoid a misdiagnosis. The favorable outcome is linked to the body site. In fact, extratesticular and extraorbital S-RMS harbor a prognosis similar to E-RMS.  S-RMS accounts for about 3% of cases submitted to the IRSG. 12.9.3.4 Alveolar RMS Alveolar RMS (ARMS) is an unfavorable prognosis subtype of RMS with a 5-YSR of about 50% and characterized typically by reticulin positive, thin fibrous septa, and delimitating cell aggregates with central dyscohesion (the so-­called alveolar pattern) (Fig. 12.16). Tumor cells are round with lymphocyte-like nuclei, coarse chromatin and one or more indistinct nucleoli, and a thin rim of eosinophilic cytoplasm. Optional features include focal LM features of striated muscle differentiation, which are often lacking, clear cells, and myxoid areas. ARMS variants are the solid and the mixed subtypes. The solid variant shows no dyscohesion and fibrous septa (retic/MG special stains highlight neoplastic aggregates), while the mixed ARMS/ERMS is a mixed pattern of both

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essential types with the requirement of more than 50% of the tumor being composed of the alveolar pattern. Extensive sampling is required in case of a solid pattern to identify typical alveolar foci that may help in the classification because the solid variant usually lacks a PAX fusion (vide infra). A helpful feature distinguishing the solid variant of A-RMS from a “solid” pattern of E-RMS NOS is the presence of diffuse myogenin expression, which is usually focal in the E-RMS. The presence of anaplasia seems not to affect the outcome in patients with ARMS. DDX includes ASPS that shows, conversely, nests of uniform cells with large eosinophilic cytoplasm and central dyscohesion, ±AB and DPAS, cytoplasmic basophilic crystalloids, +TFE3, ± DES, MSA, NSE, and S100, but – CGA, SYN, HMB45, Melan-A, CK, and EMA, ES/PNET, PD-NB or undifferentiated NB, DSRCT, PD-MSS, DLBCL, Burkitt lymphoma or lymphoblastic lymphoma (Box 12.14). • CMB: The majority of ARMS cases contain one of two recurrent chromosomal t­ranslocations: t(2;13)(q35;q14) or t(1;13)(p36;q14). The 2;13 and 1;13 translocations rearrange the PAX3 or PAX7 gene on chromosome 2 or 1 and the FOXO1 (FKHR) gene on chromosome 13 to generate either PAX3-FOXO1 or PAX7-FOXO1 fusion genes. These fusion genes encode fusion transcription factors with a PAX3 or PAX7 DNA-binding domain and FOXO1 transactivation domain at nuclear localization. The consequence is an oncogenetic effect with dysregulation of the transcription. ARMS studies identified PAX3-FOXO1-positive in ~60% of cases, PAX7-FOXO1-positive in ~20%, and

Box 12.14 A-RMS Dichotomy and Subtyping

A-RMS (−) t(1;13) OR t(2;13)  ⇒  5% of all A-RMS A-RMS (+) t(1;13) OR t(2;13) ⇒ 85% of all A-RMS →  ~30% PAX7-FKHR (+) showing higher event-free survival (4-YSR: 75%) →  ~70% PAX7-FKHR (+) showing lower event-free survival (4-YSR: 8%)

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a

b

c

d

e

f

g

h

Fig. 12.16  Alveolar Rhabdomyosarcoma. Alveolar Rhabdomyosarcoma with characteristic pseudoalevolar structure filled or partially filled with tumor (rhabdomyosarcoma) cells (a–h). MYF4 immunostaining shows a diffuse positivity (h) (a–g, hematoxylin and eosin staining; a, ×40, b, ×400, c, ×400, d, ×400, e, ×400, f, ×400, g, ×630 as original magnification respectively; f, anti-myogenin

immunostaining, Avidin-Biotin Complex, ×100 original magnification). Myogenin is one of the seven lineagerestricted transcription factors frequently used by soft tissue specialists (myoD1 [MYF3], myogenin [MYF4], FLI1, ERG, Brachyury, SOX10, and SATB2)

12.9 Skeletal Muscle Tumors

no fusion in ~20%. Gene amplification seems to be one of the underlying mechanisms to increase the expression level of the gene fusion in the neoplastic cells. Other genes implicated in ARMS are DDX1, EWSR1, FGFR4, YBX1 other than FOXO1 and PAX3. CGH studies have highlighted additional cytogenetic events in ARMS, including amplifications involving 12q13–15, 2p24, 1p36, 13q14, 2q34-qter, and 13q31 and numerical chromosomal gains, such as chromosomes 2, 12, and 20.

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sometimes seen with anti-MyoD1. Both myogenin and MYO-D1 are expressed to a higher degree in ARMS than ERMS.

• TEM: Hexagonal arrays of thick and thin myofilaments and ribosomal-myosin complexes. • DDX: It includes other SRBCTs, if the tumor is poorly differentiated, muscle infiltration of small round blue cell tumors from a variety of origin, heterologous elements of some other tumors, mixed mesenchymoma, characterized by any combination of ≥2 of osteosarcoma, 12.9.4  Pleomorphic RMS RMS, or liposarcoma without MPNST, but regardless of any undifferentiated compoPleomorphic RMS is rare in childhood, while a nents, including MFH or fibrosarcoma, maligtumor with diffuse pleomorphism ± unusual strianant triton tumor (MTT), or MPNST with tions, but no alveolar or embryonal areas. PRMS admixed RMS elements. The IRSG includes tends to occur in individuals over 45 years at the some RMS variants that need to be taken into limbs, especially the thigh. It is characterized by consideration. These include RMS with rhablarge, atypical tumor cells, often giant cells and doid features or rhabdoid RMS (R-RMS), difficult to distinguish from liposarcoma or MFH sclerosing rhabdomyosarcoma, ectomesenwithout immunohistochemistry. To make the diagchymoma, and undifferentiated sarcoma. nosis of PRMS, it is necessary to have at least one RMS with rhabdoid features shows tumor of two components, including ≥1 SM-­IHC markers cells with large copious eosinophilic cytoAND ME-evidence of polygonal rhabdomyoblasts. plasm and intermediate filament globular The sclerosing variant of RMS is characterinclusions similar to the inclusions observed ized by an unusual hyalinizing, a matrix-rich in the malignant rhabdoid tumor (MRT). RMS variant of RMS, which may resemble osteosarwith rhabdoid features has tumor cells with coma, chondrosarcoma, or angiosarcoma. The coarse nuclear chromatin pattern (not vesicusclerosing variant has been described in both lar as seen in MRT), inclusions with a characadults and children, although is a rare entity. teristic phenotype positive for VIM, DES and peri-inclusion phenotype positive for MSA, • IHC: (+) Myogenin, MyoD1, DES, MSA, and P-DES, and nuclear positivity for Myogenin myoglobin. CD99 (±) usually weak granular and INI-1, which are negative in MRT. cytoplasm. Other markers include sarcomeric Sclerosing RMS (Scl-RMS) is a subtype of alpha-actin, myoglobin, fast, slow, and fetal RMS showing a dense hyalinizing collagemyosin, creatine kinase (isoenzymes MM and nous matrix with round tumor cells architecBB), beta-enolase, Z-protein, titin, and turally forming small nests, single-file rows, vimentin. and pseudovascular alveolar structures, focal positivity for P-DES and Myogenin in conMyoD1 is a member of the family of myotrast to a diffuse uniform positivity for MyoD1. genic regulatory genes, which includes myf-4Scl-­ RMS has a morphologic overlap with herculin/myf-6 and myf-5. MYO-D1 act as a crucial other soft tissue tumors, including sclerosing point for the initiation of skeletal muscle differenepithelioid fibrosarcoma, osteosarcoma, and tiation acting binding to enhancer sequences of angiosarcoma and may become a challenge muscle-specific genes. Anti-myogenic is better for some infiltrating poorly differentiated carthan anti-MYO-D1 because it does not have non-­ cinomas. Ectomesenchymoma is a composite specific cytoplasmic immunoreactivity, which is RMS constituted by an RMS component, usu-

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ally embryonal, and a neuroblastic component. The RMS component of the ectomesenchymoma is used for the treatment, and age, sex, site distribution, and prognosis are similar to E-RMS.  The undifferentiated sarcoma is defined by the absence of any evidence of differentiation and is, historically, included in the RMS classification system and, currently, treated on non-RMS soft tissue tumor regimens in COG protocols. Current tissue sampling is paramount. In fact, the priority should be given to formalin processing for morphologic evaluation. Individual studies, including RT-PCR and other molecular biology investigations, although critical to the molecular workup of rhabdomyosarcoma, may, at least partially, be performed on FFPE tissue. In case there is enough tissue for morphologic evaluation, and this is not jeopardized, at least 100 mg of viable snap-frozen tissue as the second priority for workup should be set. Translocations may be detected using RT-PCR or FISH on touch preparations from the frozen tissue as well. The procedures that allow tissue to be taken from the patient and sent to the laboratory for processing and evaluation should be discussed at the tumor board with the pathologist and oncologist and include incisional biopsy, through cut, open surgical, excisional biopsy (local, radical, compartmentectomy), amputation, (different types), and other surgical unconventional procedures. Following the type of process, the specimen should include laterality (right, left, midline, indeterminate, not specified), site (urinary bladder, prostate, cranial para-meningeal, extremity, genitourinary-not bladder/prostate, head and neck-excluding para-­meningeal, orbit, trunk, retroperitoneum, etc. as well as not specified), greatest dimension (Ø), and additional dimensions in cm, depth (dermal, subcutaneous, subfascial, intramuscular, intra-­ abdominal, retroperitoneal, intracranial, organ-­based, or other/ not assessable), the histology type, the presence or lack of anaplasia (focal, diffuse, indeterminate, or not assessable), resection margins with the distance of sarcoma from closest margin in cm or mm if an involvement is identified, the

12  Soft Tissue

number of lymph nodes sampled, and if lymph nodal metastasis is present. It is generally considered “wide” a resection margin of 2–3 cm of distance from the tumor, but for non-RMS soft tissue sarcomas, 1–2  cm may be adequate for low-grade tumors, while >5 cm may be requested for high-grade tumors. Relevant medical history may be provided to the pathologist and includes any previous therapy, family history of malignancy, and the presence of congenital anomalies. In particular, the assessment of the percentage of necrotic and viable tumor post-therapy is essential at the time of the discussion of the patient at the tumor board. Two additional factors may include extreme cytodifferentiation and the lack or presence of nuclear pleomorphism. It is considered that a genetic predisposition is present up to 1/3 of children with soft tissue sarcomas, and some syndromes may need to be excluded if the tumor occurs in a patient younger than 2  years of age. These syndromes include Li-Fraumeni ­syndrome, basal cell nevus syndrome, neurofibromatosis, and pleuropulmonary blastoma syndrome. Some congenital anomalies have been described in patients with rhabdomyosarcoma, including CNS anomalies, GU anomalies, GIT anomalies, and CVS anomalies. The tumors with heterologous components of rhabdomyoblastic differentiation are: • Epithelial Neoplasms Carcinosarcoma (e.g., breast, urinary bladder), MMMT (uterus, cervix, ovary), thymoma • Epithelial-Mesenchymal Neoplasms Wilms tumor Hepatoblastoma Pleuropulmonary blastoma • Germ Cell Tumors or Sex Cord-Stromal Tumors Seminoma/dysgerminoma Teratoma Sertoli-Leydig cell tumor • Mesenchymal Neoplasms (Without Epithelial Component) Dedifferentiated chondrosarcoma Dedifferentiated liposarcoma Malignant mesenchymoma

12.9 Skeletal Muscle Tumors

• Neoplasms of Neuroectodermal Derivation Malignant Schwannoma (MPNST)/MTT Medulloblastoma Medulloepithelioma Ectomesenchymoma Congenital pigmented nevus or giant nevus

• PGN: It is paramount to recall favorable and unfavorable factors for RMS because these are reviewed at the tumor boards during the presentation and discussion of the pathological findings. Prognostic factors in RMS (favorable +/ unfavorable −) include:

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• Group II A: Localized tumor, gross total resection, but microscopic. residuals B: Locally large tumor (+) reg. LNs, but completely resected C: Locally large tumor (+) reg. LNs, gross total resection, but microscopic residuals • Group III A: Localized/locally broad tumor, gross residual after biopsy only B: Localized/zonal extensive tumor, gross residual after significant resection (≥50% debulking) • Group IV Any size of the primary tumor (±) reg. LNs, but with distant metastases

• Epidemiology-Based/Clinical Variables: Age at diagnosis (infants/children +) (adults −), 12.9.4.1 Late Effects of Childhood Cancer Therapy anatomic site (orbita, GUT +) (H&N-­ nonorbital, paraspinal, abdomen, biliary tract, Surgery, radiation, and multimodal chemotherapy retroperitoneum, perineum, extremities −), are involved in modern childhood cancer therapy. distant metastasis at time of diagnosis (PET There is a debate if evidence is sounding or not scan) (if no metastasis +) about an increased risk for offspring of survi• Surgery/Pathology Team-Linked Variables: vors in the absence of genetic syndromes. Some Completeness of resection sequelae of the treatment are known and debated. • Pathologist-Linked Variables: Tumor Ø They include poor school performance following (≤5 cm +) (>5 cm −), assessment of local inva- CNS irradiation, weak growth and puberty followsiveness, histopathology subtype (botryoid, ing irradiation of the pituitary gland, and reduced spindle cell +) (alveolar, pleomorphic −), and fertility following chemotherapy. It is estimated regional node involvement that approximately 3% of long-term survivors of children with cancer can develop a second tumor Also, unfavorable prognostic factors are a within 20 years. Risk factors include familial synlocal recurrence, local recurrence during therapy, dromes, use of alkylating agents, and radiotherapy. non-resectability, and diploid content. Alkylating agents are particularly active in the According to the histologic subtype, the resting phase of the cell (G0). Alkylating agents are prognosis would be different. Botryoid and cell-cycle non-specific and include mustard gas spindle-­ cell variants harbor a better prognosis derivatives (mechlorethamine, cyclophosphamide, than alveolar and undifferentiated sarcoma. The chlorambucil, melphalan, and ifosfamide), ethembryonal RMS has an intermediate prognosis. ylenimines (thiotepa and hexamethylmelamine), According to the Intergroup Rhabdomyo­ alkylsulfonates (busulfan), hydrazines and trisarcoma Study (Post-Surgery Clinical Grouping azines (altretamine, procarbazine, dacarbazine, System), four groups are distinct: and temozolomide), nitrosureas (carmustine, lomustine and streptozocin), and metal salts (car• Group I boplatin, cisplatin, and oxaliplatin). Of particuA: Localized tumor, restricted to the site of lar importance is to mention that nitrosureas are origin, wholly resected unique because they can cross the blood-brain barB: Localized tumor, infiltrating beyond the rier. Box 12.15 illustrates some pearls and pitfalls place of birth, wholly resected during the diagnostics of RMS.

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Box 12.15 Pearls and Pitfalls

• Degenerated rhabdomyoblasts with a glassy or deeply eosinophilic, hyalinized cytoplasm, and pyknotic nuclei are a frequent feature of ERMS and should not be interpreted as PRMS. • Cross-striations are rare in the roundovoid cells of the least differentiated ERMS but are more frequent in the most differentiated areas of ERMS and ERMS with a more prominent spindlecell component. • Cross-striations of RMS cells should be differentiated from those seen in residual or entrapped muscle cells by their more accentuated irregularity and incomplete transformation of the cells. • A prominent degree of cellular pleomorphism or anaplasia in RMS would make the diagnosis difficult with adult PRMS, and the discovery of cross-striations and areas of more typical ERMS would make an asset to make a proper differential diagnosis. • It is essential to keep separate the solid form of ARMS from the undifferentiated form of ERMS, as the former harbors a less favorable prognosis. • Clear cell RMS is a rare variant with abundant glycogen-rich cytoplasm, which vaguely looks like clear cell carcinoma or clear cell malignant melanoma, and IHC and MB studies are an asset to make the right diagnosis. • Polyclonal DES is more sensitive than monoclonal DES in detecting RMS tumor cells and may be the choice to associate to the monoclonal antibodies against the intranuclear myogenic transcription factors MyoD1 and myogenin.

The malignant triton tumor (MTT) or malignant nerve sheath tumor (MPNST) (malignant schwannoma) with rhabdomyoblastic differentiation is a very peculiar tumor with specimens dominated by a sheet-­like proliferation of rela-

12  Soft Tissue

tively mature rhabdomyoblastic cells with somewhat irregular vesicular nuclei. These tumor cells are smaller than those of an adult rhabdomyoma with admixed smaller rounded cells. Such prominent degree of cytodifferentiation as seen in a triton tumor is never present in a rhabdomyosarcoma (RMS). At places, it is essential to appreciate that there are, usually, small areas in which the tumor cells are basophilic with a high N/C ratio and somewhat elongated nuclei. Although IHC helps in identifying extensive positivity for DES as well as myogenin (MYF-4), i.e., the areas with rhabdomyoblastic differentiation, the hypercellular more spindled areas in the formal excision remain negative for these antigens. Conversely, there is, typically, positivity for both S100 protein and GFAP, which should be present in the hypercellular basophilic areas and also in the subset of the smaller cells scattered between the rhabdomyoblasts. In RMS the preservation and storage of some tumoral tissue are useful for both diagnosis and prognosis. Tumor tissue may be kept frozen from the tissue used for intraoperative frozen section consultation, which is usually performed to determine sample adequacy and viability or from the tissue resected at the time of surgery and sent fresh to the pathologist. In the first case, at least three tissue slides may be kept at −80 Celsius or lower, while in the second event, ≥100  mg of viable tissue may be snapfrozen in iced frozen isopentane and held at −80 Celsius or lower. Isopentane or 2-methylbutane has a high thermal conductivity and does not form a vapor halo. These two qualities are key. Isopentane chilled with liquid nitrogen freezes tissues more effectively and uniformly than putting the tissues samples directly into liquid nitrogen. Molecular biology approach to detect translocations includes RT-PCR or FISH on both frozen or FFPE tumor tissue. Alternatively, airdried or alcohol-fixed touch preparations may be used, if no tumor tissue is available. To remember is that open incisional biopsy is higher in value than core needle biopsy. Resection tumor tissue specimens may be intralesional, marginal, comprehensive, or radical in extent. Intralesional resections have gross or microscopic residual

12.10 Vascular Tumors

tumor identifiable at surgical margins; marginal resections show inflammation-involved margin surrounding the tumor, while wide/radical resection involves show surgical margins extending through healthy tissue, which are usually external to the anatomic compartment containing the tumoral tissue. Diagnosis of botryoid RMS requires ≥1 microscopic field showing a cambium layer, which is a condensed layer of rhabdomyoblasts or spindle cells with focal rhabdomyoblastic differentiation (IHC and/or EM) underlying an intact epithelium (vide supra). Spindle-cell RMS, another good outcome harboring subtype of RMS, requires ≥80% of tumor demonstrating spindle-cell morphology in one of two recognizable patterns (collagen-poor or collagen-rich).

12.10 Vascular Tumors Vascular tumors include hemangioma, epithelioid hemangioma, angiomatosis, lymphangioma, while intermediate vascular tumors include hemangioendothelioma (and subtypes), papillary intralymphatic angioendothelioma, and Kaposi sarcoma. Malignant counterparts are epithelioid hemangioendothelioma and angiosarcoma. • IHC markers of endothelial origin or differentiation: CD31, CD34, D2-40 but also FVIII and von Willebrand factor. Friend leukemia integration one transcription factor or Fli-1 protein is a member of the ETS family of DNA-binding transcription factors. Fli-1 is involved in cellular proliferation and tumorigenesis. Almost all ES/PNET show t(11;22) (q24;q12) and formation of the EWS-Fli-1 gene fusion transcript. CD31, CD34, and von Willebrand factor. FLI-1 is a marker for benign or malignant vascular tumors. It has a sensitivity and specificity similar to CD31, CD34, and von Willebrand factor in identifying endothelium and has unambiguous nuclear staining that lacks the cytoplasmic and membranous staining artifacts of other markers as a result of endogenous peroxidases or biotin.

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CD141 or thrombomodulin is an integral membrane protein expressed on the surface of endothelial cells and serves as a cofactor for thrombin reducing blood coagulation and is also shown on the human mesothelial cell, monocyte, and a dendritic cell subset. In humans, thrombomodulin is encoded by the THBD gene, and gene mutations have also been reported to be associated with the atypical hemolytic-uremic syndrome (aHUS). D2-40 is a marker of the lymphatic epithelium. It is a monoclonal antibody directed to a 40,000 O-linked sialoglycoprotein that reacts with a fixation-resistant epitope on lymphatic endothelium. GLUT1 or glucose transporter 1 is a protein that in humans is encoded by the SLC2A1 gene. GLUT1 does facilitate the transport of glucose across the plasma membranes of mammalian cells. Mutations in the GLUT1 gene are responsible for GLUT1 deficiency, or De Vivo disease, which is an AD inherited disease characterized by hypoglycorrhachia, i.e., a low CSF glucose concentration. GLUT1 is also a receptor used by a virus, the HTLV (Human T-Lymphotropic Virus), to gain entry into target cells. GLUT1 has been observed explicitly in infantile hemangioma allowing the differentiation of capillary hemangioma from pyogenic granuloma.

12.10.1  Benign Vascular Tumors The W.H.O. classifies in the benign category hemangiomas and their variants as well as lymphangiomas and the condition called angiomatosis. Pyogenic granuloma and capillary hemangioma are the most frequent variants (Figs.  12.17 and 12.18). Pyogenic granuloma is a pedunculated pseudotumor composed of granulation type tissue separated by bands of connective tissue with a collarette appearance at the edges of the lesion and a lobular arrangement of capillaries, similar to capillary hemangioma. The lobules of endothelial cells may have indistinct to prominent lumina with occasional plump endothelial cellular appearance. Pyogenic granuloma is negative for GLUT-1, while capillary hemangioma is positive for this marker (vide infra).

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a

b

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d

e

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Fig. 12.17  Pyogenic Granuloma. The microphotographs show a pyogenic granuloma with “collarette” and proliferation of capillaries as well as some plump epithelioid cells (a–d). In (e) the stromal component is quite prominent (a–e, ×100, ×200, ×200, ×200, ×200 as original

magnification, respectively). In (f) there is positivity for GLUT-1 only in the erythrocytes of preformed blood vessels by immunohistochemistry (Anti-GLUT-1, avidinbiotin complex, 200× original magnification)

12.10.1.1 Hemangioma • DEF: Common benign vascular tumor, particularly often observed in childhood localized either superficially (H&N) or internally (liver) with very rarely malignant transformation. If hemangiomas involve large segments of the body, the term angiomatosis is probably appropriated. • GRO: Variably sized vascular channels ± hemorrhage and thrombosis. • CLM: An increased number of BVs, which are lined by a single layer of non-atypical endothelial cells.

12.10.1.2 Hemangioma Variants • Capillary: The skin/subcutaneous tissue (lips, oral cavity)/viscera located hemangioma constituted of firmly packed vascular spaces containing some blood or thrombosed or organized lumina and thin fibrous septa with a tendency to regress by age 7 in ¾ of the cases (Fig. 12.18) (+) GLUT1 • Cavernous: The skin/subcutaneous tissue/viscera located hemangioma constituted of mostly firmly packed vascular spaces containing some blood or thrombosed or organized lumina and thick

12.10 Vascular Tumors

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a

b

c

d

e

f

g

h

Fig. 12.18  The capillary hemangioma and cavernous hemangioma are shown in the microphotographs (a) through (h) with positivity for GLUT-1 (b) and low proliferation rates (g and h). In (f) an intratumoral mostly thrombosized blood vessel is seen (a, hematoxylin and eosin staining, x50 original magnification; c, hematoxylin

and eosin staining, ×12.5 original magnification; d, hematoxylin and eosin staining, ×200 original magnification; e, Masson trichromic staining, ×50 original magnification; f, hematoxylin and eosin staining, ×100 original magnification)

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fibrous septa with no tendency to regress and ± VHLS (vide infra) • Sinusoidal: Cavernous hemangiomas with dilated, interconnected, thin-walled channels and sporadic pseudopapillary projections • Intramuscular: Cavernous-like hemangiomas with high cellularity, high MI, intraluminal papillary projections, plump endothelial cells, ± perineurial infiltration, but no atypia Pyogenic granuloma (aka lobular capillary hemangioma) (Fig.  12.17): Rapidly growing, exophytic red nodule, attached by a stalk to the skin or gingival mucosa with a characteristic collarette with a natural tendency to bleed and/or ulcerate and (−) GLUT1 • Epithelioid: ALHE WT1 gene expression is expressed in different tumors, including vascular neoplasms and can be useful in the distinction of vascular malformations, which are usually negative. The ISSVA or International Society for the Study of Vascular Anomalies issued in 1996 a classification of vascular lesions dividing them into two groups, including vascular tumors and vascular malformations. Vascular proliferation-associated lesions (vascular tumors) comprise hemangioma of infancy, congenital hemangioma, tufted hemangioma, pyogenic granuloma, hemangiopericytoma, kaposiform hemangioendothelioma, and other vascular lesions such as cherry angioma and angiosarcoma. Conversely, vascular malformations are associated with BV with morphologic abnormalities. They are classified according to the distorted BV type and may involve any of the structural components of the vasculature, such as capillaries, veins, arteries, and lymphatics. Both non-involuting congenital hemangioma (NICH) and rapidly involuting congenital hemangioma (RICH), two difficult lesions that may be challenging in the routine practice, are WT1 positive alike other primary tumors. Medical treatment is not useful in vascular malformations, which may benefit from surgical resections, embolization, and sclerotherapy.

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12.10.1.3 Lymphangioma • DEF: Benign vascular tumor, which can present in mediastinum or retroperitoneum, associated with thoracic duct anomalies as single neoplasm and, in the diffuse form, as lymphangio-leiomyomatosis. • CLI: It may manifest as chylothorax, chylous ascites, and chyluria (Gr. χυλός “animal or plant juice”). • CLM: Proliferation of a mixture of BVs and smooth muscle with tumor cells being plumper and paler than usually seen in leiomyoma. • IHC: (+) SMA, DES, HMB45. • DDX: Angioleiomyoma.

12.10.2  Vascular Tumors with Intermediate Malignant Potential Hemangioendothelioma and Kaposi sarcoma are the essential tumors of this category.

12.10.2.1 Hemangioendothelioma • DEF: Hemangioendothelioma classic pattern and variants except the epithelioid variant belong to the category of vascular tumors with intermediate malignant potential. Hemangioendothelioma is a middle-­ grade vascular tumor with variable histologic features and clinical behavior ranging from recurrence in about 40% of cases and metastatic rates in about 1/5 of cases, whose 15% of these patients will succumb to this entity. It is not recommended using HE as the abbreviation for hemangioendothelioma, because HE is often used to note hematoxylin and eosin, but HE can be used in combination with other adjectives identifying the variants of this vascular tumor with intermediate malignant potential. Hemangioendothelioma variants include kaposiform hemangioendothelioma (KHE), retiform (RHE), spindle cell (SHE), endovascular papillary (EVPHE), polymorphous (PHE), and the composite form (CHE). KHE is a locally

12.10 Vascular Tumors

aggressive vascular tumor of infants and children, with the involvement of the skin, retroperitoneum, and skeleton. It is associated with death due to extensive disease and severe consumption coagulopathy (aka Kasabach-Merritt syndrome), but there is no metastatic potential. Grossly, KHE is usually a cutaneous enlarged and discolored lump located involving an extremity, torso, or the cervicofacial region. Deep KHE lesions may infiltrate skeletal muscle, bone, intrathoracic organs and retroperitoneal cavity. Microscopically, there are infiltrating nodules and sheets of compact spindle cells with peculiar formation of the slit-like lumen as seen in Kaposi sarcoma (vide infra).

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cutaneous tissue of the hands and feet of young to middle-aged women. Local recurrence and metastases have been noted in some patients and should be considered at time of the clinical staging. PHE usually involves lymph nodes and soft tissue with a tendency to recur locally and rarely metastases have been recorded. PHE is characteristically a mixture of solid, primitive vascular, as well as angiomatous patterns with uniform cytology, and spindle cell or angiosarcoma-like features without epithelioid features. RHE is probably a low-grade variant of AS with limited involvement of the reticular dermis and subcutaneous tissue of distal limbs of adolescents or young adults. RHE tends to recur but • IHC: (+) CD31, CD34, factor VIII-RA, vWF, has a low rate of metastases. Microscopically, VEGFR-3. Vascular endothelial growth factor the dominant feature is the retiform architecture, receptor 3 (VEGFR-3, Flt-4) is the receptor which is net-like, similarly to rete testis. The for vascular endothelial growth factors retiform pattern is characterized by blood ves(VEGFs) C and D and is specifically expressed sels that scatter through the reticular dermis and on lymphatic endothelium (Witmer et al. subcutis and is lined by monomorphic hobnail 2001). Folpe et al. (2000) disclosed that anti- endothelial cells with scant cytoplasm and round, VEGFR-3 was positive in 23 of 24 Kaposi sar- typically naked-type nuclei with or without an comas, 8 of 16 angiosarcomas, 6 of 6 KHE, accompanying lymphocytic infiltrate. Epithelioid and 2 of 13 hemangiomas. VEGFR-3 and its areas or cytoplasmic vacuoles are not found. An ligands VEGF-C and/or VEGF-D lay impor- essential diagnosis to be ruled out comprises tant roles in cell-to-cell signaling in adult low-­grade AS, which demonstrates always areas of severe atypia, cellular pleomorphism, and blood vessel angiogenesis. • TEM: Intermediate filaments (nonspecific), brisk mitotic activity. The AS typically dissects pinocytotic vesicles, intracytoplasmic lumina, between individual collagen bundles. Another essential differential diagnosis is constituted by and pericytic cells are seen. • CMB: The underlying genetic alteration in the hobnail hemangioma, which is generally most EHEs (vide infra) is a fusion of the WW smaller, more superficial and more localized than domain-containing transcription regulator RHE.  Naturally, appropriate tumor tissue samprotein 1 gene (WWTR1) with calmodulin-­ pling is mandatory. SHE is also localized at dermis or subcutis binding transcription activator 1 (CAMTA1 of distal limbs, but male adults of any age are gene). affected. SHE tends to recur, be multicentric and • DDX: Angiosarcoma and Kaposi sarcoma. associated with Maffucci syndrome. Both cavernous hemangioma and Kaposi sarcoma feaHemangioendothelioma Variants CHE is defined by a mixture of benign, low-­ tures characterize this kind of tumor. EPHE (aka Dabska tumor) is a rare variant of grade malignant (a vascular tumor with intermediate malignant potential), and destructive hemangioendothelioma occurring in the skin or vascular components and mainly constituted by soft tissue of children with the almost exclusively epithelioid and retiform growth patterns. CHE good outcome. Maria Dabska first described remarkably affects the superficial dermis or sub- this tumor in 1969. She described 6 cases in her

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series labeling it as “malignant endovascular papillary angioendothelioma” in children and adults (Dabska 1969). EPHE is characterized by endovascular papillary “tufts” lined by plump endothelial cells (epithelioid- or histiocyticlike) within dilated lumina with or without glomeruloid figures. Folpe et al. (2001) found 4 of 4 Dabska tumors positive with antibodies against the VEGFR-3.

associated herpesvirus infection and tightly influenced by immunologic status. Thus, although historically valid, the term should be considered a misnomer for this entity. KS may involve mucocutaneous sites and viscera and develops in in one of four different epidemiologic-clinical settings (Box 12.16). KS seems to arise from cells capable of undergoing lymphatic differentiation based on anti-­podoplanin (D2-40) staining, a lymphaticspecific marker. To remember is that HHV-8 is not exclusive of KS, but such viral infection may also be detected in multicentric Castleman disease, primary effusion lymphoma, and some multiple myeloma cases.

12.10.2.2 Kaposi Sarcoma Considered very rare before the discovery of the AIDS (acquired immunodeficiency syndrome), Kaposi sarcoma (KS) is a multicentric and reactive hyperplasia or tumor of low-malignant potential rather than a sarcoma (malignant tumor of mesenchymal origin). It is now considered • GRO: Early, macule/patch; intermediate, a vascular proliferative disorder mediated by plaque; and late, nodule/tumor with multiple inflammatory cytokines and angiogenic growth red-purple skin plaques or nodules, showing factors in patients with HHV-8/Kaposi sarcoma-­ increasing in size and spreading proximally.

Box 12.16 Kaposi Sarcoma (KS) Settings Classical

Iatrogenic

African AIDS-­ associated

Epidemiology ♂ > ♀, 4th–7th, Mediterranean area and Jewish Ashkenazi ♂ = ♀, immunesuppression-­linked (AI, drugs, and TX) ♂ = ♀, 2nd–5th, Equatorial Africa ♂ = ♀, 2nd–7th, HIV+ (LGBT, IVD users)

Clinical aspects Skin (LEX) > mucosa ± viscera Skin (LEX) > mucosa ± viscera Skin (LEX) ± LN

Outcome Indolent

Notes Localized

Variable (regression if immunosuppression is stopped) Progressive

Localized

Skin (LEX), mucosa + viscera

Aggressive (ARVT-dependent)

Multiple Multiple

N.B. The mnemonic word “CIA” may be used to remember the epidemiologic-clinical settings of Kaposi sarcoma (classical-iatrogenic-African and AIDS-associated). Typically, the higher the immunosuppression (e.g., CD4 T cells 25 lesions are found, extensive oral involvement, marked significant edema or visceral involvement, rapidly progressive disease, and KS flare. The backbone of systemic cytotoxic therapy includes liposomal anthracyclines and taxanes, and novel therapies include IFN-­ alpha, thalidomide, anti-Herpes, imatinib, and matrix metalloproteinase (MMP)-inhibitors. Tissue inhibitors of metalloproteinases (TIMPs) are the major cellular inhibitors of the MMP sub-family. However, most cells of KS lesions harbor HHV8 in its latent phase. Giant cell angioblastoma is an essential tumor of pediatric age, because of its clinical implications. GCAB is rare but shows an infiltrative slow-growing pattern and should probably be considered LMP. The GCAB is often considered together with Kaposi sarcoma, because of its high locally destructive fashion and intermediate malignancy without metastatic potential. GRO: Ulcerated tumor with clear-cut infiltrating character into soft tissue and bone and quite often located in the hand or H&N areas. CLM: There is a nodular plexiform proliferation of oval-to-spindle undifferentiated mesenchymal cells with prominent, concentric perivascular aggregation with the participation of fibroblasts, myofibroblasts and (+) CD68-MNGC. DDX: Giant cell fibroblastoma (CD34+, t(17:22)), EHE with osteoclast-like giant cells (Factor VIIIRA+, no concentric perivascular aggregation), plexiform fibrohistiocytic tumor (children/young adults, no concentric perivascular aggregation), myopericytoma (elderly, no giant cells), bacillary angiomatosis (+SS for organisms, +Hx. immunosuppression).

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12.10.3  Malignant Vascular Tumors The WHO incorporates in this section the epithelioid hemangioendothelioma and the angiosarcoma.

12.10.3.1 Epithelioid Hemangioendothelioma • DEF: Angiocentric vascular malignancy that involves soft-tissue and visceral organs such as the liver and lung and composed of epithelioid endothelial cells with an arrangement variable from short cords to nests embedded in a myxohyaline stroma, arising mostly in the extremities, H&N, and mediastinum. Drs. Weiss and Enzinger established this term to describe a soft-tissue vascular tumor with a clinical course in between that of benign hemangioma and that of angiosarcoma. Currently, it is still important to discern EHE from angiosarcoma because patients harboring EHE can survive for a long term. • GRO: Tender gray-white (cutaneous) nodule that may show, at places, some hemorrhage on cut surface. • CLM: The neoplastic endothelial cells show vesicular nuclei and abundant eosinophilic cytoplasm with intracytoplasmic vacuoles (“small intracytoplasmic vascular lumina”), which are mucin negative (Fig.  12.19). Malignant features (~1/3 of the cases) include marked nuclear pleomorphism, MI > 1/10HPF, cell spindling, and necrosis. • SS/IHC: (+) VIM, CD31, vWF, CK (30%, focal), RET (around nests and cords). • CMB: t(1;3)(p36.23;q25.1) is a consistent genetic abnormality in EHEs of different anatomical locations and grades of malignancy with the formation of the gene fusion transcript WWTR1-CAMTA1. This recurrent translocation is not present in any of the morphological mimics of EHE, such as epithelioid hemangioma, epithelioid angiosarcoma, or epithelioid sarcoma-like EHE. WWTR1, aka TAZ, is a transcriptional coactivator with a conserved WW domain capable of interacting with the PDZ domain and shares amino acidic homology with YAP (Yes-­ associated protein). Interestingly, WWTR1 and YAP are down-

•

•

• •

stream effectors of the Hippo pathway, which controls organ size and contact inhibition in mammals by regulating cell proliferation and apoptosis. CAMTA1 belongs to the protein family of calmodulin-­ binding transcription activators. It is indeed a family of proteins and is a transcription activator potentially involved in cell cycle regulation and possibly interacting with Ca2þ/calmodulin and be engaged in Ca2þ signaling. DDX: Met.-Ca. (marked atypia, high MI, lack of angiocentricity, keratin+, CD31−), melanoma (S100+, HMB45+, CD31−), epithelioid sarcoma (adolescents and young adults, distal extremities, merging of tumor cells with collagenous stroma and granuloma-like pattern, strong CK+, CD31−), epithelioid angiosarcoma (irregular sinusoidal, interconnected vascular channels, solid cellular sheets harboring marked atypia and high MI, necrosis). PGN: Unpredictable clinical course, but less aggressive than AS, although 13% will recur, 20–30% metastasize (lung and LNs), and 13% die of the disease (mortality: 65%). It has been suggested that the cutaneous form of EHE has undoubtedly a better prognosis than the deeplocalized EHE (Goh & Calonje, 2008). High risk EHE (>3 MF/50 HPF and Ø > 3 cm) ⇒ 5-YSR: 59%. Low-risk EHE, wide local excision, vs. high-­ risk EHE, radical local excision ± LN-ectomy.

12.10.3.2 Angiosarcoma Angiosarcoma (AS) is a malignant endothelial cell-arising vascular tumor of the deep muscles of the lower extremities (~1/2) or other locations, including viscera, with apparent vasoformative growth and complex anastomosing channels that occurs in children and adults with a peak incidence in the seventh decade and harboring a poor prognosis with LN and distant metastases (lungs, liver, bone). Five clinical groups are differentiated: • • • • •

Cutaneous AS Lymphedema-associated AS Radiation-induced AS Breast AS Deep soft tissue AS

12.10 Vascular Tumors

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Fig. 12.19  Epithelioid Hemangioendothelioma. An epithelioid hemangioendothelioma is shown grossly (a and b) and microscopically (c–h). In c) is notable the infiltration of the tumor, while the epithelioid nature of the plump atypical endothelial cells is better shown at higher magnification, particularly in f) (c-g, hematoxylin and

eosin staining, ×12.5, ×100, ×100, ×200, ×200 as original magnification, respectively). The microphotograph in h) highlights this vascular tumor using an antibody against CD31 by conventional immunohistochemistry. (Anti-CD31 immunostaining, Avidin-Biotin Complex, ×100 original magnification)

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However, all forms share similar histology with an infiltrative character, multifocality, and a dissecting pattern of irregular, anastomosing vascular channels between collagen bundles, fatty tissue, and other structures.

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related to severe, life-threatening complications. The most relevant syndromes associated with vascular tumors are the following conditions:

1. Von-Hippel Lindau Syndrome (VHLS): Clear cell RCC  – chromosome 3 (3p25), RAF-1. pVHL inhibits the elongation step of RNA • RF: Chronic lymphedema (breast), sun exposynthesis by interacting with ELONGIN B sure, radiation, Thorotrast, polyvinyl chloride and C (mnemonics “K-PASH”: kidney (PVC). Epidemiologic studies have identified (CCRCC/renal cysts), pancreas (cysts/serous the vinyl chloride monomer (VCM) as the cystadenoma), adrenal (pheochromocytoma), causative agent (Falk 1987). skin (Cafe au lait spots), hemangioblastoma • Visceral sites: The breast, liver, lung, and skin of retina, and cerebellum (± EPO-induced (Stewart-Treves syndrome after ~ 10  years polycythemia) recalling K-PAX, the 2001 post-radical mastectomy for breast cancer-­ American Science Fiction movie with Kevin associated lymphedema). Spacey and Jeff Bridges. • GRO: Early AS  ⇒  asymptomatic, small, sharply circumscribed, multiple red nodules vs. 2. Blue Rubber Bleb Nevus Syndrome (BRBNS): It is a rare disease with an abnormal blood veslate AS ⇒ fleshy, gray-white mass with hemorsel formation and arteriovenous malformation. rhage, necrosis, deeply invasive and painful. AS may also present with coagulability abnor- 3. Proteus Syndrome is a syndrome characterized by a mosaic distribution, progressive malities, anemia, persistent hematoma, bruiscourse, and sporadic occurrence AND one ability, and high output cardiac failure. A-lesion (connective tissue nevus) OR two • CLM: Atypical vascular channels lined by neoout of three B-lesions (epidermal nevus, displastic endothelial cells with evident cytologic proportionate growth, bilateral ovarian atypia, multilayering, intracytoplasmic RBCcystadenomas in an individual CK 7 > CK 20 > CK 5/6 (94%, 72%, 48%, 22%, 15%, 30%, respectively) (Armah & Parwani, 2009). • TEM: Epithelial (desmosomes, tonofilaments, surface microvilli) and mesenchymal differentiation. • DDX: Epithelioid MPNST (S100+, rarely EMA+, CK −), epithelioid angiosarcoma, malignant melanoma (S100+, usually

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HMB45+). In considering melanocytic lesions, S-100 remains the most sensitive marker. Conversely, markers such as HMB45, MART-1/Melan-A, Tyrosinase, and MITF (Microphthalmia-associated transcription factor) harbor relatively good specificity but not as good sensitivity as S-100 antibody. • PGN: Very aggressive course with tendency to propagate along fascial planes (5-YSR ~50%) By reviewing the literature, it seems that relatively good PGN factors (Italic denotes good) are child age (Y/N), gender (female vs. male), size (Ø    5  cm), location (superficial vs. deep-seated and distal vs. proximal/axial), MI (Ø  10/HPF), hemorrhage (N/Y), necrosis (N/Y), calcifying variant (Y/N), excision (curative locally vs. multiple recurrences, Y/N), rhabdoid features (N/Y), angiolymphatic invasion (N/Y), and LN+ at diagnosis (N/Y).

12.12.6  Alveolar Soft Part Sarcoma • DEF: Alveolar soft part sarcoma (ASPS) is a malignant TUD of deep soft tissues, usually the thigh and leg but also H&N (e.g., orbit, tongue), mostly children and young adults (15–35 yrs.). • GRO: It is a poorly circumscribed tumor with quite often necrosis and hemorrhage. • CLM: Mostly regular nests of 25–50 large (>30 µm), polygonal, loosely cohesive tumor cells with large vesicular nuclei, prominent nucleoli, granular cytoplasm, with irregular (usually “rod-shaped”), +DPAS crystals with thin-walled vascular septs (Fig. 12.23). • IHC: MYO-D1 (cytoplasmic, no nuclear), (+) TFE (TFE also stains Xp11 translocation RCC, focal and less intensely MM, CCS, PEComa, and AML) (RCC, renal cell carcinoma; MM, malignant melanoma; CCS, celar cell sarcoma; PEComa, perivascular epithelioid cell neoplasm; AML, angiomyolipoma), (+) MCT1 and  (+)  CD147  in the granules (monocarboxylate transporter chaperon-like protein/SLC16A1 located on 1p13.2 and Basigin/EMMPRIN/CD147 located on

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Fig. 12.22  Epithelioid Sarcoma. There is a granulomalike pattern (a) with spindled and polygonal eosinophilic tumor cells with somewhat only occasional prominent nucleolus and atypical mitoses (b–c). At places, the cells form small nests simulating granuloma annulare or a quite typical rheumatoid nodule. There is immunophenotypical positivity for some markers, which support the diagnosis of epithelioid sarcoma (vimentin, VIM (d); actin, ACT (e); pan-cytokeratins, AE1-3 (f)), increased proliferation rate (g) and loss of INI1 (h) (a–c, hematoxylin and eosin staining, ×0.5, ×100, ×400 as original magnification, respectively; d, anti-VIM immunostaining, Avidin-Biotin

Complex, ×100 original magnification; e, anti-ACT immunostaining, ×100 original magnification; f, anti-AE1-3 immunostaining, Avidin-Biotin Complex, ×100 original magnification; g, anti-Ki67 (MIB1) immunostaining, Avidin-Biotin Complex, ×100 original magnification; h, anti-INI1 immunostaining, Avidin-Biotin Complex, ×400 original magnification). INI1 (hSNF5/SMARCB1) is a member of the SWI/SNF chromatin remodeling complex. The INI1 gene is located on chromosome 22q11.2 and is deleted or/or mutated in malignant rhabdoid tumors (MRT) of infancy, epithelioid sarcoma as well as other malignancies (see text for details)

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Fig. 12.23  Alveolar Soft Part Sarcoma. There are regular nests of large, polygonal, loosely cohesive tumor cells with large vesicular nuclei, impressively prominent nucleoli, and diffuse granular cytoplasm (a–f) (a, hematoxylin and eosin staining, ×40 original magnification; b, hema-

toxylin and eosin staining, ×100 original magnification; c, hematoxylin and eosin staining, ×200 original magnification; d, periodic acid Schiff, ×40 original magnification; e, periodic acid Schiff, ×200 original magnification; f, periodic acid Schiff, ×200 original magnification)

19p13.3), (−) MYOG (MYF4, myogenin, • DDX: ARMS, which shows variably shaped myogenic factor 4). The DNA-binding factor alveolar spaces vs. regular alveolar spaces, TFE3 is closely related to MiTF. fibrous septs vs. thin-walled vascular septs, • TEM: Membrane-bound or membrane-free 10–30 um cellular Ø, cellular pleomorphism, rhomboid crystals with periodicity of ~10 nm dense nuclei with small nucleoli vs. vesicular and “cross grid” pattern, numerous electron-­ nuclei with prominent nucleoli, no crystals, dense vesicles near Golgi apparatus, smooth nuclear MYO-D1, (+) MYOG (MYF4, tubular aggregates associated with invaginaMyogenin, Myogenic Factor 4), t(2;13) or tions of the cytoplasmic membrane, but no t(1;13) vs. der(17)t(X;17)(p11.2;q25). features of skeletal muscle differentiation. • PGN: Highly malignant tumor with a tendency • CMB: der(17)t(X;17)(p11.2;q25)  ⇒  ASPL/ to easily metastasize and lethal over a proTFE3. tracted course of 5–10 years with lung, bone,

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Fig. 12.24  Clear Cell Sarcoma. There are irregular nests of cells separated by fibrous septa as well as short interlacing fascicles. In addition, whorls or solid sheets of tumor cells are also recognized (a–b). The tumor cells are round to spindle with hyperchromatic nuclei and clear cytoplasm (c). There is immunopositivity for Human Melanoma Black 45 (HMB45) (d) (a–c, hematoxylin and eosin staining; a, ×100 original magnification; b, ×100 original magnification; c, ×400 original magnification, d,

antii-HMB45 immunostaining, Avidin-Biotin Complex, ×200 original magnification). HMB45 is a monoclonal antibody that recognizes the melanosomal glycoprotein gp100 (Pmel17). HMB45 is required to create and arrange melanosomal fibrils, facilitates maturation of stage I premelanosomes to stage II melanosomes, and detects the oncofetal glycoconjugate associated with immature melanosomes

and brain metastases (5-YSR: ~60%). Favorable PGN factors are child age (Y/N), size (Ø5 cm), and M (–) at diagnosis (Y/N). Histologic features seem to play no role.

which are round to spindle with vesicular nuclei and prominent nucleolus, clear to granular cytoplasm associated with wreathlike (or floret-like) MNGC, and occasional melanin pigment and/or Fe-granules (Fig. 12.24). • IHC: (+) S100, HMB45, Melan-A/MART1, MiTF, other than VIM, but also (±) NSE, SYN, CD57, keratins, and (−) SMA, DES, CAM5.2. CAM5.2 is a low-molecular weight marker against keratins 7 and 8 (CK8>CK7), while MITF (MiTF) or Microphthalmiaassociated Transcription Factor, which is also often also known as class E basic helix-loophelix protein 32, is a key marker. Alternatively, MiTF is also known as bHLHe32. MiTF is a transcription factor that in humans is encoded by the MITF gene. MITF is a basic leucine

12.12.7  Clear Cell Sarcoma • DEF: Soft tissue sarcoma of young adults with evidence of melanocytic differentiation occurring mostly in large tendons or aponeuroses of the extremities (feet/ankles) of young adults (♂  ♀) characterized by extended survival, but high potential for local recurrence and metastases. • GRO: Well-circumscribed tumor with multinodular gelatinous architecture delimitated by a pseudocapsule and fibrous septs, which may be festooned with intratumoral cysts and hemorrhagic areas.

12.12 Tumors of Uncertain Differentiation

12.12.9  PNET/Extraskeletal Ewing Sarcoma (ESES) • DEF: Aggressive small round blue cell neoplasm, morphologically similar to Ewing sarcoma of the bone of children and young adults at lower extremities, chest wall (Askin tumor), and paravertebral region with a spectrum of appearance from undifferentiated to forming rosettes (Homer-Wright rosettes) and may represent extension of bone tumor into soft tissue. • GRO: It is a well-circumscribed and whitish to yellowish tumor with scattered hemorrhagic necrosis. • CLM: Small round/oval cells with nuclei exhibiting fine chromatin and small nucleoli and scanty clear cytoplasm containing glycogen (PAS+); peritheliomatous pattern (concentration around blood vessels) (Fig. 12.26). Skeletal Ewing sarcoma cells have been depicted having more evident and substantial cytoplasm than extra-skeletal Ewing sarcoma cells. • IHC: (+) VIM, CD99 ± neuroendocrine lines of differentiation (e.g., S100), (+) DES only in the ectomesenchymoma variant, but it is controversially debated); (−) Pan-Keratins, AE1-3 (usually). • TEM: Abundant cytoplasmic glycogen, poorly developed cell junctions, no neural features. • CMB: The translocations are listed in Box 12.18. Slides are usually cut from paraffin blocks. The slides are deparaffinized in xylene and dehydrated in ethanol. Specimen pretreatment and fluorescence in situ hybridization (FISH) need to be applied. Vysis® (Abbott Molecular Inc.) pretreatment kit and appropriate probes are commonly used. The LSI EWSR1 dual color probe consists of a 500 kb Spectrum-Orange (red) labeled probe that specifically flanks the 5’ side of the EWSR1 gene, and extends inward into intron 4. The second probe is a 1100 kb Spectrum-Green (green) probe, which specifically flanks the 3’ side of the EWSR1 gene. It is known that the known breakpoints within the EWSR1 gene are restricted to introns 7 through 10. FISH discloses a normal pattern, which includes

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Box 12.18 PNET: Chromosomal Translocations

• t(11;22)(q24;q12) responsible for the fusion transcript of FLI1-EWS genes • t(21;22)(q12q12) creating the gene fusion transcript ERG-EWS • t(7;22)(p22;q12) making the gene fusion transcript ETV1-EWS genes • t(17;22)(q12;q12) producing the gene fusion transcript E1AF-EWS genes • t(2;22)(q33;q12) forming the gene fusion transcript FEV-EWS genes

normal nuclei containing two red/green (yellow) fusion signals. In a normal cell that lacks a t(22q12) in the EWSR1 gene region, a two fusion signal pattern is observed. However, in an abnormal cell with a simple t(22q12), the expected signal pattern will be one fusion, one red and one green signal. • The lab’s normal cut off is established at ≤10% of the cells showing an abnormal signal pattern. In each reaction it is imperative that all appropriate negative and positive controls are used. Any FISH result needs to be interpreted within the context of all available clinical, morphologic, cytogenetic, immunophenotypic, and molecular diagnostic information. The most common translocation found in PNET/ESES is the t(11;22)(q24;q12) resulting in the EWS/FLI-1 fusion gene found in approximately 90% of cases. The next most common translocation is t(21;22)(q22;q12) resulting in the fusion of EWSR1 to the ERG (21q22). The remaining translocations make up less than 5% of cases. • DDX: The DDX includes a series of tumors that are the following conditions: –– Neuroblastoma (dense chromatin, neurosecretory granules, +CGA, −CD99), RMS (nuclear irregularity, dense chromatin, variability in cytoplasmic amount, no rosettes, ±CD99, IHC evidence of myogenic differentiation, t(2;13) or t(1;13) in ARMS)

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Fig. 12.26  Extraskeletal Primitive Neuroectodermal Tumor – Extraskeletal Ewing Sarcoma (ESES). Primitive neuroectodermal cells growing in lobules where the cells are packed (a–c) showing a high nucleus to cytoplasm ratio (d). There is immunopositivity for CD99 (e) and synaptophysin (SYN) (f). The tumor shows also a high proliferation rate (g). The immunofluorescent photograph (h) demonstrates the expected chromosomal rear-

rangement (a–d, hematoxylin and eosin staining; ×40, ×200, ×400, ×630 as original magnification, e, anti-CD99 immunostaining, Avidin-Biotin Complex, ×200 original magnification; f, anti-SYN immunostaining, AvidinBiotin Complex, ×200 original magnification; g, antiKi67 immunostaining (MIB1), Avidin-Biotin Complex, ×200 original magnification)

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–– Lymphoma (LCA and B/T lineage positivvalue as a negative factor. Also, by multivariate ity) CD99 is not reliable in the differential analysis, p16/p14ARF homozygous deletion is diagnosis with lymphoproliferative prothe second most significant factor after p53 cesses, because may be positive up ½ of mutation (Hense et al. 1999; Eralp et al. 2002; cases with T-leukemia and T-lymphoblastic Desai et al. 2010; Verma et al. 2017). lymphoma. In the context of PNET, it should also be –– DSRCT (prominent DSR, +WT1, DES, AE1–3, EMA, ± CD99, t(11;22)(p13;q12) considered the melanotic progonoma or mel–– Esthesioneuroblastoma (olfactory neuro- anotic neuroectodermal tumor of infancy blastoma) (S100+ sustentacular cells, (Retinal Anlage Tumor) (Kruse-Losler et al. 2006). Melanotic progonoma occurs in children − CD99) –– Small cell osteosarcoma (malignant oste-   20% have significantly poorer overall survival • DEF: Aggressive small round blue cell tumor among patients with localized disease. In mulof mostly children, adolescents, and young tivariate analysis, p53 > 20% is one of the most adults with preferentially intra-­ abdominal influential negative prognostic factors. In ~30% location (multinodular and lobulated) with of PNET, there is a homozygous loss of p16, pain, ascites, visceral obstruction (colon, urewhich regulates cell cycle progression. By uniter, and biliary system), keratin and desmin variate analysis, a study demonstrated p16/ co-expression, and t(11;22)(p13;q12) resultp14ARF deletion alone had only marginal ing in a chimeric EWS-WT1 fusion product.

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• GRO: Large, multinodular to lobulated mass, often accompanied by several small peritoneal implants with a firm, gray-white cut surface and foci of hemorrhage and necrosis. • CLM: Nests (± confluence) with angulated edges and peripheral palisading feature embedded in a fibroblastic/myofibroblastic desmoplastic stroma. Tumor cells are small, uniformly round, and hyperchromatic with dispersed chromatin, scant cytoplasm, and indistinct cell borders. ± Focal necrosis, cysts, glands, and BV with ectasia. • IHC: (+) VIM, WT1, DES (punctate perinuclear staining), CKs, EMA, NSE, CGA, SYN, ±CD57, CD99; (−) LCA, SMA, HHF35 (MSA, muscle specific actin), MYOG, MYOD, GFAP, NF, CEA, HMB45, AFP, CK5/6, and CK20. The expression of INI1 is retained. • TEM: Paranuclear bundles of intermediate filaments that can entrap other organelles and few cell junction complexes, including desmosomes. Desmosomes are intercellular junctions that provide strong intercellular adhesion and they also link intracellularly to the intermediate filament cytoskeleton building the strong adhesive bonds in a network that gives mechanical strength to tissues. • CMB: t(11;22)(p13;q12) ⇒ C-terminus DNA-­ binding domain of WT-1 (11p13) → N-­terminus of EWS (22q12). • DDX: It includes mostly RMS and EWS. • PGN: Poor (5-YSR 1/50HPF), atypical mitoses, and coagulative cell necrosis

12.12.14  Extrarenal Wilms’ Tumor The nephroblastoma or Wilms’ tumor is one of the most common childhood solid tumors with three components, including blastema, epithelia (tubules), and stroma. It arises from primitive metanephric cells, but exceptionally it may arise in places other than kidneys. From the oncologic point of view, the extrarenal Wilms’ tumor is a rare and challenging neoplasm. Most of the authors support the thesis that the ERWT arises from primitive ectopic nephrogenic rests, but teratoid Wilms’ tumor leads to the debate whether this tumor is truly neoplastic or embryonic. A challenging staging complicates the diagnosis. If we consider the National Wilms’ Tumor Study (NWTS) recommendations, a nephroblastoma should be considered as stage II or higher as it is beyond the renal capsule. This finding means that the child will need chemotherapy, but most of the case reports illustrate favorable histology and a good outcome with surgery alone (Fig. 12.27).

12.12.15  Sacrococcygeal Teratoma and Extragonadal Germ Cell Tumor and Yolk Sac Tumor The most common teratoma in children, mainly newborns with female preponderance ♂  >  ♀.  In 95%, sacrococcygeal teratomas (SCTs) are benign, even when immature elements are present, but the risk of malignancy increases with age of the patient. Teratoma is defined by the presence of tissues from more than one of the three primitive germ cell layers (e.g., teeth, skin, and hair derived from ectoderm; cartilage, connective tissue, and bone from mesoderm; and intestinal, bronchial, or pancreatic tissue from endoderm) (Fig. 12.28). It may be considered a form of parasitic twin

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c

d

Fig. 12.27  Extrarenal Wilms’ Tumor. Gross photograph (a) of a solid tumor with soft, brain-tissue like texture showing small round blue cells growing in a solid or serpentine fashion highlighting the blastema character of the tumor cells (b–c). In (d) there is frank immunopositiv-

ity for WT1 (see text for details). (b–c, hematoxylin and eosin staining, ×12.5 and ×100 as original magnification, respectively; d) anti-WT1 immunostaining, Avidin-Biotin Complex, ×50 original magnification)

due to the presence of organs and tissue differentiated toward specific units. In fact, we could find a fully formed eye in a sacrococcygeal teratoma (Sergi et al. 1999). There is a high relevance in considering the possibility to have also malignant components, such yolk sac tumors with polytopic differentiation and choriocarcinoma as well as small round blue cell tumors. One of the challenges of the SCT is that it may be impossible to gross it entirely. The behavior of congenital teratomas remains poorly understood and is frequently considered unpredictable, but studies of large series with follow-up are limited. If it is certain that benign SCTs have a specific potential to malignant manifestations increasing with age, i.e., at

the age of 9 months in about 70% of cases of malignant SCTs, it is also stressed that malignant relapses of SCT after primary resection classified as benign initially may develop later on. Moreover, SCTs, dependent on their position, size, and composition can be associated with intrauterine complications, such as urological, anorectal, and osteo-muscular ones, which can be not entirely known at birth. In an extensive study performed at the Children’s Hospital, University of Innsbruck, Austria, Hager et al., published in 2012, one of the most extensive reviews of SCTs with follow-up was carried out spanning between January 1968 and December 2011 identifying 29 children who underwent surgical interventions for an

12.12 Tumors of Uncertain Differentiation

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a

b

c

d

e

f

Fig. 12.28  Sacrococcygeal Teratoma. In this teratoma of the sacrococcygeal region, there are lines of differentiation from the endodermal, mesodermal and ectodermal layers of the primitive embryonal differentiation that are similar to other teratomas identified in other body areas

(a–f). The neuroectodermal tissue, as an example highlighted in (b) is very important for the grading of the immaturity of the teratoma (a–f, hematoxylin and eosin staining, ×12.5, ×100, ×50, ×50, ×50, ×50 as original magnification, respectively)

SCT at the Austrian Children’s hospital, which is one of the most famous and high-ranked Children’s hospitals worldwide. One more patient was added who was treated for a malignant relapse. Clinical records of 24 children (all survived) and of the girl with the relapse were reviewed, and comparison among three of the most common histological classifications of SCT was made using the histology available

of 25 cases. Histological re-­evaluation showed no differences between the groupings. Despite the heterogeneity of treatment within the 43  years, 24 patients survived. The histological re-examination of the slides showed no significant differences. However, a yolk sac tumor could be identified in the relapse even if the original tumor seemed to be devoid of a malignant component, and benign components can

12  Soft Tissue

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a

b

c

d

e

f

g

h

Fig. 12.29  Extragonadal Germ Cell Tumor. In this pediatric tumor, there is a lot of neuroectodermal tissue (a) in addition to a component of extragonadal germ cell tumor (b). In fact, there are cystic and solid changes characteristic of yolk sac tumor as it is highlighted in (c), (e) and (g), which are accompanied by the corresponding alpha-feto-protein positivity (AFP) by immunohisto-

chemistry (Avidin-Biotin Complex) (d), (f), and (h) (a, b, c, e, and g, hematoxylin and eosin staining, ×50, ×100, ×100, ×100, ×100 as original magnification, respectively; d, f, and h, anti-AFP immunostaining, Avidin-Biotin Complex, ×100, ×100, ×100 as original magnification, respectively)

12.12 Tumors of Uncertain Differentiation

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a

b

c

d

Fig. 12.30  Extragonadal Yolk Sac Tumor. This other extragonadal germ cell tumor of a pediatric patient highlights the histologic and immunohistochemical features of a yolk sac tumor with micropapillary growth pattern (a) and microcystic growth pattern (b) with immunohistochemical positivity for alpha-fetoprotein (AFP) (c) and

high proliferation rate (d) (a, hematoxylin and eosin staining, ×100 original magnification; b, hematoxylin and eosin staining, ×100 original magnification; c, anti-AFP immunostaining, Avidin-Biotin Complex, ×100 original magnification; d, anti-Ki67 immunostaining (MIB1), Avidin-Biotin Complex, x100 original magnification)

metastasize or relapse as well, even if the coccyx has been resected. Despite accurate resection, annual control investigations should be offered to all patients harboring SCTs, because late recurrence cannot be easily predicted yet. Furthermore, except for incontinence problems in four patients and dissatisfaction with scar formation in five patients, the results were surprisingly good at this institution. Finally, two entities should be considered including the extragonadal germ cell tumor and the extragonadal yolk sac tumor (Figs. 12.29 and 12.30).

Extragonadal germ cell tumor is defined as a germ cell tumor outside of either the testes or ovaries and may be an incidental encounter or manifesting as a tumor. The germ cell tumor is mainly of the teratomatous type with mature and immature components. Yolk sac tumor of extragonadal type is either a component of the germ cell tumor of extragonadal kind or is a pure yolk sac tumor, and occasional cases have been reported in a few organs, such as the heart (Graf et al. 1999).

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 ultiple Choice Questions M and Answers • SFT-1 A 12-year-old boy presents with a 2.5  cm slow-growing, firm nodule on the scalp. The child started swimming in the pool 3 months ago. There was no clinical history of

What is the most likely diagnosis? (a) Pilomatrixoma (b) Polyomavirus infection (c) Poxvirus infection (d) Molluscum contagiosum (e) Trichoblastoma • SFT-2 Which neoplasm is characterized by the translocation t(X;17)(p11;q25)? (a) Neuroblastoma (b) Rhabdomyosarcoma (c) Synovial sarcoma (d) Alveolar soft part sarcoma (e) Myoepithelial carcinoma • SFT-3 Which of the following is CORRECT about the prognosis of a ganglioneuroma? (a) It depends on the results of five parameters, including age, stage, MYCN status, histology, and DNA ploidy. (b) It depends exclusively on the age of the patient.

12  Soft Tissue

symptoms, including lethargy, weight loss, or decreased appetite. The school performance was regular and no history of child abuse. Laboratory testing showed a normal blood cell count. A biopsy was performed, and the histology is shown here:

(c) It is good, although a long-term follow-up is required due to the potential malignant transformation of residual tumor leftover following the resection. (d) It depends on the mitotic-karyorrhexis index and MYCN status. (e) It depends if it occurs sporadically or in a setting of a genetic syndrome. • SFT-4 A soft tissue tumor biopsy shows sheets and fascicles of relatively uniform spindled cells. The tumor cells harbor a scant cytoplasm and ovoid hyperchromatic nuclei with inconspicuous nucleoli. In the tumor, there are also strands of ropy and wiry collagen as well as bands of hyalinized collagen. The mitotic index reveals 15 mitotic figures per 10 high-­ power fields. Some focal areas of myxoid change and staghorn-type vascular pattern are also seen. The immunohistochemistry shows positivity for EMA, CD99 (membranous

References and Recommended Readings

staining), and transducin-like enhancer of split 1 (TLE1) (nuclear staining), while there is negativity for CD34. Which translocation is expected to be seen in this tumor? (a) t(2;13)(q35;q14) (b) t(1;13)(p36;q14) (c) t(X;2)(q13;q35) (d) t(21;22)(q22;q12) (e) t(X;18)(p11.2;q11.2) (f) t(9;22)(q22;q12) (g) t(1;22)(q23;q12) • SFT-5 Which of the following mutations is mostly involved as a somatic mutation in angiosarcoma? (a) TP53 (b) ALK (c) BRAF V600E (d) SOX10 (e) PDGFB • SFT-6 Which of the following statements for a solitary fibrous tumor (SFT) is FALSE? (a) SFT is a fibroblastic tumor composed of relatively bland and uniform spindled cells within long, thin, parallel bands of collagen in a “patternless” pattern. (b) SFT typically occurs in adults, but young individuals have been reported. (c) SFT reveals slow growth and painless masses with low rates of infiltration and metastasis. (d) Histologic sections show bland cells with small and elongated nuclei. (e) Myxoid change is not a histologic feature. (f) Immunohistochemically, SFT is positive for CD34, CD99, bcl-2, and STAT6 but is negative for desmin, keratin, and S100. (g) Molecular studies often show NAB2-­ STAT6 fusion. • SFT-7 What is TRUE for the MYCN status of neuroblastoma? (a) Amplification of the MYCN oncogene is extraordinarily crucial for the prognosis. (b) When MYCN amplification is present, the tumor is elevated to a “middle” risk category. (c) MYCN amplification is noted in 90% of primary tumors.

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(d) The degree of MYCN amplification does not correlate with a worse prognosis. (e) The MYCN amplification status changes following chemotherapy treatment. • SFT-8 Which morphologic criterion does NOT help in the diagnosis of lipoblastoma? (a) Hypercellular lobules of adipocytes in various stages of differentiation. (b) Separation of the lobules by prominent fibrous septa. (c) Plexiform vascular pattern and abundant myxoid stroma. (d) Prominent extracellular mucinous pools can occur. • SFT-9 Myxofibrosarcoma is one of the more common subtypes of sarcoma that is very rare in childhood, occurring mostly in middle-aged to elderly adults at the extremities. Myxoid liposarcoma is an intermediategrade sarcoma that most commonly arises in the deep soft tissue of the extremities. It is also rare in childhood, but it should be kept in the differential diagnosis of myxoid tissue-rich soft tissue sarcomas. Which of the following features is most useful in separating myxofibrosarcoma from myxoid liposarcoma? (a) Plenty of Reed-Sternberg-like cells (b) DDIT3 (CHOP) translocation (c) Lack of GNAS mutation (d) MDM2/CDK4 amplification (e) Histologic evidence of vascular arcades • SFT-10 What is the translocation seen in desmoplastic small round cell tumor? (a) t(11;22)(p13;q12) (b) t(2;13)(q35;q14) (c) t(1;13)(p36;q14) (d) t(X;2)(q13;q35) (e) t(21;22)(q22;q12)

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1093 Surg. 2012;47(12):2312–5. https://doi.org/10.1016/j. jpedsurg.2012.09.046. PubMed PMID: 23217896. Kulkarni K, Desai S, Grundy P, Sergi C. Infantile myofibromatosis: report on a family with autosomal dominant inheritance and variable penetrance. J Pediatr Surg. 2012;47(12):2312–5. https://doi.org/10.1016/j. jpedsurg.2012.09.046. PubMed PMID: 23217896. Lau YS, Sabokbar A, Gibbons CL, Giele H, Athanasou N. Phenotypic and molecular studies of giant-cell tumors of bone and soft tissue. Hum Pathol. 2005;36(9): 945–54. PubMed PMID: 16153456. Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D. Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):671–8. PubMed PMID: 7820541. Luqmani RA, Bacon PA, Moots RJ, Janssen BA, Pall A, Emery P, Savage C, Adu D.  Birmingham Vasculitis Activity Score (BVAS) in systemic necrotizing vasculitis. QJM. 1994;87(11):671–8. PubMed PMID: 7820541. Luqmani RA, Exley AR, Kitas GD, Bacon PA. Disease assessment and management of the vasculitides. Baillieres Clin Rheumatol. 1997;11(2):423–46. Review. PubMed PMID: 9220084. McKillop SJ, Belletrutti MJ, Lee BE, Yap JY, Noga ML, Desai SJ, Sergi C.  Adenovirus necrotizing hepatitis complicating atypical teratoid rhabdoid tumor. Pediatr Int. 2015;57(5):974–7. https://doi. org/10.1111/ped.12674. Epub 2015 Aug 19. PubMed PMID: 26508178. Meng GZ, Zhang HY, Zhang Z, Wei B, Bu H. Myofibroblastic sarcoma vs nodular fasciitis: a comparative study of chromosomal imbalances. Am J Clin Pathol. 2009 May;131(5):701–9. https://doi. org/10.1309/AJCPV6H2WSYXLKFB. PubMed PMID: 19369631. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom LG. Extraskeletal myxoid chondrosarcoma: a reappraisal of its morphologic spectrum and prognostic factors based on 117 cases. Am J Surg Pathol. 1999;23(6):636–50. https://doi.org/10.1097/00000478-199906000-00002. PMID: 10366145. Mojiri A, Stoletov K, Carrillo MA, Willetts L, Jain S, Godbout R, Jurasz P, Sergi CM, Eisenstat DD, Lewis JD, Jahroudi N. Functional assessment of von Willebrand factor expression by cancer cells of non-­ endothelial origin. Oncotarget. 2017;8(8):13015–29. https://doi.org/10.18632/oncotarget.14273. PubMed PMID: 28035064; PubMed Central PMCID: PMC5355073. Mukhtyar C, Lee R, Brown D, Carruthers D, Dasgupta B, Dubey S, Flossmann O, Hall C, Hollywood J, Jayne D, Jones R, Lanyon P, Muir A, Scott D, Young L, Luqmani RA. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis. 2009;68(12):1827–32. https://doi.org/10.1136/ard.2008.101279. Epub 2008 Dec 3. PubMed PMID: 19054820.

1094 Neuville A, Chibon F, Coindre JM. Grading of soft tissue sarcomas: from histological to molecular assessment. Pathology. 2014;46(2):113–20. https://doi.org/10.1097/ PAT.0000000000000048. Review. PubMed PMID: 24378389. Nielsen TO, Poulin NM, Ladanyi M. Synovial sarcoma: recent discoveries as a roadmap to new avenues for therapy. Cancer Discov. 2015 Feb;5(2):124–34. https:// doi.org/10.1158/2159-8290.CD-14-1246. Epub 2015 Jan 22. PMID: 25614489; PMCID: PMC4320664. Oddone M, Marino C, Sergi C, Occhi M, Negri F, Kotitza Z, De Bernardi B, Jasonni V, Tomà P. Wilms’ tumor arising in a multicystic kidney. Pediatr Radiol. 1994;24(4):236–8. PubMed PMID: 7800438. Osasan S, Zhang M, Shen F, Paul PJ, Persad S, Sergi C.  Osteogenic Sarcoma: A 21st century review. Anticancer Res. 2016;36(9):4391–8. Review. PubMed PMID: 27630274. Peng S, Li W, Hou N, Huang N. A Review of FoxO1Regulated Metabolic Diseases and Related Drug Discoveries. Cells. 2020;9(1):184. https://doi. org/10.3390/cells9010184. PMID: 31936903; PMCID: PMC7016779. Purgina B, Rao UN, Miettinen M, Pantanowitz L.  AIDS-related EBV-associated smooth muscle tumors: a review of 64 published cases. Pathol Res Int. 2011;2011:561548. https://doi. org/10.4061/2011/561548. PubMed PMID: 21437186; PubMed Central PMCID: PMC3062098. Renzi S, Anderson ND, Light N, Gupta A. Ewing-like sarcoma: An emerging family of round cell sarcomas. J Cell Physiol. 2019 Jun;234(6):7999–8007. https://doi. org/10.1002/jcp.27558. Epub 2018 Sep 26. Review. PubMed PMID: 30257034. Santer FR, Bacher N, Moser B, Morandell D, Ressler S, Firth SM, Spoden GA, Sergi C, Baxter RC, Jansen-­ Dürr P, Zwerschke W. Nuclear insulin-like growth factor binding protein-3 induces apoptosis and is targeted to ubiquitin/proteasome-dependent proteolysis. Cancer Res. 2006;66(6):3024–33. PubMed PMID: 16540651. Scheier M, Ramoni A, Alge A, Brezinka C, Reiter G, Sergi C, Hager J, Marth C. Congenital fibrosarcoma as cause for fetal anemia: prenatal diagnosis and in utero treatment. Fetal Diagn Ther. 2008;24(4):434–6. https://doi.org/10.1159/000173370. Epub 2008 Nov 19. PubMed PMID: 19018145. Sergi C, Ehemann V, Beedgen B, Linderkamp O, Otto HF. Huge fetal sacrococcygeal teratoma with a completely formed eye and intratumoral DNA ploidy heterogeneity. Pediatr Dev Pathol. 1999;2(1):50–7. Review. PubMed PMID: 9841706. Sergi C, Kos M.  Bilateral Wilms’ tumor in trisomy 18 syndrome: case report and critical review of the litera-

12  Soft Tissue ture. Ann Clin Lab Sci. 2018;48(3):369–72. PubMed PMID: 29970442. Sergi C, Kulkarni K, Stobart K, Lees G, Noga M. Clear cell variant of embryonal rhabdomyosarcoma: report of an unusual retroperitoneal tumor – case report and literature review. Eur J Pediatr Surg. 2012;22(4):324– 8. https://doi.org/10.1055/s-0032-1308714. Epub 2012 May 10. Review. PubMed PMID: 22576307. Sergi C, Zwerschke W.  Osteogenic sarcoma (osteosarcoma) in the elderly: tumor delineation and predisposing conditions. Exp Gerontol. 2008;43(12):1039–43. https://doi.org/10.1016/j.exger.2008.09.009. Epub 2008 Sep 25. Review. PubMed PMID: 18845233. Seto ES, Bellen HJ, Lloyd TE. When cell biology meets development: endocytic regulation of signaling pathways. Genes Dev. 2002;16(11):1314–36. https://doi. org/10.1101/gad.989602. PMID: 12050111. Shojaeian R, Hiradfar M, Sharifabad PS, et al. Extrarenal Wilms’ tumor: challenges in diagnosis, embryology, treatment and prognosis. In: van den Heuvel-Eibrink MM, editor. Wilms tumor [Internet]. Brisbane: Codon Publications; 2016. Chapter 6. Available from: https:// www.ncbi.nlm.nih.gov/books/NBK373353/. https:// doi.org/10.15586/codon.wt.2016.ch6. Soles BS, Wilson A, Lucas DR, Heider A. Melanotic Neuroectodermal Tumor of Infancy. Arch Pathol Lab Med. 2018;142(11):1358–1363. https://doi. org/10.5858/arpa.2018-0241-RA. PMID: 30407852. Verma V, Denniston KA, Lin CJ, Lin C. A Comparison of Pediatric vs. Adult Patients with the Ewing Sarcoma Family of Tumors. Front Oncol. 2017 May 8;7:82. https://doi.org/10.3389/fonc.2017.00082. PMID: 28534008; PMCID: PMC5421143. Witmer AN, van Blijswijk BC, Dai J, Hofman P, Partanen TA, Vrensen GF, Schlingemann RO. VEGFR-3 in adult angiogenesis. J Pathol. 2001;195(4):490–7. doi: 10.1002/path.969. PMID: 11745682. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982; 50; 970–981. Yang Y, Shen F, Huang W, Qin S, Huang JT, Sergi C, Yuan BF, Liu SM. Glucose Is Involved in the Dynamic Regulation of m6A in Patients With Type 2 Diabetes. J Clin Endocrinol Metab. 2019;104(3):665–73. doi: 10.1210/jc.2018-00619. PMID: 30137347. Zimmermann KW. Der feinere Bau der Blutkapillaren. Z Anat Entwicklungsgesch 1923; 68: 29–109. Zhang J, Wang H, Cheng X, Wang M, Zhu Y. A case of parachordoma on the chest wall and literature review. J Can Res Ther [serial online] 2013 [cited 2020];9:114– 7. Available from: http://www.cancerjournal.net/text. asp?2013/9/5/114/119124.

Arthro-Skeletal System

13

Contents 13.1

Development and Genetics 

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13.2 13.2.1 13.2.2

Osteochondrodysplasias Nosology and Nomenclature Groups of Genetic Skeletal Disorders

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13.3 13.3.1 13.3.2 13.3.3 13.3.4

 etabolic Skeletal Diseases M Rickets, and Osteomalacia Osteoporosis of the Youth Paget Disease of the Bone Juvenile Paget Disease

 1103  1103  1104  1106  1108

13.4 13.4.1

Osteitis and Osteomyelitis Osteomyelitis

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13.5 13.5.1

Osteonecrosis Bony Infarct and Osteochondritis Dissecans

 1113  1113

13.6 13.6.1 13.6.2 13.6.3 13.6.4 13.6.5 13.6.6 13.6.7

 umorlike Lesions and Bone/Osteoid-Forming Tumors T Myositis Ossificans Fibrous Dysplasia and Osteofibrous Dysplasia Non-ossifying Fibroma (NOF) Bone Cysts Osteoma, Osteoid Osteoma, and Giant Osteoid Osteoma Giant Cell Tumor Osteosarcoma

 1115  1115  1116  1118  1120  1124  1127  1128

13.7 13.7.1 13.7.2 13.7.3 13.7.4 13.7.5

Chondroid (Cartilage)-Forming Tumors Osteochondroma Enchondroma Chondroblastoma Chondromyxoid Fibroma Chondrosarcoma

 1136  1137  1139  1140  1143  1145

13.8

Bone Ewing Sarcoma

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13.9 13.9.1 13.9.2 13.9.3 13.9.4 13.9.5

Miscellaneous Bone Tumors Chordoma Adamantinoma Langerhans Cell Histiocytosis Vascular, Smooth Muscle, and Lipogenic Tumors Hematologic Tumors

 1149  1149  1150  1151  1153  1153

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_13

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1096 13.10

Metastatic Bone Tumors

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13.11 13.11.1 13.11.2 13.11.3 13.11.4 13.11.5

Juvenile Rheumatoid Arthritis and Juvenile Arthropathies  heumatoid Arthritis and Juvenile Rheumatoid Arthritis R Infectious Arthritis Gout, Early-Onset Juvenile Tophaceous Gout and Pseudogout Bursitis, Baker Cyst, and Ganglion Pigmented Villonodular Synovitis and Nodular Tenosynovitis

 1154  1154  1156  1157  1159  1159

Multiple Choice Questions and Answers

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References and Recommended Readings 

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13.1 Development and Genetics At the onset of development of the skeleton, the embryo possesses undifferentiated mesenchymal cells that eventually condense at sites that are predestined to become the future bony structure. These amazing mesenchymal condensations follow precise molecular biology algorithms most of them still mostly unknown to us and acquire the shape of the skeletal elements they foreshadow. The endochondral ossification takes place when a cartilage template is progressively replaced by bone tissue in an exact series of events, in which chondrocytes progress from germinal zone containing stem cells to proliferating chondrocytes, chondrocytes lying in an area of maturation, and then to hypertrophic chondrocytes or hypertrophic states, and the resulting hypertrophic cartilage is then mineralized and replaced by bone. The chondro-osteogenesis steps are as follows. 1. Segregation of progenitor mesenchymal cells in the cranial portion of the neural crest (neuroectoderm), mesoderm (splanchnocranium or viscerocranium and paraxial somites), and lateral plate mesoderm (limbs). 2. Condensation of the mesenchymal cells. 3. Osteochondral differentiation toward chondrocytes occurs by the action of some transcription factors (SOX5, SOX6, SOX9). SOX9 interacts for COL2A1 expression, which is responsible for the expression of α1 of type 2 collagen and other matrix proteins.

4. ECM synthesis occurs involving proteoglycans, aggrecan, decorin, biglycan, fibromodulin, perlecan, and collagens II, IX, and XI. 5. Runx 2 (Cbfa-1) is crucial for the development of hypertrophic chondrocytes and the differentiation of the osteoblast from the primordial osteochondral cell. 6. Membranous ossification (craniofacial bones and portions of the clavicula), which is characterized by the direct differentiation of the common progenitor mesenchymal cells to osteoblasts without an intervening chondroid phase, is induced by Runx 2 and its interaction with members of the TGF-β superfamily (e.g., BMPs, SMADs, WNT, and hedgehog) (Al-Bahrani et al. 2015). 7. Endochondral ossification (axial skeleton and limbs) is characterized by the indirect differentiation of the common progenitor mesenchymal cells to osteoblasts with an intervening chondroid phase. It is subdivided in the formation of mid-shaft-located primary centers of ­ossification, VEGF-induced vascular invasion, periosteal bone collar formation, and induction of secondary centers of ossification, which remain separated from the primary centers by the growth plate where the epiphyseal cartilage proliferates and hypertriophies. They undergo programmed cell death, mostly using Indian hedgehog. 8. PTH-related peptide and its COL2A1 promoter and FGFR3-controlled receptor are essential for bone remodeling, and activating mutations of this tyrosine kinase receptor at the growth plate are responsible for the development of several forms of skeletal dysplasias.

13.2 Osteochondrodysplasias

9. Osteoclasts are the BM-derived skeletal cell crucial for bone remodeling, and their malfunction is at the basis of the osteopetrosis (‘marble bone disease’ or Albers-Schönberg disease), which is is considered to be the prototype of osteosclerosing skeletal dysplasias. In this kind of skeletal dysplasia the bones become denser and harder than normal bones, in striking contrast to osteomalacia, in which the bones progressively soften, or osteoporosis, in which the bones become less dense and more brittle. In osteopetrosis there is indeed a malfunctioning osteoclast, which makes subsequently the bone unable to continue the cycle of deposition and resorption. A range of clinical features and different molecular lesions substantiate the heterogeneity of this skeletal disorder. In mammals, the long and short bones of mammals are formed mainly by endochondral ossification, but the periosteal bone collar forms via a type of intramembranous ossification without a cartilaginous phase. In birds, the ossification of the long bones takes place via intramembranous ossification of the periosteum. In these animals, the core cartilage undergoes the same steps of endochondral ossification before the mineralization of hypertrophic chondrocytes. However, the matrix of post-hypertrophic chondrocytes is resorbed instead of being mineralized. In joint development, there are three main stages, including interzone formation, cavitation, and final morphogenesis. The study of animals, especially chicks, has been used to understand that the detailed shape of the developing knee joint emerges just following the initiation of muscle contractions.

13.2 Osteochondrodysplasias 13.2.1  Nosology and Nomenclature The nomenclature of osteochondrodysplasias, including prefixes, suffixes, and categories of limb reduction defects, may be challenging but it is necessary for understanding of numerous pedi-

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atric and adult disorders of the skeletal system. The study of the etymology of most of these disorders is particularly useful for pathologists working on skeletal dysplasia interacting closely with pediatricians and pediatric radiologists. It is not only the plethora of genes involved in osteochondrodysplasias but the complex and intricate disturbances of the skeletal development that make the study of osteochondrodysplasias in perinatal and pediatric pathology arduous. One of the most significant challenges is the translation of plain English of the various prefixes and suffixes associated with the dysplasia of the skeletal development. In the 2010 revision of the nosology and classification of genetic skeletal disorders, 40 groups have been assigned including 456 medical conditions challenging our photographic, numerical, and word memory. This nosology should be working in progress because some groups are still waiting for molecular clarification. The criteria used to set up this classification comprise medical conditions including significant bony involvement, which corresponds to osteochondrodysplasias, metabolic bone disorders, dysostoses, skeletal defects sensu lato, and/ or limb reduction syndromes. Linkage or molecular analysis, genetic counseling data, publications, and OMIM listing supported nosologic autonomy. OMIM or Online Mendelian Inheritance in Man is an authoritative compendium of human genes and clinical genetic phenotypes that comprehensively reviews human and clinical genetics and is freely available and updated daily. Some osteologic nomenclature concepts and definitions are listed below: • Acro- (Greek ἄκρον, “end”) refers to the most distal segment or topmost (acromelia is a form of dwarfism in which shortening occurs in the most distal portion of the limbs). • Meso- (Greek μέσος, “middle”) refers to the middle segment (mesomelia is a form of dwarfism in which shortening occurs in the forearms and lower legs). • Rhizo- (Greek ῥίζα, “middle”) refers to the most proximal part or roots (rhizomelia is a form of dwarfism in which shortening occurs in the upper arms and thighs).

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• -melia relates to limbs (Greek μέλος,“ limb ”). • Spondylo- (σπόνδυλος, “spine”) relates to the spine (e.g., spondylolisthesis, which is a forward displacement of a vertebra over a lower vertebra and has been characterized to be either a congenital defect or injury). • Epiphysis  – Metaphysis  – Diaphysis characterize the several growth portions of the longitudinal bone (Greek φύσις, “growth”) • Epi- (ἐπί) refers to above or “on top of” (epiphysis is the rounded end of a long bone near to the joint). Meta- (μετά, “after”) refers to a middle portion between epiphysis and diaphysis and contains the growth plate, while Dia- (διαand διά) refers to “passing through” (diaphysis is the midsection or shaft of a long bone). • -morphic arises from Greek μορφή, which means form or shape. • Amelia refers to the lack of limbs. • Preaxial refers to the anterior side as seen in aplasia or hypoplasia of thumbs, 1st metacarpal, and radius (radial hypoplasia-­ aplasia) and/or the absence of hallux, 1st metatarsal, and tibia (tibia hypoplasia-­aplasia), but also preaxial polydactyly, when the sixth digit is located near the thumb or hallux. • Postaxial refers to the posterior side, close to the fifth finger or toe (e.g., postaxial polydactyly). • Transverse: loss of distal limb structure with preservation of the proximal structure.

13.2.2  G  roups of Genetic Skeletal Disorders The genetic skeletal disorders according to the most current classification (Warman et  al. 2011) include the following 40 groups (adapted classification) (Jung et al. 1998, Sergi et al. 1997, Sergi et al. 1998, Sergi et al. 2001, Sergi et al.2001, Schiffer et al. 2007, Broome et al. 2016, Sergi et al. 2019). 1. FGFR3 chondrodysplasia group 2. Type II collagen group and allied disorders 3. Type XI collagen group 4. Sulfation disorders group 5. Perlecan group

13  Arthro-Skeletal System

6. Aggrecan group 7. Filamin group and allied disorders 8. TRPV4 group 9. Short-rib dysplasia (with or without polydactyly) group 10. Multiple epiphyseal dysplasias and pseudoachondroplasia group 11. Metaphyseal dysplasias 12. Spondylometaphyseal dysplasias 13. Spondylo-epi-(meta)-physeal dysplasias 14. Spondylodysplastic dysplasias, severe type 15. Acromelic dysplasias 16. Acromesomelic dysplasias 17. Mesomelic and rhizo-mesomelic dysplasias 18. Bent bone dysplasias 19. Slender bone dysplasia group 20. Multiple joint dislocations-associated dysplasias 21. Chondrodysplasia punctata (CDP) group 22. Osteosclerotic dysplasias, neonatal 23. Normoosteomorphic Group with increased bone density 24. Dysplasias with increased bone density and meta- and/or diaphyseal involvement 25. Dysplasias with decreased bone density, including osteogenesis imperfecta 26. Abnormal mineralization group 27. Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group) 28. Osteolysis group 29. Disorganized development of skeletal components group 30. Overgrowth syndromes with skeletal involvement 31. Genetic inflammatory/rheumatoid-like osteoarthropathies 32. Cleidocranial dysplasia and isolated cranial ossification defects group 33. Craniosynostosis syndromes 34. Dysostoses with predominant craniofacial involvement 35. Dysostoses with predominant vertebral with or without the involvement of ribs 36. Patellar dysostoses 37. Brachydactyly 38. Limb (hypoplasia) – reduction defects group 39. Polydactyly-syndactyly-triphalangism group 40. Defects in joint formation and synostoses

13.2 Osteochondrodysplasias

Groups 1–8 are built on a common underlying gene or pathway and comprise most common disorders, including thanatophoric dysplasia types 1 and 2 as well as achondroplasia. There are groups involving critical molecular structures in cartilage and bone. In group 1, disorders are associated with mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, which has been mapped to 4p16.3. FGFR3 is part of the tyrosine kinase receptor family and, in normal conditions, is a negative regulator of bone growth. In one of the osteochondrodysplasias (OCDs) of this group, i.e., the thanatophoric dysplasia, activating mutations cause a gain in function, sending negative signals to chondrocytes. In case of ligand binding within the chondrocytes, there is the induction of the receptor homodimerization and heterodimerization, which, in turn, activates tyrosine kinase function potentiating several effects on cell growth and differentiation. Activating mutations in the FGFR3 lead to the formation of cysteine residues that create disulfide bonds between extracellular domains of mutant monomers. The increased stability by activation of the homodimer receptor complex and promotion of the translocation of the compound into the nucleus affects the interference with terminal chondrocyte differentiation. Thus, there is generalized disorganization of endochondral ossification at the bony growth plate.

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•

•

•

• 13.2.2.1 Thanatophoric Dysplasia • DEF: Most familiar form of OCD divided into two clinical subtypes: thanatophoric dysplasia type I (TDI) and thanatophoric dysplasia type II (TDII). TDI, which is the more common subtype, shows a normal-shaped skull and curved, telephone receiver-shaped long bones, • while TDII is associated with a cloverleaf-­ shaped skull and straight femurs. Clinical overlap is, however, observed between these subtypes. • • EPI: 1:20,000–50,000 births, ♂ = ♀. • PUS: Growth deficiency with limb length of less than 5% (by 20 weeks’ gestation), macrocephaly, cloverleaf-shaped skull or

“Kleeblattschãdel”, ventriculomegaly, wellossified skull and spine, platyspondyly (flattening of vertebrae from Greek πλατύς “flat” and σπόνδυλος “spine”), micromelia, bowing of femurs, narrow chest cavity with shortened ribs, and polyhydramnios. EPG: AD mutations in the FGFR3 gene with 100% penetrance and currently, all cases are due to de novo mutations in FGFR3, although the theoretical possibility of germline mosaicism also needs to be taken into account. Whereas TDI is caused by several different variations that affect either the extracellular or intracellular domains of FGFR3 with two missense mutations, R248C and Y373C, accounting for as much as 80% of TDI cases, TDII has a single point mutation, SYN K650E, determining an A → G nucleotide transition in the tyrosine kinase domain of FGFR3. LAB: Chromosome analysis and molecular testing for FGFR3 with targeted and sequence mutation analyses. X-Ray/CT/MRI: Rhizomelic shortening and irregular metaphysis of the long bones and “telephone receiver-shaped” bowed femurs, platyspondyly with wide intervertebral spacing, macrocephaly with a small foramen magnum, and CNS abnormalities such as hydrocephalus, brainstem hypoplasia, temporal lobe defects, and neuronal migration abnormalities. CLM: Nonspecific severe disorganization and retardation of the physeal growth plate with disorderly proliferative and hypertrophic chondrocytes, horizontal-oriented band of fibrosis at the periphery of the physisis, as well as few, small cartilaginous spicules in the metaphysis. DDX: Achondrogenesis, achondroplasia, asphyxiating thoracic dystrophy (Jeune syndrome), hypophosphatasia, and osteogenesis imperfecta. PGN: Lethal, usually at neonatal age (COD is severe respiratory insufficiency from reduced thoracic breathing capacity and hypoplastic lungs or respiratory insufficiency due to brainstem compression).

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Groups 1–8 include most common forms, such as achondroplasia and hypochondroplasia that rarely are seen in the morgue by the pediatric pathologist. Achondroplasia is due to a disproportionate dwarfism, and during early fetal development, patients with achondroplasia do not convert all cartilage to bone, and the underlying disorder is due to mutations of the FGFR3 gene, which instructs the cells to build a protein necessary for bone growth and maintenance. FGFR3 mutations make the protein overactive and the resulting skeleton unstable. Groups 1–8 also include the sulfation disorders (group 4), which is of particular interest in pediatric pathology. The sulfation disorder group includes achondrogenesis type 1B, atelosteogenesis type 2 (AO2), and d­ iastrophic dysplasia (DD). The growth inhibition of diastrophic dysplasia affects the entire skeleton. There is usually a different expression so that a particularly high degree of growth inhibition determines disproportional dwarfism. We need to distinguish the idiopathic short stature, which is the etiologically unexplained so-called primordial form of dysostotic dwarfism from other forms of short statures and the reader should complete his/her knowledge identifying remarkable textbooks of auxology. For instance, at cranio-­ mandibular-­ facial dysmorphic syndromes, called chondrodysplasias osteopetrosis and mucopolysaccharidosis syndromes, a short stature due to hypopituitarism hormonal, hypothyroidism, hyperthyroidism, hypogonadism due and of course also in the context syndromes can occur (see Prader-Willi syndrome). Moreover, the pediatrician interested in OCDs and bone metabolism of extraskeletal disorders can encounter hypoxic dwarfism (cardiac malformations, chronic lung disease hemolytic anemia), hepatic dwarfism (metabolic diseases), intestinalrelated dwarfism or dysplasia (e.g. celiac disease), and renal dwarfism (tubular Enzymopathies or chronic glomerulo-tubular global insufficiency). Diastrophic dysplasia occurs as a result of the growth reduction or shortening of limbs. Proximal bones are more involved (shorter) than the distal ones. Also, there is joint luxation that limits the joint mobility. The phalanges of the hands are thick. Usually, the thumb is abducted

13  Arthro-Skeletal System

(“hitchhiker thumbs”). In the development of the child there is kyphoscoliosis (abnormal curvature of the vertebral column in both coronal and sagittal planes from Greek κύφος, “bent” and σκολίωσις, “twisting”). The legs are not only shorter, but also sword-like. The optional cystic deformation in the ears occurs between 1  day after birth and 12  weeks. Often other changes, e.g., cleft palate and hernias, may compromise the life expectancy of these infants harboring this condition. The psychologic development and gender development show a normal course. About the histopathological picture, the diastrophic dysplasia in newborns and children has been reported. Some publications target the fetal age as well. The chondrocytes are pyknotic and eccentric nuclear degenerative changes. The cytoplasm of the chondrocytes is distinguished by a high content of chondroitin sulfate characterizing the extracellular matrix as rarefied (so-­ called “myxoid degeneration”). The resting cartilage is affected. Moreover, the zone of the columnar cartilage is reduced in length. The differential diagnosis includes diastrophic dysplasia, pseudo-diastrophic dysplasia (PDD), and the atelosteogenesis (AO) type II. In the event of a pseudo-­ diastrophic dysplasia the metaphysis shows irregular pillars of cartilage cells that are short and far apart standing. Moreover, irregular primary trabeculae of unremarkable resting cartilage can be recognized. During the AO type II (De la Chapelle dysplasia) one can find in the metaphysis of such osteochondrodysplasia, a similar histopathological image as in the diastrophic dysplasia but more pronounced. Also, there is a strong perilacunar staining and numerous cystic areas with radiating arrangement of collagen fibers can be identified. Hästbacka et al. (1996) studied three cultures of fibroblasts from Patients with AO II and found a lack of sulfate transporter enzyme localized the gene on chromosome 5q. Also, a defect in the sulfation of proteoglycans was observed. Mutations of DTDST (diastrophic dysplasia sulfate transporter) gene determine how “diastrophic” the patients may present. AO1, the most severe form of AO, has been assigned to the filamin group (group 7) based on molecular genetics. Interestingly, AO2,

13.2 Osteochondrodysplasias

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a

b

c

d

e

f

g

h

Fig. 13.1  Hypophosphatasia. The radiological images (a–c) of hypophosphatasia (HPP) show a generalized decrease in the size of mineralized bones, asymmetric vertebral arch mineralization in the cervical spine and the absence in the remainder of the spine, irregular metaphyseal cupping of the tubular bones of the limbs, bent long bones, short ribs, and a poorly mineralized skull with island-like ossification of frontal and occipital bones. The histological images (d–h) of the growth plate in HPP show that the growth plate in the HPP patient is widened

and disorganized and large tongues and islands of unmineralized hypertrophic chondrocytes can be seen in metaphyseal bone tissue adjacent to the growth plate embedded in poorly mineralized osteoid ((d), hematoxylin and eosin staining, ×50 original magnification; (e), hematoxylin and eosin staining, ×50 original magnification; (f), Masson Goldner staining, ×25 original magnification; (g), Toluidin Blue staining, ×100 original magnification; (h), Masson Goldner staining, ×200 original magnification)

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DD, AO1B, and other epiphyseal dysplasias share common mutations in the SLC26A2 gene on chromosome 5q32-­q33.1. The SLC26A2 gene encodes a protein in cartilage that transports inorganic sulfate, and its absence results in hyposulfation of proteoglycans. The filamin group (group 7) is defined by the presence of mutations occurring in the FLNA gene on Xq28, which encodes filamin A. OCDs of this group include frontometaphyseal dysplasia, osteodysplasia MelnickNeedles, oto-palato-­digital syndrome type 1 and type 2 (OPD1 and OPD2), terminal osseous dysplasia with pigmentary defects, atelosteogenesis type I and type III (AO1 and AO3), Larsen syndrome, spondylo-­carpal-­tarsal dysplasia, FrankTer Haar syndrome, and serpentine fibula-polycystic kidney syndrome. Group 8 includes metatropic dysplasia, spondylo-epimetaphyseal dysplasia, Maroteaux type, spondylometaphyseal dysplasia, Kozlowski type, brachyolmia, and familial digital arthropathy with brachydactyly. Groups 9–17 involve OCD of significant interest to the pediatric pathologist, because of the differential diagnosis raised at the time of the prenatal ultrasonography and genetic counseling. Groups 18–20 include bent joint dysplasias, slender bone dysplasias, and OCD associated with multiple joint dislocations. Among these three groups, it is probably essential to emphasize campomelic dysplasia, although bent bones at birth can be observed in a variety of medical conditions, including osteogenesis imperfecta, Antley-Bixler syndrome, cartilage-hair hypoplasia, Cummings syndrome, hypophosphatasia (Fig.  13.1), dyssegmental dysplasia, TD, ATD, and other OCDs. Slender bone dysplasias include 3-M syndrome (3 M1 and 3 M2), Kenny-Caffey dysplasia types 1 and 2, microcephalic osteodysplastic primordial dwarfism, IMAGE syndrome (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia, and genital anomalies), osteocraniostenosis, and Hallermann-­Streiff syndrome. OCD with multiple joint dislocations includes Desbuquois dysplasia and PDD (Sergi et al. 2001, Baumgartner-Sigl et al. 2007). Groups 21–25 include the chondrodysplasia punctata (CDP) group (CDPX1 or brachyteleph-

13  Arthro-Skeletal System

alangic type, CDPX2 or Conradi-Hunermann type, CHILD syndrome or congenital hemidysplasia, ichthyosis, limb defects, Greenberg dysplasia, rhizomelic CDP types 1–3, CDP tibial-metacarpal type, and Astley-Kendall type), neonatal osteosclerotic dysplasias (Blomstrand dysplasia, desmosterolosis, Caffey disease, and Raine dysplasia), normoosteomorphic dysplasias with increased bone density but without modification of bone shape (osteopetrosis, osteopoikilosis, melorheostosis, osteopathia striata with cranial sclerosis, dysosteosclerosis, and osteomesopyknosis), dysplasias with increased bone density and meta- and/or diaphyseal involvement (craniometaphyseal dysplasia, diaphyseal dysplasia Camurati-Engelmann, hematodiaphyseal dysplasia Ghosal, hypertrophic osteoarthropathy, oculodentooseeous dysplasia, osteoectasia with hyperphosphatasia, sclerosteosis, endosteal hyperostosis, van Buchem type, trichodentoosseous dysplasia, craniometaphyseal dysplasia, diaphyseal medullary stenosis with bone malignancy, craniometaphyseal dysplasia, craniometadiaphyseal dysplasia, Wormian bone type, endosteal sclerosis with cerebellar hypoplasia, and Pyle disease), and dysplasias with decreased bone density (osteogenesis imperfecta II–VII, Bruck syndrome types 1 and 2, osteoporosis-­ pseudoglioma syndrome, Calvarial doughnut lesions with bone fragility, idiopathic juvenile osteoporosis, Cole-Carpenter dysplasia, spondylo-­ ocular dysplasia, osteopenia with radiolucent lesions of the mandible, Ehlers-­ Danlos syndrome, progeroid form, geroderma osteodysplasticum, and cutis laxa). Hypertrophic osteoarthropathy (HOA) is a clinical triad constituted by periosteal new bone deposition involving the short and long bones of the limbs, arthritis with effusion in adjacent joints, and clubbing, which is a distinctive bulbous enlargement of the tips of the fingers and toes due to edematous fibrovascular hypertrophy of the soft tissue. In pediatrics and youth, clubbing is usually seen in non-treated cyanotic heart disease, cystic fibrosis, and chronic lung infection (e.g., untreated bronchiectasis) differently from the elderly with bronchogenic carcinoma playing an important role.

13.3 Metabolic Skeletal Diseases

13.3 Metabolic Skeletal Diseases Most of the skeletal, metabolic diseases are collected in the Box 13.1. In this chapter, we do not target specific metabolic, skeletal disorders (primary hyperparathyroidism, Gaucher disease, mucopolysaccharidosis group, and osteopetrosis or Albers-Schoenberg marble bone disease) that may be found elsewhere.

Box 13.1 Metabolic Skeletal Diseases

1 3.3.1 Rickets, and Osteomalacia 13.3.2 Osteoporosis of the Youth 13.3.3 Paget Disease of the Bone 13.3.4 Juvenile Paget Disease

Box 13.2 Vitamin D Endocrine System Key Elements

1. Dietary intake of vitamin D3 (prohormone) or cutaneous photo-conversion (ultraviolet) of 7-dehydrocholesterol to vitamin D3 (cholecalciferol). 2. Vitamin D3 metabolism into 25(OH)D3 (calcidiol) by the liver. 3. Vitamin D3 metabolism with conversion of 25(OH)D3 into two main dehydroxylated metabolites, namely, 1a,25(OH)2D3 (calcitriol) and 24R,25(OH)2D3. 4. Systemic transport of the 1a,25(OH)2D3 and 24R,25(OH)2D3 to the target organs. 5. Dehydroxylated metabolite binds to a nuclear receptor in the different organs. 6. The subsequent generation of various biological responses on: –– Bone ⇒ ↑ bone tissue formation by maintaining appropriate Ca/P balance –– Kidney ⇒ ↑ Ca2+ reabsorption by the tubules –– Intestine ⇒ ↑ Ca2+ and P absorption and transport –– Parathyroid gland ⇒ ↓ PTH secretion

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–– Pancreas ⇒ ↑ insulin secretion –– Immune system ⇒ promotion of immunogenic and antitumor activities Notes: 25(OH)D3 represents the dominant form of vitamin D circulating in the blood compartment, and vitamin D-binding protein (DBP) is a plasma protein that carries vitamin D3 and all its metabolites to their different target organs. 1α,25(OH)2D3 transcriptionally controls the expression of a set of genes mediated through the nuclear vitamin D receptor (VDR) acting as a ligand-inducible factor. The biological actions of 24R,25(OH)2D3 are incompletely investigated, although it seems essential that the combined presence of both dehydroxylated metabolites is required to have the complete spectrum of biological responses attributable to vitamin D.

Box 13.3 Etiology of Vitamin D Deficiency

1. ↓ absorption (e.g., malabsorption in IBD, celiac disease, and cystic fibrosis) 2. Inadequate exposure (sunscreen with SPF rating ≥8) or intake of sun exposure 3. Metabolomics dysregulation 4. Resistance to the effects of vitamin D Notes: IBD, inflammatory bowel disease; SPF, sun protection factor

13.3.1  Rickets, and Osteomalacia Vitamin D is vital for our organism, and the vitamin D endocrine system has some essential elements, which are summarized in Box 13.2.

13.3.1.1 Vitamin D Deficiency • DEF: Bone mineralization defect (rickets/ osteomalacia and, possibly, osteoporosis) due to deficiency of vitamin D by usually either inadequate dietary intake or insufficient exposure to sunlight.

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• EPG: The causes of vitamin D deficiency are grouped in Box 13.3. Abnormal metabolism may result from deficiencies in the production of 25(OH)D3 or 1,25(OH)2D3, and individuals with chronic renal disorders usually develop rickets or osteomalacia, because of the decrease of 1,25(OH)2D3 production and increase of phosphate levels. In the case of hepatic dysfunction, there is also an interference with the formation of active vitamin D metabolites. Two types of vitamin D-dependent hereditary rickets (VDDR) are known to be caused by mutations in the 1α(OH)ase and VDR genes, including the 1α(OH)ase gene, which is responsible for VDDR type I, and 1α,25(OH)D receptor gene for type II. Both diseases display an autosomal-recessive trait, but clinical features and response to therapy are distinct. In the healing process of a fracture, first a hematoma forms, and then there is an organization by the entry of capillaries and blood vessels. This step is tightly followed by the absorption of devitalized bone, which begins to be identified about 3 days after the bony fracture. Subsequently, the first callus is formed by the bone growth of intramembranous “pseudosarcomatous” skeletal tissue, which grows across the bony break forming the procallus or primary callus. The second callus replaces, finally, the first callus by lamellar skeletal tissue. In the differential diagnosis of the four entities described in Box 13.4, it is paramount to rule out parosteal osteosarcoma, which harbors atypical bony structure and nonreactive cellular, spindle-­ shaped stroma as well as osteoblast rimming. An exuberant callus may occur in the setting of infection, inadequate blood supply, delay in the re-adsorbing process (e.g., malnutrition), and insufficient immobilization.

Box 13.4 Bony Fractures: Callus – DDX

• Avascular necrosis • Myositis ossificans • Osteomyelitis-linked sub-periosteosis of reactive nature • Parosteal osteosarcoma

13  Arthro-Skeletal System

Sequestered bone is dead bone (“sequestrum”) and may occur in pediatrics in the setting of non-neoplastic and neoplastic disease. Conversely, involucrum is new bone formed at a subperiosteal location that encloses an inflammatory focus (reactive periosteal bone). Another aspect to be considered is foreign material (e.g., screws) that may become isolated from bone by fibrous tissue which is continuous with periosteum, but no foreign body giant cell reaction occurs. Skeletal and radiographic changes associated with rickets are depicted in Fig. 13.2. Diagnosis of rickets is based on levels of calcidiol and may be suspected based on any of the following (1) history of inadequate sunlight exposure or dietary intake, (2) symptoms and signs of rickets, osteomalacia, or neonatal tetany, and (3) characteristic bony radiological findings. There is a loss of the sharpness of the diaphyseal ends. They become cup-shaped showing a spotty or fringy rarefaction. Subsequently, the ends of the radius and ulna growing noncalcified and appear radiolucent. The radiology image is striking showing an increased distance between the ends of the radius and ulna and the metacarpal bones (Sergi and Linderkamp 2001, Kato et al. 2002, Nield et al. 2006, Malloy et al. 2014, Zhang et al. 2016).

13.3.2  Osteoporosis of the Youth • DEF: Decrease in the mass of ordinarily mineralized bone differently from osteomalacia, which is an accumulation of non-mineralized bone matrix due to faulty mineralization (Bishop et al. 2014; Saraff et al. 2015; Cascio et al. 2020). • EPI: Usually seen in the elderly as a result of increased absorption, some mild degree of this condition can start early in life. • EPG: Osteoporosis is well known to occur in the postmenopausal period if no estrogen replacement takes place. However, adults experience osteoporosis following endocrine dysfunctions, neoplasms (epithelial and mesenchymal type), and immobilization. In children, osteoporosis is classified as primary when it occurs in an otherwise healthy child

13.3 Metabolic Skeletal Diseases

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a

b

c

d

Fig. 13.2  Rickets. In (a, c, d), there are some of the characteristic features of rickets, including enlargements of the costochondral junction in the chest and of the epiphyseal-­ metaphyseal junctions in long bones, with cupping and fraying of the distal ends accompanied by double contour signs at the vertebral column. The histology (b) shows widening and thickening of the physeal

growth plate with poor removal of cartilage, persistent hypertrophic chondrocytes in the zone of provisional ossification, disorder of the vascular penetration of cartilage with impairment of the correct chondrocytic proliferation, and deposition of newly formed and poorly defined broad osteoid tissue (glycol methacrylate bone sections without previous decalcification, ×0.5 original magnification)

due to an underlying genetic condition (e.g., osteogenesis imperfecta, cleidocranial dysplasia, Marfan syndrome, Ehlers-Danlos syndrome, and Hajdu-Cheney syndrome). Secondary osteoporosis occurs because of chronic illness or its treatment (e.g., high-dose glucocorticoids, antiepileptic drug therapy, immobility, leukemia, inflammatory conditions  – rheumatoid arthritis

and Crohn disease, hypogonadotrophic hypogonadism, and poor nutrition – anorexia nervosa). Risk factors for fractures include age, sex, previous fractures, genetic predisposition, poor diet, total body mass, and forceful or lack of physical activity. Mutations in PLS3 gene, which encodes PLASTIN 3, a bone regulatory protein, have been identified in early-onset X-linked osteopo-

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rosis with axial and appendicular fractures developing during childhood. Other forms of early-onset osteoporosis involve the WNT signaling pathway, which is essential for normal bone homeostasis (osteoblast cellular proliferation and differentiation). Defects in this complex signaling pathway chiefly affect bone formation and may involve WNT, low-density lipoprotein receptor-related protein 5 (LRP5), a coreceptor of WNT located on the osteoblast membrane, LGR4, and WNT16. Biallelic mutations in LRP5 cause osteoporosis-pseudoglioma syndrome (OPPG), and heterozygous LRP5 mutations cause early-onset osteoporosis. • CLI: History of recurrent low impact fractures or moderate to periods of severe backache. Asymptomatic osteoporosis is being detected through surveillance for vertebral fractures in at-risk children, such as children on high-dose glucocorticoid therapy, or through incidental osteopenia found on X-ray imaging. A low bone mass and deterioration of bony structure microarchitecture result in increased bone fragility, which is the definition of osteoporosis. The diagnosis of osteoporosis in pediatrics can be confidently made in the presence of:

13  Arthro-Skeletal System

Quantitative computed tomography (QCT) and peripheral QCT (pQCT) possess the benefit of measuring cortical geometry and volumetric densities of both cortical and trabecular bone. These measurements provide information not attainable through DXA, but there is the disadvantage of higher radiation exposure. Other techniques include the digital X-ray radiogram-metrics, which estimates BMD by hand radiographs in children, the quantitative ultrasound, magnetic resonance imaging, and the trans-iliac bone biopsy with tetracycline labeling, which is invasive and requires general anesthesia in children. There are several tests to evaluate the functional outcomes, muscle strength, and mobility in children under treatment. The most common functional tests include the 6-minute walk test, Bruininks Oseretsky Test of Motor Proficiency, gross motor function measurement, Childhood Health Assessment Questionnaire score, “faces” pain scale, “chair-­rise” test, leg mechanography, and grip force testing by dynamometry. These tests can be further evaluated using textbooks of pediatric orthopedics. • TRT: Biphosphonates, proper nutrition with a 75% implementation of fresh food in the diet, improving muscle strength with regular avoidance of passive hobbies (e.g., video-games, internet, movies, etc.), mobility with avoidance of cars or motorbikes, and rehabilitation are key, but it is paramount to target the primary disorder if it is feasible.

1. A combination of size-corrected low bone mineral density (BMD) of >2SD below the mean and a substantial history of low-trauma fractures, subjectively defined as the presence of ≥2 long bone fractures by the age of 10 years or ≥3 long bone fractures at any age, up to 19 years. 13.3.3  Paget Disease of the Bone 2. ≥1 vertebral fracture in the absence of high-­ energy trauma or local disease, independent • DEF: It is a generalized bone disease with the of BMD. acme in the adult (middle age) characterized by markedly increased bone turnover (1 mm/ • LAB: Crucial determinations are serum alkamonth). line phosphatase, calcium, phosphate, vitamin • SYN: Osteitis deformans. D and urinary bone mineral excretion, and • EPI: 90% of patients are older than 55 years, dual-energy X-ray absorptiometry (DXA), but some younger patients are present; which remains the technique of choice to mea♂ = ♀. More common countries are England, sure bony mass. DXA is highly reproducible, Northern European countries, and Australia. commonly available, and inexpensive and • EPG: It is a gene-related disorder with enviexposes the individuals to low radiation. ronmental (epigenetic) components. The

13.3 Metabolic Skeletal Diseases

genes involved in Paget Disease of the Bone (PDB) are TNFRSF11A, TNFRSF11B, SQSTM1, and valosin-­ containing protein (VCP). TNFRSF11A encodes RANK and Deleted in Colorectal Cancer (DCC), which nonetheless is frequently reduced in expression in osteosarcoma, a neoplasm, which is often seen in patients with PDB. There is nuclear factor kappa B (NF-κB) activation by RANKL signaling (receptor activator for NF-κB ligand, RANKL). Osteoprotegerin, also known as osteoclastogenesis inhibitory factor, or TNF receptor superfamily member 11B, is a protein that is determined by the TNFRSF11B gene in humans. In PDB, osteoclasts have more nuclei per single osteoclast, are markedly increased in both number and size, and have an increased rate of cellular proliferation and a significant bone-resorbing capacity per single osteoclast. Nuclear inclusions have been observed in these osteoclasts. These inclusions have been considered paramyxovirus-­like, which has raised a number of epidemiological and microbiological theories. These specific inclusions seem to be microcylindrical structures, but the true identity has not been established yet. The osteoclast precursors, circulating in the blood, show increased sensitivity to factors that stimulate bone resorption. Osteoblasts may also be the culprit and not bystanders only and several hypotheses have been formulated in the scientific literature. In fact, cultures of osteoblasts from bone lesions are abnormal because they show an increased expression of genes encoding interleukin 1, interleukin 6, and dickkopf 1. The Wnt/Fzd/LRP (frizzled, Fzd; low-density lipoprotein receptor-related protein) complex and the associated β-catenin signaling by treating cells either with Dickkopf-1 (Dkk1), a specific antagonist of the Wnt/β-catenin pathway or LRP5/LRP6 silencing, indeed promote neurite outgrowth by shifting endogenous Wnt activity from the β-catenin pathway to Fzd3mediated non-canonical pathway that is responsible for neurite formation and this pathway may have been one of the major

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•

•

•

•

routes supporting the progression or degeneration of PDB to osteosarcoma. CLI: Bowing and easily fracture of painful extremities with bony pain, fractures, increased head size, headache with audible bruit over the head (“syndrome of the pagetic vascular steal”), blindness, deafness, leg bowing, kyphosis, and high-output heart failure. High-output congestive heart failure has also other conditions that need to be distinguished clinically. They include anemia, obesity, exacerbation of hyperthyroidism or thyrotoxicosis, liver disease, lung disease, Beriberi heart disease, arterio-venous fistula, sepsis/septic shock, and pregnancy, which may be substantially kept in mind considering two main mechanisms, including the increase in the body’s demand for blood from increased metabolism and the bypass of the arteriolar and capillary bed causing an increased blood flow into venous circulation in consequence of a lack of vascular resistance. LAB: Increased rate of excretion of type I collagen breakdown products hydroxyproline, very high plasma alkaline phosphatase activity, and elevated serum osteocalcin levels. Serum calcium and phosphate are usually normal. IMG: The radiographs show coarse widening of the diaphyses with cortical thickening and “chalk-stick fracture.” Fractures are usually transverse. A circumscribed osteoporosis characterizes the initial phase in the skull and a resorption area with advancing edge in long bones, while blastic bony production along the lines of stress, widening of bones, cortical thickening, and potential fractures are added to the signs of the initial phase in the mid phase. The late phase is characterized by bones showing widening and thickened bone, “cotton wool exudates” of the skull and multiple fractures, postural bowing, kyphosis, and u­ ltimately neoplastic progression to osteosarcoma, chondrosarcoma, or fibrosarcoma among others. GRO: Many patients have a monostotic and asymptomatic disease, usually affecting the axial skeleton, mainly lumbosacral spine and

13  Arthro-Skeletal System

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•

• • •

pelvis, but other patients have a polyostotic disease. CLM: Pagetic bone lesions show evidence of ↑ osteoclastic bone resorption, enhanced but disorganized bone formation with ↑ # of osteoblasts and osteocytes (per mm3) and a ↓ grade of organization of their canalicular network, maintenance of the osteoblastic rimming, fibrosis/fibroplasia of the bone marrow, and ↑ vascularity of bone (numerous dilated capillaries). Three characterized phases are at the basis of the mosaic lamellar bone. The three stages are the osteolytic phase, the mixed (osteoclastic  – osteoblastic) phase, and the osteosclerotic phase. Initially osteolytic, the bone is followed by abnormal hyperplasia. There are thick irregular bony trabeculae, disjointed and discontinuous lamellae, and a mosaic of scalloped cement lines with astonishing advancements of the bone of about 1-mm/month. DDX: Hyperparathyroidism. TRT: Biphosphonates. PGN: Mostly, there is an increased risk of osteosarcoma (up to 20% of patients with polyostotic PDB) at the involved sites, including the femur, humerus, tibia, and skull. In the monostotic type, the risk is limited to 10%. Other tumors are also increasingly observed in patients suffering from PDB and include malignant fibro-histiocytoma (MFH), fibrosarcoma, chondrosarcoma, and malignant giant cell tumor.

•

•

• •

•

13.3.4  Juvenile Paget Disease • DEF: AR-inherited generalized bone disease (MIM 239000) with striking similarities to Paget disease of the adult (middle age) (PDB) characterized by markedly increased bone turnover. • SYN: Idiopathic hyperphosphatasia and osteoectasia with hyperphosphatasia. • EPI: About 50 cases have been reported worldwide to date. • EPG: Deletion or mutations of the TNFRSF11B gene, a member of the tumor

•

necrosis factor (TNF) receptor superfamily encoding osteoprotegerin (OPG), are considered the culprit in the etiology of Juvenile Paget Disease (JPD). CLI: Bowing and easily fracture of painful extremities. Patients suffer from short stature, kyphoscoliosis, chest wall deformity, and skull enlargement often leading to cranial nerve deficits similar to the phenotype observed in patients suffering from PBD. LAB: Increased rate of excretion of type I collagen breakdown products, very high plasma alkaline phosphatase activity, and elevated serum osteocalcin levels are key factors to consider biochemically. IMG: The radiographs show coarse widening of the diaphysis with cortical thickening. GRO: The skull shows increased thickness with wide diploic spaces and focal areas of sclerosis and uneven bone mineralization. Vertebral bodies may show osteopenia or sclerosis and sometimes manifest compression fractures. In the pelvis, in addition to thick trabeculae and areas of sclerosis, there can be some areas of rarefaction, and rib changes may incorporate sclerosis, narrowing, or widening. CLM: Increase of both osteoblasts and osteoclasts in bone tissue. Woven bone is mainly observed in the calvarium, vertebrae, and ribs. The cortex (cortices) of tubular bones are alternatively thinned or thickened along their entire lengths from accelerated endosteal bone remodeling. Conversely, increased bone formation at the periosteum thickens the diaphysis and widens individual bones. It is important to remember that woven bone is hypercellular when compared to lamellar bone on histological ground. This aspect is substantially indifferent if the woven bone is laid down by benign or malignant cells. Osteoid is pink and amorphous and contains collagen by light microscopy. Chondroid is identical to osteoid and not bluish because the content of proteoglycans is quite low differently from the cartilage. DDX: Two conditions considered in differential diagnosis should be polyostotic fibrous

13.4 Osteitis and Osteomyelitis

dysplasia and hereditary hyperphosphatasia. A marked elevation of alkaline phosphatase level is unusual in polyostotic fibrous dysplasia, and radiographs of patients with hereditary hyperphosphatasia do not reveal the typical mosaic pattern observed in patients suffering from JPD. • TRT: Bisphosphonates are often used to reduce the accelerated bone turnover. This drug can impressively meliorate the skeletal phenotype, specifically if started early enough in childhood and continued at least until completion of the bone growth. Studies using recombinant OPG or denosumab also provided favorable results. • PGN: The phenotype tends to be more severe with aging, although mild deformities are recognized after 2 years. Although JPD has some similarities to classical PDB, it is undoubtedly a more severe condition as proven by the early age at onset and the development of marked bone deformity during childhood, adolescence, and youth. Although long-term data may not be extensive, the early-onset of bone disease harbors an increase of the neoplastic potential with malignant transformation into sarcomas.

13.4 Osteitis and Osteomyelitis One of the most critical challenges for a pathologist is to distinguish between inflammation, inflammatory atypia, and neoplastic atypia. The incisional or excisional biopsy of a bony lesion may represent a challenge at some point. As a standard and good practice for patients’ quality assurance, all bone biopsies should be revised by two consultants in pathology, one of which with radiological and histological experience in skeletal and soft tissue pathology. The problems that a pathologist may encounters include the orientation of the biopsy tract that should be longitudinal and carried out in an area that could be easily identifiable radiologically. Thus, computer scanning-guided biopsies are the preferred biopsies for both clinicians and pathologists. In case of an incisional biopsy, following a careful hemostasis, the incision is carried out and that should not go

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Box 13.5 Osteitis and Osteomyelitis

13.4.1 Osteomyelitis, pyogenic 13.4.2 Osteomyelitis, tubercular 13.4.3 Osteomyelitis, mycotic 13.4.4 Chronic multifocal recurrent osteomyelitis 13.4.5 Osteitis, sclerosing (Garre Osteo myelitis)

more than one muscle compartment. Both soft tissue and bony tissue need to be sent to the pathology department. Very few fragments should be sent to the microbiology department for bacteriological and mycologic analysis (Box 13.5).

13.4.1  Osteomyelitis • DEF: Bone inflammation with or without evidence of infection with acute hematogenous, subacute focal and chronic types (Box 13.6). • EPI: Most common in infants and children but declining incidence rates have been observed recently in well-developed countries due to better diagnosis and therapy. • EPG: Staphylococcus aureus is the most common microbiological agent in all age groups. • CLI: Pain, ↓ ROM (range of mobility), “tumor” (swelling), “rubor” (erythema), fever, malaise, and irritability. • IMG: Delayed changes on imaging (2–4 weeks), lytic lesion with mottled appearance commonly seen in metaphysis, and periosteal reaction. • GRO: Variable gross morphology according to the age of the patient and age of the lesion (acute vs. chronic). Generally, an acute osteomyelitis exhibits pus tracking through bone, periosteal elevation and shell of reactive periosteal bone around a necrotic center, while a chronic disease demonstrates prominent periosteal bone formation without acute inflammatory features. • CLM: Mixed cell population with varying number of acute and chronic inflammatory cells. It is useful to distinguish between

13  Arthro-Skeletal System

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sequestrum or dead cortical bone and involucrum or new cortical bone (Figs.  13.3, 13.4 and 13.5). The algorithm approach for diagnostic and prognostic purposes should ­ contain specific items (Box 13.7). • TRT: Following biopsy and culture in case of an acute process IV antibiotics ± surgical debridement are essential, while in the chronic process IV antibiotics are always accompanied by surgical debridement. • PGN: It depends from the state and chronicity of the process because it may be highly for life. The Cierny-Mader staging system is often

Box 13.6 Chronologic Classification of Osteomyelitis

• Acute (onset 4  weeks) (septic and aseptic) –– Chronic sclerosing vs. chronic recurrent multifocal vs. chronic form with uncommon organisms (M. tuberculosis, T. pallidum)

a

b

Fig. 13.3  Osteomyelitis, acute and chronic. There is a heavy inflammatory infiltrate of acute and chronic type with neutrophils, lymphocytes, and plasma cells. (a–c; H&E staining). Three different fields show the variability

c

of the intensity of inflammatory reaction (a–c, hematoxylin and eosin staining, ×200 original magnification for all three microphotographs)

13.4 Osteitis and Osteomyelitis

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a

b

c

d

Fig. 13.4  Osteomyelitis, granulomatous. This osteomyelitis has a granulomatous character with multiple granulomas and multinucleated giant cells. (a–d; H&E staining. Different magnification of this biopsy show the intense

inflammatory reaction with macrophages, epithelioid cells, and multinucleated giant cells (a–d, hematoxylin and eosin staining, ×12.5, ×50, ×100, ×400 as original magnification, respectively)

used for staging. It includes medullary osteomyelitis (stage 1), superficial osteomyelitis (stage 2), localized osteomyelitis (stage 3), and diffuse osteomyelitis (stage 4). The factors affecting the immune surveillance, metabolism, and vascularity are shown in Box 13.8.

15% of the patients, intravenous therapy is required for 6  days or more Jagodzinski et  al. (2009). In the Jagodzinski et al. study, the median duration of inpatient stay was only 5  days. These data show that a significantly shorter period of intravenous therapy is needed than shown in most data published earlier. An initial investigation with blood cultures and hematologic markers (WCC, CRP, and ESR) is, however, necessary to evaluate the progress of the therapy remembering to protect the bone always. Appropriate imaging should also follow the proposed follow-up. Ultrasound should be used and MRI confirmation is advisable in most of the patients. There are studies contemplating series of empirical antibiotics (flucloxacillin  and co-­ amoxiclav) that should be commenced after prompt drainage of joint collections. Sequential alternate-day estimations of hematologic markers should also be taken into consideration. In case that after three full days of I.V. antibiotics, the child is clini-

High temperature on admission also seems to be specific in identifying those patients who may require prolonged treatment. A significantly raised CRP greater than 100  mg/L suggests that more prolonged therapy may be necessary. Also, the CRP responds more rapidly to effective treatment, whereas ESR can remain elevated for several weeks despite a good clinical response. If the clinical picture is one of improvements and the CRP is falling, it is wise to propose that intravenous antibiotics are converted to oral therapy. It has been assessed that approximately 60% of patients can be successfully migrated to oral therapy by day 3 and about 85% can proceed by day 5. In only about

13  Arthro-Skeletal System

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a

b

c

d

e

f

Fig. 13.5  Osteomyelitis, xanthogranulomatous. In this osteomyelitis, there is clear prevalence of foamy osteocytes justifying the term of xanthogranulomatous osteomyelitis (a–d, hematoxylin and eosin staining, ×100, ×50, ×400, and ×400 as original magnification, respectively). The osteomyelitis is particularly apparent at high-power magnification (c, d). The immunohistochemical staining

of the osteomyelitis with S100 (e) and MIB1 (f) shows some positive cells (e, ×400, original magnification) and low proliferation activity (f) (×100, original magnification). S100, CD1a, and Langerin immunohistochemistry were useful in ruling out Langerhans cell histiocytosis in this child

cally improving, the temperature is settling, and the CRP value is falling, the pediatric patient can be converted to oral antibiotics safely. Metaanalyses investigated numerous studies. It is probably key to use a three-phase bone scintigraphy followed by scintigraphy with mixed WBCs or granulocytes labeled with 111In and, more recently, with 99mTc-HMPAO (hexamethyl-propyleneamine oxime). HMPAO is

often referred to by its pharmaceutical name of exametazime. 18F-FDG (fludeoxyglucose) PET remains the most accurate method (91.9%) for the study of bone infections. The sensitivity is 94%, and the positive predictive value is 94.2%. FDG PET appears to be a valuable tool for the assessment of inflammation during follow-up of ­secondary osteomyelitis and the study of infections treated with antibiotics.

13.5 Osteonecrosis

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Box 13.7 Algorithmic (step-wise) Approach to Osteomyelitis

Box 13.8 Factors Affecting Immune Surveillance, Metabolism, and Vascularity

1. Identify the organism (blood cultures, open or needle biopsy). 2. Drainage of the bone abscess. 3. Select the appropriate antibiotic therapy. 4. Deliver the appropriate antibiotic therapy making sure that the delivery is complete. 5. Stop the tissue destruction – protecting the bone (e.g., nanotechnology). 6. Follow up (clinically: local Celsius signs, To, pain, etc.; laboratory  – ESR, CRP, WCC; imaging, X-ray, MRI, bone scan, PET-CT).

• Systemic Age extremes, chronic hypoxia, diabetes mellitus, hepatic failure, immune deficiency/disease, immunosuppression, malignancy, malnutrition, neuropathy, renal failure • Local Blood vessel compromise, chronic lymphedema, neuropathy, radiation-­ induced fibrosis, scar/keloid of extensive degree, small vessel disease, vasculitis (arteritis), venous stasis

Notes: To temperature, ESR erythrocyte sedimentation rate, CRP C-reactive protein, WCC white cells count (neutrophils), MRI magnetic resonance imaging, PET-CT positron emission tomography and computed tomography scans

Massam (1973); the Association Research Circulation Osseous (ARCO), which was originally published in 1991–1993/1994 and carefully revised in 2019 (Yoon et al. 2020); and the 1987/2001 Japanese Investigation Committee. In the University of Pennsylvania Classification of Osteonecrosis the important features are the inclusion of the measurement of lesion size and the accurate extent of joint involvement using Magnetic Resonance Imaging (MRI). In 1987 and 2001, the Japanese Investigation Committee for Avascular Necrosis emphasized the location of lesion as an crucial factor to predict impending collapse. The Japanese Investigation Committee system indicates that lesions progress from medial to lateral as these lesions become progressively larger. In the 2019 ARCO revised classification of osteonecrosis four stages are identified. In stage I, X-ray is normal, but MRI is abnormal with a band lesion of low signal intensity, which is located around the necrotic area. Bone scan exhibits a cold spot. In stage II, X-ray is abnormal and the MRI discloses osteosclerosis, osteoporosis (focal), or cystic changes localized in the femoral head. In stage III, there is subchondral fracture on X-ray or Computer Tomography (CT) scan with fracture in the necrotic portion, and/or flattening of the femoral head. In this stage III, there is a

13.5 Osteonecrosis 13.5.1  B  ony Infarct and Osteochondritis Dissecans Necrosis may be the consequence of an infarct or osteochondritis dissecans.

13.5.1.1 Bony Infarct • DEF: Triangular/wedge-shaped segment with yellow discoloration and sharply demarcation. In a comprehensive review, the osteonecrosis was reviewed. One hundred and nine studies published since 1985 regarding the results of treatment of osteonecrosis were considered, and 12 major classification systems were cited. The classification system most frequently referred to was that of Arlet and Ficat (1964), Ficat and Arlet (1980), followed by those of the University of Pennsylvania (Steinberg and Steinberg, 2014); Marcus, Enneking, and

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subclassification with IIIA (early) when the femoral head depression results ≤2 mm, while IIIB (late) when the femoral head depression is >2 mm. In stage IV, there is X-ray osteoarthritis with joint space narrowing, changes of the acetabulum bones as large cup-shaped cavity on the anterolateral aspect of the pelvis that articulates with the caput femoris to form the hip joint, and definitive bony destruction identified on plain X-rays. • SYN: Avascular (bone) necrosis (AVN), aseptic necrosis, osteonecrosis. • EPI: 1–30/105 children/adolescents, ♂:♀ = 2:1. • EPG: Post-traumatic, alcohol-related (see the Manggold et al. (2002) AVN animal model for aseptic bone necrosis), Gaucher disease (bony infarcts accompanied with Erlenmeyer flask deformity of the femurs, osteonecrosis of the femoral head, and pathologic fractures), decompression sickness or dysbarism (Greek βάρος “weight” and βαρύς “heavy”) or “caisson” disease, prolonged (mis-)use of steroidal agents, sickle cell anemia, and chronic pancreatitis. The “TISH” acronym as mnemonics can be used. In all cases, there is an impairment of the blood supply to a segment of bony tissue and bone marrow. • T: Trauma, alcoholism, dysbarism, radiation, gout, Gaucher, pancreatitis. • I: Infection. • S: Soft tissue damage, including connective tissue disorders, corticosteroids, and tumors. • H: Hemato-vascular, hemoglobinopathies, and coagulopathies. In any case, there is a disruption of blood supply by intrinsic or extrinsic factors. • CLI: Usually asymptomatic. • IMG: In the first 1–2  weeks, there are no radiological abnormalities. Subsequently, a characteristic radiographic “crescent sign” is seen. • GRO: Lemon-yellow discolored (necrotic) triangular segment with the avital subchondral

13  Arthro-Skeletal System

bony plate as the basis of the triangle and epiphysis as the apex. • CLM: Disorderly mixture of empty or enlarged osteocyte lacunae, karyopyknosis, increased basophilic staining (basophilia) of bony matrix with new bone (woven bone), fibrous and fibro-cartilaginous tissue interposed between the osteonecrotic trabeculae and the surrounding osteosclerotic bone with granulation tissue (inflammatory cells and vascularized reactive stroma) at the periphery of the lesion. • TRT: Observation only. Surgical treatment is not required because it is usually asymptomatic. • PGN: The bony infarct eventually gets osteochondral collapse and secondary arthritis but harbors an increased risk of developing a malignancy. Kienbock disease is an example of AVN and precisely of the lunate bone (semilunar bone), a carpal bone of the hand (Fig. 13.6). Symptoms include progressive wrist pain and tenderness in the dominant hand of young men (20–45) (bilateral disease, 10%). Imaging (CT, MRI) is diagnostic (sclerosis → cystic changes → fragmentation →  collapse). DDX includes dorsal wrist ganglion, synovitis or arthritis, or extensor tendinitis. TRT includes surgery aimed to relieve pressure on the lunate by surgically shortening the radius or lengthening the ulna, implanting a blood vessel or bone graft on a vascular pedicle, free-vascularized bone grafts from the knee, and total wrist arthrodesis (surgical joint fixation, aka artificial ankylosis or syndesis, Greek άρθρον “joint” and δέσις “binding” from δέειν “to bind”). PGN: Sequelae are lunate bone collapse with the fixed rotation of the scaphoid and subsequent degeneration of the carpal joints.

13.5.1.2 Osteochondritis Dissecans Post-traumatic (most often) necrosis of the articular cartilage and subchondral bone with separation from the rest of the bone usually located at the medial femoral condyle.

13.6 Tumorlike Lesions and Bone/Osteoid-Forming Tumors

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Fig. 13.6  Kienboeck Disease. There is extensive osteonecrosis with broken trabecules (a–c) and empty lacunae lacking osteocytes (d). All microphotographs are hema-

13.6 T  umorlike Lesions and Bone/ Osteoid-Forming Tumors Bone and osteoid-forming tumors may present a true challenge for the pathologist. If the bone can be recognized as well-formed lamellar or cancellous bone, osteoid is non-mineralized bony tissue that needs to be differentiated from reactive processes, including inflammation, fibrosis, and sclerosis (Box 13.9).

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toxylin-eosin stained and taken at different magnification (a–d, ×50, ×200, ×100, ×100 as original magnification, respectively)

13.6.5 Osteoma, Osteoid Osteoma, and Giant Osteoid Osteoma (Osteoblastoma) 13.6.6 Giant Cell Tumor (Osteoclastoma) 13.6.7 Osteosarcoma 13.6.8 Ewing Sarcoma 13.6.9 Miscellaneous Bone Tumors and Metastatic Tumors

13.6.1  Myositis Ossificans Box 13.9 Tumorlike Lesions and Bone/ Osteoid-Forming Tumors

13.6.1 Myositis Ossificans 13.6.2 Fibrous Dysplasia and Osteofibrous Dysplasia/Ossifying Fibroma 13.6.3 Non-Ossifying Fibroma/ Metaphyseal Fibrous Defect 13.6.4 Unicameral Bone Cyst and Aneurysmal Bone Cyst

• DEF: Solitary, nonprogressive (intramuscular, usually) tumorlike lesion of reactive type. • EPI: Young males with rapid growth. • EPG: Post-traumatic (often). • CLI: Flexors of the arms, quadriceps of the femur, thigh adductors, and soft tissue of hands. • IMG: Periosteal reaction with casing ­calcification at periphery, mostly 3–6  weeks after trauma.

13  Arthro-Skeletal System

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• GRO: It is a well-circumscribed tumor, which shows, on cut surface, a white, soft, and gelatinous aspect in the center. Conversely, a yellow-grayish and most often firm zone with a rough granular surface is identified peripherally. • CLM: Zonation (+)-lesion including three zones in the most mature stage (inner cellular core, an intermediate layer of osteoid, and peripheral shell of highly organized bony tissue). In fact, the bone formation is most bulging at the periphery of the lesion. • DDX: Fibrodysplasia (myositis) ossificans progressiva and osteosarcoma. The former lesion shows a progressive fibroblastic proliferation with subsequent calcification and ossification (central) of subcutaneous fat, muscles, as well

Fig. 13.7 Fibrous Dysplasia. Well-circumscribed lesion with curvilinear trabeculae (“Chinese letters”) of metaplastic woven bone in hypocellular (fibroblastic) stroma typically without osteoblastic rimming. No/rare mitotic figures and no atypia (a–b, hematoxylin and eosin staining, ×50 and ×200 as original magnification, respectively)

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as tendo-aponeurotic tissue and ligaments. The latter lesion is characterized by atypical cells, no zonation but disorganization with a characteristic “reverse zoning effect,” i.e., bone formation in the center of the lesion and immature spindle cells toward the periphery. • TRT: Excision. • PGN: Excellent following removal of the tumor.

13.6.2  Fibrous Dysplasia and Osteofibrous Dysplasia Fibrous dysplasia and osteofibrous dysplasia are two related lesions. The former is well-­recognized by the head and neck surgeons, while the latter is well recognized by pediatric orthopedic surgeons.

13.6 Tumorlike Lesions and Bone/Osteoid-Forming Tumors

13.6.2.1 Fibrous Dysplasia • DEF: Hamartomatous tumorlike bony lesion derived from osteoprogenitor, fibroblast-like cells and characterized by fibro-osseous metaplasia with monostotic more common than polyostotic involvement (Fig. 13.7). • EPI: 1% of biopsy of bone tumors, 1st-3rd decades of life, ♂:♀ = 1:1.2. • EPG: Activating GNAS1 gene somatic mutations on chromosome 20q13 with two distinct missense mutations in the α subunit of a G stimulatory protein that accounts for the disease process. These activating mutations activate adenylyl cyclase, and then an obvious rise of cAMP is found. This biochemical setting produces an alteration in the transcription and expression of several downstream target genes, including c-fos, which is a proto-oncogene. • CLI: Two patterns of lesions are recognized, including the monostotic type (70%) involving older children and one of the most frequent skeletal sites (splanchnocranium/skull, rib, femur, tibia) and the polyostotic type (30%) involving more than one of the most frequent skeletal sites. The monostotic disease (FD, fibrous dysplasia) can occur incidentally or be associated with pain, swelling, or pathologic fracture, while the polyostotic type is often associated with singular extraskeletal anomalies. Polyostotic FD can be seen without (Jaffe-Lichtenstein syndrome) or with endocrine dysfunction, skin hyperpigmentation (“café au lait” pigmentation with jagged “Coast of Maine”-like borders respecting the midline and Blaschko lines) and pubertas praecox (precocious puberty) (=Albright triad: endocrinopathy with pituitary hyperplasia, hyperthyroidism, and adrenal hyperplasia, precocious puberty, and bony lesions). Generally, “cafe au lait” maculae in neurofibromatosis tend to be smaller and have a smooth outline (“Coast of California”); whereas in McCune-Albright syndrome the maculae are characterized by an irregular, jagged outline (“Coast of Maine”). The differentiating radiologic features include permeative ill-defined borders, destroyed cortical outline, speculated periosteal new bone formation, and periodontal ligament space widening. Rarely,

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FD can occur with soft tissue (intramuscular) myxomas (Mazabraud syndrome). As of 2019, only 106 cases of Mazabraud syndrome have been reported in the scientific literature. IMG: Bone expansion with ground-glass osteolysis and rim of host bone sclerosis. FD causes facial asymmetry with pathologic features with pain and deformity and leg length discrepancy commonly seen due to the involvement of the upper portion of the femur (the socalled Hockey Stick deformity, Shepherd’s crook deformity, and candle flame). GRO: Fusiform mass of the bone diaphysis arising in cancellous (trabecular, spongy) bone with subsequent thinning of the o­ verlying cortex and variably gritty osseous components. CLM: “Alphabet soup pattern” or “Chinese characters”-shaped metaplastic bony spicules (narrow, curved, and misshapen bony spicules) mostly devoid of lining osteoblasts immersed in a quite often variably cellular fibrous tissue with or without giant cells. Osteoblasts are interspersed in the woven bone, but usually not lining the trabeculae. Foamy cells can be identified, and fibroblasts have plum, ovoid nuclei without pleomorphism. Multinucleated osteoclast-­type giant cells can be seen as well as cartilage with peripheral endochondral ossification. A minimal infiltrative pattern may still be present in FD, but an extensive infiltrative pattern should raise the differential diagnosis with osteosarcoma. IHC: MIB1/Ki67: low, (−) AE1–3/KER. TEM: Bone trabeculae of immature woven type and irregular osteoblast lining with cells resembling fibroblasts. DDX: –– OFD (cortically located, tibia/fibula, age    PS bones (the femur, tibia, and humerus more frequently involved than pelvis and spine) with intense, well-delimited pain proportionally more than expected in consideration of the size of the lesion. The severe pain classically occurs at night, but it can also

be constant at any time of the day, and the chief symptomatology is constituted by dull pain which is non-­radiating, persistent with nocturnal exacerbation, and relieved by aspirin in most patients. In some patients, pain may be mistaken for neurotic or psychiatric complaint, though. The pain is due to an ↑ of local concentration of PGE2 and COX1 and COX2. • IMG: Metaphysis-located cortical tumor (Ø  2.0  cm ⇒ giant osteoid osteoma). • SYN: Osteoblastoma. • EPI: 1st–3rd decades, ♂:♀ = 2:1; 1% of bone tumors. • CLI: Metaphysis-located medullary tumor, L  2 cm) with nidus showing no or minimal rim of sclerotic bone. GRO: More numerous fragments (Ø > 1.5 cm) with color depending from the osteoid/woven bone ratio and vascularity, being red if richly vascular and osteoid productive, and yellowish/whitish if the bone building is more intense with decreased vascularity. CLM: Nidus with minimal or no rim of surrounding sclerotic bone. It is mandatory to have fulfilled all conditions before signing out the diagnosis of GOO (osteoblastoma) including (1) lack of unambiguous anaplasia, (2) at least focal osteoblastic rimming, (3) lack of cartilage production, and (4) a sharp circumscription of osteoid and/or woven bone-producing lesion from host lamellar bony tissue (the so-called Bertoni zonation). In the aggressive osteoblastoma atypical cytological features, broad irregular trabeculae lined by osteoblasts and non-trabecular osteoid are seen. In general, the giant OO or osteoblastoma may be difficult to distinguish from osteosarcoma, and the identification of infiltrative margins or cartilage islands suggests malignancy, and a second opinion is warranted. The concept of “pseudoanaplasia” has been suggested for such “pseudomalignant” osteoblastomas. Four clues to the diagnosis of osteosarcoma should not be present, including sheets of elongated spindle cells, a solid stroma appearance, deposits of osteoid between woven bony trabecules, and cartilage production. IHC: Ki67 (MIB1) score may show a low proliferative rate but may also be misleading in some cases. Thus, scrutiny of all specimens and levels is needed. TRT: Nonoperative management is rarely a choice because the lesion is going to grow if left untreated. Operative management includes

13.6 Tumorlike Lesions and Bone/Osteoid-Forming Tumors

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Fig. 13.12  Giant Cell Tumor. The histological panel shows a tumor composed by numerous giant cells with nuclei harboring the same features seen in the stromal cells (a–b, hematoxylin and eosin staining, ×200 as original magnification for both microphotographs). There is an

open chromatin pattern of the nuclei of the tumor cells (c, Masson-Goldner trichromic stain, ×200 original magnification). The proliferation activity is moderate (d, avidinbiotin complex with the MIB1 antibody against Ki67, ×200 original magnification)

curettage or marginal excision with bone grafting. There is recurrence rate of 10–20%. • PGN: The osteoblastoma has the same prognosis of OO, but a variant, also known as aggressive osteoblastoma, has more tendency to recur, and its delimitation from the osteosarcoma may be quite challenging in some cases, and second opinion is often necessary.

Oberndorfer) characterized by resorbing giant cell-rich granulation tissue, a dystrophic approach constituted by a circumscribed form of fibrous cystic osteodystrophy, and a neoplastic one (Ewing-Geschickter-Copeland), which regards the GCT as a true neoplasm arising from the fibroblasts of the marrow cavity. CLI: Tumor of long bones (lower femur, upper tibia, lower radius, humerus, and fibula) with “sign of the pergameneous crepitation” and “soap bubble” aspect. IMG: Osteolytic, expansile lesion of the epiphyses with or without trabeculated appearance and usually without peripheral ­ sclerosis or periosteal reaction (except a recurrence in soft tissue, when an eggshell of ossification usually surrounds it). GRO: Variable-sized lesion with solid, tan to light brown, soft with often a hemorrhagic aspect. CLM: Numerous giant cells (S100-) with many central nuclei regularly distributed in some-

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13.6.6  Giant Cell Tumor • DEF: It is an epiphyseal osteolytic tumor of • the long bones characterized by benign appearing osteoclast-like giant cells and stromal cells arising within the epiphysis of adult bones (rarely seen in patients with open growth plates) and harboring an uncertain malignant potential (Fig. 13.12). • • EPI: 2nd–3rd decades, ♂ Western, individuals, 5% of primary bony tumors. • EPG: There are three theories, including an • inflammatory theory (Lubarsch-Konjetzny-­

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what spindle-shaped mesenchymal (stromal) cells, which form mononuclear cells and then fuse to form giant cells (nuclei are central and similar to the nuclei of mesenchymal/stromal cells) with characteristic spread to the subchondral position. Focal osteoid or bone in 1/3 of the cases. All cells of this neoplasm show nuclear vesicular cytology and do not display any objective anaplasia as seen in TAOS and GCOS.  Cells are also differentiated in type I cell (mononuclear stromal cell that look like interstitial fibroblasts or primary neoplastic cells), type II cell (mononuclear cells from peripheral blood and considered precursor of the giant cell), and type III cell (giant cell with the nuclei similar to the stromal cells). CMB: Type II and III cells have IGF-I and IGF-II activity, and 4/5 of patients have telomeric associations, and the RANK pathway, i.e., receptor activator of nuclear factor-κB or a member of the tumor necrosis factor receptor (TNFR) molecular subfamily, is crucial. DDX: Osteitis fibrosa cystica (chronic hyperparathyroidism induced osteoclastic destruction of bone with or without cystic degeneration), ABC (when occurs in an uncommon site, more likely is an ABC), telangiectatic OS (malignant cells with osteoid formation), and GC-rich OS.  The GCT of hyperparathyroidism is histologically indistinguishable from the non-­hyperparathyroidism associated GCT of the epiphysis. Other less common lesions that need to be kept in mind in the differential diagnosis include giant cell-­ rich fibrosarcoma, malignant fibrous histiocytoma, postirradiation sarcoma, the de novo malignant transformation of a formerly conventional GCT, and the differentiated chondrosarcoma with rich benign osteoclast-like giant cell component. TRT: It is not a sarcoma, but its uncertain behavioral potential with high local recurrence rate and great bony destruction suggests to the orthopedic surgeon measures similar to those adopted for low-grade malignant tumors such en bloc resection or cryosurgery. PGN: Uncertain malignant potential with up to 1/2 of the cases showing recurrence and up

13  Arthro-Skeletal System

to 1/10 of the examples showing metastases (lung). Recurrence rate: 1/3 of the cases if curettage is performed, 6  months of and prominent superficial veins. each other). –– Systemic: weight loss (specifically with met–– According to the histologic growth patastatic lung tumor), an increase of ALP (virterns: bone-rich or “sclerosing,” chondrotual drop after therapy, though not always to blastic, spindle cell-rich (fibrosarcoma-like), the level normal for the age of the patient). malignant fibro-histiocyte-rich (MFH-­ –– History of trauma (?). like), telangiectatic (ABC-like), small cell, Skeletal Distribution: Long bones (metaphysis) etc. of the knee > humerus > pelvis > skull. –– According to its inheritance or familiarity: • GEN: The genetic variations of osteosarcoma Familial and sporadic osteosarcomas. are presented in the Box 13.14. • SYN: Osteogenic sarcoma. • IMG: Radiologic features can be present, but • EPI: 2nd–3rd decade of life and the elderly, sometimes they may also be absent. In Box ♂ > ♀. 13.15 the radiologic features are summarized.

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Box 13.14 Genetic Variations of Osteosarcoma

Box 13.15 Osteosarcoma Radiologic Features

1. Germline mutation and single allelic mutation at 13q14 with “2nd hit” somatic mutation of 13q14 (RB locus) promoting hereditary retinoblastoma and 500 times risk of osteosarcoma. 2. MDM2 amplification with P53 inactivation (Li-Fraumeni syndrome due to an inherited mutant p53 allele and associated with a ↑risk of sarcomas and other malignancies; notably some 500 times ↑ risk of osteosarcoma). 3. LOH on 3, 17, and 18.

• “Fluffy” to “cumulus cloud”-like intramedullary white densities • The absence of bone expansion, periosteal bony collar, and sclerotic border of host bone • Metaphyseal location • Periosteal reactions (e.g., Codman triangle, longitudinal and perpendicular spiculations) • Soft tissue component

The differential diagnosis of the Codman triangle includes ABC, acute osteomyelitis, hemophilia-­related pseudotumor, intraperiosteal hemorrhage (e.g., trauma, parosteal fasciitis), and osteosarcoma. • GRO: Destructive and “permeative” gritty tumor with variable color according to the tissue-producing tumor cells. It includes white-yellowish tumor with gritty to stony in bone-producing regions. It is white and firm in fibrous tissue-producing regions while gray and soft in necrotic areas (particularly crucial after therapy for assessment of the response to treatment → national and international COG protocols), dark red and soft in hemorrhagic regions (particularly telangiectatic OS), and tan in zones richer of osteoclast-­ like giant cells, as well as bluish and translucent in chondroid or cartilaginous areas. In about 1/5 of cases, a gross pathologic fracture and up to 1/4 of cases extension to the joint are noted. It has been suggested that the color depends on tissue produced from the tumor. Thus, bone regions appear whitish yellow and gritty to stone hard, fibrous areas appear white and firm, necrotic areas appear soft and grey, hemorrhagic portions appear red or dark red, cartilage-bearing parts appear bluish translucent, and former zones of hemorrhage or osteoclastlike giant cells affluent areas appear tan.

Notes: The Codman triangle is an isolated cuff of reactive new bone subperiosteally with two components, i.e., an outer homogeneous thick layer of cortical bone with Haversian system and an inner layer characterized by a well-formed network of trabeculae. The OS that manifests before the development of a soft tissue mass is also called “incipient OS” and can be easily mistaken radiologically and pathologically for osteoblastoma or stress fracture. Of note, there is erosion, but not expansion of the cortical bone. • CLM: Several and different histologic patterns (“many faces and disguises”)! Growth patterns include fibroblastic (strands and clumps of osteoid with fibrillary pattern), trabecular, filigree, small cell, and telangiectatic. The small cell osteosarcoma can be a very challenging neoplasm because of the broad differential diagnosis related to the small round blue cell tumors. In the small cell growth pattern, sheets of small cells with a size similar to that seen in of Ewing sarcoma, lacy osteoid to primitive filigree bone laid down, and possibly foci of malignant cartilage are seen. • IHC: Immunohistochemical markers of osteoblastic differentiation (e.g., osteocalcin, osteonectin, SATB2) have been suggested to be useful in some difficult cases. However, the use of a good cut H&E slide and Masson trichromic are paramount for the diagnosis.

13.6 Tumorlike Lesions and Bone/Osteoid-Forming Tumors

• TEM: There is the extensive presence of dilated, inter-anastomosing, rough endoplasmic reticulum filled with granular material, tight intercellular junctions, and a variety of several cell types. • DDX: Callus, ABC, osteoblastoma, chondroblastoma, chondrosarcoma, mesenchymal chondrosarcoma, fibrosarcoma, giant cell tumor, and Ewing sarcoma (vide infra). Since the OS may have an atypical radiologic presentation, a tremendous variability in histologic patterns and minimal degree of atypia, this tumor is a primary challenge for most of the pathologists. No other tumor is equal to OS in mimicking several and different entities, including GOO, osteoid osteoma, fibrous dysplasia, nonossifying fibroma, desmoid tumor, fibrosarcoma, malignant fibrous histiocytoma, chondromyxoid fibroma as benign tumors and chondrosarcoma, Ewing sarcoma, giant cell tumor, ABC, and metastatic carcinoma as malignant tumors or tumors of uncertain or low destructive potential. • PGN: High-grade malignancy with a brisk tendency to lung metastasis and a grim prognosis (death ≤ 2  years of the diagnosis) if adjuvant chemotherapy using chemotherapy with or without radiotherapy are not implemented. Two groups are identified: (1) patients with good response to chemotherapy (≥90% of diffuse necrosis) and (2) patients with inadequate response to chemotherapy ( ♀ Key is to remember the Bassel-Hagen law, which states that the bone bearing an osteochondroma loses in length what acquires in the exophytic growth. • SYN: Exostosis, ecchondroma. • EPI: 1st–2nd decades, ♂ > ♀. • EPG: Aberrant subperiosteal residuals of growth cartilage (Virchow theory). • CLI: Asymptomatic, slightly esthetic disturbances of “LP” Long bones (lower femur, upper tibia, upper humerus), mostly around the knee + Pelvis. • IMG: Pedunculated tumor located at metaphysis growing out in a direction opposite that of the adjacent joint. • GRO: Pedunculated tumor with a cap of cartilage, rarely exceeding 1 cm. • CLM: There is a lobulated cap of hyaline cartilage (distal), covered by a fibrous membrane, with an active endochondral ossification (interface), and mature or cancellous bone (proximal to bone metaphysis) beneath, the latter making up the bulk of the lesion. The bone marrow of the diaphysis is not connected to the bone marrow of the osteochondroma. • DDX: Parosteal osteosarcoma. • PGN: As the osteochondroma ages, the cap may become thinner and disappear, and the

13  Arthro-Skeletal System

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Fig. 13.16  Osteochondroma. This panel illustrates the exostosis resected by the orthopedic surgeon from the metaphysis of a long bone (a–f). The histology of the tumor identifies a new cap with a characteristic growth phase without cellular atypia or mitotic figures (b–f, hematoxylin and eosin staining, ×40 original magnifica-

whole lesion may spontaneously regress. However, the osteochondroma harbors a malignant transformation rate of 1–2%, if single. The malignant transformation rate is higher (5–10%) in case of multiple osteochondromas. Worrisome signs portend to a possible/probable malignant transformation: tumor Ø  >  8  cm, cap >3  cm, and irregular cap. In case of a developing bursa around head, there is a potentiality to develop chondrosarcoma.

tion; c, hematoxylin and eosin staining, ×50 original magnification; d, hematoxylin and eosin staining, ×50 original magnification; e, toluidin blue staining, ×100 original magnification; f, hematoxylin and eosin staining, ×400 original magnification)

Osteochondroma Variants Osteochondromatosis (Ehrenfried hereditary deforming chondrodysplasia, Leri disease, Ombredanne disease): EXT1 or EXT2 genes-­ linked, AD-inherited disease with multiple osteochondromas  ±  Gardner syndrome with a capability to develop into chondrosarcoma (10%). Dupuytren Subungual Exostoses (DSE): Subungual-located osteochondroma with histologic patterns that need to be differentiated from chon-

13.7 Chondroid (Cartilage)-Forming Tumors

drosarcoma. DSE starts as a reactive growth of cellular fibrous tissue and metaplastic cartilage, which undergoes endochondral ossification with postadolescents and young adults mostly affected and usually on the dorsal medial aspect of the great toe. Although a benign lesion, DSE local excision is curative, recurrences are common though (~50%) after incomplete excision or when the lesion has not achieved full maturation.

13.7.2  Enchondroma • DEF: Common asymmetric, unilateral, and painless benign tumor at a medullary or cortical location in the center of the diaphysis of the bones constituted by fundamentally pure cartilage (mature hyaline) (Fig. 13.17).

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• SYN: Chondroma. • EPI: 2nd–4th decades, 5–10% of benign tumors, ♂ > ♀. • EPG: Hamartomatous origin (the so-called Hamartiae cartilagineae). Probably, the enchondromas should be considered dysontogenetic tumors arising from aberrant rests of growing cartilage. Hamartia is a defect of tissue combination during embryo-genetic development with the tissue components usually belonging to the site (Greek: ἁμαρτία, “failure, error”, and ἁμαρτάνω, which is the derived verb for “to miss the mark”). Both Greek tragedy and Christian theology have used this term, which has been used since Ancient times. Aristotle was the first using this term in his Poetics. He described “ἁμαρτία” as an error of judgment made by a

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Fig. 13.17 Enchondroma. This panel illustrates an enchondroma with characteristic lobules of hyaline cartilage, which are embedded by bone and covered by fibrous tissue (perichondrium) (a–f). The tumor may give the impression of a ­low-­grade chondrosarcoma due to hyper-

cellularity, binucleation of the neoplastic chondrocytes (b–e), and occasional prominent myxoid change (f) despite a benign appearance radiologically (a–f, hematoxylin and eosin staining; ×12.5, ×100, ×100, ×100, ×100, ×100 as original magnification, respectively)

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character in a tragedy played in theaters. Subsequently, the Italian (Tuscan) Dante Alighieri relabels “Hamartia” a “movement of spirit” played within the sphere of a protagonist. This individual was going to commit actions driving the plot towards its tragic end. When embryonic tissue is found in a non-typical location (heterotopia), the tissue composition derived from it is called choristia (Greek χωριστός “separated, separable”). CLI: Asymptomatic (usually) tumor of the small bones of hands and feet (proximal phalanges), ribs, and long bones. If pain and pathologic fracture occur, then think of low-­ grade chondrosarcoma. IMG: Well-circumscribed radiolucency with punctate opacities (“popcorn”-like densities) detected in medullary sites and characterized by sharp margination of the lesion from the surrounding bone without cortical destruction or soft tissue extension, and ring-like or punctate calcifications within the tumor. GRO: Firm slightly lobulated of gray-blue translucent masses with a Ø often T, p.T371I) of the tissue-nonspecific alkaline phosphatase gene. Bone. 2007;40(6):1655–61. Epub 2007 Feb 14. PubMed PMID: 17395561. Beccaria K, Sainte-Rose C, Zerah M, Puget S. Paediatric Chordomas. Orphanet J Rare Dis 10, 116 (2015). https://doi.org/10.1186/s13023-015-0340-8.

References and Recommended Readings Bishop N, Arundel P, Clark E, Dimitri P, Farr J, Jones G, Makitie O, Munns CF, Shaw N. Fracture prediction and the definition of osteoporosis in children and adolescents: the ISCD 2013 Pediatric Official Positions. J Clin Densitom. 2014;17:275–80. https:// doi.org/10.1016/j.jocd.2014.01.004. Broome M, Vial Y, Jacquemont S, Sergi C, Kamnasaran D, Giannoni E. Complete Maxillo-Mandibular Syngnathia in a Newborn with Multiple Congenital Malformations. Pediatr Neonatol. 2016;57(1):65–8. https://doi.org/10.1016/j.pedneo.2013.04.009. Epub 2013 Jun 15. PubMed PMID: 23778189. Cascio A, Colomba C, Di Carlo P, Serra N, Lo Re G, Gambino A, Lo Casto A, Guglielmi G, Veronese N, Lagalla R, Sergi C. Low bone mineral density in HIV-positive young Italians and migrants. PLoS One. 2020;15(9):e0237984. https://doi.org/10.1371/journal.pone.0237984. PMID: 32881882. Combe B, Landewe R, Daien CI, Hua C, Aletaha D, Álvaro-Gracia JM, Bakkers M, Brodin N, Burmester GR, Codreanu C, Conway R, Dougados M, Emery P, Ferraccioli G, Fonseca J, Raza K, Silva-Fernández L, Smolen JS, Skingle D, Szekanecz Z, Kvien TK, van der Helm-van Mil A, van Vollenhoven R. 2016 update of the EULAR recommendations for the management of early arthritis. Ann Rheum Dis. 2017;76(6):948–59. https://doi.org/10.1136/annrheumdis-2016-210602. Epub 2016 Dec 15. Cotti E, Sergi C, Bassareo A. Use of a resin-based root canal sealer followed by apicoectomy on two teeth. Dent Today. 2007;26(7):108, 110–1. PubMed PMID: 17708317. Dal Cin P, Kozakewich HP, Goumnerova L, Mankin HJ, Rosenberg AE, Fletcher JA. Variant translocations involving 16q22 and 17p13 in solid variant and extraosseous forms of aneurysmal bone cyst. Genes Chromosomes Cancer 2000;28:233–4. Emile JF, Abla O, Fraitag S, Horne A, Haroche J, Donadieu J, Requena-Caballero L, Jordan MB, Abdel- Wahab O, Allen CE, Charlotte F, Diamond EL, Egeler RM, Fischer A, Herrera JG, Henter JI, Janku F, Merad M, Picarsic J, Rodriguez-Galindo C, Rollins BJ, Tazi A, Vassallo R, Weiss LM; Histiocyte Society. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016;127(22):2672–81. https://doi.org/10.1182/ blood-2016-01-690636. Epub 2016 Mar 10. PMID: 26966089; PMCID: PMC5161007.. Ficat RP, Arlet J. Ischemia and necrosis of bone. In: Hungerford DS, editor. Baltimore/London: Williams and Wilkins; 1980. Forsman CL, Ng BC, Heinze RK, Kuo C, Sergi C, Gopalakrishnan R, Yee D, Graf D, Schwertfeger KL, Petryk A. BMP-binding protein twisted gastrulation is required in mammary gland epithelium for normal ductal elongation and myoepithelial compartmentalization. Dev Biol. 2013;373(1):95–106. https:// doi.org/10.1016/j.ydbio.2012.10.007. Epub 2012

1163 Oct 24. PubMed PMID: 23103586; PubMed Central PMCID:PMC3508155. Gardeniers JWM. ARCO Committee on terminology and staging (report from the Nijmegen meeting). ARCO News Lett 1991;3:153e9. Gardeniers JWM. ARCO Committee on terminology and staging. Report on the committee meeting at Santiago de Compostella. ARCO News Lett 1993;5:79e82. Glueckert R, Rask-Andersen H, Sergi C, Schmutzhard J, Mueller B, Beckmann F, Rittinger O, Hoefsloot LH, Schrott-Fischer A, Janecke AR. Histology and synchrotron radiation-based microtomography of the inner ear in a molecularly confirmed case of CHARGE syndrome. Am J Med Genet A. 2010;152A(3):665– 73. https://doi.org/10.1002/ajmg.a.33321. PubMed PMID: 20186814. Hästbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES. Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias. Am J Hum Genet. 1996;58(2):255–62. PubMed PMID: 8571951; PubMed Central PMCID: PMC1914552. Ho KL. Ecchordosis physaliphora and chordoma: a comparative ultrastructural study. Clin Neuropathol. 1985;4(2):77–86. Jagodzinski NA, Kanwar R, Graham K, Bache CE. Prospective evaluation of a shortened regimen of treatment for acute osteomyelitis and septic arthritis in children. J Pediatr Orthop. 2009;29(5):518–25. https://doi.org/10.1097/BPO.0b013e3181ab472d. PubMed PMID: 19568027. Johnston J, Al-Bahrani R, Abuetabh Y, Chiu B, Forsman CL, Nagamori S, Leng R, Petryk A, Sergi C. Twisted gastrulation expression in cholangiocellular and hepatocellular carcinoma. J Clin Pathol. 2012;65(10):945– 8. Epub 2012 May 25. PubMed PMID: 22639408. Johnson CA, Gissen P, Sergi C. Molecular pathology and genetics of congenital hepatorenal fibrocystic syndromes. J Med Genet. 2003;40(5):311–9. Review. PubMed PMID: 12746391; PubMed Central PMCID: PMC1735460. Jung M, Tuischer JS, Sergi C, Gotterbarm T, Pohl J, Richter W, Simank HG. Local application of a collagen type I/hyaluronate matrix and growth and differentiation factor 5 influences the closure of osteochondral defects in a minipig model by enchondral ossification. Growth Factors. 2006;24(4):225–32. PubMed PMID: 17381063. Jung C, Sohn C, Sergi C. Case report: prenatal diagnosis of diastrophic dysplasia by ultrasound at 21 weeks of gestation in a mother with massive obesity. Prenat Diagn. 1998;18(4):378–83. PubMed PMID: 9602486. Kato S, Yoshizazawa T, KitanSYN S, Murayama A, Takeyama K. Molecular genetics of vitamin D-dependent hereditary rickets. Horm Res. 2002; 57(3–4):73–8. Review. PubMed PMID: 12006701. Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: Diagnosis, differential diagno-

1164 sis, treatment, sequelae, and standardized follow-up. J Am Acad Dermatol. 2018;78(6):1047–56. https:// doi.org/10.1016/j.jaad.2017.05.060. Review. PubMed PMID: 29754886. Krooks J, Minkov M, Weatherall AG. Langerhans cell histiocytosis in children: History, classification, pathobiology, clinical manifestations, and prognosis. J Am Acad Dermatol. 2018;78(6):1035–44. https:// doi.org/10.1016/j.jaad.2017.05.059. Review. PubMed PMID: 29754885. Liu T, Li Z, Zhang Q, De Amorim Bernstein K, LozanoCalderon S, Choy E, Hornicek FJ, Duan Z. Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance. Oncotarget. 2016;7(50):83502– 83513. https://doi.org/10.18632/oncotarget.13148. PubMed PMID: 27835872; PubMed Central PMCID: PMC5347784. Luschka P. Ueber gallertartige Auswüchse am Clivus Blumenbachii. Arch Pathol Anat Physiol Klin Med. 1857;11:8–12. Manggold J, Sergi C, Becker K, Lukoschek M, Simank HG. A new animal model of femoral head necrosis induced by intraosseous injection of ethanol. Lab Anim. 2002;36(2):173–80. https://doi. org/10.1258/0023677021912460. PMID: 11943082. Marcus ND, Enneking WF, Massam RA. The silent hip in idiopathic aseptic necrosis: treatment by bone grafting. J Bone Joint Surg Am. 1973;55:1351–66. Malloy PJ, Feldman D. Genetic disorders and defects in vitamin d action. Endocrinol Metab Clin N Am. 2010;39(2):333–46, table of contents. https://doi. org/10.1016/j.ecl.2010.02.004. Review. PubMed PMID: 20511055; PubMed Central PMCID: PMC2879401. Malloy PJ, Tasic V, Taha D, Tütüncüler F, Ying GS, Yin LK, Wang J, Feldman D. Vitamin D receptor mutations in patients with hereditary 1,25-dihydroxyvitamin D-resistant rickets. Mol Genet Metab 2014;111(1):33– 40. https://doi.org/10.1016/j.ymgme.2013.10.014. Epub 2013 Nov 4. PubMed PMID: 24246681; PubMed Central PMCID:PMC3933290. Mazabraud A, Girard J. Un cas particulier de dysplasie fibreuse à localisations osseuses et tendineuses [A peculiar case of fibrous dysplasia with osseous and tendinous localizations]. Rev Rhum Mal Osteoartic. 1957;24(9-10):652–9. French. PMID: 13518962. Nield LS, Mahajan P, Joshi A, Kamat D. Rickets: not a disease of the past. Am Fam Physician. 2006;74(4):619– 26. Review. PubMed PMID: 16939184. Nowlan NC, Sharpe J, Roddy KA, Prendergast PJ, Murphy P. Mechanobiology of embryonic skeletal development: insights from animal models. Birth Defects Res C Embryo Today. 2010;90(3):203–13. https://doi. org/10.1002/bdrc.20184. Review. PubMed PMID: 20860060; PubMed Central PMCID: PMC4794623. Oliveira AM, Hsi BL, Weremowicz S, Rosenberg AE, Dal Cin P, Joseph N, Bridge JA, Perez-Atayde AR, Fletcher JA. USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res. 2004;64(6):1920–3.

13  Arthro-Skeletal System https://doi.org/10.1158/0008-5472.can-03-2827. PMID: 15026324. Oliveira AM, Perez-Atayde AR, Inwards CY, Medeiros F, Derr V, Hsi BL, Gebhardt MC, Rosenberg AE, Fletcher JA. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol. 2004;165(5):1773–80. https:// doi.org/10.1016/S0002-9440(10)63432-3. PMID: 15509545; PMCID: PMC3278819. Oliveira AM, Perez-Atayde AR, Dal Cin P, Gebhardt MC, Chen CJ, Neff JR, Demetri GD, Rosenberg AE, Bridge JA, Fletcher JA. Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene. 2005;24(21):3419–26. https://doi.org/10.1038/sj.onc.1208506. PMID: 15735689. Ono K. Diagnostic criteria, staging system and roentgenographic classification of avascular necrosis of the femoral head (steroid induced, alcohol associated or idiopathic nature) (in Japanese) Annual report of Japanese investigation committee for intractable disease, avascular necrosis of the femoral head. Tokyo: Ministry of health and Welfare; 1987. Osasan S, Zhang M, Shen F, Paul PJ, Persad S, Sergi C. Osteogenic Sarcoma: A 21st Century Review. Anticancer Res. 2016;36(9):4391–8. Review. PubMed PMID: 27630274. Panoutsakopoulos G, Pandis N, Kyriazoglou I, Gustafson P, Mertens F, Mandahl N. Recurrent t(16;17)(q22;p13) in aneurysmal bone cysts. Genes Chromosomes Cancer 1999;26:265–6. Prandini N, Lazzeri E, Rossi B, Erba P, Parisella MG, Signore A. Nuclear medicine imaging of bone infections. Nucl Med Commun. 2006;27(8):633–644. https://doi.org/10.1097/00006231-200608000-00006. Ressler S, Radhi J, Aigner T, Loo C, Zwerschke W, Sergi C. Insulin-like growth factor-binding protein-3 in osteosarcomas and normal bone tissues. Anticancer Res. 2009;29(7):2579–87. PMID: 19596932. Redondo A, Bagué S, Bernabeu D, Ortiz-Cruz E, Valverde C, Alvarez R, Martinez-Trufero J, Lopez- Martin JA, Correa R, Cruz J, Lopez-Pousa A, Santos A, García Del Muro X, Martin-Broto J. Malignant bone tumors (other than Ewing’s): clinical practice guidelines for diagnosis, treatment and follow-up by Spanish Group for Research on Sarcomas (GEIS). Cancer Chemother Pharmacol. 2017;80(6):1113–31. https:// doi.org/10.1007/s00280-017-3436-0. Epub 2017 Oct 16. PubMed PMID: 29038849; PubMed Central PMCID: PMC5686259. Rotondo M, Natale M, Mirone G, Cirillo M, Conforti R, Scuotto A. A rare symptomatic presentation of ecchordosis physaliphora: neuroradiological and surgical management. J Neurol Neurosurg Psychiatry. 2007;78(6):647–649. https://doi.org/10.1136/ jnnp.2006.109561. Sahyouni R, Goshtasbi K, Mahmoodi A, Chen JW. A historical recount of chordoma. J Neurosurg Spine.

References and Recommended Readings 2018;28(4):422–428. https://doi.org/10.3171/2017.7. SPINE17668. Santer FR, Bacher N, Moser B, Morandell D, Ressler S, Firth SM, Spoden GA, Sergi C, Baxter RC, JansenDürr P, Zwerschke W. Nuclear insulin-like growth factor binding protein-3 induces apoptosis and is targeted to ubiquitin/proteasome-dependent proteolysis. Cancer Res. 2006;66(6):3024–33. PubMed PMID: 16540651. Saraff V, Högler W. Endocrinology and Adolescence: Osteoporosis in children: diagnosis and anagement. Eur J Endocrinol. 2015;173(6):R185-97. https://doi. org/10.1530/EJE-14-0865. Epub 2015 Jun 3. PMID: 26041077. Schiffer C, Schiesser M, Lehr J, Tariverdian G, Glaeser D, Gabriel H, Mikuz G, Sergi C. Unique occurrence of Brachmann-de Lange syndrome in a fetus whose mother presented with a diffuse large B-cell lymphoma. Pathol Oncol Res. 2007;13(3):255–9. Epub 2007 Oct 7. Review. PubMed PMID: 17922056. Schiffer C, Tariverdian G, Schiesser M, Thomas MC, Sergi C. Agnathia-otocephaly complex: report of three cases with involvement of two different Carnegie stages. Am J Med Genet. 2002;112(2): 203–8. PubMed PMID: 12244557. Schmutzhard J, Glueckert R, Bitsche M, Abraham I, Falkeis C, Schwentner I, Riechelmann H, Müller B, Beckmann F, Sergi C, Schrott-Fischer A. The cochlea in fetuses with neural tube defects. Int J Dev Neurosci. 2009;(7):669–76. https://doi.org/10.1016/j. ijdevneu.2009.07.008. Epub 2009 Aug 5. PubMed PMID: 19664702. Schmutzhard J, Glueckert R, Sergi C, Schwentner I, Abraham I, Schrott-Fischer A. Does perinatal asphyxia induce apoptosis in the inner ear? Hear Res. 2009;250(1–2):1–9. https://doi.org/10.1016/j. heares.2008.12.006. Epub 2008 Dec 25. PubMed PMID: 19136052. Schmutzhard J, Schwentner I, Glueckert R, Sergi C, Beckmann F, Abraham I, Riechelmann H, SchrottFischer A, Müller B. Pelizaeus Merzbacher disease: morphological analysis of the vestibulo-cochlear system. Acta Otolaryngol. 2009;129(12):1395–9. https:// doi.org/10.3109/00016480802698866. PubMed PMID: 19922087. Sergi C, Beedgen B, Kopitz J, Zilow E, Zoubaa S, Otto HF, Cantz M, Linderkamp O. Refractory congenital ascites as a manifestation of neonatal sialidosis: clinical, biochemical and morphological studies in a newborn Syrian male infant. Am J Perinatol. 1999;16(3):133– 41. PubMed PMID: 10438195. Sergi C, Graf M, Jung C, Sohn C, Adam S, Krempien B, Otto HF. Ruhender Knorpel und Epiphysenfuge bei diastrophischer Dysplasie. Kasuistik und klinischpathologische Charakteristika im Vergleich zur pseudodiastrophischen Dysplasie und zur Atelosteogenese Typ II [Resting cartilage and the growth plate in dystrophic dysplasia: case report and clinicopathologic characteristics as compared to pseudodystrophic dysplasia and type II atelosteogenesis]. Pathologe.

1165 1998;19(5):379–83. German. https://doi.org/10.1007/ s002920050301. PMID: 9816594. Sergi C, Hentze S, Sohn C, Voigtländer T, Jung C, Schmitt HP. Telencephalosynapsis (synencephaly) and rhombencephalosynapsis with posterior fossa ventriculocele (‘Dandy-Walker cyst’): an unusual aberrant syngenetic complex. Brain Dev. 1997;19(6):426–32. PubMed PMID: 9339873. Sergi C, Linderkamp O. Pathological case of the month: classic rickets in a setting of significant psychosocial deprivation. Arch Pediatr Adolesc Med. 2001;155(8):967–8. PubMed PMID: 11483129. Sergi C, Mornet E, Troeger J, Voigtlaender T. Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Am J Med Genet. 2001;103(3):235–40. PubMed PMID: 11745997. Sergi C, Penzel R, Uhl J, Zoubaa S, Dietrich H, Decker N, Rieger P, Kopitz J, Otto HF, Kiessling M, Cantz M. Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene. Hum Genet. 2001;109(4):421–8. PubMed PMID: 11702224. Sergi C, Roth SU, Adam S, Otto HF. Mapping a method for systematically reviewing the medical literature: a helpful checklist postmortem protocol of human immunodeficiency virus (HIV)-related pathology in childhood. Pathologica. 2001;93(3):201–7. PubMed PMID: 11433613. Sergi C, Shen F, Liu SM. Insulin/IGF-1R, SIRT1, and FOXOs Pathways-An Intriguing Interaction Platform for Bone and Osteosarcoma. Front Endocrinol (Lausanne). 2019;10:93. https://doi.org/10.3389/ fendo.2019.00093. eCollection 2019. PubMed PMID: 30881341; PubMed Central PMCID: PMC6405434. Sergi C, Voigtländer T, Zoubaa S, Hentze S, MeybergSolomeyer G, Troeger J, Tariverdian G, Otto HF, Schiesser M. Ellis-van Creveld syndrome: a generalized dysplasia of enchondral ossification. Pediatr Radiol. 2001;31(4):289–93. PubMed PMID: 11321750. Sergi C, Willig F, Thomsen M, Otto HF, Krempien B. Bronchopneumonia disguising lung metastases of a painless central chondrosarcoma of pubis. Pathol Oncol Res. 1997;3(3):211–4. https://doi.org/10.1007/ BF02899923. PubMed PMID: 18470732. Sergi C, Zwerschke W. Osteogenic sarcoma (osteosarcoma) in the elderly: tumor delineation and predisposing conditions. Exp Gerontol. 2008;43(12):1039–43. https://doi.org/10.1016/j.exger.2008.09.009. Epub 2008 Sep 25. Review. PubMed PMID: 18845233. Simank HG, Manggold J, Sebald W, Ries R, Richter W, Ewerbeck V, Sergi C. Bone morphogenetic protein-2 and growth and differentiation factor-5 enhance the healing of necrotic bone in a sheep model. Growth Factors. 2001;19(4):247–57. PubMed PMID: 11811780.

1166 Simank HG, Sergi C, Jung M, Adolf S, Eckhardt C, Ehemann V, Ries R, Lill C, Richter W. Effects of local application of growth and differentiation factor-5 (GDF-5) in a full-thickness cartilage defect model. Growth Factors. 2004;22(1):35–43. PubMed PMID: 15176457. Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–2038. https:// doi.org/10.1016/S0140-6736(16)30173-8. Epub 2016 May 3. Review. Erratum in: Lancet. 2016 Oct 22;388(10055):1984. PubMed PMID: 27156434. Spain H, Plumb T, Mikuls TR. Gout as a manifestation of familial juvenile hyperuricemic nephropathy. J Clin Rheumatol. 2014;20(8):442–4. https://doi. org/10.1097/RHU.0000000000000188. PubMed PMID: 25417683. Steinberg DR, Steinberg ME. The university of pennsylvania classification of osteonecrosis. In: Koo KH, Mont M, Jones L, editors. Osteonecrosis. Springer, Berlin, Heidelberg. First Online 2014. https://doi. org/10.1007/978-3-642-35767-1_25. Print ISBN 9783-642-35766-4. Online ISBN 978-3-642-35767-1. Sugano N, Atsumi T, Ohzono K, Kubo T, Hotokebuchi T, Takaoka K. The 2001 revised criteria for diagnosis, classification, and staging of idiopathic osteonecrosis of the femoral head. J Orthop Sci Off J Jpn Orthop Assoc. 2002;7(5):601–5. Sugano N, Ohzono K. Natural Course and the JIC Classification of Osteonecrosis of the Femoral Head. In: Koo KH, Mont MA, Jones LC, editors. Osteonecrosis. Heidelberg: Springer; 2014. p. 207–10. Sultan AA, Mohamed N, Samuel LT, Chughtai M, Sodhi N, Krebs VE, Stearns KL, Molloy RM, Mont MA. Classification systems of hip osteonecrosis: an updated review. Int Orthop. 2019;43(5):1089–95. https://doi.org/10.1007/s00264-018-4018-4. Epub 2018 Jun 18. PMID: 29916002. Sun M, Forsman C, Sergi C, Gopalakrishnan R, O’Connor MB, Petryk A. The expression of twisted gastrulation in postnatal mouse brain and functional implications. Neuroscience. 2010;169(2):920–31. https://doi. org/10.1016/j.neuroscience.2010.05.026. Epub 2010 May 20. PubMed PMID: 20493240; PubMed Central PMCID: PMC2971674. Szendroi M, Antal I, Arató G. Adamantinoma of long bones: a long-term follow-up study of 11 cases. Pathol Oncol Res. 2009;15(2):209–16. https://doi. org/10.1007/s12253-008-9125-x. Epub 2008 Dec 2. PubMed PMID: 19048403. Takashima K, Sakai T, Hamada H, Takao M, Sugano N. Which classification system is most useful for classi-

13  Arthro-Skeletal System fying osteonecrosis of the femoral head? Clin Orthop Relat Res 2018;476:1240e9. Toretsky JA, Steinberg SM, Thakar M, Counts D, Pironis B, Parente C, Eskenazi A, Helman L, Wexler LH. Insulin-like growth factor type 1 (IGF-1) and IGF binding protein-3 in patients with Ewing sarcoma family of tumors. Cancer. 2001;92(11):2941–7. PubMed PMID: 11753970. Virchow R. Untersuchungen über die Entwickelung des Schädelgrundes im gesunden und krankhaften Zustande und über den Einfluss derselben auf Schädelform, Gesichtsbildung und Gehirnbau. 1857, 128 pag. G. Reimer Publisher. Wagner EF, Karsenty G. Genetic control of skeletal development. Curr Opin Genet Dev. 2001;11(5): 527–32. Review. PubMed PMID: 11532394. Wang L, Zhao P, Ma L, Shan Y, Jiang Z, Wang J, Jiang Y. Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus. J Rheumatol. 2014;41(9):1781–92. https:// doi.org/10.3899/jrheum.131025. Epub 2014 Jul 15. PubMed PMID: 25028374. Warman ML, Cormier-Daire V, Hall C, Krakow D, Lachman R, LeMerrer M, Mortier G, Mundlos S, Nishimura G, Rimoin DL, Robertson S, Savarirayan R, Sillence D, Spranger J, Unger S, Zabel B, SupertiFurga A. Nosology and classification of genetic skeletal disorders: 2010 revision. Version 2. Am J Med Genet A. 2011;155A(5):943–68. https://doi. org/10.1002/ajmg.a.33909. Epub 2011 Mar 15. PMID: 21438135; PMCID: PMC3166781. Weir J, Harris N, Sergi C. Pathology quiz case: aneurysmal bone cyst (ABC) of the maxilla. Arch Otolaryngol Head Neck Surg. 2003 Dec;129(12):1345. PubMed PMID: 14676164. Yoon BH, Mont MA, Koo KH, Chen CH, Cheng EY, Cui Q, Drescher W, Gangji V, Goodman SB, Ha YC, Hernigou P, Hungerford MW, Iorio R, Jo WL, Jones LC, Khanduja V, Kim HKW, Kim SY, Kim TY, Lee HY, Lee MS, Lee YK, Lee YJ, Nakamura J, Parvizi J, Sakai T, Sugano N, Takao M, Yamamoto T, Zhao DW. The 2019 revised version of association research circulation osseous staging system of osteonecrosis of the femoral head. J Arthroplasty. 2020;35(4):933– 940. https://doi.org/10.1016/j.arth.2019.11.029. Epub 2019 Nov 27. PMID: 31866252. Zhang M, Shen F, Petryk A, Tang J, Chen X, Sergi C. “English Disease”: Historical Notes on Rickets, the Bone-Lung Link and Child Neglect Issues. Nutrients. 2016;8(11). pii: E722. Review. PubMed PMID: 27854286; PubMed Central PMCID: PMC5133108.

Head and Neck

14

Contents 14.1

Development

 1168

14.2 14.2.1  14.2.2  14.2.3 

Nasal Cavity, Paranasal Sinuses, and Nasopharynx Congenital Anomalies Inflammatory Lesions Tumors

 1171  1171  1173  1174

14.3 14.3.1  14.3.2  14.3.3  14.3.4 

Larynx and Trachea Congenital Anomalies Cysts and Laryngoceles Inflammatory Lesions and Non-neoplastic Lesions Tumors

 1183  1183  1184  1185  1186

14.4 14.4.1  14.4.2  14.4.3  14.4.4 

Oral Cavity and Oropharynx Congenital Anomalies Branchial Cleft Cysts Inflammatory Lesions Tumors

 1189  1189  1195  1197  1197

14.5 14.5.1  14.5.2  14.5.3 

Salivary Glands Congenital Anomalies Inflammatory Lesions and Non-neoplastic Lesions Tumors

 1203  1203  1203  1205

14.6 14.6.1  14.6.2  14.6.3 

Mandible and Maxilla Odontogenic Cysts Odontogenic Tumors Bone-Related Lesions

 1209  1210  1216  1218

14.7 14.7.1  14.7.2  14.7.3 

Ear Congenital Anomalies Inflammatory Lesions and Non-neoplastic Lesions Tumors

 1218  1218  1218  1220

14.8 14.8.1  14.8.2  14.8.3 

Eye and Ocular Adnexa Congenital Anomalies Inflammatory Lesions and Non-neoplastic Lesions Tumors

 1226  1226  1226  1226

14.9

Skull

 1230

Multiple Choice Questions and Answers

 1233

References and Recommended Readings

 1235

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_14

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14.1 Development The development of the head and neck starts very early in gestation. The head and neck (H&N) early structures include the branchial apparatus, ear primordium, eye primordium, neural tube, oropharyngeal membrane, pharynx primitive, and stomodeum. The stomodeum is the natural oral cavity, lined by the ectoderm, while the neuroectodermal mesenchyme-powered neural tube will form the brain and the spinal cord. The branchial apparatus (vide infra) is constituted primarily by four elements/categories, including branchial arches, skeletal elements, muscles, nerves, and arteries; pharyngeal pouches, entoderm; branchial grooves, ectoderm; branchial membranes and, of course, membrana obturatoria. The embryological formation of the head and neck is also very complicated. When the head is beginning forming in the protoembryonic structure, the embryo is assumed to be composed of three layers of tissue, the ectoderm, mesoderm, and endoderm. These three germ layers become separate during gastrulation in the 3rd week of development. The neurulation is a process involving the fusion of the neural folds and forming the neural tube. The neurulation is completed in distinct stages that include the forming, shaping, and bending of the neural plate. Then the neural plate will progressively advance in the closing of the neural groove. We can also assume that the early head formation is defined by the migration of neural crest cells that arise from the rhombomeres, which are segments of the forming hindbrain. These structures will give rise to differentiated neurons. The two streams of neural crest cells emerge from the first two rhombomeres. These cell streams collaborate in the building of the face and branchial arch system (vide infra). The developing fetal skull is then separated into three sections, including the cranial vault, the cranial base, and the face. During the brain development, a membranous cranium is formed, which becomes the site of cranial (head) osteogenesis. Mesenchymal cells differentiate into osteoblasts without an intermediate cartilage model at week 9 of development. The osteoblasts form an osteoid matrix as well. This osteoid matrix also begins to mineralize. The cranial vault, face, and vomer do not have a cartilage model to follow

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and are of intramembranous origin. The nasal placodes are paired with prominences of ectodermal origin that arise in the 4th week of human development. A placode (neurogenic or placodae neurogenicae) is an epithelial area of condensation of the ectoderm layer of the embryonic head that generate neurons (and other structures) of the sensory nervous system. At the 8th week of embryonic human development, the cheeks and corners of the mouth will progressively form. Once the orbits over the nose form, the face will start to take an identifiable shape. The formation of the sinuses begins then to emerge, but the human development will not be considered completed until into puberty. The splanchnocranium (or visceral skeleton) is the portion of the skull that derives from pharyngeal arches. The splanchnocranium consists of both cartilage and endochondral bone. The pharyngeal or branchial arches begin to form during the 4th week of development. In the human, there are six arches, and they are divided by pharyngeal grooves outwardly and pharyngeal pouches inside. Thus, a groove is constituted of ectoderm unlike its counterpart the pouch on the endodermal side of the developing embryo. Branchial arch musculatures arise from myotomes of somitomeres, which are cell clusters originated from the disengaged masses of paraxial mesoderm that are found at the side of the developing neural tube. The word “groove” derives from the Middle English word “grofe” with the meaning of “cave” and Old English “grōf” with the meaning of “furrow”, while the word “pouch” originates from the Old Low Franconian (West Germanic language or Old Dutch) “poka” with the meaning of a pocket or pouch. The derivatives of the branchial apparatus include: 1. Branchial grooves (a) Branchial groove 1 ⇒ external acoustic meatus (b) Branchial grooves 2, 3, and 4 ⇒ no ultimate “grooving” structure after forming: 1. Cervical sinus 2. Cervical vesicle 2. Pharyngeal pouches (a) Pharyngeal pouch 1 ⇒ tympanic cavity of the middle ear and auditory tube

14.1 Development

(b) Pharyngeal pouch 2 ⇒ crypts of the palatine tonsils and sinus of tonsils (c) Pharyngeal pouch 3 ⇒ external parathyroid glands and thymic epithelial cells (d) Pharyngeal pouch 4 ⇒ internal parathyroid glands (e) Ultimobranchial body (Corpus ultimobranchiale) ⇒ contribution to the thyroid gland (parafollicular or C cells) 3 . Branchial arch musculature (a) Arch 1 gives rise to muscles of mastication (CN V) (b) Arch 2 gives rise to muscles of facial expression (CN VII) (c) Arch 3 gives rise to stylopharyngeus m. (CN IX), which elevates the larynx and the pharynx as well as dilate the phar­ynx allowing the passage of a food bolus assisting the progress of swallowing (d) Arches 4 and 6 give rise to the cricothyroid muscle and intrinsic laryngeal muscles (CN X) The development of the facial structures (splanchnocranium, contrarily with respect to the neurocranium) is highly sophisticated. The development of facial features includes: • • • • • • •

Frontonasal prominence Lens placodes Mandibular prominence Maxillary prominence Medial and lateral nasal prominences Nasal placodes/pits Nasolacrimal grooves

The development of internal structures of the splanchnocranium includes: 1. Nasal cavities and palate (primary – secondary) (a) Median and lateral nasal processes and (b) nasal septum 2. Oral cavity, teeth, glands, and tongue (a) Rostral tongue buds, (b) median tongue bud, (c) caudal tongue bud, (d) hypobranchial eminence, (e) musculature, and (f) innervation

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The specialized structures and functions of the oral cavity are as follows. 1. Taste buds (specialized nerve endings with afferents in the ninth cranial nerve for the posterior tongue and seventh cranial nerve for the anterior tongue). 2. Teeth (structures embedded in the maxilla or upper jaw and mandible or lower jaw with gum, which is the portion of mucosa that is reflected onto the bone). 3. Salivary glands constituted by numerous minor salivary glands and three major pairs, including the symmetrical parotid gland entirely serous and draining through Stensen duct (ductus parotideus) adjacent to the moral teeth, the seromucous submandibular gland emptying through Warthin’s duct into the floor of the mouth, and the seromucous sublingual gland emptying through 10–20 small ducts in the basement of the mouth. 4. Access to nutrients, chewing, lubrification of the bolus, and swallowing of the bolus are the functions of the oral cavity (Greek: βῶλος, “lump, cluster, agglomeration”). 5. Major saliva components: amylase, lysozyme, and secretory IgA. The milestones of the embryology and anatomy regarding the salivary glands are presented in Box 14.1. Another notable structure is the thyroid gland. The growth and migration of thyroid tissue are fundamental! Thyroglossal duct (stalk) eventually

Box 14.1 Embryology Milestones of the Salivary Glands

• Ectodermal origin • 4th-6th week of embryonic development • Serous and mucous cells, arranged in acini, drained by series of small ducts • Parotid gland: serous acini • Submandibular gland: serous and mucinous acini • Minor salivary glands: mucinous acini

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disappears. The thyroid gland diverticulum originates from the floor of the pharynx. In case of persistence of the thyroglossal duct, there will be an ectopic glandular tissue of the thyroid, which may become cystic, inflamed, as well as, more rarely, neoplastic. The pituitary gland primordia include (1) the infundibulum, which forms neurohypophysis and derives from the floor of the diencephalon, and (2) Rathke’s pouch, which forms the adenohypophysis and derives from the roof of the stomodeum. The dissection of complex multiple congenital anomaly syndromes such as agnathiaotocephaly syndromes requires a revision of the anatomic structures and the distribution of efferent cranial nerves. The eye and ear are to be covered later, while the brain is included in the section of the neuroanatomy of the respective chapters, and the teeth are referred to in the next paragraph. Odontogenesis is very important for the understanding of the nontumoral and tumoral pathology of the maxillofacial region. Epithelial buds on the alveolar ridge grow down into the primitive stroma, and the lower jaw or mandible grows around the developing teeth. In fact, an invagination forms and deepens, and it is essential to distinguish between epithelium, which is constituted by ameloblasts (forming enamel of tooth), and stroma represented by odontoblasts (forming dentin of tooth). The five milestones of odontogenesis include: 1. Ecto-mesenchymal projections of the dental lamina 2. Formation of the layered cap (inner/outer enamel epithelium, stratum intermedium, stellate reticulum) 3. Dentin secretion by odontoblasts and enamel secretion by ameloblasts 4. Cementum secretion by cementoblasts 5. Periodontal membrane by fibroblasts Of note, the dental lamina is a primitive epithelium overlying free margins of jaws and gives the origin of primary and permanent teeth, while epithelial rests are responsible for odontogenic cysts and tumors. The structures of the head and neck develop primarily from the branchial arches, which are numbered from cranial to caudally. Four branchial

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arches are well developed and visible on the external surface of the embryo by the 4th week of gestation. The fifth and sixth branchial arches are instead small and located internally. Clefts anatomically separate branchial arches called branchial grooves on the external surface and pharyngeal pouches on the internal surface. Apart from the first branchial groove, all other branchial grooves become obliterated. Histogenetically, each branchial arch consists of mesodermally derived mesenchyme, which is covered externally by ectoderm and internally by endoderm. The several and different mesenchymal structures (bone, muscle, cartilage) of the head and neck arise from the ectodermally derived neural crest cells that migrate into the mesenchyme, proliferate, and induce the formation of the end structures. From the vascular point, each branchial arch is supplied by the correctly numbered aortic arch and has an associated cranial nerve (fifth, seventh, ninth, and tenth, respectively) as follows for the branchial arches. The mandibular arch splits into two prominences including the maxillary (“small” prominence) forming the maxilla or upper jaw, zygomatic bone (from Greek zygon “yoke” meaning “to join”, also known as cheekbone), and a portion of the temporal bone and the mandibular (“large” prominence) forming the mandible or lower jaw. Of note is that the cartilage of the first arch (Meckel’s cartilage) forms malleus and incus. The hyoid arch (upsilonshaped bone) overgrows the third and fourth arches to form the cervical sinus. The hyoid arch also forms a portion of the hyoid bone and the muscles of facial expression, and, mainly, the cartilage of the second arch (Reichert’s cartilage) forms the stapes and the styloid. The third arch forms part of the hyoid bone and the stylopharyngeus muscle, while 4) + 6) build laryngeal cartilage and cricothyroid and pharyngeal muscles. To summarize, the pharyngeal pouch derivatives include: 1. ⇒ External meatus, middle, and inner ear structures, as well as the Eustachian tube. 2. ⇒ Palatine tonsils. 3. ⇒ Inferior parathyroid glands and thymus. 4. ⇒ Superior parathyroid glands. 5. ⇒ It is and remains rudimentary.

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The larynx anatomy is particularly complex. The supraglottic portion arises from the third and fourth branchial pouches (buccopharyngeal anlage).

14.2 N  asal Cavity, Paranasal Sinuses, and Nasopharynx

• The glottis and subglottis portions arise from the fifth and sixth branchial pouches (laryngotracheal anlage). • The cricoid, thyroid, and arytenoid cartilages are of a hyaline type. • The epiglottic cartilage is of elastic type. • Thyroid tissue may be found within the fibrous capsule of the larynx and trachea.

Congenital anomalies of these three anatomic regions include nasal glioma, nasal encephalocele, nasal dermoid, and epignathus (Fig. 14.1). Nasal glioma is a glial heterotopia at the nasal location, which presents as a congenital, firm, stable, polypoid mass with an intranasal and an extranasal component and is composed of neuroglial tissue, which is separated from the intracranial contents. Surgery is curative in almost all cases. Nasal encephalocele is an anterior neural tube defect with herniation of brain tissue through a bony defect in the frontal skull. There is an association with several syndromes. Hydrocephalus and hypertelorism have been observed with nasal encephaloceles. Hypertelorism has also been associated with basal encephaloceles. Corpus callosum agenesis and hydrocephalus are the most often associated anomalies in addition to intracranial cysts, interhemispheric lipomas, and schizencephaly (Tirumandas et al. 2013). Median cleft face syndrome is typically associated with basal encephaloceles. Nasal dermoid is a midline cyst of hamartomatous or teratomatous nature lined by squamous epithelium. There are several genetic syndromes, sequences, and associations where nasal dermoid can have a clinical feature. Hypertelorism, cleft lip and palate, hemifacial microsomia, aural atresia, branchial sinuses, cardiac, gastrointestinal, genital, and central nervous system (e.g., hydrocephalus) anomalies have been associated with nasal dermoid in up to 41% of cases (Van Wyhe et al. 2016). Epignathus is an extremely rare congenital teratoma at the pharyngeal location where all three germ layers are mixed arising in the oral cavity, usually in the nasopharynx attaching to the base of the skull, often the hard palate or mandible. Despite the excellent labeling as a benign tumor, it is associated with high mortality and morbidity rates because of severe airway obstruction and other malformations that may coincide with the presentation.

Finally, an anatomical note should be considered by the pathologist and surgeons. In the last decades, a few cases of bleeding in the tonsillar bed following tonsillectomy have been reported and the experience of the surgeon has been stressed in the most recent literature. Pediatric tonsillectomy is a common procedure. Tonsillectomy is probably one of the first skills acquired by surgical trainees, but post-tonsillectomy bleeding is one of the most significant complications and can be fatal for the patient. Of importance is the anatomy and, mainly, the blood supply of the tonsils. Blood supply is provided by tonsillar branches of five arteries, including the ascending pharyngeal artery (of the external carotid artery), dorsal lingual artery (of the lingual artery), ascending palatine artery (of the facial artery), tonsillar branch (of the facial artery), and the lesser palatine artery (a branch of the descending palatine artery, which is anatomically a branch of the maxillary artery). These blood vessels arise from the external carotid artery. It has been stressed that during surgery, attention must be paid to the internal carotid artery, lingual artery, and glossopharyngeal nerve, but all five arterial blood vessels need to be tackled properly at time of surgery. Post-operative hemorrhage remains a frequent complication of tonsillectomy, but a primary hemorrhage, which occurs in the first hours is rapidly dealt with by the surgical team. Conversely, a rash discharge of the patient with a secondary hemorrhage, which typically occurs once the child has returned home, can be fatal if it is not dealt with quickly.

14.2.1 Congenital Anomalies

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a

b

c

d

e

f

g

h

Fig. 14.1  Nasopharynx  – congenital and inflammatory lesions with chronic sinusitis (a), polyposis nasi et sinuum (b), secretion plugs in polyposis of the nose (c), inflammatory polyp with dense concretions in the lumina in a patient affected with cystic fibrosis (d; hematoxylin and eosin staining, ×200 original magnification), angiofibroma (e–f; hematoxylin and eosin staining, ×12.5 and ×200 as original magnifications), and oncocytic

Schneiderian papilloma (g; hematoxylin and eosin staining, ×40 as original magnification). Oncocytic Schneiderian papilloma, fungiform papilloma, and inverted papilloma are three separate tumors arising from the Schneiderian membrane. Classic 9 + 2 combination in normal cilia (h; transmission electron microscopy, ×20000 as direct magnification)

14.2 Nasal Cavity, Paranasal Sinuses, and Nasopharynx

• EPI: 1  in 35,000–200,000 live births (incidence), ♂  ♀, inverted type), the squamous papilloma (larynx papilloma-­like), the ectopic pituitary adenoma (rare but wide age range), the salivary gland anlage tumor or congenital PA (unusual, neonatal age), and the craniopharyngioma (exceptionally rare as originating from the nasopharynx or through downward extension from a suprasellar location and harboring an identical histology to the intracranial craniopharyngioma). Sinonasal Papilloma • DEF: Benign but locally aggressive neoplasm occurring in the nose and paranasal sinuses, usually youth to middle age, but occasionally seen in patients (♂ > ♀) quite young (Box 14.2). • CLI: Epistaxis and mass effect are two classic presentations. • CLM: Proliferating squamous or columnar epithelium intermixed with mucin-containing cells harboring mild to moderate cell atypia. • PGN: Recurrence is frequent if incompletely excised. Pediatric salivary gland-type adenomas are (1) myoepithelioma, (2) oncocytoma, and (3)

pleomorphic adenoma (PA), which are not different from the salivary gland tumors of adulthood.

14.2.3.2 Malignant Epithelial Tumors Epithelial malignancies include nasopharyngeal carcinoma and sinonasal carcinoma. Nasopharyngeal Carcinoma • DEF: Carcinoma of the nasopharyngeal mucosa (NPC), mostly arising in the fossa of Rosenmüller and superior posterior wall, with light and/or electron microscopy evidence of squamous differentiation, highly aggressive behavior, extensive locoregional infiltration, early lymphatic spread (jugulodigastric LN), and hematogenous metastases (bone > lung > liver > distant LNs). The fossa of Rosenmüller is a lateral recess of the nasopharynx situated behind the Eustachian tube orifice and also regarded as a partial persistence of the second pharyngeal pouch. The 2005 WHO classification of nasopharyngeal carcinoma includes keratinizing squamous cell carcinoma (SqCC), non-keratinizing SqCC (differentiated and undifferentiated subtypes), and basaloid SqCC. • EPI: 2% (Southeast Asia, North Africa, and Arctic regions). • EPG: Epstein-Barr Virus (EBV) (↑IgA to EBV with EBER or Epstein–Barr virusencoded small RNAs present in almost all tumor cells). EBERs are small non-coding RNAs localized in the nucleus of human cells infected with EBV. In carcinogenesis, environmental factors (nitrosamine-rich salted fish/cured meats, smoking, chemical fumes and dust, formaldehyde and radiation exposure) and genetic factors may also play a significant role, which may also be intensified by epigenetic mechanisms. Genetically, LOH on

Box 14.2 Sinonasal Papilloma (“ICE”) Type Inverted Cylindrical Everted

HPV6/11 + − +

Growth Endophytic Endo-/exophytic Exophytic

Site Middle meatus, sinuses Lateral nasal wall Nasal septum

Epidemiology 45% (late youth) 5% (late youth) 50% (early youth)

PGN 10% cancer 10% cancer  CD4 > CD20 lymphocytes, (+CD138, κ/λ-polyclonal) plasma cells, and S100 dendritic cells! It has been reported that cases with numerous lymphocytes and dendritic cells as well as few granzyme B-positive cytotoxic T lymphocytes (CTL) have a better PGN. + EBV (EBER, EBNA1, LMP-1). • DDX: The differential diagnosis of NPC, non-­ keratinizing, includes the following entities: –– Benign mimickers: Clusters of germinal center cells, tangentially sectioned crypts, reactive lymphoid hyperplasia, and lymphoid tissue-associated venules –– Sinonasal undifferentiated carcinoma (SNUC): Sinonasal, EBV (−), (−) keratinization/glandular differentiation/lymphocytes, (−) CK5/6, CK14, 34βE12, but +CK, CK19, EMA, (+) NE markers, including NSE, CGA, and SYN, small

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nuclei, low N/C, and (+) CD68. CD99, VIM, muscle markers, hematolymphoid markers, and melanocytic markers need to be associated in a IHC panel and are negative in SNUC. –– Diffuse large B-cell lymphoma (DLBCL): Hematolymphoid blastic morphology, IHC typical for high-grade B-NHL –– Hodgkin lymphoma: Reed-Sternberg and Hodgkin cells, (+) CD15, CD30, and PAX-5 –– Sarcoma: Various patterns of IHC, of which paramount is to rule out RMS –– Basaloid SqCC is characterized by basaloid differentiation as other tumors of other regions and is accompanied by lower clinical aggressiveness compared to keratinizing and non-keratinizing SqCC. ± EBV (EBER, EBNA-1, LMP-1 according to geographical areas). • PGN: After the therapy with radiation, there is a remarkable 5-YSR of ~75%. Thus, the outcome is r­elatively favorable. Favorable prognostic factors are younger age, female, low plasma/serum EBV DNA titers, euploidy, and low pre-­treatment tumor proliferating fraction. Tumor angiogenesis, c-erbB2, P53, nm23-HI, IL-10, and VEGF have also been indicated to play a role in the outcome. If the tumor is classified as T1, the neoplasm is confined to the nasopharynx or extending to the oropharynx and nasal cavity without parapharyngeal extension, but this last feature with extension beyond the pharyngeal-basilar fascia is characteristic of T2 tumors. In case of bony structures and paranasal sinus involvement, the tumor is classified as T3, while an intracranial extension and involvement of cranial nerves, infratemporal fossa, hypopharynx, orbit, or masticatory space determine the enrollment of the neoplasm as T4. About the LNs, the supraclavicular fossa is the triangle bounded by the superior margin of the sternal head of the clavicle medially, the superior margin of the lateral end of the clavicle laterally, and the point where the neck meets the shoulder posteriorly. In the nasal cavity and paranasal sinuses, several entities have been described, which are

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unusual in children, but they may occur in teenagers and young adults. Malignant epithelial tumors of these two regions include SqCC (NOS and variants), lymphoepithelial carcinoma, SNUC adenocarcinoma (intestinal-type and non-intestinal-type), salivary gland-type carcinomas (adenoid cystic carcinoma, acinic cell carcinoma, MEC, epithelial-myoepithelial carcinoma, clear cell carcinoma NOS, myoepithelial carcinoma, carcinoma ex-PA, and polymorphous low-grade adenocarcinoma or PLGA), and neuroendocrine tumors (typical, atypical and small-cell carcinoma, neuroendocrine type).

14.2.3.3 Benign Mesenchymal Tumors The following entities we may encounter in the differential diagnosis of benign mesenchymal tumor entities in childhood and youth: • Hemangioma, leiomyoma, meningioma, myxoma, nasopharyngeal angiofibroma (NAF), neurofibroma, and schwannoma However, NAF represents most likely the soft tissue tumor mostly characteristic for this location, being the other tumors characterized by histology that is not different from other soft tissue locations. In the past, pyogenic granuloma has often been confused both clinically and histologically with infantile lobular hemangioma. The erythrocyte-type glucose transporter protein (GLUT-1) is useful in the differentiation between infantile and juvenile lobular hemangioma as it is highly expressed in these benign vascular tumors, but not in congenital hemangiomas, pyogenic granulomas, granulation tissue, or vascular malformations. Congenital hemangiomas should be kept in a separate group, including two varieties, the rapidly involuting congenital hemangiomas (RICH) and the noninvoluting congenital hemangiomas (NICH) ( Leon-Villapalos et al. 2005). Nasopharyngeal Angiofibroma (NAF) • DEF: Well-demarcated tumor with the lobular arrangement and tannish to a purple-red aspect, which often manifests in adolescent and young males (androgen-dependent) with

14.2 Nasal Cavity, Paranasal Sinuses, and Nasopharynx

•

•

•

•

•

•

nasal obstruction and epistaxis ± associated with FAP. EPI: Rare (0.5% of all H&N neoplasms), 1:150,000 individuals (incidence), adolescents, and young adults (14–25 years), ♂ > ♀, Indian subcontinent > West countries. CLM: Antler-shaped (irregular) delicate blood vessels with incomplete muscular coats (thin wall without elastic laminae and minimal smooth muscle), particularly at the periphery, embedded in a collagenized stroma, which can explain the propensity to bleed extensively during surgery. The stroma contains spindle to stellate cells with plump nuclei and, occasionally, MNGC. IHC: (+) VIM, CD31, CD34, AR, but (±) SMA in the stromal cells, (+) SMA in the perivascular cells only, and (−) ER/PR in the vasculature, perivascular cells, and stromal cells. Movat pentachrome stain is useful to highlight the thin wall without elastic laminae and minimal smooth muscle. TEM: Tight nuclear RNA-protein complexes implement dense round granules in fibroblasts. DDX: 1. Lobular arranged capillary hemangioma (LACH) (lobular, (+) CD31, CD34, GLUT1) 2. Hemangiopericytoma (HPC) (Ret-rich, (+) VIM, FXIIIa, CD57, CD99, Bcl2, (−) CD34) 3. Solitary fibrous tumor (SFT) (tangled network of fibroblast-like stromal cells with abundant depots of Ret and collagen fibers, EVG-rich, (+) CD99, Bcl2, CD34, STAT6) 4. Vascular angiosarcoma (VAS) (atypia ± ↑ mitoses) PGN: After the resection with clear margins, the NAF usually does not recur. However, recurrence is reported in 1/5 of the patients (20%) with incomplete resection. Occasionally, sarcomatoid transformation following RT, and rarely metastases have been observed.

14.2.3.4 Other Tumors Bone/Cartilaginous Forming Tumors Benign tumors include giant cell lesion, giant cell tumor, osteoma, chondroma, chondroblastoma,

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chondromyxoid fibroma, osteochondroma, osteoid osteoma, osteoblastoma, ameloblastoma, and nasal chondromesenchymal hamartoma. Malignancies include osteosarcoma, chondrosarcoma NOS, mesenchymal chondrosarcoma, and chordoma. Hematolymphoid Tumors There are a few entities that may occur in the nasal cavity, sinonasal cavities, and nasopharynx of adolescents and young adults and include extranodal NK/T-cell NHL, DLBCL, Burkitt lymphoma, extramedullary myeloid sarcoma, Langerhans cell histiocytosis (LCH), and juvenile xanthogranuloma (JXG). Other entities, which are pertinent to the youth and middle-aged adults, may include follicular lymphoma, mantle cell lymphoma, extranodal marginal zone B-cell lymphoma, peripheral T-cell lymphoma NOS, extramedullary plasmacytoma, and histiocytic sarcoma. Histiocytic sarcoma that needs to be differentiated from LCH shows large pleomorphic cells with eccentric, indented nucleus and prominent eosinophilic cytoplasm with fine vacuolations showing (+) CD45, CD68, and lysozyme and (−) CD19, CD20, CD22, Cd79a, or pan-B markers, (−) CD3 or pan-T marker, (−)  MPO or myeloid marker, (−) CD1a and Langerin, and (−) CD21, CD35, aka FDC markers. Other hematolymphoid tumors that may involve the nasopharynx are Castleman disease and Rosai-Dorfman disease (sinus histiocytosis with massive lymphadenopathy or SHML). Extranodal NK/T-Cell Lymphoma (EN-NK/T-NHL) NHL with extensive effacement (see hematological chapter). Diffuse Large B-Cell Lymphoma (DLBCL) NHL (see hematological chapter). A DLBCL mimicker is the IM and needs to be suspected in the case of an adolescent or young adult. It is recognized by the presence of a range of large cells showing maturation toward plasma cells, lack of frank cytologic atypia, and polyclonal κ/λ immunophenotypic expression of the large cells.

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Extramedullary Myeloid Sarcoma (EMS) • DEF: Myeloid or granulocytic-differentiated sarcoma at extramedullary location (nasal cavity, paranasal cavities, and nasopharynx) constituted by an extramedullary manifestation of acute myeloid leukemia (AML), which can be antecedent, synchronous, or metachronous to EMS. EMS is characterized by a diffuse chloroacetate esterase reaction (histochemical special stain) in ~3/4 of cases determining the green color and the old labeling of chloroma to this lesion. • CLM: Blast cells with round to ovoid nuclei, fine chromatin, small but distinct nucleoli, and lightly eosinophilic cytoplasm with eosinophilic granules are detected mixed with eosinophilic myelocytes and metamyelocytes. Giemsa-stained touch preparation is useful to identify cytoplasmic azurophilic granules and Auer rods, when present. • IHC: + MPO, CD13, CD33, CD117, CD68/ KP1, neutrophil elastase, and lysozyme. However, EMS with monocytic differentiation is MPO (−), but CD68/PGM1 (+). • DDX: NHL. Langerhans Cell Histiocytosis (LCH) • DEF: Clonal proliferation (variable) of Langerhans cells in nodal or extranodal H&N tissue. • SYN: Eosinophilic granuloma, histiocytosis X, Langerhans cell granulomatosis. • EPI: Children 90%). Locations include the maxilla, mandible, skull, and brain. Extracranial sites are the genitals. • CLI: Painless, nonulcerative, expansile, rapidly growing lesion with intriguing pigmentation and having locally aggressive behavior. • DGN: Clinical assessment, CT/MRI, and histopathology. • CLM: Biphasic tumor, comprising neuroblast-­ like round cells and melanocytic cells. • DDX: PNET/Ewing sarcoma, desmoplastic small round cell tumor, RMS, peripheral neuroepithelioma, neuroblastoma, NHL, and malignant melanoma. • TRT: Surgical excision, CHT, and RT alone or combined. • PGN: High recurrence rate with metastases and malignant transformation rate. Mucosal Malignant Melanoma See dermatological chapter. Germ Cell Tumors Teratoma, mature and immature and with malignant transformation, yolk sac tumor (aka endodermal sinus tumor, YST/EST), sinonasal teratocarcinosarcoma, mature teratoma, and dermoid cyst represent the germ cell tumors that can occur in the nasal cavity, paranasal sinuses, and nasopharynx. These tumors are similar to the tumors of the male and female genital system. Secondary Tumors They are very rare in pediatric groups, although the neuroblastoma may be considered one

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tumor that is tending to metastasize or localize in the head and neck region.

14.3 Larynx and Trachea The non-neoplastic and neoplastic lesions of the larynx and trachea are shown in Box 14.3.

Box 14.3 Larynx and Trachea Lesions

14.3.1. Congenital Anomalies 14.3.2. Cysts and Laryngoceles 14.3.3. Inflammatory Lesions and Non-­ neoplastic Lesions 14.3.4. Tumors

14.3.1 Congenital Anomalies 14.3.1.1 T  hyroglossal Duct Cyst and Laryngeal Disturbances One of the most common etiologies for a median neck cyst is the thyroglossal duct cyst. Embryologically, the primitive anlage of the thyroid gland descends from the pharyngeal location at the 3rd week of gestation to the front of the pharynx by the 7th week. An enlargement of any persistent portion of this duct and subsequent secretion from the duct epithelium are few of the most common evolutions. Thyroglossal duct remnants are approximately seen in 1:20 individuals of a general population. In about 85% of cases, they are located between the hyoid bone and thyroid gland. In 13–14% of cases, thyroglossal duct remnants are seen at the level of the hyoid bone while in 1–2% are detected at the level of the tongue. A lingual thyroglossal duct cyst is particularly crucial for the weakening of the surrounding tissue of the laryngeal pharynx. This aspect may involve the base of the epiglottis, resulting in fragile laryngomalacia with significant clinical symptoms. An enlarged cyst may press on the epiglottis, irritate it, and become drawn into the vocal cords or ventricle of Morgagni (Morgagni’s sinus, ventriculus laryngis).

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14.3.1.2 Laryngomalacia In pediatrics, stridor is commonly observed and described as a high-pitched, wheezing sound, which is caused by a disrupted airflow of the trachea. The most common etiology of stridor in babies is laryngomalacia (Greek: μαλακία, “softness”), which affects 1/2–3/4 of all infants with congenital stridor. It is characterized by the inward collapse of laryngeal structures, resulting in a narrow air passage and turbulent airflow during inspiration. Typically, laryngomalacia is characterized by the inner destruction of laryngeal structures. This pathology occurs in a restricted air passage and turbulent airflow during inspiration. Clinically, a high-pitched intermittent inspiratory stridor during the first 2–3 weeks of the neonatal period is observed. The severity of laryngomalacia can be mild, moderate, or severe. In most cases, laryngomalacia is mild, and there is inspiratory stridor with a coordinated suck-swallow-breathe sequence. In these cases, no therapy is required, because the spontaneous resolution is seen in the first infancy in about 2/3 of children. In case of severe laryngomalacia, poor weight gain, feeding difficulties, choking, post-feeding vomiting, cyanosis, dyspnea with intercostal and suprasternal retractions, and failure to thrive may occur. Aryepiglottoplasty is the surgical treatment of choice. It has a high success rate and harbors a low complication rate. Rilliet and Barthez (1853) were the first to describe congenital stridor, while Sutherland and Lack (1897) published a detailed review including the first description of a congenital laryngeal obstruction. In 1942, Jackson first used the term “laryngomalacia,” with the meaning of “soft larynx”, to characteristically describe a disorder in which supraglottic tissue collapses onto the laryngeal airway during inspiration. Cartilage floppiness due to developmental abnormalities and immaturity, anatomical variation in the neonate larynx, gastroesophageal reflux, poor neuromuscular control, and hypotonia have been suggested to be etiologic and etiopathogenetic associated with laryngomalacia. However, cartilage is often histologically normal in patients with symptomatic laryngomalacia. Numerous pediatric centers have demonstrated that patients with laryngomalacia have impaired the senso-

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rimotor function of the larynx due to some alteration or adaptation in the laryngeal adductor reflex arch prompting more neurologic research on this topic. Some genetic syndromes have been associated with laryngomalacia, including 22q11.2 microdeletion syndrome, CHARGE syndrome, Cornelia de Lange syndrome, Costello syndrome, Cri du chat syndrome, trisomy 21 (Down) syndrome, oculo-ectodermal syndrome, Sotos syndrome, and the Pierre Robin sequence, which is a set of abnormalities affecting the splanchno- and neurocranium, consisting of micrognathia, glossoptosis, and obstruction of the airways. Congenital anomalies and genetic disorders occur between 1:10 and 1:5 as estimated incidence. However, the incidence is as high as 40% of infants with severe laryngomalacia who require surgical intervention. Noteworthy, infants with congenital anomalies and genetic disorders may often present with other medical comorbidities such as synchronous airway lesions, cardiac and vascular disease, and neurologic disease. Trisomy 21 syndrome (Down syndrome) appears to be the most commonly reported associated genetic disorder, with 50% who have respiratory symptoms presenting with laryngomalacia. Benign tumors are granular cell tumor, recurrent respiratory papillomatosis, and squamous papilloma. Dysplastic and invasive squamous lesions are squamous dysplasia, SqCC, early invasive SqCC, and invasive, usual type of SqCC, and SqCC variants (verrucous, papillary, basaloid, spindle cell). Neuroendocrine tumors are carcinoid, atypical carcinoid, small-­ cell carcinoma (SmCC), and large-cell carcinoma (LCC), while mesenchymal tumors are chondroma and chondrosarcoma.

14.3.2 Cysts and Laryngoceles According to DeSanto Classification of Laryngeal Cysts (1970), two major types are recognized, including saccular cysts and ductal cysts. The frequency is 1/4 for saccular cysts and 3/4 for ductal cysts. Two more rare cysts are the oncocytic cyst and tonsillar cyst. Congenital laryngeal cysts seem to be more common in the British-Pakistani population. The saccular cyst arises from a cystic

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enlargement of the laryngeal saccule and is supraglottic, while the ductal cyst originates from dilatation of mucous glands and is located in the true cords or epiglottis. Some neonatal airway obstruction may be associated with saccular cysts. Both squamous and respiratory epithelium can line both cysts. Saccular cysts manifest earlier, often with stridor, while ductal cysts present later with feeding difficulties and failure to thrive. Both cysts are treated with endoscopic marsupialization at the time of diagnostic laryngoscopy in most of the cases without extralaryngeal extension. As indicated above, two additional rarer cysts include the oncocytic cyst, as oncocytic metaplasia of a ductal cyst, and the tonsillar cyst, which contains thyroid glandular tissue. Unlike saccular cysts, laryngocele is an air-containing saccular dilatation, which is located at the appendix of the laryngeal ventricle. Generally, laryngoceles communicate with the lumen of the ventricle through a tiny and narrow pedicle. Laryngocele arises typically from the laryngeal ventricle and extends into peri-laryngeal space. Although the etiology is unknown, laryngocele seems to be probably related to both congenital and acquired factors. Historically, it seems that Larrey, a very influent Napoleon’s surgeon, in 1829, has given the first report on laryngocele. Larrey collected a series of laryngoceles in individuals who apparently would hourly chant the Koran from the minarets. In 1958, laryngocele was analyzed in detail from Burke and Golden. Since then, it seems that a structure to be considered as laryngocele needs to have a Morgagni’s ventricle that extends beyond the superior border of the thyroid cartilage. Subsequently, following its distinction from saccules, the definition was changed, being a laryngocele a large Morgagni’s ventricle, i.e., an air-containing saccular dilatation, which is located at the appendix of the laryngeal ventricle and explicitly communicating with the lumen. Laryngocele may substantially be due to prolonged periods of increased pressure within the laryngeal lumen as observed in people blowing in the wind musical instrument. It is more frequent in males (5:1) with the highest incidence in the late adolescence/youth, but laryngoceles in children have been described. There are some addi-

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tional associations, including laryngeal amyloidosis, laryngeal chondroma, history of a tracheotomy, papillomatosis, or ankylosing spondylitis. Patients with an internal laryngocele usually complain of some symptoms, including hoarseness, dyspnea, foreign body sensation, and cough. • CLI: Laryngoceles may manifest with coarse hoarseness, dyspnea, and chronic cough. • CLM: Cystic cavities lined by pseudostratified, columnar, ciliated epithelium with occasional foci of stratified squamous epithelium and a variable mixture of serous and mucous glands characteristically at the submucosal location. In our opinion and that of others, this peculiar composition distinguishes these lesions from laryngeal cysts, which are specially lined entirely by squamous epithelium. In evaluating a laryngocele, the CT scan shows air- or mucus-containing tumor at the level of the false cord. Laryngocele may complicate and have a theoretical risk of malignancy, having been SqCC of the larynx arising in a laryngocele described. This event, although rare, has been reported in a 20-year-old nonsmoker male (Murray et al. 1994).

14.3.3 Inflammatory Lesions and Non-neoplastic Lesions Non-neoplastic lesions that may be considered are blastomycosis, contact ulcer, laryngeal amyloidosis, laryngeal cysts (ductal, saccular, oncocytic, tonsillar), laryngocele, melanosis, laryngitis, Teflon granuloma, and vocal cord nodule/vocal cord polyp. Laryngocele and laryngeal cysts have been discussed above.

14.3.3.1 Acute Epiglottitis H. influenzae infection of the epiglottis with cherry red, markedly edematous epiglottis leading often to airway obstruction. It is life-threatening. 14.3.3.2 Chronic Laryngitis Nonspecific and usually, the result of an infective disease, overuse of the voice, physical/chemical

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exposure, or irritation by inhalants, alcohol, vaping (e-cigarettes), and tobacco

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an intermediate squamous cell with optional binucleation. • DDX: Adult laryngeal papilloma (♂ > ♀, often 14.3.3.3 Granulomatous Laryngitis solitary, more inflammatory component, usuGranulomas-accompanying chronic laryngitis ally single, moderate to severe atypia, carciwith granulomas that can be seen in a variable noma precursor) and verruca vulgaris. The clinical setting, such as tuberculosis, histoplaspapillomatous structure should be clearly evimosis, blastomycosis, but also Crohn disease, dent to make the diagnosis of a papilloma and sarcoidosis, and foreign body granuloma (aka this structure needs to be kept differentiated “teflonoma”). Also, SHML may also involve the from a polypoid structure. larynx. • TRT: Surgery, laser, and cryotherapy. • PGN: Repeated surgical revisions may lead to 14.3.3.4 Laryngeal Nodule the progressive and inexorable destruction of It is a non-inflammatory reaction of the vocal the cords. In 2018, Orita et al. studied 77 papcord, chiefly anterior 1/3, to injury, such as misilloma patients. In 21 cases with laryngeal use of the voice, and characterized by edema and papilloma, various types of HPV were identiamorphous eosinophilic material beneath intact fied: 18 (52.9%) were positive of low-risk epithelium (types/stages: telangiectatic, fibrous, HPV, 14 cases (41.2%) were positive of highhyaline, and edematous or myxoid). risk HPV, and 11 (32.4%) were positive of both high-risk HPV and low-risk HPV. Young 14.3.3.5 Contact Ulcers of Larynx patients showed a higher rate of HPV infecLively granulation tissue or pyogenic granuloma-­ tion than old patients. No malignant transforlike tissue lesion occurring on the posterior commation was observed among the patients with missure. Unlike pyogenic granuloma, the lobular laryngeal papilloma. The immunohistochemipattern is not seen. cal staining with p16 (a tumor suppressor protein, encoded in humans by the CDKN2A gene playing an important role in cell cycle 14.3.4 Tumors regulation and used as a biomarker to improve the histological diagnostic accuracy of HSIL), 14.3.4.1 Papilloma (Juvenile i.e., positive expression of p16, was observed Laryngeal Papilloma) in 20 cases. HPV infection and p16-expres• DEF: Juvenile laryngeal human papilloma sion were strongly associated with the pathovirus (HPV)-facultative/obligate papilloma logical finding of koilocytosis. It is important with single or multiple benign epithelial histo remember that overexpression of p16 is tology arising on true cords and optional usually caused by the HPV, whereas neospread to the false cords, epiglottis, and traplasms showing p16 downregulation may cheobronchial tree as well as a tendency to have other causes. recurrence. • ETP: HPV-6- and HPV-11-related neoplasms. Juvenile recurrent papillomatosis is seen as an • CLM: Papillary or acanthotic growth of well-­ HPV 6-/11-associated, multiple papillary tumors differentiated squamous epithelial cells with on the true cords, from which they may dissemimild atypia, some mitoses overlying a fibro- nate to the false cords, epiglottis, and deeper into vascular core and an accompanying mild the trachea and bronchial system. An orderly inflammatory component. Koilocytosis is maturation pattern is characteristic of the benigdefined by a cytoplasmic perinuclear cavita- nancy of this lesion, although mitotic activity is tion, nuclear hyperchromasia, irregular present and focal atypia may be present and kept nuclear border, and nuclear enlargement to at in mind when reporting such lesions. A comment least 3 times the size of a nucleus belonging to in the histopathological report is often useful to

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the clinical pediatrician for the follow-up of these patients. There is a low risk to progress to squamous cell carcinoma, differently from the adult laryngeal papilloma showing moderate to severe atypia.

14.3.4.2 Laryngeal Carcinoma • DEF: Malignant epithelial tumor of the larynx. Its delineation as oncological entity is a rarity in children and adolescents (McGuirt et al. 1997). A significant issue remains the diagnosis at late stages because early symptoms are often attributed to inflammatory diseases or developmental anomalies. This issue may be considered a worse-case scenario, but it is similar to the adult counterpart. The flexible laryngoscope allows the first visualization of vocal cords and may be essential to address neoplastic diseases at pediatric age. Juvenile laryngeal papillomatosis is on the top of the list of the neoplastic conditions in children and adolescents. However, rare neoplastic disorders occur, and in most of the cases, there are no established protocols. • EPI: Fifth to seventh decades but also children and adolescents. It is imaginable that the use of vaping (e-cigarettes) may decrease the lower range value of the age incidence for laryngeal cancer in the future. ♂ > ♀. • EPG: Tobacco (probably also e-cigarette and vaping), alcohol, GERD (controversy exists for asbestos and HPV) and Bloom syndrome (predisposition to laryngeal and hypopharyngeal cancer). The knowledge of the genetic syndromes associated with laryngeal carcinoma is essential for the pediatric pathologist. Two other genetic/dysmorphology syndromes, apart from the common cancer genetic syndromes, may be associated with the onset of laryngeal carcinoma. They include the Pierre Robin sequence and the Treacher Collins syndrome. In both conditions, the inflammation may play a role of promoting factor following an initiation process, which can be variable. Bloom syndrome is an autosomal recessive inherited syndrome characterized by short stature, sun-sensitive skin changes, high-pitched voice, long, nar-

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row face with micrognatia (small jaw), large nose, and prominent ears. BLM gene mutations have been associated with individuals affected with Bloom syndrome. Treacher Collins syndrome is an autosomal dominant/ recessive inherited syndrome characterized by underdeveloped facial bones, specially the cheek, micrognathia, cleft palate, eye abnormalities, and hearing loss. Treacher Collins syndrome may be caused by mutations in the TCOF1, POLR1C, or POLR1D genes. Pierre Robin sequence is a congenital condition characterized by micrognathia, glossoptosis (back-set tongue), and cleft palate associated with SOX9 gene mutations. • CLI: There is quite a variability, which is correlated to the anatomic site of occurrence. The site can influence the type of symptoms, stage at presentation, treatment, and prognosis. An example is a tumor localized at the base of the epiglottis that is difficult to detect during laryngoscopy (aka “Winkelkarzinom” or corner carcinoma). Second primary tumors (SPT) are tumors distinctly separated from the primary or index carcinoma and labeled as synchronous if they are detected within 6 months from the first diagnosis of the primary ­malignancy. If SPT occurs >6  months, it needs to be classified as a metachronous. neoplasm (Greek: σύγχρονος “contemporaneous” and μετάχρονος “non coeval” from respectively σῠν- “with, together” or μετά “after” with χρόνος “time”). • CLM: >95% are squamous cell carcinomas which are either well, moderately, or poorly differentiated. • PGN: The outcome of laryngeal carcinoma is linked to some prognostic factors (Box 14.4). The box contains major useful prognostic factors like those provided from the College of American Pathologists (CAP) simplified to memorize in dealing of laryngeal carcinomas in children and youth. It is important to check clinical history and consult geneticists, because in many countries genetic information is not provided in the electronic medical record or the patient’s chart.

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Box 14.4 Good (Green Highlighted) and Poor (Red Highlighted) Prognostic Factors (1) Small size (2) Location (glottic and supraglottic) (3) Overexpression of TP53 (1) Extensive cartilage invasion (2) TNM stage IV (3) Co-morbidities

Remarkably, it seems that in the hypopharynx, the outcome is inversely related to TNM stage and extracapsular spread. Moreover, trachea, mediastinal and distant metastases are very poor prognostic factors. The histologic variants and subtypes of laryngeal carcinoma are as follows. • Verrucous: Non-metastasizing (good PGN), usually glottic, carcinoma variant characterized by abundant “church-spire” arranged keratosis, broad pushing border of infiltration accompanied by dense lymphocytic and plasmacellular host response, and slow, locally invasive growth. • Papillary: Low-metastasizing (favorable PGN), exophytic papillary growth, usually supraglottic/glottic, carcinoma variant made up of well-defined papillary stalks with thin fibrovascular cores lined by immature basaloid cells ± pleomorphism and minimal keratosis. • Spindle cell (sarcomatoid): Low-­metastasizing (favorable PGN), glottic, polypoid mass with a monoclonal epithelial component with dual/ divergent differentiation showing (+) AE1/ AE3 and VIM as well as (±) SMA, MSA, and DES. • Basaloid: Aggressive (poor PGN), usually supraglottic, carcinoma characterized by a substantial lobular growth of two components, i.e., basaloid (+ 34βE12 reacting with CK1, 5/6, 10, and 14) and squamous cells, peripheral palisading, comedo-type necrosis, PAS +/AB+ intercellular microcysts, and stromal hyalinization. • DDX: NE tumors (no squamous differentiation, (+) CGA, SYN, NSE, CD56, CD57,

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PGP9.5), AdCC (myoepithelium), and ASqC (true ductulo-­ glandular differentiation and intracellular mucin). Although several biomarkers Although several IHC markers have been described to identify a NET, the most widely used and reliable NE markers remain to date CGA and SYN. • Acantholytic: Variant characterized by marked acantholysis of squamous cells forming pseudolumina, anastomosing spaces and channels slightly more aggressive than SqCC.  The acantholytic variant may simulate ASqC (+ mucin), AdCC (myoepithelium), MEC (+mucin, lobular arrangement, large clear intermediate cells, limited keratin pearls, and no CIS component), and angiosarcoma (+CD31).

• Adenosquamous: Aggressive (poor PGN) with both squamous and glandular differentiation.

The importance of the surgical report does not need more stress at this time, but often phone calls from the radiotherapists or pediatric oncologists are encountered in the routine practice because the text may be not completely clear and the CAP protocol or minimal dataset has some discordances with the text describing the lesion. Thus, maximal care in reading the reports before signing out is paramount. Critical reports require critical communication (Sergi 2018). The surgical pathology report should include the type of surgical procedure (hemi-, supraglottic, or total laryngectomy); accompanying material, such as neck dissection, thyroid gland, and parathyroid glands; site of origin; size and extent of tumor; histologic type and grade; perineural, lymphovascular, cartilaginous, and/or extralaryngeal invasion; and status of the resection margins. In hypopharyngectomy specimens, it is essential to indicate the laterality of the involvement of piriform sinus, postcricoid

14.4 Oral Cavity and Oropharynx

area, or posterolateral pharyngeal wall. If we receive a sample from a tracheal resection, the length of the trachea and the eventual intra- or extraluminal involvement also need to be on board of the report. Neck dissection findings should include the total number of nodes specified for each level, the number of nodes positive for tumor, the size of the largest positive node, and the presence or absence of extracapsular tumor spread. Other laryngeal tumors include epithelial and mesenchymal neoplasms. Epithelial tumors include lymphoepithelial carcinoma, giant cell carcinoma, malignant salivary gland-like tumors (MEC, AdCC), tumors with neuroendocrine differentiation (typical carcinoid, atypical carcinoid, and small-cell carcinoma), soft tissue tumors (benign and malignant and IMT, which is borderline or LMP), hematolymphoid tumors, tumors of bone and cartilage, mucosal malignant melanoma, and secondary tumors. The term SILs or squamous intraepithelial lesions has been proposed as an abbreviation including the whole spectrum of epithelial changes, ranging from reactive lesions to carcinoma in situ (CIS). As part of this spectrum, it has been chosen by dysplasia and later also squamous intraepithelial neoplasia (SIN) or, more precisely, laryngeal and oral SIN.  All these terms, which have been directly adopted from precursor lesions of the uterine cervix, do not include a spectrum of reactive epithelial changes, as do some systems, for instance, the Ljubljana classification. Comprehensively, all epithelial precursor lesions include squamous cell hyperplasia, mild dysplasia (aka squamous intraepithelial neoplasia/SIN 1, basal/parabasal cell hyperplasia), moderate dysplasia (aka SIN 2, atypical hyperplasia), severe dysplasia (aka SIN 3, atypical hyperplasia), and CIS (aka SIN 3).

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Box 14.5 Lesions of the Oral Cavity and Oropharynx

14.4.1. Congenital Anomalies 14.4.2. Branchial Cleft Cysts 14.4.3. Inflammatory Lesions 14.4.4. Tumors

14.4.1 Congenital Anomalies Congenital and developmental anomalies of the oral cavity and oropharynx have been part of the nonmedical literature and inspired several authors. They are itemized here as follows. 1. Fordyce granules (ectopic sebaceous tissue on the vermilion rim of lips and oral mucosa) 2. Lingual thyroid (thyroid gland tissue at the basis of the tongue) 3. Nasopalatine duct cyst (ciliated, mucous, squamous lining cyst)

14.4.1.1 Gingival Cysts Often observed in newborns with no gender bias with an origin from the dental lamina, these nodules are small, multiple, and whitish located on the crests of the maxillary and mandibular dental ridges. • CLM: Keratin-filled true cysts. • TRT: Not indicated (self-resolution).

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14.4.1.2 Epstein Pearls Asymptomatic nodules of the mid-palatal raphe region along the line of fusion with no gender bias with an origin from entrapment of epithelial remnants. Epstein pearls need to be differentiated from Fox-Fordyce spots, which are characterized by sebaceous glands in the mouth, other than face and genitals. Fox-Fordyce “pearls” are typically small, painless, raised, white spots or bumps of small size (0.1–0.3 cm) and are not associated with any disease or illness.

The lesions of the oral cavity and oropharynx are listed in Box 14.5 (Figs. 14.5, 14.6, and 14.7).

• CLM: Nonodontogenic, keratin-filled cysts. • TRT: Not indicated because of self-resolution.

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a

b

c

d

e

f

g

h

Fig. 14.5  The first three microphotographs show a chronic tonsillitis with normal polarization of the follicles (a, ×50; b, ×100) and actinomycosis (c, ×100). All three microphotographs are from histological slides stained with hematoxylin and eosin. A pauperization of the lymphoid tissue may be present in patients with HIV infection and progression to acquired immunodeficiency syndrome (d, ×100, hematoxylin and eosin staining). An irritation fibroma of the mouth is shown in (e) (×12.5, hematoxylin and eosin staining). Echinococcus cyst can be a sudden discovery in

salivary gland mass with a cystic component or a cystic expression as shown in (f) (×50, hematoxylin and eosin staining). Figure (g) shows a papilloma of the oropharynx in an adolescent (×40, hematoxylin and eosin staining), while figure (h) (×200, P16 immunostaining) shows the histology of uvula papillomatosis, human papilloma virus (HPV) driven. P16 is a cyclin-dependent kinase inhibitor that regulates the cell cycle and cell proliferation mediating the inhibition of G1 progression of the cell cycle. P16 is a useful biomarker for transforming HPV infections

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a

b

c

d

e

f

g

h

Fig. 14.6  This panel shows a hemo-lymphangioma of the tongue with enlarged cystic spaces, most of them filled with pink eosinophilic secretion (a, ×12.5), although some spaces contain also red blood cells (b, ×100; c, ×12.5; d, ×100). The immunohistochemistry panel shows

the expression of D2-40 (podoplanin) (e, ×50; f, ×100; g, ×100) and focal expression of CD31 (h, ×100). All immunostaining sections have been performed by avidin-biotin complex

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a

b

c

d

e

f

Fig. 14.7  A teratoma with ectodermal, mesodermal, and endodermal differentiation (a, ×12.5; b, ×12.5; c, ×12.5; d, ×200; e, ×200; f, ×200). Pigmented retina epithelium is

seen in (e). All microphotographs are taken from histological slides stained with hematoxylin and eosin

14.4.1.3 Bohn’s Nodules They are keratin-filled cysts with the prevalence of 47.4% with no apparent gender bias. They are derivatives of palatal salivary gland structures. They clinically appear as numerous nodules along the junction of the hard and soft palate.

impediment of the eruption by overlying dense fibrotic mucosa.

• CLM: Nonodontogenic, keratin-filled cysts. • TRT: Not indicated (self-resolution).

14.4.1.4 Eruption Cyst Cysts are originating from degenerative cystic changes in the reduced enamel epithelium or the remnants of the dental lamina due to an

• CLI: Bluish, dome-shaped, translucent, compressible mucosal nodules, which overlie the erupting tooth. • TRT: Marsupialization or surgical extraction.

14.4.1.5 Epidermoid and Dermoid Cysts • DEF: True cysts with squamous epithelial lining differentiated by the presence (dermoid) or absence (epidermoid) of adnexal tissue.

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• EPI: 7% (incidence) in the H&N region. • CLI: Slow-growing asymptomatic unpleasant cysts located commonly in the floor of the mouth and submental region with potential respiratory distress and feeding difficulty in newborns. • DGN: Prenatal/natal US, MRI/CT, FNAC, and histopathology following enucleation. • DDX: Ranula, dermoid cyst, teratoma, heterotopic gastrointestinal cyst, duplication foregut cyst, and lymphatic malformation. • CLM: Epithelial-lined cavities with lumen with or without an adnexal tissue. • TRT: Surgery. • PGN: Recurrence is rare. If it does happen, the pathologist/surgeon needs to review the slides.

14.4.1.6 Maxillary Osteomyelitis of the Newborn • DEF: Life-threatening infection of the maxillary bone observed in the neonatal period. • EPI: 1–7 per 1000 children’s hospital ­admissions with ♂ > ♀ (1.6:1) and preterm predilection. • EPG: Infection due to S. aureus, group B streptococcus, E. coli, and K. pneumoniae. RFs are iatrogenic procedures (e.g., catheterization), prolonged hospitalization, parenteral nutrition status, ventilatory support, and nosocomial infections. • CLI: Acute onset of fever followed by edema and redness of cheek, swelling of eyelids with conjunctivitis, and unilateral nasal discharge. • DGN: (+) blood cultures ((+/↑) ESR, CRP, PMNs). • TRT: Antimicrobial drugs ± surgery. • PGN: Poor with high morbidity/mortality (quoad vitam et valetudinem). 14.4.1.7 N  eonatal Herpes Simplex Virus Infection • EPI: 1 in 3000–20,000 live births. • EPG: HSV1 (orolabial and genital) and HSV2 (genital). The transmission happens during the time of birth delivery and is facilitated by the status of maternal antibody,

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maternal infection, i.e., primary or recurrent, duration of rupture of membranes, the integrity of mucocutaneous barriers, and mode of delivery, i.e., cesarean or normal. There is an incubation period of 4–21 days after delivery, and symptoms appear between 6 and 21 days. CLI: Eruptive vesicular rash (one single lesion to clusters) with 1–3 mm lesions involving the face (e.g., mouth), scalp, feet soles, and palms of the hand with a tendency to ulcer within a few days. The rash may be escorted by constitutional symptoms including cyanosis and respiratory distress, seizures, hepatitis, pneumonitis, and DIC. DGN: Serology, PCR of CSF, and viral cultures. TRT: Acyclovir (a synthetic nucleoside analogue). PGN: ~ good (0% mortality rate) in the case of SEM, but 70% for disseminated lesions.

14.4.1.8 Neonatal Candidiasis • DEF: Life-threatening Candida infection with disseminated or invasive candidiasis being, probably once, the second most common cause of mortality in the neonatal period. • EPI: 2–20% in preterm newborns. • ETP: Candida species with C. albicans in 3/4 of cases (1/4: C. glabrata, C. krusei, C. tropicalis, and C. parapsilosis). The transmission can be vertical or due to external ­contaminations. RFs include immaturity of the neonatal immune system, prolonged catheterization and hospital stay, and previous antibiotic treatment of the mother during delivery. • CLI: White plaques on oral mucosa. Complications include meningitis, endophthalmitis, endocarditis, and urinary tract infections. • CLM: Hyphae, epithelial cells, and necrotic tissue (cell debris). • DGN: Blood cultures, urine, and CSF. • TRT: Antifungal treatment. • PGN: If the pediatrician starts a calibrated antimycotic therapy efficiently and without delays, morbidity and mortality rates are remarkably decreased.

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14.4.1.9 Mucocele • DEF: Entrapped mucin (pseudocyst) of retention or extravasation type in the oral mucosa. • EPI: 2.7% of patients ♀. • CLI: Most frequent locations include the tongue (lingual choristoma), the floor of mouth, the pharynx, and the hypopharynx. The lesion can present as an asymptomatic mass of variable size causing obstruction in feeding and respiration in newborns. • DGN: Clinical examination, imaging, and histopathology. • DDX: Mucocele of extravasation type, ranula, lymphatic malformation, venous malformation, and dermoid cyst. • TRT: Surgical excision. • PGN: No recurrence is described.

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14.4.2 Branchial Cleft Cysts • DEF: Congenital ectoderm-derived (epithelial) cysts. The etiology for the branchial cleft cysts resides in a failure of the obliteration of the second branchial cleft during the development of the embryo. They are located on the lateral part of the neck. From the phylogenetical point of view, the branchial apparatus is intimately related to gill slits. In fact, the name branchial derives from the Greek branchia which means gills. The branchial arches are responsible for the development of the gills in fish and amphibians. Specifically, the event of four branchial clefts at the 4th week of embryonic life marks the formation of five ridges, which form several structures of the head, neck, and upper thorax. The growth of the second arch is caudal and covers the third arch and fourth arch. However, if a portion of the cleft, which is an ectoderm-lined cavity, fails to involute at the 7th week of gestation and persists, there is the generation of a cyst. Like a cyst, i.e., epithelium-lined cavity derives from the ectoderm and harbors commonly squamous epithelium. The entrapped remnant may or may not contain a sinus or fistula tract to the overlying skin. • EPI: Unknown, but it is a common cause of visit and surgery in a department of head, nose, and throat of a children’s hospital. In fact, branchial cysts are the most common congenital cause of a neck mass, and bilateralism occurs in 2–3% of cases, and there is a natural predisposition. Moreover, M  =  F, childhood/youth as presentation, no ethnic preferences. • CLI: The branchial cysts are congenital, but clinical presentation occurs later in life, because of inflammation. In case of a UTI infection, the underlying lymphoid tissue can become hypertrophic, and an abscess can also occur with a tendency to a spontaneous rupture with resulting purulent draining to the skin or the pharynx. The HNT surgeon may identify a tender, enlarged, reddish, and warm neck mass on the lateral neck. Depending on the size, overimposed inflammation, and the extension of the

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•

• •

branchial cleft cyst, dysphagia, dysphonia, dyspnea, and stridor may occur. GRO: Nodules or papulae that can be inflamed acquiring a reddish character and be accompanied by other inflammatory signs and symptoms. CLM: Squamous epithelium-lined cysts with keratin lamellae in the lumen and sporadic occurrence of respiratory epithelium with or without cartilage. An inflammatory component is often present, although at time of the surgery, it is chronic with lymphocytes and plasma cells. The surgeon tends to treat with antibiotics before a surgical resection is performed. Thus, neutrophils are virtually absent at the time the pathologist receives the specimen. TNT: Surgery. PGN: Recurrence is uncommon with an estimated risk of 3%, and the pathologist needs to be contacted about the potential recurrence and revision of the slides coming out from the previous surgery. The risk increases to 20% in case a previous surgery or recurrent infection was present due to the potential persistence of ectoderm-derived stem cells and an inflammatory component. In both cases, numerous schools recommend a postsurgical broad-­ spectrum antibiotic treatment for both children and adults experiencing a recurrence.

Genetic syndromes involving the head and neck region are extremely important, and a careful examination of the living child or an autopsy can reveal hints to address genetic counseling. Anomalies of the branchial structures include branchial sinuses and branchial cysts. Branchial sinuses are due to a failure of obliteration of the second branchial groove and generally manifest with a blind pit and form a “branchial fistula,” if there is an extension of the structure into the pharynx. On the other hand, branchial cysts are remnants of cervical sinus or second branchial groove and are usually asymptomatic until early adulthood when enlargement occurs due to the accumulation of fluid and cellular debris. The most common genetic syndromes are first arch syndromes or sequences, including Treacher Collins

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syndrome, characterized by an autosomal dominant pattern of inheritance, malar hypoplasia, defects of the lower eyelid, and deformed external ear, and Pierre Robin sequence (PRS), characterized by a triad of micrognathia, glossoptosis, and cleft palate. PRS may occur as isolated findings or in association with additional syndromic features, such as ocular and auditory defects. Children harboring PRS may be at risk to variable degrees of upper airway obstruction, which can be lifethreatening, and the association of neurologic deficits would probably be an indication for tracheotomy and gastrostomy tube placement to avoid chronic aspiration. Mandibular distraction osteogenesis is the only surgical technique aimed to address the underlying cause of upper airway obstruction in PRS. Congenital thymic aplasia or DiGeorge syndrome is due to a failure of differentiation of the third and fourth pouches without evidence of the thymus or parathyroid glands. The differential diagnosis of branchial cleft cysts is broad and may include neoplastic and non-neoplastic lesions. The non-neoplastic reactive oropharyngeal lesions of the oral cavity that may have relevance in childhood, adolescence, and youth include the following disorders. 1.

2.

3.

4.

5.

6.

14  Head and Neck

amorphous material with florid FBGC reaction) 7 . Tonsillar/adenoidal lymphoid hyperplasia (follicular hyperplasia of the lymphoid tissue of one or both lymphoepithelial organs with benign features, including sharp demarcation to germinal centers, no expansion of the germinal centers, no progressive transformation of the germinal centers, standard mantle zone without increase, and polarization of the germinal cell population) DDX: NHL and carcinoma

Recently, Friedman et  al. (2015) proposed a grading system for lingual tonsillar hypertrophy, another situation that may obstruct the airways and may have legal aspects in case of sudden death. The proposed grading system consists of a 0–4 scale. Grade 0 denotes a complete absence of lymphoid tissue in the tongue. Grade 1 comprises lymphoid tissue scattered over the base of the tongue. Grade 2 has lymphoid tissue covering the entirety of the tongue base with limited vertical thickness, while grade 3 consists of significantly raised lymphoid tissue covering the whole of the bottom of the tongue, roughly 5–10 mm in diameter. Finally, grade 4 represents lymphoid tissue Amalgam tattoo (black-brown granular mate- ≥1 cm in diameter that rises above the tip of the rial embedded in collagen and at perivascular epiglottis. Montgomery-Downs also modified location) DDX: Melanocytic nevi and hemo- Brodsky’s scale to include midpoint values. siderin deposition (Fe-stain) The lingual tonsils are a section of lymphoid Lymphoepithelial cyst (squamous epithelial-­ tissue in Waldeyer’s ring. Waldeyer’s tonsillar ring lined cyst overlying a dense lymphoid cell (aka pharyngeal lymphoid ring) is a ringed population) DDX: Malignant lymphoma arrangement of lymphoid tissue in the pharynx Median glossitis of rhomboid type (glossitis consisting of pharyngeal tonsil, two tubal tonsils, with elongated rete and loss of papillae and two palatine tonsils, and one lingual tonsil. The florid Candida hyphae) cause of lingual tonsil hypertrophy has not been Necrotizing sialometaplasia (nests of squa- identified. Multiple studies have found laryngomous epithelium with lobular growth with pharyngeal reflux (LPR) to be correlated with lininflammation and focal atypia ⇒ “inflamma- gual tonsil hypertrophy. Noteworthy, BMI and the tory atypia”) DDX: squamous cell carcinoma metabolism studies behind the growth of a child (SqCC) and mucoepidermoid carcinoma have also been found to be associated with lingual (MEC) tonsil hypertrophy. However, a recent survey by Ranula/mucocele (innocuous collection of Hwang et al. (2015) does not seem to be related to mucin, which is either extravasated or trapped obstructive sleep apnea-hypopnea syndrome in the duct system of the salivary gland system (OSAHS) or BMI.  High reflux symptom index of the oropharynx) DDX: MEC (RSI), which is collected during patient intake, in Teflon FBGC (foreign body giant cell) reac- younger age, and from the male gender, is assocition (refractive, polarizable, and translucent ated with increased thickness of the lingual tonsil.

14.4 Oral Cavity and Oropharynx

14.4.3 Inflammatory Lesions Inflammatory lesions of the oral cavity and oropharynx are numerous and may be found in textbooks of head and neck clinics and pathology as well as dermatology. However, it is important to stress here some that may play a role in childhood, adolescence, and youth. The immune-mediated and dermatologic lesions of the oropharynx including oral cavity are grouped together. 1. Bullous pemphigoid (bullous inflammatory lesion with infrabasal clefts accompanied by chronic inflammation at the stroma-epithelial interface) 2. Lichen planus (band-like lymphoid/lymphocytic subepithelial infiltrate + vacuolar change or liquefaction of the basal layer with a saw-­ tooth pattern of the epithelium) 3. Pemphigus vulgaris (bullous inflammatory lesion with acantholysis and suprabasal blisters and richness of “tombstones’ row” of basal epithelial cells) 4. Sjögren’s syndrome (atrophy of the glandular tissue + chronic inflammation with >50 lymphocytes or plasma cells/HPF: (i.e., 40X as objective) The fibrous and pseudogranulomatous (non-­ neoplastic) and pseudotumoral lesions of the oropharynx including the oral cavity with some inflammatory character are described here (vide infra).

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features, e.g., invasion (DDX: Osteosarcoma, fibrous dysplasia, simple bone cyst, and ABC) • Pyogenic granuloma: Small, thin-walled BVs with “collarette”, GLUT1 (−).

14.4.4 Tumors In the following sections are listed tumor lesions that occur more often in late childhood, adolescence, and youth. Most of these lesions do occur in adults but may be present in children and adolescents harboring a predisposition to develop cancer (genetic cancer syndromes) or have been in contact with carcinogens and mutagens in the environment.

14.4.4.1 Epithelial Precursor Lesions The clinical term “leukoplakia” (Greek: λευκός, “white” and πλάξ, “plate”) means “white plaque or plate.” It is a premalignant lesion, sharply demarcated that can occur anywhere in oral mucosa, more often seen in late youth in children starting smoking very early. The role of vaping is uncertain at this time. There is an orderly mucosal thickening with epidermal hyperplasia and hyperkeratosis with focal disorderly hyperplasia. Varying degrees of dysplasia up to CIS have been described in late adults only. 14.4.4.2 Benign Epithelial Tumors Five entities need to be differentiated that are squamous papillomas, lymphangioma, granular cell tumor, congenital granular cell epulis, and keratoacanthoma. However, keratoacanthoma is not seen in youth.

• Giant cell fibroma: Nodule of dense collagen scarcely to moderately cellularity and scat1 . tered giant cells. • Irritation fibroma: Nodule of paucicellular dense collagen. • Lobular capillary hemangioma: Small, thin-­ walled BVs with the lobular arrangement and 2 . GLUT1 (+). • Peripheral giant cell granuloma: Nodule of spindle cells to ovoid cells with bland cytology and scattered MNGCs, small lymphocytes, and plasma cells. • Peripheral ossifying fibroma: Nodule of high cellularity with fibroblastic stroma and scat- 3 . tered ossification with no atypia or malignant

Squamous papilloma (numerous fibrovascular cores with overlying squamous epithelium with bland cytology) DDX: Pseudoepitheliomatous hyperplasia, squamous cell carcinoma, and papillomatosis Lymphangioma (thin-walled vascular spaces with a proteinaceous material, with (+) D2–40 and (−) CD31 immunologically on the lining of the vascular areas) DDX: Hemangioma (−) D2–40 and (+) CD31 Granular cell tumor (nodule of cells with granular cytoplasm and small nuclei, charac-

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teristically situated underneath of the epithelium and favoring a pseudoepitheliomatous cell reaction and displacing and infiltrating the submucosal tissues, with (+) PAS, S100, PGP 9.5, NSE, CD68, AAT, INA) DDX: Congenital granular cell epulis 4 . Congenital granular cell epulis (proliferation of cells with granular cytoplasm admixed with small thin-walled blood vessels and lack of a pseudoepitheliomatous cell reaction, (+) NSE, VIM, but (−) S100 DDX: Granular cell tumor

14.4.4.3 Malignant Epithelial Tumors Squamous cell carcinoma (SqCC) is sporadic in childhood and youth, but occasional cases may be encountered in immunodeficient or immunosuppressed (e.g., following transplantation) young individuals and should be differentiated from squamous preneoplastic lesions. Squamous preneoplastic and neoplastic lesions are: 1. Squamous dysplasia vs. reactive atypia (presence of inflammation and downward extension of rete with regular spacing). 2. Proliferative leukoplakia of verrucous type (rare spectrum of changes from simple squamous hyperplasia through verrucous hyperplasia, verrucous carcinoma to SqCC of usual type). 3. Verrucous hyperplasia vs. verrucous carcinoma. 4. Micro- or broadly invasive squamous cell carcinoma. Squamous dysplasia (SIN, squamous intraepithelial neoplasia) and CIS are: 1. SIN1 = Mild dysplasia ⇒ low-grade dysplastic lesion 2. SIN2 = Moderate dysplasia ⇒ high-grade dysplastic lesion 3. SIN3 = Severe dysplasia ⇒ high-grade dysplastic lesion As mnemonics technique, the acronym “ASIC” can be used for the architectural disorder, size

14  Head and Neck

(nuclear) variability, irregularity of the nuclear contour, and chromatin (nuclear) changes. The variants of malignant squamous lesions are as indicated below: • Squamous cell carcinoma, early invasive (vide supra) • Verrucous (wart-like with characteristic “church-spire” proliferation, no atypia, downward growth with pushing border with DDX including verrucous hyperplasia, proliferative verrucous leukoplakia, and papillary squamous cell carcinoma) • Papillary (long fibrovascular cores of variable complexity lined by atypical squamous epithelium with lack of hyperkeratosis) • Basaloid (basaloid cell proliferation with hyperchromatic nuclei, palisading pattern, and often set in a basement membrane-like hyaline matrix) • Adenoid (squamous cell proliferation with a characteristic pseudoglandular pattern with cleft-like spaces and lack of mucin, goblet cells, and no immunoreactivity for CD31, CD34, and FVIII) • Spindle cell/pseudosarcomatous (exophytic mass of atypical spindle cells with histologic or IHC evidence of distinct keratin p­ roduction with DDX including fibrosarcoma, and malignant fibrous histiocytoma) • Non-keratinizing (vide infra) The non-keratinizing squamous lesions are classified as follows. 1. Differentiated “non-papillary urothelial carcinoma-­ like tumor” (nests or sheets of cohesive cells with hyperchromatic nuclei and small, dense nucleolar presence) 2. Undifferentiated (syncytial growth pattern of cells with pale, vesicular nuclei and prominent nucleoli described as “centroblast-like” cells) 3. Undifferentiated with lymphoid stroma (syncytial growth pattern of cells with pale, vesicular nuclei and prominent nucleoli described as “centroblast-like” cells + interspersed EBV+ lymphoid cells ⇒ Schminke’s and Regaud patterns)

14.4 Oral Cavity and Oropharynx

Non-keratinizing SqCC major DDX is with lymphoma (B-cell lymphoma, (+) CD45, CD20, CD79a) and typically either DLBCL (anaplastic, centroblastic, immunoblastic, T-cell histiocyte-­ rich) or EN-NK-TCL (+) CD2, cCD3e, CD56, TIA1, Perforin, EBV, or, even, malignant melanoma (+) S100, HMB45, and Melan-A.

14.4.4.4 Soft Tissue Tumors Benignancy is seen for focal oral mucinosis, congenital granular cell epulis, lymphangioma, and ectomesenchymal chondromyxoid tumor, while malignancy of this region is Kaposi sarcoma (KS). Congenital Epulis of Newborn • DEF: Rare benign tumors of the oral cavity with remarkable similarity to granular cell tumor of the adults, although distinguished based on its exclusive origin from the neonatal gingiva, the scattered presence of odontogenic epithelium, lack of interstitial cells with angulate bodies, and the more intricate vasculature. • EPI: 6  in 10,000 neonates (incidence rate) with female preference (♂ < ♀) (♂ : ♀ = 1:10). • EPG: There are odontogenic, neurogenic, myogenic, endocrinological, fibroblastic, or histiocytic factors that may play a role. • CLI: The alveolar ridge lesions present as a lobular or ovoid, sessile, or pedunculated swelling of variable size, which is often covered by a smooth reddish mucosa. • DGN: US, CT/MRI, and histopathology. • CLM: Granular cell tumor-similar histopathology. • DDX: Dermoid cysts, teratoma, hemangioma, lymphatic malformations, RMS, and melanotic neuroectodermal tumor of infancy (MNTI). • TRT: Complete surgical excision with no reported cases of recurrence. Pyogenic Granuloma (Lobular Capillary Hemangioma) • DEF: Inflammatory “tumor” composed of granulation tissue often localized at the maxillary labial gingiva.

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Hemangioma Hemangiomas are most common pediatric vascular benign neoplasms with a specific course including three stages: (1) rapid proliferating phase (0–1 year), (2) involuting phase (1–5 years), and (3) involuted phase (5–10 years). • EPI: 2–3% in neonates and 22–30% preterm infants, ♂ jaw>humerus) –– Endocrine dysfunction (pituitary hyperplasia or GH-secreting pituitary adenoma, hyperthyroidism, adrenal hyperplasia, as well as the early start of puberty) (mnemonic: CAFE) GNAS activation results in an abnormal version of the G protein that causes the adenylate cyclase enzyme to be always (constitutively) activated leading to excess cAMP. Fibrous dysplasia and soft tissue myxomas characterize Mazabraud syndrome.

14  Head and Neck

Osteoma is a bosselated lesion composed of dense, mature, chiefly lamellar bone, generally localized on the flat bone of the face/skull and ± protrusion into sinuses, and seen in patients with Gardner syndrome, characterized by: –– Desmoids and AD inheritance (APC gene on 5q21 with variable expressivity) –– Osteomas –– Sebaceous cysts –– Thyroid carcinoma/teeth abnormalities –– Osteochondromas –– Polyposis of colonic localization (mnemonic: DO STOP) Osteochondroma or exostosis is characterized by a lobulated cap of cartilage, covered by a fibrous membrane with cancellous bone, active endochondral ossification at the interface, and hyaline cartilage that may occur with multiple lesions in Gardner syndrome as well.

14.7.3.2 Tumors of the Middle Ear Middle ear neoplasms include middle ear adenoma (or carcinoid of the middle ear), papillary tumors (aggressive papillary tumor, Schneiderian papilloma, inverted papilloma), squamous cell carcinoma, and meningioma. Closely apposed small glands characterize middle ear adenoma with “back-to-back” pattern without desmoplastic stroma. Tumor cells are regular, cuboidal to columnar with bland cytology, rare nucleoli and no mitoses encircling some +PAS/AB luminal secretion and +  NE markers (CGA, SYN) other than Pan-CK. Grossly, a gray-white, firm lesion producing a conductive hearing loss is seen. This kind of tumors are usually benign, but may be locally aggressive with bone destruction. Moreover, papillary tumors, squamous cell carcinoma, and meningioma have been reported, but these neoplasms are rare in childhood and youth. 14.7.3.3 Tumors of the Inner Ear Inner ear neoplasms include vestibular schwannoma (or “acoustic neuroma”), lipoma, hemangi-

14.7 Ear

oma, and endolymphatic sac tumor. Vestibular schwannoma is not seen in children or adolescents without the genetic setting of neurofibromatosis type II. VS is a benign tumor of Schwann cells of the eighth cranial nerve and usually located in the region of the internal auditory canal and in the area of the cerebellopontine angle. Vestibular schwannoma is often bilateral and shows Antoni A and B areas and Verocay bodies. Neurofibromatosis I (NF I): AD-inherited disease with mutations on NF1 tumor suppressor gene located on chromosome 17 (17q11.2) is linked to neurofibromin protein and downregulates p21 ras (penetrance 100%, but variable expressivity). The diagnosis is based on cafe au lait spots (“California coast” borders); axillary, inguinal freckling; fibroma (neurofibromas constituted by loose proliferation of neurites, Schwann cells, and fibroblasts in a myxoid stroma); eye lesions (Lisch nodule or pigmented hamartoma of iris); skeletal deformities (bowing leg, etc.); pedigree/positive family history; and optic tumor (glioma). There is 2–4× risk to develop pheochromocytoma, WT, AML/ CML, RMS, optic glioma, and meningiomas. Neurofibromatosis II (NF II): AD inherited with the gene located on chromosome 22 (22q12), which codes for Merlin (Moezin-­Ezrin radixin like protein)/schwannomin. In NF II there are typically bilateral vestibular schwannomas and meningiomas but also other intracerebral and intracranial tumors. Neurofibromas are dermal. Lipoma and hemangioma are similar to lipomas and hemangiomas elsewhere. Endolymphatic sac tumor (ELST) is a tumor typically associated with VHL disease (hemangioblastomas of the cerebellum, retina or brainstem, pancreatic cysts, and hemangiomas of several organs (liver, kidneys, epididymis), pheochromocytoma, and ↑risk of RCC and testicular cystadenoma). ELST can also arise sporadically.

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• •

•

•

•

• •

• •

ELST) or not (sporadic ELST). Although initially considered as a low-grade papillary adenocarcinoma, the bland histologic appearance and the probably apparent lack of metastatic potential have since convinced ­ most pathologists and ENT surgeons to reclassify ELSTs as papillary adenomas. EPI: Rare (~175 cases reported), ♂  pons > cerebellum), swollen (edematous) cerebral hemispheres, and flattening of the gyri. The bleeding may invade the ventricular system filling its cavities. If the patient survives, the clot shows shrinkage, change in chocolate-color, and disappearance of edema. If the heme, i.e., the complex consisting of Fe as ion coordinated to a porphyrin acting as a tetradentate ligand, and to one/ two axial ligands, in the hemoglobin

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becomes oxidized, it may become methemoglobin, which is chocolate-like or brownish. Methemoglobin, which has the iron ion in Fe3+ state, not the Fe2+ of normal hemoglobin, is unable to bind O2. Consequently, there is no possibility to carry O2 to tissues. Microscopically, erythrocytic extravasates are the rule replacing the destroyed tissue with the recruitment of microglial phagocytes within 3  days, which ingest degenerating or degenerated RBC, and hemosiderin deposition within 6–10  days. The late fate is a cystic space, which corresponds to the central area of destruction when the phagocytic activity clears out the area of damage. Said that, we also need to emphasize that pathological assessment of timing of traumatic events remains associated with error, which is linked to interindividual variability, the lack of precision of gross and microscopic changes, and the primitive nature of the techniques in general use (gross observation, histopathology, Prussian special stains). Ultimately, all these factors suggest caution when attempting to assign a time interval between hemorrhage and presentation or death (Castellani et al. 2016). Risk pregnancies include low and high maternal age, drug addiction, alcohol use/abuse, consanguinity, and hereditary disorders, while maternal complications include diabetes mellitus (DM), hypertonia, preeclampsia, and prenatal infections (e.g., TORCH). The well-known acronym “TORCH” stands for the etiologic pathogens of congenital infections, including Toxoplasma gondii, “others” (including Treponema pallidum, Listeria monocytogenes, Varicella Zoster Virus, and Parvovirus B19), Rubella Virus, Cytomegalovirus, and Herpes Simplex Virus. Pregnancy-related problems include prematurity, fetal growth restriction (formerly known as intrauterine growth retardation), placental dysfunction, prolonged labor, breech presentation, twins, and premature rupture of membranes (PROM). In Box 15.8 the CNS disorders observed in prematurity are listed. The mnemonic word “PIRI” may be used. Piri is the Swahili word for pepper, and Piri Piri is a one of the sources of chili pepper that grows in Africa, mostly, but also worldwide.

15  Central Nervous System

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Box 15.8 Prematurity: Observable CNS Disorders

• • • •

Periventricular leukomalacia Immaturity-based white matter damage Retinopathy of prematurity (ROP) Intraventricular hemorrhage

15.3.1.2 Subarachnoidal Hemorrhage (SAH) SAH is etiologically more homogeneous, being caused in the majority of cases by trauma or by rupture of a berry aneurysm. Clinically, there are headache, nuchal rigidity, a very broad range of alterations of the mental status, and hydrocephalus. 15.3.1.3 Subdural Hemorrhage (SDH) SDH usually results from rupture of the superior cortical veins leading to the superior sagittal sinus (venous blood). 15.3.1.4 Epidural Hemorrhage (EDH) EDH usually results from tearing of the middle meningeal artery (arterial blood). The most important cerebrovascular accidents include atherosclerosis, embolism, intracerebral hemorrhage, and SAH. CNS, and particularly the brain, has an absolute requirement for oxygen. In fact, an arrest of blood flow to the brain may have devastating consequences, although some factors (e.g., body and external temperature) may influence brain damage. Thoresen pioneer works have helped to identify how to preserve the preterm brain using cooling devices. Blood flow arrest and brain function are paralleled as below. → →

11 s 40 s

→ →

180 s (3 min) 5–7 min

→

>7 min

Unconsciousness Polygraphy with flattening of electroencephalogram (EEG) Irreversible damage, because of the pauperization of glucose Total consumption of tissue adenosine triphosphate (ATP) Death

Sensitivity to ischemia is different in several and different cell types, and different regions of

the brain show also different sensitivities to global ischemia. Ischemia-related brain sensitivity areas include the cerebellum (Purkinje cells), the hippocampus (CA1  +  CA4  >  CA2  +  CA3), the inferior olivary neurons, the neocortex, layer 3 (external pyramidal layer), and the subthalamic nucleus. Layer 3 and layer 5 represent the two layers of the neocortex that show pyramidal neurons, while stellate cells are seen in layer 4 of the neocortex. The anoxic-ischemic injury may be evidenced on tissue sections by histologic examination. Neuronal anoxic-ischemic injury changes include: 1 . Acidophilic (eosinophilic) degeneration 2. Glassy change of the cytoplasm 3. Hyperchromasia of nuclei 4. Loss of intracellular Nissl substance 5. Neuronal (cytologic) shrinkage (↓) 6. Pericellular (perineuronal) space ↑ An acute neuronal injury displays shrinkage of the cell body, pyknosis, nucleolus disappearance, vanishing of the Nissl substance, and cytoplasmic eosinophilia, while an axonal reaction consists of rounding of the cell body with central chromatolysis (loss of central Nissl bodies) and retraction of presynaptic terminals. Factors that impair regeneration of the axons include lack of matrix proteins (e.g., laminin and fibronectin), lack of growth factors (e.g., GAP 43, Growth Associated Protein 43), the formation of inhibitory proteins (e.g., oligodendroglial glycoproteins), and the perinatal and postnatal creation of glial scars. The regions of elective parenchymal necrosis include Purkinje cells (cerebellar cortex), pyramidal cells of the cortex, hippocampus, striatal neurons, and thalamic neurons, and significant causes of elective parenchymal necrosis include anoxia/hypoxia (e.g., cardiac arrest), anemia, CO intoxication, pulmonary disease, and hypoglycemia. Consequences of infarction in the brain are different from any other organs, because of the almost unique cellular and tissue organization. Infarct may be anemic or hemorrhagic, depending upon whether no blood flow is present or circulation is reestablished through either internal carotid arteries or the vertebrobasilar

15.3 Vascular Disorders of the Central Nervous System

system at the level of the circulus cerebri (circulus Willisii). The cavitation process is progressive with a speed of 1 cm3/3 months. Types of Brain Herniation • Retrograde cerebellar herniation (infratentorial → supratentorial) • Uncus or orthograde herniation (supratentorial – infratentorial) • Subfalcial (cingulate) herniation involving the R&L supratentorial cavities • Tonsillar herniation (infratentorial → spinal cord) The mnemonic acronym “RUST” may also be used (rust is an iron oxide). A “watershed infarction” of the brain is defined as an infarct of the brain in very specific areas, e.g., between anterior and middle cerebral arterial circulation. It means that there is a susceptibility of endoarterial vascular supply (i.e., tissue will be damaged at the boundaries of limited blood flow as seen in the large bowel in the ileocolic region and splenic flexure). Thrombosis of venous sinuses and their branches causes congestion, bleeding, and necrosis of brain tissue with obvious disastrous consequences. Thrombosis of the superior sagittal sinus causes parasagittal venous infarcts. The causes of venous thrombosis are varied and include inherited thrombophilia, use of oral contraceptives, cancer, and dehydration (mostly in infants). The etiopathogenesis and characteristics of venous infarcts include: 1. Thrombosis of sinuses of dura mater or cerebral blood vessels (e.g., in case of infection or dysregulation of the Virchow’s triad) 2. Hemorrhage, bilateral with white matter over gray matter contribution 3. Superior sagittal sinus thrombosis, which induces a parasagittal hemorrhagic infarction The hypertensive cerebrovascular disease can predominantly manifest under two critical forms (multi-infarction-related disease and Binswanger disease) with three anatomic-pathologic aspects, including:

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1. Lacunar Infarcts (small, usually ≤1  cm, a subcortical gray matter of basal ganglia, brainstem, and deep white matter, HTN-­ associated, multiple and bilateral) 2. Slit Hemorrhages (bleeding of the subcortical area) 3. Hypertensive Encephalopathy (cerebral atherosclerosis in the setting of generalized atherosclerosis, cerebral arteriolosclerosis in the context of chronic HTN or DM, and thrombotic states or post-embolization from carotid arteries or directly from the heart) In more than 60% of cases, hypertensive hemorrhage occurs in the basal ganglia, although other familiar locations are thalamus, pons, and midbrain. Multi-infarct disease is characterized by mainly microinfarcts and lacunar infarcts (vide infra) of cortex and white matter, while Binswanger disease is a subcortical arteriosclerotic encephalopathy, which is a form of hypertension-­ based encephalopathy involving broad areas of subcortical basal ganglia and white matter with both myelin and axon loss. Although rare, such cerebrovascular disease may have an encephaloclastic component or be the consequence of a perinatal insult. There are different types of intracranial hemorrhage: 1. Intracerebral (intraparenchymal) hemorrhage (hypertension, Charcot-Bouchard microaneurysms, cerebral amyloid angiopathy) 2. Subarachnoidal hemorrhage (Berry aneurysm rupture, AV malformations, traumas, and stroke) Charcot-Bouchard aneurysms are microaneurysms of the cerebral vascularity, particularly of the small blood vessels (Ø 3 organ/systems), and death. The occurrence of communicating hydrocephalus following meningitis is due to the process of fibrosis, which may be a natural consequence of an inflammatory process, mainly if the inflammation is severe. Fibrosis

15  Central Nervous System

blocks CSF resorption through the Pacchioni arachnoidal granulations.

15.4.1.2 Brain Abscess • DEF: Pseudocystic cavity arising in necrosis results from encephalitis, often 1–2 weeks following infarction by direct implantation, local extension, or hematogenous spread. • EPI: Brain abscesses represent 1/5 of the incidence of the suppurative leptomeningitis, and 4/5 of the cases are associated with extramural pyogenic infections, anatomic anomaly, penetrating cranial trauma, and previous neurosurgery. • ETP: Common bacteria include staphylococci, pneumococci, and streptococci. Gram-negative bacilli, including aerobic microorganisms such as Proteus spp., E. coli, Klebsiella spp., Haemophilus spp., and Bacteroides are more rarely seen. Actinomyces israeli and Nocardia spp. are usually observed in debilitated and immunosuppressed patients. Sources for the development of a brain abscess include otitis media, mastoiditis, sinusitis of frontal location, lung abscess, pleural empyema, and bacterial endocarditis. A direct extension to cephalic structures or a spreading as infected emboli in the bloodstream is the pathogenesis. If most multiple abscesses are seen, embolic pathogenesis is most likely. Pediatric acute mastoiditis differs significantly between age groups. Typically, acute mastoiditis is most common in children younger than two years of age. The infants show more rapid progress of symptoms and more distinct signs of acute inflammation of the mastoid bone. In combination with the virulence of the bacteria the anatomy of the air cell system of the mastoid bone including its tympano-mastoid suture and vascular channels in the cribriform area play a major role for determining a higher rate of acute mastoiditis in infants than older children (Groth et al. 2012). Hematogenous-driven brain abscess includes acute bacterial endocarditis, congenital heart disease with R → L shunt, chronic pneumonia, sepsis, and immunodeficiency/ immunosuppression (e.g., primary immunodeficiency, transplantation).

15.4 Infections of the CNS

• CLI: There is often a clinical picture of mass effect (“tumor quia tumet”) due to a rapidly expanding intracranial lesion possibly associated with infection-­ related symptoms and signs with stereotyped topographic presentations. History is essential, and the source of infection (e.g., otitis media) remains key in the era of precision-medicine of the 21st century. Lumbar puncture shows an increased pressure of CSF, which also indicates inflammatory cells and hyperprotidorrachia, but glycorrhachia is within the normal range. Generally, no pathogenic microorganisms are easily identified, unless the brain abscess has ruptured and leptomeningitis ensues. • IMG: X-ray characteristics are 1. Ring enhancement due to a developing pseudo-capsule 2. “Budding” of “daughter” lesions 3. Hypodensity of adjacent white matter, which underlies the surrounding edema • GRO: Typically located in the temporal lobe and cerebellum when observed as a single lesion or in the brain located at the intersection of the gray and white matter when multiple abscesses occur, the brain abscess is a pseudocyst without an epithelial lining. It is characterized as a cavity with filled with putrid tissue containing a thick exudate surrounded by a narrow marginal band of whitish (granulation tissue) or intensely congested reddish brain tissue. The surrounding brain tissue displays marked swollen white matter with edema. • CLM: There is necrotic tissue centrally, which is separated from neighboring white matter by granulation tissue constituted by an ­angioblastic and fibroblastic zone of activity with accompanying gliosis. The absence of an epithelial lining is conformed by the negativity of the immunohistochemical investigation with antibodies against keratins (e.g., AE1/3). • PGN: Complications depend on the virulence of the microorganism, patient’s immunocompetency, and resistance or compactness of the abscess wall. In case of high virulent bacteria, immunodeficiency or immunosuppression, or inadequate development of the abscess wall or

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its early fragility, a spreading suppurative leptomeningitis and sepsis may ensue.

15.4.1.3 Septic Thrombophlebitis Septic thrombosis/thrombophlebitis is a condition occurring in patients affected with middle ear disease or mastoiditis, localized osteomyelitis, and epidural abscess and develops in transverse sinuses. Septic thrombosis/thrombophlebitis may also occur in the cavernous sinus near to the sella turcica as drainage location following suppurative infections of the face, particularly of the upper lip, with the retrograde involvement of the angular and ophthalmic veins.

15.4.2  Tuberculous (Lepto-) Meningitis Tuberculous leptomeningitis is a rare complication in immunocompetent individuals but is the most common form of TB infection in the nervous system in immunodeficient or immunosuppressed patients. Two pathogenetic ways are observed, including either miliary dissemination (particularly immunodeficient or immunosuppressed patients) or secondary to infection in the mediastinal or mesenteric glands, bones, joints, lungs, or GU tract. Clinically, there is an insidious onset with 2–3  weeks of anorexia, weight loss, and change of disposition. A specific lucid interval precedes a period of drowsiness with or without delirium. Lumbar puncture shows chronic inflammatory cells (lymphocytes), hyperprotidorrachia, hypoglycorrhachia, and acid-fast bacilli, which may be detected using either staining methods (Ziehl-Nielsen stain, auramine-rhodamine stain) or microbiological investigations. The auramine-rhodamine staining or Truant stain is a histological technique used to detect acid-fast bacilli (genus: Mycobacterium) using fluorescence microscopy. It is a mixture of auramine O and rhodamine B. Caution should be taken when using this mixture because of its carcinogenicity. Grossly, a white or gray-whitish, lacy exudate is mainly seen at the base of the brain, conversely from the acute suppurative leptomeningitis

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(vide  supra) and, particularly, in all basilar cisterns as well as in the Sylvian fissure. The exudate is marginalized by sharply outlined, round white nodules (“tubercles”). Microscopically, there is a granulomatous exudate with or without caseous necrosis and numerous lymphocytes, mononuclear cells, and single multinucleated giant cells of Langhans type. Special stains, including Ziehl-Nielsen and auramine-­rhodamine (vide supra), allow highlighting the acid-fast bacilli. It is advisable to take, at time of neurosurgery or autopsy, some tissue for microbiological investigations. Both classic special stains and microbiology may show no bacilli, owing to previous therapy or the presence of atypical mycobacteria or artifact procedures. In case of the second event, Wade-Fite stain may be useful to detect atypical mycobacteria. The special stain “AFB” uses carbol-­fuchsin to stain the lipid walls of acid-fast organisms that are present in M. tuberculosis. As indicated above, the most commonly used method is the Ziehl-Neelsen method, but there is also the Kinyoun method. The special stain, known as Wade-Fite or, simply, Fite stain, has a weaker acid for supposedly more fragile atypical mycobacteria, such as M. leprae among others. Atypical mycobacteria are much less acidand alcohol-fast as compared to Mycobacterium tuberculosis. The mycolic acid coat of atypical mycobacteria is less strong than Mycobacterium tuberculosis. Thus, the mycolic acid coat is quickly decolorized by the standard ZiehlNeelsen technique. In the Fite stain, peanut oil is used with the deparaffinizing solvent (xylene) to minimize the exposure of the bacterial cell wall to organic solvents allowing the preservation of the acid-fastness property. ZN and Fite stains are usually frustrating for the pathologist, because the search for acid-fast bacilli may take hours. This aspect is because much of the lipid in mycobacteria is removed by tissue processing, which causes extensive searches. Overall, the most sensitive stain for mycobacteria is doubtless the auramine-­rhodamine stain, which requires a fluorescence microscope for viewing. Essential caveats for the pathologist are false-positive results that may occur in infection or infestations with cryptosporidium, isospora, and cysticerci (hooklets). The role of next-generation sequenc-

15  Central Nervous System

ing is being investigated to deliver a fast diagnosis and  also to rule out laboratory-derived contamination.

15.4.3  Neurosyphilis Neurosyphilis represents the tertiary stage of an infection due to Treponema pallidum. It develops in approximately 2% of syphilis-infected patients, and two forms are specifically delineated that are not mutually exclusive. Neurosyphilis is subdivided in meningovascular and parenchymatous neurosyphilis. Cerebral cortex involvement (e.g., impaired intellectual efficiency, memory, and judgment as well as delusions) with bedriddenness and incontinence. • CSF: Hypercellularity (neurosyphilis-induced pleocytosis) (≥20 cells/μL) and hyperprotidorrachia with positive serology (reactive CSF VDRL and/or a positive CSF intrathecal T. pallidum antibody index). • GRO/CLM: Mostly frontally located, atrophy of cerebral gyri showing mild to marked lymphocytic and plasmacellular leptomeningeal infiltration and gradual capillary hypoxiaderived degeneration of neurons.

15.4.4  Viral Infections Meningoencephalitis is a combining clinical syndrome with pathologic correlate, which is often characteristic for virus infection. It targets both meningeal and neural areas, but the route of infection is heterogenous varying from gastrointestinal (poliovirus), an arthropods-­born insect bite (equine encephalitis), mucocutaneous pathway (HSV), ascending neural propagation (rabies) to hematogenous spread. Grossly, edema may be present, but an exudate is usually lacking if no suppurative component is concomitantly associated. Microscopically, there is a typically perivascular lymphocytic/mononuclear cuffing associated with neuronal degeneration and associated gliosis with accompanying intracellular (intranuclear/intracytoplasmic) inclusion bodies in both neural and glial cells.

15.4 Infections of the CNS

15.4.4.1 Poliomyelitis The etiologic agent is poliovirus (neurotropic RNA virus, sewage-contaminated water, ± GI symptoms) that induces 2nd motor neuron lesional signs with caudocranial damage to the anterior horn cells of the spinal cord. The pathologic process is characterized by initial hemorrhage and congestion and subsequent neutrophilic infiltration, degeneration, and gliosis. The clinical picture is sequential: Infection ⇒ lower limbs to brainstem ⇒ paraplegia to respiratory paralysis. Clinically, an upper motor neuron disease manifests with more muscle reflexes (hyperreflexia), more muscle contraction (spasticity), more muscle tone (hypertonicity), and disuse (atrophy), while a lower motor neuron disease manifests with less muscle reflexes (hyporeflexia), less muscle contraction (flaccidity), less muscle tone (hypotonicity), and loss of innervation (devervation atrophy). The Babinski sign shows toes pointing up in upper motor neuron diseases, while it shows toes pointing down in lower motor neuron diseases. 15.4.4.2 Rabies Rabies: is caused by Lyssaviruses, including the rabies virus and Australian bat Lyssavirus. The Rhabdovirus is an RNA virus. Rabies starts with bites from wild animals and dogs, and affected individuals experience restlessness and hydrophobia. An early death is the consequence of 1st and 2nd motor neuronal damage throughout the nervous system with or without subsequent gliosis depending from the course of disease. The Negri bodies are pathognomonic inclusions of Rabies infection. They are eosinophilic, sharp intracytoplasmic bodies (Ø: 2–10 μm) found in neurons, particularly pyramidal cells within Ammon’s horn (hippocampus). Also, they can be found in Purkinje cells of the cerebellar cortex. Negri bodies are ribonuclear proteins produced by the Rhabdovirus. 15.4.4.3 Herpes Simplex Encephalitis Herpes simplex encephalitis is an acute necrotizing hemorrhagic inflammation of the brain due to HSV. Fever, lethargy, and coma are due to necrosis and softening of the brain parenchyma (typi-

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cally frontal and temporal lobes) grossly and neuronal destruction and perivasculitis (Cowdry A inclusions and perivascular lymphocytic infiltrates) initially, and later gliosis microscopically. Complications include sepsis and MOF.  Herpes zoster is, conversely, associated with a unilateral vasculopathy (granulomatous arteritis) causing contralateral hemiparesis. There is some confusion about Cowdry A and B inclusions. Cowdry A inclusions are eosinophilic amorphous intranuclear inclusions surrounded by a clear halo with marginalization of chromatin on the nuclear membrane and composed of nucleic acid and protein observed in cells infected with HSV, VZV, and CMV. Cowdry B inclusions may represent the initial form of type A and characterized by inclusions without chromatin marginalization and found in neurons infected with Poliovirus and cells infected with Adenovirus.

15.4.4.4 Subacute Sclerosing Panencephalitis (SSPE) SSPE is defined as post-sequela of measles infection with the onset of involuntary muscular movements and dementia leading to death within 1–2 years and showing grossly multifocal areas of neuronal damage and microscopically viral inclusions, in oligodendrocytes and neurons, inflammation, myelin degeneration, and gliosis. The viral inclusions in nerve cells may be located in the nucleus and/or in the cytoplasm: • Nucleus (Cowdry type A) (i) Cytomegalovirus (ii) Herpes simplex virus (HSV) /herpes zoster virus (iii) Papova/JC (progressive multifocal leu koencephalopathy or PML) (iv) Paramyxoviridae (measles) • Cytoplasm (v) Negri/lyssa bodies (rabies)

15.4.4.5 Progressive Multifocal Leukoencephalopathy (PML) • DEF: Papovavirus (usually JC virus)-linked multifocal demyelination with o­ ligodendroglia as target containing intranuclear inclusions and presenting with multiple sclerosis-like white

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matter irregular areas of granularity and clinically as visual/motor deficit with or without dementia, particularly in the setting of an underlying disease or condition (Transplant, TB, Immunosuppression such as following natalizumab for multiple sclerosis or Crohn disease, SLE, and Hematological malignancy such as CLL → mnemonic word: “TISH”, which the pronunciation of the word “table” in German (“Tisch”), but also “table” in Yiddish (“‫ )”טיש‬and reminds the gathering of Hasidim around their Rebbe. In such events, speeches on Torah topics and singing of melodies and hymns are accompanied by refreshments). Natalizumab is a humanized monoclonal antibody against the cell adhesion molecule α4-integrin. • CLM: Oligodendrocytic demyelinization with ground-glass oligodendroglial nuclei (virion filling), large pleomorphic astrocytes, minimal or mild perivascular chronic inflammation, and minimal damage to neurons. JC virus is SV40+, because of immunohistochemical cross-reaction (BK virus, JC virus, and Simian Virus 40 are polyomaviruses). • TEM: “spaghetti with meatballs”-virions.

15.4.4.6 Human Immunodeficiency Virus (HIV): Infection Human immunodeficiency virus may damage the CNS both directly and indirectly (Box 15.10).

15.4.5  Toxoplasmosis T. gondii infestation as a parasite (protozoa) is not infrequent and may occur either transplacentally or through dissemination from an asymptomatic

Box 15.10 HIV and CNS/PNS

1. HIV-direct (early-onset dementia and dementia-like cerebropathies, vacuolar myelopathy, peripheral neuropathy) 2. Opportunistic infections (toxoplasmo sis, tuberculosis, Cytomegalovirus, cryptococcosis, JC virus) 3. Neoplasms (e.g., B-non-Hodgkin malignant lymphoma)

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infection. Congenital toxoplasmosis: hydrocephalus, bilateral chorioretinitis (focal), intracerebral calcifications, convulsions, and ocular palsies. Grossly, depressed, soft, sharply circumscribed yellowish areas on the surfaces of the cerebral hemispheres with typical stenosis of the aqueduct of Sylvius (mesencephalon) are found. Microscopically, sharply outlined necro-­ inflammatory lesions of the brain parenchyma with associated secondary leptomeningitis and Toxoplasma cysts destroying both neural and glial structures are identified. PGN is variable from early death to severe deficits due to neural damage (e.g., chronic hydrocephalus, seizures, blindness, and mental retardation). An acquired toxoplasmosis may occur in immunodeficient hosts, particularly with AIDS.

15.4.6  Fungal Infections Cryptococcal infection and coccidiomycosis play a major role. Actinomycosis is not a fungal infection, because the etiologic agent is A. israeli or other actinomycetes, which are bacteria and harbor the misnomer as mycetes.

15.5 Metabolic Disorders Affecting the CNS Neurometabolic disorders have four characteristics, including neonatal presentation or metabolic crisis in older children (e.g., hypoglycemia), regression, and dysmorphic features. Neurometabolic disorders include disorders of carbohydrate, lipid, amino acid, and organic acid metabolism as well as mitochondrial disorders, lysosomal disorders, and peroxisomal disorders. Neonatal symptoms in case of intoxication include feeding problems, vomiting, lethargy, acidosis, hypotonia, seizures, and, potentially, coma. In the case of organic aciduria, urea cycle disorders need to be considered. Energy depletion neonatal symptoms include hypoglycemia, lethargy, hypothermia, jitteriness, and seizures. Lysosomal disorders of neurometabolic category include most commonly gangliosidosis, Niemann-Pick type A and B, metachromatic leu-

15.5 Metabolic Disorders Affecting the CNS

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intolerance, poor growth, and developmental delay. The boy had macrocytic anemia, a markedly low serum vitamin B12 level, and elevated homocysteine and methylmalonic acid levels. Moreover, there were antibodies to intrinsic factor. Although rare, children presenting with failure to thrive and neurological symptoms should 15.5.1  Pernicious Anemia prompt the pediatrician to investigate for vitaPernicious anemia is vitamin B12 deficiency-­ min B12 deficiency. related megaloblastic anemia with subacute combined degeneration of the spinal cord constituted by the combined involvement of poste- 15.5.2  Wernicke Encephalopathy rior (Goll fascicles and Burdach fascicles) and lateral (spinocerebellar fascicles ± cortico-spi- Thiamine (vitamin B1) deficiency causes nal fascicles) columns of the spinal cord. Wernicke encephalopathy. Although it is often Subacute combined degeneration (SCD) is the considered to be a disease of adult alcoholics, it most common metabolic myelopathy, caused by occurs in childhood and nonalcoholic condivitamin B12 (cobalamin) or folic acid defi- tions. The global prevalence rates of hunger, ciency. The disease has been associated with poverty, and resultant nutrient deprivation have autoantibody production that is directed against decreased in the twenty-first century, but the parietal cells of the stomach, lack of intrin- Wernicke encephalopathy is still present in sic factors, malabsorption (gastrointestinal dis- underdeveloped areas as well as in children and orders), malnutrition, extreme diet, an overdose adolescents affected with malignancies, proof antacids, multiple genetic defects, and the use longed intensive care unit stays, and surgical of N2O anesthetic. The deficit of the posterior procedures for the treatment of obesity (Cefalo (Goll-Burdach tract) and lateral columns of the et al. 2014; Lallas et al. 2014; Bhat et al. 2017). spinal cord is at the basis for the proprioceptive Other predisposing conditions include magnesensory loss and corticospinal symptoms. The sium deficiency and defects in the SLC19A3 classical symptoms include proprioceptive sen- gene causing thiamine transporter-2 deficiency. sory loss and spinal ataxia, Lhermitte’s sign, The classic triad consists of encephalopathy, and spastic paraparesis or quadriparesis. oculomotor dysfunction, and gait ataxia, Furthermore, autonomic dysfunction, paresthe- although it is rarely seen in all patients. MRI sia on the trunk, polyneuropathy, optic nerve shows symmetric T2 hyperintensities in the dorlesion, psychosis, or early dementia/mental sal medial thalamus, mammillary bodies, periretardation may also develop. The peripheral aqueductal gray matter, and tectal plate. Grossly, signs of polyneuropathy may mask corticospi- marked congestion and multiple petechial hemnal tract involvement, which may make the orrhages of the periventricular gray matter, diagnosis more difficult. Other accompanying around the 3rd ventricle, the mesencephalic signs are signs of megaloblastic anemia seen in aqueduct of Sylvius (aqueductus mesencephali the blood and the bone marrow. Cheilitis, glos- cerebri, aqueductus Sylvii), and the floor of the sitis, atrophic gastritis, achlorhydria, and later 4th ventricle are found. Microscopically, there secondary stomach cancer may develop. If sub- are endothelial hypertrophy and hyperplasia of acute combined degeneration is suspected, the capillaries with acute necro-­ischemic damage of following tests should be performed: blood tests neurons supplied by these affected blood ves(blood count, vitamin B12, folic acid, homocys- sels. Treatment should include vitamin replaceteine and methylmalonic acid levels), Schilling ment and symptomatologic or physiological test, and gastroscopy. McNeil et al. (2014) promptness to salvage the organs. Wernicke described an infant with vitamin B12 deficiency. encephalopathy is a medical emergency. Delay The 7-months-old infant presented with feeding in its recognition and treatment leads to signifikodystrophy, Gaucher’s disease, and Krabbe’s disease. Peroxisomal disorders most widely include X-linked adrenoleukodystrophy and Zellweger syndrome.

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cant morbidity, irreversible neurological damage, or even death. Brain edema may have several causes, including acute liver failure, diabetic ketoacidosis, dialysis disequilibrium syndrome, highaltitude exposure, and salicylate poisoning. Tissue ischemia in these conditions induce compensatory mechanisms with the aim to enhance oxygen delivery to cells and carbon dioxide removal such as hyperventilation, increased 2,3-P2-glycerate concentration (reducing the affinity of Hb for oxygen), and capillary vasodilation. Perivascular edema is seen at autopsy.

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15.7 Head Injuries Head injuries may manifest as epidural or subdural as well as subarachnoid bleeding or as a brain concussion, contusion, or laceration.

15.7.1  Epidural Hematoma

• DEF: Hemorrhage located between the skull and the dura mater of the meninges. • EPG: Laceration of the middle meningeal artery (e.g., skull fracture). • EPI: The least common of traumatic bleeding with ~2% of pediatric closed head injury admissions and male predominance (♂:♀ = 2:1). 15.6 Trauma to the Head • CLI: Loss of consciousness after a “lucid interval” follows the skull injury in conseand Spine quence of an apparent post-traumatic recovery Box 15.11 summarizes the anatomo-pathologic and relapse with signs of ↑ICP, followed by aspects of injuries to the head and spine. Trauma respiratory depression and death unless the has a multi-etiologic origin, including motor-­ bleeding is promptly and correctly drained. vehicular accidents (MVA), falls, blows on the • IMG: “Epidural ellipse” with large angle edges. chin, and childbirth. Clinical correlation is neces- • CLM: Fresh clot, without usually granulation sary. Head injuries result in intracranial hemortissue in contrast to subdural bleeding (vide rhage (epidural, subdural, subarachnoid), infra). concussion, contusion, and brain laceration. • TNT: High pressure based bleeding with no alternatives to drainage. The epidural hematoma/hemorrhage is a life-threatening neurosurgical emergency, which requires urgent surgical evacuation. The goal is the prevention Box 15.11 Trauma to the Head and Spine of irreversible neurological injury and, subse 15.7.1 Head Injuries quently, death secondary to hematoma expan 15.7.1.1 Epidural Hematoma sion and herniation. 15.7.1.2 Subdural Hematoma • PGN: It depends from the localized area and 15.7.1.3 Subarachnoidal Hemorrhage focal cerebral compression, degree of ↑ICP, 15.7.1.4 Brain Concussion and subtentorial herniation, which is COD in 1 5.7.1.5 Brain Contusion untreated cases. 1 5.7.1.6 Brain Laceration 15.7.2 Spinal Injuries 15.7.2.1 Meningeal Hemorrhages 15.7.2  Subdural Hematoma 15.7.2.2 Hematomyelia 15.7.2.3 Spinal Cord Concussion • DEF: Hemorrhage located between the dura 15.7.2.4 “Spinal Cord Crush” mater and the arachnoid spaces of the meninges. (Compression associated • EPG: Laceration of the bridging veins (e.g., with Contusion) contrecoup or birth injury at the frontal or 15.7.2.5 Spinal Cord Laceration occipital region), which lie unprotected in the 15.7.3 Intervertebral Disk Herniation subdural space.

15.7 Head Injuries

• EPI: Quite common traumatic cause of bleeding. • CLI: Gradual decline in the level of consciousness over days to weeks but two phases may be seen, although without a well-defined “lucid interval” as in the epidural bleeding and the clot may progressively be reabsorbed. • IMG: “Sharp angle bridge” lesion. • CLM: Proliferation of capillaries, fibroblasts, and hemosiderin. • TNT: Low-pressure bleeding with alternatives to drainage. • PGN: It depends from the localized area and focal cerebral compression, but it may be self-­ contained, and clot eventually reabsorbed leaving a yellow-stained “membrane” constituted by a thin inner membrane and a thick outer membrane strongly attached to the dura. Usually, ↑ICP and subtentorial herniation may occur but are rare occurrences. They need to be evaluated progressively.

15.7.3  Subarachnoidal Hemorrhage SAH: Vide supra.

15.7.3.1 Brain Concussion There is widespread paralysis of brain function without visibly identifiable changes and a strong tendency to spontaneous recovery. The pathogenesis seems to be related to acceleration effects and shearing (rotational) strains on the brain. Clinically, dazing and transitory unconsciousness are seen first, and subsequently, there is temporary impairment of higher functions of brain activity. In severe cases, prolonged unconsciousness, arterial hypotension, bradycardia, bradypnea, and muscular flaccidity are seen. Also, headache, vomiting, and delirium may occur upon return of consciousness. Complete recovery is common. 15.7.3.2 Brain Contusion Brain bruising is consequent to a blow on the calvarium and is probably due to capillary tearing following to stress on the vascular network.

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The lesion may be located directly beneath the area of the skull trauma or opposite it, the socalled contrecoup lesions. In most cases, the frontal and temporal lobes are involved. Clinically, unconsciousness is at first observed, and progression to coma and death may follow in severe cases. Grossly, swollen gyri with multiple petechial hemorrhages are seen in early lesions, while cysts represent the characteristic feature of old contusions. Microscopically, there is edema of the cortex and subcortical white matter with numerous fresh pericapillary hemorrhages, such as Duret hemorrhages of the brainstem in the early lesions, while gliosis is the frequent finding of older contusions. Duret hemorrhage needs to be differentiated from Kernohan notch, which is an indentation of the cerebral peduncle associated with some forms of transtentorial herniation (uncal herniation). The syndrome of the shaken-baby syndrome is a severe brain injury caused by forcefully and violently shaking a baby (abusive head trauma) with severe brain damage.

15.7.3.3 Brain Laceration Injury causes laceration of the brain with wounds penetrating the brain parenchyma, and symptoms are related to the site of the lesion, and, microscopically, there is the complete destruction of all neural, glial, and vascular elements in the line of the tear.

15.7.4  Spinal Injuries Spinal injuries include meningeal hemorrhages, hematomyelia, spinal cord concussion, crush, and laceration. We need to distinguish several forms, including meningeal hemorrhages, hematomyelia, spinal cord concussion, spinal cord crush (compression and contusion), and spinal cord laceration, which may be revised in specific forensic and neuropathology books. Briefly, spinal injuries include hemorrhages in the meninges. Epidural hemorrhages follow vertebral fractures and spinal cord concussion with hematomyelia (e.g., post-spinal flexion or following a severe blow to the back, cord crush).

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Compression and contusion of the spinal cord follow a vertebral dislocation (e.g., a lower cervical region in MVA or lower dorso-lumbar region following a massive blow across the lower back or a fall from height), and spinal cord laceration is seen following stab wounds or bullet wounds with hemisecting or fully sectioning the spinal cord.

• • • • • •

15.7.5  Intervertebral Disk Herniation

• Acute disseminated encephalomyelitis (ADEM) • Demyelinating viral infections • Guillaume-Barre syndrome • Multiple sclerosis

Allergic diseases Infectious diseases Nutritional diseases Toxic diseases Traumatic diseases Vascular diseases

Acquired demyelinating disorders include the following:

Intervertebral disk herniation occurs following extrusion of the nucleus pulposus usually in men of the 3rd–5th decades of life and usually located in the lumbar or lumbosacral spinal region (L4-­ L5 or L5-S1) and presenting as low-back pain 15.8.1  Multiple Sclerosis (sciatica) following mild to moderate trauma to the back possibly associated with a prolonged • DEF: It is a demyelinating disease of the period of dehydration. The nucleus pulposus white matter with AI etiology with CD4, Th1, extrudes in the annulus fibrosus, and a tear may and Th17 cells against self-myelin antigens on be demonstrated pathologically. Symptomatic a genetic susceptibility background (25% conlumbar intervertebral disc herniation is rare in cordance between monozygotic twins). In children and adolescents. Karademir et al. (2017) some animal models, mice lacking the Th1 studied 70 pediatric patients and proposed surgicytokine IFN-γ are not protected and have cal treatment for patients only with persistent enhanced susceptibility to disease. IL-17low back pain or radicular pain with a duration producing CD4+ effector cell lineage (Th17) of more than 6 weeks, despite rest and are induced in parallel to Th1, and may have medication. the potentiality to induce inflammation and autoimmune diseases (Damsker et al. 2010). • EPI: Worldwide with prevalence in youth (onset 20–30s), 1:500, ♂ 110 mg/dl and cell counts >50/mm3 radation of myelin is secondary (Love 2006). Apart of the PML caused by a papovavirus the diagnosis of MS unlikely). described above, demyelinating CNS diseases • IMG: Old plaques are hyperintense on have probably a critical autoimmune etiologic T2-weighted and FLAIR (fluid-attenuated component. inversion recovery) MRI studies, while new Primary myelin diseases include the following (active) plaques show gadolinium disorders: enhancement.

15.8 Demyelinating Diseases Involving the Central Nervous System

• GRO: Sharply demarcated gray plaques in the periventricular region, subcortical areas, optic pathways, brainstem, and spinal cord with the characteristic feature that white matter without myelin looks like gray matter (“white turns gray” phenomenon). • CLM: Using LFB-PAS and Bielschowski stains as well as IHC stains, there is a triad of: 1. Perivascular cuffing of T-/B-lymphocytes 2. Colonization of macrophages (Mϕ) 3. Gliosis Loss of myelin with relative sparing of axons ≠ infarcts (PAS+ myelin debris in Mϕ). Luxol fast blue stain or LFB, is a commonly used stain to detect myelin under light microscopy. It has been created by Heinrich Klüver and Elizabeth Barrera in 1953 and is also called Klüver-Barrera staining. • DDX: Benign focal inflammatory demyelination (BFID) (optic neuritis, partial cord syndromes, etc.); non-benign, non-disseminated syndromes (transverse myelitis, Devic ­disease); disseminated diseases (acute disseminated encephalomyelitis and acute haemorrhagic encephalomyelitis); and, less likely, toxins (e.g., tobacco amblyopia and methanol), vitamin B12 deficiency, other inflammatory disorders (e.g., sarcoidosis, vasculitis, and SLE), infections, ischemia, and local tumors. • TNT: It involves treating relapses (acute episodes of inflammation) with high doses of steroids, but also disease-modifying therapies to prevent relapses and disease progression, physical therapy and other types of rehabilitative therapeutic protocols in addition to a healthy lifestyle. • PGN: Urinary tract infections, decubitus ulcers, and pneumonia are three essential complications that may aggravate the outcome (quoad valetudinem et quoad vitam).

15.8.2  Leukodystrophies Leukodystrophies are a group of diseases involving the white matter (Greek λευκός “white”) with abnormalities of myelin metabolism leading to ineffective myelination and subsequent demy-

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elination, and most of these disorders have an AR inheritance. The typing of demyelination can be: • Diffuse (e.g., metabolic, toxic) • Multifocal (e.g., inflammatory) • Unifocal (e.g., traumatic, neoplastic)

15.8.2.1 Metachromatic Leukodystrophy Cerebroside sulfatase (gene, chromosome) deficiency-­based leukodystrophy leading to accumulation of sulfatides within the neurons and in the perineuronal areas with patients (epidemiology) experiencing progressive motor impairment. 15.8.2.2 G  loboid Cell Leukodystrophy (Krabbe Disease) Galactocerebroside B galactoside (gene, chromosome) deficiency-based leukodystrophy leads to accumulation of unmetabolized lipids within the neurons and in the perineuronal areas with patients experiencing rigidity and decreased alertness by 6 months of age. This disease is progressive and fatal by age 2. It is due to mutations in the GALC gene on 14q31 causing a deficiency of galactosylceramidase. Rarely, Krabbe disease may be caused by a lack of active saposin A. There are demyelination and multinucleated histiocytes at perivascular sites (aka “globoid cells”). 15.8.2.3 Adrenoleukodystrophy ABCD1 (X-ALD) deficiency-based leukodystrophy with lack of a peroxisome membrane protein necessary for β-oxidation of VLCFA (very long chain fatty acid) leading to accumulation of VLCFAs and progressive loss of myelin with patients experiencing Addison disease (concurrent adrenal gland insufficiency) in addition to a demyelinating syndrome. This disease is fatal by age 3. There are large plaques of demyelination with perivascular lymphocytic infiltrates progressively seen. VLCFA is a fatty acid with 22 or more carbons and its biosynthesis occurs in the endoplasmic reticulum of the cell. Rosenthal fibers are thick, elongated, wormlike eosinophilic bundles that are found on H&E staining of the brain in specific conditions (Box 15.12).

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Box 15.12 Rosenthal Fibers

• Genetic 1: Alexander disease • Genetic 2: Giant axonal neuropathy • Reactive 1: Perineoplastic (e.g., around craniopharyngioma) • Reactive 2: Perilesional (e.g., around plaques of multiple sclerosis) • Neoplastic: Pilocytic astrocytoma

• Alexander Disease: Diffuse Rosenthal fibers, which may be secondary to GFAP gene mutations. • Canavan Disease: Megalencephaly with spongiform degeneration of the white matter and AZII astrocytosis of the gray matter. • Cockayne Disease: Patchy myelin loss, basal ganglia calcification, and fibrous thickening of the leptomeninges.

15.8.3  Amyotrophic Lateral Sclerosis • DEF: Primarily motor pathway-affecting CNS disease with neuronal loss of the lower and upper motoneurons (both 1st and 2nd alpha-­ motor neurons) with little if any sensory deficits leading to death in 1.5  years after onset with bulbar involvement or a median survival of 3 years without. • EPG: AD inheritance (10% of cases, familial ALS or FALS) with involvement of chromosome 21 (In 1991 positional cloning identified linkage of FALS to the SOD1 locus on 21q22 indicating genetic locus heterogeneity) (Siddique et al. 1991, Siddique and Siddique 2008). ALS-linked Genes include mostly –– SOD1 (Cu-Zn superoxide dismutase) –– DYNACTIN –– ALSIN –– VAMP-B • CLI: Signs of 1st and 2nd alpha-motor neurons with the weakness of the extremities (pyramidal tracts), muscular atrophy (hands as first), labio-glosso-laryngeal paralysis (bulb

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involvement) with hyperreflexia (exaggerated deep tendon reflexes), and fasciculations. • GRO: Atrophy of the anterior spinal roots. • CLM: Progressive swelling, pyknosis, and loss of alpha-motor neurons, Bunina bodies (small eosinophilic inclusions in the surviving lower motor neurons), demyelination in the white matter, and neurogenic pattern of muscle fiber atrophy. TAR (trans-activation response)-­DNA-­binding protein 43 (TDP-43) is the primary component of intraneuronal inclusions in both genetic and sporadic ALS. TDP-43 is a 43 kDa protein that in humans is encoded by the TARDBP gene. TDP-43 represses HIV-1 transcription, regulates alternate splicing of the CFTR gene as a splicing factor binding to the intron8/exon9 junction of the CFTR gene, is a splicing factor to the intron2/exon3 region of the APOA-2 gene. It has been demonstrated that TDP-43 is a low molecular weight neurofilament mRNA-binding protein in human spinal motor neurons (Strong et al. 2007).

15.8.4  Werdnig-Hoffmann Disease • DEF: AR-inherited rapidly progressive muscular weakness secondary to loss of the 2nd (lower) motor neurons of the anterior horns of the spinal cords leading to the “floppy infant syndrome,” which may also be aspecific. • EPI: 1 in 10,000 children in Caucasian populations with 1/40 as a carrier. • EPG: SMA is due to the lack of the survival motor neuron (SMN) protein due to gene alteration on SMN1. If both copies of the SMN1 gene are defective and SMN protein is absent, spinal neurons are going to die, leading to muscle weakness in the affected patients. The SMN genes are about 20  kb pairs long and both located on chromosome 5. SMN1 is situated on the telomeric portion, while SMN2 is centromeric. It is now known that only mutations in SMN1 can cause SMA, while mutations in the centromeric portion result to be “modifiers” of SMA without the potentiality to cause the neuro-

15.8 Demyelinating Diseases Involving the Central Nervous System

logic disease. Both SMN1 and SMN2 are part of a 500 kb inverted duplication on chromosome 5q13. Since this region is duplicated, it has numerous repetitive elements, harboring the consequence that an increased probability of rearrangements and deletions results in copy number variation (CNV). It is assumed that this is the reason why SMA occurs randomly at such a high frequency in several populations. SMA has a broad clinical spectrum, and five types (SMA 0–4) have been delineated based on clinical findings (ability to stand or walk, arthrogryposis, lack of breathing):

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less facies) caused by numerous factors, including adverse drug reactions and post-encephalitis event or be a genetic disease associated to a few genes, mainly α-synuclein aggregation-triggered misfolded protein/stress response. The most frequent genes and proteins in Parkinson disease are: α-SYNUCLEIN LARRK2 (leucine-rich repeat kinase 2) PARKIN DJ-1 PINK1

Protein deglycase DJ-1 is also known as Parkinson disease protein 7. PINK1- or PTEN-­ induced putative kinase 1 is a mitochondrial serine/threonine-protein kinase. PINK1 is encoded • SMA 0: Prenatal SMA (arthrogryposis) • SMA 1: Acute infantile SMA (Werdnig-­ by the PINK1 gene and protect cells from stress-­ induced mitochondrial dysfunction. Hoffmann disease) • SMA 2: Chronic infantile SMA (Werdnig-­ • EPI: Worldwide, 4th–6th decade, 1–2/1000 Hoffmann disease) population, ♂ > ♀. Juvenile-onset disease can • SMA 3: Chronic juvenile SMA (Kugelberg-­ occur rarely and can be caused by a single Welander disease) gene defect that is inherited in an AD, AR, or • SMA 4: Adult SMA X-linked manner. Suleiman et al. (2018) reported on a 10-year-old child who had juve15.8.5  Syringomyelia nile-onset Parkinson disease. Whole exome sequencing showed compound heterozygosity A rare condition in which a cyst or channel (the for two previously unreported novel mutations “syrinx”) forms within the spinal cord (Greek in ATP13A2 (PARK9). σũριγξ “channel, tube”). As this fluid-filled cyst • GRO: There are developmental abnormalities expands and lengthens over time, it provokes in the archicortex, subcortical structures, as compression and damages to part of the spinal well as the cerebellum and brainstem. The cord in a centro-peripheral fashion. occipital circumference and the brain size are increased compared to age-matched control children. This increase may be due to an increased number of neurons or an increased 15.8.6  Parkinson Disease and Parkinson Disease-­ amount of neuropil. Associated, G-Protein-­ • CLM: Cortical and non-cortical areas eviCoupled Receptor 37 dence region-specific defects in neuronal mor(GPR37/PaelR)-Related phology and cytoarchitecture. There are Autism Spectrum Disorder findings located at the prefrontal cortex, fusiform gyrus, fronto-insular cortex, cingulate cortex, hippocampus, and amygdala. The cerParkinsonism is a clinical syndrome constituted ebellum and brainstem are also involved. Loss by tremor, rigidity, brady- or akinesia, and posof pigmented neurons from the substantia tural instability. “TRAP”-Tetrad including (pill-­ nigra in the midbrain and locus caeruleus in rolling) tremor, rigidity, a-/hypokinesis (slowed the upper pons, being the lateral substantia voluntary movements), and postural (expression-

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nigra most severely affected (lateral → least neuronal pigment). Lewy body (LB): round, concentrically laminated, pale eosinophilic cytoplasmic inclusion, silver stain (−), but ubiquitin (+), and α-synuclein (+), conversely to the Pick bodies, which are silver stain (+). • TEM: A core with densely packed fine filaments and loose at the periphery is observed. • DDX: Parkinsonism with numerous etiologic factors. • PGN: If LB is found in the cortex → diffuse Lewy body disease with patients affected with dementia, while if Alzheimer disease change are seen → Lewy body variant of Alzheimer disease (β-APP gene mutations).

15.8.7  Creutzfeldt-Jakob Disease (sCJD or Sporadic), CJD-­ Familial and CJD-Variant • DEF: Subacute spongiform encephalopathy (85% sporadic, 10% familial, and 5% iatrogenic) related to “kuru” and the sheep model “scrapie” due to a conformational change of proteinase K-resistant prion (“proteinaceous infectious agent”) protein (PrP) acting as a β-pleated sheet (amyloidogenic) localized on 20p constituting the basis for abnormal protein folding (rod polymerization with amyloid features), abnormal ubiquitin, and intracellular trafficking. In fact, PrP 33–35 sc is degraded only to a 27–30 kD protein (partial digestion) by proteinase K digestion in affected individuals, conversely to the complete proteinase K digestion. • CLI: Generalized bilateral short interval periodic sharp wave complexes (~2/3 cases). • IMG: Diffusion-weighted MRI (DWI) and FLAIR MRI sequences show high-signal abnormalities situated in the caudate nucleus and putamen ≥2 cortical regions (temporal, parietaloccipital). In the setting of vCJD, patients have high-intensity signal in the posterior thalamus, which is also known as pulvinar. • CLM: Vacuolar spongiform degeneration of the neuropil with progressive and inexorable neuronal loss (“punched-out” vacuoles in gray matter–cortex and/or basal nuclei) and gliosis

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(glial proliferation) as well as amyloid plaques ± kuru plaques (10%) in the cerebellar granular cellular layer. • PGN: Fatal in all cases, usually within a half year. In 1936, Cuille` and Chelle demonstrated the transmissible nature of prion diseases experimentally through the intraocular administration of scrapie-infected spinal cord to a goat, while 30 years later, kuru, a condition of the South Fore people of New Guinea was transmitted to chimpanzees by Gajdusek, the co-recipient of the Nobel Prize in Physiology or Medicine in 1976 for work on kuru, the first known human prion disease. This population was practicing funerary cannibalism. Prion diseases can be distinguished in CJD forms and non-CJD prion diseases. Other clinical phenotypes of prion disease include kuru, fatal familial insomnia (FFI), and Gerstmann-­Straussler-­ Sheinker syndrome (GSS). Particular precaution needs to be taken into account in performing the autopsies of cases with potential CJD.  Following brain removal with CJD or CJD suspicion, 10% NaClO solution (bleach) or NaOH (caustic soda) is used to ensure decontamination of surfaces and equipment. These guidelines are like Rabies Autopsy Procedure that can be accessed online at the CDC or Centers for Disease Control and Prevention, which is the leading national public health institute of the United States of America. The CDC is a US federal agency under the Department of Health and Human Services. The CDC has innumerable guidelines providing paths for many agencies worldwide. It is headquartered in Atlanta, Georgia, USA. Ultimately, it should be mentioned the association with early Alzheimer disease and trisomy 21 syndrome (Down syndrome), which may present with a myoclonus that is different from the CJD-myoclonus.

15.8.8  West Syndrome/Infantile Spasms, ACTH Therapy, and Sudden Death West syndrome/infantile spasms (WS/IS) is a severe, tragic epilepsy syndrome consisting of the triad of infantile spasms, an interictal EEG

15.9 Neoplasms of the Central Nervous System

pattern labeled “hypsarrhythmia,” and mental retardation, but two out of three criteria are enough to make this diagnosis. The onset is between 4 and 7 months of age, and the prevalence is 1:2000 to 1:6000 live births. The etiology is multifactorial, including hypoxic-ischemic injury, congenital infections, cortex development defects, tuberous sclerosis complex (Bourneville-Pringle disease), inborn errors of metabolism, genetic multiple congenital anomaly (MCA) syndromes, and chromosomal abnormalities as well as idiopathic. ACTH is the drug of choice for treatment of WS/IS and is quite safe, but some side effects need to be taken into consideration. These include Cushingoid features, an increase of appetite and weight gain, irritability, immunosuppression, an increase of risk for joint infections (pneumonia, GU and GI infections), hypertension, glucosuria/diabetes mellitus, hypokalemia, gastritis, and cerebral ventriculomegaly. Thus, a death occurring in a child under treatment of ACTH (or steroids) needs to be examined under medico-legal aspects and take into account septicemia, shock, and brain pathology.

15.9 Neoplasms of the Central Nervous System In approximately one in ten cancer deaths, a CNS neoplasm is the cause underlying the fatal course. Age is important in CNS neoplasms because it affects the distribution and favors specific histologic types. In fact, pediatric brain tumors are in about ¾ of cases localized below the tentorium, while brain tumors are with the same rate above the tentorium in adults. Furthermore, pediatric brain tumors are about 20% of all pediatric tumors just second to leukemias, and adult brain tumors are quite rare if compared with tumors of other organs. The most common pediatric brain tumors are gliomas of the astrocytic type followed by medulloblastomas, ependymomas, and craniopharyngiomas, while the most common adult brain tumors following the astrocytic nature are metastases and meningiomas. Males are more affected than females. Neoplasms may derive from all cell

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types, although criteria of benignancy and malignancy are not entirely straightforward as seen in other organs. Separating the tumors between glial and nonglial neoplasms is useful. Glial neoplasms show sponge-like quality and a tendency to infiltrate the surrounding tissue, two features that allow categorizing this kind of tumor as biologically malignant (exceptions apply, vide infra). Nonglial neoplasms have a more robust structure and grow by expansion enabling a better resection. CNS tumors rarely metastasize outside the CNS. It is also imperative to distinguish between direct and secondary pathophysiologic effects of CNS neoplasms. Direct effects involve several invariable functions of the area where the tumor is located and also affect the inhibitory influence on afferent impulses of local neurons rendering the neurons biophysically electrically unstable with the consequence of a liability to seizures. Indirect effects include the edema of the surrounding tissue, circulatory effects due to compression of the brain and spinal cord, compression and “functio laesa” of adjacent vital structures, herniation of the brain and cerebellar tonsils with Duret hemorrhage, as well as interference with CSF circulation and progressive development of hydrocephalus and papilledema. Clinically, headache, nausea, and vomiting may be accompanied by seizures, palsy, aphasia, blindness, deafness, lethargy, or abnormal behavior. Herniation of brain and cerebellar tonsils induce loss of consciousness, central respiratory failure, and death. CSF cytology is crucial in the initial diagnostic approach and following treatment (Fig. 15.8).

15.9.1  Astrocyte-Derived Neoplasms It is essential to differentiate between astrocytoma, pilocytic astrocytoma, glioblastoma multiforme, and oligodendroglioma.

15.9.1.1 Astrocytoma Astrocytomas represent 1/3 of all gliomas and occur more frequently in the cerebellar hemispheres in children and the central white matter of the brain in adults. There are two types

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a

b

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d

e

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Fig. 15.8  This panel illustrated a cluster of four malignant cells in the CSF in Figure a (Diff-Quik staining, ×630 original magnification). The chromatin is clumped and the nuclear contour is irregular. A cluster of numerous cells is shown in Figure b (Diff-Quik staining, ×630 original magnification). This cluster shows a high nucleus to cytoplasm ratio with very dense chromatin and hyperbasophilic nucleus. Malignant cells are also shown in Figure

c (Papanicolaou staining, ×400 original magnification). Leptomeningitis proof is shown in Figure d (Papanicolaou staining, ×400 original magnification). A cluster of acute myeloblastic leukemic cells is shown in Figures e and f (Giemsa staining, ×400 original magnification) Diff-Quik is a commercial Romanowsky stain variant, which is often used to rapidly stain cytological preparations. It differentiates a variety of blood films and cytopathological smears

distinguished in protoplasmic and fibrillary according to the kind of astrocytes that predominate:

• CLM: The architecture is typical with tumors varying from highly to sparsely cellular and highly fibrillary matter. If only the edge of the lesion is biopsied, it is essential to distinguish a glial neoplasm from reactive gliosis. Reactive gliosis shows astrocytes that are evenly dispersed within the tissue, at approximately equal distances from each other.

• GRO: Gray-whitish or white, firm, poorly demarcated with difficulty to appreciate the resection margins and may harbor tiny cysts filled with clear yellow fluid.

15.9  Neoplasms of the Central Nervous System

Interestingly, in infarctions and demyelinating disease, there will be a mosaic of reactive astrocytes and macrophages, which is no present in glial neoplasms. In subacute reactive peri-abscessual gliosis, there will be few macrophages, but the astrocytes are scattered in the background neuropil. An irregular distribution of the astrocytes and disorganization with a “tendency to touch each other or clash” is characteristic of glial neoplasms. Moreover, reactive astrocytes have long, tapering, starlike cytoplasmic processes, while neoplastic astrocytes display short and irregular blunted processes and gemistocytic features. A useful IHC stain is glial fibrillary acidic protein (GFAP), which may strikingly reveal the differences between reactive and neoplastic astrocytes. Moreover, reactive astrocytes do not show nuclear atypia and high cellular density. An important caveat can be radiation therapy (external beam or stereotactic), which can cause significant cytologic atypia in astrocyte. However, true hypercellularity is lacking. Importantly, macrophages, mainly bland necrosis devoid of cellular response, fibrinoid vascular necrosis, and hyalinized and altered blood vessels, are not features of a neoplastic process, and therapy may be held. Conversely, gemistocytic (Greek: γέμιζω ‘to fill up’) astrocytes, but not reactive astrocytes, scattered with astrocytes that show angular hyperchromatic nuclei and nuclear anaplasia and pleomorphism with or without straight necrosis point to a neoplastic relapse needed to get more effective therapy. • PGN: It depends from the grade (see most recent WHO classification). Survival has a variable range from 1 to 10 years. In 2016 WHO update of the classification of tumors of the central nervous system, there is a combination of histology with tumor genetic information to create a specific diagnostic algorithm. In the first place, the histologic information is used to address a diffuse glioma/tumor grade. Second, the isocitrate dehydrogenase IDH gene mutation status is tested using immu-

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nohistochemistry (IHC) with an antibody against IDH1 R132H (~90% of all IDH mutations). Mutations in IDH1 and IDH2 occur in most of low grade gliomas and secondary high grade gliomas. These mutations have been found to occur early in gliomagenesis and are able to change the function of the enzymes, inducing them to produce 2-hydroxyglutarate, which is a potential oncometabolite. In case of the negative result by IHC, genetic sequencing is performed to identify minor IDH1/IDH2 mutations (~10% of all IDH mutations). In the case of IDH-mutant II–III grade gliomas, a set of genetic parameters can differentiate astrocytomas from oligodendrogliomas. In case of oligodendrogliomas, the proof of loss of heterozygosity due to chromosomal arms 1p and 19q deletion is required, which is a molecular hallmark of oligodendroglioma. Fluorescence in situ hybridization (FISH) is used to identify 1p19q codel. IDH-mutant astrocytomas (~80% of all astrocytomas) are distinct by mutations of ATRX and TP53 (and lack of 1p19q codel) because ATRX and TP53 mutations are not present in oligodendrogliomas. In case of GBM in individuals with age >55 years, sequencing is not recommended because of the very low likelihood for detecting other IDH mutations in this subgroup.

15.9.1.2 Pilocytic Astrocytoma • DEF: “Hairlike”-astrocytoma with lengthy, bipolar processes and excellent prognosis (WHO grade I) • EPI: Most common CNS tumor of childhood, 1:100,000 (incidence), 1st–2nd decades, ♂ = ♀ • CLI: Midline structures in posterior fossa including cerebellum, 3rd ventricle, thalamus, hypothalamus, neurohypophysis, optic nerve, optic chiasm, hypothalamus, cerebral hemispheres, brainstem, and spinal cord with the potential to be multicentric. • IMG: Well circumscribed and contrast enhancing, often cystic tumor, in which the invasion of subarachnoid space and endothelial proliferation are not considered poor prognostic factors. • GRO: Discrete, cystic (microcystic/macrocystic) mass.

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• CLM: Biphasic pattern with varying proportions of piloid areas alternating with spongy areas. Piloid regions are constituted by bipolar neoplastic cells with elongated “hairlike” cytoplasmic processes that are arranged in parallel bundles and look like rugs of hair, Rosenthal fibers (tapered twisted shaped, brightly eosinophilic, hyaline masses), eosinophilic protein droplets ± mural nodule, and calcifications. Spongy areas are constituted by multipolar cells (protoplasmic astrocytes) associated with microcysts and eosinophilic granular bodies embedded in a loose texture. Malignant transformation if hypercellularity, mitotic figures, and necrosis are present (leptomeningeal extension does not portend a sign of malignancy). However, it needs to be distinguished from degenerative changes (hyalinized blood vessels, infarct-like necrosis, degenerative nuclear atypia, calcification, hemosiderin deposits, and lymphocytic infiltrates) and vascular modifications (glomeruloid proliferation and vascular hyalinization). Rarely, a diffuse growth pattern is seen. • HSS/IHC: (+) GFAP, PTAH, PAS (protein droplets), A1ACT (protein droplets). • DDX: Diffuse astrocytoma (WHO grades II– IV), gliosis, hemangioblastoma, pleomorphic xanthoastrocytoma, ganglioglioma, and piloid gliosis (hypocellular with numerous Rosenthal fibers, but lack of spongy areas). • TRT: Resection and adjuvant radiochemotherapy for tumors of the optic pathway and hypothalamic region. • PGN: 5-YSR: >90% (10-YSR: 100% if supratentorial and gross total resection, but 74% if subtotal resection).

15.9.1.3 Glioblastoma Multiforme (GBM) • DEF: High-grade glioma with rapid growth, variable symptomatology with increased ICP. • EPI: Rare in pediatrics and youth. • GRO: Large, well-demarcated, multicolored, soft tumor in the central white matter of the brain with surrounding edema inciting marked compression, distortion, and displacement of adjacent structures potentially crossing the

•

•

•

•

midline through a direct invasion of the corpus callosum. CLM: Highly cellular and hypervascular architecture with extensive necrosis, prominent atypia and pleomorphism, and intense endothelial hyperplasia (all three features are necessary histologic features for a diagnosis of glioblastoma multiforme). TEM: Tumor cells are swollen variably and contain a large rounded nucleus with marginalized chromatin. The cytoplasm contains mitochondria and well-developed ER. In the extracellular space, myelin sheaths and cell processes are usually observed. CMB: Abnormalities of chromosomes 7, 9, and 10 with overexpression of the oncogene c-sis in more than half of the cases and c-erb B in approximately 1/3 of the cases. PGN: Poor, although adjuvant radio-­ chemotherapy seems to have increased some survival.

15.9.1.4 Oligodendroglioma • DEF: Oligodendroglioma accounts for approximately 1/20 of all intracranial tumors and is the most common glioma of the cerebral hemispheres in adulthood. • CLI: There is an indolent clinical course, and grossly, these tumors are typically well-­ circumscribed in the white matter, although they may break through into the cortex cerebri. • CLM: Uniform architecture of a honeycomb or “fried egg” appearance of the tumor cells (small rounded nuclei surrounded by clear spaces, although this feature is not seen on frozen section) is observed accompanied by prominent calcification foci. To remember is that the distinction between oligodendroglioma and astrocytoma on intraoperative frozen section is not typically necessary. • PGN: 5-YSR of ~50%.

15.9.2  Ependymoma • DEF: Tumor-derived from the ependymal lining of the ventricular system and the central canal of the spinal cord. About half of the

15.9  Neoplasms of the Central Nervous System

• • •

•

•

•

•

tumors are below the tentorium, and nearly half of the tumors are above. A few ependymomas occur in the spinal cord or filum terminale. EPI: All age groups with peak at age of 3–4 years. CLI: Papilledema and headache. GRO: It is a soft tan mass with a distinct edge from surrounding brain or spinal cord with characteristic exophytic growth into 4th ventricle and ability to fill this ventricular cavity. If the ependymoma fills the 4th ventricle and exits out through foramina of Luschka or Magendie, the ependymoma is called of plastic type. CLM: There is a classic picture of a combination of perivascular pseudorosettes (more common) and ependymal rosettes (less common) with a monomorphic nuclear morphology. Perivascular pseudorosettes are formed by tumor cells arranged in a radial fashion around blood vessels, while ependymal rosettes are formed by cylindrical cells arranged radially around central lumina resembling ependymal canals. Regressive changes may be encountered and include hemorrhage, calcification, myxoid degeneration, and, rarely, cartilage and bone islands. IHC: (+) GFAP, S100, VIM, EMA, ± AE1–3. EMA is positive along the lumen of ependymal rosettes and as dot-like cytoplasmic vacuoles illustrative of early microlumens. CMB: In 1/3–2/3 of ependymomas there are deletions of the chromosome 22, inactivation of NF2 or loss of expression of the protein in about 1/3 of cases. It is common to observe the loss of protein 4.1B and 4.1R in childhood ependymomas. Protein 4.1G deletions have been associated with a more aggressive outcome. PGN: The outcome is directly linked to the location of the tumor, carrying the infratentorial ependymomas a more benign outcome than the supratentorial ependymomas.

Histopathologic variants of ependymomas include cellular, papillary, clear cell, tanycytic, ependymoma with lipomatous differentiation,

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giant cell ependymoma of the filum terminale, ependymoma with extensive tumor cell vacuolation, melanotic ependymoma, and ovarian ependymoma. Two essential entities are the myxopapillary ependymoma and the anaplastic ependymoma. Myxopapillary ependymoma is a slow-growing ependymoma composed of cells arranged in a papillary pattern around vascularized myxoid cores and located almost solely near conus medullaris, cauda equina, and filum terminale of spinal cord (Fig.  15.9). The anaplastic ependymoma is a mainly pediatric ependymoma with localization at the brain or cerebellum and tendency to infiltrate leptomeninges and spreading like medulloblastoma (vide infra).

15.9.3  Medulloblastoma • DEF: Medulloblastoma is one small-cell tumor of the CNS and PNS and both clinically and pathologically malignant tumors with an occurrence usually below pubertal age (Figs. 15.10 and 15.11). • EPG: Four genetic groups: (1) WNT activated, (2) SHH activated (either TP53 wild type or TP53 mutated), non-WNT/non-SHH, (3) medulloblastoma group 3, and (4) medulloblastoma group 4. • EPI: It is the most common embryonal brain tumor of childhood after the pilocytic astrocytoma. The classic type has a midline location, while the desmoplastic/nodular medulloblastoma predilects the cerebellar hemispheres and midline with a bimodal age distribution. Gorlin syndrome may be present in some patients harboring medulloblastoma. • GRO: Homogenous, reddish-gray, well-­ defined tumors arising in the midline posteriorly (e.g., the roof of the fourth ventricle) with an affinity to spread along the CSF pathway. • CLM: Highly cellular, perivascular with cellular monomorphism (“carrot-shaped blue cells”) and high N/C ratio. • IHC: (+) SYN, NeuN, SMARCB1/INI1 and SMARCA4, SOX11, PAX5, TTF1, and ISL1. In medulloblastoma with melanocytic differentiation, HMB45 and melanA are positive, while

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Fig. 15.9  Myxopapillary ependymoma is a tumor which is located in the sacrococcygeal area of children and young adults at intradural level. The microphotographs stained with hematoxylin and eosin are shown in Figures a and b (a, ×100; b, ×100, both original magnifications) disclosing cuboidal to mildly elongated cells with a radial orientation around vascularized myxoid cores. In figure c (Alcian-Blue-periodic acid Schiff staining, ×100 original magnification), the myxoid cores are highlighted using a special stain. The following five immunohistochemical microphotographs show the expression of glial fibrillary

acidic protein (GFAP) (d, ×100 original magnification), S100 (e, ×100 original magnification), vimentin (f, ×100 original magnification), epithelial membrane antigen (g, ×100 original magnification), and Ki67 (h, ×100 original magnification). All imnumostainigs have been performed using the avidin-biotin complex method. GFAP is an intermediate filament protein identified in numerous cell types of the central nervous system including ependymal cells and astrocytes during development. The proliferation antigen Ki67 is a cellular marker for proliferation (MIB1 monoclonal antibody)

15.9 Neoplasms of the Central Nervous System

a WNT pathway

SHH pathway

Rod proliferation pathway (Group 3)

A-SYN/SEMA/Apoptosis pathway (Group 4)

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SHH

Wn

SMO

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References and Recommended Readings Siebert JR, Cohen MM Jr, Shaw C-M, Sulic KK, Lemire RJ.  Holoprosencephaly. New  York: Alan R Liss; 1990a. Siebert JR, Cohen MM Jr, Sulik KK, Shaw C-M, Lemire RJ. Holprosencephaly: an overview and atlas of cases. New York: Wiley-Liss; 1990b. Simmons G, Damiano TR, Truwit CL. MRI and clinical findings in rhombencephalosynapsis. J Comput Assist Tomogr. 1993;17:211–4. Sipe JC, Herman MM, Rubinstein LJ.  Electron microscopic observations on human glioblastomas and astrocytomas maintained in organ culture systems. Am J Pathol. 1973;73(3):589–606. PubMed PMID: 4358392; PubMed Central PMCID: PMC1904091. Smith MT, Huntington HW.  Inverse cerebellum and occipital encephalocele. A dorsal fusion defect uniting the Arnold-Chiari and Dandy-Walker spectrum. Neurology. 1977;27:246–51. Soejima H, Fujimoto M, Tsukamoto K, Matsumoto KI, Yoshiura KI, Fukushima Y, Jinno Y, Niikawa N. The novel PAX3 mutations observed in patients with the Waardenburg syndrome type 1. Hum Mutat. 1997;9:177–80. Starck D.  Embryologie. Ein Lehrbuch auf allgemein biologischer Grundlage. 2nd ed. Stuttgart: G Thieme; 1965. Stephens TD.  Muscle abnormalities associated with the twin reversed-arterial-perfusion (TRAP) sequence (acardia). Teratology. 1984;30(3):311–8. PubMed PMID: 6515559. Stoll C, Alembik Y, Dott B.  Associated malformations in cases with neural tube defects. Genet Couns. 2007;18(2):209–15. PubMed PMID: 17710873. Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-­ binding protein. Mol Cell Neurosci. 2007;35(2):320– 7. Epub 2007 Mar 20. PubMed PMID: 17481916. Suleiman J, Hamwi N, El-Hattab AW.  ATP13A2 novel mutations causing a rare form of juvenile-onset Parkinson disease. Brain Dev. 2018;40(9):824–6. https://doi.org/10.1016/j.braindev.2018.05.017. Epub 2018 Jun 11. PubMed PMID: 29903538. Sulik KK, Cook CS, Webster WS.  Teratogens and craniofacial malformations: relationship to cell death. Development. 1988;103(Suppl):219–31. Sun M, Forsman C, Sergi C, Gopalakrishnan R, O’Connor MB, Petryk A.  The expression of twisted gastrulation in postnatal mouse brain and functional implications. Neuroscience. 2010;169(2):920–31. https://doi. org/10.1016/j.neuroscience.2010.05.026. Epub 2010 May 20. PubMed PMID: 20493240; PubMed Central PMCID: PMC2971674. Swendeman SL, Spielholz C, Jenkins NA, Gilbert DJ, Copeland NG, Sheffery M.  Characterization of the genomic structure, chromosomal location, promoter, and development expression of the alpha-­ globin transcription factor CP2. J Biol Chem. 1994;269(15):11663–71. PubMed PMID: 8157699.

1319 Takashima S, Becker LE, Chan F, Takada K.  A Golgi study of the cerebral cortex in Fukuyama-type congenital muscular dystrophy, Walker-type ‘lissencephaly’, and classical lissencephaly. Brain Dev. 1987;9:621–6. Temming P, Jenney ME.  The neurodevelopmental sequelae of childhood leukaemia and its treatment. Arch Dis Child. 2010;95(11):936–40. https://doi. org/10.1136/adc.2008.153809. Review. Erratum in: Arch Dis Child. 2011;96(8):787. PubMed PMID: 20980277. The physics of cerebrovascular diseases: biophysical mechanisms of development, diagnosis and therapy hardcover  – Nov 20 1997 by George J.  Hademenos (Author), Tarik F.  Massoud (Author), F.  Vinuela (Foreword) Hardcover: 319 pages Publisher: American Institute of Physics; 1998 edition (Nov. 20 1997) Language: English ISBN-10: 1563965585 ISBN-13: 978-1563965586. Thomas KR, Cappechi MR.  Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature. 1990;346:847–50. Töndury G.  Entwicklungsstörungen durch chemische Faktoren und Viren. Naturwiss. 1955;42:312–9. Truwit CL, Barkovich AJ, Shanahan R, Maroldo TV. MR imaging of rhombencephalosynapsis: report of three cases and review of the literature. AJNR Am J Neuroradiol. 1991;12(5):957–65. Review. PubMed PMID: 1950929 Tubbs RS, Loukas M, Shoja MM, Mortazavi MM, Cohen-Gadol AA.  Félix Vicq d’Azyr (1746-1794): early founder of neuroanatomy and royal French physician. Childs Nerv Syst. 2011;27(7):1031–4. https://doi.org/10.1007/s00381-011-1424-y. PubMed PMID:21445631. Ulu EM, Töre HG, Bayrak A, Güngör D. Coşkun M. MRI of central nervous system abnormalities in childhood leukemia. Diagn Interv Radiol. 2009;15(2):86–92. PubMed PMID: 19517377. Van Allen MI, Smith DW, Shepard TH.  Twin reversed arterial perfusion (TRAP) sequence: a study of 14 twin pregnancies with acardius. Semin Perinatol. 1983;7:285–93. Van Allen MI, Kalousek DK, Chernoff GF, Juriloff D, Harris M, McGillivray BC, Yong SL, Langlois S, MacLeod PM, Chitayat D, Friedman JM, Wilson RG, McFadden D, Pantzar J, Ritchie S, Hall JG. Evidence for multi-site closure of the neural tube in humans. Am J Med Genet. 1993;47(5):723–43. Review. PubMed PMID: 8267004. Van der Hoeve J. Eye symptoms in tuberous sclerosis of the brain. Trans Ophthalmol Soc UK. 1920;40:329–34. Van der Hoeve J.  Eye diseases in tuberous sclerosis of the brain and in Recklinghausen’s disease. Trans Ophthalmol Soc UK. 1923;43:534–41. Vanaman MJ, Hervey-Jumper SL, Maher CO.  Pediatric and inherited neurovascular diseases. Neurosurg Clin N Am. 2010;21(3):427–41. https://doi.org/10.1016/j. nec.2010.03.001. Review. PubMed PMID: 20561493.

1320 Vasudevan C, McKechnie L, Levene M. Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations. Semin Fetal Neonatal Med. 2012;17(5):295–300. https://doi. org/10.1016/j.siny.2012.07.001. Epub 2012 Jul 25. Review. Verity C, Firth H, Ffrench-Constant C. Congenital abnormalities of the central nervous system. J Neurol Neurosurg Psychiatry. 2003;74(Suppl 1):i3–8. Review. PubMed PMID: 12611928; PubMed Central PMCID: PMC1765611. Vicq d’Azyr F.  Traité d’anatomie et de physiologie— avec des planches colorës représentant au naturel les divers organes de ‘Homme et des Animaux. Paris: F.A. Didot; 1786. Wassink G, Davidson JO, Dhillon SK, Zhou K, Bennet L, Thoresen M, Gunn AJ.  Therapeutic hypothermia in neonatal hypoxic-ischemic encephalopathy. Curr Neurol Neurosci Rep. 2019;19(2):2. https://doi. org/10.1007/s11910-019-0916-0. Review. PubMed PMID: 30637551. Weir PE, Ratten GJ, Beischer NA.  Polyhydramnios a acomplication of monozygous twins. Br J Obstet Gynaecol. 1979;86:849–53. Weprin BE, Oakes WJ.  Coccygeal pits. Pediatrics. 2000;105(5):E69. PubMed PMID: 10799633. Werthemann A.  Allgemeine Teratologie mit besonderer Berücksichtigung der Verhältnisse beim Menschen. 1. Zwillinge, Mehrlinge und Doppelbildungen in ihrer Beziehung zum Organisationsfeld. In: Büchner F, Letterer E, Roulet F, editors. Handbuch der allgemeinen Pathologie, vol. VI/1. Berlin/Göttingen/ Heidelberg: Springer; 1955. p. 100–6. White RA, Dowler LL, Angeloni SV, Pasztor LM, MacArthur CA.  Assignment of FGF8 to human chromosome 10q25-q26: mutations in FGF8 may be responsible for some types of acrocephalosyndactyly linked to this region. Genomics. 1995;30:109–11. Wildhardt G, Winterpacht A, Hilbert K, Menger H, Zabel B.  Two different PAX3 gene mutations causing Waardenburg syndrome type 1. Mol Cell Probes. 1996;10:229–31. Wilkins DE, Hallett M, Berardelli A, Walshe T, Alvarez N.  Physiologic analysis of the myoclonus of Alzheimer’s disease. Neurology. 1984;34(7):898–903. PubMed PMID: 6234478. Williams RS, Swisher CN, Jennings M, Ambler M, Caviness VS.  Cerebro-ocular dysgenesis (Walker-­ Warburg syndrome): neuropathologic and etiologic analysis. Neurology. 1984;34:1531–41. Wright CVE. Vertebrate homeobox genes. Curr Opin Cell Biol. 1991;3:976–82. Wyllie DH, Robinson E, Peto T, Crook DW, Ajileye A, Rathod P, Allen R, Jarrett L, Smith EG, Walker AS.  Identifying mixed Mycobacterium tuberculosis

15  Central Nervous System infection and laboratory cross-contamination during mycobacterial sequencing programs. J Clin Microbiol. 2018;56(11) https://doi.org/10.1128/JCM.0092318. pii: e00923-18. Print 2018 Nov. PubMed PMID: 30209183; PubMed Central PMCID: PMC6204665. Yakovlev PI. Pathoarchitectonic studies of cerebral malformations. J Neuropathol Exp Neurol. 1959;18:22–55. Yakovlev PI, Wadsworth RC.  Double symmetrical Porencephalies (Schizencephalies). Tr Am Neurol A. 1941;67:24–9. Yakovlev PI, Wadsworth RC. Schizencephalics. A study of the congenital clefts in the cerebral mantle. Clefts with fused lips. J Neuropath Exp Neurol. 1946;5:116–30. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD.  IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73. https://doi.org/10.1056/ NEJMoa0808710. PubMed PMID: 19228619; PubMed Central PMCID: PMC2820383. Yazigi F, Kahwash BM, Al Sufiani F, Conces M, Prasad V, Kahwash SB.  Histopathologic identification and pattern recognition of common viral infections in the general pathology practice: an illustrated review. Ibnosina J Med Biomed Sci. 2016;8:28. https://doi. org/10.4103/1947-489X.210214. Yoganathan S, Thomas MM, Mathai S, Ghosh U.  Neuroregression as an initial manifestation in a toddler with acquired pernicious anaemia. BMJ Case Rep. 2015;2015 https://doi.org/10.1136/bcr2015-213540. pii: bcr2015213540. PubMed PMID: 26678841; PubMed Central PMCID: PMC4691932. Yoshiura K, Leysens NJ, Chang J, Ward D, Murray JC, Muenke M.  Genomic structure, sequence, and mapping of human FGF8 with no evidence for ist role in craniosynostosis/limb defect syndromes. Am J Med Genet. 1997;72:354–62. Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-­ Sarnat L, Sergi CM, Topçu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA.  Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nat Genet. 2010;42(11):1015–20. https://doi.org/10.1038/ng.683. Epub 2010 Oct 3. PubMed PMID:20890278; PubMed Central PMCID: PMC2969850. Zamorano L, Chuaqui B.  Teratogenetic periods for the principal malformations of the central nervous system. Virchows Arch A Pathol Anat Histol. 1979;384(1):1– 18. Review. PubMed PMID: 159540. Zupanc ML. Infantile spasms. Expert Opin Pharmacother. 2003;4(11):2039–48. Review. PubMed PMID: 14596657.

Peripheral Nervous System

16

Contents 16.1

Development

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16.2 16.2.1  16.2.2  16.2.3  16.2.4  16.2.5  16.2.6 

Disorders of the Peripheral Nervous System Peripheral Neuropathy Traumatic Neuropathy Vascular Neuropathy Intoxication-Related Neuropathy Infiltration (e.g., Amyloid) Related Neuropathy Neoplasms of the Peripheral Nervous System

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16.3 16.3.1  16.3.2  16.3.3  16.3.4  16.3.5  16.3.6  16.3.7 

Neuromuscular Disorders Muscle Biopsy Test Neurogenic Disorders Myopathic Disorders Glycogen Storage Diseases Mitochondrial Myopathies Inflammatory Myopathies: Non-infectious Inflammatory Myopathies: Infectious

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Multiple Choice Questions and Answers

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References and Recommended Readings

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16.1 Development The formation of the muscular system begins about the 4th week of embryonic development, and the primitive cells are called myoblasts and are derived directly from the mesodermal germ layer. The muscles arise from the fusion of myoblasts to form a multinucleated syncytium or syncytial unit called a myotube which stimulates the formation of myofibrils. Exceptions to the mesodermal germ layer origin are the smooth muscles

from the ocular pupil, cutaneous sweat glands, and a mammary gland that derive from ectoderm. Skeletal muscles originate from paraxial mesoderm, which forms somites from the occipital to the sacral regions and somitomeres in the head. Cardiac muscles originate from splanchnic mesoderm surrounding the heart tube, while the smooth muscles differentiate from splanchnic mesoderm surrounding the gut. In a cranio-caudal fashion, somites form and differentiate into sclerotome, dermatome, and two-­muscle-­forming

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regions, of which one is located in the dorsolateral area of the somite providing progenitor cells for limb and body wall ­ musculature (the socalled hypomeric musculature). The other muscle-forming region is located in the dorsomedial region and builds the myotome (the so-called epimeric musculature). It is by the end of the 3rd month that myofibrils appear in the sarcoplasm of the myoblasts and ­cross-striation appears in the skeletal muscle. When the muscles become innervated, diffusely distributed acetylcholine receptors become concentrated at motor end plate. With the conclusion of the 5th week of embryonic development, the primitive musculature is divided into epimere (small dorsal portion), which is innervated by the primary dorsal ramus, and hypomere, which is innervated by the primary ventral ramus. The epimere forms the extensor muscle of the vertebral column, while from the hypomere originate the muscles of the limbs and body wall. With the elongation of the limb buds, the muscle tissue splits into flexor and extensor parts. The myofibril is composed of alternating bands. The I-bands (isotropic in polarized light) appear light in color, and the A-bands (anisotropic in polarized light) are dark in color. The alternating pattern of these bands results in the striated appearance of skeletal muscle. The Z-lines (Zwischenschieben) bisect the I-bands, while a light band called the H-band (Heller) is located within each A-band and the M-line (Mittelschiebe) bisects each A-band and, of course, also each H-band. Each myofibril is a series of contractile units (sarcomeres) that contains two types of filaments: thick filaments, composed of myosin, and thin filaments, composed of actin. The thick filaments are a bipolar array of polymerized myosin motors, while the thin filaments are attached to a disc-like zone that appears histologically as the Z-line. Skeletal muscles are separated into two muscle fiber types: slow-twitch (type I) and fast-twitch (type II). Type I muscle fibers contract more slowly, rely on aerobic metabolism, and have many mitochondria and myoglobin, which gives the reddish color of the fibers (“red fibers”). Type I muscles can maintain continuous contraction and are useful in activities such as the maintenance of pos-

16  Peripheral Nervous System

ture. Type II muscle fibers contract more rapidly due to the presence of a faster myosin and are subdivided into fibers that have large amounts of mitochondria and myoglobin and those that have few mitochondria and little myoglobin. In the former subtype, aerobic metabolism plays a major role, while the anaerobic glycolysis plays a major role in the latter. The lack of myoglobin results in a paler color than the slow-twitch muscles (“white fibers”). These muscles are essential for intense but sporadic contractions. Some special stains are useful in pathology. NADH is a stain for lipid and is not as useful as the ATPase reaction since denervation causes both fiber types to stain dark. Nonspecific esterase reaction stains type I fibers slightly darker than type II but stains denervated fibers of either type very dark, owing to the diffuse distribution of acetylcholine esterase activity. Alkaline phosphatase reaction stains regenerating fibers.

16.2 Disorders of the Peripheral Nervous System 16.2.1 Peripheral Neuropathy Causes of peripheral neuropathy include diabetes mellitus, alcohol, nutrition-related vitamin B deficiency, Guillain-Barré syndrome, trauma, hereditary (e.g., Friedreich ataxia, Charcot-­ Marie-­ Tooth syndrome), environmental toxins/ drugs (e.g., metronidazole, Fe, Pb), paraneoplastic, amyloidosis, porphyria, inflammatory, syphilis, and tumor. Mononeuropathy indicates a focal process, while polyneuropathy and polyneuritis point to a widespread degeneration of the peripheral nerves. Any combination of peripheral nerves may be affected, although the distal portions of the upper and lower limbs seem most often the target of polyneuropathies. No gross abnormalities are seen, but, microscopically, there is swelling of the myelin sheaths with fragmentation and globalization (aka Wallerian degeneration). These myelin sheaths stain progressively poorly and then disappear, and, later, axons show also swelling, fragmentation, and disappearance. Wallerian degeneration is a pro-

16.2 Disorders of the Peripheral Nervous System

cess of progressive demyelinization and disintegration of the distal axonal segment following the damage to the neuron. There are a few causes associated with Wallerian degeneration which include trauma, cerebral infarction, hemorrhage, necrosis, and focal demyelinization. Four stages have been delineated: • Stage I: The physical disintegration of the axons and myelin sheaths. • Stage II: The brisk destruction of the myelin fragments with central involvement of breakdown of the myelin fats in single lipids and neutral fat. • Stage III: Glia proliferation (gliosis) develops in the areas of degenerated axons and myelin sheaths. • Stage IV: Volume loss, which is the final consequence of the atrophy of the white matter.

16.2.2 Traumatic Neuropathy Traumatic neuropathy may occur by compression (e.g., neoplasm, callus, aneurysm, prolonged pressure, necrosis, and bandages), tension or stretching (e.g., overextension of a limb, bony fracture), and disconnection (e.g., knife bullet, jagged edge of skeletal fracture). Regeneration of the peripheral nerves is possible after injury, although the degree of disruption, the degree of blood supply, and simultaneous infections of the injury site may compromise the regeneration process.

16.2.3 Vascular Neuropathy Vascular neuropathy may occur in either vasculitis or DM, and ischemic pathogenesis is the underlying condition for the neuropathy.

16.2.4 Intoxication-Related Neuropathy Intoxication-related neuropathies may occur in the setting of arsenic (As), lead (Pb), and ethanol (CH3CH2OH) intoxication or poisoning.

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16.2.5 Infiltration (e.g., Amyloid) Related Neuropathy Infiltrative conditions amyloidosis.

include

most

often

16.2.6 Neoplasms of the Peripheral Nervous System Neoplasms include schwannomas or neurilemmomas (Fig.  16.1), neurofibromas (Figs.  16.2 and 16.3), as well as malignant peripheral nerve sheath tumor (MPNST or malignant schwannomas) (Figs. 16.4, 16.5, and 16.6). To mention also is the neuroblastoma that may develop from the paraspinal ganglia (Fig.  16.7) and the ganglioneuroma (Fig. 16.8) that are described elsewhere in this book.

16.2.6.1 Schwannoma • DEF: Biphasic tumor with highly ordered cellular component (Antoni A areas) that palisades (Verocay bodies) plus myxoid hypocellular component (Antoni B areas) associated with a perceptible nerve and strong S100 immunoreactivity. The schwannoma of cellular type is usually a centrally or axially located benign neoplasm with no tendency to malignant transformation (Fig. 16.1). • SYN: Neurilemmoma, neurinoma. • EPG: In familial tumor syndromes (e.g., NF2, schwannomatosis, or Carney complex) or sporadically. There is a loss of function of the tumor suppressor gene merlin (Schwannomin) or direct genetic change involving the NF2 gene or secondarily to merlin inactivation. • EPI: Vast age range (second to fourth decade), ♂  =  ♀, 90% as a sporadic tumor, while the remaining 10% as a tumor in NF-2, schwannomatosis, and meningiomatosis ± NF-2 type 2. • CLI: Upper limbs but also head and neck area, posterior mediastinum, retroperitoneum, gastrointestinal tract, and endocrine glands. More rare locations may also occur. According to the site, there may be pain and neurological symptoms being the tumor waxing and wan-

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Fig. 16.1  Schwannoma. The gross photograph of an unusual cystically degenerated and hemorrhagic schwannoma is presented (a). The microphotographs (b–f) show the microscopic appearance of this schwannoma with well-­ differentiated Schwann cells (hematoxylin-eosin staining). The tumor shows an alternating representation of areas with compact spindle cells (Antoni A) and hypocellular less orderly areas (Antoni B) with myxoid and microcystic appearance. Antoni A areas show the characteristic nuclear palisading. The alternating rows of palisading nuclei and intervening nuclei-free stroma constitute the Verocay bodies (b, ×100 original magnification; c,

×100 original magnification; d, ×100 original magnification; e, ×100 original magnification; f, ×100 original magnification). Two immunohistochemical microphotographs (g, ×100 original magnification; h, ×100 original magnification) disclose the expression of S100 and CD31, an endothelial cell marker. Typically, S100 proteins are mostly expressed in cells derived from the neural crest (Schwann cells, and melanocytes), chondrocytes, adipocytes, myoepithelial cells, macrophages, Langerhans cells, and dendritic cells. All immunohistochemistry stains have been performed using the avidin-biotin complex method

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Fig. 16.2  Neurofibroma. In (a) the schematic differentiation between schwannoma (upper tumor colored in brown not infiltrating the nerve) and neurofibroma (lower tumor colored in brown infiltrating the nerve). The hematoxylin-­ eosin microphotographs (b) through (g) show the characteristic features of a neurofibroma with all elements of peripheral nerves that proliferate in this tumor. There are Schwann cells with wire-­ like collagen fibrils showing wavy serpentine nuclei and harboring pointed ends. Also,

Wagner-Meissner corpuscles (g) and Pacinian corpuscles can be seen. Stromal mucosubstances, mast cells, axons, fibroblasts, and collagen may complement the histologic appearance (b, ×50 original magnification; c, ×50 original magnification; d, ×50 original magnification; e, ×400 original magnification; f, ×400 original magnification; g, ×400 original magnification). (h) The immunohistochemical expression of S100 (×12.5 original magnification) using the avidin-­biotin complex method

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Fig. 16.3  Plexiform Neurofibroma. Neurofibromatosis I and II belong to the group of the RASopathies (see text). In (a) are shown the criteria for the diagnosis of this disease. The microphotographs (b) and (c) are from hema-

toxylin-eosin-stained slides of a plexiform neurofibroma showing a distorted and tortuous appearance of a neurofibroma (b, c, ×50 original magnification)

ing in size, which may be related to the amount of cystic degeneration it encompasses. • IMG: Well-circumscribed masses displacing adjacent structures without direct ­invasion ± cystic and fatty degeneration, hemorrhage, and calcification. • GRO: The tumor is often eccentric to the nerve. In fact, the nerve of origin may be present at the periphery but does not penetrate the substance of tumor. • CLM: Characteristic fusiform growth pattern composed of Schwann cells. There are Antoni A areas with cellular fascicular spindled areas, wavy and slightly plump nuclei, pink cytoplasm, and eosinophilic hyalinization of

stroma and around vessels, with or without the well-formed Verocay bodies of classic schwannoma. Moreover, there are Antoni B areas with the hypocellular myxoid (probably neurofibroma-like) growth pattern. Histologic features of malignant change (marked pleomorphism, atypical mitoses, or geographic necrosis) are not observed and need to be carefully identified and need to be distinguished from some good degenerative changes, including cystic degeneration, necrosis, cytologic atypia, and mild increase of the mitotic figures. Reactive xanthoma cell inflammation is typically seen in the setting of central degeneration.

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Fig. 16.4  Malignant Peripheral Nerve Sheath Tumor. The malignant peripheral nerve sheath tumor (MPNST) can exhibit a disguising histology and a number of differential diagnoses need to be kept in mind. The microphotographs (a–g) show the hematoxylin-­eosin-stained histology of an MPNST (a, ×12.5 original magnification; b, ×100 original magnification; c, ×100 original magnification; d, ×50 original magnification; e, ×400 original magnification; f, ×630 original magnification, g, ×100 original magnification).

The tumor shows a heterogeneity with variation in cellularity and growth pattern. It can be recognized from tightly packed spindle cells, which can be arranged in either a herringbone or interwoven fasciculated growth pattern (b and c). In (d) and (g), a chondroid differentiation may be recognized. The microphotograph (h) shows the immunohistochemical expression of S100 (×100, original magnification). The avidin-biotin complex has been used for the immunostaining of this tumor

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Fig. 16.5  The malignant triton tumor is a specific subtype of malignant peripheral nerve sheath tumor (MPNST) with rhabdomyoblastic differentiation (e–h) in addition to a a classic morphology of MPNST (a–d) (a, hematoxylineosin staining, ×12.5 original magnification, b, hematox-

ylin-eosin staining, ×100 original magnification; c, hematoxylin-­eosin staining, ×100 original magnification; d, hematoxylin-­eosin staining, ×100 original magnification; e–h, hematoxylin-­ eosin staining, ×400 original magnification)

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Fig. 16.6  Malignant Peripheral Nerve Sheath Tumor. This immunohistochemical panel of a malignant peripheral nerve sheath tumor (MPNST) shows the expression of GFAP (a, ×200 original magnification), S100 (b, ×200 original magnification), DES (c–e, ×200 original magnifi-

cation), MYF4 (f, ×200 original magnification), AE1-3 (g, ×200 original magnification), and of the proliferation antigen Ki67 (h, ×12.5 original magnification). All immunohistochemical stainings have been performed using the avidin-biotin complex method

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Fig. 16.7  Paraspinal Neuroblastoma. The panel illustrates paraspinal neuroblastoma with five hematoxylin and eosinstained histologic slides showing a classic poorly differentiated neuroblastoma with small round blue cell tumors with high nucleus to cytoplasm ratio and less discernible cytoplasm (a, ×200 original magnification; b, ×200 original magnification; c, ×200 original magnification; d, ×200

original magnification; e, ×200 original magnification). Three microphotographs from immunohistochemical-­ stained slides show the expression of CD56, CD57, and neurofilaments (f, ×200 original magnification; g, ×200 original magnification; h, ×200 original magnification). The tumor was also positive for synaptophysin (SYN) and chromogranin A (CGA) (not shown)

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Fig. 16.8  Ganglioneuroma. The gross photograph of this ganglioneuroma discloses the gross appearance of this tumor, which is well circumscribed with a firm texture, gray-white on cut surface and harboring a trabecular or whorled appearance (a). The hematoxylin-eosin microphotographs (b–h) show a mixture of Schwann cells and ganglion cells (d–f) and the whorled appearance can be

recognized microscopically as well (c). Occasionally, calcification (g) and scattered chronic inflammatory cells (h) can be seen (b, ×50 original magnification; c, ×100 original magnification; d, ×100 original magnification; e, ×200 original magnification; f, ×200 original magnification; g, ×200 original magnification; h, ×200 original magnification)

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• IHC: (+) S100, GFAP (focal), AE1–AE3 (focal, cross-reactivity), EMA (capsular area with staining of the perineurial or epineurial cells) but (−) CD34, NFP, HMB45, SMA, and DES. Immunohistochemically, S100 and calretinin can help in the diagnosis. S100 is a protein belonging to a family of low molecular weight found in vertebrates and characterized by two Ca-­ binding sites of the helix-loop-helix (“EF-­hand type”) configuration and consists of two identical polypeptides linked by non-covalent bonds. S100 is expressed in cells arising from the neural crest (Schwann cells, melanocytes, and glial cells), chondrocytes, fat cells, myoepithelial cells, macrophages, Langerhans cells, dendritic cells, and keratinocytes. S100 is involved in protein phosphorylation, transcription factor regulation, Ca2+ homeostasis, cytoskeleton dynamics, cell growth and differentiation, and inflammation. Calretinin is a Ca-binding protein belonging to the family of EF-hand proteins and is expressed in some neurons of the CNS and PNS, as well as several other cells, including mesothelial cells, and is useful in differentiating mesothelioma from adenocarcinoma, ovarian sex cord-­ stromal tumors, Leydig cell tumors of the testis, adrenal cortical tumors, and adenomatoid tumors. S100 is expressed in both tumors, although it is higher in schwannomas than neurofibromas, while calretinin is usually detected in schwannomas and very few neurofibromas. • DDX: Six diagnoses need to be kept in mind  – neurofibroma (nerve-arising tumor with internally located entering and exiting nerve with a central more neural-like and peripheral more edematous aspect, (+) S100, CD34, NFP, EMA, (−) GFAP), SFT (eosinophilic appearance with haphazard plump cells, scant mitotic activity, (+) CD34, (−) S100), synovial sarcoma (hemangiopericytoma-like vasculature, ovoid cells, and denser cellularity than cellular schwannoma, geographic necrosis, and S100 limited to residual intratumoral wavy neurons), MPNST (high-grade sarcoma with invasion of surrounding structures or pseudocapsule, peri-

16  Peripheral Nervous System

vascular tumor sparing and geographic necrosis, high N/C imparting a blue tumor appearance, (+) S100, GFAP, but (−) AE1– AE3, DES, HMB45, CD34), sarcomatoid carcinoma (malignant morphologic features with clues of origin, e.g., primary pulmonary adenocarcinoma (CK18 and TTF1 +) or squamous cell carcinoma (CK5/6 +)), and spindle cell melanoma (prominent cherry red nucleoli and/or intranuclear cytoplasmic inclusions and often atypical mitotic activity, marked cytologic atypia and geographic necrosis, negativity of melanoma markers, including HMB45, Melan-A, tyrosinase, and MITF, but (+) SOX10, NGFR, KBA.62, and clusterin). • TEM: The tumor cells simulate the appearance of differentiated Schwann cells differently from the neurofibromas, which have a mixture of different tumor cells, including Schwann cells, perineurial cells, and endoneurial fibroblasts. In TEM, elongated cells with continuous basal lamina, thin cytoplasmic processes, aggregates of microfibrils in the cytoplasm, intracytoplasmic lamellar bodies, and long-­ spacing (exceeding 100  nm) extracellular collagen “bodies” (Luse bodies) are observed. • PGN: There is a low tendency for malignant transformation, but signs that portend into this direction include (1) sudden progressive increase in size, (2) epithelioid features in cellular schwannoma, (3) melanotic (pigmented) schwannoma, and (4) angiosarcoma-like areas.

16.2.6.2 Neurofibroma (Figs. 16.2 and 16.3) • DEF: Benign, common, spindle cell tumor ± NF-1, in the case of multiple tumors, with a malignant transformation more common in NF-1 neurofibromas than in sporadic neurofibromas. Subtypes include plexiform neurofibroma with irregularly expanded nerve bundles with nodular appearance and prominent myxoid matrix; associated with NF-1, diffuse cutaneous, focal cutaneous, and intraneural (Figs. 16.2 and 16.3).

16.3 Neuromuscular Disorders

• CLI: Small, pedunculated nodules over the skin if superficial or tumor-mass effect if deeply located and large. • GRO: Not encapsulated with a softer consistency than schwannoma. • CLM: It is characterized by the proliferation of all fundamental components of peripheral nerves (Schwann cells with wavy serpentine nuclei, pointed ends, stromal mucosubstances, mast cells, Wagner-Meissner corpuscles, Pacinian corpuscles, axons) with perineurial cells in plexiform types, low MI, and a focally infiltrative character with myxoid areas and potential epithelioid morphology. There are neither Verocay bodies nor nuclear palisading or hyalinized thickening of vessel walls. • HSS/IHC: (+) Silver or AcHE stain, NSE, NF, S100, CD34 (focal), FXIIIa (focal), EMA (plexiform neurofibromas only). • TEM: Schwann cells enclose axons in invaginations of plasmalemmal type. • DDX: Myxoid lipoma and myxoid liposarcoma. • TRT: Resection. • PGN: Meager chance of malignant transformation for sporadic neurofibromas, but a tendency to transform in MPNST is present in multiple neurofibromas.

16.2.6.3 M  alignant Peripheral Nerve Sheath Tumor (Figs. 16.4, 16.5, 16.6, 16.7, and 16.8) • DEF: It is a large deep-seated tumor arising from significant nerves in the neck, buttock, and limbs and associated with NF-1, previous radiation, or malignant transformation of a neurofibroma or plexiform neurofibroma. • SYN: Malignant schwannoma. • CLI: Apart from the tumor-mass effect, signs, and symptoms related to NF-1. • GRO: It is a large mass-producing fusiform expansion of a major nerve. • CLM: Monomorphic serpentine cells, palisading, large gaping vascular spaces, perivascular plump tumor cells, necrosis, imparting a “geographic” appearance with

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tumor palisading at edges with atypical mitoses and 1/10 cases harboring metaplastic cartilage, bone, and muscle with not uncommon glandular differentiation and intracellular melanin pigmentation (Figs.  16.4, 16.5, and 16.6). IHC: (+) S100, CD99, CD57, PGP 9.5, p53, but also (+) KER, EMA, CEA, and CGA (glandular). TEM: Infoldings of the cellular membrane with the lamellar arrangement, intermittent basal lamina, obvious intercellular junctions, and dense-core granules (occasionally). CMB: t(X;18) negative. DDX: MFH, pleomorphic liposarcoma, and synovial sarcoma as well as neuroblastoma and ganglioneuroma that are described elsewhere in this book (Figs. 16.7 and 16.8). TRT: Resection with safe margins. PGN: MPNST can recur locally, even if wholly excised, and distant metastases are frequent. The plexiform variant in children seems to have a better prognosis.

16.3 Neuromuscular Disorders 16.3.1 Muscle Biopsy Test The interpretation of diagnostic muscle biopsies has as a condition that we understand and remember the skeletal muscle histology. This information is basilar in differentiating several patterns that may be associated with congenital hypotonia of the infant. Skeletal muscle fibers or aka myofibers are delimitated by sarcolemma (cell membrane) composed of sarcoplasmic reticulum (particularly important for transport and storage of calcium) and myofibrils, which are arrays of actin (thin) and myosin (thick) filaments surrounded by sarcoplasmic reticulum (Box 16.1). Multiple such displays may be present per myofiber. The functional unit of the skeletal muscle cell is the sarcomere, which is the collection of actin and myosin filaments between two Z-bands. Sarcomere banding includes five bands labeled with letters. Two of these letters are A and I, which stand for

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anisotropic and isotropic, i.e., they can rotate plane polarized light, although both bands are anisotropic, being the A-band more anisotropic than I-band. Muscle contraction is based on sarcomere shortening, which consists of Z-bands approaching each other. During the sarcomeric shortening, the A-band remains the same, and I- and H-bands become shorter than before the contraction. When evaluating muscle biopsies, it is important to discern between neuropathic or myopathic, although in chronicity, there can be a mixture of both features. Myopathic processes usually demonstrate coexistent degeneration and regeneration. Of note, a characteristic feature of the regenerating fibers is their tendency to show rounded edges and central nuclei with a prominent nucleolus and be strongly stained with the alkaline phosphatase reaction. In the case of a myopathic process, it is essential to distinguish between inflammatory and non-inflammatory processes. The identification of neutrophils and mononuclear cells within the muscle with or without an accompanying vasculitis is crucial. Non-inflammatory processes show coagulative necrosis and “raggedred” fibers. Moreover, variation in fiber size and internal nuclei are standard at the site of tendinous insertion. Rhabdomyolysis is characterized by diffuse destruction or lysis of skeletal muscle, which may be acute, subacute, or chronic. The subsequent massive myoglobinuria can induce renal failure.

Box 16.1 Muscle Fiber Types Color Speed Duration/ fatigue/use Muscle prevalence Metabolism Glycogen content Lipid content Mitochondria/ myoglobin

Type I Red Slow Protracted/ slow/ posture ~ 30%

Type II White Fast Swift/rapid/ strength ~70%

O2-based (aerobic) +

Non-O2-based (anaerobic) +++

+++ +++/High

+ +/Low

The two types of muscle fibers can be differentiated using a series of histochemical stains (Box 16.2). Special invaginations of the sarcolemma, aka transverse tubules, extend to the sarcoplasmic reticulum of each myofibril of a myofiber and allow myofiber depolarization, i.e., the rapid transmission of an electrical stimulus. Connective tissue has three different sheath functional roles, including epimysium surrounding entire muscle, perimysium separating muscle fascicles (groups of myofibers), and endomysium surrounding each myofiber. The motor unit is a single lower motor neuron of the anterior horn of the spinal cord connected to myofibers that innervate. The

Box 16.2 Histochemical Stains for Skeletal Muscle Fibers ATPase, acid (pH 4.6) ATPase, basic (pH9.4) NADH-TR Non-specific esterase

Notes: Nonspecific esterase reaction is peculiarly useful in detecting denervated fibers, while alkaline phosphatase reaction is particularly useful in highlighting regenerating myofibers, light (IIA)/intermediate (IIB). Nonspecific esterase shows stronger stain in denervated myofibers. Dark is brown color, while light is green color with intermediate in yellow. No stain is represented by no color. NADR-TR, nicotinamide adenine dinucleotide tetrazolium reductase.

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number of myofibers per motor neuron is vari- may be necessary from a pathophysiology able between less than 10 for fine motor control perspective. and more than 1000 for large leg muscles. Except for the extraocular muscles, any myofiber is 16.3.2.1 Denervation innervated by a single motor neuron. Skeletal (Figs. 16.9 and 16.10) muscle histogenesis is based on a syncytial pro- A loss of myofibrils or atrophy is the consecess, which refers to the fusion of embryonic quence of denervation, and all the myofibers in myoblasts to form a multinucleated syncytium, the motor unit associated with the lower motor aka myotube, able to stimulate the formation of neuron are lost (type II fibers first, then type I). myofibrils, and on innervation process intimately According to the extension of the damage or loss linked to the distribution of acetylcholine recep- of individual neurons, there will be small group tors at motor end plate. The evaluation of muscle atrophy for individual neurons and considerable biopsies progresses with diagnostic degrees of group atrophy for larger nerves. Histologically, certainty, including first if changes are neuro- there is angulation of the myofibers on cross-­ pathic or myopathic and then in the case of a section and nuclear aggregation into hyperchromyopathic process if an inflammatory compo- matic clumps. Two additional histologic patterns nent is at the basis of the phenotypically based may be seen. A fiber with central pallor with conclinical abnormalities. However, in chronic pro- densed eosinophilic or hyper-eosinophilic rim cesses, which are usually rare in youth, a mixture surrounded by normal-appearing muscle is of both neuropathic and myopathic may co-exist. labeled target fibers. A renervation pattern is recInflammatory myopathies often show neutro- ognized when the previously randomly distribphils, and mononuclear cells within the myofi- uted type I and type II fibers are converting into bers and between the bundles and vasculitis may type “grouping” fibers and usually coincides with also be an accompanying feature. Non-­ denervation. Two conditions may need to be inflammatory myopathies show, instead, coagu- recalled, including Werdnig-Hoffmann disease lative necrosis of the myofibers and “ragged-red” (WHD) and amyotrophic lateral sclerosis (ALS). fiber morphological patterns. Three patterns need WHD or infantile spinal muscular atrophy is an to be distinguished in the evaluation of skeletal AR congenital hypotonia showing progressive muscle biopsies, in particular, regeneration, group atrophy with decline and death within which shows rounded edges-associated myofi- 1  year of age. The histology of the spinal cord bers with central nuclei and strongly positive for shows loss of lower motor neurons of the anterior alkaline phosphatase; rhabdomyolysis, which horn and extensive group atrophy. ALS is a group refers to complete and diffuse destruction of skel- of rare neurological diseases that involve the neuetal myofibers with acute, subacute, or chronic rons responsible for controlling voluntary muscle progression and complicated by myoglobinuria-­ movement. The disease is progressive with early associated renal failure; and ex non-usu atrophy symptoms in the 30s with a median survival of with selective loss of type II fibers. Patients using 3 years. Homozygous loss-of-function mutations high doses of steroids may show disuse atrophy in the ALS2 gene determine the diagnosis of as well. juvenile-­onset ALS, one of the several neurological conditions having overlapping symptoms with different neurological phenotypes. In case of involvement of both upper and lower motor 16.3.2 Neurogenic Disorders neurons, there are fasciculations and group atroNeurogenic disorders that will be treated are phy. In the setting of tumors, the traumatic neudenervation and some diseases associated roma and the granular cell tumor have been with denervation process and myasthenia gra- described in association with denervation, at least vis, which is rare in pediatric age, but is partly and are described elsewhere in this book related to autoimmune dysregulations and (Figs. 16.9 and 16.10).

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a

Fig. 16.9  Traumatic Neuroma. The two microphotographs of hematoxylin and eosin-­ stained histological slides show the typical presentation of a traumatic neuroma, which is a non-neoplastic lesion (a, ×50 original magnification; b, ×200 original magnification). The histo-

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logic examination reveals an irregular arrangement of nerve fascicles embedded in fibrous scar tissue. Sometimes, there is a concentric condensations of fibrous tissue around individual fascicles with the suggested appearance of multiple separate nerves

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Fig. 16.10  Granular Cell Tumor. This panel illustrates the histology of a granular cell tumor with the first two microphotographs (a, b) showing a poorly circumscribed tumor with large cells harboring a highly granular cytoplasm (a, hematoxylin and eosin, ×12.5 original magnification; b, hematoxylin and eosin staining, ×200 original

magnification). Two additional microphotographs show the positivity of this tumor for neuron specific enolase (NSE) (c, ×200 original magnification) and S100 (d, ×200 original magnification). The immunohistochemistry was performed using the avidin-biotin complex

16.3.2.2 Myasthenia Gravis MG is an autoimmune disorder affecting usually young women in the third to fourth decades of life showing auto-Ab against the neuromuscular receptors of acetylcholine, but pediatric cases have been reported and the term of Juvenile Myasthenia Gravis (JMG) is often in use in the literature. JMG

is a rare condition, which is defined as MG in children younger than 18 years of age (O’Connell et al. 2020). Although clinical phenotypes are similar to the adult counterpart, there are a number of situations (pitfalls) that may influence management. These aspects include a broader differential diagnosis, a higher rate of spontaneous remission, and

16.3 Neuromuscular Disorders

the requirement to start appropriate treatment early with the aim to avoid the both long-term physical and psychosocial morbidities. There are antibodies against the acetylcholine (ACh) receptors (AChR) at the post-synaptic membrane. Both antibodies block stimulation by acetylcholine and induce a downregulation of the AChR. It may be associated with AI thyroid disorders, rheumatoid arthritis, SLE, and pernicious anemia. IgG and complement may interfere with neural transmission. Clinically, there is weakness relieved by rest and worsened by exercise with mostly involvement of cranial and adjacent extraocular muscles. There is positivity for the edrophonium/neostigmine test. There is a fluctuant course with partial remissions, followed by relapses and progression. EMG shows the decrement of the responses to repeated nerve stimulation. In up to 4/5 of the patients, there is thymic hyperplasia, and 1/10– 1/3 patients exhibit a thymoma. Microscopically, there is lymphocytic infiltration with hemorrhages around degenerating myofibers on light microscopy, and abnormal myoneural junctions with widened clefts are seen on TEM. Ultrastructurally, there are irregular motor end plates with the simplified postsynaptic region. The outcome is poor with death due to recurrent infections of the lower respiratory tract (pneumonia with respiratory, muscular weakness), although thymectomy has been correlated with remission of the myasthenia. Although up to 1/3 of patients may develop thymoma, the rest may have thymic hyperplasia. Myasthenia gravis may be life-threatening in case the respiratory function is compromised. Eaton-Lambert syndrome is a paraneoplastic, myasthenia-like syndrome, which occurs in about 2/3 of patients suffering from small cell carcinoma of the lung.

16.3.3 Myopathic Disorders Myopathic disorders may be subclassified in muscular dystrophies and congenital myopathies. Muscular dystrophies are common in the young adult, while the congenital myopathies may start early in life. These include muscular dystrophies and congenital myopathies (Fig. 16.11).

16.3.3.1 Muscular Dystrophies Muscular dystrophies are hereditary diseases of the neuromuscular and motor unit with the pro-

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gressive tendency. The prototype of muscular dystrophies is the X-linked recessively inherited Duchenne (pseudo-hypertrophic) muscular dystrophy, affecting mainly boys. Clinically, weakness (proximal > distal, symmetric, legs and arms, mostly adductor magnus in legs and relatively spared the muscles gracilis and Sartorius) and falling off the child beginning to walk due to the involvement of the pelvic girdle are encountered by clinical history and physical examination. Subsequently, there may be the participation of other muscular groups and a very high level of CK is detected in serum. Other clinical features include DCM of the heart (>15  years), mental retardation, night blindness, and pseudoobstruction as well as gastric dilatation. The diagnosis is based on the lack of the gene product of dystrophin. The DYSTROPHIN gene is on Xp21.2-p21.1 with 96% with a frameshift mutation. Most often, 30% demonstrate new variations. In particular, 10–20% of new mutations are of a gonadal mosaic type. Grossly, there are atrophy and yellow discoloration of the muscles. Microscopically, there is a pattern characterized by variable fiber size with small rounded fibers and hypercontracted (opaque) muscle fibers and the tendency to cluster necrotic muscles (myopathic grouping) with muscle fiber degeneration and regeneration (particularly at early stages). The muscle fiber internal architecture is standard or shows some immature features. Dystrophin immunostaining is absent, whereas other membrane proteins, such as sarcoglycans and ­aquaporin-­4, are reduced in staining. Fibrosis of the endomysia is a characteristic of the late stages. In case of absent dystrophin, DMD phenotype is severe; there is a reduction in sarcoglycans and other proteins in the dystrophin-glycoprotein complex. In case of functional consequences of loss of dystrophin on muscle fibers, there is an increased movement of membrane-impermeant molecules into and out of muscle cells, decreased force production, and decreased hypersensitive to lengthening or eccentric contraction. Force decrement with eccentric contraction typically correlates with acutely increased sarcolemmal permeability. Death is most commonly observed between 15 and 25  years and is due to cardiac or respiratory failure, although life may be prolonged with respiratory support.

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Fig. 16.11  Mitochondrial cytopathy panel with excessive blue staining due to increased mitochondria (a), excessive red staining due to increased mitochondria (b), scattered darker fibers on succinate dehydrogenase histochemical staining as ragged red fiber equivalents (c), scattered negative fibers on cytochrome oxidase (d), inclusion body in

mitochondria (e) (a, hematoxylin and eosin staining, ×200 original magnification, b, modified muscle trichrom, ×200 original magnification, c, succinate dehydrogenase (SDH) staining, ×100 original magnification; d, cytochrome oxidase (COX), ×200 original magnification; e, transmission electron microscopy, bar = 100 nm)

16.3.3.2 Congenital Myopathies Congenital myopathies include a group of disorders which are not progressive but restrict the activity of the patient and are complicated by secondary skeletal problems such as kyphoscoliosis. Clinically, they start at birth with hypotonia, hyporeflexia (↓ deep tendon reflexes), and low muscle mass. The progression of the disease shows that motor milestones are delayed. Skeletal muscle biopsy reveals that morphologic abnor-

malities are restricted to the type I fibers, which predominate, while the type II fibers are decreased in number but structurally normal. Central core disease is a sporadic, AR/AD-inherited congenital myopathy with type I fibers showing a central core of lucency running the length of the cell due to a loss of membranous organelles and often with disorganization of the surrounding myofibrils. The NADH-TR (nicotinamide adenine dinucleotide dehydrogenase tetrazolium reduc-

16.3 Neuromuscular Disorders

tase) reaction is advantageous to demonstrate the cores. Nemaline (rod) myopathy exhibits inclusions within the type I myofibers of rod-­shaped structures which arise from the Z-bands. They are stainable with trichrome stain or with PTAH.

16.3.4 Glycogen Storage Diseases Glycogen storage disorders may accompany a presentation of hypotonia and need to be kept in the differential diagnosis. For the discussion of this group, please refer to the liver chapter.

16.3.5 Mitochondrial Myopathies (Fig. 16.11) Mitochondriopathies (MCP) are usually multisystemic disorders with involvement of visceral organs, such as endocrine organs, heart, gastrointestinal tract, liver, kidney, or hematopoietic system, other than central and peripheral nervous system, eyes, or ears (Finsterer 2006, Mohammed et al. 2012, Cave et al. 2013, Hsu et al. 2016). The diagnosis of MCP may be a real challenge, because of their extensive, variable, and diversified clinical and genetic heterogeneity. The specific diagnostic determination depends on clinical, blood chemical, electrophysiological, imaging, histological, immunological, biochemical, polarographic, magnetic spectroscopic, and genetic investigations. Human mtDNA is a 16.5 kb circular mini-chromosome consisting of two complementary strands (H and L strand). MtDNA contains 13 mitochondrial genes encoding for subunits of the respiratory chain complexes I (NADH dehydrogenase (ND)1–4, ND4L, ND5–6), III (cytochrome b), IV (cytochrome-­ c-oxidase (COX)I-III), and V (ATPase 6, ATPase 8) and 24 syn genes encoding for 22 tRNAs (ribonucleic acid) and 2 rRNAs. Only the D-loop is a noncoding stretch. This portion contains the promoters for the transcription of L and H strands. Since the mtDNA genetic code differs from the universal code, the expression of mtDNA genes relies on the specific mitochondrial protein synthesis, depending on the

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interplay between nuclear-encoded transcriptional and translational factors with mitochondrial tRNAs and rRNAs. Neuropathologists use the term mitochondrial cytopathies. The mitochondrial cytopathies have distinct histology, although they represent a heterogeneous group of disorders which primarily affect the neuro-­ muscular systems. The mitochondrial cytopathies are caused either by mutations in the mitochondrial genome or by mutations in the ­ nuclear genome (Fig. 16.5). Genetics of mitochondria differs from the genetics of nuclei. In particular, some features can be better delineated as follows: 1 . Mitochondrial DNA is maternally inherited. 2. Polyploidy is a characteristic feature of mitochondria, containing 2–10 mtDNA copies per organelle (each cell includes hundreds of mitochondria). 3. All mtDNA copies are identical (homoplasmy), but there is the tendency of mtDNA to mutate randomly, and the coexistence of wild-type mtDNA and mutant mtDNA in a single cell and organ is called “heteroplasmy.” 4. There is a stochastic distribution of mitochondria and mutant mtDNA to daughter cells, which gives rise to a changing mutation load in a different generation and consequent phenotypic variation of MCP. 5. Phenotypic expression is based on a threshold effect because of mitotic segregation and polyploidy. Phenotype expression of mtDNA mutations often requires the influence of nuclear modifier genes, environmental factors, or the presence of mtDNA haplotypes (polymorphisms). Chronic progressive external ophthalmoplegia (CPEO) is the most prevalent manifestation of mtDNA rearrangements and often associated with ptosis. Subsequently, cataract, retinitis pigmentosa, deafness, fatigue, ataxia, limb weakness, neuropathy, arrhythmias, or renal insufficiency may develop. The clinical course is usually benign because organ failure is mild. CPEO is due to mtDNA deletions or mutations in the tRNALeu, tRNAIle, tRNALys, or tRNAAsn genes.

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Kearns-Sayre syndrome (KSS) is characterized by retinitis pigmentosa, arrhythmias, cerebellar ataxia, raised CSF protein, and onset before the age of 20. Proximal myopathy develops with the progression of the disease, and other features include mental retardation, deafness, syncope, bulbar symptoms such as dysphagia, stroke-like episodes, and endocrine dysfunction, such as delayed puberty, primary amenorrhea, or diabetes mellitus, sideroblastic anemia, and lactic acidosis. The prognosis of KSS is poor because organ failure is severe and the patients do not survive the third decade. KSS is due to sporadic, single or multiple large-scale deletions or from mtDNA duplications. Mitochondrial, encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is the commonest of the encephalomyopathies and is characterized by stroke-like episodes with hemisyndrome, migraine, nausea, or vomiting. Other features include deafness, DM, seizures, dementia, ataxia, cortical blindness, optic atrophy, retinitis pigmentosa, DCM, exercise intolerance, and short stature. The course is slowly progressive, and the prognosis relies mostly on the cardiac involvement. MELAS is due to mtDNA point mutations in tRNA, COX3, or ND5 genes or due to small-scale mtDNA deletions. A frequently detected variation in MELAS patients is the transition A3242G. Myoclonic epilepsy with ragged red fiber (MERRF) syndrome presents between childhood and early adulthood with photosensitive general tonic-clonic seizures, myopathy, including ptosis and ophthalmic paralysis, cerebellar ataxia, dementia, and deafness. Other features include stroke-like episodes, optic atrophy, dorsal column loss, cardiomyopathy, heart block, heart failure, respiratory failure, paralytic ileus, pancytopenia, lipomatosis, pes cavus, and polyneuropathy. MERRF is caused by mtDNA tRNALys point mutations or multiple mtDNA deletions resulting from nDNA mutations. A variation frequently found in MERRF patients is the mtDNA transition A8344G. Other mitochondriopathies include maternally inherited diabetes and deafness (MIDD), Leber’s hereditary optic neuropathy, neuropathy, ataxia,

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and retinitis pigmentosa (NARP), and maternally inherited Leigh syndrome (MILS). Nonsyndromic, mitochondrial MCPs with visceral manifestations include myopathy associated with cardiomyopathy due to tRNALeu mutations and hypertrophic cardiomyopathy due to 12rRNA, tRNASIle, tRNALys, tRNAGly or cytb mutations among others. Syndromic, nuclear mitochondriopathies with visceral manifestations include nuclear Leigh syndrome, myo-neuro-gastrointestinal encephalopathy (MNGIE), also termed POLIP (polyneuropathy, ophthalmoplegia, leukoencephalopathy, intestinal pseudo-obstruction), diabetes insipidus, DM, optic atrophy, deafness (Wolfram syndrome) or DIDMOAD syndrome, mitochondrial DNA depletion syndrome, and Barth syndrome. The mtDNA depletion syndrome has mtDNA depletion of various degrees, which leads to a fatal multisystem infantile disorder, characterized by weakness, muscle hypotonia, CPEO, and severe lactic acidosis. Other features include hepatopathy, Fanconi syndrome, encephalopathy, seizures, cardiomyopathy, and cataract. Total mtDNA levels in these patients are below 35% of those in controls. Although no mtDNA mutations are found, the underlying defect is an impaired replication or maintenance of mtDNA due to nuclear DNA (nDNA) mutations in the thymidine kinase or deoxyguanosine kinase gene, causing gastrointestinal abnormalities; deoxyguanosine kinase (DGUOK) gene, resulting in encephalo-myopathy and hepatopathy; and polymerase gamma (POLG) gene causing hepatopathy with lactic acidosis. Barth syndrome is a rare X-linked disease, characterized by the triad dilated cardiomyopathy, skeletal myopathy, and neutropenia. Other features include growth retardation and 3-methyl-­ glutaconic aciduria. Barth syndrome is due to mutations in the Tafazzin gene, which is located on chromosome Xq28. The Tafazzin gene is suspected to encode for one or more acyltransferases, resulting in reduced cardiolipin synthesis and thus cardiolipin deficiency in the skeletal muscle, myocardium, and platelets. Other syn-

Multiple Choice Questions and Answers

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dromes include Friedreich ataxia, Mohr-­ zone of suppuration of muscle due to Tranebjaerg syndrome, nuclear chronic Staphylococcus in about 90% of the cases. progressive external ophthalmoplegia, and nuclear myoclonic epilepsy with ragged red fibers. Multiple Choice Questions Nonsyndromic, nuclear mitochondriopathies and Answers with visceral manifestations include several disorders, i.e., fatal, multisystem complex I defi- • PNS-1 Which statement regarding acetylchociency due to mutations in the NDUFS4 gene, linesterase (AChE) is TRUE? familial idiopathic cardiomyopathy due to multi (a) It is a neurotransmitter. ple, secondary mtDNA, and thiamine-responsive (b) It catalyzes the breakdown of acetylchomegaloblastic anemia among others. line and of some other choline esters that function as neurotransmitters. (c) It has enhanced activity from organophos16.3.6 Inflammatory Myopathies: phorus compounds. Non-infectious (d) It does not belong to carboxylesterase family of enzymes. These include polymyositis/dermatomyositis, • PNS-2 Which statement regarding the enteric viral myositis, and inclusion body myositis. They nervous system is FALSE? are presented in other chapters. (a) The myenteric plexus is located between the longitudinal and circular layers of muscle in the tunica muscularis. 16.3.7 Inflammatory Myopathies: (b) The submucous plexus is embedded in the Infectious submucosa and plays a role in sensing the environment within the lumen, regulating Several microorganisms may be associated with blood flow and controlling cell function. infective myositis. Infectious myopathies are (c) In the enteric plexuses, there are three infections-related inflammatory myopathies, types of neurons (motor neurons, sensory which have, typically, a good prognosis. However, neurons, and interneurons), most of which the outcome is strictly dependent on the immune are bipolar. response of the child or young adult. Numerous (d) Sympathetic stimulation determines the viral infections can cause temporary inflammainhibition of gastrointestinal secretion tory myopathies and be part of a fleeting visit to and motor activity. It also acts to contract clinics. HIV myopathy may occur early in the gastrointestinal sphincters and blood HIV infection. However, it is currently more vessels. often observed as a complication of AIDS.  The (e) Parasympathetic stimulation typically influenza virus myositis is more severe in adults stimulates the gastrointestinal secretion than in children. In patients affected by epidemic and motor activity, and contraction of myalgias, group B coxsackievirus has been isogastrointestinal sphincters and blood lated from the striated muscle of the patients. vessels. Parasitic infections of the tissue include trichino- • PNS-3 Which statement regarding myasthenia sis, toxoplasmosis, and cysticercosis. The most gravis is TRUE? common parasitic myositis is due to the round (a) Myasthenia gravis is a neurodegenerative worm Trichinella spiralis or Trichinella spp. disease. Trichinosis symptoms include diarrhea, abdomi(b) Myasthenia gravis is associated to an nal cramps, muscle pain, and fever. Individuals inadequacy of the organism to release acquire trichinosis by eating raw or undercooked enough amounts of acetylcholine. contaminated meat. Pyomyositis is a located

1342

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•

•

•

(c) An anti-AChE is not efficacious in myasthenia gravis. (d) Most patients affected with myasthenia gravis have weakness in the muscles of the eyes, eyelids, and face. (e) Thymectomy is not recommended for myasthenia gravis. PNS-4 Verocay bodies are histologic areas lacking nuclei between areas of nuclear palisading. In which tumor are they found characteristically? (a) Glioblastoma multiforme (b) Schwannoma (c) Neurofibroma (d) Plexiform neurofibroma (e) Ependymoma PNS-5 Which of the following statements regarding the traumatic neuroma is FALSE? (a) It is a reparative lesion at the site of traumatic injury of peripheral nerves. (b) Wallerian degeneration is present initially after nerve interruption, which is followed by an exuberant regeneration of Schwann cells, axons, and fibrous cells. (c) Histologic sections show haphazard presentation of nerves within a collagenous scar with entrapped smooth muscle elements. (d) The lesion is immunohistochemically S100 negative, but neurofilaments are positive. PNS-7 Which of the following statements regarding classic neurofibromatosis (von Recklinghausen’s disease) is FALSE? (a) Malignant peripheral nerve sheath tumor (MPNST) can occur. (b) Iris hamartomas may be present. (c) Hemangioblastomas of the cerebellum can occur later in life. (d) Acoustic neuroma is an important finding. (e) Both meningiomas and pheochromocytoma can be found. PNS-8 Which of the following statements of MPNST is FALSE? (a) MPNST occurs in the setting of NF1 probably due to a biallelic inactivation of the NF1 gene.

16  Peripheral Nervous System

(b) MPNST often displays disruption of the RB1 pathway. (c) CDKN2B and RB1 tumor suppressor genes may be inactivated in a subset of MPNSTs. (d) Dominantly acting genes in the RB1 pathway (precisely CDK4, MDM2, and CCND2) may be overexpressed or amplified in a subset of patients harboring MPNSTs. (e) The TP53 gene is biallelically affected in most of the MPNSTs. • PNS-9 In the case of a young woman affected with a mitochondrial disorder, who will most likely inherit the disorder? (a) All her daughters, but none of her sons (b) All her sons, but none of her daughters (c) All her children (d) All her grandsons (e) All her granddaughters • PNS-10 Environmental pollution has an enormous burden currently. Thus, some diseases may occur at an early age than before. A 25-year-old man presents to the family doctor with weakness and cramping of both hands. Upon examination, the physician identifies atrophy of the muscles of both hands, hyperresponsive “deep tendon” reflexes, muscular fasciculation involving both arms and legs, and an abnormal positive Babinski response. The neurological examination of the sensation reveals normal feeling in both arms and legs. What is the most likely diagnosis in this patient? (1) Wilson disease (2) Guillain-Barré syndrome (3) Huntington disease (4) Amyotrophic lateral sclerosis (5) Metachromatic leukodystrophy

References and Recommended Readings Attarian S, Azulay JP. Myopathies infectieuses [Infectious myopathies]. Rev Prat. 2001;51(3):284– 88. Review. French. PubMed PMID: 11265425.

References and Recommended Readings Bahitham W, Liao X, Peng F, Bamforth F, Chan A, Mason A, Stone B, Stothard P, Sergi C.  Mitochondriome and cholangiocellular carcinoma. PLoS One. 2014;9(8):e104694. https://doi.org/10.1371/journal. pone.0104694. eCollection 2014. PubMed PMID: 25137133; PubMed Central PMCID: PMC4138114. Cave D, Ross DB, Bahitham W, Chan A, Sergi C, Adatia I. Mitochondrial DNA depletion syndrome-an unusual reason for interstage attrition after the modified stage 1 Norwood operation. Congenit Heart Dis. 2013;8(1):E20–E23. https://doi.org/10.1111/j.17470803.2011.00569.x. Epub 2011 Oct 20. PubMed PMID: 22011012. Chiu B, Jantuan E, Shen F, Chiu B, Sergi C. Autophagy-­ inflammasome interplay in heart failure: a systematic review on basics, pathways, and therapeutic perspectives. Ann Clin Lab Sci. 2017;47(3):243–252. Review. PubMed PMID: 28667023. Finsterer J. Overview on visceral manifestations of mitochondrial disorders. Neth J Med. 2006;64(3):61–71. Review. PubMed PMID: 16547358. Gray SW, Skandalakis JE.  Embryology for surgeons: the embryological basis for the treatment of congenital defects. Philadelphia: WB Saunders Co; 1972. p. 263–82. Hsu YH, Yogasundaram H, Parajuli N, Valtuille L, Sergi C, Oudit GY.  MELAS syndrome and cardiomyopathy: linking mitochondrial function to heart failure pathogenesis. Heart Fail Rev. 2016;21(1):103–116. https://doi.org/10.1007/s10741-015-9524-5. Review. PubMed PMID: 26712328. Katona I, Weis J.  Diseases of the peripheral nerves. Handb Clin Neurol. 2017;145:453–474. https://doi. org/10.1016/B978-0-12-802395-2.00031-6. Review. PubMed PMID: 28987189. Mohammed S, Bahitham W, Chan A, Chiu B, Bamforth F, Sergi C. Mitochondrial DNA related cardiomyopathies. Front Biosci (Elite Ed). 2012;1(4):1706–1716. Review. PubMed PMID: 22201986.

1343 O’Connell K, Ramdas S, Palace J. Management of Juvenile Myasthenia Gravis. Front Neurol. 2020; 11:743. https://doi.org/10.3389/fneur.2020.00743. PMID: 32793107; PMCID: PMC7393473. Parasca I, Damian L, Albu A. Infectious muscle disease. Rom J Intern Med. 2006;44(2):131–141. Review. PubMed PMID: 17236294. Pestronk A. Acquired immune and inflammatory myopathies: pathologic classification. Curr Opin Rheumatol. 2011;23(6):595–604. https://doi.org/10.1097/ BOR.0b013e32834bab42. Review. PubMed PMID: 21934500. Röhrich M, Koelsche C, Schrimpf D, Capper D, Sahm F, Kratz A, Reuss J, Hovestadt V, Jones DT, BewerungeHudler M, Becker A, Weis J, Mawrin C, Mittelbronn M, Perry A, Mautner VF, Mechtersheimer G, Hartmann C, Okuducu AF, Arp M, Seiz-Rosenhagen M, Hänggi D, Heim S, Paulus W, Schittenhelm J, Ahmadi R, Herold-Mende C, Unterberg A, Pfister SM, von Deimling A, Reuss DE.  Methylation-based classification of benign and malignant peripheral nerve sheath tumors. Acta Neuropathol. 2016;131(6): 877–87. https://doi.org/10.1007/s00401-016-1540-6. Epub 2016 Feb 8. PubMed PMID: 26857854. Schulz A, Grafe P, Hagel C, Bäumer P, Morrison H, Mautner VF, Farschtschi S.  Neuropathies in the setting of neurofibromatosis tumor syndromes: complexities and opportunities. Exp Neurol. 2018;299 (Pt B):334–344. https://doi.org/10.1016/j.expneurol.2017.06.006. Epub 2017 Jun 3. Review. PubMed PMID: 28587874. van der Knaap MS, Bugiani M.  Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol 2017;134(3):351–382. https://doi. org/10.1007/s00401-017-1739-1. Epub 2017 Jun 21. Review. PubMed PMID: 28638987; PubMed Central PMCID: PMC5563342.

17

Skin

Contents 17.1 17.1.1 17.1.2 17.1.3

 evelopment, General Terminology, and Congenital Skin Defects D Development General Terminology Lethal Congenital Contractural Syndromes

 1347  1347  1348  1348

17.2 17.2.1 17.2.2 17.2.3 17.2.4

Spongiotic Dermatitis Conventional Spongiosis Eosinophilic Spongiosis Follicular Spongiosis Miliarial Spongiosis

 1352  1352  1354  1354  1354

17.3 I nterface Dermatitis 17.3.1 V  acuolar Interface Dermatitis 17.3.2 Lichenoid Interface Dermatitis

 1355  1355  1360

17.4  soriasis and Psoriasiform Dermatitis P 17.4.1 Psoriasis 17.4.2 Psoriasiform Dermatitis

 1360  1360  1360

17.5  erivascular In Toto Dermatitis (PID) P 17.5.1 Urticaria 17.5.2 Non-urticaria Superficial and Deep Perivascular Dermatitis

 1361  1361  1362

17.6 17.6.1 17.6.2 17.6.3 17.6.4

 odular and Diffuse Cutaneous Infiltrates N Granuloma Annulare Necrobiosis Lipoidica Diabeticorum (NLD) Rheumatoid Nodule Sarcoid

 1363  1363  1364  1364  1364

17.7 I ntraepidermal Blistering Diseases 17.7.1 Pemphigus Vulgaris, Pemphigus Foliaceus, and Pemphigus Paraneoplasticus 17.7.2 IgA Pemphigus and Impetigo 17.7.3 Intraepidermal Blistering Diseases

 1364

17.8  ubepidermal Blistering Diseases S 17.8.1 Bullous Pemphigoid and Epidermolysis Bullosa

 1367  1367

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_17

 1364  1366  1366

1345

17 Skin

1346 17.8.2 E  rythema Multiforme and Toxic Epidermal Necrolysis 17.8.3 Hb-Related Porphyria Cutanea Tarda, Herpes Gestationis, and Dermatitis Herpetiformis 17.8.4 Lupus (Systemic Lupus Erythematodes)

 1368  1368  1369

17.9

Vasculitis

 1369

17.10

Cutaneous Appendages Disorders

 1369

17.11 Panniculitis 17.11.1 Septal Panniculitis 17.11.2 Lobular Panniculitis

 1369  1369  1370

17.12 Cutaneous Adverse Drug Reactions 17.12.1 Exanthematous CADR

 1370  1371

17.13

Dyskeratotic, Non-/Pauci-­Inflammatory Disorders

 1372

17.14

Non-dyskeratotic, Non-/Pauci-Inflammatory Disorders

 1372

17.15

Infections and Infestations

 1372

17.16

Cutaneous Cysts and Related Lesions

 1372

17.17 Tumors of the Epidermis 17.17.1 Epidermal Nevi and Related Lesions 17.17.2 Pseudoepitheliomatous Hyperplasia (PEH) 17.17.3 Acanthoses/Acanthomas/Keratoses 17.17.4 Keratinocyte Dysplasia 17.17.5 Intraepidermal Carcinomas 17.17.6 Keratoacanthoma 17.17.7 Malignant Tumors

 1373  1373  1376  1376  1377  1378  1378  1378

17.18 Melanocytic Lesions 17.18.1 Lentigines, Solar Lentigo, Lentigo Simplex, and Melanotic Macules 17.18.2 Melanocytic Nevi 17.18.3 Variants of Melanocytic Nevi 17.18.4 Spitz Nevus and Variants 17.18.5 Atypical Melanocytic (Dysplastic) Nevi 17.18.6 Malignant Melanoma and Variants

 1381  1381  1381  1382  1384  1385  1385

17.19 Sebaceous and Pilar Tumors 17.19.1 Sebaceous Hyperplasia 17.19.2 Nevus Sebaceous (of Jadassohn) (NSJ) 17.19.3 Sebaceous Adenoma, Sebaceoma, and Xanthoma 17.19.4 Sebaceous Carcinoma 17.19.5 Benign Hair Follicle Tumors 17.19.6 Malignant Hair Follicle Tumors

 1387  1387  1387  1388  1388  1388  1390

17.20 Sweat Gland Tumors 17.20.1 Eccrine Gland Tumors 17.20.2 Apocrine Gland Tumors

 1390  1391  1393

17.21 Fibrous and Fibrohistiocytic Tumors 17.21.1 Hypertrophic Scar and Keloid 17.21.2 Dermatofibroma 17.21.3 Juvenile Xanthogranuloma 17.21.4 Dermatofibrosarcoma Protuberans

 1394  1394  1394  1394  1396

17.22

Vascular Tumors

 1396

17.23

Tumors of Adipose Tissue, Muscle, Cartilage, and Bone

 1396

17.24 Neural and Neuroendocrine Tumors 17.24.1 Merkel Cell Carcinoma 17.24.2 Paraganglioma

 1396  1396  1399

17.1 Development, General Terminology, and Congenital Skin Defects

1347

17.25 Hematological Skin Infiltrates 17.25.1 Pseudolymphomas 17.25.2 Benign and Malignant Mastocytosis

 1400  1400  1400

17.26

Solid Tumor Metastases to the Skin

 1400

Multiple Choice Questions and Answers

 1403

References and Recommended Readings

 1405

17.1 Development, General Terminology, and Congenital Skin Defects 17.1.1  Development The development of the tegument in humans originates at the early gastrula from the juxtaposition of two embryonic elements, including the ectoderm and mesoderm. The mesoderm is essential for the differentiation of adnexal epidermal structures such as hair follicles and participates in the maintenance of the adult epidermis. At the 3rd week of embryonic development, there is a single layer of glycogen-filled cells. These entirely undifferentiated cells are called periderm. At 4–6 weeks old, two layers are present, i.e., the periderm or epithelium and the germinative layer. The periderm is a purely embryonic structure that will not be present later. At 8–11  weeks, a middle layer is formed, and the glycogen is still quite copious in all segments. The embryo is at this specific time 26–50 mm as crown-rump length (CRL).  At 12–16  weeks (CRL 69–102  mm), one or more intermediate layers of cells appear with a more complex ultrastructural compartmentalization, including mitochondria, Golgi apparatus, few tonofilaments, and numerous microvilli. It is at this determined stage that a dome-shaped bleb starts to project from the center of the periderm. At 16–26 weeks, there is an increase of intermediate layers. At 21  weeks, keratohyalin granules appear in the uppermost layer, and at 24 weeks, the periderm is continuously recycled in the amniotic fluid and caseous vernix of the intrauterine fetus. The proteins of desmosomes are detected by the 10th week gestation and the basal keratins demonstra-

ble by the 14th week. Hair follicles and apocrine glands appear first at the 9th week. The pregerminative or pregerm stage is characterized by the crowding of nuclei at the basal layer of epidermis hair germ. The germ stage is characterized by elongation of the basal cells and their nuclei and the growth toward the dermis. At this time, mesenchymal cells and fibroblasts increase in number to form the hair papilla beneath the germ with the outer cells of hair peg becoming more cylindrical and arranged radially according to the long axis. There is also an oblique growth downward with the advancing axis growing bulbous gradually enveloping the mesodermal papilla. In many hair follicles, a third pulp appears above the sebaceous rudiment to form the apocrine gland. The peg growth is accompanied by the development of the cells of the inner root sheath above the matrix, the downward extension of the matrix, and the upward growth of the internal cells to form the hair canal. Sebaceous glands form as solid hemispherical protuberances on the posterior surface of the hair peg, while the eccrine glands start to develop at about 12 weeks of gestation. Nails grow at about 12  weeks as well. Melanocytes develop from the neural crest and travel to the mesenchyme before 4–6 months of gestation when they travel to the basal layer. Langerhans cells are derived from monocyte-­ macrophagic lineage and enter the epidermis at 12  weeks gestation as well, while Merkel cells penetrate the epidermis at 16 weeks of pregnancy. The dermis originates from the ventrolateral part of the somite dermatome and is very cellular up to the 2nd month. Regular bundles of collagen appear at the end of the 3rd month, and by the 5th month, papillary and reticular dermis become distinguishable. Elastic fibers start at 22nd week gestation. In the dermis, three types of cells are

17 Skin

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seen at 14  weeks of embryonic development, including stellate, macrophages, and granular secretory cells (melanoblasts or mast cells). At 14–21 weeks, there is the clear-cut appearance of fibroblasts, perineural cells, pericytes, mast cells, histiocytes, Langerhans cells, and Merkel cells. The dermo-epidermal junction lamina densa becomes distinct at the 2nd month, while hemidesmosomes are definitely seen at the 3rd month.

17.1.2  General Terminology The following definitions according to major dermatology books may promote a proper interdisciplinary communication. Type of skin lesions Macula Flat discoloration ≤1 cm Patch Flat discoloration >1 cm Papula Solid elevated lesion ≤1 cm Plaque Solid elevated flat lesion >1 cm Nodule Solid elevated round lesion >1 cm Vesicle Small fluid-filled blister ≤1 cm Bulla Large fluid-filled blister >1 cm Telangiectasia Dilated capillaries Scale Cluster of cornified cells Crust Scale subtype with serum Type of skin patterns Acanthosis Thickening of the epidermal layer Lichenification Thickening of the skin due to chronic rubbing Hyperkeratosis Increase of the thickness of the cornified layer Parakeratosis Residual pyknotic nuclei in an increased or not cornified layer Hypogranulosis Thin granular cell layer due to fast cell turnover (e.g., psoriasis) Hypergranulosis Thick granular cell layer due to slow cell turnover Acantholysis Loss of cell-cell adhesion Ballooning Intracellular edema Spongiosis Intercellular edema Vacuolar Cell vacuoles separating the degeneration epithelium from the upper dermis Dyskeratosis Premature (abnormal) keratinization in the squamous epithelium Papillomatosis Elongation of dermal papillae

17.1.3  Lethal Congenital Contractural Syndromes Free fetal movements are necessary for a healthy intrauterine development of the fetus. In fetuses with reduced movements, a complex of severe consequences occurs. This complex of consequences has been termed fetal akinesia deformation sequence, a condition which has to be distinguished from the scleredema and sclerema of premature infants. Sclerema neonatorum and scleredema are special forms of edema characterized by an extensive induration of the skin with (scleredema) or without edema (sclerema). In scleredema, the skin is hard and taut, while in sclerema the skin is hard and dried out from a clinical point of view. Both the proportions between the palmitic and stearic acids (saturated fats) and the oleic acid (unsaturated fat) and the hypothermia and the circulatory weakness of the premature babies are considered as etiopathogenetic factors. An increase of the lipid peroxidation and a decrease of the superoxide dismutase activity have been suggested. In subcutaneous fat necrosis, the areas of subcutaneous induration are sharply defined and nonelevated and appear in large, well-developed, otherwise healthy infants. To the phenotype of fetal akinesia deformation sequence belong restrictive dermopathy (RD), Pena-Shokeir syndromes, and the Neu-Laxova syndrome primarily. Differently from RD, which shows no visceral defect, the reduction of the body movements in Pena-­Shokeir syndromes and NeuLaxova syndrome, which do not present tautness of the skin, is due to a primary defect of the central nervous system (e.g., ischemic-anoxic brain damage, brain anlage disorders, lack of anterior horn cells that should be reside in the spinal cord). Regarding the Pena-­Shokeir syndrome, three main types are known. Pena-Shokeir syndrome type I (MIM 208150) shows multiple ankyloses, camptodactyly, facial anomalies, and pulmonary hypoplasia. In 1983, it was suggested that the Pena-Shokeir type I phenotype is not specific. It is rather the result of a deformation sequence caused by fetal akinesia. In 1986, Hall could identify at least five specific subgroups among the 16 multiplex families by distinguishing features. Pena-Shokeir ­syndrome type II (MIM 214150) or cerebro-oculofacial-­skeletal syndrome (COFS) is an autosomal

17.1 Development, General Terminology, and Congenital Skin Defects

recessive (AR) inherited degenerative disease of the CNS leading to brain atrophy with calcifications, bilateral congenital cataract, microcornea, optic atrophy, progressive joint contractures, and growth failure (Le Van Quyen et al. 2020; Faridounnia et al. 2015; Suzumura and Arisaka 2010). A further main type has been described, and it is a phenotype intermediate between the COFS syndrome and the Neu-Laxova syndrome suggesting that the two last conditions may represent different degrees of severity of the same AR mutation in the homozygote state. Concerning the NeuLaxova syndrome, it has been described as a unique entity characterized by severe intrauterine growth retardation, a peculiar cerebro-arthro-digital phenotype, ectodermal dysplasia, and edema. In 1982, Curry suggested dividing the Neu-Laxova syndrome into two types: the first one showing no edema and no increased fat layer, the second one showing an increased layer of subcutaneous adipose tissues with hypertrophy of fat cells. Other syndromes presenting with congenital contractural syndromes include the lethal multiple pterygium syndrome and the aplasia cutis congenita. In addition to the classic multiple pterygium syndrome, Hall (1984) commented on two other possible distinct forms: the first one with spinal fusion and the second one with congenital bone fusions. However, Aslan et al. (2000) could identify at least 15 different entities characterized by multiple pterygia or web of the skin and multiple congenital anomalies and proposed one of their own. The relationship between RD and aplasia cutis congenita (MIM 107600, congenital skull and scalp defect; MIM 207700, congenital scalp defect only) was described in a rather confusing way in the past. In an invited editorial comment, Toriello indicated that five infants with extensive skin erosions and contractures had been initially diagnosed as aplasia cutis congenita. It is, however, known that aplasia cutis congenita may occur as an isolated defect or associated with different phenotypes. These phenotypes include gastrointestinal atresia (Carmi syndrome), cone-rod dysfunction with high myopia and congenital nystagmus, epibulbar dermoids and cutaneous hyperpigmentation (oculo-ectodermal syndrome), intestinal lymphangiectasis, type I hereditary motor and sensory neuropathy (X-linked Charcot-Marie-Tooth peroneal muscular atrophy),

1349

distal limb reduction anomalies (Adams-Oliver syndrome), coarctation of the aorta, hereditary symmetrical bitemporal skin aplasia (“forceps marks” or Setleis syndrome), and ear abnormalities with unilateral facial palsy and ear abnormalities with amastia and/or athelia (Finley-Marks syndrome). In the 1st year of life, pathological hair loss is a rare event per se but is a potential leading symptom of congenital diseases. Congenital should be differentiated from acquired hair loss. Age of onset, history, and associated symptoms are important components to be considered to reach the diagnosis. The most frequent etiologies of hair loss among 1–3-year-­old children are hair shaft anomalies (genotrichoses) with or without associated defects, alopecia areata, and mycotic scalp infestation (e.g., Tinea capitis). Between 4 and 11 years, the most significant causes are alopecia areata, loose anagen hair, artificial hair loss (trichotillomania, traction alopecia), and hair loss of infectious origin (Microsporidia, Tinea capitis, folliculitis). Adolescents (12–18 years) may suffer from alopecia areata and androgen hair loss or androgenetic alopecia. The age group of 1–3 years may be the most challenging because the hair shaft anomalies may be associated with other defects. There may be congenital localized or diffuse hypotrichosis. Alopecia areata and mycotic infection of the hair shaft are more often seen in children older than 3  years. At all times, both the dermatologist and pediatric pathologist should search for characteristic features of genetic syndromes in this age group. Figure 17.1a–c shows a case of congenital alopecia in a toddler. One of the most important differential diagnoses is congenital triangular alopecia (CTA), which is an uncommon disorder and no gender preference. Most cases present in 2–9-year-old patients. In 15% of cases, CTA is associated with other diseases, including pigmented-­vascular phakomatosis, trisomy 21 syndrome (Down syndrome), leukonychia, hip dislocation, mental retardation, epilepsy, and tracheoesophageal fistula. Diagnosis is mainly clinical, and microscopic examination shows a normal number of follicular units, the majority being vellus-type hairs. The main differential diagnosis remains alopecia areata, although other forms of non-scarring alopecia should also be investigated. In Fig.  17.1d–e, the characteristic features of RD with an age-matched

1350

related newborn are presented (Fig. 17.1f). In Box 17.1 are shown the most common lethal congenital contractural syndromes by analysis of the phenotype. However, a complete clinical-pathological workup needs also to exclude the ichthyosis congenita of the harlequin fetus type, by which the entire body of the infant is covered with thick, horny plaques separated by fissures and ectropion of the eyes, nostrils, and mouth is seen. In contrast to the RD, in the ichthyosis congenita of the harlequin fetus type, there is marked hyperkeratosis of the skin with papillomatosis and nonobstructive plugging of hair follicles and sweat ducts. A collodion baby phenotype clinically manifests the lamellar ichthyosis also occurring at birth. The lamellar ichthyosis is characterized by erythema, generalized scales of plate-like type, and ectropion. An entity which should be cited here is the collodion baby phenotype associated to a rare subset of infants with type 2 Gaucher disease, an acute neuronopathic form culminating in early death as a result of the severe neurological disease ­resulting from the inherited deficiency of the lysosomal enzyme glucocerebrosidase. Finally, two other pathologies should be included in the differential diagnosis of RD: the “stiff skin syndrome” and the “Parana hard skin syndrome.” The former shows that the skin of the entire body is thickened and indurated, and there is a limitation of joint mobility with flexion contractures. The latter shows that the skin of the entire body becomes progressively thicker, and “freezing” of all joints occurs. A few hypotheses about the pathogenesis of this rare genodermatotic disease have been proposed. The clinical and histological features of RD were variably interpreted either as the expression of an ectodermal dysplasia or as a more specific morphogenetic alteration of the epidermis and dermis. Holbrook et al. (1987) found an abnormal differentiation of keratins with arrested development of hair follicles and eccrine sweat glands and suggested an underlying disorder of skin differentiation, involving dermal-epidermal interactions. Impaired skin maturation was also demonstrated by the weak or no labeling of cytokeratin with antibodies. Witt et al. (1986) found a decreased amount of high molecular weight keratins in the skin of a brother and a sister with RD.  Dean et  al. (1993) pointed out that RD is a disorder of skin differentia-

17 Skin

tion due to impaired cell adhesiveness but assumed to be due to abnormal integrin expression. However, Sillevis Smitt et al. (1998) did not show any abnormal α1β1 and α2β1 integrin expression in fibroblast cultures taken from five patients. No preference for any race is known because RD occurs in almost all ethnics. Consanguinity was demonstrated in only a few cases. The survival time was not correlated to the birth weight or to the time of delivery (Sergi et al. 2001). The values of the time of delivery (weeks of gestation) were distributed along a regression line with a significant slope (r2, 0.27; p-value, 0.0084; significant p-value 5 years) and showing an eczematous rash at the site of exposure usually in the previously sensitized host (allergic, e.g., poison ivy, nickel, or irritants, e.g., soaps) with three stages: –– Acute: Spongiosis  +  vesiculation  +  superficial perivascular lymphocytic/eosinophilic infiltrate + intraepidermal inflammatory cells –– Subacute: Thickening of the epidermis + spongiosis + superficial perivascular lymphocytic and eosinophilic infiltrate +/variable exocytosis –– Chronic: Psoriasiform hyperplasia, + superficial perivascular lymphocytic and eosinophilic infiltrate • DDX: Other types of spongiotic dermatitis, particularly irritant and photoallergic reactions, scabies, parasites, drug reactions, and bullous pemphigoid 17.2.1.3 Seborrheic Dermatitis • DEF: Spongiotic dermatitis, psoriasis-like, with prominent spongiosis targeting infants (aka Leiner disease) and early adolescents with manifestation onward on the scalp (dandruff), forehead, cheeks, upper chest, and back and evolving with greasy, scaly, redbrown, often pruritic patches. • CLM: Psoriasiform hyperplasia with hyperand parakeratosis + spongiosis + neutrophilic

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exocytosis + superficial perivascular lymphocytic and eosinophilic infiltrate. • DDX: Other types of spongiotic dermatitis (e.g., contact dermatitis), psoriasis, impetigo, drug reaction, dermatophytosis, secondary syphilis, pityriasis rosea. • PGN: In childhood and youth, there is a strong association of seborrheic dermatitis with epilepsy, obesity, and malabsorption and HIV infection.

17.2.1.4 Nummular Dermatitis • DEF: Spongiotic dermatitis with pruritic coin-­ shaped plaques on lower legs, backs of hands, and forearms and often seen in 15–30 years old individuals with ♂ < ♀ tendency. • SYN: Discoid dermatitis. • CLM: Three stages as described above as seen in another spongiotic dermatitis (vide supra for histological details). 17.2.1.5 Stasis Dermatitis • DEF: Spongiotic dermatitis of lower legs of usually middle-aged women with increased venous hypertension (HTN) and showing red, edematous, scaling lesions with variable oozing on legs (especially medially/internally) and evidence of stasis, such as brown skin pigmentation, ulcers, varicosity, and atrophic scars. • CLM: Acute, subacute, and chronic spongiotic dermatitis pattern with the lobular proliferation of capillaries  +  hemorrhage  +  hemosiderin  ±  fibrosis. Other forms of spongiotic dermatitis of childhood and youth include pityriasis alba, pityriasis rosea, papular acrodermatitis of Gianotti-Crosti, erythema ­ neonatorum, and incontinentia pigmenti. 17.2.1.6 Pityriasis Alba • DEF: Spongiotic dermatitis of children (3–16  years of age) with >1 hypopigmented maculae (average # of melanocytes) on face > trunk/limbs with spontaneous remission and re-pigmentation 20 mg/dL, glycemia > 250 mg/dL, and tachycardia (beats per minute greater than 120). Precisely, the identification of a score of 0-1 indicates dramatically a mortality risk of 3.2%; a score of 2, 12.1%; score of 3, 35.3%; while a score of 4, 58.3%; and, finally, a score of 5 or more, 90%. Mortality is variable from 1% of SJS up to 35% of TEN and can be even higher in immunocompromised patients or older patients. Management involves a multidisciplinary approach with rapid diagnosis, SCORTEN evaluation, identification and interruption of the triggering drug, and specialized supportive care ideally PICU/ ICU, with or without the introduction of immunomodulating agents (e.g., high-dose IV immunoglobulin therapy).

17.3 Interface Dermatitis

17.3.1.6 G  raft Versus Host Disease (GVHD) • DEF: Medical complication following the receipt of transplanted tissue from a genetically different person. In graft versus host disease (GVHD), the skin is the earliest and most commonly involved organ leading to address promptly patient management following an accurate interpretation of skin biopsy specimens. Erythematous macule/patches develop typically within the 1st month after bone marrow transplantation (BMT) as a manifestation of the acute disease (Box 17.2). Chronic GVHD, which may arise after acute GVHD or as de novo, is divided into lichenoid form (>60  days post-BMT, LP-like histology) and sclero-dermoid form of GVHD (>100  days post-BMT, progressive superficial toward deep thickening of collagen bundles from papillary dermis unlike PSS and morphea, which show upward dermal sclerosis). In the sclero-dermoid form of chronic GVHD, epidermal subset atrophy, rete ridges abolition, loss of adnexal structures, and scarring of superficial and deep dermis are often recognized.

17.3.1.7 Fixed Drug Eruption A fixed drug eruption is seen following trimethoprim-­sulfamethoxazole, ASA, tetracycline, and barbiturates and is characterized clinically by a variable number of well-defined erythematous to purple edematous plaques with central duskiness and blistering tendency, usually recurring at the same site with each drug administration. Microscopically, all elements of interface dermatitis are observed in a fixed drug eruption. Compared to interface dermatitis of EM or TEN, fixed drug eruption contains usually more neutrophils, involves the deep vascular

Box 17.2 Acute GVHD: Grading Grade 1 Grade 2 Grade 3 Grade 4

Vacuolization of the basal layer Vacuolization + dyskeratosis, exocytosis, necrotic keratinocytes “Subepidermal clefting” of the skin Bulla and loss of the epidermis

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plexus, and harbors melanophages accumulation or pigment incontinence.

17.3.1.8 L  ichen Sclerosus et Atrophicus (LSA) • DEF: A rare event occurring in females >435 years of age on genitals and characterized by white or ivory angulated maculae or papulae, often with an edematous center, and over time, dermal sclerosis may ensue, resulting in the clinical term of scleroderma, but rarely in adolescence. On the penis, this lesion is called balanitis xerotica obliterans (BXO), which is most commonly observed in childhood. • SYN: Balanitis xerotica obliterans (penis). • CLM: There are hyperkeratosis, epidermal atrophy, prominent homogeneous eosinophilic hyalinization of the papillary dermis, and a subjacent band-like lymphoid infiltrate. • PGN: Telangiectasia can be seen, and there is a SqCC risk up to 5%, which may mean one case out of 20. Thus, all cases need to be microscopically evaluated. 17.3.1.9 Infections • DEF: Infections associated with interface dermatitis that needs to be mentioned here are secondary syphilis, acrodermatitis chronica atrophicans, and HIV (human immunodeficiency virus, types I and II). Secondary syphilis may present, clinically, with a wide range of clinical findings, but the mostly papulosquamous eruption of variable distribution, particularly palms and soles. • CLM: Interface dermatitis with a superficial and deep perivascular and interstitial lymphoid-­ plasma cellular infiltrate. Psoriasiform acanthosis, spongiosis, exocytosis, PMN  ±  dyskeratosis, basal vacuolation, edema, lymphoplasmacytic infiltrate, and perivascular lymphocytes and plasma cells. • CLI: Genital chancre, 20–30 days post-T. pallidum exposure, painless ulcer, which resolves by itself and secondary cutaneous lesions. • Acrodermatitis chronica atrophicans occurs following infection with B. afzelii subspecies of B. burgdorferi, which is most commonly seen in Europe, and begins, clinically, as erythematous patches on arms and legs with pro-

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gressive atrophy of epidermis, dermis, and adnexal structures with an upper dermis plasma cellular infiltrate, which helps in the DDX with LE and LSA. • HIV-interface dermatitis is characterized by erythematous patches and plaques, which become purple over time and result in hyperpigmentation, and has been correlated to HIV drug therapy, which targets the skin and is prone to photosensitization.

17.3.2  Lichenoid Interface Dermatitis Interface dermatitis with lichenoid leukocytic infiltrate refers to basal keratinocyte necrosis with band-like lymphocytic infiltrate and colloid Civatte bodies, the irregular border of the basal membrane, and lymphocytic exocytosis with or without pigmentary incontinence. The lichenoid type of interface dermatitis may be encountered in lichen planus, lichenoid drug eruptions, lichen nitidus, and other conditions with vacuolar changes (vide supra). Here, the lichen planus (LP) is described. • Lichen planus is the idiopathic, self-limited prototype of lichenoid interface dermatitis and is characterized by pruritic, purple, polygonal, planar papulae, and plaques with white dots (fine scale) mostly on limbs (wrist, elbow, glans penis). • EPI: Adolescents and young adults but also children. • CLM: Histology characterized by the tetrad, including: (1) Hyperplasia of stratus granulosum (slow turnover) (2) Hydropic change/liquefaction of the basal layer with eosinophilic “colloid or Civatte bodies” (3) “Saw-toothing” phenomenon of rete ridges (irregular epidermal hyperplasia) (4) Tight superficial dermal band-like chronic lymphocytic (CD3+, CD4+) inflammation, which fills the papillary dermis entirely and obscures incontrovertibly the DEJ • Variant: Lichen plano-pilaris, which preferentially affects the epithelium of hair follicles.

• DDX: Other oral vesiculo-ulcerative conditions such as pemphigus vulgaris and benign mucous membrane pemphigoid, SLE, chronic ulcerative stomatitis, frictional keratosis, and morsicatio buccarum (persistent cheek biting), oral leukoplakia, and oral candidiasis.

17.4 Psoriasis and Psoriasiform Dermatitis 17.4.1  Psoriasis • DEF: Dermatitis with regular elongation of the epidermal rete ridges and affects up to 2% of the general population with a chronic relapsing clinical feature. There is evidence of inheritance or abnormal genetics in psoriasis and linkage disequilibrium with HLA-B13, and HLA-Bw17 have been described as well as a genetic susceptibility locus (PSORS1). Typically, psoriasis is a disease of young adults (3rd decade) with the involvement of the elbows, knees, and scalp. Three stages may be differentiated: (1) Plaque: sharply demarcated, scaly surface with positive Auspitz sign (2) Gutta: eruptive lesion on the trunk and proximal extremities (3) Pustule: multiple sterile pustular lesions over trunk and limbs following fever and surrounding generalized erythema • CLM: Three main features characterize the histology: (1) Hyper-/parakeratosis with hypogranulosis (fast cell turnover) (2) Acanthosis with long rete ridges and thinning of epidermis over dermal papillae (3) Munro microabscesses with neutrophils within the squamous layer • Variants: Pustular psoriasis and spongiform pustule of Kogoj

17.4.2  Psoriasiform Dermatitis Psoriasiform dermatitis is seen in several conditions with different etiologies and clinical manifestations. A familiar psoriasiform pattern of inflammation of

17.5 Perivascular In Toto Dermatitis (PID)

the dermis is seen. Psoriasiform dermatitis is seen in Reiter syndrome (urethritis, arthritis, and conjunctivitis), pityriasis rubra pilaris, lichen simplex chronicus, parapsoriasis en plaques, subacute and chronic spongiotic dermatitis (or eczematous dermatitis), erythroderma and mycosis fungoides, pityriasis rosea, dermatophytosis, scabies, inflammatory linear verrucous epidermal nevus (ILVEN), Bazex syndrome or acrokeratosis neoplastica, pellagra, acrodermatitis enteropathica, glucagonoma syndrome, syphilis at secondary stage, Bowen disease, clear cell acanthoma, and lamellar ichthyosis. Reiter disease lesions are crusted erythematous to pustular papules and plaques on the feet, genitalia, buttocks, and scalp. • CLM: There is psoriasiform hyperplasia with parakeratosis and numerous neutrophils, often forming microabscesses, practically indistinguishable from pustular psoriasis without clinical knowledge. Inflammatory linear verrucous epidermal nevus, or shortened as ILVEN, is a form of hamartoma of the epidermis, which occurs as a sporadic or familial lesion in children usually up to 5 years of age in 75% of cases. Clinically, there is a linear arrangement of grouped or coalescent lichenoid, psoriasiform, or verrucous papulae in the lower limbs, characteristically along the Blaschko lines. Skeletal malformations may be observed in some patients. • CLM: There is an alternation of portions of hyperkeratosis and underlying hypergranulosis and portions of hypokeratosis with underlying hypogranulosis, thickening of the rete ridges, slight spongiosis, and focal neutrophilic exocytosis. The upper dermis shows a perivascular lymphocytic infiltrate. Acrodermatitis enteropathica is an AR-­inherited disease with mutations of the SLC39A4 gene on chromosome 8q24.3. The SLC39A4 gene encodes a transmembrane Zn-­transport protein that serves as a zinc uptake protein. The disease usually starts as an infant is weaned from breast milk. Since Zn supplementation may reverse the disease, the defect is not complete.

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17.5 Perivascular In Toto Dermatitis (PID) The diagnosis of perivascular in toto (superficial and deep) dermatitis (PID) includes urticaria and non-urticarial dermatitis with superficial and deep lymphocytic infiltrate.

17.5.1  Urticaria • DEF: It is a disease of the 3rd and 4th decades of life with individual lesions (diffuse or scattered edematous papulae or wheals, often annular with itching) that typically develop and fade within 24 h, when new lesions appear elsewhere and characterized by acute, chronic, symptomatic (dermatographism), and physical forms (cold, pressure, solar, and cholinergic). • CLM: The histology (Fig. 17.2) shows: (1) Superficial and deep perivascular chronic inflammatory cellular infiltrates of mixed type (lymphocytes, neutrophils, and eosinophils) (2) Dermal edema constituted by separation of collagen bundles (3) Dilation of lymphatic channels in the absence of epidermal changes (4) Mast cells with granules (Giemsa stain for mast cells is a crucial stain!) and degranulated within the interstitium. • DDX: Insect bite reaction, persistent dermal hypersensitivity to drugs, cutaneous contact hypersensitivity, viral exanthemas, gyrate erythema, and vasculitides involving small blood vessels. Urticaria, which is also subdivided into acute and chronic, needs to be differentiated by urticarial-­like conditions. Acute urticaria of ordinary type, from a few hours to 6  weeks after onset (time 0), while chronic urticaria of usual kind, more than 6 weeks after start (time 0). Infection, food components, or drugs induce acute urticaria of typical kind and are self-limiting, while idiopathic is chronic urticaria of usual kind, often considered of autoimmune type. Angioedema may accompany

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both types. Physical urticaria is a response to an external factor and is subclassified in dermographism, cholinergic urticaria, cold urticaria, contact urticaria, actinic urticaria, and delayed pressure urticaria according to the responsible agent.

17.5.2  Non-urticaria Superficial and Deep Perivascular Dermatitis This heterogeneous group includes toxic erythema of pregnancy, gyrate erythema, pityriasis lichenoides, perniosis, rickettsia infections and viral infections, polymorphous light eruption (papular, papulovesicular, plaque eruption, or diffuse type occurring on the sun-exposed skin within 24  h post-actinic exposure with the postpubertal onset and nonspecific histology), and photosensitive eruptions. Superficial and deep perivascular dermatitis may also be seen in discoid LE, leprosy, syphilis, borreliosis, leukemia, and, of course, urticaria pigmentosa. Urticarial skin lesions include several entities as follows: • Insect bites (± sting, exposed sites, summer/ fall, central blister, asymmetrical distribution of groups of lesions, days to weeks, brown discoloration later, spongiosis of epidermis + inflammatory infiltrate including eosinophils) • Urticarial dermatitis (± CADR, persistent red itchy plaques with either a smooth or dry scratched surface, symmetrical distribution of the lesions on trunk, upper arms, and thighs, dermal inflammatory infiltrate + minimal spongiosis of the epidermis) • Contact dermatitis (± identification of the provoking factor, ± allergic contact dermatitis, clearing up of lesions over days to weeks, ± (+) patch test) • Erythema multiforme (urticaria-like plaques with concentric rings with lesions persisting for 1–3 weeks, ± HSV infection, characteristic histology)

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• Urticaria-like drug eruption (1 cm, tender/painful,

Box 17.4 Panniculitis Box 17.3 Vasculitides

17.9.1 Leukocytoclastic Vasculitis (LCV) 17.9.2 Polyarteritis Nodosa (PAN) 17.9.3 Wegener Granulomatosis (WG)

17.11.1 Septal Panniculitis 17.11.2 Lobular Panniculitis 17.11.3 Mixed Septal and Panniculitis

Lobular

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self-limited on anterior and lateral lower legs. If pyrexia, malaise, and joint pain are present, it is also often the case of a granulomatous fibrosing septal panniculitis. • CLM: Septal inflammation of neutrophils ± eosinophils, then lymphocytes, edematous and thickened septa with the peripheral involvement of fat lobules ± granulomatous inflammation with giant cells (aka Miescher’s granulomas). Miescher’s radial granulomas (MRGs) are “radial” nodules consisting of small histiocytes, “radially” placed around a central cleft and mainly located in the interlobular septa and in the deeper layers of the skin (Sánchez Yus et al. 1989). • DDX: Other septal panniculitides (sclerosing panniculitis, connective tissue diseases).

17.11.2  Lobular Panniculitis 17.11.2.1 Vasculitis-Associated Lobular Panniculitis (Erythema induratum) • DEF: Lobular panniculitis with vasculitis, characteristic of “tender, dusky, bluish nodules” of the posterior calves of adult obese women with a controversial relationship to tuberculosis (“tuberculide”). • SYN: “Deep inflammatory necrotizing nodular disease of the calves.” • CLI: Erythematous, tender, dusky nodule. • CLM: Extensive intralobular inflammatory infiltration of lymphocytes, MNGCs, and epithelioid histiocytes with necrotizing vasculitis of medium-sized blood vessels, which may become occluded with a subsequent ulcer, necrosis, and lipophagic granulomas. • DDX: Other lobular panniculitides with vasculitis.

17.12 C  utaneous Adverse Drug Reactions One of the most challenging tasks for a pathologist is to liaise with therapy-related diseases, e.g., cutaneous adverse drug reactions (CADRs).

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CADRs or cutaneous adverse drug reactions are a common diagnosis in clinical pediatrics and youth and may represent a challenge for some pathologists who are not aware of the numerous new drugs that every year are added in the repertoire of the pharmacopeia of both pediatricians and adult medical internists. It seems that a good starting figure to tackle this important, but difficult, chapter is to say that a rate of 5.5% of ADRs occurs per drug exposure (about one in 20 drugs used clinically), of which CADRs are 2.2% (about one in 40 drugs used clinically). Although CADRs are substantially half of the ADRs, they are rarely considered severe. The parents or relatives have, nevertheless, significant concerns, and CADRs account for a good number of clinic visits. Thus, CADRs may also represent a topic for healthcare econometrics. In assessing a CADR, a relationship of causality needs to be started. Causality assessment utilizes investigation tools aiming to weigh the biological plausibility or “culpability” of a drug causing a reaction. Naranjo et al.’s (1981) criteria for the “definitive culpability” in ADRs setting include (1) temporal sequence between drug administration and assessed drug level in body fluids, (2) recognition of a well-­determined response to the suspected drug from literature data or clinical records, (3) improvement following drug withdrawal, and (4) ADRs’ reappearance following drug re-exposure. We consider it appropriate to state that fullfilled criteria 1 and 3 determine a reaction as “probable,” while criterion 1 only determines a reaction as “possible” only. ADRs may be classified as type A and type B ADRs, accounting type A reactions for the majority of ADRs. Type A ADR: Reactions related to the well-known pharmacologic effects of a drug, dose-dependent, predictable, and mild-­moderate in the degree of clinical seriousness. Type B ADR: Reactions NOT related to the well-­known pharmacologic effects of a drug, dose-­independent, unpredictable, and moderate-severe in the degree of clinical seriousness. Although 29 drug-related CADRs have been identified, most of them are extremely rare, and only 5 are common in children and youth.

17.12 Cutaneous Adverse Drug Reactions

17.12.1  Exanthematous CADR • CLI: Morbilliform OR scarlatiniform maculopapular exanthema. • DDX: Viral exanthems or scarlet fever. • DAT-CADR Time: ♀. • CLI: Scaly, erythematous sharply demarcated papula showing enlargement slowly and occurring anywhere on mucocutaneous sites, but devoid of adnexae. • CLM: Full-thickness dysplasia of the squamous epithelium showing nuclear hyperchromasia, moderate to marked cytoplasmic vacuolization, multinucleated keratinocytes, dyskeratosis, parakeratosis and increased MI (Ki67 score). • PGN: 1/20 ⇒ invasive SqCC. 17.17.5.2 Erythroplasia of Queyrat • DEF: Squamous cell carcinoma in situ with full-thickness dysplasia of the glans penis of uncircumcised men and presenting as asymptomatic, erythematous, sharply defined papula. 17.17.5.3 Bowenoid Papulosis • DVEF: Bowen disease-like multiple erythematous lesions of uncircumcised glans penis/ vulva, rapidly developing of youth (20– 40 years) showing similarities to Bowen disease, but more orderly cellular background with the presence of some noticeable maturation of the surface cells.

Keratoacanthoma in children and youth can arise on nevus sebaceous and in patients with xeroderma pigmentosum (XP), which is a rare AR inherited disorder caused by defective DNA repair in various cutaneous and ocular cells following exposure to sunlight. XP occurs in about 1/65,000–1/100,000, with 3/4 of patients diagnosed before age 4.

17.17.7  Malignant Tumors Probably it is quite challenging to think about malignant tumors of the epidermis in childhood and youth, but they indeed occur. The reasons for an early appearance of this unusual tumor in childhood and adolescence may be linked to an abnormal genetic status or abnormal immunologic surveillance as well as the increase of environmental factors, sunbed culture, and inappropriate solar protection as well as nutrition, which may be not healthy. It is known that “loci of minoris resistentiae” may be skin exposed inadequately to sun, to thermal burns, to chemicals, and to PUVA (renal transplantation). PUVA is a combination treatment consisting of Psoralens (P) and then exposing the affected skin to UVA (long wave ultraviolet radiation). Chemicals may induce skin cancer in a wide variety of experimental animals and humans as

17.17 Tumors of the Epidermis

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well. The most common benign experimental tumors are papillomas and keratoacanthomas (vide supra), while common malignancies are carcinomas and melanomas. The carcinogeninduced deoxyribonucleic acid damages lead to a genetic change. The most common carcinogens are polycyclic aromatic hydrocarbons, alkylating agents, and nitrosamines. Historically, the Harvey ras gene is the prototype of genes involved in the initiation stage, which is a gene involved in epidermal proliferation. In the second stage or tumor promotion, there is a repeated exposure of the initiated skin. Non-carcinogenic promoting agents include phorbol esters, benzoyl peroxide, anthralin, or some halogenated aromatic hydrocarbons, which create a tissue environment that is permissive to the selective clonal outgrowth of the initiated cell population. In the third stage of carcinogenesis, premalignant cells go further to progress to frank malignancy. This third stage may occur either spontaneously or following exposure to mutagens that also include several initiating agents. One of the problems of our civilization is indeed the exposure to some poisons that are invisible for the most of cases. Arsenic (As) exposure may be acute or chronic, and this latter may lead to benign skin changes, skin malignancies, and internal cancers. High levels of As in drinking water have been identified in various studies of epidemiology from all over the world constituting a significant problem in regions of the world with poor environmental sensitivity. In New Zealand, an area with a high risk for overexposure to UVA, it is estimated that about 50,000 new cases of nonmelanoma skin cancer occur each year. Chronic skin disease, such as discoid lupus erythematosus, may also be a predisposing factor for the development of squamous cell carcinoma of the epidermis. Carcinoma duplex is a term used to define the combination of a basal cell carcinoma with a squamous cell carcinoma.

• EPI: 2nd most common cutaneous malignancy following basal cell carcinoma (BCC). • GRO: Protuberant skin lesion with or without ulceration. • CLM: There is an invasive solid growth of cells, which show compactness (Box 17.6). • Variants: Well-differentiated, spindle cell, acantholytic (aka adenoid or pseudoglandular), verrucous, and clear cell. • Broder classification: differentiation and keratinization entail the following categories: (1) >75% of keratinization present ⇒  well-­ differentiated SqCC (2) 25–75% of keratinization present ⇒ moderately differentiated SqCC (3)  G1-G2). Box 17.6 Low-Grade (LG) Versus High-Grade (HG) SqCC

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Neoplastic transformation of nevus sebaceous of Jadassohn (NSJ) is rare but has been reported in an 11-year-old girl (Belhadjali et al. 2009) and in a 15-year-old girl (Hidvegi et  al. 2003), and altogether only five well-documented cases of SqCC arising in an NSJ have been described, thus pointing to a rare, but potential occurrence of SqCC transformation of NSJ.

17.17.7.2 Basal Cell Carcinoma • DEF: Most common skin cancer on the mainly sun-exposed skin and proportionally to the number of pilosebaceous units, characterized by the slow and indolent growth of synchronous or metachronous appearance. • SYN: “Basalioma” (this term should not be used because it may indicate a benign nature, instead of the true malignancy behind basal cell carcinoma. However, this term is still in use in some countries). • EPI: Worldwide, ♂ > ♀, in childhood and youth, mainly seen in transplant patients. • CLI: Papule or nodule with telangiectasias, which may be eroded or ulcerated (ulcus rodens), and pigmented BCC may simulate melanocytic lesions. • CLM: The neoplastic proliferation of basal cells with peripheral palisading, characteristic separation artifact with the surrounding tissue, stromal mucin, and incomplete differentiation toward adnexal structures, particularly pilar adnexae. • Variants include baso-squamous, clear cell, diffuse sclerosing (morphea-type), localized, cystic/ulcerative, and superficial. • IHC: Bcl-2 (+), CD10 (+), Ki67 > 20% (unrelated to PGN). • (−) CK20, (−) CD15, (−) CD34, (−) EMA, (−) CEA, but (+) stromelysin-3 (stroma). • DDX: SqCC, which is usually CD10 (−). • PGN: Rare metastases (2/10,000), but if (+) ⇒  fatal within 1  year. Incompletely excised BCC does recur in 1/3 of cases. In addition to the above-described variants, two more conditions need some words, particularly fibroepithelial tumor of Pinkus and Gorlin syndrome or basal cell nevus syndrome (BCNS). Fibroepithelial tumor of Pinkus is a “BCC” of

the back, abdomen, and thigh with a “skin tag”like shape and constituted by 2–3 cell thick basaloid epithelial strands, which peculiarly anastomize to divide the fibrous stroma in compartments. BCCS or Gorlin syndrome is an AD inherited genetic disease characterized by multiple BCCs starting when the patients are quite young and accompanied by jaw cysts, bony abnormalities, skull anomalies (e.g., Falx cerebri calcification), and palmar pits. An important differential diagnosis for the pathologist is distinguishing BCC from trichoepithelioma, which shows lobules of basaloid cells disconnected from the epidermis (Box 17.7).

Box 17.7 BCC Versus Trichoepithelioma

• (−) “Follicle-like structures”/(+) “follicle-like structures” • (+) “Separating cleft”/(−) “separating cleft” • (+) Programmed cell death/(−) programmed cell death • (+) Melanin pigmentation/(−) melanin pigmentation Notes: Follicle-like structures are abortive hair-papillae. Moreover, trichoepithelioma is (−) Bcl-2 and (+) CD34  in the stroma. In addition, there are more “tricho”features which are absent or not well represented in BCC, including well-­delimited organoid architecture (no infiltrative growth pattern), unfolding of the stroma into the nests or cell clusters (e.g., “papillary mesenchymal bodies,”) eosinophilic collagenous cuticle surrounding the cell clusters, distinct nucleoli, and IHC.  The IHC panel required to differentiate between the two tumors is CD10, CK15, CK20, and D2–40 (all four leading to trichoepithelioma) and low MI (Ki67 20%), (±) Bcl-2, which may show some expression limited to peripheral basal cells, unlike the usual diffuse staining pattern as seen in BCC.

17.18 Melanocytic Lesions

17.17.7.3 Paget Disease • DEF: Mammary Paget is associated with underlying carcinoma, and the most common extramammary sites are perineum (vulva, penis, scrotum, anus), axillae, umbilicus, and eyelids. • CLM: Paget cells are dispersed singly or in clusters at an epidermal location with PAS (+), eosinophilic cytoplasm, and vesicular nuclei and show a characteristic IHC phenotype: CK7 is very useful because it is not expressed by the surrounding epidermal cells. However, normal Toker cells and Merkel cells are positive for CK7 and must be distinguished morphologically (atypia). GCDFP15 (BRST2) and CK20 are useful for separating primary from secondary Paget disease, being GCDFP15 (+) in primary Paget disease (GCDFP15 is low expressed in secondary Paget) and CK20 (+) in secondary Paget disease (CK20 is low expressed in primary Paget). The nature of the underlying carcinoma will also dictate the phenotype in secondary Paget disease. Most cases with underlying rectal adenocarcinoma are CK7+ and CK20+, albeit 90% of rectal adenocarcinomas are CK7− and CK20+. Since S100 can be expressed by Paget cells, MelanA should be used in the differential diagnosis with melanoma.

17.18 Melanocytic Lesions The diagnosis of CNS anomalies goes further the general implications for the parental decision to carry on pregnancy or terminate it. Parental expectations are important, but long-term outcomes of birth defects affecting the CNS are vital to be able to provide the neonatology and pediatric team with appropriate information. The CNS is highly susceptible to damage. Three cell types need to be kept separate: –– Melanocytes –– Melanoblasts –– Melanophages Melanocytes are neuroectodermally derived cells with melanin granules that can be detected using Fontana-Masson stain, but also other silver stains, and immunohistochemi-

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cally using antibodies against S-100 and VIM and are positive using DOPA reaction. Melanocytes are negative for antibodies against keratins, neurofilaments, and GFAP. These findings are useful for the DDX of carcinoma, neuroblastoma, NET, and glial tumors. The immature forms are called melanoblasts, while melanophages are macrophages (anti-CD68+), which have phagocytosed melanin pigment. According to the location of the melanin-­containing cells, there is a different color by inspection of the skin. In the epidermis, the color is brown, and in the superficial dermis, the nevus will assume a black color, while nevus cells located in the deep dermis will give a blue nevus.

17.18.1  L  entigines, Solar Lentigo, Lentigo Simplex, and Melanotic Macules (Box 17.8) 17.18.2  Melanocytic Nevi DEF: Any localized benign abnormality of melanocytes with nesting (theques) with initial occur-

Box 17.8 Five Benign Disorders of Pigmentation

1. Albinism: ↓ Melanin (hypopigmentation), melanocytes present, but not melanin-producing 2. Freckles (aka Ephelis): ↑ Melanin deposition, melanocyte hypertrophy with normal number of melanocytes, sunlight-reactive, 1–10  mm, irregular borders 3. Melasma gravidarum: ↑ Melanin deposition, melanocyte hypertrophy with normal number, pregnancy-associated (often) 4. Vitiligo: ↓ Melanin (hypopigmentation), absence of melanocytes 5. Lentigo simplex: Melanocyte hyperplasia and hyperpigmentation, but no melanocyte nesting, sunlight-unresponsive, 5–10  mm, well-­ demarcated borders, common in children

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rence at 2–6 years of age until age 20 (Box 17.9) (Figs. 17.7 and 17.8).

Box 17.9 Melanocytic Nevi Junctional Intradermal Compound J + ID features Flat/slightly Papillary, elevated pedunculated, flat Brown~ Pigmentation colored Nesting DEJ Intradermal DEJ + Intradermal Risk MM Nil MM

Gross

17.18.3  Variants of Melanocytic Nevi Melanocytic nevi variants include the following: Blue Nevus Deep located melanocytic nevus with a band of uninvolved dermis between the epidermis and

a

b

c

d

e

f

Fig. 17.7  This dermatopathology panel illustrates the first panel of non-melanocytic and melanocytic nevi and melanoma with a nevus sebaceous of Jadassohn in (a) (H&E stain, 12.5×), a connective tissue nevus in (b) (H&E stain, 50×), hyperplasia of nevus cells in (c)

(Fontana Masson stain, 50×), an intradermal nevus with melanocytes single and in cluster in the papillary dermis in (d) (H&E stain, 200×), an intradermal nevus in (e) (antibody anti-S100 immunostain, 50×), and excoriated intradermal nevus in (f) (H&E stain, 100×)

17.18 Melanocytic Lesions

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a

b

c

d

e

f

Fig. 17.8 The second panel of nevi and melanocytic lesions shows an ILVEN in (a) (H&R stain, 50×), a cavitated intradermal epithelioid Spitz nevus in (b) (H&R stain, 100×), a Spitz nevus compound with atypical features in (c) (H&R stain, 400×), a Reed nevus or pigmented spindle cell

lesion usually situated at H&N or upper limbs with natural abundant melanin pigment. Unusual forms of blue nevus are the following lesions:

nevus of Reed in (d) (H&R stain, 50×), a malignant melanoma with atypical epithelioid nevus cells with nodular architecture and cytologically a vesicular nucleus with prominence of nucleoli in (e and f) (H&E stain for both (e) and (f) with (e) taken at 50× and (f) taken at 400×)

Cellular blue nevus: Deep melanocytic nevus with a band of uninvolved dermis between the dermis and the lesion, which is usually located at the buttock, lower back, and back of hands or feet (3 “b”: buttock, back, and back of hands and • Mongolian spot: Sacral area feet). It shows high cellularity, pushing margins, • Nevus of Ota: Melanocytic blue nevus (fuso-­ dermal sclerosis, and elongated dendritic process ceruleus) at ophthalmic-maxillary site with fine melanin granules without junctional • Nevus of Ito: Melanocytic blue nevus (fuso-­ activity or inflammation (benign, 1/4 of cases: ceruleus) at acromion-deltoideus site congenital).

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Deep penetrating nevus: Melanocytic nevus, usually located on the face and upper trunk, showing nevus cell nesting with scattered melanocytes filling the dermis and tendency to infiltrate the erector pili muscles as well as through the dermis into the subcutis (favorable outcome, 10–30 years, not prone to recurrence or metastases). Congenital nevus (non-giant): Melanocytic nevus with the involvement of reticular dermis, subcutaneous tissue, and skin adnexa (benign, not prone to recurrence or metastases). Giant congenital (pigmented) nevus (GCPN): Melanocytic nevus with the involvement of the reticular dermis, subcutis, and skin adnexa and specific bathing-trunk distribution and large, coarse skin with folds and satellite lesions (benign, but requiring multiple surgeries → scar tissue in 1+ resections). Halo nevus: Melanocytic nevus showing nonpigmented skin secondary to regression. Balloon nevus: Melanocytic nevus showing large foamy macrophages. Bulky perineal neurocytoma: Uncommon congenital variant of GCPN showing innate features (vide supra) with or without cystic structures lined by nevus cells and large numbers of small bodies (Messner bodies-like), S100+, HMB-45+ (cave), usually large, polypoid or pedunculated and hyperpigmented located in the genital area, often obscuring the genitals (aggressive histology, but rare malignant transformation 0.5 cm, border irregularity, variegated appearance, and “pebbly” surface and considered precursor for MM. The “ABCDE” rule includes Asymmetry, Border irregularity, Color not uniform, Diameter >6 mm, and Evolving size, shape or color. Microscopically, atypical melanocytes (nuclear hyperchromasia, prominent nucleoli, dusty melanin pigment), lymphocytic infiltrate in the papillary dermis, bridging of rete ridges by fusion of melanocytic nests, intradermal extending junctional component, dermal fibroplasia with eosinophilic concentric, or lamellar fiber deposition. Activating mutations in CDKN2A, CDK4, NRAS, and BRAF have been described associated with atypical melanocytic (dysplastic) nevi!

17.18.6  Malignant Melanoma and Variants Malignant melanoma does occur in childhood and youth and the misconception that a juvenile melanoma harbors a better outcome than melanoma in adulthood has perseverated for many

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years. The same name “juvenile melanoma” was sometimes used for Spitz tumor. MM in situ →  Lentigo maligna (aka “Hutchinson freckle”): Sun-exposed skin areas (e.g., cheek), tan to black, slow-growing melanocytic lesion of elderly with individual ± nesting with confluence of atypical junctional activity of melanocytes with epidermal atrophy (“consumption of epidermis”), solar elastosis, and no or minimal transepidermal migration or adnexal involvement. PGN: Invasion in 30–40% of cases. Malignant melanoma (invasive) → MM with invasion (transepidermal migration): Melanocytic lesions with significant propensity to occur in sunlight exposed skin areas, redhaired whites, 1/5 of MM originating from preexisting melanocytic nevus with a common junctional component (if intradermal, MM is probably metastatic). Predisposing factors: Inherited genes (vide infra) + sunlight exposure. Melanin (special) stains: Fontana-Masson, DOPA-oxidase, and Schmorl stains. The DOPAoxidase reaction involves the conversion of L-dopa (L-3,4-dihydroxyphenylalanine) to dopachrome (red). IHC markers include: • S100 (nuclear and cytoplasmic): sensitive, but not specific! • HMB-45 (cytoplasm): sensitive and specific, but (−) in the desmoplastic MM (D-MM). • Melan A/MART1: sensitive, but not specific being (+) in the ovary, testis, and adrenal gland. • Tyrosinase: sensitive, but also stains PNST and NET. • MTF (microphthalmia transcription factor): sensitive, but also stains DF and SMT. MTF is negative in D-MM. MM altered pathways include (1) RAS-RAF-­ MEK-ERK (MAPK: mitogen-activated protein kinase) with activating mutations of NRAS, (2) p16-CDK4-RB, (3) ARF-TP53, (4) KIT (activating mutations), (5) PTEN (epigenetically silenced), (6) CDKN2A gene mutations (three TSGs including p14, p15, and p16), CMM1 gene mutations, MSI, and multiple chromosomal genes and losses.

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MM-subtypes other than conventional type: With “radial growth phase” (MM in situ with ≥3 rete ridges beyond the infiltrative component):

• Level III: Papillary dermis (fully) filling and expansion (only!) • Level IV: Reticular dermis infiltration • Level V: Subcutis infiltration

1. Lentigo maligna melanoma (LMM) (15%  – all ages): Better PGN-harboring MM-subtype associated with sun exposure and elderly arising on lentigo maligna in hair follicles and sweat ducts with atypical cells on superficial dermis (macular→ papular→ nodular). 2. Superficial spreading melanoma (60%  – all ages): Most common form on the trunk and legs and sun exposure-related with both macular and nodular appearance clinically, blue hue with admixed tan and brown (early stage) but white, pink, and blue when areas of regression are present. 3. Acral-lentiginous melanoma (10% – all ages): Intraepidermal MM mostly on palms, soles, nails, and genitals, particularly in dark-­ skinned individuals and characterized by the hyperplastic epidermis.

DDX: Dysplastic nevi! Dysplastic nevi – Features include some characteristics grouped with the acronym “BAJIF,” including (B) bridging of nests, (A) atypia of melanocytes, (J) junctional shouldering, (I) inflammation, and (F) fibrosis of lamellar type. The following features are useful to distinguish DYSPLASTIC NEVI from MM using the acronym “TAMM”: (T) transepidermal migration of melanocytes, (A) angio-invasion of melanocytes, (M) mitotic activity, and (M) maturation of descending melanocytes. PGN: See Box 17.10 for favorable prognostic factors. Regression: It is essential to ponder that a primary lesion can spontaneously regress, while metastases do not. By clinical inspection, regression is white, often with a bluish hue. Microscopically, there are irregularities along the DEJ, focal necrotic cells, band-like lymphocytic infiltrate, melanophages, subepidermal fibrosis, and atrophy of rete ridges. The presence of regression is NOT a good prognostic sign, because it indicates that the lesion was once more abundant. The tumor regression distinguishing features include (1) dermal fibrosis of nonlaminated type with scattered inflammatory cells, (2) epidermal attenuation, (3) melano-phagocytosis, (4) replacement of tumor cells by lymphocytic infiltrate, and (5) telangiectasia.

With “vertical growth phase” (≥1 dermal cluster more substantial than the most massive epidermal group and/or MI > 1 in the dermis): 1. Nodular melanoma (15%  – all ages): Young age, raised lesion, short duration, symmetrical ± amelanotic, and no intraepidermal component. Desmoplastic MM: MM-variant with fascicles of spindle cells, (+) S100, (+) TIL. Breslow index and Clark levels are useful for the grading of MM. Breslow index entails the tumor invasion/ thickness (θ) and grades I if θ ≤0.75 mm; II, if θ, 0.75–1.5  mm; III if θ, 1.5–2.25  mm; IV if θ, 2.25–3 mm; and V if θ >3 mm. Clark levels use the anatomic level of invasion: • Level I: Intraepidermal localization (only!) = MM in situ • Level II: Papillary dermis infiltration

Box 17.10 MM: Prognosis Factors → Favorable PGN (1) Gender, age (2) Location (central body vs. limbs) (3) Tumor depth (θ = thickness) (4) Tumor regression (5) TILs (tumor infiltrating lymphocytes) (6) MI

♀, youth Limbs < 1.5 mm (−) (+) 0/low

17.19 Sebaceous and Pilar Tumors

Malignant features include the “trailing off” phenomenon (i.e., a lateral extension of individual cells), ↓ nesting cohesiveness, adnexal epithelium extension, fine dusty melanin granules, ↑ MI, intratumoral lymphocytes, lack of maturation, large Ø, melanocyte necrosis, poorly circumscription, prominent nucleoli, and size/shape variation. In Box 17.11, some pearls and pitfalls of MM are listed.

Box 17.11 Pearls and Pitfalls

• To distinguish between pT1a and pT1b is of primary importance because sentinel node examination should be performed on pT1b and above according to AJCC recommendations, 6th edition, TNM classification system. • The pN status is evaluated on the lymph nodes: 50 μm in Ø located in the Breslow index tissue slide section either in the reticular dermis, panniculus subcutaneous, or blood vessels beneath the primary infiltrating tumor but separated from it by ≥300 μm. • In the case of sentinel node examination, the following advice should be followed: –– If LN   0.5 cm → bisect the LN and/ or slice it at 2 mm intervals.

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17.19 Sebaceous and Pilar Tumors The diagnosis of sebaceous tumors is quite impressive because it is mainly linked to possible clinical manifestations.

17.19.1  Sebaceous Hyperplasia Sebaceous hyperplasia is unusual in children and youth but mostly present on the face of older individuals as yellowish dome-shaped papule and constituted, microscopically, by hyperplastic glands in the upper dermis that drain into the central duct.

17.19.2  N  evus Sebaceous (of Jadassohn) (NSJ) • DEF: Benign, congenital hamartoma of the follicular-sebaceous apocrine unit and epidermis presenting clinically as a single, round, yellow melanocytic, pebble-like, papule or plaque located on H&N with a warty tendency (aka organoid nevus). • CLM: Hamartomatous lesion composed of large sebaceous glands, heterotopic apocrine glands, defective hair follicles, acanthosis, and epithelial papillomatosis and hyperkeratosis. The nevus sebaceous of Jadassohn often presents at birth, appears to regress in childhood, and grows during puberty, pointing to possible hormonal control. NSJ may develop syringocystadenoma papilliferum, benign hair follicle tumors, and BCC.  The differential diagnosis includes sebaceous hyperplasia and seborrheic keratosis, both of them typical lesions of older patients. As indicated above nevus sebaceous is a hamartoma with sebaceous, follicular, and apocrine gland in addition to epidermal abnormalities. Nevus sebaceous is well known as a background for the development of cutaneous neoplasms such as trichoblastoma, syringocystadenoma papilliferum, basal cell carcinoma and keratoacanthoma, and rarely squamous cell carcinoma.

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showing an irregular lobular pattern in upper dermis with basophilic sebaceous cells containing small granular nuclei with eosinophilic nucleoli. Mebazaa et  al. (2007) reported a recent sebaceous carcinoma in a 12-year-old male child on the eyebrow and reviewed the literature identifying seven more cases described in the English literature. Age varied from 3.5 to 16 years, and sites included upper eyelid or eyelid (4 cases), eyebrow (1), Meibomian gland (1), buccal mucosa (1), and thorax (1). Following surgical excision, recurrence was observed in one case only, although short follow-­up times and no specific followup were found in the other cases. • DDX: The differential diagnosis of poorly differentiated sebaceous carcinoma includes 17.19.3  Sebaceous Adenoma, cutaneous clear cell tumors, chiefly squamous Sebaceoma, and Xanthoma cell carcinoma with sebaceous differentiation, clear cell acanthoma, clear cell hidradenoma, Sebaceous adenoma is a rare benign epithelial clear cell hidradenocarcinoma, cutaneous tumor looking like a BCC clinically as yellow clear cell carcinoma, tricholemmoma, pilar papule and showing, microscopically, individual tumor, balloon cell melanoma, and metastasis lobules, collagen-formed pseudocapsule and from an RCC.  The clear cell acanthoma is a peripheral small germinative cells with round-to-­ well-demarcated tumor that may arise from ovoid vesicular nuclei and eosinophilic cytointraepidermal eccrine ducts. It presents with plasm. The term “adenoma sebaceum,” which a solitary (raised moist red) lesion on lower occurs in tuberous sclerosis, is something else, limbs of middle-aged to elderly, and histologii.e., is an angiofibroma. cally there is plenty of glycogen. Sebaceoma or sebaceous epithelioma is a tumor with focal sebaceous differentiation showing more or less mature sebaceous cells, which 17.19.5  Benign Hair Follicle Tumors are mixed randomly with basophilic, immature epithelial cells. In the hair follicle can develop tumors that may Xanthoma is an accumulation of fat-laden harbor the tendency to recurrence, if not commacrophages in dermis or subcutis located on pletely excised (Fig. 17.9). tendons, the synovium, or bone. Although most of these cutaneous neoplasms develop in patients older than 16  years of age, some are present in childhood and need to be identified at the time of diagnosis for proper follow-­up from the pediatric or adult dermatologist. Since follicular, sebaceous, and apocrine elements have different distribution depending on the area, nevi sebacei of the face or scalp have different biological behaviors. In fact, nevus sebaceous of the scalp is more often complicated by tumors than nevus sebaceous of other localizations, although only the face is the site where seems to occur keratoacanthoma on nevus s­ ebaceous. The neoplastic transformation of NSJ is extremely rare, but it has been reported as mentioned above.

17.19.4  Sebaceous Carcinoma Sebaceous carcinoma is not usually seen in children or young individuals, although familial cancer syndromes and individuals with congenital or acquired immune deficiencies may theoretically develop this kind of tumors. • DEF: An aggressive periocular variant with a relatively less aggressive extraocular form

17.19.5.1 Pilar Sheath Acanthoma Pilar sheath acanthoma (PSA) and dilated pore of Winer (DPW) are two related lesions, which belong to benign hair follicle tumors. PSA is a solitary tumor with central pore with the keratinaceous material in the upper lip and constituted by a multiloculated lobulated neoplastic masses radiating into surrounding dense stroma. DPW shows a more dilated pore than present in PSA showing an enlarged open follicular cystic cavity filled with keratin and irregularly proliferating rete ridges.

17.19 Sebaceous and Pilar Tumors

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a

b

c

d

e

f

g

h

Fig. 17.9  This panel illustrates three non-melanocytic tumors in children and youth. In (a) and (b), a pilomatrixoma is shown. In (c and d), an eccrine poroma is shown, and in (e) through (h), a rare plexiform fibrohistiocytic tumor. The pilomatrixoma (a, H&E, 12.5×; b, H&E, 100×) shows a basaloid proliferation with similarity to hair matrix cells, which matures into structureless eosinophilic cells without nuclei (the so-called ghost cells). The

eccrine poroma (c, H&E, 100×; d, H&E, 200×) shows a nodular proliferation of cords and nests of small keratinocytes attached to the epidermis, while the plexiform fibrohistiocytic tumor (e, H&E, 50×; f, H&E, 50×; g, H&E, 50×; h, H&E, 100×) shows a plexiform proliferation of fibrohistiocytic cells with minimal atypia, osteoclast-like giant cells, and a lymphocytic infiltrate

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17.19.5.2 Trichilemmoma Trichilemmoma may be associated to Cowden syndrome and is a small warty or smooth papule on the face of older individuals showing a proliferation of outer root sheath with uniform small cells with variably clear cytoplasm forming one or more sharp-delimited lobules arising from the epidermis and keeping extensive connections with the epidermis, peripheral palisading, and thickened BM.

17.19.6  M  alignant Hair Follicle Tumors

17.19.5.3 Trichofolliculoma Trichofolliculoma is a dome-shaped lesion with a central pore with silky white threat-like hairs and showing a dilated hair follicle with numerous secondary follicles of the mature and immature type with “caput medusae” appearance arising from its stratified squamous wall. Two characteristic features are the infundibular squamous epithelium with prominent granular layer and tight connections with the epidermis.

17.20 Sweat Gland Tumors

Malignant hair follicle tumors are very rare malignancies of the adnexa of the skin that have a preference for the head and neck region. These tumors can be listed into several different types. The reader should refer to texts of dermatopathology for this topic.

Adnexal cutaneous tumors can be differentiated toward the ductal and or/glandular portion of the eccrine or apocrine glands, although they are often seen as a mixture of patterns on the histological ground. Sweat gland with ductal differentiation show some glandular/duct structures and/ or intracytoplasmic glandular lumens. Special stains, including PAS, and immunohistochemical stains, including EMA and CEA, may highlight 17.19.5.4 Trichoepithelioma true ducts and intracytoplasmic lumens, while Trichoepithelioma is a small, flesh-colored cuta- apocrine differentiation may show a decapitation neous nodule showing lobules of basaloid cells secretion pattern with ducts showing “apocrine disconnected from the epidermis with follicle-­ snouts” (Box 17.12). These “snouts” represent like structures, horn cysts, peripheral palisading without clefting, and cellular fibrotic stroma surrounding the lobules. Most importantly, the priBox 17.12 Sweat Gland (Eccrine and mary differential diagnosis of trichoepithelioma Apocrine) Tumors is BCC, which shows no follicle-like structures, 17.20.1 Eccrine Gland Tumors but clefting around the peripheral palisading of 17.20.1.1 Cylindroma the basaloid cells. 17.20.1.2 Syringoma 17.20.1.3 Chondroid Syringoma 17.19.5.5 Pilomatrixoma 17.20.1.4 Eccrine Poroma Pilomatrixoma (aka calcifying epithelioma of 17.20.1.5 Eccrine Acrospiroma Malherbe) is a slowly growing, firm nodule with 17.20.1.6 Eccrine Spiradenoma chalky consistency usually located on the face 17.20.1.7 Eccrine Carcinoma and showing a specific biphasic cell population 17.20.2 Apocrine Gland Tumors of basaloid cells and ghost cells (hair matrix dif 17.20.2.1 Syringocystadenoma ferentiation) and prominent tendency to calcify in Papilliferum (Apocrine at least ¾ of cases. Nevus) 17.20.2.2 Apocrine Tubular 17.19.5.6 Piloleiomyoma Adenoma Piloleiomyoma is a small, firm, intradermal tumor 17.20.2.3 Hidradenoma constituted by several nodules which are located as groups or linear arrays on the trunk or limbs.

17.20 Sweat Gland Tumors

accumulations of secreted granules in the apical cytoplasm spilling into the lumen of the ducts. Apocrine glands should be considered “mammary glands” or “mammary”-like glands of the skin, especially in the anogenital and axillary regions. Both eccrine and apocrine glands express EMA, CEA, and LMWCK (e.g., CAM5.2). Thus, these three markers are not used to differentiate between eccrine and apocrine differentiation. The expression of CK14 of the eccrine glands is characteristically seen in the and also due to acrosyringium, which is the spiraled intraepidermal ductal component.

17.20.1  Eccrine Gland Tumors Eccrine gland tumors include cylindroma, syringoma, chondroid syringoma, eccrine poroma, eccrine acrospiroma, eccrine spiradenoma, and eccrine carcinoma.

17.20.1.1 Cylindroma Cylindromas are benign adnexal tumors showing an eccrine and an apocrine differentiation and often as a single lesion. If multiple lesions (“turban tumors”) are observed, cylindromas are frequently linked to the Brooke-Spiegler syndrome, an irregular AD syndrome with variable penetrance caused by mutations in the CYLD gene on 16q12-q13. Other adnexal tumors, such as trichoepitheliomas and spiradenomas have also been observed. Brooke-Spiegler syndrome (BSS), familial cylindromatosis (FC), and multiple familial trichoepitheliomas (MFT), initially described as distinct syndromes, share overlapping clinical features. CYLD inhibition increases resistance to apoptosis, leading to oncogenesis. Brooke-Spiegler syndrome manifests in adolescence. Cylindromas can reach considerable size, and malignant transformation has been described. In almost 100% of the cases, cylindromas are located on H&N (scalp) with a female preference, are slow-growing tumors and show, microscopically, epidermal disconnected multiple lobules in a jigsaw pattern in the upper dermis. In each lobule, a thick PAS  +  -BM, hyperchro-

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matic basal cells, and central cells with vesicular nuclei are seen. No regional nodal involvement has been described for cylindromas, but the differential diagnosis includes AdCC.  However, signs of malignant transformation include ulceration, bleeding, sudden growth, and color change.

17.20.1.2 Syringoma Syringomas are multiple symmetrical small papules on lower eyelids with pubertal appearance and female preponderance. Microscopically, the acrosyringium is involved, and there are small cysts/bilayered ducts with comma tails (some of the tadpole shape) with lumina lined by cuticle and filled with eosinophilic granular material. Clear cell variant of syringoma may occur in the setting of DM. 17.20.1.3 Chondroid Syringoma Chondroid syringoma (aka benign mixed tumor of the skin) is a firm, solitary, lobulated nodule in dermis or fat located on H&N with no symptoms. Two characteristic features are (1) well-­ delimitated, multilobulated mass with nests or cords of polygonal cells with basophilic nuclei and a significant amount of eosinophilic cytoplasm and (2) pseudo-cartilagineous/chondroid stroma. 17.20.1.4 Eccrine Poroma • DEF: Eccrine glandular-arising benign adnexal cutaneous tumor (outer acrosyringium: upper dermal eccrine duct) showing “anastomosing ribbons.” • EPI: Worldwide, children and adults, ♂ = ♀. • CLI: Solitary, scaly red nodule of soles at the sides of feet. • CLM: Epidermis-replacing tumor with anastomosing ribbons, growing down into the dermis and sharp demarcated to the not affected skin and constituted by monomorphic, cuboidal cells and occasional duct differentiation. • DDX: Both benign and malignant diagnoses should enter in the differential: –– Benign DD include eccrine acrospiroma and clonal seborrheic keratosis. –– Malignant DD include BCC, SqCC in situ, Paget disease, melanoma, clonal

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seborrheic keratosis, acrospiroma, and porocarcinoma. • PGN: Malignant eccrine poroma is a rare variant and shows marked nuclear pleomorphism.

17.20.1.5 Eccrine Acrospiroma • DEF: Eccrine gland-arising adnexal cutaneous tumor with large intradermal lobules with ductal structures that are accompanied by cystic spaces and hyalinized stroma.

• SYN: Eccrine hidradenoma, clear cell hidradenoma. • EPI: Worldwide, any age, ♂ < ♀. • CLI: Papula/nodule of almost any location. • CLM: Large intradermal (superficial dermis) lobules of monomorphic cuboidal cells with a basophilic cytoplasm mixed with clear cells showing ductal structures, cystic spaces, and hyalinized stroma (Fig. 17.10).

a

b

c

d

e

f

Fig. 17.10  This panel shows a malignant eccrine acrospiroma (MEAS) (a, H&E, 50×; b, H&E, 50×; c, H&E, 200×; d, H&E, 200×; e, Anti-CK5/6, 100×; f, Anti-CK5/6, 12.5×). The MEAS shows solid lobules of tumor cells located in the dermis and extending into the subcutaneous tissue without connection between the epidermis and the

tumor. Some of the lobules contain small cystic spaces filled with homogenous, clear or eosinophilic material. Interstitial thick hyaline collagenization is seen around lobules. The cell population is made up of two cells types, clear cells and spindle cells

17.20  Sweat Gland Tumors

• DDX: Glomus tumor, apocrine-mixed carcinoma, and metastasis of carcinoma, mostly renal cell carcinoma.

17.20.1.6 Eccrine Spiradenoma • DEF: Benign eccrine gland-arising cutaneous adnexal tumor with a characteristic organoid pattern of intradermal cannon blue balls enriched with hyaline droplets, blood vessels, and lymphocytes. • EPI: Worldwide, youth, ♂ = ♀. • CLI: Solitary, bluish or skin-colored, usually painful nodule on ventral surfaces of the upper body. • CLM: Rounded intradermal lobules “cannon blue balls” without epidermal connection or jigsaw puzzle pattern, delimitated by BM-­material and hyaline droplets, rich vascular supply, and intralesional scattered lymphocytes. • DDX: BCC, eccrine cylindroma, glomus tumor, other vascular tumors. Skin lesions presenting as painful nodules need to be taken into consideration (Box 17.13). • PGN: Good. Variants include the Ancell-Spiegler syndrome and the multifocal spiradenomatosis.

17.20.1.7 Eccrine Carcinoma There are several variants, including classical, syringoid, microcystic adnexal, mucinous, and

Box 17.13 Skin Lesions Presenting as Painful Nodules

–– Blue Rubber Bleb Nevus (= asyndromic vascular nevus) –– Cutaneous Tumors: Dermatofibroma, eccrine spiradenoma, pilomatrixoma –– Vascular Tumors: Angioleiomyoma, angiolipoma, glomus tumor/ glomangioma –– Nerve Tumors: Schwannoma, neurofibroma, neuroma (traumatic), granular cell tumor –– Endometriosis

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adenoid cystic variants, all of them including nuclear pleomorphism and more or less obvious features of malignancy.

17.20.2  Apocrine Gland Tumors Apocrine gland tumors include syringocystadenoma papilliferum, apocrine tubular adenoma, and hidradenoma papilliferum.

17.20.2.1 Syringocystadenoma Papilliferum • DEF: Benign apocrine glandular-arising cutaneous adnexal tumor with “EPIDERMAL cystic invagination, papillae with plasma cell rich fibrovascular core, and bilaminar apocrine epithelium with decapitation snouts.” • EPI: Worldwide, youth, ♂ = ♀. • CLI: Solitary, gray to brown, moist nodule on the scalp. • CLM: Epidermal cystic invagination with papillae showing a plasma cell-rich fibrovascular core and a bilayered lining of apocrine epithelium with decapitation secretion. • DDX: Nevus sebaceus, hidradenoma papilliferum. • PGN: Good. 17.20.2.2 Apocrine Tubular Adenoma • DEF: Benign apocrine glandular-arising cutaneous adnexal tumor characterized by lobular masses of tubular structures and apocrine secretion pattern. • EPI: Worldwide, youth, ♂ = ♀. • CLI: Dome-shaped nodule on the scalp. • CLM: Poorly circumscribed intradermal tumor with lobular masses of tubular structures showing columnar epithelium, apocrine secretion, and myoepithelial layer within foci of ductular communication with the epidermis. • DDX: Papillary eccrine adenoma, hidradenoma papilliferum. • PGN: Good. 17.20.2.3 Hidradenoma Papilliferum • DEF: Benign apocrine glandular-arising cutaneous adnexal tumor with intradermal cyst

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intersected by papillary folding of cells with plasma cell-rich fibrovascular core and bilaminar epithelium of apocrine type with decapitation snouts. EPI: Worldwide, youth, ♂ < ♀. CLI: Solitary, gray to brown, dome-shaped nodule on the perineum and genital region. CLM: Intradermal cyst with papillae showing a plasma cell-rich fibrovascular core and a bilayer lining of apocrine epithelium with decapitation secretion. DDX: Syringocystadenoma papilliferum, apocrine tubular adenoma. PGN: Good.

17 Skin

• CLM: Plaque-like growth pattern of fascicles of myoid-appearing spindle cells located in the reticular dermis with a Grenz zone sparing the superficial subepithelial dermis (DDX: Dermatofibroma showing a storiform pattern and “encapsulation” of single collagen bundles) and lacking a significant extension into fat and subcutaneous tissue or CD34 staining (DDX: DFSP).

17.21.3  Juvenile Xanthogranuloma

• DEF: Benign tumor of dendritic cell origin with potential spontaneous regression. • SYN: Nevoxanthoendothelioma. 17.21 Fibrous and Fibrohistiocytic • EPI: Uncommon, infants, ♂ > ♀. • CLI: The skin of the face or trunk but all sites Tumors can be affected. Rarely, non-cutaneous sites Fibrous and fibrohistiocytic tumors are listed in are involved (the subcutis, skeletal muscle, their complexities in textbooks of dermatopatholeye, peripheral nerve, testis, liver). Multiple ogy. Here, we will discuss the scar, dermatofibroma lesions in 1/5 patients. There is a clinical or benign fibrous histiocytoma (BFH), dermatofiassociation with glaucoma and amblyopia brosarcoma protuberans (DFSP), and juvenile xan(iris and ciliary body involvement), NF-I, thogranuloma (JXG). Other entities are described in NPD, urticaria pigmentosa, and CMV other chapters or dermatopathology books. infection. • GRO: Yellow-red, papula/nodule. • CLM: Dense poorly circumscribed, the lym17.21.1  Hypertrophic Scar phohistiocytic proliferation of dermis with and Keloid foamy and Touton giant cells, short fascicles of spindle cells, fibrohistiocytic cells and Both hypertrophic scar and keloid are the result of a fibrosis with the thin epidermis, elongated rete cutaneous injury. Both hypertrophic scars and ridges, preservation of adnexa, lymphocytes, keloids are manifestations of the same fibroprolifand eosinophils as well as no or scattered erative skin disorder, and they may differ in the mitotic figures (Fig. 17.11). intensity and duration of inflammation (vide supra). • IHC: (+) CD68, A1ACT, lysozyme, VIM, FXIIIa, (−) S100, CD1a. • TEM: Cytoplasmic lipid (+), but Birbeck granules (−). 17.21.2  Dermatofibroma • DDX: Epidermoid cyst (cyst of keratinized epithelium with distinct granular layer con• DEF: It is a benign fibrous tumor of the upper taining lamellated keratin), BFH (dense coltrunk or neck of adolescents and young adults lagenous stroma, storiform growth pattern, presenting as pale pink or hypopigmented pseudoepitheliomatous hyperplasia), xanplaque composed of bundles of myoid-­ thoma (tumor of uniform foamy histiocytes), appearing spindle cells in the reticular dermis LCH (nuclear grooves, S100+, CD1a+, (Fig. 17.11). Langerin+. Birbeck granules by TEM), lipoma • SYN: Benign fibrous histiocytoma (BFH). •

17.21 Fibrous and Fibrohistiocytic Tumors

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Fig. 17.11  This panel shows a dermatofibroma (a–d) and a juvenile xanthogranuloma (e–h). In the dermatofibroma, there is a nodular proliferation of fibroblasts and myofibroblasts with some whorling but no atypia (a, H&E, 12.5×; b, H&E, 100×; c, Anti-CD34, 50; d,

Anti-F13, 50×). In the juvenile xanthogranuloma, there is dense lymphohistiocytic proliferation of dermis with Touton giant cells (e, H&E, 2×; f, H&E; 50×; g, Anti-CD68 immunostain, 50×; h, Anti-F13 immunostain, 50×)

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(tumor of mature adipocytes), and reticulohistiocytoma (random distribution of MNGC with eosinophilic or ground glass cytoplasm). • TRT: Excision. • PGN: Although spontaneous regression is potential, newborns may develop the systemic disease and liver failure. Recurrence rate: 5–10%.

17.21.4  Dermatofibrosarcoma Protuberans • DEF: Fibrohistiocytic tumor with high rate of recurrence rate and prone to metastasis if incompletely excised. DFSP carries a t(17;22) (q22;q13), which results in the fusion gene COL1A1-PDGFB. • EPI: Rare in children but seen in youth. • GRO: Red-brown raised tumor located in the trunk (e.g., shoulder) and limbs. • CLM: Poorly/uncircumscribed, highly cellular tumor with tight storiform pattern prone to infiltrate deeply into subcutaneous tissue entrapping adipocytes and forming characteristic honeycomb pattern (Fig. 17.12). • IHC: (+) VIM, CD34, (±) SMA, Bcl2, CD99, NKI-C3, ApoD, (−) FXIIIa, AE1–3, EMA, DES, S-100, HMB-45, CD117. • TRT: Excision with negative margins. • PGN: Metastasis in 5% of the cases.

17.22 Vascular Tumors (Fig. 17.13) Vascular tumors are mainly described in Chap. 1 (vide supra) but also in some other sections.

17.23 Tumors of Adipose Tissue, Muscle, Cartilage, and Bone These tumors are described in the chapter of soft tissue. The autochthonous tumors need to be differentiated from skin infiltration from contiguous lipogenic neoplasms, adjacent myogenic tumors, contiguous cartilaginous neoplasms, and skin infiltration from contiguous osteogenic neoplasms.

17.24 Neural and Neuroendocrine Tumors Neural and neuroendocrine tumors of the skin are extremely rare entities but have occasionally been described, mainly, in immune-deficient patients and need to be taken into consideration during the diagnostic procedure of blue cell tumors with cutaneous localization or neuro-­ differentiated neoplasms.

17.24.1  Merkel Cell Carcinoma • DEF: Highly aggressive malignant neuroendocrine tumor of the skin at probable viral etiology, i.e., Merkel cell polyomavirus (MCPyV), with a characteristic perinuclear dot-like CK20 stain. • SYN: Trabecular carcinoma, neuroendocrine carcinoma. • EPG: Merkel cell polyomavirus (MCPyV) is a DNA polyomavirus that has been identified as the probable etiological agent of Merkel cell carcinoma (MCC), which is a particularly aggressive cutaneous carcinoma of neuroendocrine origin. Polyomaviruses encode for large and small T-antigens, which bind to host proteins facilitating both replications of the viruses and inactivation of p53 and pRb. Interestingly, the integration of MCPyV preceded the metastatic spreading of the carcinoma. MCPyV is also responsible for high specific seroprevalence, starting in childhood and reaching up to 90% in adults, a finding that has been observed in both blood donors and individuals from Western countries. Recently, Martel-Jantin et  al. (2013) emphasize that most primary MCPyV infections occur before the age of 6 years! Mother-fetus transmission is not a significant route of MCPyV transmission, but MCPyV seems to be transmitted from mother to child through close interpersonal contact involving saliva and/or the skin. • CLI: Pink, firm, raised, painless nodule located on H&N and limbs. • CLM: Neural crest-derived Merkel cell NET of the skin, which shows a predominantly dermal

17.24 Neural and Neuroendocrine Tumors

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Fig. 17.12  This panel illustrates a dermatofibrosarcoma protuberans with highly cellular, tight storiform pattern with cells radiating in spokes and infiltrates deeply into subcutaneous tissue entrapping fat cells (a–f) (a, H&E, 20×; b, H&E, 20×; c, Anti-CD34 immunostain, 100×; d,

Anti-CD34 immunostain, 200×; e, Anti-F13a, 50×; f, Anti-F13a, 200×). The two microphotographs (g) and (h) illustrate a hybrid form of giant cell fibroblastoma and dermatofibrosarcoma protuberans (g, H&E, 100×; h, Anti-CD34 immunostain, 100×)

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Fig. 17.13  In (a–c), there is capillary hemangioma (a, H&E stain, 50×; b, H&E stain, 200×; c, Anti-CD31 immunostain, 100×). In (b) it is possible to identify some plump endothelial cells, but no atypia. The microphotographs (d) and (e) show an involuted hemangioma (d,

H&E stain, 50×; e, Anti-Glut-1 immunostain, 50×). The microphotograph (f) shows a lymphangioma circumscriptum (H&E stain, 50×). The microphotograph (g) shows an angiokeratoma (H&E stain, 100×). The microphotograph (h) shows an angioleiomyoma (H&E stain, 50×)

17.24 Neural and Neuroendocrine Tumors

•

• •

•

localization with sparing of the epidermis (“Grenz” zone) with trabecular growth pattern and collagen-dissecting features by small basophilic cells with high N/C ratio, inconspicuous eccentric nucleolus, and nuclear molding. IHC: (+) CD57, NSE, CGA, SYN, and characteristic perinuclear dot-like CK20 positivity, unlike another small cell carcinoma except for the small cell carcinomas of the salivary gland tissue as well as (±) CD99, FLI1, and CD117. TEM: 100–150  nm neurosecretory granules and paranuclear filament whorls. TNT: Surgery and chemotherapy, but therapy options and recommendations may vary accordingly to site of origin. PGN: Recurrences and metastases are up to 1/3 of cases.

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17.24.2  Paraganglioma • • DEF: Neuroendocrine neoplasm arising parallel the sympathetic chain ganglion in the thoracic-­lumbar region of the vertebral column and parasympathetic nervous system in

Box 17.14 Paraganglioma of Head and Neck, Differential Diagnosis

Granular cell tumor (polygonal cells with eosinophilic granular cytoplasm, central oval nuclei, S100+, EM of granules→ degenerated lysosomes) Hibernoma (small round adipocytes with granular eosinophilic cytoplasm interspersed with large cells with both eosinophilic and vacuolated cytoplasm and mature adipocytes) Spitz nevus, epithelioid type (nests and lobules of large polygonal cells with enlarged nuclei, prominent nucleoli, and copious eosinophilic cytoplasm, S100+, HMB-45+, MART-1+) Meningioma, cutaneous (whorl arrangement of spindle cells and sheets and nests of polygonal or spindle cells, psammoma bodies = laminated calcified bodies, intranuclear pseudoinclusions, EMA+, VIM+, S100)

•

the cranial and sacral areas and classified as a neoplasm of uncertain malignant potential. A rich neural network is present in the skin, but ganglia are not present. EPI: Rare tumor in childhood. CLI: Asymptomatic or as a painless mass, but up to 3% of the paragangliomas show symptoms related to the secretion of hormones from neurosecretory granules. CLM: Characteristic “Zellballen” constituted by aggregates of NSE+, SYN+ neuroendocrine cells separated by fibrovascular stroma (S100+ sustentacular cells). TEM: Electron-dense cytoplasmic granules with characteristic surrounding halo may be present in some tumor cells. DDX: Granular cell tumor, hibernomas, epithelioid Spitz nevi, cutaneous meningiomas, juvenile xanthogranulomas, and ectopic neural hamartomas (Box 17.14). TNT: Surgery and radiation therapy, but therapy options and recommendations vary accordingly to site of origin. PGN: Tumor with uncertain malignant potential.

LCH (Langerhans cells, eosinophils, S100+, CD1a+, Langerin+, Birbeck granules on TEM) JXG (mixed inflammatory infiltrate of lymphocytes, plasma cells, neutrophils, eosinophils, and many large histiocytes with foamy or granular eosinophilic cytoplasm, Toutontype giant cells, CD68+, FXIII) Neuroblastoma (small round blue cells, (+) CGA, SYN, CD56, (−) CD99, neurosecretory granules) PNET (small to the medium-sized spindle to more polygonal cells with the perivascular arrangement, hyperchromasia, CD99+) Neurothekeoma (multinodular mass, myxoid matrix, peripheral fibrosis, (+) VIM, imentin, NKI-C3, CD10, MITF, (−) S100, GFAP, MelanA) Notes: Gr. θήκη, sheath; LCH, Langerhans cell histiocytosis; JXG, juvenile xanthogranuloma; PNET, primitive neuroectodermal tumor.

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Two cases of paraganglioma of the scalp have been described in the English literature. DDX is important, and neuroblastoma, Langerhans cell histiocytosis, and lymphoma should be considered first. The rare occurrence of paragangliomas in the skin of the head is intriguing and may be argued that this is due to aberrant migration of neural crest cells.

17.25 Hematological Skin Infiltrates Some conditions may be seen in the skin and be associated with or originated from a neoplastic involvement of the hematopoietic system. Tumors and related lesions of the hematopoietic and lymphoid systems include: • • • • • • • •

Cutaneous infiltration of leukemia Cutaneous pseudolymphomas Langerhans cell histiocytosis Malignant lymphomas Mastocytosis maligna Mycosis fungoides Sezary syndrome Urticaria pigmentosa

The following is the list of the entities that have been discussed in the chapter dedicated to the hematopathology (Box 17.15).

17.25.1  Pseudolymphomas This is a very heterogeneous group including conditions that have not been fully understood or diseases with poor description. The group includes perivascular lymphocytic infiltrates of Jessner-Kanoff of benign nature, sarcoid of

Box 17.15 Hematological Infiltrates of the Skin

17.25.1 Cutaneous T-Cell Lymphomas 17.25.2 Cutaneous Non-T-Cell Lymphomas (Fig. 17.14) 17.25.3 Cutaneous Pseudolymphomas

Spiegler-­Fendt, lymphomatoid papulosis, lymphomatoid granulomatosis, and localized forms of cutaneous reticulosis that may be in situ forms of Langerhans cell histiocytosis (vide infra).

17.25.2  Benign and Malignant Mastocytosis Urticaria pigmentosa (infants, few to many papulae/wheals on the trunk and limbs ± systemic involvement with flushing and faintness, +++ mast cell infiltrate).

17.26 Solid Tumor Metastases to the Skin Cutaneous metastases can occur in the setting of a pediatric (children) or adult (youth) tumor. Pediatric neoplasms include neuroblastoma, PNET/Ewing sarcoma, rhabdomyosarcoma, lymphoblastic lymphoma, other non-common SRBCTs, malignant rhabdoid tumor, congenital fibrosarcoma, and epithelioid sarcoma. Youth neoplasms include PNET/Ewing sarcoma, breast carcinoma, lung carcinoma, gastrointestinal carcinoma, carcinoma of the oral cavity and sinus-­ nasal carcinomas, urinary tract tumors, and tumors of the genital tract. Special stains are useful in distinguishing the nature of “clearing” of tumor cells, being intracytoplasmic lipid and glycogen (PAS+ and DPAS-) in CCRCC.  Urothelial carcinomas are usually strongly positive for both CK7 and CK20, which are also both positive in most of the pancreatic carcinomas and some ovarian mucinous carcinomas.

17.25.4 Leukemia with Skin Infiltration and Myeloid Sarcoma 17.25.5 Langerhans Cell Histiocytosis (Fig. 17.15) 17.25.6 Benign and Malignant Mastocytosis

17.26  Solid Tumor Metastases to the Skin

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Fig. 17.14  DLBCL. This panel shows a rare diffuse large B-cell lymphoma (see hematopathology chapter for detail) (a, H&E, 50×; b, H&E, 50×; c, H&E, 200×; d, Anti-

CD79a immunostain, 200×; e, Anti-CD3 immunostain, 100×; f, Anti-CD10 immunostain, 100×; g, Anti-­Bcl6 immunostain, 50×; h, Anti-Ki67 immunostain, 200×)

17 Skin

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Fig. 17.15  Subungual Langerhans cell histiocytosis. Nail involvement is distinctly uncommon in Langerhans cell histiocytosis (LCH), which may present with longitudinal grooving, purpuric striae, hyperkeratosis, subungual pustules, deformity, loss of nail plate, paronychia, onycholysis, and pitting. This panel shows the microphotographs of pediatric case of subungueal LCH.  In (a, b) there is an effacement of the subungual plate and an infiltration with Langerhans cells in combination with other leukocytes, mainly lymphocytes and eosinophils (a, H&E stain, 40×;

b, H&E stain, 400×). Langerhans cells have abundant, pale eosinophilic cytoplasm, irregular and elongated nuclei with nuclear grooves and folds, fine chromatin and indistinct nucleoli. The microphotographs (c), (d), and (e) show the immunostains with antibodies against CD45 (400×), CD3 (400×), and CD1a (400×), respectively. An electron microscopy investigation of the formalin-­fixed and paraffin-embedded block identified Birbeck granules, which present as structures with a size variable between 200 and 400 nm × 33 nm and double outer contour

Multiple Choice Questions and Answers

 ultiple Choice Questions M and Answers

1403

growing firm nodule near the site of a recent ear-piercing. The nodule is excised, and the histology is shown here:

• DER-1 An 18-year-old girl surviving osteosarcoma of the right leg presents with a slowly

What is the most likely diagnosis? (a) Metastasis of an osteosarcoma (b) Metastasis of a synovial sarcoma (c) Hamartoma (d) Teratoma (e) Keloid

• DER-2 A 2-year-old boy presented with a nodule on the right leg. The nodule is pink-colored with a dimple in the center, firm, and 3 millimeters in diameter. In the last week, the nodule became itchy, sore, and red. He started swimming in the pool a few months ago. The nodule is excised, and the histology is shown here:

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What is the most likely diagnosis? (a) Molluscum contagiosum (b) Juvenile xanthogranuloma (c) Pilomatrixoma (d) Scar (e) Ecthyma • DER-3 What is the exact proof of tuberculosis infection in an active stage? (a) Acid-fast staining on tissue (b) Ziehl-Neelsen stain (c) Tuberculin test (d) Microbiological isolation of M. tuberculosis • DER-4 A 6-month-old female infant developed otitis media for which she was given a course of antibiotics. A few days later, the infant developed widespread peeling of the skin. Upon examination, the pediatrician does not note any mucosal lesions, and the baby was not “toxic”. What is the most likely diagnosis in this baby? (a) Infantile pemphigus (b) Toxic epidermal necrolysis (c) Steven Johnson syndrome (d) Staphylococcal scalded skin syndrome • DER-5 An 18-month-old developmentally normal boy was brought to the pediatrician by the parents. He showed generalized itching and symmetrical skin lesions predominantly on the extensor aspect of all four extremities for the 1-week duration. The symptomatology was evident 3 days following DPT (diphtheria, pertussis, tetanus) immunization and vaccination against poliomyelitis with some increases of the body temperature that subsided 3 days later. There was no history of drug intake or atopy. The lesions started to progress from both upper limbs to the ­buttocks, lower limbs, and face, which was accompanied by generalized lymphadenopathy. On examination, the rash consisted of multiple, small, skin-colored nontender, pruritic papules. What is the most likely diagnosis in this infant? (a) Gianotti-Crosti syndrome (b) Acrodermatitis enteropathica (c) Erythema infectiosum (d) Erythema multiforme

•

•

•

•

(e) Henoch-Schönlein purpura (f) Kawasaki disease DER-6 A 19-year-old girl suffering from inflammatory bowel disease for more than 10 years presents to the family doctor with dome-­ shaped slightly polypoid reddish, painful nodules located on anterior and lateral lower legs. She is not pregnant and denies any drug administration. Septal panniculitis is diagnosed following a skin biopsy. What is the most likely diagnosis? (a) Alpha-1-antitrypsin deficiency (b) Non-Hodgkin lymphoma (c) Lupus panniculitis (d) Erythema nodosum (e) Nodular fat necrosis (f) Necrobiosis lipoidica (g) Necrobiotic xanthogranuloma (h) Scleroderma (i) Subcutaneous granuloma DER-7 Epidermal nevi are a cellular proliferation of hamartomatous character. An epidermal nevus (non-melanocytic nevus) is an overgrowth of the epidermis that can be present at birth or develop during infancy. Which of the following features does NOT belong to epidermal nevi? (a) Epidermal ortho-hyperkeratosis (b) Hypergranulosis (c) Hyperpigmentation (d) Papillomatosis (e) Basal layer hyperpigmentation DER-8 Which of the following conditions predispose to squamous cell carcinoma in childhood? (a) Nevus sebaceous (b) Down syndrome (c) Patau syndrome (d) Pilomatrixoma (e) Spitz nevus DER-9 What is the most common type of malignant melanoma? (a) Acral lentiginous melanoma (b) Mucosal melanoma (c) Nodular melanoma (d) Juvenile melanoma (e) Polypoid melanoma (f) Superficial spreading melanoma

References and Recommended Readings

• DER-10 Which of the following pathways is NOT altered in malignant melanoma? (a) RAS-RAF-MEK-ERK (MAPK (mitogen-­ activated protein kinase)) with activating mutations of NRAS (b) p16-CDK4-RB (c) ARF-TP53 (d) FAP (e) KIT (activating mutations) (f) PTEN (epigenetically silenced) (g) CDKN2A gene mutations (three TSGs including p14, p15, and p16) (h) CMM1 gene mutations, MSI, and multiple chromosomal genes and losses

References and Recommended Readings Abedi Kiasari B, Vallely PJ, Klapper PE. Merkel cell polyomavirus DNA in immunocompetent and immunocompromised patients with respiratory disease. J Med Virol. 2011;83(12):2220–4. https://doi.org/10.1002/ jmv.22222. PubMed PMID: 22012732. Agelli M, Clegg LX. Epidemiology of primary Merkel cell carcinoma in the United States. J Am Acad Dermatol. 2003;49(5):832–41. Erratum in: J Am Acad Dermatol. 2004;50(5):733. PubMed PMID: 14576661. Altaykan A, Ersoy-Evans S, Erkin G, Ozkaya O.  Basal cell carcinoma arising in nevus sebaceous during childhood. Pediatr Dermatol. 2008;25(6):616–9. https://doi.org/10.1111/j.1525-1470.2008.00726.x. PubMed PMID: 19067866. Ashena Z, Alavi S, Arzanian MT, Eshghi P.  Nail involvement in langerhans cell histiocytosis. Pediatr Hematol Oncol. 2007;24(1):45–51. PubMed PMID: 17130113. Aslan Y, Erduran E, Kutlu N. Autosomal recessive multiple pterygium syndrome: a new variant? Am J Med Genet. 2000;93(3):194–7. PubMed PMID: 10925380. Banerjee SS, Agbamu DA, Eyden BP, Harris M.  Clinicopathological characteristics of peripheral primitive neuroectodermal tumour of skin and subcutaneous tissue. Histopathology. 1997;31(4): ­ 355–66. PubMed PMID: 9363452. Barnhill RL. Childhood melanoma. Semin Diagn Pathol. 1998;15(3):189–94. Review. PubMed PMID: 9711668. Barnhill RL, Crowson AN. Textbook of Dermatopathology, Volume 355. McGraw-Hill, Medical Pub. Division, 2004 - Medical - 1093 pages Bastuji-Garin S, Rzany B, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-­Johnson syndrome, and erythema multiforme. Arch Dermatol. 1993;129(1):92–6. PubMed PMID: 8420497.

1405 Belhadjali H, Moussa A, Yahia S, Njim L, Zakhama A, Zili J. Simultaneous occurrence of two squamous cell carcinomas within a nevus sebaceous of Jadassohn in an 11-year-old girl. Pediatr Dermatol. 2009;26(2):236–7. https://doi.org/10.1111/j.1525-­1470.2009.00895.x. PubMed PMID: 19419489. Bialasiewicz S, Lambert SB, Whiley DM, Nissen MD, Sloots TP.  Merkel cell polyomavirus DNA in respiratory specimens from children and adults. Emerg Infect Dis. 2009;15(3):492–4. https://doi.org/10.3201/ eid1503.081067. PubMed PMID: 19239774; PubMed Central PMCID: PMC2681122. Bizzozero G.  Delle cellule cigliate, del reticolo Malpighiano dell’epidermide. Annal Univ Med. 1864;190:110–8. Bostanci S, Akay BN, Kirmizi A, Okcu Heper A, Farabi B. Basosquamous carcinoma and melanoma collision tumor in a child with xeroderma pigmentosum. Pediatr Dermatol. 2020;37(2):390–392. https://doi. org/10.1111/pde.14097. Epub 2020 Jan 19. PubMed PMID: 31957124. Broders AC. Microscopic grading of cancer. In: Treatment of cancer and allied diseases. p. 9. Broders AC.  The grading of carcinoma. Minn Med. 1925;8:726. Broders AC. Grading of Cancer. In: Treatment of Cancer and Allied Diseases. Pack GT, Livingston EM. ed. 1, New York. Paul B. Hoeber, Inc., 1940, pp. 19–41. Brunner J, Freund M, Prelog M, Binder E, Sailer-­Hoeck M, Jungraithmayr T, Huemer C, Sergi C, Zimmerhackl LB.  Successful treatment of severe juvenile microscopic polyangiitis with rituximab. Clin Rheumatol. 2009;28(8):997–9. https://doi.org/10.1007/s10067009-1177-0. Epub 2009 Apr 24. PubMed PMID: 19390907. Busam KJ, Mentzel T, Colpaert C, Barnhill RL, Fletcher CD.  Atypical or worrisome features in cellular neurothekeoma: a study of 10 cases. Am J Surg Pathol. 1998;22(9):1067–72. PubMed PMID: 9737238. Calkins CC, Setzer SV.  Spotting desmosomes: the first 100 years. J Invest Dermatol. 2007;127:E2–3. Caulfield JB, Wilgram GF. An electron microscopic study of blister formation in erythema multiforme. J Invest Dermatol. 1962;39:307–316. DOI: 10.1038/ jid.1962.118. Chen T, Hedman L, Mattila PS, Jartti T, Ruuskanen O, Söderlund-Venermo M, Hedman K.  Serological evidence of Merkel cell polyomavirus primary infections in childhood. J Clin Virol. 2011;50(2):125–9. https:// doi.org/10.1016/j.jcv.2010.10.015. Epub 2010 Nov 19. PubMed PMID: 21094082. Cohen MC, Kaschula RO, Sinclair-Smith C, Emms M, Drut R.  Pluripotential melanoblastoma, a unifying concept on malignancies arising in congenital melanocytic nevi: report of two cases. Pediatr Pathol Lab Med. 1996;16(5):801–12. PubMed PMID: 9025878. Comar M, Cuneo A, Maestri I, Melloni E, Pozzato G, Soffritti O, Secchiero P, Zauli G.  Merkel-cell polyomavirus (MCPyV) is rarely associated to B-chronic lymphocytic leukemia (1 out of 50) samples and occurs late in the natural history of the disease. J Clin

1406 Virol. 2012;55(4):367–9. https://doi.org/10.1016/j. jcv.2012.08.011. Epub 2012 Sep 7. PubMed PMID: 22959215. Cordon M. Extrait d’une lettre au sujet de trois enfants de la meme mere avec partie des extremites denuee de peau. J Med Chir Pharm. 1767;26:556–7. Cribier B, Scrivener Y, Grosshans E.  Tumors arising in nevus sebaceus: a study of 596 cases. J Am Acad Dermatol. 2000;42(2 Pt 1):263–8. PubMed PMID: 10642683. Curry CJ. Further comments on the Neu-Laxova syndrome. Am J Med Genet. 1982;13(4):441–4. PubMed PMID: 6891563. Dasgupta T, Wilson LD, Yu JB.  A retrospective review of 1349 cases of sebaceous carcinoma. Cancer. 2009;115(1):158–65. https://doi.org/10.1002/ cncr.23952. PubMed PMID: 18988294. Dean JC, Gray ES, Stewart KN, Brown T, Lloyd DJ, Smith NC, Pope FM. Restrictive dermopathy: a disorder of skin differentiation with abnormal integrin expression. Clin Genet. 1993;44(6):287–91. PubMed PMID: 8131298. Demmel U.  Clinical aspects of congenital skin defects. I. Congenital skin defects on the head of the newborn. Eur J Pediatr. 1975;121(1):21–50. Review. PubMed PMID: 765133. El Hachem M, Diociaiuti A, Latella E, Zama M, Lambiase C, Giraldi L, Surrenti T, Callea F. Congenital myxoid and pigmented dermatofibrosarcoma protuberans: a case report. Pediatr Dermatol. 2013;30(5):e74–7. https://doi.org/10.1111/pde.12131. Epub 2013 Mar 28. PubMed PMID: 23534369. Elston D, Ferringer T, Ko C, Peckham S, High W, DiCaudo D. Dermatopathology, 2nd Edition. Saunders Ltd. 2013:1–464. eBook ISBN: 9780702055287. eBook ISBN: 9780702055294 Erovic I, Erovic BM.  Merkel cell carcinoma: the past, the present, and the future. J Skin Cancer. 2013;2013:929364. https://doi. org/10.1155/2013/929364. Epub 2013 Apr 16. PubMed PMID: 23691324; PubMed Central PMCID: PMC3652192. Faridounnia M, Wienk H, Kovačič L, Folkers GE, Jaspers NG, Kaptein R, Hoeijmakers JH, Boelens R. The Cerebro-oculo-facio-skeletal Syndrome Point Mutation F231L in the ERCC1 DNA Repair Protein Causes Dissociation of the ERCC1-XPF Complex. J Biol Chem. 2015 Aug 14;290(33):20541-55. https:// doi.org/10.1074/jbc.M114.635169. Epub 2015 Jun 17. PubMed PMID: 26085086; PubMed Central PMCID: PMC4536458. Faust H, Andersson K, Ekström J, Hortlund M, Robsahm TE, Dillner J. Prospective study of merkel cell polyomavirus and risk of merkel cell carcinoma. Int J Cancer. 2014;134(4):844–8. https://doi.org/10.1002/ijc.28419. Epub 2013 Aug 29. PubMed PMID: 23922031. Frieden IJ.  Aplasia cutis congenita: a clinical review and proposal for classification. J Am Acad Dermatol. 1986;14(4):646–60. Review. PubMed PMID: 3514708. Gallager RL, Helwig EB.  Neurothekeoma  – a benign cutaneous tumor of neural origin. Am J Clin Pathol. 1980;74(6):759–64. PubMed PMID: 7446487.

17 Skin Gorlin RJ, Cohen MM, Levin LS.  Syndromes of head and neck. 3rd ed. New York: Oxford University Press; 1990. p. 417–9. Hall JG. The lethal multiple pterygium syndromes. Am J Med Genet. 1984;17(4):803–7. PubMed PMID: 6539071. Hall JG. Analysis of Pena Shokeir phenotype. Am J Med Genet. 1986;25(1):99–117. Review. PubMed PMID: 3541610. Hamm H, Höger PH.  Skin tumors in childhood. Dtsch Arztebl Int. 2011;108(20):347–53. https://doi. org/10.3238/arztebl.2011.0347. Epub 2011 May 20. Review. PubMed PMID: 21655460; PubMed Central PMCID: PMC3109276. Harr T, French LE.  Toxic epidermal necrolysis and Stevens-Johnson syndrome. Orphanet J Rare Dis. 2010;5:39. Heelan K, Shear NH.  Cutaneous drug reactions in children: an update. Paediatr Drugs. 2013;15(6):493–503. https://doi.org/10.1007/s40272-013-0039-z. Review. PubMed PMID: 23842849.) Hidvegi NC, Kangesu L, Wolfe KQ. Squamous cell carcinoma complicating naevus sebaceous of Jadassohn in a child. Br J Plast Surg. 2003;56(1):50–2. PubMed PMID: 12706152. Holbrook KA, Dale BA, Witt DR, Hayden MR, Toriello HV. Arrested epidermal morphogenesis in three newborn infants with a fatal genetic disorder (restrictive dermopathy). J Invest Dermatol. 1987;88(3):330–9. PubMed PMID: 2434579. Horn TD. Interface dermatitis. In: Barnhill R, Crowson AN, eds. Textbook of Dermatopathology. 2nd ed. New York, NY: McGraw-Hill Co; 2004:35–60. Jacobson-Dunlop E, White CR Jr, Mansoor A. Features of plexiform fibrohistiocytic tumor in skin punch biopsies: a retrospective study of 6 cases. Am J Dermatopathol. 2011;33(6):551–6. https://doi.org/10.1097/DAD. 0b013e318206a648. PubMed PMID: 21697703. Jafarian F, McCuaig C, Kokta V, Hatami A, Savard P.  Plexiform fibrohistiocytic tumor in three children. Pediatr Dermatol. 2006;23(1):7–12. Review. PubMed PMID: 16445402. Joshi RR, Nepal A, Ghimire A, Karki S. Eccrine poroma in neck of a child  – a rare presentation. Nepal Med Coll J. 2009;11(1):73–4. PubMed PMID: 19769246. Kazakov DV, Sima R, Vanecek T, Kutzner H, Palmedo G, Kacerovska D, Grossmann P, Michal M.  Mutations in exon 3 of the CTNNB1 gene (beta-­catenin gene) in cutaneous adnexal tumors. Am J Dermatopathol. 2009;31(3):248–55. https://doi.org/10.1097/ DAD.0b013e318198922a. PubMed PMID: 19384065. Kempf W, Kazakov DV, Belousova IE, Mitteldorf C, Kerl K.  Paediatric cutaneous lymphomas: a review and comparison with adult counterparts. J Eur Acad Dermatol Venereol. 2015;29(9):1696–709. https://doi. org/10.1111/jdv.13044. Epub 2015 Feb 25. Review. PubMed PMID: 25715748. Kim LIJ, Park MC, Kim JH, Lim H.  Cutaneous paraganglioma of the vertex in a child. J Craniofac Surg. 2012;23(4):e338–40. https://doi.org/10.1097/ SCS.0b013e3182564b3a. Review. PubMed PMID: 22801173.

References and Recommended Readings Koens L, Qin Y, Leung WY, Corver WE, Jansen PM, Willemze R, Vermeer MH, Tensen CP.  MicroRNA profiling of primary cutaneous large B-cell lymphomas. PLoS One. 2013;8(12):e82471. https://doi. org/10.1371/journal.pone.0082471. eCollection 2013. PubMed PMID: 24358187; PubMed Central PMCID: PMC3865085. Köksal Y, Toy H, Talim B, Unal E, Akçören Z, Cengiz M. Merkel cell carcinoma in a child. J Pediatr Hematol Oncol. 2009;31(5):359–61. https://doi.org/10.1097/ MPH.0b013e3181984f6b. PubMed PMID: 19415020. Kose D, Ciftci I, Harmankaya I, Ugras S, Caliskan U, Koksal Y.  Pilomatrixoma in childhood. J Cancer Res Ther. 2014;10(3):549–51. https://doi. org/10.4103/0973-1482.137918. PubMed PMID: 25313737. Kulkarni K, Desai S, Grundy P, Sergi C. Infantile myofibromatosis: report on a family with autosomal dominant inheritance and variable penetrance. J Pediatr Surg. 2012;47(12):2312–5. https://doi.org/10.1016/j. jpedsurg.2012.09.046. PubMed PMID: 23217896. Küster W, Traupe H. Klinik und Genetik angeborener Hautdefekte [Clinical aspects and genetics of congenital skin defects]. Hautarzt. 1988;39(9):553–63. Review. German. PubMed PMID: 3053531. Kwan TH. Spongiotic dermatitis. In: Barnhill R, Crowson AN, Busam K, Granter S ed’s. Textbook of Dermatopathology. New York: McGraw-Hill Co. 1998:17–32. Le Van Quyen P, Calmels N, Bonnière M, Chartier S, Razavi F, Chelly J, El Chehadeh S, Baer S, Boutaud L, Bacrot S, Obringer C, Favre R, Attié-Bitach T, Laugel V, Antal MC. Prenatal diagnosis of cerebrooculo-facio-skeletal syndrome: Report of three fetuses and review of the literature. Am J Med Genet A. 2020 Feb 13. https://doi.org/10.1002/ajmg.a.61520. [Epub ahead of print] PubMed PMID: 32052936. Leclerc-Mercier S, Pedeutour F, Fabas T, Glorion C, Brousse N, Fraitag S. Plexiform fibrohistiocytic tumor with molecular and cytogenetic analysis. Pediatr Dermatol. 2011;28(1):26–9. https://doi.org/10.1111/ j.1525-1470.2010.01370.x. Epub 2011 Jan 25. PubMed PMID: 21261704. Levi N, Bastuji-Garin S, Mockenhaupt M, Roujeau JC, Flahault A, Kelly JP, et al. Medications as risk factors of Stevens–Johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. Pediatrics. 2009;123(2):e297–304. Litt J.  Drug eruption reference manual. New  York: Parthenon; 2000. Loh J, El-Hakim H, Sergi CM, Fiorillo L. Branchiooculofacial syndrome and bilateral ectopic thymus: report of a family. Pediatr Dermatol. 2012;29(6):759–61. https://doi.org/10.1111/ j.15251470.2012.01877.x. PubMed PMID: 23106675. Lyell A.  Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol. 1956;68:355–61. Mandt N, Vogt A, Blume-Peytavi U.  Differential diagnosis of hair loss in children. J Dtsch Dermatol Ges. 2004;2(6):399–411. Review. PubMed PMID: 16281597.

1407 Martel-Jantin C, Pedergnana V, Nicol JT, Leblond V, Trégouët DA, Tortevoye P, Plancoulaine S, Coursaget P, Touzé A, Abel L, Gessain A. Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings. J Clin Virol. 2013;58(1):288–91. https://doi.org/10.1016/j.jcv.2013.06.004. Epub 2013 Jul 2. PubMed PMID: 23829968. Massi D (Ed.). Dermatopathology. Springer. 2016. Mataix J, Bañuls J, Botella R, Laredo C, Lucas A. Sindrome de Brooke-Spiegler: una entidad heterogenea [Brooke-Spiegler syndrome: an heterogeneous entity]. Actas Dermosifiliogr. 2006;97(10):669-72. Review. Spanish. PubMed PMID: 17173833. Maximova N, Granzotto M, Kiren V, Zanon D, Comar M.  First description of Merkel cell polyomavirus DNA detection in a patient with Stevens-Johnson syndrome. J Med Virol. 2013;85(5):918–23. https://doi. org/10.1002/jmv.23550. PubMed PMID: 23508917. Mebazaa A, Boussofara L, Trabelsi A, Denguezli M, Sriha B, Belajouza C, Nouira R.  Undifferentiated sebaceous carcinoma: an unusual childhood cancer. Pediatr Dermatol. 2007;24(5):501–4. PubMed PMID: 17958796. Mori O, Hashimoto T.  Plexiform fibrohistiocytic tumor. Eur J Dermatol. 2004;14(2):118–20. PubMed PMID: 15197003. Nair PS.  A clinicopathologic study of skin appendageal tumors. Indian J Dermatol Venereol Leprol. 2008;74(5):550. PubMed PMID: 19086136. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, Janecek E, Domecq C, Greenblatt DJ. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30(2):239–45. PubMed PMID: 7249508. Saadat P, Cesnorek S, Ram R, Kelly L, Vadmal M.  Primary cutaneous paraganglioma of the scalp. J Am Acad Dermatol. 2006;54(5 Suppl):S220–3. PubMed PMID: 16631945. Orlandi C, Arcangeli F, Patrizi A, Neri I. Eccrine poroma in a child. Pediatr Dermatol. 2005;22(3):279–80. PubMed PMID: 15916587. Ozbay M, Kiniş V, Firat U, Bakir S, Yorgancilar E. Seborrheic keratosis of the external auditory canal in a 1-year-old boy. Turk J Pediatr. 2012;54(5):543–4. PubMed PMID: 23427523. Pandey P, Dixit A, Chandra S, Tanwar A.  Cytological features of malignant eccrine acrospiroma presenting as a soft tissue mass axilla: a rare sweat gland tumor with histologic correlation. Int J Appl Basic Med Res. 2015;5(2):145–8. https://doi.org/10.4103/2229-­ 516X.157173. PubMed PMID: 26097826; PubMed Central PMCID: PMC4456892. Pointdujour-Lim R, Marous MR, Satija CE, Douglass AM, Eagle RC Jr, Shields JA, Shields CL. Cutaneous Horn of the Eyelid in 13 Cases. Ophthalmic Plast Reconstr Surg. 2017;33(4):233–236. https://doi.org/10.1097/ IOP.0000000000000816. PubMed PMID: 27811637. PubMed PMID: 21697703. Salamanca J, Rodríguez-Peralto JL, de la Torre JP G, López-Ríos F. Plexiform fibrohistiocytic tumor without multinucleated giant cells: a case report. Am J Dermatopathol. 2002;24(5):399–401. PubMed PMID: 12357200.

1408 Sánchez Yus E, Sanz Vico MD, de Diego V. Miescher’s radial granuloma. A characteristic marker of erythema nodosum. Am J Dermatopathol. 1989;11(5):434–42. PubMed PMID: 2679196. Schmid C, Beham A, Feichtinger J, Auböck L, Dietze O. Recurrent and subsequently metastasizing Merkel cell carcinoma in a 7-year-old girl. Histopathology. 1992;20(5):437–9. PubMed PMID: 1587495. Segal AR, Doherty KM, Leggott J, Zlotoff B. Cutaneous reactions to drugs in children. Pediatrics. 2007;120(4):e1082–96. Review. PubMed PMID: 17908729. Sergi C, Beedgen B, Kopitz J, Zilow E, Zoubaa S, Otto HF, Cantz M, Linderkamp O.  Refractory congenital ascites as a manifestation of neonatal sialidosis: clinical, biochemical and morphological studies in a newborn Syrian male infant. Am J Perinatol. 1999;16(3):133–41. PubMed PMID: 10438195. Sergi C, Kahl P, Otto HF. Immunohistochemical localization of transforming growth factor-alpha and epithelial growth factor receptor in human fetal developing skin, psoriasis and restrictive dermopathy. Pathol Oncol Res. 2000;6(4):250–5. PubMed PMID: 11173656. Sergi C, Penzel R, Uhl J, Zoubaa S, Dietrich H, Decker N, Rieger P, Kopitz J, Otto HF, Kiessling M, Cantz M. Prenatal diagnosis and fetal pathology in a Turkish family harboring a novel nonsense mutation in the lysosomal alpha-N-acetyl-neuraminidase (sialidase) gene. Hum Genet. 2001;109(4):421–8. PubMed PMID: 11702224. Sergi C, Poeschl J, Graf M, Linderkamp O.  Restrictive dermopathy: case report, subject review with Kaplan-­ Meier analysis, and differential diagnosis of the lethal congenital contractural syndromes. Am J Perinatol. 2001;18(1):39–47. PubMed PMID: 11321244. Sharma VK, Dhar S.  Clinical pattern of cutaneous drug eruption among children and adolescents in North India. Pediatr Dermatol. 1995;12(2):178–83. PubMed PMID: 7659648. Shin HT, Chang MW.  Drug eruptions in children. Curr Probl Pediatr. 2001;31(7):207–34. Review. PubMed PMID: 11500668. Sia PI, Figueira E, Allende A, Selva D.  Malignant hair follicle tumors of the periorbital region: a review of literature and suggestion of a management guideline. Orbit. 2016;35(3):144–56. https://doi.org/10.1080/01 676830.2016.1176048. Epub 2016 May 12. Review. PubMed PMID: 27171562. Sillevis Smitt JH, van Asperen CJ, Niessen CM, Beemer FA, van Essen AJ, Hulsmans RF, Oranje AP, Steijlen PM, Wesby-van Swaay E, Tamminga P, BreslauSiderius EJ. Restrictive dermopathy. Report of 12 cases. Dutch Task Force on Genodermatology. Arch Dermatol. 1998;134(5):577–9. Review. PubMed PMID: 9606327. Singh DD, Naujoks C, Depprich R, Schulte KW, Jankowiak F, Kübler NR, Handschel J. Cylindroma of head and neck: review of the literature and report of two rare cases. J Craniomaxillofac Surg. 2013;41(6):516–

17 Skin 21. https://doi.org/10.1016/j.jcms.2012.11.016. Epub 2012 Dec 21. PubMed PMID: 23260808. Sourvinos G, Mammas IN, Spandidos DA.  Merkel cell polyomavirus infection in childhood: current advances and perspectives. Arch Virol. 2015;160(4):887–92. https://doi.org/10.1007/s00705-015-2343-0. Epub 2015 Feb 10. Review. PubMed PMID: 25666196. Stevens AM, Johnson FC. A new eruptive fever associated with stomatitis and ophtalmia: report of two cases in children. Am J Dis Child. 1922;24:526–33. Suzumura H, Arisaka O. Cerebro-oculo-facio-skeletal syndrome. Adv Exp Med Biol. 2010;685:210-4. Review. PubMed PMID: 20687508. Sybert VP.  Aplasia cutis congenita: a report of 12 new families and review of the literature. Pediatr Dermatol. 1985;3(1):1–14. Review. PubMed PMID: 3906608. Tebcherani AJ, de Andrade HF Jr, Sotto MN. Diagnostic utility of immunohistochemistry in distinguishing trichoepithelioma and basal cell carcinoma: evaluation using tissue microarray samples. Mod Pathol. 2012;25(10):1345–53. https://doi.org/10.1038/modpathol.2012.96. Epub 2012 Jun 8. PubMed PMID: 22684216. Terrier-Lacombe MJ, Guillou L, Maire G, Terrier P, Vince DR, de Saint Aubain Somerhausen N, Collin F, Pedeutour F, Coindre JM. Dermatofibrosarcoma protuberans, giant cell fibroblastoma, and hybrid lesions in children: clinicopathologic comparative analysis of 28 cases with molecular data  – a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol. 2003;27(1):27–39. PubMed PMID: 12502925. Ujiie H, Kato N, Natsuga K, Tomita Y. Keratoacanthoma developing on nevus sebaceous in a child. J Am Acad Dermatol. 2007;56(2 Suppl):S57–8. PubMed PMID: 17224391. Vanchinathan V, Marinelli EC, Kartha RV, Uzieblo A, Ranchod M, Sundram UN.  A malignant cutaneous neuroendocrine tumor with features of Merkel cell carcinoma and differentiating neuroblastoma. Am J Dermatopathol. 2009;31(2):193–6. https:// doi.org/10.1097/DAD.0b013e31819114c4. PubMed PMID: 19318809. Wartchow EP, Goin L, Schreiber J, Mierau GW, Terella A, Allen GC. Plexiform fibrohistiocytic tumor: ultrastructural studies may aid in discrimination from cellular neurothekeoma. Ultrastruct Pathol. 2009;33(6):286– 92. https://doi.org/10.3109/01913120903348860. PubMed PMID: 19929176. Witt DR, Hayden MR, Holbrook KA, Dale BA, Baldwin VJ, Taylor GP. Restrictive dermopathy: a newly recognized autosomal recessive skin dysplasia. Am J Med Genet. 1986;24(4):631–48. PubMed PMID: 2426945. Zheng JF, Mo HY, Wang ZZ.  Clinicopathological characteristics of xeroderma pigmentosum associated with keratoacanthoma: a case report and literature review. Int J Clin Exp Med. 2014;7(10):3410–4. eCollection 2014. PubMed PMID: 25419376; PubMed Central PMCID: PMC4238483.

Placenta, Abnormal Conception, and Prematurity

18

Contents 18.1

Development and Useful Pilot Concepts and Tables

 1410

18.2 18.2.1 18.2.2 18.2.3 18.2.4 18.2.5

 athology of the Early Pregnancy P Disorders of the Placenta Formation Disorders of the Placenta Maturation Disorders of the Placenta Vascularization Disorders of the Placenta Implantation Site Twin and Multiple Pregnancies

 1422  1423  1431  1434  1434  1442

18.3 18.3.1 18.3.2 18.3.3 18.3.4

 athology of the Late Pregnancy P Acute Diseases Subacute Diseases Chronic Diseases Fetal Growth Restriction

 1449  1450  1457  1468  1482

18.4  on-neoplastic Trophoblastic Abnormalities N 18.4.1 P  lacental Site Nodule 18.4.2 Exaggerated Placental Site

 1485  1485  1485

18.5 18.5.1 18.5.2 18.5.3 18.5.4

 estational Trophoblastic Diseases, Pre- and Malignant G Invasive Mole Placental Site Trophoblastic Tumor Epithelioid Trophoblastic Tumor Choriocarcinoma

 1486  1486  1486  1486  1486

18.6 18.6.1 18.6.2 18.6.3 18.6.4

Birth Defects Birth Defects: Taxonomy Principles Birth Defects: Categories Birth Defects: Pathogenesis (Macro- and Micromechanisms) Birth Defects: Etiology (Mendelian, Chromosomal, Multifactorial)

 1488  1490  1493  1496  1515

18.7 18.7.1 18.7.2 18.7.3

I nfection in Pregnancy, Prom, and Dysmaturity Infection in Pregnancy Premature Rupture of Membranes (PROM) Fetal Growth Restriction (FGR) and Dysmaturity

 1533  1533  1541  1541

© Springer-Verlag GmbH Germany, part of Springer Nature 2020 C. M. Sergi, Pathology of Childhood and Adolescence, https://doi.org/10.1007/978-3-662-59169-7_18

1409

18  Placenta, Abnormal Conception, and Prematurity

1410

18.8 I UFD and Placenta 18.8.1 F  etal Death Syndrome (Intrauterine Fetal Demise, IUFD) 18.8.2 Step-by-Step Approach in the Examination of a Placenta

 1546  1546  1548

Multiple Choice Questions and Answers

 1552

References and Recommended Readings

 1554

18.1 Development and Useful Pilot Concepts and Tables

cologists in treating maternal conditions in the post-delivery period and perinatologists for the cure or treatment of the sick infant. In case of the A variety of non-neoplastic lesions can present unfortunate event of fetal or neonatal death, clinically and radiologically as uneventful or life-­ pathologic examination of the placenta is an threatening conditions and may result in a hyster- essential component of the postmortem investiectomy. In such situations, the pediatric gation, often giving useful insights for the diagpathologist, general pathologist and/or gyneco- nosis of the sick baby. In the past two decades, all logic pathologist has an important role to play in three problems have been targeted by perinatal determining the nature of these lesions. Awareness pathologists. Currently, there is more familiarity of the development of the embryo at an early of the general pathologist with placental lesions, stage and entities that can mimic malignancies more understanding of the placental diagnoses by will assist the pathologist in the diagnosis of the obstetricians and gynecologists, and there is a most common lesions with confidence. The pla- better terminology and fined criteria for most of centa was probably one of the very few underuti- the placental lesions. Moreover, the placenta may lized or poorly evaluated assessment of become a “gold” organ sometimes in the right pathological routine. The roots of the problems hands; it was once said. In fact, some people were lying in (1) poor adaptability and familiarity would suggest that we might make this field quite of the clinical or surgical pathologist with placen- lucrative, although it may be argued that it would tal lesions, (2) variable acceptance of the placen- be considered unethical. Dr. Drucilla Roberts’ tal diagnoses in clinics, and (3) relative categories of situations where a pathologic examnonuniform terminology and standard diagnostic ination of the placenta may be clinically, geneticriteria used in different centers. Although this cally, or forensically relevant include (1) legal was the rule in the 1980s and 1990s, the situation issues regarding the presence and relevance of changed in the twentieth century, when the acute vs. chronic perinatal stress, (2) legal quespathologist correlated the gross and histopatho- tions regarding the significance of potential acute logic data with the functionality of the placenta vs. chronic perinatal insults, (3) diagnosis of during pregnancy and the cardiotocography and fetal/neonatal/maternal diseases in the setting of the evolution of the birth with the neurological abnormal pregnancies, (4) determination of status of the newborn. Reasons for undervalua- zygosity in multiple pregnancies, (5) OB/GYN tion of the placenta have been ascribed to some advise for the management of subsequent preghistorical ”incompetence” or low confidence of nancies, and (6) genetic counseling of the family some pathologists in dealing with placenta speci- and risk assessment for newborn and mother. In Fig.  18.1 are pictured some usual early mens but also to the extreme variable heterogeneity of samples that may lead to different data and appearances of the placenta. The pregnancy outinconclusive or too speculative directions. There come for the conceptus is as follows: about 15% has been a huge advancement in the last couple of of the oocytes undergo no fertilization, about decades, which has delineated important factors 15% of the fertilized oocytes undergo no implanthat may be clinically relevant for both mother tation, about 15% of the implanted blastocysts do and fetus. Today, a detailed examination of the not survive the end of the 2nd week, about 15% placenta provides, in most cases, a wealth of of the survived embryos harbor fatal malformainformation. This information may help gyne- tions, and about 40% of the survived embryos are

18.1  Development and Useful Pilot Concepts and Tables

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a

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e

f

Fig. 18.1  Development of the placenta at early gestation. (a) From the chorion plate or primitive allantois, there is a centrifugal growth and proliferation of intermediate trophoblast (dark cells located in the lower right corner). (b) A close-up of the early placenta proliferations illustrates the polarized growth of the intermediate trophoblast. (c) In other sections of the placenta, the intermediate trophoblast may create an calyx shape on the top of the polarized villus (the renal calyx is a peculiar chamber in the kidney parenchyma that surrounds the apex of the renal pyramids). (d) A characteristic feature of the early gestation is the presence of nucleated red blood cells (NRBC)

or progenitors of the erythrocytes that populate the cross sections of the blood vessels in the 2nd trimester. (e) This microphotograph sh ows the early embryo with the formation of the primitive neural tube. (f) This microphotograph shows the neural tube in a more advanced stage, although it has been transected during the preparation of the slide. All photographs are from H&E stained histological slides (a, original magnification x100; b, original magnification x200; c, original magnification x100; d, original magnification x200; e, original magnification x100; f, original magnification x100)

alive up to the second/third trimester or birth healthy or show some congenital defects. “We ought not to set them aside with idle thoughts or idle words about ‘curiosities’ or ‘chances’. Not one of them is without meaning; not one that might not become the beginning of excellent knowledge, if only we could answer

the question – why is it rare, or being rare,why did it in this instance happen?” This sentence was written by James Paget at the end of the nineteenth century emphasizing how important is to identify the anomalous pathways behind the congenital or perinatal anomaly detected in life (Fig. 18.2). The main milestones of the embryo

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18  Placenta, Abnormal Conception, and Prematurity

b

c

Fig. 18.2  Ontogenesis and early defects. In (a) is shown a graphic with the time on the X-axis and the degree of differentiation on the Y-axis. The graphic illustrates the severity of the birth defects in the early gestation with conjoined twins, heteropagus, epignathus, sacrococcygeal teratoma (red columns), and less severe disorders (yellow

columns) later in the pregnancy. The figure (b) illustrates the same concept specifying the sensitive periods for the single systems of the body. In (c) is illustrated the formation of the morula and the respective major malformations that can originate in the early pregnancy

18.1  Development and Useful Pilot Concepts and Tables

Box 18.1 Main Milestones of the Embryo Development (First Embryonic Development)

• 1st week of the tubal migration –– Stage 1: Fertilization –– Stage 2 (2nd–3rd day): Furrowing (2 up to 25 cells) and differentiation –– Stage 3 (4th–5th day): Free blastocyst • 2nd week: embryo implantation and twolayered germinal disc –– Stage 4 (5th–6th day): Attachment and implantation collapse –– Stage 5 (7th–12th day): Two-layered germinal disc, amniotic cavity, and primary yolk sac • 3rd week: three-layered germinal disc –– Stage 6 (13th–15th day): Extraembryonal mesoderm, chorionic cavity, villi, primitive streaks

Box 18.2 Placenta Development: Villous Tree Branching Villous branching Connective tissue  2-years Villus

Gradual ↓ ∅ (day 15 p.c. → term)

(++/+++ mesenchymal substance)  3-years Villus (+ mesenchymal substance)  Hofbauer cells (↓ # as gestation proceeds) Vasculature (weeks – gestational age):  0–6 weeks: No capillary lumina  6–8 weeks: Lumina + 100% nucleated hematologic precursors  10–12 weeks: 10% nucleated hematologic precursors  >12 weeks: Lack of nucleated hematologic precursors

Notes: ∅ diameter, # number development in the first 4 weeks are summarized in Box 18.1. The embryogenesis entails 8 weeks after the fertilization. In comparison to the embryo of the 8 weeks, the fetus during the rest of the 38-week gestation has more identifiable

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–– Stage 7 (15th–17th day): Chorda extension, stalk, allantois pouch, hemo- and angiogenesis –– Stage 8 (17th–19th day): Primitive pit, chorda channel, axial channel –– Stage 9 (19th–21st day): Neural folds, heart anlage, yolk sac folding • 4th week: embryo folding –– Stage 10: Fusion of the neural folds, two pharyngeal arches, and eye furrows –– Stage 11: Closure of the neuroporus anterior and optical vesicles –– Stage 12: Closure of the neuroporus posterior, three pharyngeal arches, and arm buds –– Stage 13: Leg buds, lens placode, otic vesicles

Box 18.3 Placental Barrier (From External-­ Intervillous Space to Internal-Villus)

1. The outer layer of syncytiotrophoblast (STB) (continuous) 2. The inner layer of cytotrophoblast (CTB) (dis/-continuous) 3. Trophoblastic basal lamina 4. Connective tissue 5. Fetal endothelium

external features and a quite more complete set of developing organs. In Box 18.2 the placental development concerning the villous tree branching, which is a fundamental unit of the placenta, is summarized. The placenta barrier concerning the exchange of oxygen between maternal and fetal blood is presented in Box 18.3. This concept is particularly important for the understanding of the function of the placenta and to direct new research topics in this very precious and fragile barrier. The trophoblast changes during gestation. By the start of the 2nd month, the trophoblast is categorized by an increased number of second- and third-order villi that give rise to his unique radial

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appearance. With the progression of the placenta maturation, several settings are characterized. These include the chorionic plate, the outer cytotrophoblast shell, the lacunar or intervillous spaces, and the syncytial knots. Regarding stages of development, in the placenta, there is both a prelacunar and a lacunar stage. The prelacunar stage entails the apposition (days 7–8 postconception), syncytiotrophoblast (cellular fusion), and cytotrophoblast (stem cell-like) formation. The lacunar stage involves the formation of the lacunae (days 8–13 postconception), primary chorionic plate, lacunar system, trophoblastic shell, and cytotrophoblast and syncytiotrophoblast (day 12 postconception). The chorion frondosum and decidua basalis are also a critical component of the placenta and need to be adequately investigated. By the 4th month, the placenta has two components: fetal portion and maternal portion, i.e., chorionic and decidual plates, junctional zone, and decidual septa and cotyledons.

Moreover, the most critical aspect of the placenta and its pathologies is to understand the fetoplacental circulation.

Mature Placenta At term, the placenta is a discoid organ with a mean diameter of about 15–25 cm, is about 3 cm thick, and weighs about 500–600 g (Box 18.4). The margin of coincidence between fetal and maternal surfaces is essential for the assessment of the presence or not there is a circumvallate or circummarginate placentation (vide infra).

Amniotic cells produce the clear, watery fluid, which fills the amniotic cavity. The amniotic fluid is derived primarily from maternal blood. The functions of the placenta are essentially an exchange of metabolic and gaseous products between maternal and fetal blood streams, exchange of gases, exchange of nutrients and electrolytes, transmission of maternal antibodies, and production of hormones. In the placenta, the normal trophoblast is made up of cytotrophoblast (CTB), syncytiotrophoblast (STB), and intermediate trophoblast (IT). STB invades the endometrium allowing the implantation of the blastocyst and produces hCG, while CTB acts as a supplier to the STB with cells progressively becoming the chorionic villi covering the chorionic sac. Thus, the functional placenta is formed by the villous chorion adjacent to the endometrium and one basal layer of the endometrium together. The IT is localized in the villi, implantation site, and, apparently, in the chorionic sac.

Box 18.4 Placenta: Gross Main Features

• Discoid shape (15–25 cm in Ø, 3 cm in θ, ~500 g of weight) • Two surfaces (fetal surface or chorionic plate, smooth, and maternal surface, rough) • One insertion of the umbilical cord to the fetal surface • Two arteries and one vein inside of the umbilical cord • One margin with the coincidence of the diameters between fetal and maternal surfaces • Placental membranes: amnion, chorion, and decidua

Fetoplacental Circulation 1. Two circulatory systems, including (A) maternal blood that runs from the spiral arteries of decidua around villous bodies, intervillous space (through the syncytial-capillary membranes), and back via sinuses and (B) fetal blood that runs from the umbilical cord (vein), blood vessels of the chorionic plate on surface (in front of the fetus and antipodal to the maternal side), down stem villi, and then secondary and tertiary villi and reverse to the umbilical cord (arteries). 2. The intervillous space of the placenta at term (mature placenta) contains ~150 ml of blood, which is satisfactorily replenished ~3–4 times per minute.

Placenta Weight Placental weight is a critical parameter to evaluate the functionality of the placenta during pregnancy. It was considered to having such an importance in the ancient time, and we are still

18.1  Development and Useful Pilot Concepts and Tables

Box 18.5 Placental Weight Normality and Abnormalities 16 weeks of 60 g fetus: ~60 g (×1) gestation – placenta: 25 weeks of 200 g fetus: ~600 g (×3) gestation – placenta: 40 weeks of 500 g fetus: gestation – placenta: ~3500 g(×7) If PW at term >650 g ⇒ placenta >90th centile If PW at term   A), which is more often seen at the fetal end of the UC. • PGN: Prematurity, neurodisability with cerebral palsy, and early-onset sepsis about

18  Placenta, Abnormal Conception, and Prematurity

the fetal inflammatory response and with the cascade of cytokines in the fetal circulation. • Prognostic salient features include amnion necrosis, subchorionic microabscesses, concentric umbilical perivasculitis (aka sub-­necrotizing funisitis), umbilical arteritis or perivasculitis, severe chorionic vasculitis, and chorionic vasculitis with recent nonocclusive mural thrombosis. The relative risk (RR) is high (following VLBW delivery) because predisposing factors are likely to remain (VLBW, very low birth weight).

a

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Fig. 18.21  Amnion fluid infection. In (a) is the current classification of chorioamnionitis, funisitis, and villitis with degrees from 0 to 3, while (b) shows a gray-yellowish change of the color of the membranes with opacification and thickening, a gross feature of chorioamnionitis. In (c) and (d) are microphotographs of a chorioamnionitis with severe inflammation constituted by a marked infiltra-

tion of neutrophils. Figures (e) and (f) show the histopathology of a funisitis with infiltration of the wall of the blood vessels as well as Wharton’s jelly by neutrophils. Figures (g) and (h) show a necrotic chorioamnionitis. All photographs are taken from histologic slides stained by hematoxylin and eosin (c–h, original magnification x200, x400, x100, x200, x20, and x40)

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f

g

h

Fig. 18.21 (continued)

Acute chorioamnionitis is suspected in a pregnant woman with a fever (e.g., in case of the premature rupture of membranes or PROM). In studies involving chorioamnionitis, acute inflammation is defined by evidence of amniotic fluid infection/acute inflammatory pathology. Maternal acute inflammation is identified by neutrophilic infiltration of chorion (stage 1), amnion (stage 2), and necrotizing chorioamnionitis (stage 3). Neutrophils’ diapedesis recognizes fetal involvement through the wal (subchorionic abscesses)l ls or umbilical vein (stage 1), umbilical artery (stage 2), and necrotizing funisitis (stage 3) defined by neutrophils’ karyorrhexis in a band-like configuration within Wharton’s jelly. Chronic inflammation is defined as the presence of significant persistent (lymphocytic or histiocytic) infiltrates in the membranes (chorion and/or amnion), chorionic

villi, intervillous space, or basal plate. Chronic villitis was defined as lymphocytes or histiocytes infiltrating the chorionic villi and is graded as low (few, small foci) or high (multiple, large foci). Chronic intervillositis is identified when a lymphohistiocytic infiltrate is present in the intervillous space without an identifiable villous infiltrate. Basal chronic intervillositis is considered a diagnostic term for chronic deciduitis when plasma cells are identified within the chronic inflammatory infiltrate. The usua staging and grading of chorioamnionitis and the fetal inflammatory response syndrome (FIRS) are very crucial aspects. If the inflammatory process involves the umbilical cord (umbilical vein, umbilical artery, and Wharton’s jelly), the term acute funisitis is used and is the histologic counterpart of the FIRS).

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Staging and Grading of Chorioamnionitis (CAI) are in blue and Fetal Inflammatory Response Syndrome (FIRS) are in red. Stage = Duration ±Fetal Maturity on 1) Subchorionitis/Chorionitis, 2) Acute chorioamnionitis as a combination of chorion and amnion involvement 3) Necrotizing Chorioamnionitis Grade = intensity: mild degree (subchorionic PMN) and severe degree (subchorionic abscesses) FIRS stages: 1) Cord phlebitis (stage 1/3)/ arteritis (stage 2/3)/ perivasculitis (concentric) (stage 3/3), AND 2) Necrotizing funisitis or concentric umbilical perivasculitis (>25% amniocytes) Grade = Intensity:mild degree (subchorionic PMN) & severe degree (subchorionic abscesses) Note: PMN, polymorphonucleates; UC, umbilical cord.

The histopathology is key for the diagnosis and differential diagnosis (Fig.  18.22). Special stains and culture are used in the routine for placental pathology and include Gram stain mostly for L. monocytogenes and Group B Strep (streptococcus) (GBS); silver stains (Dieterle, WarthinStarry, Steiner) for anaerobic bacteria, C. fetus, T. pallidum, and other bacteria; and PAS and GMS for Candida spp. and other fungi. The differential diagnosis includes laminar (ischemic) necrosis and T-cell-driven eosinophilic vasculitis. The former is characterized by necrotic tissue localized in the decidua capsularis, which is often escorted by varying numbers of neutrophils with a variable degree of cellular degradation. Laminar necrosis has been interpreted as maternal small-vessel disease or meconium toxicity-related. The latter is substantially an infiltration of chorionic and major fetal stem villous blood vessels by T lymphocytes (CD3-positive by immunohistochemistry) and eosinophils (Luna special stain by histochemistry). The T-cell-driven eosinophilic vasculitis is not polarized toward the cavity of the amnion differently from the fetal inflammatory response seen in acute chorioamnionitis. Listeria monocytogenes is a Gram-­positive bacillus found in soil, sewage, and animal silage which is a type of fodder made from green foliage crops. The crops are preserved by acidification, which is achieved through fermentation.. Periodically, there are outbreaks of listeriosis, and the food industry is particularly aware of this infection of meat and meat-related products as well as dairy

products. In fact, L. monocytogenes is well known and contaminated food source for deli foods, which are particularly contraindicated in pregnancy. Lunch meats, cold cuts, or other deli meats, may contain this bacterium and should not be eaten by pregnant women unless they are heated to an internal temperature of 165°F or 74°C before serving.Listeriosis tends to occur in clusters, and notifications by public health agencies (e.g., FDA and the Canadian Food Inspection Agency or Health Canada) are routinely issued yearly. An intervillositis is commonly seen in cases of listeriosis of the placenta. However, the same histology may be encountered with infections by Campylobacter fetus, Chlamydia psittaci, Francisella tularensis, Klebsiella pneumoniae, and Coccidioides immitis. Occasionally, other bacteria can be behind this histologic pattern. M. tuberculosis has been indeed detected in the absence of any granulomatous reaction. The listeriosis histopathology slides show a variable mixture of acute intervillositis with intervillous abscesses and chorioamnionitis. The histopathology may also include the so-called septic infarcts that may be grossly appreciable as irregular, firm, yellow opacities on the placenta cut surface. However, more often, there are gross cut surface opacities and green discoloration of the membranes as well as acute deciduitis of the basal plate showing a pallor change of the basal plate. In the intervillous space other than the neutrophilic exudate in the form of small clusters or diffusely there may be villous

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Fig. 18.22  Villitis and perivillitis. Figures (a) through (h) show villitis and perivillitis of inflammatory character with neutrophils infiltrating the syncytiotrophoblast and the perivillous space. In (c) and (d), the etiology of the inflammation is an infection with Listeria monocytogenes

(a–h, H&E stain; a, original magnification x100; b, original magnification x100; c, original magnification x100; d, original magnification x200; e, original magnification x200; f, original magnification x200; g, original magnification x100; h, original magnification x100)

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necrosis and perivillous fibrin deposition. Importantly, neutrophils are not accompanied by other chronic inflammatory cells, including lymphocytes, eosinophils, plasma cells, and giant cells. Acute villitis, i.e., neutrophils inside the villi, may infrequently be seen in conjunction with acute intervillositis. The finding of the acute villitis in the setting of a listeriosis infection is interpreted as secondary spread to villi by a primary acute intervillositis process. Similar to the acute villitis, another infrequent finding is the vasculitis of the stem villi. Gram staining of the placenta at the time of delivery may disclose the nature of the bacteria. L. monocytogenes has been named after Joseph Lister and is a facultative anaerobic bacterium, which can rapidly grow and reproduce inside the host’s cells. Currently, L. monocytogenes is considered one of the most virulent foodborne pathogens. It has been assessed that up to 30% of foodborne listeriosis infections in high-risk individuals may result in the death of the host. Listeriosis grades third in a total number of deaths among foodborne bacterial pathogens. Its fatality rates exceeding even Salmonella and Clostridium botulinum infections in both the USA/Canada and European Union. One of the most frightening landscapes of this bacterium is its ability to grow at 0 °C (32 °F). Thus, the standard refrigerator with a temperature of 4–10  °C (39.2–50  °F) is optimal for its growth and multiplication inside of the food. Soft cheeses (e.g., Brie, Camembert, feta, and queso blanco fresco) are frequently contaminated with this bacterium. As indicated above, listeriosis outbreaks can also occur by consuming deli meats, frankfurters, tacos, and a variety of other foods with meat. Moreover, celery, sprouts, and cantaloupe are also often contaminated. L. monocytogenes can move within eukaryotic cells by polymerization of the actin filaments. L. monocytogenes is the third most common cause of ­meningitis in newborns after group B streptococci (GBS; Streptococcus agalactiae) and E. coli. L. monocytogenes can infect the brain, the spinal cord membranes, and/or the bloodstream of the host through the ingestion of contaminated food (e.g., unpasteurized dairy or raw foods) found to the table or in the crib. Fusobacterium nucleatum is an anaerobic bacterial organism,

18  Placenta, Abnormal Conception, and Prematurity

which is now recognized as a relatively common cause of acute chorioamnionitis and preterm labor. F. nucleatum chorioamnionitis may originate from fecal flora contamination but also from oral cavity-­contaminated food. Secondary hematogenous dissemination following maternal periodontal disease should also be considered. Fusobacterium histopathology includes acute chorioamnionitis, with or without funisitis, and copious filamentous organisms, which coat the surface of the amnion. Other than H&E with numerous filamentous bacterial organisms coating the surface of the partially denuded amnion, Giemsa stain and Warthin-Starry silver stain can be used to detect the microorganism. In the differential diagnosis, L. monocytogenes and E. coli should be considered, but acute villitis and perivillositis are useful features because they are not typical features of F. nucleatum infection but more pointing to listeriosis or E. coli infection. Candida infection results in acute chorioamnionitis with peripheral microabscesses on the umbilical cord. In the differential diagnosis, Corynebacterium kutscheri, H. influenzae, and L. monocytogenes should be considered. In case of ACI, it is important to assess the extent of cord involvement, i.e., if it is segmental, regional, or total and which blood vessels involve (funicular phlebitis, funicular arteritis, or funisitis). The term funisitis should be left to the umbilical cord involvement of blood vessels (≥1) and Wharton’s jelly stroma. Thus, it is recommended to take three blocks with cross sections of the umbilical cords (three centimeters from the cord insertion to the placental disc, three centimeters from the distal end, and three blocks with cross sections of the central region of the umbilical cord).

18.3.2.2 Meconium-Stained Amniotic Fluid-Related Disorders (MAFD) Meconium aspiration syndrome (MAS) is a chemical pneumonitis which occurs in 1:20–1:10 live births with evidence of meconium staining. Babies show respiratory distress syndrome (RDS) requiring oxygen supply and display an abnormal chest X-ray. Babies are at risk of multiple thrombi, extrapulmonary air leaks, pulmonary hypertensionassociated PFC, and neonatal encephalopathy. Subacute hypoxia changes can occur in MAFD and include presence or increase of eryth-

18.3  Pathology of the Late Pregnancy

• DEF: Transient fetal hypoxia-related greenish staining of the amniotic fluid (AF) with universal variable CTG deceleration (Fig. 18.23). • SYN: “Green water” syndrome. • CLI: Postdates (>42  weeks), macrosomia (LGA), oligohydramnios. • EPG: Umbilical cord occlusion, vagal stimulation, and reflex peristalsis. • CLM: According to the contact time of meconium with the amniotic epithelium, several degrees may be identified, including: 1. Early stage (1  h) and decidua (>3 h). 2. Intermediate/late stage (>6–12  h): Green-­ staining of the umbilical cord, chorionic plate meconium, chorionic plate meconium with necrosis of fetal BVs, and apoptotic vascular smooth muscle cells (cytoplasmic eosinophilia, nuclear pyknosis, cellular dehiscence) due to the caustic effects of bile acids and phospholipases of the AF on myocytes. • PGN: Neurodisability, IUFD, neonatal death, meconium aspiration syndrome (MAS), or persistent fetal circulation (PFC). RFs: LGA, hypercoiled, entangled, or tethered cord, peripheral cord insertion, and ↓ AF.

rocytic progenitors or nucleated red blood cells (NRBC) defined by >10 NRBC/10 HPF (40×) and are indicative of significant hypoxia at intrauterine onset, which leads to the release of ­erythropoietin and chorangiosis or hyper -capillarization of the villous tree. The chorangiosis, which is a nonspecific finding, is defined by Altshuler’s rule of >10 capillaries/villus in >10 villi in >10 fields of the placenta at 10×. Prussian blue special stain (Perl’s stain) may be useful to

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separate the deposition of hemosiderin granules from meconium pigment.

18.3.2.3 Fetomaternal Hemorrhage (FMH) ± Intervillous Thrombus(i)

• DEF: Fetal bleeding/villous rupture (± villous immaturity) into maternal circulation (↓fetal blood supply) associated with intervillous thrombus development, ↑ intravillous NRBC, ± fetal hypovolemia. • EPI: 1–3:1000 deliveries (RFs: genetic factors/MCA, maternal trauma, OB/ GYN procedures). • EPG: Idiopathic (>4/5) or linked to placental abruption, chorangioma, choriocarcinoma, preeclampsia, maternal trauma, and OB/GYN procedures (e.g., external cephalic version or amniocentesis). • CLI: ↓ fetal movement (US/CTG), sinusoidal fetal heart rate, NIHF, (+) Kleihauer-Betke test (HbF resists the cell elution in an acid medium) (+) HbF detection by flow cytometry. • GRO/CLM: Damage of the trophoblastic coat of the placental villi with the escape of fetal blood into the maternal intervillous space with resulting FMH.  At some point, a breach of the placental villi coat may either heal with perivillous fibrin deposition or result in massive acute blood loss and fetal death. Perivillous thrombosis may be a protective mechanism to limit the extent of FMH. An ↑ of NRBC occurs in case of profound/sustained hypoxia and is a bone marrow response. It needs >6–12 h to develop (Fig. 18.18). • PGN: In case of small FMH (0.5– 40  ml), there is minimal sequela, but large GMH (>40 ml) are associated with neurodisability and IUFD.  There is no apparent recurrence risk.

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Fig. 18.23  Membranes changes.The figures (a) through (h) show the changes observed in presence of meconium exposure with cylindrical appearance of the amniocytes, papillary foldings, and bulbous change as well as incorporation of athetoid changes (f), hemosiderin (g), and frank necrotic of the epithelium (h). Figure (c) gross photograph corresponds to the inset with cylindrical change of the epithelium. All microphotographs have been taken

from histological slides stained with hematoxylin and eosin apart from (g), in which a Pearls blue stain for iron was carried out (a, original magnification x400; b, original magnification x400; c, original magnification x400 [inset]; d, original magnification x400; e, original magnification x100; f, original magnification x100; g, original magnification x200; h, original magnification x400)

18.3  Pathology of the Late Pregnancy

In details, clinical features include reduced fetal movements with CTG abnormalities, including decreased variability and sinusoidal rhythm with variable fetal outcome dependent from the rate of bleeding and increase in maternal hematocrit as a subtle sign of FMH. The acute form is characterized by rapid blood loss, which is followed by perinatal hypoxia and intrauterine death or severe anemia and hypoxia at birth. The chronic form shows compensatory mechanisms of increased hemopoietic activity revealed by increased erythroblasts and reticulocytes in the peripheral smear and active erythropoiesis in the fetal liver at time of the autopsy. The sequela for the inadequate compensatory reaction is hydrops. Fetal growth and ultrasound are usually within the normal range. As explained earlier, the Kleihauer-Betke test is useful in women presenting with a decrease of fetal movements or decreased variability and sinusoidal pattern. This test is a convenient tool to assess FMH.  This investigation takes into account that adult hemoglobin is more readily eluted through the plasmatic membrane in the presence of acid (e.g., citrate-phosphate buffer) than is fetal hemoglobin (HbF). It occurs after fixation on a slide with ethanol 80% and finally stained with erythrosine B. The number of fetal cells and maternal cells is counted, and this rate is directly proportional to the estimate of fetal blood volume (ml) to maternal blood volume (ml). Massive FMH are often defined by reaching of the thresholds of 80  ml and 150 ml of fetomaternal bleeds, respectively. Moreover, a 250-ml fetal blood loss or a 5% fetal Hb level in the maternal circulation may be associated with fetal death. Apt test or flow cytometry which means quantifying the number of fetal cells present by measuring the intensity (fluorescence) of specific monoclonal antibodies binding to HbF is also used in cases of suspicious FMH. The crucial mimickers of the NRBCs are hypoxic-­ischemic disorders (hours-days, normoblasts), fetal blood loss (days-weeks, normoblasts in most terminal villi), and fetal anemia/ hydrops (weeks/months, pre-normal blast precursors and EMH). The pitfalls of the KleihauerBetke test(KBT) are distinct in false positive and false negative. False-positive KBT (may) occur

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in maternal HbF cells, maternal thalassemia minor, maternal sickle cell anemia, and hereditary persistence of HbF.  False-negative KBT (may) occur in case of ABO incompatibility and Rh incompatibility. Substantially, to remember is that: • CTG abnormalities are late signs and often associated with the reduced fetal outcome if delivery is performed outside of the hospital. • Consider FMH in cases of unexplained IUFD, fetal distress, NIHF, neonatal shock, and nonhemolytic neonatal anemia. • Timing is essential to save the fetus and prompt delivery followed by neonatal transfusion or in the case of a fetus cord sampling and intrauterine transfusion. • Settings where an FMH test is appropriate to include, in order of severity, are unexplained stillbirth, hydrops, the persistent maternal perception of decreased fetal movements, neonatal anemia, as well as the unexplained elevation of the middle cerebral artery Doppler consistent with anemia. In fact, ultrasound evaluation of the peak systolic blood flow velocity through the fetal middle cerebral artery is critical to identify fetal anemia. In case of fetal anemia, there is an increase of cerebral blood flow to preserve oxygen to the brain, and this can be demonstrated by ↑ peak systolic blood flow (>1.5  multiples of the median → red flag!). FMH may recur in subsequent pregnancies, but the risk and management are unclear as our knowledge of FMH remains far from complete as well as the long-term ­neurodevelopmental consequences of the surviving neonates.

18.3.2.4 S/P Prolonged/Repetitive Hypoxia • DEF: Neuro-placental concept combining specific patterns of brain injury of the newborn with prolonged partial asphyxia emphasized by sustained or repetitive periods of significant hypoxia or other systemic stress affecting the fetus over time of many hours to days. • SYN: Prolonged hypoxia-cerebral palsy.

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• CLI: Cerebral palsy and patterns of neurodisability. • EPG: Severe fetal acute vasculitis, prolonged meconium exposure with fetal vascular necrosis, chronic intermittent umbilical cord o­cclusion, subacute abruption (abruptio placentae), and fetomaternal hemorrhage (FMH). • GRO/CLM: Histology characteristic of the specific etiopathogenic factors. • PGN: Several meta-analyses support the association of the above-delineated risk factors with subsequent cerebral palsy and neurodisability of the newborn.

18.3.3 Chronic Diseases Chronic diseases of the placenta include maternal vascular underperfusion (MVUP), vasculopathy of thrombotic type of fetal origin, villitis of chronic type, perivillous fibrin deposition (PVFD), and circumvallate placenta and related lesions. In case of the identification of retroplacental hemorrhage, placental abruption as a whole, marginal abruption, and chronic abruption need to be distinguished.

18.3.3.1 Maternal Vascular Underperfusion (MVUP) (Figs. 18.24, 18.25, 18.26, and 18.27)

• DEF: Multifactorial placental syndrome due to inadequate tissue perfusion and cellular oxygenation affecting the placenta as a whole. • SYN: “Chronic placental insufficiency.” • EPI: Risk factors include primipara, FHx (+), and Hx (+) of underlying disease (e.g., metabolic syndrome, renovascular or autoimmunity, thrombophilia). • CLI: Preeclampsia, IUGR, PTL, PROM, HELLP (hemolysis, elevated liver enzymes, low platelets) (Figs.  18.24, 18.25, 18.26, and 18.27).

18  Placenta, Abnormal Conception, and Prematurity

• EPG: Perfusion may be decreased either systemically (e.g., hypotension, intravascular volume expansion failure) or limited to regional maldistribution (failure of appropriate trophoblastic invasion and consequent remodeling of the uterine spiral arteries, anatomical abnormalities of the pelvic and uterine blood supply, infection of the female genital tract). Regardless of etiology or severity, all forms of MVU have the common property of perfusion, which is inadequate to meet metabolic demands at the cellular level. Decreased organ perfusion leads naturally to tissue hypoxia, anaerobic metabolism, activation of the inflammatory cascade, and organ dysfunction. • GRO/CLM: Gross and microscopic features are identifiable and include: 1. Placental hypotrophy (decrease of placental weight and increase of fetoplacental weight ratio) 2. Decidual arteriopathy (i.e., mural hypertrophy of decidual arteries, acute atherosis, or fibrinoid necrosis of the vascular smooth muscle wall and scattered clusters of lipid-­laden macrophages) 3. Villous/intervillous changes (placental villous tree immaturity with distal villous hypoplasia, an increase of the intervillous fibrin deposition, villous agglutination, and increase in syncytial nuclear clumping and basophilia by accelerated syncytiotrophoblast turnover, which is the so-called “Tenney-Parker” or knotting changes of the terminal villi) 4. Placental infarction 5. Nonspecific findings, such as thin umbilical cord and laminar membrane necrosis • PGN: Prematurity, IUGR, adult cardiovascular disease, recurrence in subsets (severe preterm birth, underlying disease).

18.3  Pathology of the Late Pregnancy

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Fig. 18.24  Maternal vascular underperfusion. Maternal vascular underperfusion shows fibrotic changes on the chorionic plate (a) as well as at the basal plate (b). Figure (c) is an old infarct with necrosis of the placental parenchyma, and its histopathology is shown in Figure (d).

g

Another old infarct is shown in Figure (e). Figures (f–g) show fresh acute placenta infarctions. All microphotographs have been taken from histological slides stained with hematoxylin and eosin (d, original magnification x20; e-g, original magnification x40)

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a

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Fig. 18.25  Pre-Eclampsia. In (a) is shown the physiopathology concepts evolving to fetal growth restriction or intrauterine fetal demise in consequence of a conversion failure of spiral arteries to vascular sinuses, which the histopathologic correlates for preeclampsia. Figures (b–c) show different degrees of preeclampsia histopathology

changes with atherosis and fibrinoid necrosis. All microphotographs have been taken from histological slides stained with hematoxylin and eosin (b, original magnification x100; c, original magnification x200; d, original magnification x100; e, original magnification x400; f, original magnification x100; g, original magnification x100; h, original magnification x200)

18.3  Pathology of the Late Pregnancy

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Fig. 18.26  HELLP (hemolysis, elevated liver enzymes, and a low platelet count) syndrome. HELLP syndrome may be dreadful complication of a multisystemic or multiorganic preeclampsia with liver involvement. The histopathology of preeclampsia is shown in these figures (see text for details), and fibrinoid necrosis is more diffuse than a classic preeclampsia. All microphotographs have been taken from histological slides stained with hematoxylin

and eosin (b, original magnification x20; c, original magnification x100; d, original magnification x100; e, original magnification x40; f, original magnification x200; g, original magnification x200; h, original magnification x200; the microphotograph f is the same of the microphotograph h of Fig. 18.25 reproduced due to a patient with initial pre-eclampsia developing later HELLP syndrome)

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Fig. 18.27  Cysts. Cysts may be an intriguing encounter by the grossing of a placenta (a), and the histopathology frequently involves the presence of intermediate trophoblast lined cavities (b, c). In (d), a cyst is seen at level of the

chorionic plate. All microphotographs have been taken from histological slides stained with hematoxy  lin and eosin apart c, which is periodic acid Schiff stained (b, original magnification x20; c, original magnification x40; d, original magnification x40)

In studies involving MVUP, the target is recording pathologic findings in the maternal vasculature of the parietal and basal decidua (vessel changes), which included mural fibrinoid necrosis/acute atherosis, muscularized basal plate arteries, and mural hypertrophy of membrane arteries (MHMA). Moreover, villous hypoxic lesions (villous changes) including infarcts, increased syncytial knots, villous agglutination, increased perivillous fibrin, distal villous hypoplasia/small terminal villi need to be documented. The degree of MVUP may be graded as severe if one or more vascular lesions are present, one or more villous lesions are seen, and the placental weight is 1 focus of some affected villi/some slides 1 focus of some affected villi/some slides ≥15 with type (a) involving large foci while type (b) only small foci (10 villi/focus in case

of patchy (≤3 foci) and diffuse (>5% of all villi). Some common pitfalls of the VUE diagnostics due to VUE mimickers are shown in Box 18.40. Chronic histiocytic intervillositis (HIV) is a rare placental lesion which is often associated with autoimmune disorders of the mother. There is diffuse infiltration of the intervillous space by mononuclear inflammatory cells, i.e., macrophages (CD68+) ± fibrin exudation occurring in spontaneous recurrent miscarriage, FGR, and IUFD with a high perinatal mortality rate up to 3/4 of cases. Most often, there is a positive family history of autoimmunity and steroid response.

Box 18.39 VUE Pearls

• When you see endothelialitis, viral inclusions, and villous plasma cells, then think of CMV • When you see necrotizing cord periphlebitis or stem villous periarteritis, then think of syphilis • When you see necrosis, calcification, and inclusions, then think of HSV/VZV • When you see umbilical cord pseudocysts, then think of toxoplasmosis

Box 18.40 Pitfalls VUE Histologic Mimickers

1. Maturitas tarda (delayed villous maturation with increased intravillous Hofbauer cells) 2. Maternal floor infarction (fibrinoid, intermediate trophoblast, no inflammation) 3. Chronic histiocytic intervillositis (CHIV) 4. Fetal thrombotic vasculopathy (no lymphocytes) 5. Villous agglutination-associated Terrey-­ Parker phenomenon (↑ syncytial knots) 6. Villous stromal-vascular karyorrhexis (a secondary thrombo-occlusive villous lesion)

18.3  Pathology of the Late Pregnancy

18.3.3.4 M  assive Perivillous Fibrin Deposition (MPFD) and “Maternal Floor Infarction”

• DEF: Massive deposition of fibrin or fibrinoid at the basal plate or in the perivillous space (Figs. 18.28 and 18.29). • EPI: 0.1–0.5% pregnancies. RFs: autoimmunity, thrombophilia, and HTN. • EPG: ↓ perfusion, hypercoagulability, and excessive matrix secretion are leading to a massive (i.e., strikingly significant) deposition of perivillous fibrin or fibrinoid ⇒ ↓ perfusion, hypercoagulability, and excessive matrix secretion. • CLI: Oligohydramnios, SGA, and fetal distress. • GRO/CLM: Two radically alternative histologic patterns constitute the morphologic basis for MPFD, which are fibrinoid with intermediate trophoblast (“X cells”) and villous degeneration with bright red fibrin at the perivillous location. • PGN: PTL, FGR, neurodisability, IUFD, recurrent miscarriage (RR: 1/10–8/10).

MPFD mimickers, so-called the non-massive depositions, may be found in a series of conditions including (1) MVU with ↑ intervillous fibrin (subchorionic, basal, stem villi located, or marginal atrophy) and (2) nonspecific perivillous (intervillous) fibrin plaques (term placentas without clinical correlates or adverse outcomes). Of note, localized intervillous fibrin (marginal atrophy) induces diffuse intervillous fibrin deposition with X-cells (uteroplacental insufficiency), which in turn leads to an increased basal perivillous fibrin with X-cells (FGR, IUFD). A perivillous fibrin plaque induces a “localized” maternal floor infarction, which in turn leads to “diffuse” maternal floor infarction (perinatal mortality and recurrence).

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18.3.3.5 “Chronic” Placental Abruption (CPA) Abortion and miscarriage may be used interchangeably, but the origin of the former is Latin (abortus), while the source of the latter is Russian. In both cases, the event is a termination of pregnancy up to 28 weeks of pregnancy, i.e., in the period when the fetus is unable to survive without mechanical support outside the mother’s body. The interruption of pregnancy can be spontaneous or artificial. In case of community-acquired miscarriage, it is important to differentiate among different types of miscarriages according to the dynamics of the miscarriage (Box 18.41). Each form of abortion corresponds to a specific clinical picture. Threatening miscarriage is characterized by the mother feeling a small, occasionally emerging, pain in the lower abdomen (contractions), slight bleeding as blood stains on the strip, and the external orifice of the uterus closed. In starting miscarriage, more frequent and severe pain in the lower abdomen occurs and there is an obvious beginning separation of chorionic villi, which manifests with more fresh blood. Vaginal examination shows an external orifice of the uterus with a finger passing the cervical canal. In both conditions, pregnancy can be saved if there are strict bed rest, analgesia, progesterone, and oxygen inhalation. If this therapeutic regimen fails, miscarriage is in progress. Pain and bleeding are more accentuated, and the fertilized egg can be palpable at the vaginal examination. In the event of an incomplete miscarriage, which is the most common clinical form, there is profuse uterine bleeding. In the blood clots, a fertilized egg can be visualized. Complete abortion is characterized by the complete detachment of the chorionic villi from his uterine bed without ensuring that they were cut out and did not stay in the uterus at the site of implantation. Uterine curettage is always justified, although a lack of pain and bleeding characterizes this form. Missed miscarriage (delayed miscarriage, silent miscarriage, or missed abortion) is characterized by pregnancy signs in the mother’s body accompanied by the death of the embryo or fetus, although a miscarriage did not occur yet. The chorionic villi are the specific functional unit of the placental disc.

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18  Placenta, Abnormal Conception, and Prematurity

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Fig. 18.28  Maternal perivillous fibrin deposition and maternal floor infarction. Maternal perivillous fibrin deposition (MPVFD) and maternal floor infarction (MFI) are part of the same process involving an impressive amount of fibrin deposition in the intervillous space obturating the space that should allow for exchange of oxygen

and nutrients. Figure (a) lists the current criteria, while (b) and (c) show gross photographs of MPVFD with features reaching the MFI with more than 50% of basal villi associated with hypovascular or fibrotic villi (d and e). All microphotographs have been taken from histological slides stained with hematoxylin and eosin (d-e, original magnification x100)

18.3  Pathology of the Late Pregnancy

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Fig. 18.29  Maternal floor infarction. A maternal floor infarction (MFI) is depicted in (a) and (b), and the histology of (c) and (d) is the characteristic of MFI with clearly

more than 50% of the basal villi being hypovascular or fibrotic. All microphotographs have been taken from histological slides stained with hematoxylin and eosin (c-d, original magnification x20)

• DEF: Chronic peripheral (marginal) separation of the placenta from the uterus. • EPG: Marginal uteroplacental separation due to inadequate support by the surrounding endometrium or when subjected to elevated intramural pressure. There is an abnormality involving the marginal anatomy with alteration of the geometry of the placenta located in utero AND ↑ maternal venous pressure. Both the geometric aberration and the increased maternal venous pressure are not relevant enough to determine an acute event of peripheral abruption, yet chronic. • CLI: Chronic vaginal bleeding (continued/intermittent dark brown vaginal spotting) and oligohydramnios. • GRO: Peripheral (marginal) hematoma and/or circumvallate placenta.

• MIC: Old blood clot with chorionic/ amniotic hemosiderin and/or Hb-related pigment (biliverdin) deposition and/or histology of circumvallate placenta. • Pearls: When you see pigment in a premature placenta, then think of chronic abruption! • When you see pigment ≥37 weeks placenta, then think of meconium release! • PGN: Threatened miscarriage (abortus imminens) (see below) in early pregnancy or vaginal bleeding in late pregnancy, preterm delivery, atypical form of neonatal lung disease, and neurological impairment of the newborn (neurodisability), such as cerebral palsy. RF: multiparity, PROM, smoking, oligohydramnios, excessive low uterine implantation. RR: rare/minimal.

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Box 18.41 Abortus/Miscarriage Classification

1 . Threatening miscarriage (abortus imminens) 2. Starting miscarriage (abortus incipiens) 3. Miscarriage in progress (abortus protragens) 4. Incomplete miscarriage (abortus incompletus) 5. Complete miscarriage (abortus completus) 6. Missed miscarriage or missed abortion (abortus amissus)

These villi provide oxygen and sustenance to the fetus and serve as an excretory unit. The histological appearance of chorionic villi varies with the gestational age and with the stage of development and maturation of the villous tree. Normal villi contain numerous thin-walled patent vascular channels, and the examination of several cross sections of chorionic villi can bring the average count to 8–10 blood vessels. Avascular or hypovascular villi indicate poor blood supply to the fetus and result into FGR. In the examination of spontaneous miscarriages, the pathologist can identify a reduced number of blood vessels (up to 97%), stromal fibrosis (~85%), fibrinoid degeneration (~75%), and prominent Hofbauer macrophages (~67%). Avascular villi point to an obliterative fetal vasculopathy characterized by diffuse perivillous fibrin deposition. Redline and Pappin have demonstrated that when avascular villi account for more than 2.5% of the placental parenchyma, a few events can occur. They include an increased rate of FGR, abnormal fetal Doppler, oligohydramnios, and maternal coagulopathy. Placentas with avascular villi indicate fetal thrombotic vasculopathy (FTV) and may coexist with chronic villitis, membrane hemosiderin, meconium in all three membrane layers, and villous chorangiosis. A Virchow’s triad associated FTV may be due to severe fetal inflammation and any damage involving the integrity of the blood vessels as vascular damage. A prolonged maternal cord obstruction, an increased central venous pressure, and an altered hematocrit have been

18  Placenta, Abnormal Conception, and Prematurity

ascribed to intraluminal abnormalities. Clotting anomalies include hemoglobinopathies, such as platelet disorders, maternal DM, and thrombophilia, including protein C, protein S, Factor V Leiden (FVL), prothrombin gene (PT G20210A) and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. Pediatric pathologists and embryologists often work in the same environment and frequently join quality assurance or clinicopathological conferences (aka multidisciplinary meetings) in the same institution. Pediatric pathologists are also asked about their interpretation in different conditions. The assessment of the embryo vitality is probably one of the most important and challenging tasks in IVF.  Microscopy was traditionally the assessment method of choice until a few years ago. It provided a relatively simple and somewhat reliable method for this aim. However, numerous factors contributing to the oocyte and/ or embryo quality are often not picked up by morphology only, and new methods have been proposed in the recent years. In the range of the secretome, which is the total amount of all compounds that are secreted by the oocyte and/or embryo into its environment, the metabolome is probably the fascinating procedure that gained interest in the last few years. It refers to the study of several factors present in the culture medium that are secreted by the oocyte and/or embryo into the environment because of metabolic processes that occur at the cellular level or due to leakage from cell damage. Metabolomics can identify several processes of the preimplantation development, a period when a major metabolic pathway is a switch in ATP synthesis from carboxylic acid to glucose metabolism around the time of compaction. Visual grading of embryos is likely to be highly subjective, and intra- and interobserver inconsistency has been reported and controversially debated. Metabolomic profiling of embryos has stated to be the object of extensive investigation, although it is mostly impractical for a clinical setting. In IVF, metabolomic profiling is usually less challenging due to the longer culture periods during which several metabolites can accumulate and therefore detectable in the medium. There are additional methods of analysis, and specific reviews have been a study object.

18.3  Pathology of the Late Pregnancy

18.3.3.6 Villous Capillary Proliferation Disorders (VCPD)

• DEF: Primary and secondary lesions characterized by an intravillous proliferation of capillaries. • EPI: Risk factors include DM, BWS, high altitude, smoking, twin pregnancy, and preeclampsia (BeckwithWiedemann syndrome, BWS). • EPG: Unknown in the autonomous forms but associated with MVU lesions as reactive (subacute hypoxia and associated with growth factors and other cytokines). There is often Hx. (+) for DM, BWS, high altitude, and smoking in chorangiosis and an association of twins and preeclampsia in chorangioma. • CLI: Variable according to the underlying lesion with a spectrum ranging from asymptomatic to hydrops fetalis and IUFD. • CLM: 1. Chorangiosis (common or reactive), i.e., >10 capillaries/villus in >10 villi in several areas. 2. Chorangioma (single or multifocal), i.e., autonomous proliferation (placental hemangioma). 3. Chorangiomatosis (localized OR diffuse), i.e., large areas of the placenta or diffuse autonomous proliferation (immature placenta). • PGN: Adaptive when accompanying chronic lesions while consumptive vasculopathy, A-V shunt with hydrops, and IUGR in case of chorangioma or chorangiomatosis.

Vascular-syncytial or syncytial-vascular membranes (SVMs) is a characteristic feature of the placenta at term with syncytial trophoblasts and absent cytotrophoblast. Syncytial trophoblasts

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evidence nuclear knots and attenuated cytoplasm over the villous surface. If a cross section is performed on the last (terminal) villous tree, the histological slides will show most of the cross section occupied by capillary profiles with and one or more peripheral capillaries bulging under attenuated syncytiotrophoblastic cytoplasm. There is typically no stroma between maternal (intervillous) and fetal (villi) blood cells. In case there is an obstruction between maternal and fetal blood, chronic hypoxia is the consequence and fetal death at the final event. Thus, the determination of the satisfactory presence of SVMs is essential to the obstetrician and perinatologist.

18.3.3.7

Distal Villous Immaturity (DVI)

• DEF: Immaturity of the distal villous completion for an appropriate placental function. • EPI: Prepregnancy (+) glucose tolerance test, metabolic disorders leading to hyperglycemia (vide supra). • CLI: Gestational DM, T1DM, (+) glucose tolerance test, maternal obesity, excessive weight gain, TORCH infections, severe maternal anemia, hydrops fetalis, fetal overgrowth syndromes (e.g., BWS), metabolic storage diseases. • GRO/CLM: Placentomegaly (>90th centile) (