Atlas of diagnostic pathology of the cervix : a case-based approach 9783030499549, 3030499545

Table of contents :
Preface
Contents
Contributors
1: Anatomy, Histology, Cytology, and Colposcopy of the Cervix
1.1 Anatomy, Histology, and Cytology of the Cervix
1.1.1 The Epithelium of the Ectocervix
1.1.1.1 Cytological Correlation in Squamous Epithelium
1.1.2 The Epithelium of the Endocervix
1.1.2.1 Cytological Correlation in Glandular Epithelium
1.1.3 The Epithelium of the Transformation Zone
1.1.3.1 Transformation Mechanisms
1.1.3.2 Cytological Correlation in the Epithelium of the Transformation Zone
1.2 Cervical Stroma
1.3 Cervical Adventitia
1.4 Cervical Vascularization and Innervation
1.5 Changes of the Cervix During Pregnancy
1.6 Colposcopy of the Cervix
References
2: Pathologic Sampling Methods of the Cervix
2.1 Cervical Punch/Wedge Biopsy and Endocervical Curettage
2.1.1 Specimen Handling and Histopathological Processing
2.1.2 Histopathological Reporting
2.1.3 Case Example
2.2 Cervical Cone Biopsy
2.2.1 Specimen Handling and Histopathological Processing
2.2.2 Histopathological Reporting
2.2.3 Case Example
2.3 Trachelectomy
2.3.1 Specimen Handling and Histopathological Processing
2.3.2 Histopathological Reporting
2.3.3 Case Example
2.4 Hysterectomy
2.4.1 Specimen Handling and Histopathological Processing
2.4.2 Histopathological Reporting
2.4.3 Case Example
2.5 Pelvic Exenteration
2.5.1 Specimen Handling and Histopathological Processing
2.5.2 Histopathological Reporting
2.6 Lymph Nodes
2.6.1 Specimen Handling and Histopathological Processing
2.6.2 Histopathological reporting
References
3: Benign Lesions and Physiologic Changes in the Cervix
3.1 Squamous Metaplasia
3.1.1 Definition
3.1.2 Synonyms
3.1.3 Etiology
3.1.4 Macroscopy
3.1.5 Microscopy
3.1.6 Differential Diagnosis
3.1.7 Prognosis
3.2 Transitional Metaplasia
3.2.1 Definition
3.2.2 Etiology
3.2.3 Macroscopy
3.2.4 Microscopy
3.2.5 Differential Diagnosis
3.2.6 Prognosis
3.3 Tubal and Tubo-Endometrioid Metaplasia
3.3.1 Definition
3.3.2 Etiology
3.3.3 Macroscopy
3.3.4 Microscopy
3.3.5 Differential Diagnosis
3.3.6 Prognosis
3.4 Endometriosis
3.4.1 Definition
3.4.2 Etiology
3.4.3 Macroscopy
3.4.4 Microscopy
3.4.5 Differential Diagnosis
3.4.6 Prognosis
3.5 Other Metaplasias
3.5.1 Definition
3.5.2 Etiology
3.5.3 Microscopy
3.5.4 Differential Diagnosis
3.5.5 Prognosis
3.6 Ectopic Tissues
3.6.1 Definition
3.6.2 Etiology
3.6.3 Macroscopy
3.6.4 Microscopy
3.6.5 Differential Diagnosis
3.6.6 Prognosis
3.7 Microglandular Hyperplasia
3.7.1 Definition
3.7.2 Etiology
3.7.3 Macroscopy
3.7.4 Microscopy
3.7.5 Differential Diagnosis
3.7.6 Prognosis
3.8 Lobular Endocervical Glandular Hyperplasia (LEGH)
3.8.1 Definition
3.8.2 Etiology
3.8.3 Macroscopy
3.8.4 Microscopy
3.8.5 Differential Diagnosis
3.8.6 Prognosis
3.9 Tunnel Clusters
3.9.1 Definition
3.9.2 Etiology
3.9.3 Macroscopy
3.9.4 Microscopy
3.9.5 Differential Diagnosis
3.9.6 Prognosis
3.10 Deep Glands and Nabothian Cysts
3.10.1 Definition
3.10.2 Etiology
3.10.3 Macroscopy
3.10.4 Microscopy
3.10.5 Differential Diagnosis
3.10.6 Prognosis
3.11 Mesonephric Remnants and Hyperplasia
3.11.1 Definition
3.11.2 Macroscopy
3.11.3 Microscopy
3.11.4 Differential Diagnosis
3.11.5 Prognosis
3.12 Inflammatory (Non-infectious) Processes
3.12.1 Definition
3.12.2 Etiology
3.12.3 Microscopy
3.12.4 Differential Diagnosis
3.12.5 Prognosis
3.13 Infections
3.13.1 Definition
3.13.2 Etiology
3.13.3 Macroscopy
3.13.4 Microscopy
3.13.5 Differential Diagnosis
3.13.6 Prognosis
3.14 Arias-Stella Reaction
3.14.1 Definition
3.14.2 Etiology
3.14.3 Macroscopy
3.14.4 Microscopy
3.14.5 Differential diagnosis
3.14.6 Prognosis
3.15 Other Reactive and Reparative Changes
3.15.1 Definition
3.15.2 Etiology
3.15.3 Macroscopy
3.15.4 Microscopy
3.15.5 Prognosis
References
4: Benign Tumors and Tumor-like Lesions of the Cervix
4.1 Giant Condyloma
4.1.1 Definition
4.1.2 Synonyms
4.1.3 Etiology
4.1.4 Macroscopy
4.1.5 Microscopy
4.1.6 Differential Diagnosis
4.1.7 Prognosis
4.2 Endocervical Polyp
4.2.1 Definition
4.2.2 Synonyms
4.2.3 Etiology
4.2.4 Macroscopy
4.2.5 Microscopy
4.2.6 Differential Diagnosis
4.2.7 Prognosis
4.3 Adenofibroma
4.3.1 Definition
4.3.2 Synonyms
4.3.3 Etiology
4.3.4 Macroscopy
4.3.5 Microscopy
4.3.6 Differential Diagnosis
4.3.7 Prognosis
4.4 Adenomyoma
4.4.1 Definition
4.4.2 Synonyms
4.4.3 Etiology
4.4.4 Macroscopy
4.4.5 Microscopy
4.4.6 Differential Diagnosis
4.4.7 Prognosis
4.5 Leiomyoma
4.5.1 Definition
4.5.2 Synonyms
4.5.3 Etiology
4.5.4 Macroscopy
4.5.5 Microscopy
4.5.6 Differential Diagnosis
4.5.7 Prognosis
4.6 Fibroepithelial Stromal Polyp
4.6.1 Definition
4.6.2 Synonyms
4.6.3 Etiology
4.6.4 Macroscopy
4.6.5 Microscopy
4.6.6 Differential Diagnosis
4.6.7 Prognosis
4.7 Other Lower Genital Mesenchymal Lesions
4.7.1 Definition
4.7.2 Synonyms
4.7.3 Etiology
4.7.4 Macroscopy
4.7.5 Microscopy
4.7.6 Differential Diagnosis
4.7.7 Prognosis
4.8 Lesions with Neuroectodermal and Nerve Sheath Differentiation
4.8.1 Definition
4.8.2 Synonyms
4.8.3 Etiology
4.8.4 Macroscopy
4.8.5 Microscopy
4.8.6 Differential Diagnosis
4.8.7 Prognosis
4.9 Lipoma
4.9.1 Definition
4.9.2 Synonyms
4.9.3 Etiology
4.9.4 Macroscopy
4.9.5 Microscopy
4.9.6 Differential Diagnosis
4.9.7 Prognosis
4.10 Hemangioma
4.10.1 Definition
4.10.2 Synonyms
4.10.3 Etiology
4.10.4 Macroscopy
4.10.5 Microscopy
4.10.6 Differential Diagnosis
4.10.7 Prognosis
4.11 Cervical Diverticulum
4.11.1 Definition
4.11.2 Synonyms
4.11.3 Etiology
4.11.4 Macroscopy
4.11.5 Microscopy
4.11.6 Differential Diagnosis
4.11.7 Prognosis
4.12 Placental Site Nodule
4.12.1 Definition
4.12.2 Synonyms
4.12.3 Etiology
4.12.4 Macroscopy
4.12.5 Microscopy
4.12.6 Differential Diagnosis
4.12.7 Prognosis
References
5: Precursor Lesions of the Cervix: Squamous Precursor Lesions
5.1 Low-Grade Squamous Intraepithelial Lesion (LSIL)
5.1.1 Condyloma Acuminatum
5.1.1.1 Definition
5.1.1.2 Synonyms
5.1.1.3 Etiology
5.1.1.4 Macroscopy
5.1.1.5 Microscopy
5.1.1.6 Cytology/Ancillary Studies
5.1.1.7 Differential Diagnosis
5.1.1.8 Prognosis
5.1.1.9 Case
5.1.2 Cervical Intraepithelial Neoplasia 1 (CIN 1/LSIL)
5.1.2.1 Definition
5.1.2.2 Synonyms
5.1.2.3 Etiology
5.1.2.4 Macroscopy
5.1.2.5 Microscopy
5.1.2.6 Cytology/Ancillary Studies
5.1.2.7 Differential Diagnosis
5.1.2.8 Prognosis
5.1.2.9 Case
5.2 High-Grade Squamous Intraepithelial Lesion (HSIL)
5.2.1 Definition
5.2.2 Synonyms
5.2.3 Etiology
5.2.4 Macroscopy
5.2.5 Microscopy
5.2.6 Cytology/Ancillary Studies
5.2.7 Differential Diagnosis
5.2.8 Prognosis
5.2.9 Cases
5.3 Mimics of Squamous Intraepithelial Lesions
5.3.1 Benign Entities
5.3.2 Neoplastic Mimics
5.3.3 Cases
References
6: Precursor Lesions of the Cervix: Glandular Precursor Lesions
6.1 Intraepithelial Glandular Neoplasm
6.1.1 Synonyms
6.1.2 Etiology
6.1.3 General Features
6.1.4 Macroscopy
6.1.5 General Comments
6.1.6 Cytology
6.2 HPV-Associated AIS
6.2.1 Immunohistochemistry and In Situ Hybridization
6.2.2 Differential Diagnosis
6.2.3 Cases
6.3 HPV-Independent AIS
6.3.1 Histochemistry and Immunohistochemistry
6.3.2 Differential Diagnosis
6.4 Case
6.5 Clinical Management
Suggested Reading
7: Epithelial Malignant Tumors of the Cervix: Squamous Carcinoma
7.1 Etiology
7.2 Clinical Features
7.3 Macroscopic Appearance
7.4 Microscopic Appearance
7.4.1 Histologic Subtypes
7.4.1.1 Keratinizing Squamous Cell Carcinoma
7.4.1.2 Non-Keratinizing Squamous Cell Carcinoma
7.4.1.3 Basaloid Squamous Cell Carcinoma
7.4.1.4 Papillary Squamous Cell Carcinoma
7.4.1.5 Warty-Type (Condylomatous) Squamous Cell Carcinoma
7.4.1.6 Lymphoepithelioma-like Carcinoma
7.4.1.7 Cases
7.4.2 Cytologic Appearance
7.4.3 Grading Controversy
7.4.4 Differential Diagnosis
7.4.4.1 Reactive Squamous Changes
7.4.4.2 Decidual Change
7.4.4.3 Placental Site Nodule and Epithelioid Trophoblastic Tumor
7.4.4.4 Neuroendocrine Carcinoma
7.4.4.5 Adenocarcinoma/Adenosquamous Carcinoma, Including Glassy Cell Carcinoma
7.4.4.6 Melanoma
7.4.4.7 Other Carcinomas
7.4.4.8 Radiation Changes
7.4.4.9 Cases
7.5 Ancillary Studies
7.5.1 p16
7.5.2 HPV DNA and RNA In Situ Hybridization
7.5.3 Cases
7.6 Assessing Depth of Invasion
7.6.1 Challenges with Assessing Depth of Invasion
7.6.2 Patterns of Invasion
7.6.3 Depth of Invasion and Staging
7.6.4 Cervical Stromal Involvement by Thirds
7.6.5 Cases
7.7 Measuring Tumor
7.7.1 Horizontal/Lateral Extent
7.7.2 Tumor Diameter
7.7.3 Multifocal Invasion
7.8 Lymphovascular Invasion
7.8.1 Cases
7.9 Perineural Invasion
7.10 Extra-Cervical Involvement
7.10.1 Parametrial Involvement
7.10.2 Involvement of Uterine Corpus and Adnexa
7.11 Lymph Node Involvement
7.12 Margin Status
7.13 Staging and Prognosis
7.14 Predictive Biomarkers
7.14.1 Case
References
8: Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma
8.1 Definition
8.2 Synonyms
8.3 Etiology and Pathogenesis
8.4 Clinical Presentation and Macroscopy
8.5 Cytological Features
8.6 Microscopic Classification of Endocervical Adenocarcinoma
8.6.1 HPV-Associated Endocervical Adenocarcinomas (HPVA)
8.6.1.1 Usual Type Adenocarcinoma (Including Villoglandular and Micropapillary Architectural Variants)
8.6.1.2 Mucinous Type Adenocarcinoma (Including Mucinous NOS, Intestinal, Signet-Ring, and Invasive Stratified Mucinous Variants)
8.6.1.3 Adenocarcinoma NOS Type
8.6.1.4 Assessment of Stromal Invasion by ECA
8.6.1.5 Cases
8.6.2 HPV-Independent Endocervical Adenocarcinomas (HPVI)
8.6.2.1 Gastric type, Including Minimal Deviation Adenocarcinoma
8.6.2.2 Clear Cell Adenocarcinoma
8.6.2.3 Mesonephric Type Adenocarcinoma
8.6.2.4 Endometrioid Type Adenocarcinoma
8.6.2.5 Adenocarcinoma NOS Type, (HPVI)
8.6.2.6 Cases
8.7 Differential Diagnosis
8.8 Prognosis
References
9: Epithelial Malignant Tumors of the Cervix: Other Epithelial Tumors (Adenosquamous Carcinoma, Adenoid Basal Carcinoma, Carcinoma with Adenoid Cystic-like Features, Undifferentiated Carcinoma)
9.1 Adenosquamous Carcinoma
9.1.1 Definition
9.1.2 Synonyms
9.1.3 Etiology
9.1.4 Macroscopy
9.1.5 Microscopy
9.1.6 Differential Diagnosis
9.1.7 Prognosis
9.1.8 Cases
9.2 Adenoid Basal Carcinoma
9.2.1 Definition
9.2.2 Synonyms
9.2.3 Etiology
9.2.4 Macroscopy
9.2.5 Microscopy
9.2.6 Differential Diagnosis
9.2.7 Prognosis
9.2.8 Cases
9.3 Carcinoma with Adenoid Cystic-Like Features
9.3.1 Definition
9.3.2 Synonyms
9.3.3 Etiology
9.3.4 Macroscopy
9.3.5 Microscopy
9.3.6 Differential Diagnosis
9.3.7 Prognosis
9.3.8 Cases
9.4 Undifferentiated Carcinoma
9.4.1 Definition
9.4.2 Synonyms
9.4.3 Etiology
9.4.4 Macroscopy
9.4.5 Microscopy
9.4.6 Differential Diagnosis
9.4.7 Prognosis
9.4.8 Cases
References
10: Epithelial Malignant Tumors of the Cervix: Neuroendocrine Tumors
10.1 Low-Grade Neuroendocrine Tumor
10.1.1 Definition
10.1.2 Synonyms
10.1.3 Macroscopy
10.1.4 Microscopy
10.1.4.1 Grade 1 (Carcinoid)
10.1.4.2 Grade 2 (Atypical Carcinoid)
10.1.5 Immunohistochemistry
10.1.6 Differential Diagnosis
10.1.7 Prognosis
10.1.8 Case
10.2 High-Grade Neuroendocrine Carcinoma
10.2.1 Definition
10.2.2 Synonyms
10.2.3 Macroscopy
10.2.4 SCNEC: Microscopy, Immunohistochemistry, and Other Tests
10.2.4.1 Case
10.2.5 LCNEC: Microscopy, Immunohistochemistry, and Other Tests
10.2.5.1 Cases
10.2.6 Microscopy of Mixed Neuroendocrine and Non-neuroendocrine Carcinoma
10.2.6.1 Cases
10.2.7 Differential Diagnosis of SCNEC
10.2.8 Differential Diagnosis of LCNEC
10.2.9 Prognosis and Treatment of SCNEC and LCNEC
10.2.10 Additional Comments
References
11: Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix
11.1 Embryonal Rhabdomyosarcoma, Botryoid-Type (RMS-B)
11.1.1 Definition
11.1.2 Synonyms
11.1.3 General Features
11.1.4 Etiology
11.1.5 Macroscopy
11.1.6 Microscopy
11.1.7 Differential Diagnosis
11.1.8 Prognosis
11.1.9 Cases
11.2 Müllerian Adenosarcoma
11.2.1 Definition
11.2.2 Synonyms
11.2.3 General Features
11.2.4 Etiology
11.2.5 Macroscopy
11.2.6 Microscopy
11.2.7 Differential Diagnosis
11.2.8 Prognosis
11.2.9 Cases
11.3 Atypical Polypoid Adenomyoma
11.3.1 Definition
11.3.2 Synonyms
11.3.3 General Features
11.3.4 Etiology
11.3.5 Macroscopy
11.3.6 Microscopy
11.3.7 Differential Diagnosis
11.3.8 Prognosis
11.3.9 Case
11.4 Mesonephric Carcinosarcoma
11.4.1 Definition
11.4.2 Synonyms
11.4.3 General Features
11.4.4 Etiology
11.4.5 Macroscopy
11.4.6 Microscopy
11.4.7 Differential Diagnosis
11.4.8 Prognosis
11.4.9 Case
11.5 Leiomyosarcoma
11.5.1 Definition
11.5.2 Synonyms
11.5.3 General Features
11.5.4 Etiology
11.5.5 Macroscopy
11.5.6 Microscopy
11.5.7 Differential Diagnosis
11.5.8 Prognosis
11.5.9 Cases
11.6 Endometrial/Endometrioid Stromal Sarcoma
11.6.1 Definition
11.6.2 Synonyms
11.6.3 General Features
11.6.4 Etiology
11.6.5 Macroscopy
11.6.6 Microscopy
11.6.7 Differential Diagnosis
11.6.8 Prognosis
11.6.9 Cases
11.7 Undifferentiated Sarcoma
11.7.1 Definition
11.7.2 Synonyms
11.7.3 General Features
11.7.4 Etiology
11.7.5 Macroscopy
11.7.6 Microscopy
11.7.7 Differential Diagnosis
11.7.8 Prognosis
11.7.9 Cases
11.8 Fibroblastic Sarcoma
11.8.1 Definition
11.8.2 Synonyms
11.8.3 General Features
11.8.4 Etiology
11.8.5 Macroscopy
11.8.6 Microscopy
11.8.7 Differential Diagnosis
11.8.8 Prognosis
11.8.9 Cases
11.9 Rhabdoid Sarcoma
11.9.1 Definition
11.9.2 Synonyms
11.9.3 General Features
11.9.4 Etiology
11.9.5 Macroscopy
11.9.6 Microscopy
11.9.7 Differential Diagnosis
11.9.8 Prognosis
11.9.9 Case
11.10 Rhabdomyosarcoma and Osteosarcoma of Adulthood
11.10.1 Definition
11.10.2 Synonyms
11.10.3 Etiology
11.10.4 Macroscopy
11.10.5 Microscopy
11.10.6 Differential Diagnosis
11.10.7 Prognosis
11.10.8 Case
11.11 Perivascular Epithelioid Cell Tumor (PEComa)
11.11.1 Definition
11.11.2 Synonym
11.11.3 General Features
11.11.4 Etiology
11.11.5 Macroscopy
11.11.6 Microscopy
11.11.7 Differential Diagnosis
11.11.8 Prognosis
11.11.9 Cases
11.12 Inflammatory Myofibroblastic Tumor
11.12.1 Definition
11.12.2 Synonym
11.12.3 General Features
11.12.4 Etiology
11.12.5 Macroscopy
11.12.6 Microscopy
11.12.7 Differential Diagnosis
11.12.8 Prognosis
11.12.9 Case
11.13 Alveolar Soft Part Sarcoma
11.13.1 Definition
11.13.2 General Features
11.13.3 Etiology
11.13.4 Macroscopy
11.13.5 Microscopy
11.13.6 Differential Diagnosis
11.13.7 Prognosis
11.13.8 Case
11.14 Primitive Neuroectodermal Tumors (Peripheral and Central Types)
11.14.1 Definition
11.14.2 Synonyms
11.14.3 General Features
11.14.4 Etiology
11.14.5 Macroscopy
11.14.6 Microscopy
11.14.7 Differential Diagnosis
11.14.8 Prognosis
11.14.9 Cases
11.15 Angiosarcoma
11.15.1 Definition
11.15.2 Synonyms
11.15.3 General Features
11.15.4 Etiology
11.15.5 Macroscopy
11.15.6 Microscopy
11.15.7 Differential Diagnosis
11.15.8 Prognosis
11.15.9 Case
11.16 Liposarcoma
11.16.1 Definition
11.16.2 Synonyms
11.16.3 General Features
11.16.4 Etiology
11.16.5 Macroscopy
11.16.6 Microscopy
11.16.7 Differential Diagnosis
11.16.8 Prognosis
11.16.9 Case
Suggested Reading
Embryonal Rhabdomyosarcoma
Müllerian Adenosarcoma
Mesonephric Carcinosarcoma
Leiomyosarcoma
Endometrial Stromal Tumors
Undifferentiated Sarcoma
Fibroblastic Sarcoma
Liposarcoma
Recent Advances
12: Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)
12.1 Melanocytic Tumors (Malignant Melanoma)
12.1.1 Definition
12.1.2 Synonyms
12.1.3 Etiology
12.1.4 Macroscopy
12.1.5 Microscopy
12.1.6 Differential Diagnosis
12.1.7 Prognosis
12.2 Germ Cell Tumors
12.2.1 Teratoma
12.2.1.1 Definition
12.2.1.2 Synonyms
12.2.1.3 Etiology
12.2.1.4 Macroscopy
12.2.1.5 Microscopy
12.2.1.6 Differential Diagnosis
12.2.1.7 Prognosis
12.2.2 Yolk Sac Tumor
12.2.2.1 Definition
12.2.2.2 Synonyms
12.2.2.3 Etiology
12.2.2.4 Macroscopy
12.2.2.5 Microscopy
12.2.2.6 Differential Diagnosis
12.2.3 Choriocarcinoma
12.3 Trophoblastic Tumors
12.3.1 Choriocarcinoma
12.3.1.1 Definition
12.3.1.2 Synonyms
12.3.1.3 Etiology
12.3.1.4 Macroscopy
12.3.1.5 Microscopy
12.3.1.6 Differential Diagnosis
12.3.1.7 Prognosis
12.3.2 Placental Site Trophoblastic Tumor
12.3.2.1 Definition
12.3.2.2 Synonyms
12.3.2.3 Etiology
12.3.2.4 Macroscopy
12.3.2.5 Microscopy
12.3.2.6 Differential Diagnosis
12.3.2.7 Prognosis
12.3.3 Epithelioid Trophoblastic Tumor
12.3.3.1 Definition
12.3.3.2 Synonyms
12.3.3.3 Etiology
12.3.3.4 Macroscopy
12.3.3.5 Microscopy
12.3.3.6 Differential Diagnosis
12.3.3.7 Prognosis
12.4 Lymphoid Tumors
12.4.1 Definition
12.4.2 Synonyms
12.4.3 Etiology
12.4.4 Macroscopy
12.4.5 Microscopy
12.4.6 Differential Diagnosis
12.4.7 Prognosis
12.5 Myeloid Tumors
12.5.1 Definition
12.5.2 Synonyms
12.5.3 Etiology
12.5.4 Macroscopy
12.5.5 Microscopy
12.5.6 Differential Diagnosis
12.5.7 Prognosis
References
13: Metastases to the Cervix
13.1 Definition
13.2 Synonyms
13.3 Etiology
13.4 Macroscopy
13.5 Microscopy
13.5.1 Histology
13.5.2 Cytology
13.6 Differential Diagnosis
13.7 Prognosis
References
Index

Citation preview

Robert A. Soslow Kay J. Park Simona Stolnicu Editors

Atlas of Diagnostic Pathology of the Cervix A Case-Based Approach

123

Atlas of Diagnostic Pathology of the Cervix

Robert A. Soslow  •  Kay J. Park  •  Simona Stolnicu Editors

Atlas of Diagnostic Pathology of the Cervix A Case-Based Approach

Editors Robert A. Soslow Department of Pathology Memorial Sloan Kettering Cancer Center New York, NY USA

Kay J. Park Department of Pathology Memorial Sloan Kettering Cancer Center New York, NY USA

Simona Stolnicu Department of Pathology

University of Medicine, Pharmacy, Sciences and Technology of Targu Mures Targu Mures Romania

ISBN 978-3-030-49953-2    ISBN 978-3-030-49954-9 (eBook) https://doi.org/10.1007/978-3-030-49954-9 © Springer Nature Switzerland AG 2021 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, expressed 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 Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

To my family, with gratitude. Simona To my family, colleagues, and mentors. Rob To my family and mentors, with love and gratitude. Kay

Preface

Many gynecologic pathology textbooks are mostly encyclopedic, with a limited number of illustrations. In contrast, we intended to create a practical atlas to facilitate accurate and reproducible diagnosis of cervical lesions, using a case-based approach to give context to the pathologic descriptions and illustrations. This book is meant to be a guide for trainees and more experienced practitioners by providing the most accurate and data-driven diagnoses of cervical lesions of various types. Most general pathologists see large numbers of cervical lesions in routine practice, but the field is changing rapidly, particularly regarding the impact of diagnostic criteria and classification on patient management. In this book, we have aimed to provide the most relevant diagnostic criteria and diagnostic algorithms using ancillary tests for every cervical lesion. After a short description of each entity, the reader will be given multiple illustrated examples of basic as well as more difficult cases, and this case-based learning method will provide the most important clues for reaching the correct diagnosis. This book is divided into thirteen chapters with coverage of both non-neoplastic and neoplastic conditions of the cervix. We have included the most important and frequent benign and malignant lesions of the cervix. We have also included a separate chapter dedicated to normal cervical anatomy and histology, which is extremely important for understanding cervical pathology. Sampling is essential in cervical pathology, and for this reason, we have demonstrated the grossing method in a separate chapter. We hope that both pathologists and clinicians with a particular interest in this area will find this book interesting and useful. New York, NY New York, NY  Targu Mures, Romania 

Robert A. Soslow Kay J. Park Simona Stolnicu

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Contents

1 Anatomy, Histology, Cytology, and Colposcopy of the Cervix�������������������������������   1 Simona Stolnicu and Deborah Goldfrank 2 Pathologic Sampling Methods of the Cervix ���������������������������������������������������������   25 Xiaoming Zhang and Maria Carolina Reyes 3 Benign Lesions and Physiologic Changes in the Cervix �����������������������������������������  45 Lynn N. Hoang 4 Benign Tumors and Tumor-like Lesions of the Cervix �������������������������������������������  77 Carlos Parra-Herran 5 Precursor Lesions of the Cervix: Squamous Precursor Lesions ��������������������������� 105 Kay J. Park 6 Precursor Lesions of the Cervix: Glandular Precursor Lesions ��������������������������� 125 Robert A. Soslow 7 Epithelial Malignant Tumors of the Cervix: Squamous Carcinoma��������������������� 137 Michael P. Crawford, Taylor M. Jenkins, and Anne M. Mills 8 Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma��������������������������������������������������������������������������������������������������������� 169 Simona Stolnicu 9 Epithelial Malignant Tumors of the Cervix: Other Epithelial Tumors (Adenosquamous Carcinoma, Adenoid Basal Carcinoma, Carcinoma with Adenoid Cystic-like Features, Undifferentiated Carcinoma)������������209 Anjelica Hodgson 10 Epithelial Malignant Tumors of the Cervix: Neuroendocrine Tumors ����������������� 229 Erna Forgó and Brooke E. Howitt 11 Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix������������������������������������������������������������������������������������������������� 239 Robert A. Soslow and Meera Hameed 12 Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)���������������������������������������������������� 283 Gulisa Turashvili 13 Metastases to the Cervix��������������������������������������������������������������������������������������������� 323 Gulisa Turashvili Index�����������������������������������������������������������������������������������������������������������������������������������  347

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Contributors

Michael P. Crawford, MD  Department of Pathology, University of Virginia, Charlottesville, VA, USA Erna  Forgó, MD Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA Deborah Goldfrank, MD  Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Meera  Hameed, MD  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA Lynn  N.  Hoang, MD  Department of Anatomical Pathology, Vancouver General Hospital, Vancouver, BC, Canada Anjelica Hodgson, MD  Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada Brooke E. Howitt, MD  Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA Taylor  M.  Jenkins, MD  Department of Pathology, University of Virginia, Charlottesville, VA, USA Anne M. Mills, MD  Department of Pathology, University of Virginia, Charlottesville, VA, USA Kay J. Park, MD  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA Carlos  Parra-Herran, MD  Department of Pathology, Brigham and Women’s Hospital & Harvard Medical School, Boston, MA, USA Maria Carolina Reyes, MD  Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA Robert A. Soslow, MD  Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA Simona Stolnicu, MD, PhD  Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania Gulisa  Turashvili, MD, PhD  Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada Xiaoming Zhang, MD  Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

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1

Anatomy, Histology, Cytology, and Colposcopy of the Cervix Simona Stolnicu and Deborah Goldfrank

Contents 1.1    Anatomy, Histology, and Cytology of the Cervix 1.1.1   The Epithelium of the Ectocervix 1.1.1.1  Cytological Correlation in Squamous Epithelium 1.1.2   The Epithelium of the Endocervix 1.1.2.1  Cytological Correlation in Glandular Epithelium 1.1.3   The Epithelium of the Transformation Zone 1.1.3.1  Transformation Mechanisms 1.1.3.2  Cytological Correlation in the Epithelium of the Transformation Zone

 1  3  8  9  11  13  13  16

1.2    Cervical S troma

 16

1.3    Cervical Adventitia

 19

1.4    Cervical Vascularization and Innervation

 20

1.5    Changes of the Cervix During Pregnancy

 20

1.6    Colposcopy of the Cervix

 21

References

 22

Surgical pathologists should be aware of these changes to avoid misinterpretation of precursor lesions and malignant tumors of the cervix, and to understand how the various lesions develop. Being able to correlate a lesion’s colposcopic appearance with cytologic and histologic changes is similarly important.

S. Stolnicu (*) Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania D. Goldfrank Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: [email protected]

1.1

 natomy, Histology, and Cytology A of the Cervix

In adults, the cervix is approximately 3  cm in length and 2.5 cm in diameter, but these dimensions may vary depending on many factors, including the parity of the woman; in multiparous women, the cervix is larger than in nulliparous ones. Its shape is elongated (cylindrical). The lower portion, which protrudes into the vagina, is also called the vaginal portion of the cervix (portio vaginalis). The upper portion is located above the vaginal vault and is called the supravaginal portion (portio supravaginalis). Both portions are approximately equal in length. On the anterior side, the cervix is separated from the bladder by loose connective tissue that extends into the broad ligaments laterally. Posteriorly, the cervix is covered by peritoneum and is separated from the rectum by the retrovaginal space. Also, the cervix is attached to the second to fourth sacral vertebrae through the uterosacral ligaments, the main source of fixation, support, and suspension of the organ.

© Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_1

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The outer surface of the vaginal portion, called the ectocervix or exocervix, is covered mostly by a stratified squamous epithelium and continues as the epithelium lining the vaginal mucosa, which is histologically almost identical. The folds formed by the reflections of the vaginal mucosa at the front, back, and sides of the cervix are known as the vaginal fornices. In the center of the external surface of the ectocervix, one can detect the external opening of the endocervical canal, also called the external os. This opening is round in nulliparous women, but in parous woman it has the shape of a transverse groove (slit-shaped), dividing the ectocervix into two portions, the anterior lip and the posterior lip (Fig. 1.1). The endocervical canal, measuring approximately 8  mm in length, connects the vagina with the uterine cavity and extends from the external os (where it opens into the vagina) to the internal os (thus improperly

named), which marks the passage to the uterine isthmus. The internal os is basically not an opening, but rather a widening of the endocervical canal (Fig. 1.2). The junction between the cervix and the uterine corpus, located at the level of the internal os, is represented by the uterine isthmus (or lower uterine segment)—in fact, the lower portion of the uterine corpus. The endocervical canal is lined by a mucin-producing columnar, unstratified epithelium. The two types of epithelia, ectocervical and endocervical, cover the cervical stroma. The area where the ectocervical squamous epithelium continues with the endocervical glandular epithelium is called the squamocolumnar junction area. Normally, this area is located at the ectocervical level, but this location is highly variable during life, depending on a number of parameters, which are described below.

a

b

Fig. 1.1  The external opening of the endocervical canal, also called the external os, is round in nulliparous women (such as this 27-year-old patient) (a). In parous women, it has the shape of a transverse groove (slit-shaped), as in this 49-year-old patient (b)

Fig. 1.2  The endocervical canal connects the vagina with the uterine cavity and extends from the external os (where it opens into the vagina) to the internal os

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

1.1.1 The Epithelium of the Ectocervix

3

chromatin distribution and are usually associated with other changes in the epithelium (see Fig.  1.6b). Because of its Normally, the mature squamous epithelium that covers the PAS-positivity (deep pink), the intracytoplasmic glycogen ectocervix is stratified, non-keratinized, and glycogen-rich, can be highlighted by hematoxylin-PAS staining. related to the level of circulating estradiol (Fig. 1.3). In the In both the intermediate and superficial layers, keratinizafirst years of life and during postmenopause, when the level tion can sometimes occur. The keratinization of the intermeof circulating estrogen is low, the squamous epithelium is not diate and superficial cells has the role of protecting the rest of mature and consequently is glycogen-free, though shortly the epithelial cells and the subepithelial vascularization from after birth, the squamous epithelium becomes mature various types of trauma and infections. The cells in the superbecause of maternal estrogens (Fig. 1.4). Histologically, the ficial layer become flat, have more eosinophilic cytoplasm, cervical squamous epithelium is similar to the vaginal epi- and exfoliate physiologically (Fig. 1.7). The squamous epithelium, but it does not show the epithelial ridges character- thelium is completely replaced by a new population of cells istic of the vaginal epithelium (Fig. 1.5). every 4 to 5  days. These exfoliating cells can be sampled, In the mature cervical squamous epithelium, three layers constituting the Papanicolaou (Pap) smears examined for can be distinguished: the basal/parabasal layer (stratum early detection of cervical cancer and its precursor lesions. cylindricum, or the germinal cell layer), the intermediate In women of reproductive age, the cervical squamous epithelayer (stratum spinosum), and the superficial layer (Fig. 1.6a): lium undergoes changes due to estrogen-progesterone hormone stimulation during the menstrual cycle, with a predominance of • The stratum cylindricum consists of basal and parabasal superficial cells under the influence of estrogen, and of intermecells. The basal layer is represented by one layer of epi- diate cells with the effect of progesterone after ovulation. thelial cells of small size (10 μm in diameter) with scant In postmenopause, when estrogen levels are low, the ectocytoplasm and oval nuclei with dense chromatin, arranged cervical epithelium is thin, composed only of basal and paraperpendicularly to the basement membrane (in a picket-­ basal cells that are uniform in appearance, with reduced fence arrangement). These cells usually do not exhibit cytoplasm and no intracytoplasmic glycogen (Fig. 1.8). The mitotic activity, and as a consequence, do not stain with nucleus is larger, so that the nuclear/cytoplasmic ratio is Ki-67. The cells above them are called parabasal cells (a slightly modified in favor of the nucleus, a change that the term used mainly in cytology and less often in histopa- pathologist must be aware of, in order to avoid misdiagnosthology), forming four to five cell layers. Parabasal cells ing a cervical squamous intraepithelial lesion (SIL). The are polyhedral in shape and larger than basal cells, with atrophic epithelium has no mitotic activity and can no longer slightly more cytoplasm. The nuclei are vesicular, have protect the subepithelial vascularization from trauma, which less dense chromatin, and sometimes have mitotic figures; can lead to frequent bleeding and inflammation during this these cells are positive for Ki-67 [1]. period. The same morphologic appearance of the squamous • The intermediate layer is composed of more mature cells epithelium can be seen before puberty. with more abundant cytoplasm and smaller and more In contrast, thickening of the squamous epithelium may vesicular nuclei than in the basal layer, arranged with the be seen in various conditions: long axis parallel to the basal membrane. These cells are called intermediate cells. Their cytoplasm is fine, granular • Squamous cell hyperplasia, usually related to uterovagior clear, due to variable amounts of glycogen. The presnal prolapse, when the epithelium is also associated with ence of glycogen is responsible for the uptake of iodine hyperkeratosis (Fig. 1.9). with the Schiller test performed by the gynecologist to • Basal cell hyperplasia, a rare condition with no clinical detect abnormal areas, particularly squamous intraepitherelevance, in which the basal layer and adjacent part of lial lesions. Normal areas containing cytoplasmic glycothe parabasal layer increase in thickness, forming a well-­ gen will stain brown, whereas abnormal areas devoid of defined stratum. Nuclear pleomorphism and hyperchroglycogen will stain white on colposcopic examination. masia are absent, but the picket-fence appearance is lost. • The superficial layer is composed of cells with a diameter • Healing after trauma due to treatment by laser ablation, of 50  μm, abundant and clear cytoplasm (as a result of laser excision, or large loop diathermy excision. glycogen accumulation), and a small, round, pyknotic nucleus that is centrally located. These changes may be focal or may extensively involve the ectocervix. The accumulation of intracytoplasmic glycogen in both In about 40% of patients, the squamous epithelium may the superficial and intermediate layers can be localized dif- also contain other cells [2–5]: fusely or can be perinuclear. In the latter case, these cells may resemble koilocytes, a cellular change related to human • Endocrine cells. These cells are scattered and appear to be papillomavirus (HPV) infection, but koilocytes must have the origin of cervical tumors with neuroendocrine large and hyperchromatic, irregular nuclei with irregular differentiation.

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• Langerhans cells and lymphoid-derived cells. Various lymphocytes, plasma cells, and dendritic macrophages are found not only in the squamous epithelium but also in the endocervical epithelium and subepithelial stroma. • Melanocytes. These may be located in the basal layer of the epithelium, from which nevi and malignant cervical melanomas can develop. Immunohistochemically, all squamous epithelial cells are cytokeratin-positive (Fig.  1.10). Basal layer cells are positive for cytokeratin 18 and 19. Parabasal, intermediate, and superficial layer cells are positive for cytokeratin 4 and 13. Other types, such as cytokeratin 7 or 5/6, may be positive in the cervical squamous epithelium, varying by location [6–10]. The basal and parabasal cells are positive for epidermal growth factor and for HER-2/neu [11]. Also, basal cells are positive for bcl-2 [12, 13]. Cyclin D1 and CD44 are positive in both basal and parabasal cells, but cyclin D1 occurs only in parabasal cells [14–16]. The squamous epithelium is also positive for p63 and p40 (Fig. 1.11), but the squamous cells are negative for CEA. The parabasal cells are positive for Ki-67, as mentioned above, but the rest

of the normal squamous epithelium is Ki-67-negative [13, 17] (Fig. 1.12). p16, a surrogate marker for high-risk HPV infection, is negative (patchy pattern) in normal squamous epithelium (Fig. 1.13), whereas it is positive (strong and diffuse block-like) in high-­grade and in a significant proportion of low-grade SILs. These two markers are very helpful to differentiate between normal epithelium and an epithelium harboring an HPV-­driven high-grade SIL.  Estrogen receptors (ERs) have been revealed in the nuclei of the basal and parabasal cells, as well as in the nuclei of the intermediate cells (Fig. 1.14). During the menstrual cycle, the variation of ER expression in the cervix is less than in the endometrium [12, 14, 18]. During the follicular phase, ERs are slightly increased, compared with the luteal phase. In atrophic epithelium, as well as in those with inflammatory infiltrate, the expression of ERs is reduced. As for progesterone receptors (PRs), they are not detected in the ectocervical epithelium during the follicular phase, but in the luteal phase and in pregnancy, they are detected in the parabasal layer (Fig. 1.15). In the stromal cells of the cervix, ERs and PRs are evident in both phases of the menstrual cycle.

a

b

c

d

Fig. 1.3  Squamous epithelium of the exocervix is immature and glycogen-­free in the first year of life (a) and at 15 years (b). In women of reproductive age, the mature squamous epithelium that covers the

exocervix is stratified, non-keratinized, and glycogen-rich (c), whereas in postmenopause, it is glycogen-free (d)

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

Fig. 1.4  Squamous epithelium of the exocervix shortly after birth, with glycogen due to maternal estrogens

a

Fig. 1.6  Mature cervical squamous epithelium, in which three layers can be distinguished: the basal/parabasal layer, the intermediate layer, and the superficial layer (a). In contrast, koilocytes present large, hyper-

5

Fig. 1.5  Histologically, the cervical squamous epithelium is similar to the vaginal epithelium, but it does not show the epithelial ridges characteristic of the vaginal epithelium

b

chromatic, irregular nuclei with irregular chromatin distribution and are usually associated with other changes in the epithelium (b)

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Fig. 1.7  Keratinization in superficial layers in a postmenopausal patient with genital prolapse; the cells in the superficial layer are flat and have a more eosinophilic cytoplasm

Fig. 1.9  Squamous cell hyperplasia associated with hyperkeratosis, usually related to uterovaginal prolapse

Fig. 1.8  Squamous epithelium in postmenopause is thin

Fig. 1.10  Both squamous and glandular epithelium are positive for pan-cytokeratin

a

b

Fig. 1.11  The squamous epithelium is positive for both p63 (a) and p40 (b)

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Fig. 1.12  The parabasal cells are positive for Ki-67, but the rest of the normal squamous epithelium is Ki-67-negative

Fig. 1.14  The nuclei of the basal and parabasal cells are positive for estrogen receptors (ER); stromal cells are also positive for ER

Fig. 1.13 p16 is negative (patchy pattern) in normal squamous epithelium

Fig. 1.15  Progesterone receptors (PRs) are positive in the parabasal layer during luteal phase and pregnancy; the picture also shows stromal cells positive for PR

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1.1.1.1 Cytological Correlation in Squamous Epithelium During microscopic examination of a Pap, three types of normal squamous cells can be identified: parabasal squamous cells, intermediate squamous cells, and superficial squamous cells. Parabasal cells are the smallest with dense, green/blue cytoplasm and a dark, large nucleus (occupying most of the cell size) with evenly distributed chromatin (Fig. 1.16). Some of these cells show only the free nuclei present in the Pap. The intermediate cells are larger, with pale blue cytoplasm and nuclei that are round and smaller than those in the parabasal cells, with finely granular chromatin (Fig. 1.17). The superficial cells are the largest with a polyhedral shape, a pyknotic, small nucleus and pink cytoplasm (Fig. 1.18). Keratinization does not normally occur in the cervix. The proportion of superficial versus intermediate squamous cells in a Pap may vary throughout the menstrual cycle. Before ovulation, during estrogenic influence, the superficial

cells predominate, whereas at midcycle, there are few intermediate squamous cells, with a background of neutrophils. This is the best time to take a cervical Pap if the patient is enrolled in a national cervical screening program. Under the influence of progesterone, intermediate cells are most numerous, with an increased background of neutrophils occurring during the late secretory phase. In postmenopausal women, the Pap shows a predominance of parabasal cells with occasional intermediate cells, while endocervical cells are usually not identified (Fig. 1.19). Similar changes occur postpartum, but squamous metaplasia, regenerative changes, and endocervical cells can be identified. Menstrual specimens contain many neutrophils, red blood cells, and endometrial cells. The endometrial cells are small with dark, coarse chromatin, round nuclei, and scant basophilic cytoplasm. These cells are usually clustered in small, darkly stained groups, but they also can be observed as individual cells.

Fig. 1.16  Parabasal cells are the smallest in size, have a dense, green/ blue cytoplasm, a dark, large nucleus with evenly distributed chromatin (Papanicolaou stain)

Fig. 1.18  Superficial cells are the largest and present a polyhedral shape, with a pyknotic, small nucleus and pink-staining cytoplasm (Papanicolaou stain)

Fig. 1.17  Intermediate cells are larger, have pale blue cytoplasm, and round nuclei that are smaller than the ones in the parabasal cells, with finely granular chromatin (Papanicolaou stain)

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

a

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b

Fig. 1.19  Atrophy: The smear from a postmenopausal woman shows a predominance of parabasal cells with occasional intermediate cells (a); endocervical cells are usually not identified (b) (Papanicolaou stain)

1.1.2 The Epithelium of the Endocervix The endocervical epithelium is composed of a single layer of columnar cells, with small elongated nuclei containing dense chromatin, arranged at the base of the cell, with abundant cytoplasm due to mucin secretion (Fig. 1.20). This mucin is pale blue on hematoxylin and eosin (H&E)-stained slides. Mucicarmine and Alcian blue are positive, revealing acidic mucopolysaccharides in the mucin. Neutral mucopolysaccharides may also occur in smaller quantities. Columnar cells are 20–30 μm high and 5–9 μm wide. Nuclear overlapping can be seen as a normal phenomenon at the base of these cells and should not be mistaken for endocervical glandular neoplasia (Fig.  1.21). In normal endocervical epithelium, mitotic figures are rarely observed, and nucleoli are usually indistinct. The nuclei can become larger, with prominent nucleoli, and mitotic figures are numerous in reactive and regenerative processes, as well as in various neoplastic lesions (Fig. 1.22). In addition to these cells, other types of cells are among those found in the endocervical epithelium: • Goblet (caliciform) cells. When they are numerous, the condition is diagnosed as intestinal metaplasia (Fig. 1.23), which is highly correlated with glandular neoplasia and must be reported even in association with discrete nuclear atypia. • Ciliated cells. When they are numerous and associated with tubal type secretory cells and reserve or intercalary cells, they are diagnosed as tubal metaplasia (Fig. 1.24). This condition, found in up to 30% of patients, is not related to hormonal changes or inflammation; it should not be mistaken for endocervical glandular neoplasia (adenocarcinoma in situ). Tubal metaplasia does not show atypia or brisk mitotic activity; it is located close

to the superficial inner third of the cervical wall. p16 is negative (patchy) and the Ki-67 index is low. Of interest, tubo-­endometrioid metaplasia following conization can also occur. Tubo-endometrioid metaplasia is part of a spectrum of changes that include tubal metaplasia. In contrast to tubal metaplasia, tubo-endometrioid may lack cilia, imparting an appearance similar to endometrium; typical endometrial stroma is lacking. Instead, there is a vague cuff of surrounding bland and spindled stroma. • Reserve subcolumnar cells. These should not be confused with lymphocytes, which may migrate into the endocervical epithelium in inflammatory processes. • Argyrophilic and argentaffin-positive endocrine cells. These cells are identified in about 20% of patients and potentially represent the origin of various tumors in the cervix with neuroendocrine differentiation [19]. The endocervical epithelium covers the surface of the endocervical canal, with architecture ranging from flat to villous. The villous appearance is due to invaginations of epithelium into underlying stroma, forming elongated clefts (also called crypts) (Fig.  1.25). As a result, the underlying fibroconnective tissue assumes a papillary shape, with a central capillary. On longitudinal and transverse sections through the clefts, they resemble glands, which is a false impression. There are no true endocervical glands. About 60 years ago, Fluhmann demonstrated through serial sections and three-­ dimensional reconstruction that the endocervical clefts actually represent protrusions of the endocervical epithelium in the underlying stroma [20, 21]. The literature currently uses all terms, “endocervical glands” and “crypts” or “clefts.” Sometimes a lobular pattern is seen, with a cystically dilated cleft associated with what appear to be acini, organized in a lobular configuration (Fig. 1.26). When the endocervical epi-

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thelium lining the crypts proliferates, secondary channels appear in the adjacent stroma, giving rise to a lesion that Fluhmann termed tunnel clusters (also known in the literature as Fluhmann’s lumens or cervical adenomatous hyperplasia). These secondary channels multiply further during pregnancy. They may have empty lumina or intraluminal secretions that appears on H&E as eosinophilic material. If the secretions are abundant, the epithelium of the channels may appear flattened. The depth to which endocervical crypts can extend into the cervical stroma varies from person to person, but it usually does not exceed 5 mm (though it can reach up to 1 cm) [22, 23]. This information is important to keep in mind to avoid confusion with lesions such as minimal deviation adea

S. Stolnicu and D. Goldfrank

nocarcinoma of mucinous type (a well-differentiated variant of gastric type endocervical adenocarcinoma), an adenocarcinoma that features epithelium that can be difficult to ­distinguish from normal endocervix and in which deep neoplastic glands are often present. The details concerning this lesion are covered in Chap. 8. The endocervical epithelium undergoes minimal morphological changes during the menstrual cycle, which are represented only by a change in the position of the nuclei; in the proliferative phase of the cycle, they are arranged in the middle of the cell, due to the presence of subnuclear vacuoles. Biochemical changes are more important, consisting of decreased viscosity and alkalization of the mucus in the proliferative phase, facilitating the penetrab

Fig. 1.20  Both superficial and glandular columnar epithelium (a) is composed of a single layer of columnar cells, with small, elongated nuclei, dense chromatin arranged at the base of the cell, and abundant cytoplasm due to mucin secretion (b)

Fig. 1.21  Nuclear overlapping can be seen as a normal phenomenon at the base of these columnar cells

Fig. 1.22  The nuclei of the columnar endocervical epithelium can become larger, rounded, with prominent nucleoli in a reactive process in association with numerous neutrophils in various inflammatory infiltrates

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

Fig. 1.23  Intestinal metaplasia: numerous goblet cells replacing the normal glandular epithelium of the cervix

a

b

Fig. 1.24  Tubal metaplasia: Dark blue endocervical glands (a) presenting secretory, reserve, intercalary, and ciliated cells (b)

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Fig. 1.25  The endocervical epithelium covers the surface of the endocervical canal with a villous architecture but also penetrates the underlying stroma, forming elongated clefts (crypts)

tion of sperm, whereas in the luteal phase, the viscosity of the mucus increases, it becomes acidic, and it contains numerous leukocytes, acting as a barrier against penetration. The acidic mucin content of normal epithelium changes during the menstrual cycle, with sialomucins increasing during the ovulation period and sulphomucins increasing in the secretory phase [24]. Immunohistochemically, the endocervical epithelium is positive for various types of cytokeratins, such as cytokeratin 7, 8, 18, and 19, as well as various mucin antigens such as MUC1, MUC4, and MUC5, whereas MUC2 is typically absent [8, 25–28]. Normal endocervical epithelium is also positive for EMA (epithelial membrane antigen), CEA, and PAX8, Cyclin D1, ER, PR, and HER-2 [12, 14, 15, 18]. Of interest, gastric and intestinal markers (such as CLDN18, CDH17, TFF2, SATB2) are negative in normal columnar epithelium, which can be helpful in differentiating between cervical lesions and metastases to the cervix from the gastrointestinal tract [29].

1.1.2.1 Cytological Correlation in Glandular Epithelium Columnar endocervical cells are easily identified in a Pap, occurring in sheets or small groups, or even as isolated cells. These glandular cells are much larger than endometrial cells. They have round or elongated nuclei with finely granular chromatin, sometimes with small nucleoli and pale blue/ gray, abundant cytoplasm, usually vacuolated, with indistinct cell borders and a characteristic “honeycomb” ­appearance when present in sheets and clusters due to the central location of the nuclei in the cytoplasm (Fig. 1.27).

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b

c

Fig. 1.26  Crypts (a, b) sometimes presenting a lobular pattern with a cystically dilated cleft and peripheral grooves organized in a uniform lobular distribution (c)

a

Fig. 1.27  The columnar endocervical cells are much larger than the endometrial cells, have round/elongated nuclei with finely granular chromatin, sometimes with small nucleoli and pale blue/gray abundant cytoplasm with indistinct cell borders. They may occur in sheets or

b

small groups (a) or with a characteristic “honeycomb” appearance (b) due to the central location of the nuclei in the cytoplasm (Papanicolaou stain)

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

1.1.3 The Epithelium of the Transformation Zone The endocervical epithelium has a different location throughout life as a response to hormonal stimulation. At birth, the endocervical epithelium appears in the ectocervix, but it moves to the endocervical canal during the first year of life, where it remains until the first menstrual cycle. At puberty, it moves again to the ectocervix, more prominently on the anterior lip than the posterior lip. As the cervix grows larger, the endocervical epithelium runs further outward onto the ectocervix (more markedly anteriorly and posteriorly than at the sides), giving rise to ectropion (cervical ectopia). Ectropion is even more pronounced during pregnancy or after progesterone therapy. Some authors have termed this lesion an “erosion” because upon inspection the ectropion epithelium appears red (as the columnar epithelium is one cell layer thick and transparent to the underlying blood vessels) and rough (related to the villous pattern of the endocervical tissue). This phenomenon is important when pathologists refer to the type of tissue they examine under the microscope. Most pathologists do not refer to the position of the tissue from which it was sampled, but rather to the type of the tissue. Thus, a biopsy specimen consisting of stroma and glandular epithelium in the form of surface epithelium or crypts may be described as “endocervical,” although the tissue may come from the ectocervix, which can be clinically misleading. Throughout the reproductive years, the endocervical epithelium in the ectropion is gradually replaced by squamous epithelium (squamous metaplasia) resulting in the areas referred to as the transformation zone or T zone. The term “squamocolumnar junction” is used in two settings: at birth, it is the area where the ectocervical squamous epithelium is contiguous with the endocervical glandular epithelium (original squamocolumnar junction); during reproductive life, the junction includes squamous metaplasia (functional squamocolumnar junction). The area between the original and functional junctions, the transformation zone, is considered to be the area where most HPV-associated neoplastic processes occur, and because it is located in the ectocervix during the reproductive life, it can be seen on colposcopic examination. During premenopause, the functional squamocolumnar junction migrates to the outer opening of the cervical canal. Later, because of the decrease in cervical size, it is located in the endocervical canal, a phenomenon called inversion, which explains why the transformation zone cannot be visualized with the naked eye or during colposcopic examination in postmenopausal patients.

1.1.3.1 Transformation Mechanisms Two mechanisms are responsible for the transformation of endocervical epithelium into squamous epithelium: squamous epithelialization and squamous metaplasia [30]:

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During squamous epithelialization, direct development of mature squamous cells occurs in the ectocervix. These cells initially appear between the basal membrane of the epithelium and the endocervical glandular cells. As they grow, they push the glandular cells outward. The degenerated columnar cells will subsequently detach from the epithelium. Initially, squamous epithelialization occurs in the openings of endocervical clefts (Fig. 1.28), and subsequently, the clefts are also involved. If epithelialization of the cleft openings causes their obstruction by continuous accumulation of mucus, the clefts dilate cystically and Nabothian cysts appear (Fig.  1.29). Crypts in which the columnar epithelium has been replaced by squamous epithelium, especially in cross sections, should not be confused with invasive squamous cell carcinoma. Even though the cells in squamous epithelialization have enlarged nuclei and nucleoli, they do not present anaplasia, pleomorphism, chromatin abnormalities, or mitotic figures. They do not infiltrate the adjacent stroma, and there is no stromal desmoplasia. Squamous epithelialization is not accompanied by tissue granulation, but only by a chronic inflammatory infiltrate. Squamous metaplasia is part of a process that involves an initial proliferation of endocervical reserve cells and their subsequent differentiation into squamous cells [20, 31]. This phenomenon is also called epidermalization, and the stimulus for this phenomenon is thought to be the increased acidity of the vaginal environment compared with that of the cervical canal. The reserve cells are cuboidal, with round nuclei and scant cytoplasm, and are located beneath the columnar epithelial cells (Fig.  1.30). They resemble the basal or parabasal cells of the ectocervical squamous epithelium. Their origin has been widely discussed; some authors consider that they derive from columnar mucin-producing cells, basal cells of the squamous epithelium, embryonic remnants of urogenital origin, and yet others suggest that they derive from stromal cells [32, 33]. Immature squamous metaplasia is covered by a layer of endocervical cells. As these reserve cells proliferate and stratify, their cytoplasm becomes more abundant as they differentiate towards squamous cells (immature squamous metaplasia). Later, these cells acquire cytoplasmic glycogen, identical to the superficial cells of the exocervical epithelium (mature squamous metaplasia) (Fig.  1.31). Neither condition (mature and immature squamous metaplasia) is associated with a risk for developing subsequent malignancy. Immature squamous metaplasia should not be confused with squamous intraepithelial lesion (SIL). Although cells constituting immature squamous m ­ etaplasia have reduced cytoplasm with an increased nuclear/cytoplasmic ratio and elongated, sometimes hyperchromatic nuclei, the nuclei are nonetheless uniform, without chromatin changes, there are few mitoses, and the nucleoli are distinct. Unlike most SILs, the Ki-67 index is less than 15% in squamous metaplasia and p16 is negative or displays patchy staining, but not block-like staining, which is a surrogate for the presence of integrated

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S. Stolnicu and D. Goldfrank

high-risk HPV, seen in nearly all high-grade SILs and a significant proportion of LSILs [34, 35]. Immunohistochemically, the cells in immature squamous metaplasia are cytokeratinpositive, and some may be positive for mucicarmine, MUC2, and MUC5 [27]. Immature squamous metaplasia may sometimes have nuclear atypia, which is described as atypical immature metaplasia [36]. Distinguishing between atypical immature metaplasia and HSIL can therefore be difficult. In atypical immature metaplasia, the nuclei of the cells are only slightly enlarged and round, with fine chromatin and prominent nucleoli, whereas in high-grade SIL, the nuclei are more pleomorphic and hyperchromatic, and mitotic figures appear, some of which may be atypical. High-grade SIL displays greater cellularity and cellular disorganization with lack of polarity. Transitional metaplasia is an incidental finding

occurring in postmenopausal patients that shares some features with atrophy. It involves the ectocervix but sometimes also the endocervix; it is composed of basal and parabasal cells with high nuclear/cytoplasmic ratio, oval or fusiform nuclei, and longitudinal grooves that are oriented vertically in the deep layers and horizontally in the superficial ones, extending throughout the thickness of the epithelium, resembling transitional epithelium [37, 38] (Fig.  1.32). Some authors call this cervical Walthard islands. The nucleoli are small or indistinct, and mitoses are absent or rare. Frequently, cells have a clear perinuclear halo, but the nuclear/cytoplasmic ratio is usually low. Immunohistochemically, transitional cell metaplasia (like urothelium epithelium) expresses cytokeratin 13, 17, and 18, but in contrast to the urothelium, it is negative for cytokeratin 20.

Fig. 1.28  Squamous epithelialization occurred in the openings of endocervical clefts, causing obstruction

Fig. 1.29  From continuous accumulation of mucus, the clefts dilate cystically, forming Nabothian cysts

a

b

Fig. 1.30  Immature squamous metaplasia: proliferation of endocervical reserve cells (upper right) and their subsequent differentiation into squamous cells (a) with cuboidal shape, round nuclei, and scanty cytoplasm, located beneath the columnar epithelial cells (b)

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

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a

b

c

d

Fig. 1.31  Mature squamous metaplasia replacing the original glandular epithelium (a); the mature squamous cells are larger, and the cytoplasm is filled with glycogen (b). These cells can extend into the clefts (c), sometimes coexisting with immature squamous metaplasia (left) (d)

The cervical squamocolumnar junction and the “T zone” are the sites of the recently described embryonic cell population that was proposed as the cell of origin for cervical carcinoma and its precursors. This discrete population of cuboidal to low columnar cells has a unique genetic and immunohistochemical profile (squamo-columnar markers such as cytokeratin 7, AGR2, GDA, and MMP7) shared with high-grade SIL, a subset of low-grade SIL infected with high-risk HPV, adenocarcinoma in situ, and invasive cervical cancer [39, 40]. Crum et  al. [36] proposed that direct infection of squamo-columnar embryonic cells by high-risk HPV results in transdifferentiation of these cells with an outgrowth of subjacent squamous cells (so-called top-down differentiation) leading to SIL, most often of high grade and with the propensity to progress [41]. In contrast, infection of the kera-

tinocytes derived from ectocervical or squamous metaplastic epithelium usually results in low-grade SIL that is likely to regress [39, 40]. The presence of embryonic cells would also explain the markedly different risks for vaginal and cervical HSIL and cancer [42]. In routine practice, the term squamous metaplasia is used by the pathologist to designate both epithelialization and squamous metaplasia. Also, squamous metaplasia is an irreversible permanent process; the cells will never change into glandular epithelium. When the transformation zone moves back to the cervical canal, the squamous epithelium moves too, lining the cervical canal. Squamous metaplasia involves not only the surface epithelium, but also the clefts (sometimes only focally). Caution must be taken when examining the cervix, as these areas should not be interpreted as invasive carcinoma.

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S. Stolnicu and D. Goldfrank

a

b

c

Fig. 1.32  Transitional metaplasia: endocervical glands in which the columnar epithelium has been replaced by basal and parabasal cells, which extend throughout the thickness of the epithelium (a), with high nuclear/cytoplasmic ratio, oval or fusiform nuclei, small nucleoli, no

mitotic figures, and longitudinal grooves oriented vertically in the deep layers and horizontally in the superficial ones (b). Immunohistochemically, they express cytokeratin 7 (c)

1.1.3.2 Cytological Correlation in the Epithelium of the Transformation Zone Both mature and immature squamous cells can be identified on microscopic examination of Paps. Immature squamous metaplasia cells are small and round with large, dark hyperchromatic nuclei with coarse chromatin, occasional nucleoli and basophilic green, dense cytoplasm with well-defined cell borders. They usually occur in small groups. The cells with mature squamous metaplasia have more abundant blue or pink cytoplasm and a larger nucleus with fine chromatin (Fig. 1.33).

1.2

Cervical Stroma

The cervical stroma is composed of a mixture of fibrous, muscular, and elastic tissue, with a predominance of the fibrous component (Fig.  1.34). In the upper portion of the

Fig. 1.33  Mature  squamous metaplastic cells have a more abundant blue or pink cytoplasm and a larger nucleus with fine chromatin (Papanicolaou stain)

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

cervix, the stroma merges with the endometrial stroma. The cervical stroma is predominantly fibrotic, whereas the corpus stroma is more muscular in appearance, but the demarcation between the two types of stroma may be unclear because of a hybrid endocervical-endometrial appearance. Some pathologists use the type of stroma to assign the anatomical site of origin of a tumor, but this can lead to erroneous conclusions because of the hybrid nature of the stroma at the junction between the lower uterine segment and the upper endocervix. The muscular layer is more abundant in the endocervix than the ectocervix due to extension of the muscular fibers from the myometrium inferiorly along the periphery of the portio supravaginalis of the cervix, allowing marked dilation of the cervix at the time of birth. The cervical stroma contains many blood vessels (Fig. 1.35). At the epithelial-­stromal junction, there is a rich capillary network, which sometimes may be prominent; however, this should not be confused with a hemangioma (Fig. 1.36). The endocervical stroma normally has a lymphoid population, sometimes forming lymphoid aggregates, with or without germinal centers (Fig. 1.37). The lymphoid cells are involved in mucosal immunity and defense mechanisms against viral and bacterial pathogens. The lymphoid cells of the endocervix are part of the mucosal-associated lymphoid system (MALT) and secrete IgA. They can also migrate into the endocervical epithelium, giving the appearance of “clear cells” (these cells being formerly considered reserve cells). In the cervical stroma, there is also a population of scattered plasma cells and dendritic cells (also called Langerhans cells), some of which contain Birbeck granules. For the diagnosis of chronic cervicitis, a large number of inflammatory cells is required. There is a tendency to incorrectly diagnose chronic cervicitis in the presence of normally occurring, small inflammatory infiltrates in the cervical stroma [43]. This should be avoided. Mesonephric remnants may be identified in the cervical stroma in more than 22% of cases, especially in the lateral portion of the cervix, in the deep stroma, but sometimes also below the endocervical epithelium [44]. In the embryo, the kidneys develop from the mesonephros, and in males, the mesonephros gives rise to the epididymis and its append-

17

ages, as well as the epididymis and rete testis; the mesonephric duct is responsible for the formation of the deferential vessels, the seminal vesicles, and part of the urethra and prostate [45]. In the female, however, in the absence of testosterone, there is regression of the mesonephric tubules and ducts, so that only mesonephric remnants occur in adults, and their function is not well known. In women, the incompletely developed Wolffian system can be divided into two areas: the upper part, derived from mesonephric tubules, and the lower part of the Gartner or Wolffian duct, which extends laterally along the uterine corpus and cervix and ends with an ampullary dilatation in the vagina. Mesonephric remnants come from the lower Wolffian system [45, 46] and in optimally oriented tissue, there is an elongated central duct, surrounded by smaller tubular structures. These round glands are lined by a single layer of cuboid cells with small nuclei (Fig. 1.38). The cytoplasm lacks mucin and is therefore PAS and mucicarmine negative. The lumen contains eosinophilic material, which is PAS-positive. Mesonephric remnants should not be confused with invasive adenocarcinoma. Typically, mesonephric remnants are variably positive for calretinin, CD10, and GATA3, helping to differentiate these embryological remnants from diagnostic mimics other than mesonephric adenocarcinoma [47, 48]. Mesonephric remnants can be associated with mesonephric hyperplasia or mesonephric adenocarcinomas of the cervix. In the cervical stroma, tissues derived from the ectoderm also may appear, including epidermis and appended structures such as sebaceous glands, mature hyaline cartilage, or bone (Fig. 1.39). Multinucleated giant cells (isolated or multifocal) also may appear, sometimes with enlarged, hyperchromatic nuclei that are bizarre in appearance, with smudged chromatin and prominent nucleoli (Fig.  1.40). These cells have no mitotic activity and should not be confused with a neoplastic process. Immunohistochemistry can assist, as these cells have a low Ki-67 index, are invariably positive for vimentin, ER, PR and androgen receptor (AR), and are occasionally and focally positive for CD10 and smooth muscle markers such as actin, desmin, and h-­caldesmon [49–53]. Atypical stromal cells are consistently negative for cytokeratins, EMA, myogenin, CD34, factor VIII, and macrophage marker [54].

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Fig. 1.34  Cervical squamous epithelium lines the cervical stroma

S. Stolnicu and D. Goldfrank

Fig. 1.36  Cervical hemangioma: proliferation of blood vessels forming a mass at the junction between epithelium and stroma

a

Fig. 1.35  The cervical stroma is predominantly fibrotic and contains a large number of vessels

b

Fig. 1.37  The endocervical stroma presents a lymphocyte population (a), forming lymphoid aggregates, with or without germinal centers (b)

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

Fig. 1.38  Mesonephric remnants: tubular, round structures lined by a round, central nucleus and a single layer of cuboid cells

a

19

Fig. 1.39  Sebaceous glands in the cervical stroma

b

Fig. 1.40  Multinucleated giant cells, isolated or multifocal (a), sometimes show enlarged, hyperchromatic nuclei that are bizarre in appearance, with smudged chromatin and containing prominent nucleoli but without mitotic activity (b)

1.3

Cervical Adventitia

In the external part of the cervical wall, there is a layer called adventitia, made up of loose connective tissue with numerous vessels (Fig.  1.41). This layer extends in the

lower part of the cervix to the vaginal fornix; in the upper part, it is continuous with the isthmus and the uterine body, up to the part where the peritoneum is attached, where serosa begins.

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S. Stolnicu and D. Goldfrank

a

b

Fig. 1.41  Adventitia: In the external part of the cervical wall, there is a layer made up of loose connective tissue (a), with numerous vessels (b)

1.4

Cervical Vascularization and Innervation

The lymphatic drainage of the cervix is organized into three beds: one underlying the squamous and endocervical epithelium, one deeper into the stroma, and a third one at the outer surface of the cervix. All these lymphatic vessels connect with pelvic lymph nodes divided into external iliac, internal iliac, and common iliac nodes. The blood supply of the cervix is provided by the descending branches of the uterine arteries entering the lateral walls along the upper margin of the paracervical ligaments. The innervation is limited to the endocervix and peripheral area of the ectocervix and is provided by nerves from the pelvic autonomic system, including the superior, middle, and inferior hypogastric plexuses.

1.5

 hanges of the Cervix During C Pregnancy

During pregnancy, the ectropion is obvious, with a proliferation of endocervical epithelium leading to a consequent increase in the surface area of mucus-secreting glandular epithelium. One result is a more papillary appearance of the endocervical canal epithelium, along with the appearance of endocervical glandular hyperplasia or endocervical microglandular hyperplasia (not to be confused with an identical lesion produced by oral contraceptive medication) (Fig.  1.42a). These glands secrete an increased amount of

viscous mucus, which acts as a barrier between the vagina and the uterine cavity. In the endocervical stroma, collagen fibers degenerate and acidic mucopolysaccharides accumulate, causing the cervix to have a soft consistency and allow it to become flattened during pregnancy. At the same time, there is an increase in vascularization and edema accompanied by an acute inflammatory infiltrate (see Fig. 1.42b). Another change is the Arias-Stella reaction, which consists of the focal transformation of the endocervical epithelium into an epithelium containing large cells with clear, vacuolated, abundant cytoplasm and enlarged and hyperchromatic nuclei with indistinct nucleoli (Fig. 1.43). Biotin vacuoles in the form of nuclear pseudoinclusions can also be present. The nuclei can project into the glandular lumen in a hobnail pattern. Typically, there is no mitotic activity, but rare mitoses are occasionally present. This change should not be confused with clear cell carcinoma, especially since the Arias-Stella reaction does not form a tumor mass. A cervical stromal change that occurs in one third of cervices examined during pregnancy is stromal pseudodecidualization, a phenomenon that is mediated by high levels of progesterone during pregnancy; it disappears by 2  months after birth. In cervical pseudodecidualization, the cervical stromal cells are identical to gestational decidual cells of the endometrium: they are large, with abundant pink cytoplasm and well-defined borders. The nuclei are not atypical, which can help differentiation from invasive squamous carcinoma in a scant biopsy. Immunohistochemistry can also assist, as stromal cells with pseudodecidualization are negative for cytokeratins and p16.

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix

a

21

b

Fig. 1.42  Pregnancy-related changes: Hyperplasia of the endocervical glands, presenting squamous metaplasia (a) with increased vascularization and acute inflammatory infiltrate into the stroma (b)

Fig. 1.43  Arias-Stella changes replacing normal epithelium of endocervical glands

1.6

Colposcopy of the Cervix

Colposcopy is the standard of care for evaluation of an abnormal Pap test. Pap screening, with cytologic evaluation and HPV testing, is used for population-based cervical cancer screening. Patients are referred for more specific, diagnostic evaluation by colposcopy for a wide range of abnormal findings on Pap, including abnormal cytologic findings, HPV positive tests, and for inadequate cell sampling. Colposcopy can also be indicated for evaluation of visible or palpable cervical abnormalities on examination. The goal of colposcopy is to identify precancerous lesions or cancer.

Colposcopy involves close examination of the cervix and vagina with various magnifying lenses (colposcope) and with targeted biopsy sampling when indicated. The cervix and upper vagina are inspected grossly and after application of 3–5% acetic acid to identify any areas of whitening (acetowhite changes) under white light and with a green or blue light filter. Lugol’s solution (aqueous iodine) can be used as well to identify areas that do not stain brown with application of the solution to the cervix and upper vagina. It is important to inspect and document visibility and findings on the squamocolumnar junction. In 2015, the American Society for Colposcopy and Cervical Pathology (ASCCP) initiated an effort to standardize colposcopy technique and terminology within the United States [55]. Colposcopic evaluation needs to include systematic examination and description of findings. Per ASCCP recommendations [56], this should include: 1. Indication for colposcopy 2. Examination of the vulva, vagina, and cervix grossly 3. Description of cervical and transformation zone visibility 4. Presence and description of acetowhite lesions, vascular changes, non-staining areas with Lugol’s solution, other lesions or abnormalities 5. Colposcopic impression of normal/benign versus low-­ grade lesions versus high-grade lesions versus cancer 6. If biopsies are indicated, biopsies should be taken at the squamocolumnar junction, with documentation of location 7. Document whether endocervical sampling, with curettage or brush, was performed.

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Beyond the absence of abnormal findings, normal colposcopic findings include visualization of smooth squamous epithelium, either with a premenopausal, well-vascularized appearance or with a postmenopausal, atrophic, and pale appearance. Benign lesions such as cervical ectropion, Nabothian cysts, and gland openings can be identified and are not concerning. Colposcopy is a cornerstone of global cervical cancer screening and prevention, and the importance of performing and documenting colposcopy in a standard, systematic manner cannot be overstated.

References 1. Konishi I, Fujii S, Nonogaki H, Nanbu Y, Iwai T, Mori T.  Immunohistochemical analysis of estrogen receptors, progesterone receptors, Ki-67 antigen, and human papillomavirus DNA in normal and neoplastic epithelium of the uterine cervix. Cancer. 1991;68:1340–50. 2. Cid JM.  Melanoid pigmentation of the endocervix: a neurogenic visceral argument. Anat Pathol. 1959;4:617–28. 3. Fetissof F, Arbeille B, Boivin F, Sam-Giao M, Henrion C, Lansac J.  Endocrine cells in ectocervical epithelium. An immunohistochemical and ultrastructural analysis. Virchows Arch A Pathol Anat Histopathol. 1987;411:293–8. 4. Fetissof F, Serres G, Arbeille B, de Muret A, Sam-Giao M, Lansac J.  Argyrophilic cells and ectocervical epithelium. Int J Gynecol Pathol. 1991;10:177–90. 5. Morris HH, Gatter KC, Stein H, Mason DY.  Langerhans’ cells in human cervical epithelium: an immunohistological study. Br J Obstet Gynaecol. 1983;90:400–11. 6. Moll R, Franke WW, Schiller DL, Geiger B, Krepler R. The catalog of human cytokeratins: patterns of expression in normal epithelia, tumors and cultured cells. Cell. 1982;31:11–24. 7. Moll R, Levy R, Czernobilsky B, Hohlweg-Majert P, Dallenbach-­ Hellweg G, Franke WW.  Cytokeratins of normal epithelia and some neoplasms of the female genital tract. Lab Investig. 1983;49:599–610. 8. Franke WW, Moll R, Achtstaetter T, Kuhn C. Cell typing of epithelia and carcinomas of the female genital tract using cytoskeletal proteins as markers. In: Peto R, editor. Viral etiology of cervical cancer. Banbury report 21. New York: Cold Spring Harbor Laboratory; 1986. p. 121–44. 9. Nielsen LN, Hørding U, Daugaard S, Rasmussen LP, Norrild B.  Cytokeratin intermediate filament pattern and human papillomavirus type in uterine cervical biopsies with different histological diagnosis. Gynecol Obstet Investig. 1991;32:232–8. 10. Smedts F, Ramaekers F, Troyanovsky S, Pruszczynski M, Robben H, Lane B, et al. Basal-cell keratins in cervical reserve cells and a comparison to their expression in cervical intraepithelial neoplasia. Am J Pathol. 1992;140:601–12. 11. Berchuck A, Rodriguez G, Kamel A, Soper JT, Clarke-Pearson DL, Bast RC Jr. Expression of epidermal growth factor receptor and HER-2/neu in normal and neoplastic cervix, vulva, and vagina. Obstet Gynecol. 1990;76:381–7. 12. Saegusa M, Takano Y, Hashimura M, Shoji Y, Okayasu I. The possible role of bcl-2 expression in the progression of tumors of the uterine cervix. Cancer. 1995;76:2297–303. 13. ter Harmsel B, Kuijpers J, Smedts F, Jeunink M, Trimbos B, Ramaekers F.  Progressing imbalance between proliferation and

S. Stolnicu and D. Goldfrank apoptosis with increasing severity of cervical intraepithelial neoplasia. Int J Gynecol Pathol. 1997;16:205–11. 14. Kanai M, Shiozawa T, Xin L, Nikaido T, Fujii S. Immunohistochemical detection of sex steroid receptors, cyclins, and cyclin-dependent kinases in the normal and neoplastic squamous epithelia of the uterine cervix. Cancer. 1998;82:1709–19. 15. Cho NH, Kim YT, Kim JW.  Correlation between G1 cyclins and HPV in the uterine cervix. Int J Gynecol Pathol. 1997;16:339–47. 16. Ibrahim EM, Blackett AD, Tidy JA, Wells M. CD44 is a marker of endocervical neoplasia. Int J Gynecol Pathol. 1999;18:101–8. 17. McCluggage WG, Buhidma M, Tang L, Maxwell P, Bharucha H. Monoclonal antibody MIB1 in the assessment of cervical squamous intraepithelial lesions. Int J Gynecol Pathol. 1996;15:131–6. 18. Fujiwara H, Tortolero-Luna G, Mitchell MF, Koulos JP, Wright TC Jr. Adenocarcinoma of the cervix. Expression and clinical significance of estrogen and progesterone receptors. Cancer. 1997;79:505–12. 19. Tateishi R, Wada A, Hayakawa K, Hongo J, Ishii S. Argyrophil cell carcinomas (apudomas) of the uterine cervix. Light and electron microscopic observations of 5 cases. Virchows Arch A Pathol Anat Histol. 1975;366:257–74. 20. Fluhmann CF.  Focal hyperplasis (tunnel clusters) of the cervix uteri. Obstet Gynecol. 1961;17:206–14. 21. Fluhmann CF. The nature and development of the so-called glands of the cervix uteri. Am J Obstet Gynecol 1957;74:753–66; discussion 766–8. 22. Anderson MC, Hartley RB. Cervical crypt involvement by intraepithelial neoplasia. Obstet Gynecol. 1980;55:546–50. 23. Clement PB, Young RH. Deep nabothian cysts of the uterine cervix. A possible source of confusion with minimal-deviation adenocarcinoma (adenoma malignum). Int J Gynecol Pathol. 1989;8:340–8. 24. Wakefield EA, Wells M.  Histochemical study of endocervical glycoproteins throughout the normal menstrual cycle and adjacent to cervical intraepithelial neoplasia. Int J Gynecol Pathol. 1985;4:230–9. 25. Maes G, Fleuren GJ, Bara J, Nap M. The distribution of mucins, carcinoembryonic antigen, and mucus-associated antigens in endocervical and endometrial adenocarcinomas. Int J Gynecol Pathol. 1988;7:112–22. 26. Gipson IK, Spurr-Michaud S, Moccia R, Zhan Q, Toribara N, Ho SB, et al. MUC4 and MUC5B transcripts are the prevalent mucin messenger ribonucleic acids of the human endocervix. Biol Reprod. 1999;60:58–64. 27. Riethdorf L, O’Connell JT, Riethdorf S, Cviko A, Crum CP. Differential expression of MUC2 and MUC5AC in benign and malignant glandular lesions of the cervix uteri. Virchows Arch. 2000;437:365–71. 28. Baker AC, Eltoum I, Curry RO, Stockard CR, Manne U, Grizzle WE, Chhieng D.  Mucinous expression in benign and neoplastic glandular lesions of the uterine cervix. Arch Pathol Lab Med. 2006;130:1510–5. 29. Moh M, Krings G, Ates D, Aysal A, Kim GE, Rabban JT. SATB2 expression distinguishes ovarian metastases of colorectal and appendiceal origin from primary ovarian tumors of mucinous or endometrioid type. Am J Surg Pathol. 2016;40:419–32. https://doi. org/10.1097/PAS.0000000000000553. 30. Moore KL.  The developing human. Clinically oriented embryology. 3rd ed. Philadelphia: WB Saunders; 1982. p. 207–21. 31. Forsberg JG.  Cervicovaginal epithelium: its origin and development. Am J Obstet Gynecol. 1973;115:1025–43. 32. Weikel W, Wagner R, Moll R.  Characterization of subcolum nar reserve cells and other epithelia of human uterine cervix. Demonstration of diverse cytokeratin polypeptides in reserve cells. Virchows Arch B Cell Pathol Incl Mod Pathol. 1987;54:98–110. 33. Smedts F, Ramaekers F, Leube RE, Keijser K, Link M, Vooijs P.  Expression of keratins 1, 6, 15, 16, and 20  in normal cervical

1  Anatomy, Histology, Cytology, and Colposcopy of the Cervix epithelium, squamous metaplasia, cervical intraepithelial neoplasia, and cervical carcinoma. Am J Pathol. 1993;142:403–12. 34. Mittal K. Utility of proliferation-associated marker MIB-1 in evaluating lesions of the uterine cervix. Adv Anat Pathol. 1999;6:177–85. 35. McCluggage WG.  Immunohistochemistry as a diagnostic aid in cervical pathology. Pathology. 2007;39:97–111. 36. Herfs M, Yamamoto Y, Laury A, Wang X, Nucci MR, McLaughlin-­ Drubin ME, et al. A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer. Proc Natl Acad Sci USA. 2012;109:10516–21. 37. Herfs M, Vargas SO, Yamamoto Y, Howitt BE, Nucci MR, Hornick JL, et al. A novel blueprint for ‘top down’ differentiation defines the cervical squamocolumnar junction during development, reproductive life, and neoplasia. J Pathol. 2013;229:460–8. https://doi. org/10.1002/path.4110. 38. Crum CP, Egawa K, Fu YS, Lancaster WD, Barron B, Levine RU, et al. Atypical immature metaplasia (AIM). A subset of human papilloma virus infection of the cervix. Cancer. 1983;51:2214–9. 39. Herfs M, Parra Herran C, Howitt B, Laury A, Nucci MR, Feldman S, et al. Cervical squamocolumnar junction-specific markers define distinct, clinically relevant subsets of low-grade squamous intraepithelial lesions. Am J Surg Pathol. 2013;37:1311–8. https://doi. org/10.1097/PAS.0b013e3182989ee2. 40. de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, Plummer M. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13:607– 15. https://doi.org/10.1016/S1470-2045(12)70137-7. 41. Stern JE, Givan AL, Gonzalez JL, Harper DM, White HD, Wira CR. Leukocytes in the cervix: a quantitative evaluation of cervicitis. Obstet Gynecol. 1998;91:987–92. 42. Ferry JA, Scully RE. Mesonephric remnants, hyperplasia and neoplasia in the uterine cervix. A study of 49 cases. Am J Surg Pathol. 1990;14:1100–11. 43. Nogales FF. Mesonephric (Wolffian) tumours of the female genital tract: Is mesonephric histogenesis a mirage and trap? Curr Diag Pathol. 1995;2:94–100. 44. Sneeden VD.  Mesonephric lesions of the cervix; a practical means of demonstration and a suggestion of incidence. Cancer. 1958;11:334–6.

23 45. Ordi J, Nogales FF, Palacin A, Márquez M, Pahisa J, Vanrell JA, Cardesa A.  Mesonephric adenocarcinoma of the uterine corpus: CD10 expression as evidence of mesonephric differentiation. Am J Surg Pathol. 2001;25:1540–5. 46. Silver SA, Devouassoux-Shisheboran M, Mezzetti TP, Tavassoli FA.  Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemical findings. Am J Surg Pathol. 2001;25:379–87. 47. Norris HJ, Taylor HB. Polyps of the vagina. A benign lesion resembling sarcoma botryoides. Cancer. 1966;19:227–32. 48. Elliott GB, Elliott JD. Superficial stromal reactions of lower genital tract. Arch Pathol. 1973;95:100–1. 49. Clement PB. Multinucleated stromal giant cells of the uterine cervix. Arch Pathol Lab Med. 1985;109:200–2. 50. Abdul-Karim FW, Cohen RE.  Atypical stromal cells of lower female genital tract. Histopathology. 1990;17:249–53. 51. Metze K, Andrade LA. Atypical stromal giant cells of cervix uteri – evidence of Schwann cell origin. Pathol Res Pract 1991;187:1031– 5; discussion 1036–8. 52. Rodrigues MI, Goez E, Larios KK, Cuevas M, Fernandez JA, Stolnicu SS, Nogales FF. Atypical stromal cells as a diagnostic pitfall in lesions of the lower female genital tract and uterus: a review and presentation of some unusual cases. Patol Rev Latinoam. 2009;47:103–7. 53. Wentzensen N, Massad LS, Mayeaux EJ Jr, Khan MJ, Waxman AG, Einstein MH, et  al. Evidence-based consensus recommendations for colposcopy practice for cervical cancer prevention in the United States. J Low Gent Tract Dis. 2017;21:216–22. 54. Wentzensen N, Schiffman M, Silver MI, Khan MJ, Perkins RB, Smith KM, et al. ASCCP colposcopy standards: risk-based colposcopy practice. J Low Gent Tract Dis. 2017;21:230–4. 55. Munsick RA, Janovski NA. Walthard cell rest of the cervix uteri. Report of a case. Am J Obstet Gynecol. 1961;82:909–12. 56. Weir MM, Bell DA, Young RH. Transitional cell metaplasia of the uterine cervix and vagina: an underrecognized lesion that may be confused with high-grade dysplasia. A report of 59 cases. Am J Surg Pathol. 1997;21:510–7.

2

Pathologic Sampling Methods of the Cervix Xiaoming Zhang and Maria Carolina Reyes

Contents 2.1   Cervical Punch/Wedge Biopsy and Endocervical Curettage  2.1.1  Specimen Handling and Histopathological Processing  2.1.2  Histopathological Reporting  2.1.3  Case Example 

 25  26  27  27

2.2   Cervical Cone Biopsy  2.2.1  Specimen Handling and Histopathological Processing  2.2.2  Histopathological Reporting  2.2.3  Case Example 

 28  28  30  31

2.3   Trachelectomy  2.3.1  Specimen Handling and Histopathological Processing  2.3.2  Histopathological Reporting  2.3.3  Case Example 

 32  32  34  34

2.4   Hysterectomy  2.4.1  Specimen Handling and Histopathological Processing  2.4.2  Histopathological Reporting  2.4.3  Case Example 

 35  35  37  37

2.5   Pelvic Exenteration  2.5.1  Specimen Handling and Histopathological Processing  2.5.2  Histopathological Reporting 

 40  40  41

2.6   Lymph Nodes  2.6.1  Specimen Handling and Histopathological Processing  2.6.2  Histopathological reporting 

 41  42  43

References 

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The cervix is among one of the most frequently sampled organs in the human body, with a wide variety of specimens sent to surgical pathology laboratories. Proper specimen handling and processing are essential prerequisites for accurate pathological evaluation, which, in turn, influences subsequent management for patients. This chapter aims to provide a comprehensive description of specimen handling, histopathological processing, and histopathological reportX. Zhang · M. C. Reyes (*) Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA e-mail: [email protected]; carolina. [email protected]

ing for cervical biopsies, conization, trachelectomy, hysterectomy, pelvic exenteration, and lymph node dissection, including sentinel lymph nodes. Additionally, several real cases are presented as examples to illustrate these principles in practice.

2.1

 ervical Punch/Wedge Biopsy C and Endocervical Curettage

Cervical biopsies are usually carried out as a diagnostic procedure during colposcopy in the management of women with abnormal Pap smears or abnormal findings on gross exami-

© Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_2

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nation of the cervix, with the use of long biopsy instruments such as Kevorkian biopsy forceps. These specimens are pale tissue fragments ranging from 4 to 7 mm in greatest dimension [1], consisting of an epithelial surface and a small amount of underlying stroma. The proper orientation of these specimens is essential for accurate pathological evaluation, so that perpendicular sections can be taken through the epithelial surface. The gynecologist may aid orientation by mounting the freshly biopsied tissue on a filter paper with the stromal surface facing downwards to create a flat base, which assists in orientation [2]. Other techniques have also been described [2, 3], such as fixation in a solution of 0.05% eosin in formalin, but their use has not been proven to improve the differentiation between epithelium and stroma. Nonetheless, the orientation can be achieved satisfactorily with thorough gross examination by experienced pathologists and histotechnicians. An endocervical curettage (ECC) specimen is usually provided along with cervical biopsy specimens in non-­ pregnant patients. ECC is performed using a narrow instrument, called a curette, to scrape the lining of the endocervical canal. For low-grade squamous intraepithelial lesions (LSILs) reported by cytology but with no visible lesions on colposcopy, an ECC may be done alone. ECC specimens are often mucoid in nature, admixed with scant strands of pale tissue and blood.

2.1.1 Specimen Handling and Histopathological Processing Cervical biopsy and ECC specimens should be submitted in neutral buffered formalin for pathological evaluation. When received in the pathology laboratory, the specimens should be processed as follows: Cervical biopsy specimens: • Examine the specimen container carefully, including the inner surface of the lid, to identify all tissue fragments and mucoid material. • Document the number, color, and consistency (friable, firm, soft, granular, or rubbery) of the fragments. • Measure the size of each fragment in three dimensions. For mucoid material admixed with unmeasurable small fragments, an aggregate size can be measured in three dimensions. • Orient the specimen to identify the epithelial surface, so that the specimen can be positioned well to allow the section to be taken through the epithelial surface. The squamous epithelium is pale, smooth, and shiny in appearance, whereas the columnar epithelium appears

X. Zhang and M. C. Reyes

•

•

• •

reddish, mucoid, granular, and velvet-like [4] (Fig. 2.1). More than 90% of cervical cancers develop within the transformation zone [5], a small region of metaplastic squamous epithelium at the squamocolumnar junction (SCJ) between the endocervix and ectocervix. Thus, if the SCJ can be identified grossly, the fragment should be submitted and sectioned perpendicularly to the SCJ, although this is often quite difficult to achieve. Excessive manipulation should be avoided, to protect epithelial integrity. Tissue fragments smaller than 5 mm should be completely transferred to the cassette and sandwiched between sponges to prevent tissue loss and to maintain orientation [6]. (See Fig. 2.2 for an example.) A fragment larger than 5 mm may be bisected perpendicularly to the epithelial surface, preferably parallel to the axis of the cervical canal, to include the SCJ if identifiable [1]. Embed the flat cut surface downwards for cutting with the microtome. All tissue should be processed and embedded, including mucoid material. Standard hematoxylin and eosin (H&E) should be used. There is no consensus regarding the exact number of levels examined for cervical biopsies, though two to three levels are generally recommended [6–8]. It has been reported, however, that 10% to 17.5% of dysplastic lesions would have been missed if sectioning was limited to three levels [9, 10], including 19.6% of low-grade lesions and 5.6% of high-grade lesions [9]. Therefore, additional deeper levels might be considered in cases where the histopathological finding does not match the colposcopic impression or cytology. ECC specimens:

• Examine the specimen container carefully, including the inner surface of the lid, to identify all tissue fragments and mucoid material. • Document the aggregate dimension and the percentage of tissue admixed in the mucoid material. The size can often be measured more accurately after the entire specimen is filtered into a fine-mesh biopsy bag. • Place the entire specimen into a fine-mesh biopsy bag before placing it into a cassette. (See Fig.  2.2 for an example.) • The entire specimen should be processed and embedded. Even if no tissue is grossly visible, the mucoid material and blood should still be submitted for histopathological evaluation. • Standard H&E should be used, and usually two to three levels are recommended [6, 7].

2  Pathologic Sampling Methods of the Cervix

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• If there are major discrepancies between cytology and histopathological findings, cytologic-histologic correlation should be performed and documented whenever available [11]. According to the 2013 College of American Pathologists (CAP) Consensus Conference on Gynecologic Cytopathology Quality [12], at a minimum, available slides should be reviewed for high-grade squamous intraepithelial lesion (HSIL) Pap tests with negative biopsies. • Excisional margins are not assessed in such specimens.

2.1.3 Case Example Fig. 2.1  The gross appearance of squamous epithelium compared with that of columnar epithelium. The squamous epithelium (outside the blue circle) is pale, smooth, and shiny, whereas the columnar epithelium (inside the blue circle) appears reddish, mucoid, granular, and velvet-like.

2.1.2 Histopathological Reporting The following histopathological information should be included in the surgical pathology report for cervical biopsies and ECC: • Type of mucosa (ectocervical, endocervical, or transformation zone mucosa) • Report all grades of squamous intraepithelial lesion (SIL), adenocarcinoma in situ (AIS), invasive carcinoma (histological type, grade, size if small and measurable, and lymphovascular space invasion [LVSI]), and all other pathological lesions. • If fragments of endometrium are present, this should be recorded. • Document any artifact and inadequacy of the specimen that compromises interpretation, such as severe cautery artifact, epithelial loss, or an inability to visualize the transformation zone.

The patient is a 68-year-old G3P3003 woman who presented to the gynecology clinic with an abnormal Pap smear (LSIL with positive HPV test). She is asymptomatic, and no prior history of abnormal Pap smear was noted. A colposcopy was carried out and no definitive lesions were identified. A random cervical biopsy and ECC were then performed. The specimens were sent for pathological evaluation. • Gross description (Fig. 2.2): Specimen 1 is designated “colposcopy 12 o’clock” and consists of a tan-pink, irregular, rubbery tissue fragment 0.5 × 0.3 × 0.2 cm in size. The specimen is submitted in toto in one cassette labeled 1A. Specimen 2 is designated “endocervical curettage” and consists of a 0.4 × 0.3 × 0.1 cm aggregate of pink-brown mucoid material admixed with scant pieces of tan tissue, which comprises approximately 10% of the overall specimen volume. The specimen is submitted in toto in one cassette labeled 2A. • Final diagnosis: 1. Cervix, 12 o’clock, biopsy: Benign squamous mucosa; no transformation zone is present for evaluation. 2. Endocervix, curettings: Rare fragments of benign endocervical glands and squamous epithelium.

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Fig. 2.2  The histopathological processing of a cervical punch biopsy specimen and an endocervical curettage (ECC) specimen from a 68-year-old woman with an abnormal Pap smear. Insets: 1A (H&E, ×50), 2A (H&E, ×400)

2.2

Cervical Cone Biopsy

Cervical cone biopsy, also known as conization, is a surgical procedure that is both diagnostic and therapeutic. It involves the excision of a cone-shaped portion of the uterine cervix, including the transformation zone. This procedure is generally performed for HSIL, AIS, persistent LSIL, and superficially invasive disease [13]. Three techniques can be used for conization: cold knife conization, laser conization, and loop electrosurgical excision procedure (LEEP). No evidence has been provided to show that one technique is significantly better than the others [14], but LEEP is most commonly used. Cold knife and laser conization are usually performed in the operating room and remove a larger volume of tissue than LEEP. LEEP, also called large loop excision of the transformation zone, is technically easier and is usually performed as an outpatient procedure. It utilizes a thin wire in the shape of a loop with various sizes, and less tissue is removed with this procedure as compared to cold knife or laser cones. As a result, LEEP

more commonly produces fragmented specimens rather than an intact cone, making orientation of the specimen difficult. In addition, an undesirable consequence of LEEP may be thermal artifact, which hinders the histological assessment of the margins [13, 15], although to a lesser extent than for laser conization. Cold knife conization is performed with a scalpel and does not cause thermal damage to the margins of the specimen. Regardless of the technique, accurate histopathological evaluation of cone biopsy specimens is critically important to determine subsequent management for the patient.

2.2.1 Specimen Handling and Histopathological Processing Cervical cone biopsy specimens should be handled carefully to avoid excessive manipulation that could damage or disrupt the epithelial surface. When received in the pathology laboratory, the specimens are processed as follows:

2  Pathologic Sampling Methods of the Cervix

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Intact cone biopsy specimen (Fig. 2.3):

tudinal slices. This method can produce sections with even thickness, allowing accurate assessment of the tumor size for small lesions [6, 13]. A wedge-shaped section obtained from by the radial sectioning method, on the other hand, has variable thickness and could pose an issue in tumor size estimation. • Place the sections into cassettes. All of the tissue should be submitted and embedded. Although it has been suggested that two or more pieces of tissue can be placed into one cassette if they are small enough (for reasons of convenience and economy), doing so could pose a challenge in interpreting whether a lesion is unifocal or multifocal [7], so it is preferable to place each piece of tissue in its own cassette. The sections should be placed and embedded sequentially with the cut faces oriented in the same direction, to enable estimation of the third dimension of the tumor, if needed [1, 7]. • Standard H&E should be used. In general, one single, full-face level from each block is sufficient [1, 7]. Deeper levels should be requested if sections are incompletely cut or if there is a discrepancy between cytology/punch biopsies and cone biopsies. It has been shown that just a single further level is adequate in these situations [19], but if invasive disease is suspected, two further levels should be examined [20].

• Orient the specimen. The specimen is commonly oriented by the gynecologist with suture marking the 12 o’clock position (from the viewer’s perspective). If no orientation is provided by the clinician, “12 o’clock” can be arbitrarily designated during gross examination. In this situation, photographing the specimen with an illustration of the designated “12 o’clock” position is recommended, so that further orientation can be achieved if needed. • Measure and document the diameter at the ectocervical margin, the diameter at the endocervical margin, and the length of the specimen, corresponding to the endocervical canal. • Ink the endocervical mucosal margin with one color and use another color to ink the ectocervical mucosal and deep (stromal) margins. • Most cone biopsy specimens are received in formalin and are ready for dissection. If received fresh, a large cone biopsy specimen may be opened along the cervical canal, pinned on a corkboard with the mucosal side facing up, and fixed in neutral buffered formalin for 3 hours to obtain optimal sections [16]. • Describe the color, size, and consistency of any lesions grossly identified. • Section the specimen. Two methods are widely used for sectioning an intact cone biopsy specimen [1, 6, 7, 13], but there is no definitive evidence that one technique is superior to the other. Each center should establish its own protocol for dissection of cone biopsies. 1. Radial sectioning method: The specimen is serially sectioned parallel to the endocervical canal at intervals of 2 to 3 mm, similar to cutting a pizza into wedges. Using this method, wedge-shaped sections are taken according to the hours on a clock face, so that a lesion can be accurately mapped into the specimen [17]. For an unpinned cone, dividing it into four quarters before radial sectioning may make the sections more even and well-oriented. 2. Sagittal and parasagittal sectioning method: For an unopened cone biopsy specimen, serially section it perpendicularly to the transverse axis of the external cervical os at intervals of 2 to 3 mm, beginning at 3 o’clock or 9 o’clock. The reason for beginning at either 3 o’clock or 9 o’clock is that most cervical lesions arise in the midline of the cervix (the 12 and 6 o’clock positions) [18]. If the specimen has been opened and pinned out, serially and parallelly section it into longi-

Fragmented cone biopsy specimen: • Document the number of fragments received, the size of each fragment (or smallest and largest fragments, if multiple), and the color, size, and consistency of any lesions. • If the fragments have been designated by the clinician (e.g., “top-hat,” “12 o’clock–3 o’clock”), maintain the orientation and submit accordingly. • Inking of the specimen is often not necessary, given its fragmented nature, unless the fragment is large and its margins are identifiable [21]. • Try to distinguish squamous mucosa from endocervical mucosa (see Sect. 2.1.1 and Fig. 2.1 for the differentiation between these two types of mucosa) to identify the SCJ. • Serially section the fragments perpendicularly to the SCJ.  For large fragments with ectocervical and ­endocervical margins, the radial and sagittal/parasagittal sectioning methods previously described can be applied. • For cassetting and number of levels to examine, follow the same rules as described above for intact cone biopsy specimens.

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Fig. 2.3  Schematic illustration of sectioning a cone biopsy specimen

2.2.2 Histopathological Reporting The following histopathological information should be included in the surgical pathology report for cervical cone biopsy: • Procedure performed • Type of tissue components (ectocervix, endocervix, or transformation zone) • If an invasive lesion is present, report the following findings: 1. Size (depth of invasion, largest horizontal tumor dimension)

2. Histological type  and predicted HPV status for adenocarcinomas 3. Histological grade 4. LVSI • Report all grades of SIL, AIS, and all other pathological lesions. • Report the status of margins (ectocervical, endocervical, and deep margins) if SIL, AIS, invasive carcinoma, or other types of tumors are present. • Document any artifact and inadequacy of the specimen if the interpretation is compromised, such as severe cautery artifact, epithelial loss, inability to visualize the transformation zone, or fragmentation precluding the evaluation of margins.

2  Pathologic Sampling Methods of the Cervix

• If there are major discrepancies between previous cytology/punch biopsy and current cone biopsy findings, all slides should be reviewed, if available.

2.2.3 Case Example The patient is a 33-year-old nulligravida woman who presented with cervical dysplasia. Her first co-test was reported as cytology-negative and HPV-positive. A repeat co-test at 1  year showed the same result. She then underwent a colposcopic evaluation with an impression of cervical intraepithelial neoplasia grade 1 (CIN 1). Biopsies were performed, and pathology reported focal HSIL (CIN 2) at 10 o’clock. After a discussion with the patient, LEEP was performed. • Gross description (Fig. 2.4): Specimen 1 is designated “LEEP, 12 o’clock stitch” and consists of a pink-tan to red, focally hyperemic, rubbery conical portion of tissue consistent with a LEEP specimen. The ectocervical margin measures 1.7 cm, the endo-

Fig. 2.4  The histopathological processing of a loop electrosurgical excision procedure (LEEP) specimen from a 33-year-old woman with a cervical high-grade squamous intraepithelial lesion (HSIL). The speci-

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cervical margin measures 0.8  cm, and the length of the endocervical canal measures 1.2 cm. A single white suture designates the 12:00 aspect. The ectocervical mucosa is pink-tan smooth to focally shaggy and transitions to a pink-red hyperemic and granular endocervical aspect. The endocervical mucosal margin is inked green. The ectocervical mucosal and stromal margins are inked black. The specimen is radially sectioned from 12 o’clock and entirely submitted in 12 cassettes labeled 1A through 1L (see Fig. 2.4 insets), as follows: 1A–1C: 12 o’clock to 3 o’clock 1D–1F: 3 o’clock to 6 o’clock 1G–1I: 6 o’clock to 9 o’clock 1J–1L: 9 o’clock to 12 o’clock • Final diagnosis: 1. Cervix, LEEP: High-grade squamous intraepithelial lesion (CIN 2) with changes consistent with prior biopsy site. Endocervical and ectocervical margins are free of dysplasia.

men is intact without fragmentation. The radial sectioning method was used in this case. Insets: 1A–1L (H&E, ×20)

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2.3

X. Zhang and M. C. Reyes

Trachelectomy

A trachelectomy is a more extensive version of a conization, as the entire cervix is removed in a cylinder shape, with or without the vaginal cuff. This may be carried out in cases with persistent abnormal cytology after cervical conization, or it may be performed to manage cervical disease after prior supracervical hysterectomy [22]. Additionally, young patients with early-stage invasive disease who wish to preserve fertility are considered potential candidates for trachelectomy, which includes simple trachelectomy and radical trachelectomy (Fig.  2.5). Radical trachelectomy, which involves the removal of parametria in addition to the entire cervix, can be performed vaginally, abdominally, or laparoscopically. Cold knife conization alone for women with stage 1A1 invasive carcinoma without LVSI or positive margins is a standard treatment option [23–25]. If fertility-preserving surgery is considered, upfront radical trachelectomy can be used for selected patients with invasive lesions ≥2 cm [26, 27]. Optimal pregnancy outcomes are thought to require a radiographically tumor-free zone between the tumor and the internal os. For invasive lesions that fall between the two aforementioned situations (e.g., stage IA1 with LVSI, IA2, and IB1 5 mm from the endocervical (proximal) margin [30, 32]. Currently, there is no consensus regarding the best approach for examination of the trachelectomy margin. Some methods have been described: • 1. Transverse section (en face) [8, 30, 33]. A 2 mm–thick slice of proximal tissue is shaved off parallel to the plane of the endocervical margin and submitted en face. This technique is generally used when the tumor is grossly visible; the entire proximal margin surface can be examined microscopically. However, the distance between tumor and the endocervical margin can only be measured grossly. 2. Perpendicular sections [34]. The proximal 1-cm segment is cut off from the rest of the specimen and further radially sectioned into sections 2 to 3 mm thick. These sections are submitted perpendicularly for fro-

2  Pathologic Sampling Methods of the Cervix

zen sections, which may allow the exact measurement of the distance between the tumor and the endocervical margin. The disadvantage of this method is that the full circumference of the endocervical margin will not be covered. 3. A combination of transverse and perpendicular sections [30]. This method is used when there is a gross abnormality that is macroscopically indefinite for tumor. First, a 2  mm–thick transverse section of the endocervical margin is shaved off and submitted en face for frozen section. Then, one perpendicular section that includes the lesion and the edge is submitted. If the tumor is present in this perpendicular section microscopically, then the final margin distance is 2 mm plus the distance from the tumor to the edge of the perpendicular section. • For radical trachelectomy, cut off the parametria. Serially section the parametrial tissue in the parasagittal plane and submit the entire left and right sides separately. Document the presence of lymph nodes in the parametria and submit separately. • Pin the specimen on a corkboard and fix in formalin overnight. • The specimen should be submitted in its entirety unless it is very large and the tumor is grossly visible, in

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which case the sections should be taken following the same rules as described for radical hysterectomy (see Sect. 2.4.1), with the exception of the endocervical margin. There are two approaches to block the specimen [1, 8, 35]: 1. Shave a 2 mm–thick transverse section of the endocervical margin and submit it en face if not submitted for frozen section. This section can be divided into two halves to obtain better full-face slides. The remaining specimen is then handled as a cone. (See Fig. 2.7 for a case example.) 2. Serially section the specimen in parallel, transverse slices of 2–3 mm in thickness, starting from the proximal end and stopping 10–15 mm above the external os. All transverse slices are submitted and embedded in the same direction to allow the superior surface to form the cutting face of the block. The first slice will be the proximal margin if not submitted for frozen section. Bisect, trisect, or quadrisect each slide through the endocervical canal to fit into cassettes. The remaining distal portion of the specimen (including the vaginal cuff, if present) should be sectioned radially and submitted perpendicularly. • Standard H&E should be used. In general, one single full-­ face level from each block is sufficient.

Fig. 2.6  Schematic illustration of processing a radical trachelectomy specimen

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2.3.2 Histopathological Reporting The following histopathological information should be included in the surgical pathology report for trachelectomy: • Procedure performed • If an invasive lesion is present, report the following findings: 1. Size (depth of invasion, largest horizontal tumor dimension) 2. Histological type  and predicted HPV status for adenocarcinomas 3. Histological grade 4. LVSI 5. Other tissue/organ involvement: right/left parame trium and vagina • Report all grades of SIL, AIS, and all other pathological lesions. • Report the status of margins (distal ectocervical/vaginal cuff margin, endocervical margin, and radial margins) when SIL, AIS, invasive carcinoma, or other types of tumors are found. • Report the status of lymph nodes, if sent (see Sect. 2.6.2).

2.3.3 Case Example The patient is a 28-year-old nulligravida woman who was diagnosed with a stage IA2 squamous cell carcinoma of the cervix. She was initially noted to have an abnormal Pap smear with HSIL.  A colposcopic evaluation showed an impression of moderate to severe dysplasia. Punch biopsies sent for pathologic examination showed invasive squamous cell carcinoma (stromal invasion 4 mm in depth) arising in a background of HSIL. An MRI scan of the pelvis was performed and showed no evidence of parametrial invasion or distant metastasis. Clinical staging allocated her to stage IA2 disease. She underwent a vaginal simple trachelectomy for reproductive purposes.

X. Zhang and M. C. Reyes

• Gross description (Fig. 2.7): Specimen 1 is designated “trachelectomy, stitch marks 12 o’clock” and consists of a 2.5 × 2.3 × 2.2–cm trachelectomy specimen (2.2 cm in length, 2.5 cm in diameter at the distal ectocervical margin, and 1.8  cm in diameter at the proximal resection margin). No vaginal cuff is identified. A suture is present marking the 12 o’clock position. The anterior aspect of the specimen (9 to 12 to 3 o’clock) is inked black, and the posterior aspect of the specimen (3 to 6 to 9 o’clock) is inked green. The mucosal surface of the ectocervix is mostly smooth and focally shaggy with patchy erosions and hemorrhagic appearance. The endocervical mucosa is pink-tan and unremarkable. The proximal resection margin is shaved, and the specimen is radially sectioned in a clockwise manner beginning at 12 o’clock to reveal a tan-white, rubbery cut surface. No definitive mass lesions are grossly identified. The specimen is entirely submitted as follows: 1A: Proximal resection margin, shave 1B–1D: 12 o’clock to 3 o’clock, full-thickness sections, with trimmed stromal tissue in 1D 1E–1G: 3 o’clock to 6 o’clock, full-thickness sections, with trimmed stromal tissue in 1E 1H–1J: 6 o’clock to 9 o’clock, full-thickness sections, with trimmed stromal tissue in 1J 1K–1M: 9 o’clock to 12 o’clock, full-thickness sections, with trimmed stromal tissue in 1K • Final diagnosis: 1. Cervix, vaginal simple trachelectomy: High-grade squamous intraepithelial lesion (CIN 3), no invasion identified. Endocervical and ectocervical margins of resection are free of dysplasia. Note: The original biopsies were reviewed and a diagnosis of invasive squamous cell carcinoma is verified. No invasive carcinoma was found in this trachelectomy specimen.

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Fig. 2.7  The handling and processing of a simple trachelectomy specimen from a 28-year-old nulligravida woman with a stage IA2 squamous cell carcinoma of the cervix. Red arrows: sections of trimmed stromal

tissue, which can be placed into the same cassette with the corresponding full-thickness section

2.4

2.4.1 Specimen Handling and Histopathological Processing

Hysterectomy

Total hysterectomy, also called simple hysterectomy, refers to the surgical removal of the uterus including the cervix; it can be performed vaginally, abdominally, or laparoscopically. With regard to cervical disorders, common indications for total hysterectomy include high-grade cervical dysplasia in women who do not desire future fertility, persistent abnormal cytology after therapeutic conization, and stage IA1 cervical cancer with no LVSI [25]. If tissue near to the cervix (parametria and portion of vagina up to the upper one-half) is also excised, then the procedure is called radical hysterectomy; this is usually performed for stage IB2 and IIA cervical cancers [25]. Compared with radical hysterectomy, a modified radical hysterectomy removes only the upper one-fourth of the vagina and is the standard treatment for stage IA2, IB1, and most IB2 cervical cancers [25, 36]. Bilateral salpingooophorectomy may also be performed in post-menopausal patients. Surgical evaluation of lymph nodes is also performed, as discussed in Sect. 2.6. The type of hysterectomy and characteristics of the lesion (if invasive and grossly visible) determine the approach for processing the specimen.

Hysterectomy specimens are usually sent fresh for histopathological examination. When received in the pathology laboratory, the specimen is processed as follows: Preparation for both simple and radical hysterectomy specimens: • Weigh the specimen. • Orient the specimen (Fig. 2.8). The peritoneal reflection is lower on the posterior aspect, with a V shape for vaginal hysterectomy and a U shape for abdominal hysterectomy [3]. It is higher on the anterior aspect, with a blunter lower end. Another way to orient the specimen is based on observation of the adnexa, if available. The round ligaments insert anterior to the fallopian tubes, and the ovaries are located posterior to the fallopian tubes [3, 21]. • Measure the specimen: corpus uteri in three dimensions (superior to inferior, cornu to cornu, and anterior to posterior); cervix in three dimensions (length, lateral-to-lateral, and anterior-to-posterior); length of vaginal cuff, if present (give a range if variable); and right/left parametrium in three dimensions, if present.

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• Describe the shape of the specimen: unremarkable, globular, barrel-shaped, distorted, etc. • Examine the serosal surface for adhesions or tumor invasion. • Ink the specimen, including parametria. Ink the anterior and posterior of the uterus in two different colors. For radical hysterectomy, ink the vaginal cuff margin in a third color. • For radical hysterectomy, cut off the parametria. Serially section the parametrial tissue in the parasagittal plane and submit the entire left and right sides separately. If the tumor involves parametrial tissue  grossly, it is better to submit the inner parametrium in continuity with tumor sections. Document the presence of lymph nodes in the parametria and submit them separately. • Bivalve the uterus by passing a pair of forceps into the canal and cutting with a knife between the arms of the forceps. (See Fig. 2.9 for a case example.) Cut through the lateral sides of the cervical os to expose the entire endometrial cavity. • Describe internal dimensions: endocervical canal (length and width), endometrial cavity (length and width), thickness of endometrium, and thickness range of myometrium. • Make perpendicular cuts at 5- to 10-mm intervals through the endometrium and myometrium to facilitate fixation and to assess for lesions. Leave all tissue attached to maintain orientation. Serial sectioning should not be performed before fixation if there is uncertainty as to whether the tumor is cervical or endometrial. Serially sectioning endometrial carcinomas before fixation results in tumor contamination of normal structures. • Pin the uterus on a corkboard and fix in formalin. • After fixation, dissect the specimen and take sections based on the type of hysterectomy and characteristics of the lesion, as described below. Simple hysterectomy for high-grade dysplasia and simple/radical hysterectomy for invasive tumor with no grossly visible lesion: • For radical hysterectomy, shave the whole circumferential vaginal cuff margin, if large, and submit en face as four designated quadrants. If the vaginal cuff is short, it can be taken in continuity with the cervix. • The cervix must be submitted entirely [6]. Amputate the distal cervix and proximal vaginal cuff, if present, and process as a cone biopsy (see Sect. 2.2.1). It may be necessary to do two cones, depending on the length of the cervix. • Submit two sections of the lower uterine segment, one each from the anterior and posterior aspects. • Submit one section of the anterior endomyometrium and one section of the posterior endomyometrium.

X. Zhang and M. C. Reyes

• Describe and submit any other lesions: fibroids, adenomyosis, endometrial polyps, etc. • Standard H&E should be used. In general, one single full-­ face level from each block is sufficient. Simple/radical hysterectomy with a grossly visible lesion: (See Fig. 2.9 for a case example.) • Submit the vaginal cuff margin based on the distance between the lesion and the margin: 1. If the lesion is distant from the vaginal margins, shave the whole circumferential vaginal cuff margin and submit en face as four designated quadrants. 2. If the lesion is close to the vaginal margin, submit perpendicular sections showing the relationship between the cervical tumor and the closest vaginal cuff margin; then shave the remaining vaginal cuff margin and submit en face [1]. • Serially section the cervix at 3-mm intervals to examine the lesion. • Describe the lesion in the cervix: size in three dimensions, location, shape, color, consistency, distance to margins, and extent of lesion (e.g., involvement of vagina, parametrium, or lower uterine segment). • Measure depth of invasion and thickness of cervical wall. • Submit representative sections of the lesion (at least one section per centimeter) to demonstrate the following relationships: 1. The maximum depth of invasion with full thickness of cervical wall 2. Relationship to parametrial tissue, if close 3. Inferior extent: tumor in relation to distal ectocervix and/or proximal vagina 4. Superior extent: tumor in relation to proximal endocervix and/or lower uterine segment (Corpus involvement does not change the stage of the tumor, but it might affect prognosis [6].) 5. Relationship to adjacent normal-appearing cervical mucosa 6. Relationship to resection margins, including vaginal cuff margin (if close) and closest radial margins (anterior/posterior paracervical tissue and/or parametrial margin); this already may have been included in the section of maximum depth of invasion with full thickness of cervical wall. • Submit a section of lower uterine segment from the anterior aspect and one from the posterior aspect. • Submit one section of anterior endomyometrium and one section of posterior endomyometrium. • Describe and submit any other lesions: fibroids, adenomyosis, endometrial polyps, etc. • Standard H&E should be used. In general, one single full-­ face level from each block is sufficient.

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Fig. 2.8  Orientation of a hysterectomy specimen. The peritoneal reflection is lower on the posterior aspect and higher on the anterior aspect. The ovaries are located posterior to the fallopian tubes

2.4.2 Histopathological Reporting The following histopathological information should be included in the surgical pathology report for hysterectomy: • Procedure performed • If an invasive lesion is present, report the following findings: 1. Size (depth of invasion, largest horizontal tumor dimension) 2. Histological type  and predicted HPV status for adenocarcinomas 3. Histological grade 4. LVSI • Other tissue/organ involvement: right/left parametrium, lower uterine segment, and vagina (Although corpus involvement does not change the stage of the tumor, it might affect prognosis [6].) • Report the presence of SIL, AIS, and all other pathological lesions in the cervix. • Report the presence of any other lesions in the corpus uteri and vagina. • Report the status of margins (distal ectocervical/vaginal cuff margin and radial margins) when SIL, AIS, invasive carcinoma, or other types of tumors are found. • Report the status of lymph nodes, if sent (see Sect. 2.6.2).

2.4.3 Case Example The patient is a 37-year-old G10P5045 woman who presented to the gynecology clinic with vaginal discharge. On physical  examination, a friable bulky cervical mass was noted. Pelvic MRI and CT showed no extracervical involvement. A PET-CT was performed and showed hypermetabolic bilateral pelvic lymph nodes concerning for metastatic disease. A cervical biopsy confirmed the diagnosis of cervical cancer. The clinical stage for the tumor was stage IB2 (based on FIGO 2009 staging). The decision was made to proceed with radical hysterectomy and bilateral pelvic lymph node dissection.

• Gross examination (Fig. 2.9): Specimen 1 is designated “left pelvic nodes” and consists of multiple fragments of yellow-tan, soft tissue measuring 5.5  ×  3.5  ×  0.8  cm. It contains seven potential lymph nodes ranging from 0.4 × 0.4 × 0.3 cm to 1.8 × 1.0 × 0.5 cm. The largest node is bisected to show potential tumor involvement. The specimen is submitted as follows: 1A: Bisected largest node 1B–1C: Six intact nodes Specimen 2 is designated “right pelvic nodes” and consists of one fragment of yellow-tan, soft tissue measuring 5.4  ×  2.2  ×  1.6  cm. The specimen is dissected to reveal three potential lymph nodes measuring from 0.6 × 0.5 × 0.3 cm up to 1.5 × 1.2 × 0.6 cm. The two largest nodes are bisected to show potential tumor ­ involvement. The specimen is submitted as follows: 2A: One bisected node 2B: One bisected node 2C–2D: Three intact nodes Specimen 3 is designated “uterus, cervix, parametrium, vaginal cuff” and consists of a 223.1  g radical hysterectomy (10.7 × 8.0 × 7.5 cm overall), comprising the uterus (8.5 cm superior to inferior, 7.0 cm cornu to cornu, 5.5 cm anterior to posterior), cervix (3.0 cm in length, 7.0 cm lateral to lateral, and 6.4 cm anterior to posterior), the vaginal cuff (2.7  cm to 3.9  cm in length), the left parametrium (2.8  ×  2.5  ×  1.8  cm), and the right parametrium (3.3 × 3.0 × 2.5 cm). The uterine serosa is smooth and glistening. The specimen is inked as follows: anterior, green; posterior, black; vaginal cuff margin, red. The cervix and vaginal cuff have a globally distorted appearance with a brown-red, fungating, friable mass seen in the ectocervix. The uterus and cervix are bivalved along the anterior-­ posterior border to reveal that the endocervical canal (2.0 cm in length and 0.4 cm in width) is compressed by the ectocervical mass. The ectocervical mass measures 5.7 × 5.2 × 2.5 cm and arises from the left anterior/posterior quadrants of the ectocervix. Its surface appears necrotic. Serial sectioning reveals that the mass invades a depth of 1.2  cm with a moderately circumscribed, tan-white, firm

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X. Zhang and M. C. Reyes

cut surface. The cervical wall is 1.5 cm thick. The mass is grossly confined within the ectocervix, with no involvement of parametria and vagina. It is situated 0.1 cm from the external os, 2.7 cm from the vaginal cuff, 2.8 cm from the right parametrial margin, 1.5 cm from the left parametrial margin, 1.8 cm from the anterior radial margin, 2.2 cm from the posterior radial margin, and 2.1 cm from the lower uterine segment. The endometrial cavity measures 3.6 cm in width × 4.2 cm in length. It is lined by a velvety, hemorrhagic endometrium ranging from 0.1  cm to 0.3  cm in thickness, with a 1.2 × 0.5 × 0.4–cm red-brown, polypoid area on the posterior aspect. The remainder of the endometrial cavity is otherwise unremarkable. The myometrium is 1.9 cm thick and is unremarkable. The left and right parametrial tissue is serially sectioned and is grossly unremarkable. The specimen is submitted as follows: 3A: Right parametrium 3B: Left parametrium 3C: Shave margin of vaginal cuff at left posterior quadrant 3D: Shave margin of vaginal cuff at left anterior quadrant 3E: Shave margin of vaginal cuff at right posterior quadrant 3F: Shave margin of vaginal cuff at right anterior quadrant 3G: Tumor with deepest invasion, right parametrium, and closest radial margin (right parametrial margin) 3H: Tumor in relation to endocervical canal and lower uterine segment 3I: Tumor in relation to vaginal cuff 3J: Tumor in relation to normal cervix

3K–3L: Additional sections of tumor, representative 3M: Representative section of posterior lower uterine segment 3N: Representative section of anterior lower uterine segment 3O: Representative section of posterior endometrium and myometrium 3P: Representative section of anterior endometrium and myometrium 3Q–3R: Entire 1.2-cm red-brown polypoid area from posterior endometrial cavity • Final diagnosis: 1. Lymph node, left pelvic, dissection: Metastatic carcinoma to one of seven lymph nodes (1/7), no extranodal extension identified 2. Lymph node, right pelvic, dissection: Metastatic, carcinoma to one of five lymph nodes (1/5), no extranodal extension identified 3. Uterus, cervix, parametrium and vaginal cuff, 223.1 grams, radical hysterectomy: –– Squamous cell carcinoma, moderately differentiated, 5.7 cm, with associated high-grade squamous intraepithelial lesion, invasive to a depth of 1.5 cm, confined to uterine cervix –– No lymphovascular space invasion seen –– Bilateral parametrium not involved –– Vaginal cuff margin and radial margins negative for involvement by tumor –– Uterus with proliferative endometrium and focus of necrosis, 1.2 cm (slide 3Q–3R)

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Fig. 2.9  The histopathological processing of a radical hysterectomy specimen from a 37-year-old woman with biopsy-proven cervical cancer. Insets: H&E, ×10; see Sect. 2.4.3 for section key

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2.5

X. Zhang and M. C. Reyes

Pelvic Exenteration

Pelvic exenteration is a rarely performed, ultraradical surgical procedure. For patients with recurrent or persistent cervical cancers that are confined to the central pelvis after primary radiation therapy or after surgery followed by radiation, pelvic exenteration is a potentially curative option if no metastatic disease is found after complete evaluation [25, 37]. Resection with clear margins can be achieved in 75–97% of patients who underwent pelvic exenteration [38]. The 5-year survival rate after the procedure ranges from 16% to 61% [38], which is not optimal but still presents an opportunity for patients with late-stage disease. Total exenteration refers to an en bloc resection of the female reproductive organs (uterus, fallopian tubes, ovaries, and vagina), parametria, bladder, urethra, bowel, and a portion of the levator muscles. If the bowel is preserved, the procedure is called anterior exenteration; posterior exenteration is the term used when the bladder and urethra are spared. Nonetheless, the extent of resection is usually individualized in a given patient depending on the location of the cancer, anatomy, prior radiotherapy, and difficulties that may arise during surgery. Pelvic exenteration specimens can appear complex and daunting, but the key point is to evaluate the tumor extension with its relation to the surrounding organs and resection margins. It should be emphasized that given the procedure’s curative—not palliative—intent, special consideration should be given to dissecting the specimen in a manner that does not compromise assessment of all resection margins.

2.5.1 Specimen Handling and Histopathological Processing

•

•

•

•

•

•

Pelvic exenteration specimens are usually sent fresh for histopathological examination. When received in the pathology laboratory, the specimen is processed as follows: • Orient the specimen and note the organs present. • Measure the specimen: overall size in three dimensions and dimensions of each organ, which might include the corpus uteri in three dimensions (superior to inferior, cornu to cornu, and anterior to posterior), the cervix in three dimensions (length, lateral to lateral, and anterior to posterior), length of vaginal cuff (give a range if variable), right/left parametrium in three dimensions, the right/left ovary in three dimensions, the right/left fallopian tube (length and diameter), the bowel segment (length and diameter), the bladder in three dimensions, the right/left ureter (length and diameter), and the urethra (length and diameter). • Ink the specimen. Ink the anterior and posterior aspects of the specimen in two different colors. Ink the mucosal

• •

margins (vaginal cuff, urethral, ureteral, and/or bowel) in a third color (preferably a bright color, such as yellow or orange) to facilitate margin orientation. The urethral and ureteral margins can be shaved and placed in different cassettes, as it may be difficult to find them after fixation. Fix the specimen in formalin. A method that provides an excellent cut surface of the entire specimen (to demonstrate the relationship between the tumor and surrounding organs) is to fill the vagina with formalin-soaked gauze pads and distend the bladder and bowel with formalin [3, 16]. Then submerge the specimen in formalin overnight. After fixation, the entire specimen can be hemisected through the tumor in a sagittal plane by using probes in the urethra, uterine canal, and bowel lumen as midline guides. It is recommended to request the surgeon’s assistance in orienting the specimen, if necessary. Further dissection should be performed in a manner that allows assessment of the tumor extent and resection margins. Describe the lesion: size in three dimensions, location, shape, color, consistency, distance to margins, and extent of lesion (e.g., involvement of vagina, parametrium, corpus uteri, bilateral ovary/fallopian tube, bowel, bladder, urethra, ureters). Submit resection mucosal margins (vaginal cuff, bowel, urethral and ureteral margins) that are far away from the tumor by taking shaved sections. The urethral and ureteral margins may already have been shaved off prior to fixation. Submit representative sections of the lesion (at least one section per centimeter) to demonstrate: 1. The maximum depth of invasion with full thickness of the cervical wall 2. Relationship to parametrial tissue 3. Anterior extent: tumor in relation to the full thickness of the bladder wall 4. Posterior extent: tumor in relation to the full thickness of the bowel wall 5. Inferior extent: tumor in relation to the vagina 6. Superior extent: tumor in relation to the corpus uteri/ ovaries/fallopian tubes 7. Relationship to adjacent normal-appearing cervical mucosa 8. Relationship to resection margins (if close), including vaginal cuff margin, closest radial soft-tissue margins, and bowel margins; this may already have been included in other sections. Describe and submit any other lesions: polyps, fibroids, diverticula, etc. Submit sections of uninvolved corpus uteri, vagina, ovaries, fallopian tubes, bowel, and bladder.

2  Pathologic Sampling Methods of the Cervix

• Dissect the soft tissue surrounding the cervix and bowel separately to search for lymph nodes (see Sect. 2.6.1). • Standard H&E should be used. In general, one single full-­ face level from each block is sufficient. If the uterus has been previously removed, the specimen can still be handled in the same manner, omitting any steps that involve the uterus.

2.5.2 Histopathological Reporting The following histopathological information should be included in the surgical pathology report for pelvic exenteration: • Procedure performed • Tumor description: 1. Size (depth of invasion, largest horizontal tumor dimension) 2. Histological type  and predicted HPV status for adenocarcinomas 3. Histological grade 4. LVSI 5. Other tissue/organ involvement: right/left parame trium, vagina, right/left ovary, right/left fallopian tube, bladder mucosa/wall, bowel mucosa/wall, pelvic wall, omentum, and any other tissue or organs sent • Report the presence of SIL, AIS, and all other pathological lesions in the cervix. • Report the presence of any other lesions in the corpus uteri, vagina, ovaries, fallopian tubes, bowel, bladder, and other organs present in the specimen • Report the status of margins (vaginal cuff margin, radial margins, urethral and ureteral margins for bladder, and proximal and distal bowel margins). • Report the status of lymph nodes if sent (see Sect. 2.6.2).

2.6

Lymph Nodes

Surgical evaluation of lymph nodes is generally carried out in patients with stage IA1 with LVSI, IA2, IB, and IIA cervical cancer who undergo hysterectomy or trachelectomy. The extent of lymphadenectomy depends on disease stage and radiological imaging studies [25]. In addition, lymph node dissection (extraperitoneal or laparoscopic) may also be considered in women treated with primary chemoradiation. Recent studies suggest that sentinel lymph node (SLN) biopsy may be useful for reducing the need for pelvic lymphadenectomy in patients with early-stage cervical cancer; reported sensitivities have been 79.2% to 95.4% [39–41]. The sensitivity increased to 91% to 100% by using

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pathological ultrastaging (the identification of micrometastasis and small macrometastasis by examination of multiple H&E-stained sections and cytokeratin immunohistochemistry) for bilateral SLN examination [42, 43]. The methodology for proper SLN biopsy performance is described by the National Comprehensive Cancer Network (NCCN) Cervical Cancer Panel. Accurate assessment of lymph nodes involves not only removal of the “hot” nodes, but also removal of contralateral pelvic lymph nodes when SLN mapping is unilateral. Any large or suspicious lymph nodes should also be removed. Based on the satisfactory data from prospective studies, the NCCN Cervical Cancer Panel recommends consideration of SLN biopsy and/or pelvic lymph node dissection as an alternative to full pelvic lymphadenectomy with or without para-aortic lymphadenectomy, especially for tumors smaller than 2 cm in diameter [25, 44]. In an effort to decrease morbidity due to the combination of radical surgery and pelvic radiotherapy, the new European Society of Gynaecological Oncology/ European Society for Radiotherapy and Oncology/ European Society of Pathology (ESGO/ESTRO/ESP) guidelines recommend intraoperative assessment of SLNs and/or any suspicious lymph nodes as a first step to triage patients with T1b1/T2a1 cervical cancer [45]. If these nodes are positive for malignancy on frozen sections, further pelvic lymph node dissection and radical hysterectomy are not recommended. However, if intraoperative lymph node assessment is negative or not done, pelvic lymph node dissection should be performed. Because SLN biopsies are still not  widely performed, each center may have its own policy regarding whether SLN evaluation is desired and how the SLN specimens are processed. Pathologically confirmed involvement of lymph nodes is one of the criteria for high-risk cervical cancer (Peter’s criteria) [46, 47]. The recurrence risk is about 40% and the mortality rate is up to 50% following surgery alone for patients with high-risk cervical cancer [48], therefore, postoperative chemoradiation therapy is recommended to improve overall survival for this population [49]. To emphasize its importance in predicting prognosis and planning treatment, the status of lymph nodes (determined either clinically or by pathology) has now been included in the 2018 revised International Federation of Gynecology and Obstetrics (FIGO) staging for cervical cancer [50]. The number and location of lymph nodes affected by metastases are crucial information for the surgeons in determining the volume and fields of radiation. Regional lymph nodes include pelvic (parametrial, obturator, internal iliac, external iliac, common iliac, sacral, and presacral) and para-aortic lymph nodes [16]. It is worth mentioning that any positive non-regional lymph nodes should be categorized as pM1 rather than pN1.

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2.6.1 Specimen Handling and Histopathological Processing For radical hysterectomy/trachelectomy, lymph nodes are usually sent in separate containers, labeled according to the site of origin. Lymph node specimens (both SLN and non-SLN) sent for frozen sections: • Describe the size (in three dimensions), color, and consistency of the tissue in each specimen. • Carefully dissect the nodes from the surrounding adipose tissue and measure the sizes of the nodes in three dimensions. • Bisect or serially section each node at 2-mm intervals depending on its size. • Freeze all slices of lymph nodes. More than one slice can be frozen into a single block. • Obtain one or two levels from each block for intraoperative assessment. • Additional deeper levels should be avoided, to preserve tissue for pathologic ultrastaging on a permanent block. As a side note, intraoperative frozen sections result in the detection of lymph node metastasis in only about 50% of patients with positive lymph nodes [51, 52]. SLN specimens sent for routine pathology: At present, there is no standard protocol in cervical cancer for handling SLN specimens. Pathologic ultrastaging, which requires examination of each node at multiple levels with standard H&E and immunohistochemical (IHC) stains, has been recommended in different guidelines [16, 25, 45]. In general, the specimens should be processed as follows: • Describe the size (in three dimensions), color, and consistency of the tissue in each specimen site. • Carefully dissect each node from the surrounding adipose tissue and measure the size of each node in three dimensions. • Each node should be serially sectioned at 2-mm intervals parallel to the long axis. • If the node is grossly positive, one section including any area suspicious for extracapsular extension (usually hilum) is sufficient. In this case, pathologic ultrastaging is unnecessary. • If the node is grossly negative or equivocal, all slices of the node should be submitted and embedded. More than one slice from the same node can be placed in each cassette. • Regarding the levels and stains to be examined for each paraffin block, several methods have been described: 1. Method 1 [42]: One routine section (H&E-­stained) for each block is examined first. If metastatic carcinoma is

X. Zhang and M. C. Reyes

not appreciable in this slide, one adjacent section is examined by using AE1/AE3 IHC stain. With this method, the sensitivity for node metastasis detection had a range of 79.2% to 92% [41, 42]; 2.3% of the cases were identified only by AE1/AE3 stain [41]. 2. Method 2 [53]: One routine section (H&E-­stained) for each block is examined first. If metastatic carcinoma is not appreciable in this slide, two adjacent sections (one AE1/AE3 stain and one negative control) and another two consecutive sections (one H&E and one AE1/AE3 IHC stain) at a level 50 μm deeper are examined. This method generates a total of five slides for each block and has a reported sensitivity of 87.5% for positive node detection; it detected metastasis in an additional 29% of patients that would otherwise be missed on routine processing [44, 53]. 3. Method 3 [43, 52, 54]: One routine section (H&Estained) for each block is examined first. If metastatic carcinoma is not appreciable in this slide, the entire block is cut at regular intervals which vary at individual centers (150–500 μm). Three or four consecutive sections (one H&E, one AE1/AE3 stain, and one or two unstained slides for further studies when necessary) are examined at each level. The sensitivity for node metastasis detection was 91% to 97% using this method [43], and up to 39.1% of cases with positive nodes were found only by IHC [55]. Non-SLN specimens sent for routine pathology: • Describe the size (in three dimensions), color, and consistency of the tissue in each specimen. • Dissect tissue to identify lymph nodes. • Describe number of nodes and range of sizes (in three dimensions). • Small lymph nodes (5  mm in largest dimension [8]) should be bisected or serially sectioned. Grossly positive nodes do not need to be submitted entirely. One section including any area suspicious for extracapsular extension (usually hilum) is sufficient. All grossly negative or equivocal lymph nodes should be submitted in their entirety. Each bisected or serially sectioned node should have its own separate cassette(s). • Document the number of lymph nodes in each cassette; otherwise it will be impossible to distinguish between a serially sectioned single node and several intact nodes in one cassette. • It is not necessary to submit additional soft tissue that does not grossly contain nodes.

2  Pathologic Sampling Methods of the Cervix

43

• Standard H&E should be used. In general, one single full-­ 8. Singh N, Horn L-C. Appendix 1: Surgical cutup of cervical specimens. In: Herrington CS, editor. Pathology of the cervix. New York: face level is sufficient from each block. Springer; 2017. p. 237–46. 9. Fadare O, Rodriguez R. Squamous dysplasia of the uterine cervix:

tissue sampling-related diagnostic considerations in 600 consecuFor pelvic exenteration, in addition to processing the tive biopsies. Int J Gynecol Pathol. 2007;26:469–74. lymph nodes sent in individual containers, the mesorectum/ 1 0. Golbang P, Scurry J, de Jong S, McKenzie D, Planner R, Pyman J, pericolic adipose tissue and parametrial soft tissue should be et al. Investigation of 100 consecutive negative cone biopsies. Br J searched separately for lymph nodes. These lymph nodes are Obstet Gynaecol. 1997;104:100–4. submitted in the same manner as described above for non-­ 11. Crothers BA. Cytologic-histologic correlation: where are we now, and where are we going? Cancer Cytopathol. 2018;126:301–8. SLN specimens.

2.6.2 Histopathological reporting The following histopathological information should be included in the surgical pathology report for lymph nodes: • Number of nodes with isolated tumor cells (tumor deposit ≤0.2  mm), micrometastasis (tumor deposit >0.2 and ≤ 2 mm), or macrometastasis (tumor deposit >2 mm) in each specimen site [25]. However, reporting the number of lymph nodes with isolated tumor cells is required only in the absence of metastasis >0.2  mm in other lymph nodes [16]. • Total number of lymph nodes examined in each specimen • For SLNs, the results of AE1/AE3 staining • Presence or absence of extranodal involvement Please also see Sect. 7.11 for additional information on staging and management of lymph node involvement, including sentinel lymph nodes.

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12. Crothers BA, Jones BA, Cahill LA, Moriarty AT, Mody DR, Tench WD, et  al. Quality improvement opportunities in gynecologic cytologic-histologic correlations: findings from the College of American Pathologists Gynecologic Cytopathology Quality Consensus Conference Working Group 4. Arch Pathol Lab Med. 2013;137:199–213. 13. Girardi F, Reich O, Tamussino K. Cervical conization: techniques and histologic processing of the specimen. In: Girardi F, Reich O, Tamussino K, editors. Burghardt’s colposcopy and cervical pathology: textbook and atlas. New York: Thieme; 2015. p. 172–9. 14. Martin-Hirsch PL, Paraskevaidis E, Kitchener H.  Surgery for cervical intraepithelial neoplasia. Cochrane Database Syst Rev. 2000:Cd001318. 15. Montz FJ, Holschneider CH, Thompson LD. Large-loop excision of the transformation zone: effect on the pathologic interpretation of resection margins. Obstet Gynecol. 1993;81:976–82. 16. Krishnamurti U, Movahedi-Lankarani S, Bell DA, Birdsong GG, Biscotti CV, Chapman CN Jr, et  al. Protocol for the examination of specimens from patients with primary carcinoma of the uterine cervix. In: Cancer Protocol Templates. 2018. College of American Pathologists (CAP): https://www.cap.org/protocols-and-guidelines/ cancer-reporting-tools/cancer-protocol-templates. Accessed Aug 2018. 17. Kurman RJ, Ellenson LH, Ronnett BM.  Blaustein’s pathology of the female genital tract. New York: Springer; 2012. 18. Heatley MK. Distribution of cervical glandular intraepithelial neoplasia: are hysterectomy specimens sampled appropriately? J Clin Pathol. 2002;55:629–30. 19. Heatley MK.  How many histological levels should be exam ined from tissue blocks originating in cone biopsy and large loop ­excision of the transformation zone specimens of cervix? J Clin Pathol. 2001;54:650–1. 20. al-Nafussi AI, Hughes DE. Histological features of CIN3 and their value in predicting invasive microinvasive squamous carcinoma. J Clin Pathol. 1994;47:799–804. 21. Lester SC.  Gynecologic and perinatal pathology. In: Manual of surgical pathology. 3rd ed. Philadelphia: Elsevier Saunders; 2010. p. 423–71. 22. Hilger WS, Pizarro AR, Magrina JF. Removal of the retained cervical stump. Am J Obstet Gynecol. 2005;193:2117–21. 23. Bisseling KC, Bekkers RL, Rome RM, Quinn MA.  Treatment of microinvasive adenocarcinoma of the uterine cervix: a retrospective study and review of the literature. Gynecol Oncol. 2007;107:424–30. 24. Wright JD, NathavithArana R, Lewin SN, Sun X, Deutsch I, Burke WM, et  al. Fertility-conserving surgery for young women with stage IA1 cervical cancer: safety and access. Obstet Gynecol. 2010;115:585–90. 25. Koh WJ, Abu-Rustum NR, Bean S, Bradley K, Campos SM, Cho KR, et al. Cervical cancer. In: NCCN Clinical Practice Guidelines in Oncology. 2019. https://jnccn.org/view/journals/jnccn/17/1/article-p64.xml. Accessed Jan 2019. 26. Park JY, Joo WD, Chang SJ, Kim DY, Kim JH, Kim YM, et  al. Long-term outcomes after fertility-sparing laparoscopic radical trachelectomy in young women with early-stage cervical cancer:

44 an Asan Gynecologic Cancer Group (AGCG) study. J Surg Oncol. 2014;110:252–7. 27. Wethington SL, Sonoda Y, Park KJ, Alektiar KM, Tew WP, Chi DS, et al. Expanding the indications for radical trachelectomy: a report on 29 patients with stage IB1 tumors measuring 2 to 4 centimeters. Int J Gynecol Cancer. 2013;23:1092–8. 28. Plante M, Renaud MC, Sebastianelli A, Gregoire J. Simple vaginal trachelectomy: a valuable fertility-preserving option in early-stage cervical cancer. Int J Gynecol Cancer. 2017;27:1021–7. 29. Tseng JH, Aloisi A, Sonoda Y, Gardner GJ, Zivanovic O, Abu-­ Rustum NR, et al. Less versus more radical surgery in stage IB1 cervical cancer: a population-based study of long-term survival. Gynecol Oncol. 2018;150:44–9. 30. Park KJ, Soslow RA, Sonoda Y, Barakat RR, Abu-Rustum NR. Frozen-section evaluation of cervical adenocarcinoma at time of radical trachelectomy: pathologic pitfalls and the application of an objective scoring system. Gynecol Oncol. 2008;110:316–23. 31. Tanguay C, Plante M, Renaud MC, Roy M, Tetu B. Vaginal radical trachelectomy in the treatment of cervical cancer: the role of frozen section. Int J Gynecol Pathol. 2004;23:170–5. 32. Covens A, Shaw P, Murphy J, DePetrillo D, Lickrish G, Laframboise S, et al. Is radical trachelectomy a safe alternative to radical hysterectomy for patients with stage IA-B carcinoma of the cervix? Cancer. 1999;86:2273–9. 33. Dargent D, Martin X, Sacchetoni A, Mathevet P.  Laparoscopic vaginal radical trachelectomy: a treatment to preserve the fertility of cervical carcinoma patients. Cancer. 2000;88:1877–82. 34. Ismiil N, Ghorab Z, Covens A, Nofech-Mozes S, Saad R, Dube V, et al. Intraoperative margin assessment of the radical trachelectomy specimen. Gynecol Oncol. 2009;113:42–6. 35. Prat J. Pathology of cancers of the female genital tract. Int J Gynecol Cancer. 2015;131:S132–45. 36. Suprasert P, Srisomboon J, Charoenkwan K, Siriaree S, Cheewakriangkrai C, Kietpeerakool C, et  al. Twelve years experience with radical hysterectomy and pelvic lymphadenectomy in early stage cervical cancer. J Obstet Gynaecol. 2010;30:294–8. 37. Sardain H, Lavoue V, Redpath M, Bertheuil N, Foucher F, Leveque J. Curative pelvic exenteration for recurrent cervical carcinoma in the era of concurrent chemotherapy and radiation therapy. A systematic review. Eur J Surg Oncol. 2015;41:975–85. 38. Hockel M, Dornhofer N.  Pelvic exenteration for gynaecological tumours: achievements and unanswered questions. Lancet Oncol. 2006;7:837–47. 39. Rob L, Robova H, Halaska MJ, Hruda M, Skapa P. Current status of sentinel lymph node mapping in the management of cervical cancer. Expert Rev Anticancer Ther. 2013;13:861–70. 40. Selman TJ, Mann C, Zamora J, Appleyard TL, Khan K. Diagnostic accuracy of tests for lymph node status in primary cervical cancer: a systematic review and meta-analysis. CMAJ. 2008;178:855–62. 41. Diaz-Feijoo B, Temprana-Salvador J, Franco-Camps S, Manrique S, Colas E, Perez-Benavente A, et al. Clinical management of early-­ stage cervical cancer: the role of sentinel lymph node biopsy in tumors  3 mm, ≤5 mm; (IA2) horizontal spread ≤ 7 mm pT1b Clinically visible lesion (IB) and/or microscopic lesion >T1a2 pT1b1 ≤4 cm greatest dimension (IB1) pT1b2 >4 cm greatest dimension (IB2) IB3 N/A Invades beyond uterus, pT2 (II) but without involvement of the lower 1/3 of vagina or pelvic sidewall

FIGO 2009 N/A

FIGO 2018 N/A

Confined to uterusa Diagnosed only by microscopy, maximum depth ≤ 5 mm; horizontal spread ≤7 mm

Confined to uterusa Diagnosed only by microscopy, maximum depth ≤ 5 mm

Invasion ≤ 3 mm; horizontal spread ≤ 7 mm Invasion > 3 mm, ≤5 mm; horizontal spread ≤ 7 mm Clinically visible lesion and/or microscopic lesion >T1a2

Invasion ≤ 3 mm

≤4 cm greatest dimension

≤2 cm greatest dimension

>4 cm greatest dimension

>2 cm, ≤4 cm greatest dimension

Invasion > 3 mm, ≤5 mm Invasion >5 mm

N/A >4 cm greatest dimension Invades beyond uterus, but without involvement of the Invades beyond uterus, but without involvement of the lower 1/3 of vagina or lower 1/3 of vagina or pelvic sidewall pelvic sidewall

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163

Table 7.2 (continued) Stage pT2a (IIA)

AJCC eighth Edition Involvement of upper 2/3 of vagina without parametrial involvement

FIGO 2009 Involvement of upper 2/3 of vagina without parametrial involvement

FIGO 2018 Involvement of upper 2/3 of vagina without parametrial involvement

pT2a1 (IIA1) pT2a2 (IIA2) pT2b (IIB) pT3 (III)

≤4 cm greatest dimension

≤4 cm greatest dimension

≤4 cm greatest dimension

>4 cm greatest dimension

>4 cm greatest dimension

>4 cm greatest dimension

With parametrial involvement Involves lower 1/3 of vagina and/or pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney Involves lower 1/3 of vagina with no extension to pelvic sidewall Extends to pelvic sidewall and/or hydronephrosis or nonfunctioning kidney related to carcinoma N/A

With parametrial involvement

With parametrial involvement

Involves lower 1/3 of vagina and/or pelvic sidewallb and/or causes hydronephrosis or nonfunctioning kidney.

Involves lower 1/3 of vagina and/or extends to pelvic sidewall and/or causes hydronephrosis or nonfunctioning kidney and/or involves pelvic/ para-aortic lymph nodes

Involves lower 1/3 of vagina with no extension to pelvic sidewall

Involves lower 1/3 of vagina with no extension to pelvic sidewall

Extends to pelvic sidewall and/or hydronephrosis or nonfunctioning kidney related to carcinoma

Extends to pelvic sidewall and/or hydronephrosis or nonfunctioning kidney related to carcinoma

N/A

Involvement of pelvic and/or para-aortic lymph nodes (including micrometastasis), irrespective of tumor size or extent (add r and p notations to specify radiologic vs. pathology confirmation) Pelvic lymph node metastases only Para-aortic lymph node metastases Extends beyond the true pelvis and/or has biopsy-­ proven involvement of bladder mucosa or rectum

pT3a (IIIA) pT3b (IIIB)

IIIC

IIIC1 IIIC2 pT4 (IV)

N/A N/A Extends beyond the true pelvis and/or has involvement of bladder mucosa or rectumc IVA N/A IVB N/A pN0 No regional lymph node metastases pN0(i+) Isolated tumor cells in regional lymph nodes ≤0.2 mm pN1 Regional lymph node metastases pM1 Distant metastases including peritoneal spread; involvement of supraclavicular, mediastinal, or distant lymph nodes; lung, liver, or bone involvement

N/A N/A Extends beyond the true pelvis and/or has clinical involvement of bladder mucosa or rectumc Spread to adjacent pelvic organs Spread to distant organs N/A

Spread to adjacent pelvic organs Spread to distant organs N/A

N/A

N/A

N/A

N/A

N/A

N/A

AJCC American Joint Committee on Cancer, FIGO International Federation of Gynecology and Obstetrics a: Uterine corpus involvement does not impact staging for any of the systems b: Both FIGO systems clarify that pelvic sidewall involvement is defined as the absence of cancer-free space between tumor and pelvic sidewall. The pelvic sidewall includes the muscle, fascia, neurovascular structures, and skeletal portions of the bony pelvis c: Bullous edema is not sufficient to classify as involvement under any of the three systems. The 2018 FIGO system specifies that biopsy-proven involvement is required

164

7.14 Predictive Biomarkers The recent US Food and Drug Administration (FDA) approval of the anti-PD-1 checkpoint inhibitor pembrolizumab for the treatment of recurrent and advanced cervical squamous cell carcinoma has led to the use of PD-L1 immunohistochemistry as a predictive biomarker in this setting (Fig. 7.52) [94, 95]. Patient candidacy for this drug is based on a PD-L1 combined positive score (CPS) of at least 1. The CPS is based on the total number of PD-L1positive tumor cells, macrophages, and lymphocytes divided by the total number of tumor cells present, multiplied by 100. Practically speaking, this means that more than 80% of cervical cancer patients will qualify, because only a single positive cell—be it tumor, macrophage, or lymphocyte—is required per 100 tumor cells in order to attain the minimum score of 1 [96]. Occasionally, immunohistochemical staining for DNA mismatch repair proteins is requested for cervical cancers, owing to the approval of pembrolizumab in all mismatch repair-deficient solid tumors [97, 98]. Given the rarity

a

Fig. 7.52  PD-L1 immunohistochemistry in cervical squamous cell carcinoma: This squamous cell carcinoma (a) shows strong PD-L1 expression (b) not only in tumor cells, but also in associated inflamma-

M. P. Crawford et al.

of mismatch repair deficiency in cervical squamous cell carcinoma and the high frequency of PD-L1 positivity of CPS ≥ 1 in these tumors, such testing is generally imprudent until PD-L1 immunohistochemistry is first performed, as patients are far more likely to qualify via that pathway. Overall, checkpoint inhibitor-based immunotherapy has shown promise in a subset of patients with cervical squamous cell carcinoma, but it fails to provide a durable response for most [92, 93, 95]. Given that most cervical cancers enlist multiple mechanisms of immune evasion, combination approaches that target multiple immune modulatory molecules are of interest in cervical squamous carcinoma and may ultimately lead to an expansion of the predictive biomarkers enlisted clinically [99].

7.14.1 Case A 45-year-old woman with squamous cell carcinoma demonstrating strong PD-L1 expression in tumor cells and the associated lymphoid infiltrate (Fig. 7.52).

b

tory cells. This high level of positivity is well beyond the FDAapproved pembrolizumab treatment threshold of a combine positive score (CPS) ≥1

7  Epithelial Malignant Tumors of the Cervix: Squamous Carcinoma

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166 36. Tempfer CB, Tischoff I, Dogan A, Hilal Z, Schultheis B, Kern P, Rezniczek GA. Neuroendocrine carcinoma of the cervix: a systematic review of the literature. BMC Cancer. 2018;18:530. 37. Burk RD, Terai M, Gravitt PE, Brinton LA, Kurman RJ, Barnes WA, et al. Distribution of human papillomavirus types 16 and 18 variants in squamous cell carcinomas and adenocarcinomas of the cervix. Cancer Res. 2003;63:7215–20. 38. Quddus MR, Manna P, Sung CJ, Kerley S, Steinhoff MM, Lawrence WD. Prevalence, distribution, and viral burden of all 15 high-risk human papillomavirus types in adenosquamous carcinoma of the uterine cervix: a multiplex real-time polymerase chain reaction-­ based study. Hum Pathol. 2014;45:303–9. 39. Lee H, Lee H, Cho YK.  Cytokeratin7 and cytokeratin19 expression in high grade cervical intraepithelial neoplasm and squamous cell carcinoma and their possible association in cervical carcinogenesis. Diagn Pathol. 2017;12:18. https://doi.org/10.1186/ s13000-017-0609-4. 40. Jung YY, Nahm JH, Kim HS.  Cytomorphological characteristics of glassy cell carcinoma of the uterine cervix: histopathological correlation and human papillomavirus genotyping. Oncotarget. 2016;7:74152–61. 41. Koh SS, Cassarino DS. Immunohistochemical expression of p16 in melanocytic lesions: an updated review and meta-analysis. Arch Pathol Lab Med. 2018;142:815–28. 42. Alexander RE, Hu Y, Kum JB, Montironi R, Lopez-Beltran A, Maclennan GT, et al. p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma. Mod Pathol. 2012;25:1526–33. 43. Rambau PF, Vierkant RA, Intermaggio MP, Kelemen LE, Goodman MT, Herpel E, et  al. Association of p16 expression with prognosis varies across ovarian carcinoma histotypes: an Ovarian Tumor Tissue Analysis Consortium study. J Pathol Clin Res. 2018;4:250–61. 44. Yemelyanova A, Ji H, Shih I, Wang TL, Wu LS, Ronnett BM. Utility of p16 expression for distinction of uterine serous carcinomas from endometrial endometrioid and endocervical adenocarcinomas: immunohistochemical analysis of 201 cases. Am J Surg Pathol. 2009;33:1504–14. 45. El-Bahrawy M.  Expression of p16  in post-radiotherapy cervical biopsies. Histopathology. 2011;58:1174–6. 46. Munger K, Gwin TK, McLaughlin-Drubin M. p16  in HPV-­ associated cancers. Oncotarget. 2013;4:1864–5. 47. Klaes R, Benner A, Friedrich T, Ridder R, Herrington S, Jenkins D, et al. p16INK4a immunohistochemistry improves interobserver agreement in the diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol. 2002;26:1389–99. 48. Darragh TM, Colgan TJ, Thomas Cox J, Heller DS, Henry MR, Luff RD, et  al. The Lower Anogenital Squamous Terminology Standardization Project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology. Int J Gynecol Pathol. 2013;32:76–115. 49. Rodríguez-Carunchio L, Soveral I, Steenbergen RDM, Torné A, Martinez S, Fusté P, et  al. HPV-negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis. BJOG. 2015;122:119–27. 50. Pirog EC.  Cervical adenocarcinoma: diagnosis of human papillomavirus-­ positive and human papillomavirus-negative tumors. Arch Pathol Lab Med. 2017;141:1653–67. 51. Mills AM, Dirks DC, Poulter MD, Mills SE, Stoler MH. HR-HPV E6/E7 mRNA in situ hybridization: Validation against PCR, DNA in situ hybridization, and p16 immunohistochemistry in 102 samples of cervical, vulvar, anal, and head and neck neoplasia. Am J Surg Pathol. 2017;41:607–15. 52. Rooper LM, Gandhi M, Bishop JA, Westra WH.  RNA in-situ hybridization is a practical and effective method for determining HPV status of oropharyngeal squamous cell carcinoma including

M. P. Crawford et al. discordant cases that are p16 positive by immunohistochemistry but HPV negative by DNA in-situ hybridization. Oral Oncol. 2016;55:11–6. 53. Amin MB, Edge S, Greene F, Byrd DR, Brookland RK, Washington MK, et al., editors. AJCC cancer staging manual. 8th ed. New York: Springer; 2017. 54. Van De Putte G, Lie AK, Vach W, Baekelandt M, Kristensen GB. Risk grouping in stage IB squamous cell cervical carcinoma. Gynecol Oncol. 2005;99:106–12. 55. Delgado G, Bundy BN, Fowler WC, Stehman FB, Sevin B, Creasman WT, et al. A prospective surgical pathological study of stage I squamous carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol. 1989;35:314–20. 56. Ryu SY, Kim MH, Nam BH, Lee TS, Song ES, Park CY, et  al. Intermediate-risk grouping of cervical cancer patients treated with radical hysterectomy: a Korean Gynecologic Oncology Group study. Br J Cancer. 2014;110:278–85. 57. Samlal RA, van der Velden J, Ten Kate FJ, Schilthuis MS, Hart AA, Lammes FB. Surgical pathologic factors that predict recurrence in stage IB and IIA cervical carcinoma patients with negative pelvic lymph nodes. Cancer. 1997;80:1234–40. 58. Kodama J, Fukushima C, Kusumoto T, Nakamura K, Seki N, Hongo A, Hiramatsu Y. Stage IB1 cervical cancer patients with an MRI-measured tumor size < or = 2 cm might be candidates for less-­ radical surgery. Eur J Gynaecol Oncol. 2013;34:39–41. 59. Kodama J, Mizutani Y, Hongo A, Yoshinouchi M, Kudo T, Okuda H. Optimal surgery and diagnostic approach of stage IA2 squamous cell carcinoma of the cervix. Eur J Obstet Gynecol Reprod Biol. 2002;101:192–5. 60. Horn L-C, Bilek K, Fischer U, Einenkel J, Hentschel B.  A cut-­ off value of 2  cm in tumor size is of prognostic value in surgically treated FIGO stage IB cervical cancer. Gynecol Oncol. 2014;134:42–6. 61. Wagner AE, Pappas L, Ghia AJ, Gaffney DK. Impact of tumor size on survival in cancer of the cervix and validation of stage IIA1 and IIA2 subdivisions. Gynecol Oncol. 2013;129:517–21. 62. Day E, Duffy S, Bryson G, Syed S, Shanbhag S, Burton K, et al. Multifocal FIGO stage IA1 squamous carcinoma of the cervix: criteria for Identification, staging, and its good clinical outcome. Int J Gynecol Pathol. 2016;35:467–74. 63. McIlwaine P, Nagar H, McCluggage WG.  Multifocal FIGO stage 1a1 cervical squamous carcinomas have an extremely good prognosis equivalent to unifocal lesions. Int J Gynecol Pathol. 2014;33:213–7. 64. Wittekind C, Brierley JD, Lee A, van Eycken E, editors. TNM supplement: a commentary on uniform use. 5th ed. Hoboken, NJ: Wiley-Blackwell; 2019. 65. Sakuragi N, Takeda N, Hareyama H, Fujimoto T, Todo Y, Okamoto K, et  al. A multivariate analysis of blood vessel and lymph vessel invasion as predictors of ovarian and lymph node metastases in patients with cervical carcinoma. Cancer. 2000;88:2578–83. 66. Creasman WT, Morrow CP, Bundy BN, Homesley HD, Graham JE, Heller PB.  Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group Study. Cancer. 1987;60:2035–41. 67. Pallavi VR, Devi KU, Mukherjee G, Ramesh C, Bafna UD. Relationship between lymph node metastases and histopathological parameters in carcinoma cervix: a multivariate analysis. J Obstet Gynaecol. 2012 Jan;32(1):78–80. 68. Bhatla N, Berek JS, Cuello Fredes M, Denny LA, Grenman S, Karunaratne K, et al. Revised FIGO staging for carcinoma of the cervix uteri. Int J Gynecol Obstet. 2019;145:129–35. 69. Bhatla N, Aoki D, Sharma DN, Sankaranarayanan R. Cancer of the cervix uteri. Int J Gynecol Obstet. 2018;143:22–36. 70. Chandacham A, Charoenkwan K, Siriaunkgul S, Srisomboon J, Suprasert P, Phongnarisorn C, et  al. Extent of lymphovascular space invasion and risk of pelvic lymph node metastases in

7  Epithelial Malignant Tumors of the Cervix: Squamous Carcinoma stage IB1 cervical cancer. J Med Assoc Thail. 2005;88(Suppl 2):S31–6. 71. Sevin B-U, Nadji M, Averette HE, Hilsenbeck S, Smith D, Lampe B. Microinvasive carcinoma of the cervix. Cancer. 1992;70:2121–8. 72. Elliott P, Coppleson M, Russell P, Liouros P, Carter J, MacLeod C, Jones M. Early invasive (FIGO stage IA) carcinoma of the cervix: a clinico-pathologic study of 476 cases. Int J Gynecol Cancer. 2000;10:42–52. 73. Cui L, Shi Y, Zhang GN. Perineural invasion as a prognostic factor for cervical cancer: a systematic review and meta-analysis. Arch Gynecol Obstet. 2015;292:13–9. 74. Cho HC, Kim H, Cho HY, Kim K, No JH, Kim YB.  Prognostic significance of perineural invasion in cervical cancer. Int J Gynecol Pathol. 2013;32:228–33. 75. Horn L-C, Meinel A, Fischer U, Bilek K, Hentschel B. Perineural invasion in carcinoma of the cervix uteri  – prognostic impact. J Cancer Res Clin Oncol. 2010;136:1557–62. 76. Shimada M, Kigawa J, Nishimura R, Yamaguchi S, Kuzuya K, Nakanishi T, et al. Ovarian metastasis in carcinoma of the uterine cervix. Gynecol Oncol. 2006;101:234–7. 77. Holman LL, Levenback CF, Frumovitz M.  Sentinel lymph node evaluation in women with cervical cancer. J Minim Invasive Gynecol. 2014;21:540–5. 78. Diaz JP, Gemignani ML, Pandit-Taskar N, Park KJ, Murray MP, Chi DS, et al. Sentinel lymph node biopsy in the management of early-stage cervical carcinoma. Gynecol Oncol. 2011;120:347–52. 79. Guani B, Dorez M, Magaud L, Buenerd A, Lecuru F, Mathevet P. Impact of micrometastasis or isolated tumor cells on recurrence and survival in patients with early cervical cancer: SENTICOL Trial. Int J Gynecol Cancer. 2019;29:447–52. 80. Delomenie M, Bonsang-Kitzis H, Bats AS, Ngo C, Balaya V, Xuan HTN, et al. The clinical implication of lymph nodes micrometastases and isolated tumor cells in patients with cervical cancer: a systematic review. Eur J Obstet Gynecol Reprod Biol. 2019;241:71–6. 81. McCann GA, Taege SK, Boutsicaris CE, Phillips GS, Eisenhauer EL, Fowler JM, et  al. The impact of close surgical margins after radical hysterectomy for early-stage cervical cancer. Gynecol Oncol. 2013;128:44–8. 82. Viswanathan AN, Lee H, Hanson E, Berkowitz RS, Crum CP.  Influence of margin status and radiation on recurrence after radical hysterectomy in stage IB cervical cancer. Int J Radiat Oncol Biol Phys. 2006;65:1501–7. 83. Khanna N, Rauh LA, Lachiewicz MP, Horowitz IR.  Margins for cervical and vulvar cancer. J Surg Oncol. 2016;113:304–9. 84. Corrigendum to “Revised FIGO staging for carcinoma of the cervix uteri” [Int J Gynecol Obstet 145(2019) 129–135]. Int J Gynaecol Obstet. 2019;147(2):279–80. 85. Landoni F, Maneo A, Cormio G, Perego P, Milani R, Caruso O, Mangioni C. Class II versus class III radical hysterectomy in stage IB-IIA cervical cancer: a prospective randomized study. Gynecol Oncol. 2001;80:3–12. 86. Landoni F, Colombo A, Milani R, Placa F, Zanagnolo V, Mangioni C. Randomized study between radical surgery and radiotherapy for

167 the treatment of stage IB–IIA cervical cancer: 20-year update. J Gynecol Oncol. 2017;28:e34. 87. Landoni F, Maneo A, Colombo A, Placa F, Milani R, Perego P, et al. Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet. 1997;350:535–40. 88. Grigsby PW, Perez CA. Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ. Int J Radiat Oncol Biol Phys. 1991;21:375–8. 89. Eifel PJ, Morris M, Wharton JT, Oswald MJ.  The influence of tumor size and morphology on the outcome of patients with FIGO stage IB squamous cell carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys. 1994;29:9–16. 90. Moore DH, Blessing JA, McQuellon RP, Thaler HT, Cella D, Benda J, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: A Gynecologic Oncology Group study. J Clin Oncol. 2004;22:3113–9. 91. Frenel JS, Le Tourneau C, O'Neil BH, Ott PA, Piha-Paul SA, Gomez-Roca CA, et al. Pembrolizumab in patients with advanced cervical squamous cell cancer: Preliminary results from the phase Ib KEYNOTE-028 study. J Clin Oncol. 2016;34(suppl):5515. https://doi.org/10.1200/JCO.2016.34.15_suppl.5515. 92. Frenel JS, Le Tourneau C, O’Neil B, Ott PA, Piha-Paul SA, Gomez-­ Roca CA, et al. Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1-positive cervical cancer: results from the phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017;35:4035–41. 93. Borcoman E, Le Tourneau C.  Pembrolizumab in cervical cancer: latest evidence and clinical usefulness. Ther Adv Med Oncol. 2017;9:431–9. 94. US Food and Drug Administration. FDA approves pembroli zumab for advanced cervical cancer with disease progression during or after chemotherapy. 2018. https://www.fda.gov/Drugs/ InformationOnDrugs/ApprovedDrugs/ucm610572.htm. 95. Chung HC, Ros W, Delord JP, Perets R, Italiano A, Shapira-­ Frommer R, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2019;37:1470–8. 96. Kulangara K, Hanks DA, Waldroup S, Peltz L, Shah S, Roach C, et  al. Development of the combined positive score (CPS) for the evaluation of PD-L1 in solid tumors with the immunohistochemistry assay PD-L1 IHC 22C3 pharmDx. J Clin Oncol. 2017;35:e14589. 97. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-­high solid tumors. Clin Cancer Res. 2019;25:3753–8. 98. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13. 99. Chinn Z, Stoler MH, Mills AM. PD-L1 and IDO expression in cervical and vulvar invasive and intraepithelial squamous neoplasias: implications for combination immunotherapy. Histopathology. 2019;74:256–68.

8

Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma Simona Stolnicu

Contents

8.1

8.1    Definition

 169

8.2    Synonyms

 170

8.3    Etiology and Pathogenesis

 170

8.4    Clinical Presentation and Macroscopy

 170

8.5    Cytological Features

 170

8.6    Microscopic Classification of Endocervical Adenocarcinoma 8.6.1   HPV-Associated Endocervical Adenocarcinomas (HPVA) 8.6.1.1  Usual Type Adenocarcinoma (Including Villoglandular and Micropapillary Architectural Variants) 8.6.1.2  Mucinous Type Adenocarcinoma (Including Mucinous NOS, Intestinal, Signet-Ring, and Invasive Stratified Mucinous Variants) 8.6.1.3  Adenocarcinoma NOS Type 8.6.1.4  Assessment of Stromal Invasion by ECA 8.6.1.5  Cases 8.6.2   HPV-Independent Endocervical Adenocarcinomas (HPVI) 8.6.2.1  Gastric type, Including Minimal Deviation Adenocarcinoma 8.6.2.2  Clear Cell Adenocarcinoma 8.6.2.3  Mesonephric Type Adenocarcinoma 8.6.2.4  Endometrioid Type Adenocarcinoma 8.6.2.5  Adenocarcinoma NOS Type, (HPVI) 8.6.2.6  Cases

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8.7    Differential Diagnosis

 200

8.8    Prognosis

 204

References

 206

Definition

ECA is the second most prevalent epithelial malignant tumor of the cervix. Despite robust national screening programs in most developed countries, the incidence of ECA has increased in recent decades, and it now represents up to 25% of all invasive malignant cervical tumors [1]. Very

 171  175  180  180  185  186  186  190  195  199  200  200

little was known about ECAs decades ago, when the tumor was rare, but with recent developments we have gained more knowledge. ECAs are a heterogeneous group of tumors comprising different tumor types characterized by varying etiology, molecular drivers, morphology, and prognosis.

S. Stolnicu (*) Department of Pathology, University of Medicine, Pharmacy, Sciences and Technology, Targu Mures, Romania © Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_8

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8.2

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Synonyms

Glandular invasive carcinoma of the cervix.

8.3

Etiology and Pathogenesis

Most ECAs are related to human papillomavirus (HPV); the most prevalent subtypes are HPV 18, 16, and 45 [1–3]. Unlike squamous cell carcinoma of the cervix, however, 10–15% of all ECAs are not HPV-driven [4–7], an important consideration for many reasons, which are discussed below. One is prophylaxis, as these HPV-independent types of ECAs would not necessarily be prevented by the HPV vaccine or detected by HPV-based screening. For ECAs not related to HPV infection, different associated molecular abnormalities have been demonstrated recently, particularly for gastric, mesonephric, and clear cell adenocarcinomas. Prevalent genetic alterations include mutations in PIK3CA, KRAS, and PTEN and other members of the PI3K/Akt/mTOR signaling cascade,  some of them with predictive and prognostic value [8–11]. A genetic predisposition for the development of gastric type adenocarcinoma was found in women with Peutz-Jeghers syndrome, and, anecdotally, Li-Fraumeni syndrome [12–14]. The origin of ECA is thought to be pluripotent subcolumnar reserve cells. Risk factors such as multiple sexual partners, young age at first intercourse, use of oral contraceptives for more than 10 years, hormonal replacement therapy, and obesity are similar to risk factors for the development of cervical squamous cell carcinoma.

8.4

Clinical Presentation and Macroscopy

Mean age at presentation is 50 years, similar to the age for squamous cell carcinoma, but ECAs related to HPV infection occur in younger patients than the HPV-independent ECAs [7]. Also, patients presenting with ECA unrelated to HPV are diagnosed at a higher FIGO stage [7, 15]. Most ECAs develop within the transformation zone, with a minority of cases (mostly gastric type ECA) located within the endocervical canal, adjacent to the lower uterine segment. Also, the mesonephric type develops more frequently deep in the lateral part of the cervical wall, where mesonephric remnants are usually found. Similarly, the endometrioid type

is thought to develop more frequently in the deep part of the cervical wall, originating from cervical endometriosis. In most cases, the symptoms consist of vaginal bleeding and/or discharge. In gastric type ECA, a watery vaginal discharge can occur. The tumor can be visible on imaging examinations such as CT scans or MRI. On clinical and macroscopic examination, ECAs can appear as an exophytic, ulcerated mass, or less frequently, as a thickening of the cervical wall (“barrel-shape”). The size is quite variable. When the tumor has a large diameter and is visible to the naked eye, it is usually of white-gray color and friable, with soft consistency, and it presents infiltrative margins.

8.5

Cytological Features

The cytological examination of Papanicolaou (Pap) smears, originally envisioned for detection of squamous cell carcinoma and its precursor lesions, is less powerful in detecting invasive adenocarcinoma. The sensitivity of the Papanicolaou smear to detect ECA is 45–76% on conventional smears (being higher in liquid-based cytology), but the specificity is high [16, 17]. Cytological features encountered in invasive adenocarcinomas are represented by a background of heavy blood and tumor diathesis (both supporting invasion) and abundant abnormal glandular epithelium with columnar configuration, with super-crowding of sheets, papillary clusters, and three-­ dimensional clusters, as well as monolayered, honeycomb sheets and single tumor cells with yellowish-orange intracytoplasmic mucin, nuclear enlargement and pleomorphism, nuclear membrane irregularities, and the presence of macronucleoli. Mitotic figures and apoptotic bodies can be present (Fig.  8.1). All these features are characteristic of invasive adenocarcinomas associated with HPV infection (specifically the usual type). For the HPV-independent lesions (especially the gastric  type), characteristic features are the presence of atypical cells with vacuolar and/or foamy cytoplasm, marked intracytoplasmic neutrophil entrapment, intracytoplasmic mucin, and vesicular nuclei with conspicuous nucleoli [18, 19]. A commercially available latex agglutination test, which uses HIK1083 to screen for gastric mucin in cervical discharge, is available in Japan; it offers excellent specificity and sensitivity for detection of cervical gastric type lesions [20].

8  Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma

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Fig. 8.1 Invasive HPV-associated (HPVA) adenocarcinoma. Pap smear with background of heavy blood supporting invasion and clusters of super-crowded, three-dimensional, atypical cells (a) with yellowish-­

orange intracytoplasmic mucin, nuclear enlargement, pleomorphism, and nuclear membrane irregularities (b) (Papanicolaou stain)

8.6

that have been recently described, such as invasive stratified mucin-producing carcinoma and invasive micropapillary carcinoma of the cervix [26, 27]. This new classification is very easy to work with in routine practice in any laboratory, as it does not need expensive and sophisticated additional tests. Although IECC classifies ECAs based on association with HPV infection, p16 immunohistochemistry/HPV testing should not be performed routinely but can be reserved for diagnostically difficult cases. Recent studies have demonstrated that IECC is more reproducible than the WHO 2014 classification, which will soon be replaced [1, 22].

Microscopic Classification of Endocervical Adenocarcinoma

Microscopically, ECA is a heterogeneous group of tumors. A new classification proposal has recently been incorporated into the forthcoming WHO 2020 classification for tumors of the female genital tract. This new International Endocervical Criteria and Classification (IECC) of ECAs is based on morphological features, linked to etiology, specifically, HPV infection. The IECC has allowed study of p16 expression and HPV testing in various type of ECA, as well as prognostic parameters, survival, and response to treatment [7, 21]. The IECC classification proposal has been validated by subsequent work, showing superior interobserver agreement among gynecological pathologists and high correlation with HPV molecular results, suggesting that it is a more biologically congruent and clinically valuable system to classify ECAs [22, 23]. IECC is easy to apply in daily practice based on identifying mitotic figures and apoptotic bodies on hematoxylin-­ eosin (H&E) stained slides on scanning magnification. If these features are present, the tumor is likely to be HPV-­ associated (HPVA). If these features are absent or difficult to detect on scanning magnification, a brief review at 200x magnification is performed. Without easily appreciated mitotic activity and apoptosis, the tumor is interpreted as HPV-independent (HPVI) [25]. Both distinct subgroups (HPVA and HPVI) are subsequently classified based on cytoplasmic features  and architecture (for HPVAs) and existing classification criteria (for HPVIs). This classification also includes new histological entities

8.6.1 HPV-Associated Endocervical Adenocarcinomas (HPVA) This category includes three types: usual type, mucinous type, and adenocarcinoma not otherwise specified (NOS). All these tumor types can be associated with an in situ component such as in situ adenocarcinoma, high-grade squamous intraepithelial lesion (HSIL), and stratified mucin-producing intraepithelial lesion (SMILE).

8.6.1.1 Usual Type Adenocarcinoma (Including Villoglandular and Micropapillary Architectural Variants) Usual type ECA is the most frequent HPVA type, accounting for 75–80% of all ECAs [7]. The IECC classification provides a cutoff for the intracytoplasmic mucin content and arbitrarily defines usual type ECA as a tumor with 0–50% of

172

tumor cells containing appreciable intracytoplasmic mucin assessed on H&E-stained slides [7]. Usual type ECA with destructive stromal invasion contains desmoplastic stroma with inflammatory infiltrates and, rarely, mucin pools. LVI can be found at the tumor’s periphery. Infiltration with a microcystic elongated and fragmented (MELF) pattern similar to endometrioid adenocarcinoma of the corpus can also occur. From the point of view of architecture, usual type ECA is most frequently characterized by glands with irregular shape and size, but papillary, cribriform, and solid areas may occur. The tumor glands can be intact or fragmented, single or fused. Also (rarely), villoglandular, micropapillary, macrocystic, microcystic, trabecular, and single tumor cell patterns can be identified (Fig. 8.2). Characteristically, the tumor cells are columnar, with pseudostratified, elongated, and hyperchromatic nuclei. Prominent mitotic activity, especially at the luminal aspect of the cell, and basal karyorrhexis define HPV association and is typical of the entity (Figs. 8.3, 8.4, and 8.5). In some cases, benign squamous metaplasia can occur in association with usual type ECA, and sometimes the metaplasia can be extensive, mimicking an invasive adenosquamous carcinoma (Fig. 8.6). Villoglandular adenocarcinoma is worth special mention, as it was previously considered a distinct type of ECA with excellent prognosis [1]. The villoglandular architecture is characterized by prominent exophytic papillary growth in the superficial part of the tumor, usually said to be “finger-­like” and frequently branching, lined by columnar, pseudostratified epithelial cells. The deep aspect of the tumor is represented in most cases by crypts that resemble HPV-­ associated adenocarcinoma in situ. This pattern is very rarely encountered in routine practice in its pure form; most frequently it is mixed with invasive, usual type ECA in the deepest areas of the tumor. Even when pure, the tumor is always HPV-positive and presents apical mitoses and apoptotic bodies, and its immunohistochemical profile and prognosis are similar to usual type ECA. It is best to consider this tumor type an HPVA adenocarcinoma with a villoglandular pattern. When the villoglandular pattern is unassociated with destructive  stromal invasion, it is reasonable to diagnose HPVA endocervical adenocarcinoma (villoglandular pattern) without stromal invasion. These exophytic tumors used to be considered at least FIGO stage IB1 because they are mass-forming and, usually, clinically visible; however, the most recent FIGO staging scheme assigns stage IB1 based on depth of invasion (>5 mm). Villoglandular-pattern ECAs should

S. Stolnicu

therefore be staged based on deepest invasion and largest tumor dimension.  Conservative treatment can  be considered only in tumors displaying a superficial papillary growth without deep cervical stromal invasion or lymphovascular invasion (LVI) (Fig. 8.7). Another special architectural pattern worth mentioning is the micropapillary pattern. This pattern can be pure or mixed with other HPVA types, most frequently with usual type ECA.  It is a recently recognized architectural variant of ECA, microscopically represented by small, tightly cohesive papillary groups of neoplastic cells, with eosinophilic cytoplasm and atypical nuclei, surrounded by clear spaces resembling vascular channels [27]. This architectural pattern is always associated with LVI and often with LNM and a poor prognosis. For this reason, it is important for this morphologic variant to be recognized by the pathologist and included in the final histopathological report (Fig. 8.8). With ancillary testing, usual type ECA is almost always positive for p16 and HPV [25, 29]. Interestingly, both p16 and HPV can be found to be negative in poorly fixed tissues and older paraffin blocks, or by using different detection methods. The best method to detect the presence of high-risk HPV subtypes is in situ hybridization using probes that recognize E6 and E7 oncoprotein mRNA that is associated with high-risk HPV infection [25]. Of note, usual type ECA is generally negative for ER, PR, vimentin, MUC6, HNF1beta, napsin A, GATA3, PAX2, p53, AR, and HER2, but these markers can sometimes be positive [30]. These findings are especially important when differentiating usual type ECA from other ECA types or from tumors that secondarily involve the cervix (uterine corpus tumors or tumors metastasizing from remote organs).

Diagnostic Highlights

• apical mitoses and apoptotic bodies easily identified at scanning magnification • enlarged and hyperchromatic pseudostratified nuclei • various architectural patterns including villoglandular and micropapillary • stromal invasion present in either non-destructive or destructive patterns • p16 overexpression • HPV detection

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Fig. 8.2  Usual type adenocarcinoma characterized by glands (a) with irregular shape and size; cribriform areas may occur (b). The glands can be small (microcystic pattern) (c, d) or cystically dilated (macrocystic pattern), but mitotic figures are present even in flattened epithelium (e, f)

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Fig. 8.3  Usual type adenocarcinoma is characterized by columnar tumor cells (a) with pseudostratified elongated and hyperchromatic nuclei. The cytoplasm is usually mucin-depleted, but at the apical area, the presence of mitotic figures and apoptotic bodies is pathognomonic (b, c)

Fig. 8.4  Usual type adenocarcinoma with more abundant cytoplasmic mucin

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Fig. 8.5  Usual type adenocarcinoma in a 40-year-old patient, with mucin-depleted cytoplasm (a) mimicking an endometrioid carcinoma (b). In this case, p16 is positive (c), as is HPV in situ hybridization (d); these are very helpful for the diagnosis of usual type ECA

8.6.1.2 Mucinous Type Adenocarcinoma (Including Mucinous NOS, Intestinal, Signet-Ring, and Invasive Stratified Mucinous Variants) The 2014 WHO publication grouped together HPVA and HPVI. The following discussion pertains to mucinous HPVAs and it recognizes the following subcategories, all with abundant intracytoplasmatic mucin and features of HPV infection such as apical mitotic figures and apoptosis evident on scanning magnification:

Fig. 8.6  Usual type invasive endocervical adenocarcinoma (ECA) with extensive benign squamous metaplasia. This pattern should not be reflexively diagnosed as adenosquamous carcinoma, which requires identification of two components—glandular and squamous—both with malignant features

• Mucinous not otherwise specified (NOS) type. ≥ 50% of tumor cells have detectable intracytoplasmic mucin recognizable on H&E slides in a background of usual type ECA (Figs. 8.9 and 8.10) • Intestinal. Goblet cells, Paneth cells and other entero-­ endocrine cells represent ≥50% of cells with goblet morphology in a background of usual type ECA (Fig. 8.11) • Signet-ring. Round cells with a mucinous vacuole that displaces the nucleus to the side represent ≥50% of cells

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Fig. 8.7  Usual type ECA with villoglandular architecture in a 38-year-­ old patient. Seen are prominent exophytic papillary growth in the superficial part of the tumor (a), composed of papillae of various thickness and length, containing central fibrous cores and lined by columnar, pseudostratified epithelial cells (b). Sometimes the papillae have focal cribriform areas (c) and are shorter (d) and thicker (e). This tumor pres-

ents apical mitoses and apoptotic bodies; the cells have a variable amount of mucin and uniform nuclei. Please note that the exophytic portion of the tumor is not considered evidence of destructive stromal invasion, but in contrast the few glands at the tumor’s base (marked with red arrows) are stromal-invasive

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Fig. 8.8  Usual type ECA in a 45-year-old patient, with a micropapillary pattern infiltrating the endocervical canal (a), mixed with usual type (b). Microscopically, it is represented by small, tightly cohesive papillary groups of neoplastic cells with  eosinophilic cytoplasm and

atypical nuclei, surrounded by clear spaces resembling vascular channel; multiple psammoma bodies seen in this case mimic serous adenocarcinoma (c). However, p16 and HPV were positive (not shown). The lymph node metastasis displays micropapillary architecture as well

with signet-ring morphology in a background of usual type ECA (Fig. 8.12) • Invasive stratified mucinous carcinoma (ISMC or iSMILE). Invasive nests of stratified columnar cells with variable amounts of intracytoplasmic mucin and peripheral palisading (Fig. 8.13) The recently described ISMC  deviates from other HPVAs because of its morphology, immunohistochemical profile and aggressive clinical outcomes, as it has been reported to have a poorer prognosis than other histological subtypes of HPV-associated ECA [26, 31]. ISMC can occur in pure form or can be associated with usual or mucinous HPVAs, as well as adenosquamous or neuroendocrine carcinoma. Within the tumor, intraepithelial neutrophilic infiltrates, apoptotic bodies, and frequent mitotic figures are commonly and easily identified. Invasive stratified mucinous carcinoma can display a wide range of architectural diversity: insular, glandular, solid, papillary, trabecular,

micropapillary, or single cells with variable amounts of stroma. There is also a spectrum of  cytological appearances, with a varying amount of mucin (mucin-rich to mucin-poor) but also eosinophilic cytoplasm, cytoplasmic clearing, histiocytoid-like features, “glassy cell”-like features, signet ring-like features, bizarre nuclear atypia, or “squamoid differentiation” in the form of cells with eosinophilic cytoplasm lacking intercellular bridges and keratinization. These features are important to recognize when making a diagnosis of ISMC, as it can mimic another tumor subtype [24, 26]. All mucinous HPVA types are positive for p16 and HPV testing [25]. Also, mucinous HPVA is usually negative for ER, PR, vimentin, MUC6, p63, p40, and GATA3, but it can be positive for CAIX, HNF1 beta, and napsin A. The intestinal subtype can be positive for PAX8, CDX2, CK20 and p53 [28]. AR and HER2 are always negative [29].

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Fig. 8.9  Mucinous not otherwise specified (NOS) type adenocarcinoma. Proliferation of glands of various sizes and shapes (a), focally with a papillary architecture (b), or cribriform architecture (c). At least

50% of tumor cells have intracytoplasmic mucin (d), and mitotic figures are present at scanning magnification and at 200x, evidence of HPV infection (e)

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Fig. 8.10  Mucinous adenocarcinoma (HPVA), NOS in a 47-year-old patient. Proliferation of glands lined by tumor cells with abundant intracytoplasmic mucin and in association with mitotic figures as evidence

of HPV infection (a). The glands are positive for p16 (b) and CAIX (c) but are negative for HIK1083 (d) and MUC6 (e), helpful in differentiation from gastric type ECA

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8.6.1.3 Adenocarcinoma NOS Type This is, essentially, a poorly differentiated adenocarcinoma lacking overt differentiating features. Block-like p16 staining and/or HPV testing would then qualify this tumor as “HPVA, NOS type.” Microscopically, it usually looks solid, with high-grade, atypical nuclei and a reduced amount of intracytoplasmic mucin. Mitotic figures and apoptotic bodies can be detected. Very little is known regarding the immunohistochemical profile of the NOS subtype other than that the tumor is positive for p16 and HPV testing (Figs. 8.16, 8.17, and 8.18). Fig. 8.11  Intestinal type of mucinous adenocarcinoma. At least 50% of cells show goblet morphology

Fig. 8.12  Signet-ring type of mucinous adenocarcinoma presents round cells with a mucinous vacuole that displaces the nucleus, representing at least 50% of cells with signet-ring morphology

Regarding the immunohistochemical profile of  ISMC, frequent positivity for MUC6 supports glandular differentiation, whereas patchy p40 and p63 in the peripheral palisade of the same nests supports some degree of primitive squamous differentiation [29]. Unlike other HPVAs, however, ISMC may show mutation-type p53 staining and, less PAX8 staining (Figs. 8.14 and 8.15) [29].

Diagnostic Highlights

• apical mitoses and apoptotic bodies easily identified at scanning magnification • abundant intracytoplasmic mucin • p16 overexpression • HPV detection

8.6.1.4 Assessment of Stromal Invasion by ECA In HPVA endocervical adenocarcinoma, stromal invasion can have a variety of histologic patterns. Some of them overlap with in situ adenocarcinoma morphology. The usual criteria to assess invasion include the presence of single or incomplete malignant glands with irregular and angulated contour into the stroma, paradoxical maturation of the cytoplasm, similar to that observed in invasive squamous carcinoma and the presence of stromal desmoplasia. Lymphovascular invasion seen in the absence of stromal invasion should prompt examination of  deeper sections to recognize the invasive component. In difficult cases, one can also rely on the loss of the normally undulating contour of the endocervical mucosal compartment and expansion of neoplastic glands into stroma in a fashion that is incompatible with normal endocervical architecture, as described below. In routine practice, however, one can encounter the following circumstances in which the distinction between in situ and invasive adenocarcinoma is challenging: • Extensive in situ adenocarcinoma with lobular configuration • Presence of distorting elements that can obscure the presence of invasion (such as ulceration of the mucosa, biopsy site changes, massive inflammation, or edema) • Complex exophytic appearance with papillary/villoglandular growth It is worth mentioning that a clear distinction between in situ and invasive glandular malignant lesions is not possible in up to 20% of cases [32]. Many of these cases are currently reported as invasive adenocarcinomas with  pattern A invasion, as discussed below, but the benefits and drawbacks of this practice are uncertain. Staging and management of invasive adenocarcinomas is based on the FIGO/AJCC staging system, taking into account tumor size and depth of invasion (DOI). Reporting DOI has implications especially in early-stage endocervical adenocarcinoma in which a DOI of more than 3 mm indicates a different stage and a more extensive surgical treatment. However, DOI is difficult to assess in endocervical adenocar-

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Fig. 8.13  Invasive stratified mucinous carcinoma (ISMC): Pure invasive nests of stratified cells with variable amounts of intracytoplasmic mucin and peripheral palisading (a); mixed ISMC with usual type ECA

in association with an in situ component (high-grade squamous intraepithelial lesion and in situ adenocarcinoma) (b); ISMC  can present with various amounts of signet-ring cells (c)

cinoma. Ideally, DOI should be measured from the base of the epithelium from which the tumor arose to the point of maximum invasion of the tumor, similar to squamous cervical carcinoma (see also Chap. 7, section 7.6.3). This can be difficult with glandular tumors since the endocervical epithelium naturally undulates, in contrast to squamous epithelium, which is usually displayed horizontally across the slide with a regular epithelial-stromal junction (see also Chap. 1). Some lesions may show glandular or papillary complexity, superficial papillary architecture, extensive in situ adenocarcinoma, superficial invasion, superficial ulceration, presence of normal mucosa overlying the main invasive component, or a polypoid configuration of the tumor. In these cases, the pathologist can have problems identifying the site of origin from which to measure DOI. An estimate of tumor thickness rather than DOI can be reported when these features are present. The exception to this rule is exophytic tumors: one can measure the thickness of exophytic tumors  but this

should not be reported as the depth of invasion. Rather, estimate and report  the thickness of only  the stromal-invasive component as the DOI with a comment detailing how the various measurement were derived. No instructions regarding measurement of DOI are provided by international guidelines for glandular cervical tumors. Pathologists, led by the Silva group, became concerned about overtreating patients whose tumors lacked aggressive features. This resulted in the Silva system for evaluation of patterns of stromal invasion [33]. Patients whose tumors lacked destructive patterns of stromal invasion had excellent clinical outcomes, independent of FIGO substage, as described below. The Silva system identifies three groups of tumors with distinct patterns of invasion and different clinical behavior: Silva A, Silva B, and Silva C (Table 8.1) [33]. In the Silva A pattern, there is preserved lobular architecture, with a pushing pattern of invasion. In most cases, well-­ demarcated glands are present, while neither destructive

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Fig. 8.14  Invasive stratified mucinous carcinoma (ISMC) (a), positive for p16 (b)

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Fig. 8.15  Invasive stratified mucinous carcinoma (ISMC) (a), positive for HPV (b). p63 (c) and p40 (d) are positive as a rim at the periphery of the tumor cell nests

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Fig. 8.16  Adenocarcinoma NOS type, HPVA, shows proliferation of small glands and solid areas (a) in association with inflammatory infiltrate (b). HPV testing is positive in this case

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Fig. 8.17  Adenocarcinoma NOS type, HPVA, in a 54-year-old patient. Microscopically, the lesion usually looks solid, with high-grade nuclear atypia and a reduced amount of intracytoplasmic mucin (a), but p16 is positive (b)

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Fig. 8.18  Adenocarcinoma NOS type, HPVA, in a 34-year-old patient. Solid sheets of tumor cells with abundant eosinophilic cytoplasm and pleomorphic nuclei, associated with massive inflammatory infiltrate

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(a), have been mistakenly diagnosed as glassy cell carcinoma. No areas of squamous differentiation were found in the tumor; p16 was positive (not shown) (b)

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Table 8.1  The Silva System Tumor group Silva pattern A

Silva pattern B

Silva pattern C

Pattern and behavior Usually preserved lobular architecture; pushing pattern of invasion; well-demarcated glands with rounded contour; no destructive stromal invasion; no single cells or cell detachment; irrelevant relationship with large cervical vessels or depth of tumor, no LVI present Similar architecture to pattern A at low magnification; early (limited) destructive stromal invasion arising from well-demarcated glands (pattern A–like glands); individual tumor cells or small groups of tumor cells separated from the rounded glands and associated with stromal reaction; the tumor cells can present paradoxical cytoplasmic maturation; LVI may be present Extensive and diffuse destructive stromal invasion; angulated glands with canalicular pattern; extensive desmoplastic stromal response; solid, poorly differentiated stromal component; high nuclear grade; LVI may be present

LVI—lymphovascular invasion

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stromal invasion, nor LVI is detected (Fig. 8.19). Silva B pattern has similar architecture but displays limited destructive stromal invasion in the form of single cells or groups of cells with paradoxical maturation of the cytoplasm and associated with stromal desmoplasia arising from well-demarcated glands; LVI may be present (Fig. 8.20). In the Silva C pattern, there is extensive and diffuse destructive invasion by angulated glands with confluent or solid growth; the tumor cells may have a high nuclear grade, and LVI is present more often than in pattern B (Fig. 8.21). Silva A is almost always stage FIGO I and is generally not associated with lymph node metastases, recurrence, or death from disease (Fig. 8.22). In Silva B, most lesions are stage FIGO I, while lymph node metastasis is very rare (4%), as are vaginal recurrences (1%); death from disease has not been  ­encountered. Silva C may be associated with lymph node metastasis in up to 25% of cases, can recur in up to 22% of cases, and death may occur in up to 10% of cases [33].

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Fig. 8.19  Silva A pattern: Preserved lobular architecture (a) with well-demarcated glands but no destructive stromal invasion and no lymphovascular invasion (LVI) (b); a high-power view shows mitotic figures (c)

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Fig. 8.20  Silva B pattern: Similar architecture but with limited destructive stromal invasion (a) as single cells or groups of cells with paradoxical maturation of the cytoplasm and associated with stromal desmoplasia, arising from well-demarcated glands (b)

Fig. 8.21  Silva C pattern: Extensive and diffuse destructive invasion by angulated glands with a canalicular pattern associated with stromal desmoplasia

Recently, it has been demonstrated that genomic abnormalities correlate with the pattern of invasion. There is significantly higher prevalence of certain mutations  (such as KRAS and PIK3CA) in the Silva B and C patterns, suggesting that Silva A non-destructive ECAs are biologically different from destructive B and C ECAs. This finding not only gives molecular support to the Silva system, but also suggests that these findings can be used  for risk stratification [34]. The Silva system should be incorporated into future staging systems and treatment algorithms, as pattern A can be treated conservatively and patterns B and C more radically, including regional lymphadenectomy (for Silva C tumors) or sentinel lymph node biopsy (for Silva B tumors with LVI). Silva B tumors with LVI. The Silva system can only be applied for HPVAs, as nearly all HPVIs are Silva pattern C [30].

Fig. 8.22  Proliferation of well-differentiated glands with pushing margins suggests Silva A pattern, but the architecture is too complex and the lesion is clinically visible (2 cm in size); exophytic tumors with this pattern are currently being studied to determine whether this pattern should be designated Silva A or C

The Silva system can be applied with good interobserver reproducibility on cone  biopsies and loop electrosurgical excision procedure (LEEP) with negative margins, and hysterectomy specimens, as it requires the examination of the entire tumor. On biopsy material, the Silva system has limitations, as only the surface of the tumor can be examined, and the tumor can be significantly upgraded in  excisional material [35].

8.6.1.5 Cases 1. A 45-year-old patient presents to her gynecologist for a routine screening. Pap smear shows atypical glandular cells in a dirty and very bloody background (Fig. 8.1).

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2. A 50-year-old female presents to the Gynecology Department for vaginal bleeding. At clinical examination an exophytic and ulcerated mass was found in the cervix and she underwent a biopsy (Fig. 8.3). 3. A 38-year-old patient with an exophytic and clinically visible cervical mass of 1.5  cm diameter underwent a cone biopsy (Fig. 8.7). 4. A 47-year-old patient underwent a cervical biopsy for an exophytic tumor (Fig. 8.10) 5. A 34-year-old patient presented to Gynecology Department for vaginal bleeding and biopsy of a cervical mass was performed (Fig. 8.18).

8.6.2 HPV-Independent Endocervical Adenocarcinomas (HPVI) This category includes gastric type  adenocarcinoma, clear cell adenocarcinoma, mesonephric adenocarcinoma, endometrioid adenocarcinoma, and HPVI adenocarcinoma not otherwise specified (NOS) type. None of these types is related to HPV infection. Their pathogenesis is being investigated. Currently it is postulated that gastric type  cervical adenocarcinoma develops from a related spectrum of rare benign and premalignant lesions exhibiting gastric pyloric differentiation. The benign lesions are represented by simple and complex gastric (pyloric) metaplasia, type A tunnel clusters, and lobular endocervical glandular hyperplasia (LEGH). The premalignant lesions are represented by atypical LEGH and gastric type in situ adenocarcinoma [36–39]. The precursor lesions of the other HPV-independent cervical adenocarcinomas are not well defined. Mesonephric adenocarcinoma is thought to arise from normal or hyperplastic mesonephric remnants, but the premalignant morphological features are not defined. Similarly, the precursor lesion of cervical clear cell adenocarcinoma is unclear, and primary cervical endometrioid adenocarcinomas are thought to arise from endometriosis, but again, the premalignant lesion is not defined.

8.6.2.1 Gastric type, Including Minimal Deviation Adenocarcinoma Gastric type ECA is the second most frequent invasive adenocarcinoma of the cervix; Kojima et al. described a variable geographical distribution, accounting for 7.2% of all cervical adenocarcinomas in China to 20% in Japan [7, 40, 41]. Gastric type adenocarcinoma is defined by IECC as a tumor with cells displaying gastric pyloric  differentiation, with abundant clear or pale eosinophilic cytoplasm; distinct cyto-

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plasmic borders; generally low nuclear-cytoplasmic ratio; and irregular, basally located nuclei; with no or limited HPVA-like features. Mitotic figures and apoptosis are present but are rare and are not easily detected on scanning magnification [42].  Tumor cells also often have a foamy cytoplasmic quality. In contrast to usual HPVA adenocarcinoma that typically  presents with elongated and stratified hyperchromatic nuclei, gastric type ECA is characterized by rounded nuclei located basally in a single row when well differentiated. The nuclei have clear or delicate, diffuse chromatin with a distinct nucleolus and appear pale, in comparison with hyperchromatic nuclei of usual ECAs, which typically show coarse or granular chromatin. Atypia ranges from nonexistent (characteristic of minimal deviation adenocarcinoma) to marked atypia with pleomorphic nuclei, loss of nuclear basal alignment, and the presence of macronucleoli in poorly differentiated tumors. Architecturally, the tumor cells form glands or solid areas, but trabeculae or single cells can be encountered. The glands vary in size and shape, from small glands to cystically dilated ones; some have intraluminal papillary infoldings. Minimal-deviation adenocarcinoma of the mucinous type (also referred to as adenoma malignum) represents the highly differentiated, but paradoxically aggressive, variant of gastric type ECA (Figs. 8.23, 8.24, and 8.25). Intestinal differentiation in the form of goblet cells and neuroendocrine-like eosinophilic granular cytoplasm can be encountered in both gastric type and minimal deviation adenocarcinoma. Gastric type ECAs produce gastric (pyloric) neutral mucin (magenta on Alcian blue/PAS staining), as opposed to endocervical glands lacking gastric pyloric mucin; in both morphology and immunohistochemical profile, they more closely resemble pancreaticobiliary tract adenocarcinoma (pancreatic ductal adenocarcinoma or cholangiocarcinoma). Recent papers have described the morphology of gastric type ECA as a spectrum from very well differentiated, minimal deviation  adenocarcinoma to poorly differentiated tumors. Gastric type ECA can present (at least focally) with a number of histologic appearances [43]: • Foamy or densely eosinophilic cytoplasm • Goblet cells mimicking HPVA of intestinal type • Glands with elongated, stratified nuclei • Glands with small cuboidal cells resembling mesonephric adenocarcinoma • Glands with flattened cells • Pools of mucin extravasated in the cervical wall

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Fig. 8.23  Gastric type adenocarcinoma with minimal deviation morphology in a 66-year-old patient. Well-differentiated glands of various size and shape infiltrate the cervical stroma (a); most of the glands are

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lined by tumor cells with abundant eosinophilic cytoplasm and rounded and basally located, bland, uniform nuclei, but more atypical nuclei can be appreciated, as well as pools of mucin and desmoplastic stroma (b)

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Fig. 8.24  Gastric type adenocarcinoma in a 60-year-old patient. The tumor is superficially infiltrating the cervical wall (a). Most glands have clear cytoplasm and uniform, basally located nuclei and no mitotic fig-

ures (b), but some other glands harbor cells with foamy cytoplasm and more pleomorphic nuclei (c) or eosinophilic cytoplasm (d), while the stroma is desmoplastic (e)

• Papillary growth mimicking serous carcinoma metastasizing to the cervix or clear cell cervical adenocarcinoma • Single-cell infiltration with densely eosinophilic cytoplasm, as in endometrioid adenocarcinoma of the uterine corpus

• Infiltration with a microcystic elongated and fragmented pattern similar to endometrioid adenocarcinoma of the corpus (Fig. 8.26) Characteristically, the tumor tends to be widely infiltrative, and the diagnosis of stromal invasion is usually straight-

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Fig. 8.24 (continued)

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Fig. 8.25  Gastric type adenocarcinoma (a). At the periphery of the tumor, one can recognize areas of lobular endocervical glandular hyperplasia (LEGH) without (left side) and with atypia (right side) separated by the curved line (b)

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Fig. 8.26  Gastric type adenocarcinoma can present with a spectrum of recently recognized morphologic features that can mimic other types of cervical adenocarcinoma: glands lined by mucinous columnar cells without mitotic figures at scanning magnification (a) infiltrating the

cervical wall with smaller glands, similar to mesonephric adenocarcinoma (b); papillary areas (c); a micropapillary component mimicking serous carcinoma (d); cytoplasmic clearing (e) 

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forward in excisional specimens. The tumor extends deep within the cervical wall and spreads axially in both directions, to the ectocervix and lower uterine segment. Also, gastric type ECA can directly invade the ectocervix, producing an erosion through the ectocervical squamous mucosa—a pattern not typically seen in usual subtype [43]. Tumor emboli are frequently encountered. Immunohistochemically, gastric type ECA is usually negative (or patchy) for p16 and HPV, but caution must be taken; rare cases are diffusely positive for p16, which can occur in up to 30% of cases, unrelated to HPV [4, 29, 44] or displaying a hybrid morphology with mixed features between usual and gastric types. Immunohistochemically, they show gastric differentiation in most cases [45]. Gastric type ECA shows aberrant expression (overexpressed or null phenotype) for p53 in up to 50% of cases [30]. ER, PR, vimentin, p63, p40, AR, and HER2 are negative in most cases [30]. Interestingly, PAX8 is positive in up to 80% of cases (useful to distinguish from tumors of gastrointestinal or pancreatobiliary origin), whereas SATB2 is always negative [30]. PAX2 is typically negative. Gastric-type mucin markers such as MUC6 and HIK1083 are positive in up to 60–80% of cases [30, 40, 44]. Unfortunately, HIK1083 is not available in most countries. Gastric type ECA is positive for TFF2 (trefoil factor 2), CK7, CEA, and CAIX; CK20 and CDX2 can be positive in up to 50% of cases [30, 44]. Of interest, HNF1beta and napsin A can be positive in up to 90% of cases, similar to clear cell carcinoma (Figs. 8.27, 8.28, and 8.29) [30]. Gastric type has been reported to occur in patients with Peutz-Jeghers syndrome, an autosomal dominant disorder caused by germline mutation of the STK11 gene, and somatic mutations of the STK11 gene have been  identified in over half of sporadic cases [46, 47]. Recent molecular analyses described genetic alterations such as somatic mutations in TP53, CDKN2A, ERBB2/ERBB3, and STK11, and less common mutations in GNAS, SMAD4, and PIK3CA [46–49].

Diagnostic Highlights

• Mitotic figures and apoptotic bodies absent or not easily detected at scanning magnification • Atypical tumor cells with abundant pale eosinophilic to clear or foamy cytoplasm and distinct cell borders • Destructive stromal invasion • Negative or patchy p16 staining • Negative HPV testing

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8.6.2.2 Clear Cell Adenocarcinoma This rare tumor of the cervix represents 4% of all cervical adenocarcinomas. It has a bimodal age distribution, occurring in young women exposed to diethylstilbestrol (DES) in utero (in whom the tumor usually involves the ectocervix or vagina), or without this association in older, postmenopausal women (in whom the tumor predominantly involves the endocervix) [50]. Morphologically, clear cell adenocarcinoma of the cervix, similar to those arising in the uterine corpus or ovary, is characterized by solid, papillary, and/or tubulocystic architecture with polygonal or hobnail cells, large amount of clear cytoplasm and highly atypical but uniform nuclei. Papillae usually have hyalinized fibrovascular cores. Mitotic figures and apoptotic bodies are rare. “Non-clear” cells with a vaguely eosinophilic and granular cytoplasm  (so-called oxyphilic features) can be present (Figs. 8.30 and 8.31). Clear cell adenocarcinoma is negative for HPV testing, but p16 can be positive  (block-like) in one-third of cases [29]. CK7 and PAX8 are positive in most cases, and CDX2, ER, PR, vimentin, TFF2, TTF1, MUC6, HIK1083, CAIX, p63, p40, HER2, and AR are negative. P53 can be aberrant in up to 15% of cases [30]. HNF1beta and napsin A are positive in at least 40% of cases (Fig. 8.32) [30].

Diagnostic Highlights

• Mitotic figures and apoptotic bodies absent or not easily detected at scanning magnification • Various architectural patterns with a mixture of tubulocystic, papillary and/or solid architecture • Clear/eosinophilic/hobnail tumor cells with prominent, but usually uniform atypia • Negative or patchy p16 staining • Negative HPV testing

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Fig. 8.27  Gastric type adenocarcinoma. In a 42-year-old patient, biopsy revealed glands lined by mucinous cells without mitotic figures (a); HIK1083 was positive (b). Another case, in a 49-year-old woman showed similar morphology (c), and similarly HIK1083 was positive (d)

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Fig. 8.28  Gastric type adenocarcinoma in a 58-year-old patient, with proliferation of atypical glands in association with areas of LEGH (a) and desmoplastic stroma (b); both atypical glands and LEGH are lined by mucin-producing columnar epithelium (c). The epithelium lining the

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atypical glands has either bland nuclei (d) or rounded pleomorphic nuclei (e), and mitotic figures can be detected at scanning magnification. This case was negative for p16 and HPV while being positive for HIK1083 and MUC6 (not shown)

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Fig. 8.28 (continued)

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Fig. 8.29  Gastric type adenocarcinoma in a 59-year-old patient, with proliferation of glands of various sizes and shapes infiltrating the cervical stroma (a) and lined by a columnar mucin-producing epithelium (b) in which mitotic figures can be detected at scanning magnification (c).

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This case was positive for MUC6 (d) and HIK1083 (e), and was also positive for CAIX (f), HNF1beta (g), and napsin A (not shown), which can complicate the differential diagnosis with other types of ECAs such as clear cell adenocarcinoma

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Fig. 8.29 (continued)

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Fig. 8.30  Clear cell adenocarcinoma of the cervix in a 66-year-old patient, with tubulocystic and papillary proliferation of various glands and papillary structures (a) lined by cells with clear  and eosinophilic  cytoplasm (b). Papillae usually have hyalinized fibrovascular cores (c) surrounding a normal endocervical gland (d). The cells are

polygonal, with large amounts of clear cytoplasm and highly atypical, uniform nuclei. Mitotic figures cannot be detected at scanning magnification (e); some tumor cells have a hobnail appearance (f), but others have non-clear and more eosinophilic cytoplasm (g)

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Fig. 8.30 (continued)

8.6.2.3 Mesonephric Type Adenocarcinoma Mesonephric adenocarcinoma of the cervix is very rare, representing less than 1% of all cervical adenocarcinomas. It is thought to originate from mesonephric remnants of the Wolffian duct system, deep in the lateral cervical wall. Morphologically, these tumors show an admixture of growth patterns such as ductal, tubular, papillary, cord-like, retiform, solid, sex cord-like, or spindle/sarcomatoid, as well as intraluminal eosinophilic colloid-like material resembling mesonephric remnants. The tumor cells usually have scant cytoplasm and the nuclei tend to be small. Many nuclei may be oval, optically clear, grooved and overlapping, similar to papillary thyroid carcinoma. Other nuclei are hyperchromatic. Exceptions occur. Mitotic figures and apoptotic ­bodies are rare and are not easily detected on scanning magnification. P16, HPV, ER, PR, and vimentin are negative in mesonephric adenocarcinoma [29]. However, GATA3 and PAX8 are usually positive, and calretinin, CD10, HNF1beta, and TTF1 are positive in some cases (Figs. 8.33 and 8.34) [51–55].

Recent molecular studies have demonstrated KRAS mutations in most mesonephric adenocarcinomas of the cervix, and a smaller number show activating NRAS mutations. Also, mutations in ARID1A/B genes are common, as well as chromosomal abnormalities with copy number gains in 1q, loss of 1p, and gain of chromosomes 10 and 12 [56, 57].

Diagnostic Highlights

• Mitotic figures and apoptotic bodies absent or not easily detected at scanning magnification • Admixture of growth patterns • Tumor cells with scant cytoplasm and atypical hyperchromatic nuclei or nuclei that resemble those of papillary thyroid carcinoma • Associated with adjacent mesonephric remnants and/or mesonephric hyperplasia • Negative or patchy p16 staining • Negative HPV testing

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Fig. 8.31  Clear cell adenocarcinoma of the cervix in a 60-year-old patient, with tubulocystic proliferation (a) infiltrating the cervical wall with tumor emboli (b). The tubular structures are lined by an epithelium

with more eosinophilic (c) and foamy cytoplasm (d); some areas have prominent hobnail cells (e)

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Fig. 8.32  Clear cell adenocarcinoma of the cervix. Tubular structures and papillae are lined by hobnail cells with eosinophilic cytoplasm, but no mitotic figures are seen at scanning magnification (a). The tumor is positive for HNF1beta (b)

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Fig. 8.33  Mesonephric adenocarcinoma of the cervix. This 35-year-­ old patient had a tumor mass in the cervix (a), represented by a proliferation of atypical glands resembling endometrioid glands lined by a stratified epithelium. Cytologically, the nuclei show mild to moderate atypia; some have prominent nucleoli but there is little or no intracytoplasmic mucin and no mitotic figures (b). Infiltrating the cervical wall, some glands present intraglandular papillae (c). At the periphery of the

tumor, the atypical glands are in continuity with smaller, back-to-back tubules lined by flattened cells and containing eosinophilic material, resembling native mesonephric remnants (d). The tumor was initially misdiagnosed as endometrioid adenocarcinoma, but immunohistochemical stains revealed that it was positive for CD10; there was no endometriosis and no primary tumor in the corpus or lower uterine segment (e)

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Fig. 8.33 (continued)

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Fig. 8.34  Mesonephric adenocarcinoma of the cervix, with solid and tubular proliferation of tumor cells (a, b) focally presenting mitotic figures (c, d). HPV was negative in this case and GATA3 was positive (not

shown). Extensive spindle cell growth (see Fig. 8.34a and d) may raise the differential diagnosis of mesonephric carcinosarcoma, discussed in Chap. 11

8  Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma

8.6.2.4 Endometrioid Type Adenocarcinoma When modern  diagnostic criteria are used, endometrioid adenocarcinomas represents about 1% of cervical malignant tumors [7]. Older literature suggested that this tumor could represent up to 50% of all cervical adenocarcinomas, but recent studies have shown that most of the tumors diagnosed as endometrioid type actually represent mucin-depleted usual ECA (HPVA). According to IECC 2018, endometrioid adenocarcinoma of the cervix should show the following “confirmatory endometrioid features”: at least focal low-­ grade endometrioid morphology with low-grade endometrioid glands lined by columnar, usually eosinophilic cells with pseudostratified, usually bland, nuclei, with or without squamous differentiation. A corpus or lower uterine segment primary tumor must be excluded and HPVA features such as abundant apical/floating mitoses and abundant karyorrhexis/ apoptosis should not be present [7]. There are rare reported cases of endometrioid adenocarcinoma associated with cervical endometriosis, which suggests that endometriosis-­ associated cervical adenocarcinoma is the prototype or, perhaps, the only type of bona fide “endometrioid adenocarcinoma of cervix.” p16 is usually negative, but it can be positive in high-­ grade tumors; HPV is negative [25]. ER, PR, vimentin, and

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CK7 are usually positive, whereas aberrant p53 and MUC6 positivity and SATB2 positivity occur in one third of cases; p63, p40, HER2, AR, GATA3, HIK1083, HNF1beta, napsin A, CK20, and TTF1 are negative [30]. CAIX is positive in 50% of cases and PAX8 in two- thirds [30]. Ten to 20% of endometrioid adenocarcinomas of the lower uterine segment are mismatch repair (MMR) deficient, which can be recognized with DNA MMR immunohistochemical stains. Such abnormalities are thought to be rare in primary cervical adenocarcinoma (Figs. 8.35 and 8.36).

Diagnostic Highlights

• Mitotic figures and apoptotic bodies are not easily detected at scanning magnification • Confirmatory endometrioid morphologic features • Association with cervical endometriosis • Negative or patchy p16 staining • Rigorously exclude HPV+ adenocarcinomas as well as primary corpus and lower uterine segment endometrioid adenocarcinomas

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Fig. 8.35  Endometrioid adenocarcinoma of the cervix in a 50-year-old depleted columnar cells, and mitotic figures are not detected (b). This patient, with proliferation of atypical glands infiltrating the cervical case was HPV-negative (not shown) wall (a). At scanning magnification, the glands are lined by mucin-­

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Fig. 8.36  Endometrioid adenocarcinoma of the cervix, poorly differentiated in a 55-year-old patient. There is mostly solid architecture (a) with focal confirmatory endometrioid features and only rare mitoses (b). Necrosis is also present (c). This case was HPV-negative (not shown)

8.6.2.5 Adenocarcinoma NOS Type, (HPVI) These HPVI tumors cannot be classified by IECC criteria. Morphologically, these are poorly differentiated tumors with predominantly solid architecture, highly atypical nuclei, and a reduced amount of intracytoplasmic mucin. p16 and HPV are negative (Fig. 8.37). 8.6.2.6 Cases 1. A 66-year-old patient with watery vaginal discharge presented to her gynecologist. At clinical examination the cervical wall was indurated. A cervical biopsy was performed (Fig. 8.23). 2. A 60-year-old patient with abnormal Pap smear and vaginal bleeding underwent a cervical biopsy for a cervical mass (Fig. 8.31). 3. A 35-year-old patient was found with abnormal Pap smear. At clinical and radiologic examinations, a tumor mass was detected in the cervix and a biopsy was obtained (Fig. 8.33). 4. A 55-year-old patient presented with a large ulcerated cervical tumor (Fig. 8.36).

8.7

Differential Diagnosis

• HPVA versus HPVI. In general, HPVA tumors can be differentiated from HPVI tumors based on the presence of abundant mitotic figures and apoptotic bodies in the former. Also, p16 and HPV testing could help in difficult cases, with HPVA tumors being positive for p16 and HPV, whereas most HPVIs are negative for HPV and, usually, p16. • Usual type from endometrioid type. The major differential diagnosis for usual type ECA (HPVA) is endometrioid adenocarcinoma (HPVI) of cervix, lower uterine segment, or corpus. Endometrioid adenocarcinoma of the cervix is very rare and is HPV negative. When strict criteria are used, this tumor is not difficult to diagnose. As a rule, mucin-depleted invasive adenocarcinomas of the cervix should not be diagnosed as endometrioid type in the presence of abundant mitotic figures and apoptotic bodies, as these lesions are probably usual type adenocarcinomas lacking intracytoplasmic mucin. As for endometrioid adenocarcinoma of the uterus, this differential

8  Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma

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Fig. 8.37  Adenocarcinoma NOS type, HPVI. This was a poorly differentiated tumor with predominantly solid and trabecular architecture (a) and highly atypical nuclei, with a reduced amount of intracytoplasmic mucin (b); p63 was negative (c) and CEA was focally positive,

suggesting glandular differentiation (d). MUC6, HIK1083, p16, and HPV were negative in this case; caution is needed when interpreting these markers, as high-grade endometrioid adenocarcinoma of the uterus can be negative for ER and PR and can be p16 block-positive

diagnosis is particularly important on a biopsy or curettage, because the management of the two lesions is usually different. ER, PR, and vimentin are typically positive in endometrioid adenocarcinoma of the uterus, whereas  HPV is negative and p16 usually negative. Caution when interpreting these markers is needed, as high-­grade endometrioid adenocarcinoma of the uterus can be negative for ER and PR and can be p16 blockpositive. Also, usual type ECA of adenocarcinoma of the cervix can be positive for ER, PR, and vimentin, and in some cases, these tumors can be p16-negative. Mismatch repair (MMR) proteins (MLH1, PMS2, MSH2, MSH6) may also be of help, as the loss of one or more in tumor cells would most likely indicate an endometrioid adenocarcinoma of the uterus with microsatellite instability. CEA has limited diagnostic usefulness, as focal staining can be observed in both tumors. In difficult cases, mRNA HR-­HPV in situ hybridization together with clinical fea-

tures can be diagnostically helpful. Sometimes, usual type ECA can be associated with bland, metaplasticappearing squamous differentiation covering the surface of the tumor, which should not be confused with either endometrioid adenocarcinoma with squamous differentiation or cervical adenosquamous carcinoma (Fig. 8.38). • Usual type versus serous carcinoma. Usual type ECA also can present a papillary architecture with high-grade nuclear features, mimicking a drop metastasis of a serous carcinoma of tubo-ovarian or endometrial origin. Importantly,  serous adenocarcinoma of the cervix is no longer accepted as a primary tumor type, as some of the previously diagnosed examples of cervical serous carcinoma lacked p53 mutation and were positive for HPV, features indicating HPVA rather than serous carcinoma. Clinical information is very useful to correctly diagnose a drop metastasis to the cervix (Fig. 8.39).

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Fig. 8.38  Usual type adenocarcinoma with mucin-depleted cytoplasm. This lesion can mimic endometrioid adenocarcinoma, and this differential diagnosis is particularly important on a biopsy or curettage because the management of the two lesions is usually different

(a). At scanning magnification, mitotic figures can be detected (b) and p16 is positive in this case as is HPV testing (not shown here) (c). Although PR is negative in most usual type ECAs, it can be focally or diffusely positive (d)

• Usual type versus benign glandular lesions. Another differential diagnosis for usual type ECA, especially in curettage material, involves various benign glandular lesions of the cervix. Among these, microglandular hyperplasia can mimic a well-differentiated usual type of adenocarcinoma, but it lacks mitoses and apoptotic features and presents a rim of basal cells at the periphery of the glands, which are p63 or p40 positive (Fig. 8.40). • Gastric type versus usual type. Gastric type ECA can show glands with elongated and stratified nuclei, which are difficult to differentiate from usual type ECA in occasional cases. Identifying the mitotic figures and apoptotic bodies is very useful, along with HIK1083, p16, HPV testing, and detecting an in situ component. HSIL and in

situ adenocarcinoma will favor a usual type ECA, whereas LEGH or in situ gastric adenocarcinoma will favor an invasive gastric type ECA. • Gastric type versus clear cell type. Gastric type ECA can be  particularly difficult to differentiate from clear cell adenocarcinoma, especially in  biopsy material, as both lesions are HPVIs and can feature cells with clear cytoplasm. HNF1beta and napsin A are not useful in distinguishing between the two entities, as they can be positive in both lesions, but a combination of positive HIK1083 and TFF2 can be useful to diagnose gastric type ECA (Fig. 8.41). Architectural growth patterns also differ.

8  Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma

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Fig. 8.39  Usual type adenocarcinoma can present with papillary architecture (a) with high-grade nuclear features (b), mimicking a drop metastasis or a primary “serous adenocarcinoma” of the cervix. This case was p16-positive (c) and HPV-positive (not shown)

• Gastric type versus benign glandular lesions. When distinguishing between minimal deviation adenocarcinoma (i.e. well-differentiated gastric type ECA/HPVI) and a benign entity such as a deep Nabothian cyst or diffuse laminar glandular hyperplasia, ER/PR immunohistochemistry is useful, as gastric-type ECAs (and minimal deviation adenocarcinoma) are negative. • Gastric type versus precursor lesions. The claw-like shapes and deep placement of glands, along with at least mild nuclear atypia and the presence of at least focal stromal desmoplasia favor adenoma malignum, and these features are very helpful when differentiating adenoma malignum from LEGH in which a preserved lobular architecture with minimal cytological atypia is observed. Immunohistochemical stains can also assist in difficult

cases, as positive smooth muscle actin staining may be seen in cervical stromal cells adjacent to invasive glands of  minimal deviation  adenocarcinoma, and this stain is negative in LEGH [43]. Also, minimal deviation lesions can show aberrant p53 positivity in 50% of cases (LEGH is negative) and are negative for PAX2 (whereas LEGH is positive for this marker) [44, 58]. • Gastric type versus metastases. In rare cases, a metastasis, especially from the pancreas, needs to be ruled out with clinical correlation because the morphology and immunophenotype of gastric type  ECAs and pancreatic ductal adenocarcinomas can be very similar, if not identical. PAX8 positivity favors a primary cervical tumor, but not all gastric type  adenocarcinomas of the cervix are

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Fig. 8.40  Microglandular hyperplasia: this benign lesion can have a cribriform architecture and mimic a well-differentiated usual type adenocarcinoma or clear cell carcinoma (a), but it lacks atypia, mitoses,

and apoptotic features (b) and presents a rim of basal cells at the periphery of the glands (c), which are p63 positive (d)

PAX8 positive, and in difficult cases, correlation with radiological findings is very helpful (Fig. 8.42). • Mesonephric type versus usual type. It is important to differentiate between mesonephric and usual type ECA with limited cytoplasmic mucin. HPV and GATA3 testing can be diagnostically useful in these cases, as mesonephric adenocarcinoma will be negative for HPV and positive for GATA3. In contrast to mesonephric ECAs, endometrioid adenocarcinomas of endometrium are mostly ER/PR positive and show confirmatory endometrioid features. Florid mesonephric hyperplasia can mimic mesonephric ECA, but it usually does not form a mass lesion or have atypical nuclei, mitotic activity, stromal desmoplasia,  LVI, or morphological patterns other than small tubules with or without associated ducts.

8.8

Prognosis

Statistically significant differences in overall survival, disease-­free survival, and progression-free survival have been found between HPVA and HPVI tumors [23, 30]. Patients with HPVA adenocarcinoma treated with surgery and adjuvant treatment have a better prognosis than patients with HPVI tumors receiving the same treatment. HPVA tumors  with LVI have a better prognosis than HPVI tumors  with LVI.  Similarly, HPVA tumors with pelvic recurrences have a better survival than HPVI tumors with pelvic recurrences. Differences in survival have also been found between mucinous HPVA versus usual HPVA, between HPVA tumors with LNM versus HPVI tumors with LNM, and between HPVA tumors with distant metastases and HPVI tumors with distant metastases [30].

8  Epithelial Malignant Tumors of the Cervix: Endocervical Adenocarcinoma

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Fig. 8.41  Gastric type invasive adenocarcinoma (a) is particularly difficult to differentiate from clear cell carcinoma, as both lesions are HPVI. A combination of TFF2 (Trefoil factor 2) (b) and HIK1083 (c) is useful to diagnose gastric type ECA

FIGO stage and Silva pattern of invasion are independent prognostic parameters for HPVA tumors in multivariate analysis, whereas age, FIGO stage, and tumor size are independent prognostic parameters for HPVI tumors [30]. HPV status is nearly significantly associated with overall survival and disease-specific survival [15, 23, 30, 40]. Furthermore, among HPVA tumors, recent studies have revealed that ISMCs  (part of the spectrum of mucinous HPVAs) are more aggressive than other HPVA  ­adenocarcinomas. Clinically, ISMCs  are associated with large tumor size, pelvic lymph node involvement at the time of diagnosis, a potential for early recurrent disease, and a substantial risk of distant metastatic disease, especially to the lungs [23, 31]. Among HPVA tumors, a micropapillary pattern is associated with worse survival regardless of  its extent [27].

Among HPVI tumors and in comparison with the usual type HPVA ECA, gastric type ECA, including minimal deviation adenocarcinoma, has been found to be more biologically aggressive. It is characterized by significantly higher rates of ovarian, pelvic, and abdominal metastases, as well as regional and distal lymph node involvement. Its 5-year disease-­free survival is 30%, and overall survival is 42%, compared with 77% and 91%, respectively, for  usual type tumors [15, 40]. Gastric type ECA appears to be resistant to current adjuvant therapies [21, 30]. Very little is known at this point about the prognosis of clear cell adenocarcinoma, mesonephric adenocarcinoma, or endometrioid adenocarcinoma, as these tumors are very rare. Most patients with cervical clear cell adenocarcinoma are diagnosed at an early stage (FIGO stage I or II) and have an overall good prognosis. Pelvic lymph node involvement is

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Fig. 8.42  Metastatic ampullary carcinoma to cervix. Curettage material from the endocervical canal shows multiple fragments of tumor (a) represented by a proliferation of atypical glands surrounded by a desmoplastic stroma (b). The glands are lined by a mucin-secreting columnar epithelium with round, uniform nuclei, but mitotic figures are

absent at scanning magnification, suggesting gastric type of adenocarcinoma of the cervix (c). However, PAX8 was negative in this case (not shown), and the radiologic findings suggested that the patient had a pancreatic mass. (Courtesy of Dr. Kay Park)

seen in 25% of patients; chemotherapy and radiation have been reported to be useful in advanced-stage tumors or with high-risk factors [50, 59]. The biological behavior of mesonephric adenocarcinoma appears to be more favorable than that of Müllerian cervical adenocarcinomas when adjusted for stage, but recurrences have been reported in early-stage cases and adverse outcome is usually seen in cases with advanced stage [60, 61].

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208 42. Stewart CJ, Frost F, Leake R, Mohan GR, Tan J. Foamy gland changes in gastric-type endocervical neoplasia. Pathology. 2015;47(7):653–8. doi:10.1097/PAT.0000000000000329. 43. Pirog EC, Park KJ, Kiyokawa T, Zhang X, Chen W, Jenkins D, Quint W.  Gastric-type adenocarcinoma of the cervix: tumor with wide range of histologic appearances. Adv Anat Pathol. 2019;26:1– 12. https://doi.org/10.1097/PAP.0000000000000216. 44. Carleton C, Hoang L, Sah S, Kiyokawa T, Karamurzin YS, Talia KL, et  al. A detailed immunohistochemical analysis of a large series of cervical and vaginal gastric type adenocarcinomas. Am J Surg Pathol. 2016;40:636–44. 45. Wada T, Ohishi Y, Kaku T, Aman M, Imamura H, Yasutake N, et al. Endocervical adenocarcinoma with morphologic features of both usual and gastric types: clinicopathologic and immunohistochemical analyses and high-risk HPV detection by in situ hybridization. Am J Surg Pathol. 2017;41:696–705. 46. Nagaria T, Garg S, Stockley T, et al. Molecular landscape of gastric-­ type endocervical adenocarcinomas (GAS)—next generation sequencing of 14 cases (abstract). Mod Pathol. 2018;31(S2):1241. 47. Kuragaki C, Enomoto T, Ueno Y, Sun H, Fujita M, Nakashima R, et al. Mutations in the STK11 gene characterize minimal deviation adenocarcinoma of the uterine cervix. Lab Investig. 2003;83:35–45. 48. Murali R, De Filippo M, Weigelt B, Park KJ. Genomic characterization of gastric type endocervical adenocarcinomas. Mod Pathol. 2016;29(suppl 2):279A. 49. Gilks CB, Young RH, Aguirre P, DeLellis RA, Scully RE. Adenoma malignum (minimal deviation adenocarcinoma) of the uterine cervix. A clinicopathological and immunohistochemical analysis of 26 cases. Am J Surg Pathol. 1989;13:717–29. 50. Hasegawa K, Nagao S, Yasuda M, Millan D, Viswanathan AN, Glasspool RM, et al. Gynecologic cancer InterGroup (GCIG) consensus review for clear cell carcinoma of the uterine corpus and cervix. Int J Gynecol Cancer. 2014;24:S90–5. https://doi.org/10.1097/ IGC.0000000000000297. 51. Goyal A, Yang B.  Differential patterns of PAX8, p16, and ER immunostains in mesonephric lesions and adenocarcinomas of the cervix. Int J Gynecol Pathol. 2014;33:613–9. 52. Howitt BE, Emori MM, Drapkin R, Gaspar C, Barletta JA, Nucci MR, et al. GATA3 is a sensitive and specific marker of benign and

S. Stolnicu malignant mesonephric lesions in the lower female genital tract. Am J Surg Pathol. 2015;39:1411–9. 53. Roma AA, Goyal A, Yang B.  Differential expression patterns of GATA3 in uterine mesonephric and nonmesonephric lesions. Int J Gynecol Pathol. 2015;34:480–6. 54. McCluggage WG, Oliva E, Herrington CS, McBride H, Young RH.  CD10 and calretinin staining of endocervical glandular lesions, endocervical stroma and endometrioid adenocarcinomas of the uterine corpus: CD10 positivity is characteristic of, but not specific for, mesonephric lesions and is not specific for endometrial stroma. Histopathology. 2003;43:144–50. 55. Kenny SL, McBride HA, Jamison J, McCluggage WG. Mesonephric adenocarcinomas of the uterine cervix and corpus: HPV-negative neoplasms that are commonly PAX8, CA125, and HMGA2 positive and that may be immunoreactive with TTF1 and hepatocyte nuclear factor 1-b. Am J Surg Pathol. 2012;36:799–807. 56. Mirkovic J, Sholl LM, Garcia E, Lindeman N, MacConaill L, Hirsch M, et al. Targeted genomic profiling reveals recurrent KRAS mutations and gain of chromosome 1q in mesonephric carcinomas of the female genital tract. Mod Pathol. 2015;28:1504–14. 57. Mirkovic J, Schoolmeester JK, Campbell F, Miron A, Nucci MR, Howitt BE.  Cervical mesonephric hyperplasia lacks KRAS/NRAS mutations. Histopathology. 2017;71:1003–5. 58. Rabban JT, McAlhany S, Lerwill MF, Grenert JP, Zaloudek CJ.  PAX2 distinguishes benign mesonephric and mullerian glandular lesions of the cervix from endocervical adenocarcinoma, including minimal deviation adenocarcinoma. Am J Surg Pathol. 2010;34:137–46. 59. Thomas MB, Wright JD, Leiser AL, Chi DS, Mutch DG, Podratz KC, Dowdy SC.  Clear cell carcinoma of the cervix: a multi-­institutional review in the post-DES era. Gynecol Oncol. 2008;109:335–9. https://doi.org/10.1016/j.ygyno.2008.02.007. 60. Silver SA, Devouassoux-Shisheboran M, Mezzetti TP, Tavassoli FA.  Mesonephric adenocarcinomas of the uterine cervix: a study of 11 cases with immunohistochemical findings. Am J Surg Pathol. 2001;25:379–87. 61. Bagué S, Rodríguez IM, Prat J. Malignant mesonephric tumors of the female genital tract: a clinicopathologic study of 9 cases. Am J Surg Pathol. 2004;28:601–7.

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Epithelial Malignant Tumors of the Cervix: Other Epithelial Tumors (Adenosquamous Carcinoma, Adenoid Basal Carcinoma, Carcinoma with Adenoid Cystic-like Features, Undifferentiated Carcinoma) Anjelica Hodgson

Contents 9.1   Adenosquamous Carcinoma  9.1.1  Definition  9.1.2  Synonyms  9.1.3  Etiology  9.1.4  Macroscopy  9.1.5  Microscopy  9.1.6  Differential Diagnosis  9.1.7  Prognosis  9.1.8  Cases 

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9.2   Adenoid Basal Carcinoma  9.2.1  Definition  9.2.2  Synonyms  9.2.3  Etiology  9.2.4  Macroscopy  9.2.5  Microscopy  9.2.6  Differential Diagnosis  9.2.7  Prognosis  9.2.8  Cases 

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9.3   Carcinoma with Adenoid Cystic-Like Features  9.3.1  Definition  9.3.2  Synonyms  9.3.3  Etiology  9.3.4  Macroscopy  9.3.5  Microscopy  9.3.6  Differential Diagnosis  9.3.7  Prognosis  9.3.8  Cases 

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9.4   Undifferentiated Carcinoma  9.4.1  Definition  9.4.2  Synonyms  9.4.3  Etiology  9.4.4  Macroscopy 

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A. Hodgson (*) Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada e-mail: [email protected] © Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_9

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Microscopy  Differential Diagnosis  Prognosis  Cases 

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References 

9.1

Adenosquamous Carcinoma

9.1.1 Definition According to the 2014 WHO Classification of Tumours of the Female Reproductive Organs, both unequivocal malignant glandular and squamous elements must be present in order to make a diagnosis of cervical adenosquamous carcinoma [1]. These tumors are relatively uncommon neoplasms, and although the diagnostic criteria for this entity are relatively strict, varied application has led to a wide-ranging reported prevalence for this tumor type.

9.1.2 Synonyms Originally called “mixed carcinoma” [2], however this term is no longer applied when dealing with this entity.

9.1.3 Etiology Most but not all cervical adenosquamous carcinomas are associated with high-risk human papillomavirus infection [3–7]. It has been postulated that these neoplasms arise from cervical subcolumnar pluripotential reserve cells, which have the capacity to differentiate into both endocervical and squamous epithelium [8]. Interestingly, it has been shown that both tumor components of adenosquamous carcinoma—that is, both malignant glandular and squamous elements—appear to be monoclonal in origin and show identical patterns of X chromosome inactivation in addition to human papillomavirus type and physical status [9]. A subset of these tumors has been shown to demonstrate loss of ARID1A protein expression, but the significance of this finding and its role in tumor pathogenesis is not well understood in this tumor type [10].

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9.1.4 Macroscopy Adenosquamous carcinoma may present as a nodular enlargement of the cervix or as a frank exophytic mass; ulceration, hemorrhage, and necrosis also may be seen.

9.1.5 Microscopy In order to make the diagnosis of adenosquamous carcinoma, the tumor must display unequivocal and overtly malignant glandular and squamous elements (often intimately admixed). Both elements should be morphologically distinguishable and recognizable, and both low-grade and high-­grade morphology may be seen for both glandular and squamous components. High-grade glandular morphology usually takes the form of solid growth and diffuse high-grade nuclear atypia. High-grade squamous morphology typically exhibits sheetlike growth, high nuclear-to-cytoplasmic ratios, and lack of keratinization. Human papillomavirus infection-related features may be identified in the glandular component (which is most commonly of the “usual” type) while the squamous component may exhibit keratinization. Of note, precursor lesions, including high-grade squamous intraepithelial lesion, adenocarcinoma in situ, and stratified mucin-producing intraepithelial lesion, may be identified in association with the invasive adenosquamous carcinoma component. From an ancillary test point of view, mucin histochemical stains may be used to confirm the presence of a morphologically evident glandular component. Immunohistochemically, block-like nuclear and cytoplasmic expression of p16 and positivity for high-risk human papillomavirus by in situ hybridization is seen in the majority of cases. Immunoexpression of other markers including cytokeratin 7, PAX8, p63, p40, MUC6, carbonic anhydrase IX, and HNF-1β may be variably seen in a subset of cases.

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In cervical cytological preparations, malignant glandular and/or squamous elements are present (with features identical to invasive adenocarcinoma and squamous cell carcinoma, respectively), often in a necrotic and inflammatory background. Practically speaking, a definitive diagnosis of adenosquamous carcinoma is often difficult to make on cytological material alone. Diagnostic Highlights

• Unequivocal malignant glandular and squamous elements should be morphologically identifiable • A range of associated precursor lesions may be seen • These tumors tend to be associated with high-risk human papillomavirus infection and thus frequently demonstrate block-like p16 expression and positivity for human papillomavirus by in situ hybridization • Glassy cell carcinomas and mucoepidermoid carcinomas of the cervix are probably unrelated to true adenosquamous carcinomas of the cervix (See Differential diagnosis)

9.1.6 Differential Diagnosis A number of lesions may be considered in the morphological differential diagnosis of cervical adenosquamous carcinoma (Table 9.1). • Tumors with squamous and glandular differentiation. The presence of mucin in an otherwise typical squamous cell carcinoma does not warrant the designation of adenosquamous carcinoma. Likewise, a typical usual-type endocervical adenocarcinoma with benign squamous metaplasia also should not be classified as an adenosquamous carcinoma. Endometrioid adenocarcinoma of the cervix with squamous metaplasia has historically been considered in the differential diagnosis of adenosquamous carcinoma, but it is now recognized that endometrioid carcinoma of the cervix is exceedingly rare and is not associated with human papillomavirus infection. Although “clear cell adenosquamous carcinoma” was previously described [11], tumors fitting this description often do not meet the stringent criteria for a diagnosis of adenosquamous carcinoma. • Invasive stratified mucin-producing carcinoma. This recently described neoplasm is a human papillomavirus– associated endocervical adenocarcinoma subtype which

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displays a relatively characteristic morphology that includes peripherally palisaded nests composed of stratified tumor cells with variable amounts of cytoplasmic mucin. Interestingly, a retrospective review of a cohort of cases originally classified as adenosquamous carcinoma demonstrated that a number of tumors in fact showed a morphology that was more consistent with the diagnosis of invasive stratified mucin-producing carcinoma. • Mucoepidermoid carcinoma and glassy cell carcinoma. Historically, a number of different cervical tumors have been classified under the cervical adenosquamous umbrella, including glassy cell carcinoma and mucoepidermoid carcinoma. So-called glassy cell carcinomas are described as being characteristically composed of sheets of tumor cells with abundant “ground glass” eosinophilic cytoplasm, distinct cell borders, and enlarged nuclei with prominent nucleoli; necrosis and a prominent eosinophilic and/or neutrophilic infiltrate also are often seen. Given that glassy cell carcinomas do not exhibit definitive morphologic evidence of both squamous and glandular elements, it is thought by some that these tumors should not be classified under the adenosquamous carcinoma umbrella. A recent study evaluating the histological, immunohistochemical, and clinicopathological features of a cohort of adenosquamous carcinomas included two tumors originally classified as glassy cell carcinoma. Both of these tumors were reclassified as poorly ­differentiated adenocarcinomas, given the lack of overt glandular or squamous differentiation and the lack of immunohistochemical expression of p63 and p40. Overall, the diagnosis of glassy cell carcinoma should be used very sparingly, if at all. Cervical mucoepidermoid carcinomas are described as being morphologically identical to those arising in salivary gland–type tissue; that is, they are classically composed of three cell types—squamoid cells, intermediate cells, and mucous cells—that do not exhibit overt glandular formation. Architecturally, they may be solid or cystic. Importantly (and in contrast to true adenosquamous carcinomas of the cervix), these tumors have not been shown to be associated with human papillomavirus infection, and they commonly harbor genetic alterations in the genes (CRTC1, MAML2) that are characteristically altered in mucoepidermoid carcinomas at other sites [12]. Thus it is thought that these tumors may in fact be a distinct entity, separate from true adenosquamous carcinomas.

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Table 9.1  Differential Diagnosis of Cervical Adenosquamous Carcinoma

Morphology

Adenosquamous carcinoma Unequivocal malignant glandular and squamous components

Association with HPV Most Immunohistochemistry Variable immunoexpression of cytokeratin 7, PAX8, p63, p40, MUC6, carbonic anhydrase IX, and HNF-1β; diffuse and block-like p16 expression and positive HPV in situ hybridization in the majority of cases

Invasive stratified mucin-producing carcinoma Stratified and palisaded nests of tumor cells which display HPV-­ associated features and have variable intracytoplasmic mucin Yes Cytokeratin 7 in all cases; p63/p40 expression in peripherally palisaded cells; PAX8 and abnormal p53 expression in a subset of cases

Squamous cell carcinoma with mucin production Typical squamous cell carcinoma with intracytoplasmic mucin (usually focal); no evident glandular formation Yes Yes Variable immunoexpression of Positivity for high-­ cytokeratin 7, PAX8, HNF-1β molecular-­weight and napsin-A, rare estrogen and keratin, cytokeratin 5/6, p63/p40, p16 (diffuse, progesterone receptor block-like), and HPV in expression. Areas with situ hybridization squamous differentiation frequently show p63/p40 expression

HPV-associated adenocarcinoma with benign squamous metaplasia Malignant glands with HPV-associated features and (often abrupt) benign-appearing squamous differentiation

HPV—human papillomavirus

9.1.7 Prognosis Some studies have suggested that cervical adenosquamous carcinomas may behave more aggressively than pure cervical glandular or squamous malignancies [13], but others have refuted this idea [14]. In a recent study that compared adenosquamous carcinomas to some of its invasive glandular mimics in the cervix, there was no significant difference between these groups [3].

9.1.8 Cases 1. A 59-year-old woman undergoes a hysterectomy after a cervical biopsy demonstrates the presence of a malignant tumor with both glandular and squamous differentiation (Fig. 9.1)

2. A 56-year-old woman undergoes a biopsy of a large cervical tumor (Fig. 9.2) 3. A 71-year-old woman undergoes a hysterectomy after initially presenting with vaginal bleeding; a large cervical mass was detected and a cervical biopsy showed a poorly differentiated neoplasm with a prominent inflammatory infiltrate (Fig. 9.3) 4. A small cervical mass was identified in a 49-year-old woman who presented with post-coital bleeding; hysterectomy was performed after a biopsy demonstrated a neoplasm with distinctive morphological variability including areas of both squamous and mucinous differentiation (Fig. 9.4)

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Fig. 9.1 Adenosquamous carcinoma. (a) Low-power examination shows the glandular component of the tumor on the left, adjacent to the squamous component on the right. (b) The glandular and squamous elements are mostly separate but show some intermixing towards the bottom right of the image. (c) Both components infiltrate into the cervi-

cal stroma. (d) Malignant glands and squamous elements. Note the comedo-necrosis in the center of the large squamous nest at the top right of the image. (e) High-power morphological comparison between the glandular component on the left and the squamous component on the right (Courtesy of Dr. Simona Stolnicu)

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Fig. 9.2  Adenosquamous carcinoma associated with high-risk human papillomavirus infection. (a) Malignant glandular elements are seen in close proximity to malignant squamous elements. (b) Squamous and glandular components are intimately admixed; note the human papillomavirus infection-related features (luminal mitoses and apoptosis)  seen in the glandular component. (c) Diffuse and block-like

expression of p16. (d) Positivity for human papillomavirus by in situ hybridization for high-risk virus types. Final remarks: Although morphological malignant squamous and glandular elements should be present in order to make the diagnosis of adenosquamous carcinoma, different components may be difficult to distinguish when the tumor is poorly differentiated

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Fig. 9.3  So-called glassy cell carcinoma. (a) Large, irregular nests of tumor cells are surrounded and infiltrated by an inflammatory infiltrate rich in plasma cells and eosinophils. (b) The tumor cells have abundant “ground glass” eosinophilic cytoplasm and irregular nuclei with promi-

nent single nucleoli. (c) Nuclear irregularity is evident at high power; note the inflammatory infiltrate surrounding and within the tumor. Final remarks: The diagnosis of glassy cell carcinoma of the cervix should be used very sparingly, if at all

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Fig. 9.4  Mucoepidermoid carcinoma of the cervix. (a) Low-grade tumors typically have abundant cystic spaces. (b) Closer examination may be necessary in order to appreciate the triphasic nature of the tumor. (c) Squamoid and intermediate cells may predominate. (d) Mucous cells may be sparse or difficult to appreciate. In this case, they were numerous and easily identified; note the abundant foamy

cytoplasm in the cells towards the top of the image. Final remarks: True mucoepidermoid carcinoma of the cervix is exceedingly rare and appears to be a distinct entity from cervical adenosquamous carcinoma. Molecular testing to identify rearrangements involving the characteristic genes (MAML2, CRTC1) can be used to confirm the diagnosis

9.2

9.2.2 Synonyms

Adenoid Basal Carcinoma

9.2.1 Definition Adenoid basal carcinoma is a rare low-grade carcinoma most commonly occurring in women older than 50  years of age [15], but these tumors have been reported in women as young as 20 years of age [16]. These tumors are frequently seen in association with high-grade squamous intraepithelial lesion and may occur in pure form or can be admixed with another carcinoma subtype such as carcinoma with adenoid cystic-­ like differentiation, squamous cell carcinoma, adenocarcinoma, adenosquamous carcinoma, and small cell carcinoma.

“Adenoid basal epithelioma” has been proposed for pure tumors without significant nuclear atypia or a stromal reaction to invasion [15, 17], but this term is not widely accepted.

9.2.3 Etiology It has been postulated that adenoid basal carcinomas arise from pluripotential subcolumnar reserve cells. High-risk human papillomavirus infection is implicated in the pathogenesis of most tumors [18–21]. Some authors have postulated that adenoid basal lesions may be precursors to cervical

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“adenoid cystic carcinoma”, given that these two tumors appear to exist along a morphological continuum and often co-exist [18]. In addition, both tumor types are often identified with other carcinoma subtypes.

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• May be seen in association with a more aggressive neoplasm therefore, sampling is critically important

9.2.4 Macroscopy

9.2.6 Differential Diagnosis

Pure adenoid basal carcinomas are most commonly clinically occult (asymptomatic, no cervical mass) and are identified only at the time of microscopic examination. When admixed with another carcinoma subtype, cervical enlargement or a frank cervical mass may be identified.

Both benign and malignant lesions may enter into the differential diagnosis of adenoid basal carcinoma; care should be taken to distinguish a pure adenoid basal lesion from a more aggressive tumor with an adenoid basal component. • Adenoid basal hyperplasia. Adenoid basal hyperplasia shows morphological features similar to those of adenoid basal carcinoma, but it is differentiated from its invasive counterpart by its small size and superficial location [25]. • “Adenoid cystic carcinoma”. Cervical tumors with adenoid basal and adenoid cystic differentiation share a common putative precursor and are both pathogenetically driven by high risk human papillomavirus infection. Modern studies have shown that pure adenoid cystic carcinomas of the cervix are very rare, and that it is more common for tumors with “adenoid cystic-like differentiation” to occur with other HPV-associated  carcinoma types, including adenoid basal carcinoma (See Adenoid cystic carcinoma below). • Tumors with squamous and/or glandular differentiation. Care should be taken to distinguish an adenoid basal carcinoma with squamous or glandular differentiation from an invasive squamous cell carcinoma or adenosquamous carcinoma. Adenoid basal carcinomas most commonly form rounded tumor nests, exhibit banal nuclear features, and do not elicit a desmoplastic stromal response, whereas squamous cell and adenosquamous carcinomas are expected to more commonly infiltrate a desmoplastic stroma in irregular or jagged nests and demonstrate greater nuclear atypia. As with tumors with adenoid cystic-­like differentiation, adenoid basal carcinoma may co-occur with other invasive carcinoma subtypes. Immunohistochemistry may be of some value in the evaluation of difficult cases, as residual low-molecular-weight keratin–positive basaloid cells will be evident around the periphery of adenoid basal carcinoma tumor nests with abundant squamous differentiation, whereas a true squamous cell carcinoma will lack these. In addition, the basaloid cells of adenoid basal carcinoma are expected to lack cytokeratin 7 expression, whereas the cells of an adenosquamous carcinoma should express cytokeratin 7. • Well-differentiated neuroendocrine tumors. Adenoid basal carcinomas with compact nest-like architecture may also be confused with primary well-differentiated neuro-

9.2.5 Microscopy Adenoid basal carcinomas are typically composed of rounded/ lobulated small or large tumor nests and cords infiltrating into the cervical wall without a desmoplastic stromal reaction. The nests and cords are composed of peripherally palisaded small and uniform basaloid tumor cells with regular oval nuclei, inconspicuous or no nucleoli, and minimal mitotic activity. Glandular and squamous differentiation may be evident and central lumina with cystic dilatation and debris may be seen in some nests. Necrosis, lymphovascular invasion, and perineural invasion should not be seen in pure tumors. These neoplasms are often seen in association with high-grade squamous intraepithelial lesion and other carcinoma subtypes, especially squamous cell carcinoma. Immunohistochemically, the basaloid tumor cells should exhibit positivity for low-molecularweight keratin, p63/p40, and p16 (nuclear and cytoplasmic expression in diffuse block-like pattern). CD117 expression, if present, should be only weak and focal. The Ki-67 proliferation index is variable, depending on the phenotype of tumor cells [22, 23]. The presence of human papillomavirus genetic material may be detected by in situ hybridization or polymerase chain reaction. Adenoid basal carcinomas are not typically identified in cervical cytological preparations, as it usually does not involve the surface, but high-grade squamous intraepithelial lesion can be seen [24].

Diagnostic Highlights

• Low-grade basaloid-appearing carcinoma arranged in solid or cystic nests/cords, invading into the cervical wall without a stromal response to invasion • Frequently associated with high-risk human papillomavirus infection and often seen underlying highgrade squamous intraepithelial lesion involving the cervical surface epithelium

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endocrine tumors (carcinoids) arising in the cervix. Metastatic neuroendocrine tumors also must be excluded. Both primary and metastatic neuroendocrine tumors exhibit immunopositivity for neuroendocrine markers including synaptophysin and chromogranin A; adenoid basal carcinomas do not. • Ectopic prostate tissue. Because it may exhibit squamous differentiation, ectopic prostate tissue may also mimic an adenoid basal carcinoma, but this lesion is usually superficial and does not infiltrate into the cervical stroma. Immunohistochemical stains including NKX3.1, prostate specific antigen and/or prostate specific acid phosphatase can be expressed in both ectopic prostate tissue and adenoid basal carcinoma and, therefore, cannot be used to differentiate between the two lesions.

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sis is extremely favorable [1]. As such, conservative treatment is usually employed. In contrast, when admixed with another carcinoma subtype, tumor aggressiveness is largely determined by the non–adenoid basal carcinoma component.

9.2.8 Cases 1. A 45-year-old woman with history of high-grade squamous intraepithelial lesion (diagnosed by cytological examination of Pap smear material) undergoes a cone biopsy (Fig. 9.5) 2. A 43-year-old woman underwent a hysterectomy for the treatment of abnormal uterine bleeding attributed to multiple uterine fibroids (Fig. 9.6)

9.2.7 Prognosis When completely excised, pure adenoid basal carcinomas behave in an essentially benign fashion, and the overall progno-

a

Fig. 9.5  Adenoid basal carcinoma of the cervix associated with high-­ grade squamous intraepithelial lesion and focal squamous cell carcinoma. (a) At low power, a nested proliferation is seen infiltrating the cervical stroma; note the benign endocervical glands at the top left of the image. (b) Rounded and partially lobulated basaloid tumor nests are seen embedded within in a nonreactive cervical stroma. (c) High-grade squamous intraepithelial lesion is seen overlying basaloid tumor nests. (d) In some foci, banal-appearing basaloid tumor nests (right) were

b

seen adjacent to larger nests composed of cells with abundant eosinophilic cytoplasm, abrupt keratinization, and highly irregular nuclei with evident mitotic activity (left), compatible with squamous cell carcinoma. (e) High-power examination shows rounded tumor nests composed of basaloid cells with regular, oval-shaped nuclei and pinpoint nucleoli; mitotic activity is not appreciated. (f) p16 expression was diffuse and block-like in all tumor cells

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Fig. 9.5 (continued)

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c d

e

Fig. 9.6  Adenoid basal carcinoma with large nests and cystic spaces. (a) Within the cervix, a basaloid-appearing infiltration was seen extending deep into the cervical wall; note the normal endocervical glandular epithelium at the surface and the cystic spaces within some of the tumor nests. (b) Tumor nest size variability was evident. (c) High-power examination shows bland and monotonous basaloid tumor cells surrounding a central cystic space lined by cells with apical snouts; scattered mitotic activity is appreciated. (d) Low-molecular-weight keratin expression is seen in both glandular and basaloid components, although

f

expression is strongest in the cells lining the cystic spaces. (e) p63 was strongly expressed in the basaloid component of the tumor nests; note the distinct lack of expression in the glandular cells lining the cystic spaces within the center of the nests. (f) p16 expression was diffuse and block-like in all tumor cells. Final remarks: Adenoid basal carcinomas of the cervix are often incidentally discovered but are frequently seen in association with epithelial in situ lesions. Diligent care should be taken to ensure that another, more aggressive tumor component is not present

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9.3

 arcinoma with Adenoid Cystic-Like C Features

9.3.1 Definition True adenoid cystic carcinoma of the cervix likely does not exist and is no longer recognized as a distinct entity in the 2020 WHO Classification of Tumors of the Female Genital Tract. Rather, tumors can show adenoid cystic-like features. These are rare tumors and have been reported to most often occur in women older than 40  years of age, with an average age of diagnosis between 60 and 70 years [26]. Adenoid cystic-like morphology may be very rarely pure or, more commonly, be admixed with another carcinoma subtype (“mixed carcinoma with adenoid cystic-like differentiation”) [27].

9.3.2 Synonyms Not applicable.

9.3.3 Etiology Like their adenoid basal carcinoma counterpart, cervical carcinoma with adenoid cystic-like features are thought to arise from cervical pluripotential subcolumnar reserve cells [18]. This putative shared origin explains why cervical tumors with adenoid cystic-like differentiation may co-occur with adenoid basal carcinomas, in addition to other carcinoma subtypes. High-risk human papillomavirus infection is thought to play a pathogenic role in most tumors, particularly those that cooccur in a mixed fashion with other tumor types [28]. “True” adenoid cystic carcinomas  lack this association with human papillomavirus [27] but, have  the characteristic (t6;9)(MYBNFIB) gene fusion seen in adenoid cystic carcinomas of the salivary gland, breast, and even vulva [29]. Interestingly, HPVrelated carcinomas with adenoid cystic-­like features that show a varied morphology and lack the characteristic MYB-NFIB fusion have also been described in the sinonasal tract (“HPVrelated multiphenotypic sinonasal carcinoma”). Although they may be morphologically similar, cervical adenoid cystic-like carcinomas  are, in fact, biologically distinct from their “true” counterparts occurring in other parts of the body.

9.3.4 Macroscopy These tumors have most often been reported to present as a palpable, hard mass. The tumor may be ulcerated or friable.

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9.3.5 Microscopy Tumors with adenoid cystic-like features commonly show the prototypical features associated with adenoid cystic carcinomas occurring outside of the genital tract. These tumors are composed of heterogeneous tubular and cribriform (“punched out” or “sieve-like”) arrangements with eosinophilic hyaline (basement membrane) or basophilic/myxoid-­appearing material. Solid architecture and/or peripheral palisading may be prominent [30]. The tumor cells are basaloid and display hyperchromatic and angulated nuclei without obvious nucleoli. In contrast to their counterpart in the salivary gland, cervical carcinomas with adenoid cystic-like features may lack or show minimal myoepithelial cells. Necrosis, perineural invasion, and lymphovascular invasion may be prominent. Tumors may be seen in association with high-grade squamous intraepithelial lesion and may occur as a component of a mixed carcinoma with adenoid basal carcinoma, squamous cell carcinoma, small cell carcinoma, and others. From an ancillary testing point of view, a Periodic acid-­ Schiff histochemical stain may be used to highlight the basement membrane material. Immunohistochemically, the tumor cells may variably express epithelial membrane antigen, lowmolecular-weight keratin, and S100. CD117 expression has been reported in some tumors, particular those existing as a component of a mixed carcinoma [31]. Collagen IV and laminin immunohistochemistry may be used to highlight the extracellular basement membrane material. MYB immunopositivity has been reported in some mixed carcinomas [32]. Block-like nuclear and cytoplasmic expression of p16 and positivity for human papillomavirus by in situ hybridization will be seen in tumors with adenoid cystic-like differentiation, in contrast to pure adenoid cystic carcinomas [27]. Cytologically, these may be challenging to identify, as they typically do not involve the surface; high-­grade squamous intraepithelial lesions may be seen in addition to three-dimensional cell clusters with acini-like architecture and irregular, angulated nuclei with coarse and granular chromatin [33].

Diagnostic Highlights

• Basaloid tumor cells with cribriform, tubular, or solid architecture and extracellular eosinophilic (basement membrane) and/or basophilic/myxoid-­ appearing material • May occur as a component of a mixed carcinoma; human papillomavirus plays a pathogenetic role in mixed carcinomas which show adenoid cystic-like differentiation

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9.3.6 Differential Diagnosis As previously discussed, carcinoma of the cervix with adenoid cystic-like features may occur in pure form or as a component of a mixed carcinoma (“mixed carcinoma with adenoid cystic-like  features”); adequate sampling and diligent microscopic examination are needed to distinguish these biologically distinct entities. • Basaloid-appearing neoplasms. Given that tumors with adenoid cystic-like differentiation exhibit a predominant basaloid morphology, a number of other basaloid-­ appearing neoplasms should be kept in the differential diagnosis including adenoid basal carcinoma, basaloid squamous cell carcinoma, and high-grade neuroendocrine carcinoma (Table 9.2) [34]. Of course, tumors in the differential diagnosis may all co-occur in the context of adenoid cystic-like differentiation. Immunohistochemical evaluation may be necessary to distinguish a tumor with adenoid cystic-like differentiation with solid architecture from basaloid squamous cell carcinoma or high-grade neuroendocrine carcinoma (both small-cell and large-cell types). Depending on the clinical scenario,

b­ asaloid-­appearing metastases and some exceedingly rare primary tumors (such as extrarenal Wilms tumor) should also be considered [35].

9.3.7 Prognosis These tumors behave aggressively and often display a propensity for local recurrence and distant metastases.

9.3.8 Cases 1. A 71-year-old woman presents with a 2-month history of vaginal bleeding. Bimanual examination revealed an enlarged and firm cervix, and speculum examination showed that the cervix was mostly replaced by an ulcerated mass. The patient was sent for urgent colposcopic examination and biopsy (Fig. 9.7) 2. A 68-year-old woman underwent hysterectomy after a cervical biopsy revealed the presence of an infiltrative basaloid neoplasm (Fig. 9.8)

Table 9.2  Main differential diagnoses for high-grade basaloid carcinoma occurring in the cervix

Basaloid morphology “Punched out” or “sieve-like” architecture Solid architecture Keratinization Extracellular hyaline material Immunohistochemical expression of p63 and p40 Immunohistochemical expression of collagen IV and laminin Immunohistochemical expression of neuroendocrine markers

Carcinoma with adenoid cystic-like features Yes Yes Yes May be present Yes Possible Yes

Basaloid squamous cell carcinoma Yes No Yes May be present No Yes No

High-grade neuroendocrine carcinoma Yes No Yes No No No No

No

No

Yes

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a

b

c

d

e

f

Fig. 9.7  Carcinoma with adenoid cystic-like features, identified at the time of cervical biopsy. (a) Cervical squamous epithelium overlies a proliferation composed of basaloid nests of varying sizes. (b) Variably sized, rounded tumor nests are composed of basaloid tumor cells; note the peripheral palisading and extracellular eosinophilic hyaline material. (c) High-power examination demonstrates nuclear atypia and evi-

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dent cylinders of lightly basophilic material; note the background desmoplastic cervical stroma. (d) p16 expression was diffuse and block-like in all tumor cells. (e) CD117 (c-kit) expression was seen in most tumor cells, but staining intensity was highly variable. (f) Estrogen receptor was not expressed in the tumor cells; note the background stromal cell expression

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a

b

c

d

Fig. 9.8  Carcinoma with adenoid cystic-­like features  with variable architectural patterns. (a) The tumor was architecturally heterogeneous; in this field, small nests and compressed cords are readily apparent. (b) Other areas showed larger nests with “punched out” spaces (left) and foci rich in extracellular hyaline material (right, top and bottom). (c) Note the rigid, cyst-like spaces and basaloid appearance of the tumor cells. (d) Focally, larger solid tumor nests were identified. Final

remarks: “True  Adenoid cystic carcinoma” of the cervix  occurs only very rarely. More commonly, adenoid cystic-like differentiation is associated with one or more carcinoma subtypes. When classic cribriform architecture and basement membrane material is not readily apparent, it may be difficult to distinguish this neoplasm from some of its highgrade basaloid-appearing mimics, including basaloid squamous cell carcinoma and high-grade neuroendocrine carcinoma

9.4

9.4.2 Synonyms

Undifferentiated Carcinoma

9.4.1 Definition Undifferentiated carcinoma of the cervix is a very rare lesion [1], and little has been described in the literature concerning this entity. As its name suggests, this tumor is an undifferentiated epithelial neoplasm that does not show any evidence of glandular, squamous, or neuroendocrine differentiation, either morphologically or by immunohistochemical evaluation. These neoplasms may occur in isolation or can be associated with a more well-differentiated tumor component.

Not applicable.

9.4.3 Etiology Undifferentiated carcinomas of the cervix are of epithelial origin and may represent a “de-differentiated” component of a more well-differentiated carcinoma. Most will be associated with oncogenic human papillomavirus infection [36].

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9.4.4 Macroscopy

9.4.6 Differential Diagnosis

The cervix may be bulky or may be involved by a frank mass; ulceration, hemorrhage, and necrosis may be prominent.

• Various high-grade and/or undifferentiated neoplasms. Given the undifferentiated and high-grade nature of undifferentiated carcinoma of the cervix, a number of malignant neoplasms may enter the differential diagnosis, including primary poorly differentiated carcinomas of squamous, glandular, or neuroendocrine origin; mesenchymal neoplasms; malignant melanoma; and neoplasms of hematolymphoid origin, such as high-grade lymphomas, plasma cell neoplasms, or myeloid neoplasms. Cervical involvement by upper tract drop metastases or direct involvement by undifferentiated endometrial carcinoma should also be considered, in addition to metastases to the cervix arising from non-gynecological organs. As such, the diagnosis of undifferentiated carcinoma of the cervix is essentially a diagnosis of exclusion.

9.4.5 Microscopy Undifferentiated carcinomas are composed of sheets of often discohesive enlarged cells with variable amounts of cytoplasm, highly irregular nuclei, and often prominent nucleoli. True glandular, squamous, and neuroendocrine differentiation should not be morphologically evident. No evident mucin should be identified by routine examination or by evaluation with mucin histochemical stains. These tumors may be seen in isolation, adjacent to or as a component of a more well-differentiated carcinoma, or as a component of a carcinosarcoma. A background inflammatory infiltrate may be prominent [37]. Epithelial origin should be confirmed by epithelial membrane antigen and cytokeratin expression; expression may be focal and/or weak. Block-like nuclear and cytoplasmic expression of p16 and positivity for human papillomavirus DNA or RNA by in situ hybridization may be used to definitively localize the tumor to the cervix. Distinct lack of expression for markers of squamous differentiation (34βE12, cytokeratin 5/6, p63, p40) or neuroendocrine differentiation (synaptophysin, chromogranin A) is typical.

Diagnostic Highlights

• Undifferentiated carcinoma is rare in the cervix and is essentially a diagnosis of exclusion; a primary tumor in the uterine corpus or lower uterine segement should be excluded • May be a component of a “de-differentiated” carcinoma • Expression of epithelial membrane antigen and cytokeratins may be focal and weak • p16/human papillomavirus positivity can be used to localize the tumor to the cervix; otherwise, involvement of the cervix by a tumor centered in the corpus/lower uterine segment or other various high grade and/or undifferentiated neoplasms should be considered (See Differential diagnosis)

9.4.7 Prognosis Undifferentiated carcinomas are expected to behave aggressively.

9.4.8 Cases 1. A 64-year-old woman with no prior history of cervical screening presents with vaginal bleeding; speculum examination shows a large, ulcerated tumor. Staging investigations showed that the tumor was confined to the cervix and that no other lesions were present (Fig. 9.9).

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a

A. Hodgson

b

d c

e

Fig. 9.9  Undifferentiated carcinoma of the cervix. (a) At low power, a diffuse, sheet-like proliferation is seen below an entirely ulcerated surface. (b) The tumor cells exhibit evident discohesion. Note the focus of incipient necrosis seen in the middle of the field. (c) Discohesive tumor cells with a plasmacytoid morphology. Nuclear atypia, nucleoli, and mitotic activity are easily appreciated. (d) Patchy pankeratin expression

was seen throughout the tumor. (e) Epithelial membrane antigen expression was focal and weak. Final remarks: Undifferentiated carcinomas of the cervix should be distinguished from other primary, poorly differentiated epithelial tumors, in addition to non-epithelial malignancies and metastases to the cervix. A more well-differentiated component may be present

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Cherry CP, Glucksmann A.  Incidence, histology, and response to carcinoma of the uterine cervix: comparative morphologic, mucin, radiation of mixed carcinomas (adenoacanthomas) of the uterine and immunohistochemical profile of two rare neoplasms of putative cervix. Cancer. 1956;9:971–9. “reserve cell” origin. Am J Surg Pathol. 1999;23:448–58. 3. Stolnicu S, Hoang L, Hanko-Bauer O, Barsan I, Terinte C, Pesci 19. Senzaki H, Osaki T, Uemura Y, Kiyozuka Y, Ogura E, Okamura A, et al. Cervical adenosquamous carcinoma: detailed analysis of A, et  al. Adenoid basal carcinoma of the uterine cervix: immumorphology, immunohistochemical profile, and clinical outcomes nohistochemical study and literature review. Jpn J Clin Oncol. in 59 cases. Mod Pathol. 2019;32:269–79. 1997;27:437–41. 4. Yoshida T, Sano T, Oyama T, Kanuma T, Fukuda T.  Prevalence, 20. Jones MW, Kounelis S, Papadaki H, Bakker A, Swalsky PA, viral load, and physical status of HPV 16 and 18 in cervical adenoFinkelstein SD. The origin and molecular characterization of adesquamous carcinoma. Virchows Arch. 2009;455:253–9. noid basal carcinoma of the uterine cervix. Int J Gynecol Pathol. 5. Yamakawa Y, Forslund O, Teshima H, Hasumi K, Kitagawa T, 1997;16:301–6. Hansson BG. Human papillomavirus DNA in adenocarcinoma and 21. Parwani AV, Smith Sehdev AE, Kurman RJ, Ronnett BM. Cervical adenosquamous carcinoma of the uterine cervix detected by polyadenoid basal tumors comprised of adenoid basal epithelioma assomerase chain reaction (PCR). Gynecol Oncol. 1994;53:190–5. ciated with various types of invasive carcinoma: clinicopathologic 6. Pirog EC, Kleter B, Olgac S, Bobkiewicz P, Lindeman J, Quint features, human papillomavirus DNA detection, and P16 expresWGV, et  al. Prevalence of human papillomavirus DNA in differsion. Hum Pathol. 2005;36:82–90. ent histological subtypes of cervical adenocarcinoma. Am J Pathol. 22. Cviko A, Briem B, Granter SR, Pinto AP, Wang TY, Yang YC, et al. 2000;157:1055–62. Adenoid basal carcinomas of the cervix: a unique morphological 7. Quddus MR, Manna P, Sung CJ, Kerley S, Steinhoff MM, Lawrence evolution with cell cycle correlates. Hum Pathol. 2000;31:740–4. WD. Prevalence, distribution, and viral burden of all 15 high-risk 23. Liang Y, Lü B, Zhou C.  Cervical adenoid basal carcinoma: human papillomavirus types in adenosquamous carcinoma of the Clinicopathologic features of 9 cases with reference to CK17 and uterine cervix: a multiplex real-time polymerase chain reaction-­ Ki-67 expression. J Low Genit Tract Dis. 2019;23:77–81. based study. Hum Pathol. 2014;45:303–9. 24. Powers CN, Stastny JF, Frable WJ.  Adenoid basal carcinoma of 8. Martens JE, Smedts F, van Muyden RC, Schoots C, Helmerhorst the cervix: a potential pitfall in cervicovaginal cytology. Diagn TJ, Hopman A, et al. Reserve cells in human uterine cervical epiCytopathol. 1996;14:172–7. thelium are derived from Müllerian epithelium at midgestational 25. Kerdraon O, Cornélius A, Farine M-O, Boulanger L, Wacrenier age. Int J Gynecol Pathol. 2007;26:463–8. A.  Adenoid basal hyperplasia of the uterine cervix: a lesion of 9. Ueda Y, Miyatake T, Okazawa M, Kimura T, Miyake T, Fujiwara K, reserve cell type, distinct from adenoid basal carcinoma. Hum et al. Clonality and HPV infection analysis of concurrent glandular Pathol. 2012;43:2255–65. and squamous lesions and adenosquamous carcinomas of the uter 26. Ferry JA, Scully RE. “Adenoid cystic” carcinoma and adenoid ine cervix. Am J Clin Pathol. 2008;130:389–400. basal carcinoma of the uterine cervix. A study of 28 cases. Am J 10. Katagiri A, Nakayama K, Rahman MT, Rahman M, Katagiri H, Surg Pathol. 1988;12:134–44. Ishikawa M, et al. Frequent loss of tumor suppressor ARID1A pro 27. 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Am J Surg Frequent NFIB-associated gene rearrangement in adenoid cystic Pathol. 2009;33:835–43. carcinoma of the vulva. Int J Gynecol Pathol. 2017;36:289–93. 13. Farley JH, Hickey KW, Carlson JW, Rose GS, Kost ER, Harrison 30. Albores-Saavedra J, Manivel C, Mora A, Vuitch F, Milchgrub S, TA. Adenosquamous histology predicts a poor outcome for patients Gould E. The solid variant of adenoid cystic carcinoma of the cerwith advanced-stage, but not early-stage, cervical carcinoma. vix. Int J Gynecol Pathol. 1992;11:2–10. Cancer. 2003;97:2196–202. 31. Chen T-D, Chuang H-C, Lee L.  Adenoid basal carcinoma of the 14. Shingleton HM, Bell MC, Fremgen A, Chmiel JS, Russell AH, Jones uterine cervix: clinicopathologic features of 12 cases with reference WB, et  al. Is there really a difference in survival of women with to CD117 expression. Int J Gynecol Pathol. 2012;31:25–32. squamous cell carcinoma, adenocarcinoma, and adenosquamous 32. Shi X, Wu S, Huo Z, Ling Q, Luo Y, Liang Z. Co-existing of adecell carcinoma of the cervix? Cancer. 1995;76(10 Suppl):1948–55. noid cystic carcinoma and invasive squamous cell carcinoma of 1 5. Russell MJ, Fadare O.  Adenoid basal lesions of the uterine certhe uterine cervix: a report of 3 cases with immunohistochemical vix: evolving terminology and clinicopathological concepts. Diagn study and evaluation of human papillomavirus status. Diagn Pathol. Pathol. 2006;1:18. 2015;10:145.

228 33. Jeong J, Ha SY, Cho HY, Chung DH, An J. Comparison of cytologic characteristics between adenoid cystic carcinoma and adenoid basal carcinoma in the uterine cervix. J Pathol Transl Med. 2015;49:396–402. 34. Grayson W, Cooper K.  A reappraisal of “basaloid carcinoma” of the cervix, and the differential diagnosis of basaloid cervical neoplasms. Adv Anat Pathol. 2002;9:290–300. 35. Muc RS, Grayson W, Grobbelaar JJ. Adult extrarenal Wilms tumor occurring in the uterus. Arch Pathol Lab Med. 2001;125:1081–3.

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Epithelial Malignant Tumors of the Cervix: Neuroendocrine Tumors

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Erna Forgó and Brooke E. Howitt

Contents 10.1 10.1.1 10.1.2 10.1.3 10.1.4 10.1.4.1  10.1.4.2  10.1.5 10.1.6 10.1.7 10.1.8

Low-Grade Neuroendocrine Tumor  Definition  Synonyms  Macroscopy  Microscopy  Grade 1 (Carcinoid)  Grade 2 (Atypical Carcinoid)  Immunohistochemistry  Differential Diagnosis  Prognosis  Case 

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10.2 10.2.1 10.2.2 10.2.3 10.2.4 10.2.4.1  10.2.5 10.2.5.1  10.2.6 10.2.6.1  10.2.7 10.2.8 10.2.9 10.2.10

 igh-Grade Neuroendocrine Carcinoma  H Definition  Synonyms  Macroscopy  SCNEC: Microscopy, Immunohistochemistry, and Other Tests  Case  LCNEC: Microscopy, Immunohistochemistry, and Other Tests  Cases  Microscopy of Mixed Neuroendocrine and Non-neuroendocrine Carcinoma  Cases  Differential Diagnosis of SCNEC  Differential Diagnosis of LCNEC  Prognosis and Treatment of SCNEC and LCNEC  Additional Comments 

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References 

Neuroendocrine tumors of the cervix are epithelial neoplasms with morphologic and immunophenotypic evidence of neuroendocrine differentiation. This group of tumors includes low-grade neuroendocrine tumors (grades 1–2) and high-grade neuroendocrine carcinomas (considered grade 3),

E. Forgó · B. E. Howitt (*) Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA e-mail: [email protected]; [email protected]

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the latter of which may be either small cell or large cell type [1, 2]. Neuroendocrine tumors comprise about 2% of all invasive cervical neoplasms; the vast majority are high-grade neuroendocrine carcinomas. Neuroendocrine tumors also may co-occur with other cervical carcinomas such as adenocarcinoma and squamous cell carcinomas, as well as with their noninvasive precursor lesions. Neuroendocrine carcinomas can have paraneoplastic manifestations including carcinoid syndrome, hypoglycemia, Cushing syndrome, and syndrome of inappropriate antidiuretic hormone (SIADH), as a result of the production

© Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_10

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of serotonin, insulin, adrenocorticotropic hormone, and antidiuretic hormone, respectively [3–7]. In most cases, regardless of grade, high-risk human papillomavirus (HPV), type 16 or 18, is identified as an etiologic factor [8–15].

10.1 Low-Grade Neuroendocrine Tumor 10.1.1 Definition Low-grade cervical neuroendocrine tumors are rare primary cervical neoplasms. The histomorphologic criteria are similar to those used for neuroendocrine tumors in other sites. Low-grade neuroendocrine tumors are by definition grade 1 or grade 2 tumors [16].

10.1.2 Synonyms Carcinoid tumor: low-grade neuroendocrine tumor, grade 1. Atypical carcinoid tumor: low-grade neuroendocrine tumor, grade 2.

10.1.3 Macroscopy Low-grade neuroendocrine tumors usually measure 2 cm or less and are polypoid or indurated.

have abundant, finely granular cytoplasm, conferring a low nuclear-to-cytoplasmic (N:C) ratio. Mitoses should be infrequent. Necrosis should not be present.

10.1.4.2 Grade 2 (Atypical Carcinoid) Architectural growth patterns are similar to those seen in grade 1 tumors. Mild to moderate cytologic atypia, a higher mitotic index (5–10 mitoses/10 HPF), and small foci of necrosis are characteristic of these tumors.

10.1.5 Immunohistochemistry Unlike their gastrointestinal counterparts, there are no specific criteria for the use of the Ki-67 proliferation index for low-grade neuroendocrine tumors of the cervix. Immunoreactivity with chromogranin, synaptophysin, and/ or CD56 support the presence of neuroendocrine differentiation [16, 17].

Diagnostic Highlights: Grade 1 Neuroendocrine Tumor

• Organoid nested, corded, trabecular, insular, and/or spindled growth patterns • Abundant granular cytoplasm conferring low nuclear:cytoplasmic (N:C) ratio • Bland nuclei with fine chromatin and inconspicuous nucleoli • Inconspicuous mitotic activity • Absent necrosis

10.1.4 Microscopy Table 10.1 lists the diagnostic highlights useful to differentiate grade 1 and grade 2 neuroendocrine tumors of the cervix.

10.1.4.1 Grade 1 (Carcinoid) Tumors most commonly show an organoid, nested growth pattern. Inter-anastomosing corded and trabecular, insular, and spindled patterns also may be present. Cytologic features of grade 1 tumors include small, round to oval, monotonous nuclei with “salt and pepper” chromatin, inconspicuous nucleoli, and absent to minimal cytologic atypia. The cells Table 10.1  Diagnostic highlights useful to differentiate grade 1 and grade 2 neuroendocrine tumors of the cervix Diagnostic features Atypia Mitoses Necrosis

Grade 1 Absent to minimal Infrequent Absent

Grade 2 Mild to moderate 5–10 mitoses/10 HPF Small foci

Diagnostic Highlights: Grade 2 Neuroendocrine Tumor

• Organoid nested, corded, trabecular, insular, and/or spindled growth patterns • Mild to moderate nuclear atypia • 5–10 mitoses/10 HPF • Small foci of necrosis

10.1.6 Differential Diagnosis High-grade neuroendocrine carcinoma (large cell type) must be considered in the differential diagnosis of a low-grade neuroendocrine tumor, as these tumors can exhibit an organoid growth pattern and express immunoreactivity for ­neuroendocrine markers. Features helpful in distinguishing high-grade from low-grade neuroendocrine tumors include the presence of large pleomorphic cells, abundant geo-

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graphic/comedo-like necrosis, and an increased mitotic rate (>10 mitoses/10 HPF) in large cell neuroendocrine carcinomas (LCNEC).

10.1.7 Prognosis The prognosis of low-grade neuroendocrine tumors of the cervix is not well-established, given the lack of large series in the literature. Generally, the prognosis is related to the disease stage, which is often FIGO stage I [18]. Although grade 1 neuroendocrine tumors of the cervix (carcinoid tumors) carry the best prognosis of cervical neuroendocrine tumors, they do have metastatic potential. Grade 2 neuroendocrine tumors (atypical carcinoid tumors) have a worse prognosis, with higher risk of metastasis, closer to that of high-grade neuroendocrine carcinoma [19].

Fig. 10.2  Adenocarcinoma in situ, intestinal type, was also identified coexistent with the grade 2 neuroendocrine tumor. No invasive adenocarcinoma component was identified

10.1.8 Case A 51-year-old woman presented with an abnormal Pap smear showing a high-grade squamous intraepithelial lesion (HSIL) and atypical glandular cells. On loop electrosurgical excision procedure (LEEP), a grade 2 neuroendocrine tumor associated with adenocarcinoma in situ (usual and intestinal types) was identified (Figs. 10.1–10.3).

Fig. 10.3  Neuroendocrine tumor (grade 2). A higher-power magnification of the neuroendocrine tumor reveals abundant granular eosinophilic cytoplasm, nuclei with moderate atypia, and occasional mitotic figures, consistent with grade 2

10.2 High-Grade Neuroendocrine Carcinoma 10.2.1 Definition

Fig. 10.1 Neuroendocrine tumor (grade 2). This neuroendocrine tumor was growing as a polypoid mass undermining the endocervical mucosa. In this low-power view, the solid growth pattern and abundant eosinophilic cytoplasm are apparent. Note a lack of necrosis in this case

High-grade neuroendocrine carcinomas are highly aggressive tumors even when low-stage; by definition, they are considered to be grade 3 tumors. There are two histomorphologic subtypes: the small cell type (SCNEC) and the large cell type (LCNEC) [15–17, 19–24]. SCNEC is the most common form of all neuroendocrine tumors of the cervix.

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10.2.2 Synonyms Small cell neuroendocrine carcinoma (SCNEC): small cell carcinoma; neuroendocrine carcinoma, small cell type, grade 3. Large cell neuroendocrine carcinoma (LCNEC): neuroendocrine carcinoma, large cell type, grade 3.

10.2.3 Macroscopy Variable gross features can be seen. Cervical high-grade neuroendocrine carcinomas can present as large, polypoid, barrel-­shaped, and circumferential tumors that can be exophytic, with protrusion through the cervical os. Tumors also may be ulcerated and associated with extensive hemorrhage.

10.2.4 SCNEC: Microscopy, Immunohistochemistry, and Other Tests By definition, SCNEC comprises a densely cellular and monotonous population of round, ovoid, or spindled small cells in diffuse, nested, corded, trabecular, or insular patterns. The cytologic features include hyperchromatic nuclei with characteristic nuclear molding, inconspicuous nucleoli, and scant cytoplasm, which accounts for the high N:C ratio. Single-cell apoptosis and significant necrosis can be striking features. High mitotic activity is present, often at a rate of >10 mitoses/10 HPF. Lymphovascular and perineural invasion are frequently seen. Significant crush artifact may be present and can be a useful clue to the diagnosis. Rendering a diagnosis of SCNEC does not require the expression of neuroendocrine markers in the presence of classic morphologic features, but the markers are helpful when positive. Immunoreactivity with chromogranin, synaptophysin, and CD56 support the diagnosis [15–17]. Of the neuroendocrine markers, synaptophysin and CD56 are the most sensitive, but CD56 is not specific and must be interpreted with caution. Low-molecular-weight (LMW) cytokeratin with a characteristic paranuclear dot-like pattern, EMA, CEA, p16, and p53 immunohistochemical stains can be variably positive [25, 26]. Ki-67 proliferation index is markedly increased (>90%). Thyroid transcription factor-1 (TTF1) positivity is seen in about 40% of cervical SCNEC [26, 27]. Insulinoma-­ associated protein 1 (INSM1) is often positive [28]. There are no immunohistochemical markers that reliably distinguish between SCNEC and LCNEC.

10.2.4.1 Case A 48-year-old woman presented with a polypoid cervical mass and underwent hysterectomy. Figures 10.4, 10.5, 10.6, 10.7, and 10.8 show findings typical of a small cell neuroendocrine carcinoma (SCNEC).

Fig. 10.4  Small cell neuroendocrine carcinoma. An exophytic, polypoid mass is centered in the cervix and composed of diffuse sheets of cells with a high N:C ratio.

Fig. 10.5 Small cell neuroendocrine carcinoma. The discohesive tumor cells have minimal cytoplasm and hyperchromatic nuclei with coarse chromatin. Nuclear molding is evident. Abundant apoptotic figures are present.

Fig. 10.6  Small cell neuroendocrine carcinoma. The tumor is diffusely positive for chromogranin.

10  Epithelial Malignant Tumors of the Cervix: Neuroendocrine Tumors

Fig. 10.7  Small cell neuroendocrine carcinoma. The tumor is diffusely positive for synaptophysin.

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Peripheral palisading can be a striking feature and is a useful clue for distinguishing LCNEC from SCNEC. Admixture of LCNEC with SCNEC can occur. Juxtaposition of invasive adenocarcinoma, squamous cell carcinoma, or  their in situ components can occur and should not invoke a diagnosis of invasive adenocarcinoma or squamous carcinoma with neuroendocrine features (see Sect. 10.2.6 for mixed neuroendocrine and non-neuroendocrine carcinomas). In contrast to SCNEC, rendering a diagnosis of LCNEC requires the expression of neuroendocrine markers. Immunoreactivity with chromogranin, synaptophysin, CD56, INSM1, and Leu-7, which may be variable, is supportive of the diagnosis given the proper morphologic appearance [16, 17]. Of the neuroendocrine markers, synaptophysin, CD56, and, possibly, INSM1 are most sensitive, but CD56 is not specific and must be interpreted with caution. LMW cytokeratin positivity, often with characteristic paranuclear dot-like pattern, EMA, CEA, p16, and p53 immunohistochemical stains are variably positive [25, 26]. Ki-67 proliferation index is markedly increased. TTF1 immunoreactivity has been reported in cervical LCNEC, so it is not a useful marker for distinguishing cervical primary tumors from lung metastasis [26, 29].

10.2.5.1 Cases Figures 10.9 and 10.10 show findings of LCNEC in the case of a 34-year-old pregnant woman who underwent removal of a bleeding 3-cm endocervical polyp. Figure 10.11 demonstrates LCNEC in a 41-year-old woman who was 6 weeks status post cesarean section. She presented for hysterectomy after a cervical biopsy taken during pregnancy (at 16  weeks), which revealed adenocarcinoma. Fig. 10.8  Small cell neuroendocrine carcinoma. The tumor demonstrates a high Ki-67 proliferative index (about 80%)

10.2.5 LCNEC: Microscopy, Immunohistochemistry, and Other Tests LCNEC, similar to SCNEC, can grow in diffuse, nested, corded, trabecular, or insular patterns. Organoid growth comparable to that seen in low-grade neuroendocrine tumors can occur. The distinguishing features of LCNEC are the presence of large pleomorphic and hyperchromatic cells with prominent nucleoli and conspicuous eosinophilic cytoplasm, resulting in a lower N:C ratio. A high mitotic rate (>10 mitoses/10 HPF), abundant geographic/comedo-like necrosis, and the presence of lymphovascular invasion are also frequently present.

Fig. 10.9  Large cell neuroendocrine carcinoma (LCNEC). This tumor is composed of sheets of cells with moderate eosinophilic cytoplasm and nuclei with moderate to severe nuclear atypia.

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10.2.6.1 Cases Figures 10.12 and 10.13 show mixed adenocarcinoma and high-grade neuroendocrine carcinoma in a 61-year-old woman with an endocervical polypoid mass. Figures 10.14 through 10.19 illustrate high-grade neuroendocrine carcinoma with features intermediate between small cell and large cell type in a 41-year-old woman who presented with abnormal vaginal bleeding and had a cervical mass on physical examination. In some cases, a diagnosis of “highgrade neuroendocrine carcinoma” without making a distinction between small cell and large cell types is acceptable.

Fig. 10.10  Large cell neuroendocrine carcinoma. Variably coarse chromatin and prominent nucleoli, along with markedly increased mitotic activity, characterize the large cell variant of neuroendocrine carcinoma

Fig. 10.12  Mixed adenocarcinoma and high-grade neuroendocrine carcinoma. On the right is usual type  endocervical adenocarcinoma (HPV-associated) adjacent to a densely cellular proliferation growing in diffuse sheets, representing the small cell neuroendocrine carcinoma component. Typical “crush” artifact is present in the small cell carcinoma component

Fig. 10.11  Large cell neuroendocrine carcinoma. Overt nuclear atypia with conspicuous nucleoli in cells with visible eosinophilic cytoplasm is consistent with LCNEC. In this case, both synaptophysin and chromogranin were positive

10.2.6 Microscopy of Mixed Neuroendocrine and Non-neuroendocrine Carcinoma Association with a conventional epithelial component can be present, including squamous cell carcinoma, adenocarcinoma in situ, and usual type  endocervical adenocarcinoma with the expected histologic features [23, 24, 30, 31]. Diagnostic caution must be taken, as focal expression of neuroendocrine markers can be present in the non-­neuroendocrine carcinomatous component. Mixed mesonephric adenocarcinoma and high-grade neuroendocrine carcinoma has been reported [32]. Mixed LCNEC and intestinal type mucinous adenocarcinoma of the cervix has been described [33].

Fig. 10.13  Mixed adenocarcinoma and high-grade neuroendocrine carcinoma. The neuroendocrine carcinoma component of this mixed tumor is composed of tumor cells with minimal cytoplasm, producing prominent nuclear molding. Abundant mitotic figures and apoptosis are present. Note the lack of prominent nucleoli, consistent with the small cell type of neuroendocrine carcinoma (SCNEC)

10  Epithelial Malignant Tumors of the Cervix: Neuroendocrine Tumors

235

Fig. 10.14 High-grade neuroendocrine carcinoma. This cervical tumor demonstrates solid and nested architecture at low power, which may be seen in both small cell and large cell neuroendocrine carcinoma

Fig. 10.16  High-grade neuroendocrine carcinoma. Other areas of this tumor have a more cohesive epithelioid appearance with conspicuous eosinophilic cytoplasm and central areas of necrosis within a tumor cell nest (“comedo” pattern of necrosis), suggestive of a large cell neuroendocrine carcinoma

Fig. 10.15  High-grade neuroendocrine carcinoma. Some areas of the tumor show a spindled growth of malignant cells with scant cytoplasm, abundant necrosis, apoptotic debris, and mitoses, suggestive of a small cell neuroendocrine carcinoma

Fig. 10.17  High-grade neuroendocrine carcinoma. The tumor is diffusely positive for synaptophysin. Note that immunohistochemistry does not aid in distinguishing between SCNEC and LCNEC

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Diagnostic Highlights: LCNEC

• Diffuse, nested, organoid,  corded, trabecular, or insular patterns • Large pleomorphic and hyperchromatic cells with prominent nucleoli, often with peripheral palisading of nuclei within nests • Conspicuous eosinophilic granular cytoplasm resulting in a lower N:C ratio • Geographic comedo-type necrosis is common • Mitotic activity high (>10 mitoses/10HPF) • Immunohistochemical positivity for synaptophysin, chromogranin, INSM1, and CD56 • p16 overexpression and HPV positive Fig. 10.18  High-grade neuroendocrine carcinoma. The tumor is diffusely positive for chromogranin. Note that immunohistochemistry does not aid in distinguishing between SCNEC and LCNEC

10.2.7 Differential Diagnosis of SCNEC

Fig. 10.19  High-grade neuroendocrine carcinoma. The tumor demonstrates a high Ki-67 proliferative index (>90%). Note that immunohistochemistry does not aid in distinguishing between SCNEC and LCNEC

Metastatic small cell carcinoma must be considered when entertaining the diagnosis of cervical SCNEC. Prior history of SCNEC of other anatomic sites and additionally involved sites will be helpful clues to the diagnosis. Virtually all cases of cervical SCNEC are associated with HPV, which may serve as a helpful biomarker in determining whether a cervical NEC is primary or metastatic. SCNEC also must be distinguished from poorly differentiated squamous cell carcinoma with basaloid morphology. In this scenario, p63 immunoreactivity and lack of immunoreactivity for neuroendocrine markers would be supportive of squamous cell carcinoma. Lymphoma also is in the differential for SCNEC because of its cytologic features and the possible appearance of extensive crush artifact. However, lymphoma will be negative for keratins and neuroendocrine marker expression, and often a prior history of lymphoma is known.

10.2.8 Differential Diagnosis of LCNEC Diagnostic Highlights: SCNEC

• Round, ovoid, or spindled small cells in diffuse, nested, corded, trabecular or insular patterns • High N:C ratio, nuclear molding, crush artifact • Conspicuous mitotic activity, abundant apoptotic bodies, and necrosis are common • Immunohistochemical positivity for synaptophysin, chromogranin, INSM1, and CD56 • Thyroid transcription factor-1 (TTF1) positivity in about 40% • p16 overexpression and HPV positive

Adenocarcinoma with a solid growth pattern, lymphoepithelial-­ like carcinoma, and lymphoma may be considered in the histomorphologic differential diagnosis of LCNEC.  Single isolated or scattered neuroendocrine cells (well-differentiated) may be found in cervical adenocarcinomas, but these should not be interpreted as a component of NEC [34]. Likewise, lymphoepithelial-like carcinoma lacks expression of neuroendocrine markers, and a significant mature T-cell lymphocytic infiltrate is conspicuous. Misdiagnosis of LCNEC as poorly differentiated squamous cell carcinoma or adenosquamous carcinoma can occur, given the solid patterns of LCNEC with eosinophilic

10  Epithelial Malignant Tumors of the Cervix: Neuroendocrine Tumors

cytoplasm, which can impart a squamoid appearance. The correct diagnostic classification can prove to be more challenging when the tumor is a mixed LCNEC and squamous cell carcinoma, as either the neuroendocrine or the squamous component may be missed entirely. A careful search for keratinization and intercellular bridges and the utilization of immunohistochemistry can help avoid this important diagnostic pitfall. Lymphomas will be negative for keratins and neuroendocrine marker expression; they also are negative for HPV. In the case of lymphoma involving the cervix, often a prior history is apparent. Rare cases of primary or metastatic malignant melanoma of the cervix have been reported [35], and the presence of melanin pigment and the expression of S100, HMB-45, or other melanoma markers in conjunction with the absence of neuroendocrine markers and keratin positivity will aid in their distinction.

10.2.9 Prognosis and Treatment of SCNEC and LCNEC High-grade neuroendocrine carcinomas (SCNEC and LCNEC) have a poor outcome for all stages, with high recurrence rates and a 5-year survival of 15–40% [36–41]. High-­ grade neuroendocrine carcinomas often present with an advanced stage at time of diagnosis. Patients with LCNEC tend to have better outcomes than those with SCNEC. Although some cases are associated with a high initial response to chemoradiation, most patients develop widespread metastases and ultimately succumb to their disease. Treatment for early-stage, high-grade neuroendocrine carcinomas is radical hysterectomy, followed by adjuvant chemotherapy or chemoradiation. If the stage is advanced or surgery is not a viable option, chemoradiation with either neoadjuvant or adjuvant chemotherapy is offered. Palliative chemotherapy also may be given for aggressive metastatic disease [18, 42–46]. Fertility-sparing surgery is generally not considered suitable because of the high-risk nature of these tumors [47].

10.2.10

Additional Comments

The most common molecular alterations identified in high-­ grade neuroendocrine carcinomas include amplification of 3p; mutations in PIK3CA, KRAS, TP53, ATRX, ERBB4, and MAPK; and PI3K/Akt/mTOR and TP53/BRCA pathway aberrancies [48–51]. Recently, loss of mismatch repair (MMR) protein expression was noted in at least two cases of HPV-positive SCNEC, and the same group found programmed death ligand 1 (PD-L1) expression in 70% of cases [44]. The U.S.  Food and Drug Administration’s

237

approval in 2017 of pembrolizumab for the treatment of progressive MMR-deficient solid tumors [52] suggests that some patients with SCNEC may be eligible to receive immune checkpoint therapy as adjunctive therapy or as an alternate treatment for their aggressive, often metastatic disease.

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E. Forgó and B. E. Howitt 35. Clement PB. Miscellaneous primary neoplasms and metastatic neoplasms. In: Clement PB, Young RH, editors. Tumors and tumorlike lesions of the uterine corpus and cervix. New York: Churchill Livingstone; 1993. p. 371–418. 36. Chan JK, Loizzi V, Burger RA, Rutgers J, Monk BJ. Prognostic factors in neuroendocrine small cell cervical carcinoma: a multivariate analysis. Cancer. 2003;97:568–74. 37. Stecklein SR, Jhingran A, Burzawa J, Ramalingam P, Klopp AH, Eifel PJ, Frumovitz M. Patterns of recurrence and survival in neuroendocrine cervical cancer. Gynecol Oncol. 2016;143:552–7. 38. Margolis B, Tergas AI, Chen L, Hou JY, Burke WM, Hu JC, et al. Natural history and outcome of neuroendocrine carcinoma of the cervix. Gynecol Oncol. 2016;141:247–54. 39. Ishikawa M, Kasamatsu T, Tsuda H, Fukunaga M, Sakamoto A, Kaku T, et al. A multi-center retrospective study of neuroendocrine tumors of the uterine cervix: Prognosis according to the new 2018 staging system, comparing outcomes for different chemotherapeutic regimens and histopathological subtypes. Gynecol Oncol. 2019;155:444–51. 40. Ishikawa M, Kasamatsu T, Tsuda H, Fukunaga M, Sakamoto A, Kaku T, et al. Prognostic factors and optimal therapy for stages I-II neuroendocrine carcinomas of the uterine cervix: A multi-center retrospective study. Gynecol Oncol. 2018;148:139–46. 41. Cohen JG, Kapp DS, Shin JY, Urban R, Sherman AE, Chen LM, et al. Small cell carcinoma of the cervix: treatment and survival outcomes of 188 patients. Am J Obstet Gynecol. 2010;203:347.e1–6. 42. Gadducci A, Carinelli S, Aletti G.  Neuroendocrine tumors of the uterine cervix: A therapeutic challenge for gynecologic oncologists. Gynecol Oncol. 2017;144:637–46. 43. Gardner GJ, Reidy-Lagunes D, Gehrig PA. Neuroendocrine tumors of the gynecologic tract: A Society of Gynecologic Oncology (SGO) clinical document. Gynecol Oncol. 2011;122:190–8. 44. Morgan S, Slodkowska E, Parra-Herran C, Mirkovic J. PD-L1, RB1 and mismatch repair protein immunohistochemical expression in neuroendocrine carcinoma, small cell type, of the uterine cervix. Histopathology. 2019;74:997–1004. 45. McCann GA, Boutsicaris CE, Preston MM, Backes FJ, Eisenhauer EL, Fowler JM, et  al. Neuroendocrine carcinoma of the uterine cervix: the role of multimodality therapy in early-stage disease. Gynecol Oncol. 2013;129:135–9. 46. Zivanovic O, Leitao MM Jr, Park KJ, Zhao H, Diaz JP, Konner J, et al. Small cell neuroendocrine carcinoma of the cervix: analysis of outcome, recurrence pattern and the impact of platinum-based combination chemotherapy. Gynecol Oncol. 2009;112:590–3. 47. Viswanathan AN, Deavers MT, Jhingran A, Ramirez PT, Levenback C, Eifel PJ. Small cell neuroendocrine carcinoma of the cervix: outcome and patterns of recurrence. Gynecol Oncol. 2004;93:27–33. 48. Ishida GM, Kato N, Hayasaka T, Saito M, Kobayashi H, Katayama Y, et al. Small cell neuroendocrine carcinomas of the uterine cervix: a histological, immunohistochemical, and molecular genetic study. Int J Gynecol Pathol. 2004;23:366–72. 49. Frumovitz M, Burzawa JK, Byers LA, Lyons YA, Ramalingam P, Coleman RL, Brown J.  Sequencing of mutational hotspots in cancer-related genes in small cell neuroendocrine cervical cancer. Gynecol Oncol. 2016;141:588–91. 50. Cho SY, Choi M, Ban HJ, Lee CH, Park S, Kim H, et al. Cervical small cell neuroendocrine tumor mutation profiles via whole exome sequencing. Oncotarget. 2017;8:8095–104. 51. Xing D, Zheng G, Schoolmeester JK, Li Z, Pallavajjala A, Haley L, et al. Next-generation sequencing reveals recurrent somatic mutations in small cell neuroendocrine carcinoma of the uterine cervix. Am J Surg Pathol. 2018;42:750–60. 52. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: Pembrolizumab for the treatment of microsatellite instability-­high solid tumors. Clin Cancer Res. 2019;25:3753–8.

Mesenchymal and Mixed Epithelial– Stromal Malignant Tumors of the Cervix

11

Robert A. Soslow and Meera Hameed

Contents 11.1 11.1.1 11.1.2 11.1.3 11.1.4 11.1.5 11.1.6 11.1.7 11.1.8 11.1.9

 mbryonal Rhabdomyosarcoma, Botryoid-Type (RMS-B) E Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 242  242  242  242  242  242  242  242  243  243

11.2 11.2.1 11.2.2 11.2.3 11.2.4 11.2.5 11.2.6 11.2.7 11.2.8 11.2.9

Müllerian Adenosarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 245  245  245  245  246  246  246  247  247  247

11.3 11.3.1 11.3.2 11.3.3 11.3.4 11.3.5 11.3.6 11.3.7 11.3.8 11.3.9

Atypical Polypoid Adenomyoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

 250  250  250  250  250  250  250  251  251  251

11.4 11.4.1 11.4.2 11.4.3 11.4.4 11.4.5 11.4.6 11.4.7 11.4.8 11.4.9

Mesonephric Carcinosarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

 252  252  252  252  252  252  252  253  253  253

R. A. Soslow (*) · M. Hameed Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA e-mail: [email protected]; [email protected] © Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_11

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R. A. Soslow and M. Hameed 11.5 11.5.1 11.5.2 11.5.3 11.5.4 11.5.5 11.5.6 11.5.7 11.5.8 11.5.9

Leiomyosarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 254  254  254  254  254  254  254  255  256  256

11.6 11.6.1 11.6.2 11.6.3 11.6.4 11.6.5 11.6.6 11.6.7 11.6.8 11.6.9

 ndometrial/Endometrioid Stromal Sarcoma E Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 257  257  257  257  258  258  258  259  259  259

11.7 11.7.1 11.7.2 11.7.3 11.7.4 11.7.5 11.7.6 11.7.7 11.7.8 11.7.9

Undifferentiated Sarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 261  261  261  261  262  262  262  262  262  262

11.8 11.8.1 11.8.2 11.8.3 11.8.4 11.8.5 11.8.6 11.8.7 11.8.8 11.8.9

Fibroblastic Sarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 263  263  263  263  263  264  264  264  264  265

11.9 11.9.1 11.9.2 11.9.3 11.9.4 11.9.5 11.9.6 11.9.7 11.9.8 11.9.9

Rhabdoid Sarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

 266  266  266  266  266  266  266  266  267  267

11.10 11.10.1 11.10.2 11.10.3 11.10.4 11.10.5 11.10.6 11.10.7 11.10.8

 habdomyosarcoma and Osteosarcoma of Adulthood R Definition Synonyms Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

 267  267  267  267  267  267  267  267  268

11.11 11.11.1

 erivascular Epithelioid Cell Tumor (PEComa) P Definition

 268  268

11  Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix

241

11.11.2 11.11.3 11.11.4 11.11.5 11.11.6 11.11.7 11.11.8 11.11.9

Synonym General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

 268  268  269  269  269  269  270  270

11.12 11.12.1 11.12.2 11.12.3 11.12.4 11.12.5 11.12.6 11.12.7 11.12.8 11.12.9

Inflammatory Myofibroblastic Tumor Definition Synonym General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

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11.13 11.13.1 11.13.2 11.13.3 11.13.4 11.13.5 11.13.6 11.13.7 11.13.8

 lveolar Soft Part Sarcoma A Definition General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

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11.14 11.14.1 11.14.2 11.14.3 11.14.4 11.14.5 11.14.6 11.14.7 11.14.8 11.14.9

 rimitive Neuroectodermal Tumors (Peripheral and Central Types) P Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Cases

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11.15 11.15.1 11.15.2 11.15.3 11.15.4 11.15.5 11.15.6 11.15.7 11.15.8 11.15.9

Angiosarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

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11.16 11.16.1 11.16.2 11.16.3 11.16.4 11.16.5 11.16.6 11.16.7 11.16.8 11.16.9

Liposarcoma Definition Synonyms General Features Etiology Macroscopy Microscopy Differential Diagnosis Prognosis Case

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Suggested Reading

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11.1 Embryonal Rhabdomyosarcoma, Botryoid-Type (RMS-B) 11.1.1  Definition A grape-like, exophytic, polypoid tumor composed of primitive rhabdomyoblasts.

11.1.2  Synonyms

R. A. Soslow and M. Hameed

Diagnostic Highlights

• Grape-like structures lined by native epithelium, usually lacking invaginations into the polyp stroma • Cambium layer containing primitive rhabdomyoblasts • Stroma with variable cellularity; cellular zones contain aggregates of primitive rhabdomyoblasts • Skeletal muscle differentiation can be confirmed with myogenin and/or myoD1 immunohistochemical stains

Botryoid sarcoma; sarcoma botryoides.

11.1.3  General Features This is the most common sarcoma of the cervix. Most arise before or during adolescence, with two thirds occurring between the ages of 1 and 6, and the rest occurring between 15 and 20 years of age or, rarely, in older individuals. Vaginal bleeding with a polypoid tumor is a common clinical presentation.

11.1.4  Etiology DICER1 mutations may be important in the genesis of these tumors. Germline DICER1 mutations are encountered and may signify the presence of DICER1 syndrome.

11.1.5  Macroscopy These are grape-like, polypoid tumors that are sometimes hemorrhagic.

11.1.6  Microscopy Beneath the native epithelium, there is a cambium layer (subepithelial stromal condensation) composed of primitive rhabdomyoblasts with a high mitotic index. The cambium layer usually lacks strap cells, and plump, round rhabdomyoblasts with abundant eosinophilic cytoplasm. The substance of the polyps, deep to the cambium layer, is edematous and contains cellular aggregates of primitive rhabdomyoblasts. Fetal-type cartilage is found in approximately 40% of cases. The rhabdomyoblasts express desmin, and a minority of cells also express myogenin and myoD1, both markers of skeletal muscle differentiation. ER/PR staining is typically negative.

11.1.7  Differential Diagnosis • Adenosarcoma with heterologous differentiation. Adenosarcoma with rhabdomyoblastic differentiation may resemble RMS-B because of polypoid architecture, subepithelial stromal condensation, and the occasional presence of fetal-type cartilage. Tumor architecture is the most important determinant of diagnosis. Adenosarcoma has a “cauliflower-like” architecture, whereas RMS-B usually has a “grape-like” architecture lacking intraglandular stromal papillae and rigid cysts. In adenosarcoma, there are deep and complex invaginations of epithelium, frequently metaplastic, within the tumor itself, but in RMS-B the native epithelium surrounds the edematous substance of the polyps with only rare epithelial entrapment within the polyp. Unlike the stromal cuffs of low-­ grade Müllerian adenosarcoma, the cambium layer in RMS-B is ER- and PR-negative. The clinical management of adenosarcoma (surgical, usually hysterectomy) and RMS-B (chemotherapy +/− radiotherapy +/− limited surgery) differ, so care should be taken to distinguish between these two entities. • Benign polyp. Benign polyps lack a cambium layer, evident mitotic activity, and primitive-appearing stromal cells, although nuclear atypia may be present. Nuclei may be enlarged, hyperchromatic, and multinucleated, but the chromatin is often smudged, akin to the atypical nuclei found in bizarre/symplastic leiomyomas. • Uterine sarcomas with a subepithelial distribution. These entities are discussed in the sections entitled Müllerian Adenosarcoma (Sect. 11.2) and Rhabdoid Sarcoma (Sect. 11.9). • Genital rhabdomyoma. This is included in the differential diagnosis because of the presence of skeletal muscle differentiation, but these rare tumors are found primarily in the vagina and vulva of young or middle-aged patients. The con-

11  Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix

stituent cells are mature and hypoproliferative, in contrast to rhabdomyosarcoma, and no cambium layer is present.

11.1.8  Prognosis It may be important to  differentiate between vaginal and cervical tumors, as vaginal tumors, in general, may have a better prognosis. This difference may be related to the wider age range of patients with tumors arising in the cervix; it is thought that older patients may have poorer prognoses. Risk stratification and therapy are based on pathologic staging (TNM), Intergroup Rhabdomyosarcoma Pretreatment Clinical Staging, the Intergroup Rhabdomyosarcoma Clinical Grouping System, and the Children’s Oncology Group Stratification for Rhabdomyosarcoma. The female genitourinary (GU) tract is considered a favorable location. Without distant metastases, lesions are all considered Stage 1 and either low-risk (if completely or marginally resected, so Group I or II) or

Fig. 11.1 Botryoid embryonal rhabdomyosarcoma demonstrating grape-like growth in a trachelectomy specimen performed for preservation of the uterine corpus (Courtesy of Dr. Amir Momeni-Boroujeni)

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intermediate-risk (if gross residual disease exists either at the primary site or in unresected nodes, so Group III). Optimal treatment using chemotherapy and/or radiation is defined by the International Rhabdomyosarcoma Collaborative Groups. Optimum therapy for “intermediate risk” has not been defined. The presence of distant metastases in the pediatric and adolescent population is extremely rare at the time of initial diagnosis; this seems to be less true for adults. The presence of regional nodal involvement appears to be a risk factor for inferior outcome.

11.1.9  Cases 1. A 7-year-old girl with a polypoid mass extending into the vagina from the cervix (Figs. 11.1, 11.2, 11.3, 11.4, 11.5, 11.6, 11.7, and 11.8). 2. Embryonal rhabdomyosarcoma, botryoid type, in a 10-year-old girl who was treated with chemotherapy (Fig. 11.9).

Fig. 11.2  Embryonal rhabdomyosarcoma, botryoid type. Polypoid mass with cellular aggregates beneath surface epithelium and cuffing entrapped, normal glands

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Fig. 11.3  Embryonal rhabdomyosarcoma, botryoid type. Intermediate-­ power magnification of the same tumor shows aggregates of immature cells beneath native epithelium

Fig. 11.5  Embryonal rhabdomyosarcoma, botryoid type. High-power image demonstrating anaplastic and highly proliferative primitive rhabdomyoblasts

Fig. 11.4  Embryonal rhabdomyosarcoma, botryoid type. Cambium layer and patches of cellularity in myxoid stroma

Fig. 11.6  Embryonal rhabdomyosarcoma, botryoid type. Fetal-type cartilage

11  Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix

Fig. 11.7  Embryonal rhabdomyosarcoma, botryoid type. Differentiated rhabdomyoblasts composed of polygonal cells with abundant eosinophilic cytoplasm. Confirmed cross-striations should be present, or immunohistochemistry (myogenin/myoD1) should provide evidence for skeletal muscle differentiation.

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Fig. 11.9  Mature-appearing rhabdomyoblasts. These may predominate when there is residual disease post-therapy

11.2 Müllerian Adenosarcoma 11.2.1  Definition A malignant stromal neoplasm, usually with a benign epithelial component.

11.2.2  Synonyms Adenosarcoma.

11.2.3  General Features

Fig. 11.8  Embryonal rhabdomyosarcoma, botryoid type. Differentiated rhabdomyoblasts showing a strap-like appearance. Confirmed cross-striations should be present or immunohistochemistry (myogenin/myoD1) should provide evidence for skeletal muscle differentiation

Most patients are perimenopausal or postmenopausal, although younger patients can be affected. Tumors of the uterine corpus are much more common than those arising in the cervix. Vaginal bleeding is the most common clinical presentation.

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11.2.4  Etiology

R. A. Soslow and M. Hameed

and, occasionally, smooth muscle. Mitotic activity is variable, but generally low (less than 10 mitotic figures per 10 The genetic underpinnings of cervical Müllerian adenosar- high power fields) or very low (1 or 2 mitotic figures per 10 coma have not been studied, but they are currently assumed high power fields). Most mitotic activity is present in stromal to be similar to adenosarcomas that arise in the uterine cor- cuffs. Rare adenosarcomas contain sex-cord-like elements, pus. These are mesenchymal neoplasms with a non-­ such as Sertoliform tubules (including cords and trabeculae) neoplastic epithelial component. There are associations with and lipidized cells. breast carcinoma, tamoxifen, radiation therapy to pelvic “High-risk” features: It is estimated that approximately structures, unopposed estrogen, and a history of recurrent 20% of adenosarcomas contain one or more high-risk feaendometrial or endocervical polyps. ture, which are associated with decreased survival: Stromal overgrowth. Stromal overgrowth, defined as a cytologically high-grade sarcomatous component growing 11.2.5  Macroscopy independently of epithelium in more than 25% of the tumor, is a clinically high-risk feature. According to one published series of cervical adenosarcomas, Histologically high-grade sarcoma without stromal overthe tumor size ranged from 1.5 to 4.5 cm; most adenosarcomas growth. This is arbitrarily defined as pleomorphic spindle of the corpus measure more than 3 cm. Adenosarcomas com- cells with increased mitotic activity relative to areas showing monly present as bulbous, polypoid masses containing clefts typical low-grade sarcomatous growth. Even the focal presand cysts. Invasion into underlying stroma may or may not be ence (perhaps more than 1 mm) of pleomorphic sarcoma can present. Hemorrhage and necrosis can be found, particularly be associated with diminished clinical outcomes, so it is reain tumors with high-risk features, described below. sonable to comment upon this in the surgical pathology report. Mutation-type p53 expression in stroma. Increased 11.2.6  Microscopy mitotic activity in atypical nuclei within stromal cuffs (arbitrarily, perhaps more than 10 mitotic figures per 10 high Architectural features: Müllerian adenosarcomas almost power fields) should lead to consideration of high-grade always display characteristic low-power architecture, com- Müllerian adenosarcoma with mutation-type p53 labeling or prising phyllodes-like growth; intraglandular stromal papil- subepithelial rhabdomyoblasts, discussed below. Mutation-­ lae (leaf-like); rigid, round cysts; and subepithelial stromal type p53 expression is established, most commonly, when condensation. The stroma between glands is typically pauci- nearly every neoplastic stromal cell shows intense nuclear cellular and vaguely fibroblastic. The tumor’s architecture is labeling. more important diagnostically than the presence of obvious Heterologous elements. Fetal-type cartilage and scatmitotic activity. The mesenchymal component of low-grade tered rhabdomyoblasts are the most commonly encounMüllerian adenosarcoma usually expresses ER and PR, tered heterologous elements. The presence of strap cells, which is most apparent in the cellular stromal cuffs. High-­ cytoplasmic cross-striations or myogenin/myoD1 staining grade sarcoma (see following) arising from adenosarcoma, confirms the presence of rhabdomyoblasts, which are including tumors with stromal overgrowth, usually lose thought to be particularly associated with disappointing expression of ER and PR. Rarely, endometrioid hyperplasia clinical outcomes. Primitive rhabdomyoblasts (lacking or focal, well-differentiated endometrioid adenocarcinoma appreciable cytoplasm) may show only rare cells with myocan be found within the tumor or adjacent to it. This should genin/myoD1 labeling. not be diagnosed as “carcinosarcoma.” Invasion of cervical/lower uterine segment stroma. This Cytologic features: Most Müllerian adenosarcomas con- usually demonstrates a destructive pattern of invasion, unlike tain a histologically low-grade mesenchymal component in endometrial stromal sarcomas (discussed in 11.6). The depth subepithelial stromal cuffs, composed of ovoid and/or spin- of invasion should be recorded, as it is used to stage disease dle cells, which resembles proliferative endometrial stroma confined to the uterus. (and low-grade endometrial stromal neoplasia), fibroblasts,

11  Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix

Diagnostic Highlights

• Polypoid tumor demonstrating clefts and rigid cysts • Benign and frequently metaplastic epithelial component with sarcomatous components • Phyllodes-like proliferation of stroma that projects into cysts (leaf-like) • Peri-epithelial stromal cuffs containing bland, usually hypoproliferative stromal cells resembling endometrial stromal neoplasia • Botryoid embryonal rhabdomyosarcoma and rhabdoid sarcoma should be excluded in young patients

11.2.7  Differential Diagnosis

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• Uterine sarcomas with adenosarcoma-like architecture. Sarcomas lacking an intrinsic, benign-appearing epithelial component may occasionally colonize the superficial lower uterine segment or cervical stroma, leading to an architectural arrangement that simulates adenosarcoma. Subepithelial stromal condensation, however, is usually absent. Two rare and newly described sarcoma types have been reported to resemble adenosarcoma: uterine rhabdoid sarcoma and fibroblastic sarcoma. Uterine rhabdoid sarcoma is a clinically aggressive neoplasm affecting premenopausal women, composed of monomorphic, undifferentiated tumor cells and/or rhabdoid cells lacking expression of desmin and BRG-1 (SMARCA4); germline SMARCA4 mutations may be present. Certain types of fibroblastic sarcomas also tend to affect premenopausal women. They are typically centered in the cervix and are composed of neoplastic spindle cells lacking desmin expression. A chromosomal rearrangement involving NTRK is diagnostically confirmatory. • Adenofibroma. This is thought to be an extremely rare tumor. Although broad papillary fronds are typical of this entity, the stroma is uniformly paucicellular, without stromal condensation or mitotic activity. This diagnosis should be avoided in biopsies and curettings, because the polyp needs to be comprehensively sampled to exclude the presence of stromal condensation and mitotic activity.

• Benign polyp, including those with atypical features. An endometrial polyp that prolapses through the internal os may have condensed and highly cellular stroma, but polyps typically measure less than 3  cm and lack the characteristic architectural features of Müllerian adenosarcoma. Some polyps may have focal or incomplete features of adenosarcoma. These are referred to as atypical endometrial polyps; in a small series of cases with limited clinical follow-up, they seemed to be benign. • Embryonal rhabdomyosarcoma, botryoid-type. Tumor architecture is the most important determinant of diagnosis, as discussed in Sect. 11.1. The cambium layer is ER/ 11.2.8  Prognosis PR negative, whereas the subepithelial cuffs of adenosarcoma (when homologous) are ER/PR positive. Adenosarcomas lacking the high-risk features described • Adenomyoma. Adenomyoma contains benign-appearing above have a very low frequency of recurrence and morbidglandular and mesenchymal elements, but the architec- ity, no more than 10%. As many as 70% of patients with ture of adenosarcoma is lacking, as is subepithelial stro- high-risk features experience recurrence/metastasis. mal condensation. • Atypical polypoid adenomyoma. This lesion, frequently centered in the lower uterine segment, is biphasic, con- 11.2.9  Cases taining a crowded or hyperplastic endometrioid glandular proliferation within smooth muscle or myofibroblastic 1. A 30-year-old woman with vaginal bleeding and a 4.7-cm stroma. Adenosarcoma architecture is lacking, as is sublobulated cervical mass, filling the endocervical canal and epithelial stromal condensation. prolapsing through the external os (Figs.  11.10, 11.11, • Carcinosarcoma. Primary cervical carcinosarcoma is 11.12, 11.13, and 11.14). extremely rare, with most cases representing extension 2. A 42-year-old woman with a 6-cm hemorrhagic and from a primary tumor in the uterine corpus. By definition, partly necrotic polyp originating either in the lower uterconventional carcinosarcomas contain malignant-­ ine segment or upper endocervix (Fig. 11.15). appearing glandular and stromal elements, almost always 3. A 45-year-old woman with a 5.5-cm lobulated polyp histologically high-grade, unlike adenosarcoma. (Figs. 11.16, 11.17, and 11.18).

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Fig. 11.10  Low-grade Müllerian adenosarcoma with intraglandular stromal papillae and a phyllodes-like appearance. Stromal cuffs around non-neoplastic epithelium are present

Fig. 11.12  Low-grade Müllerian adenosarcoma. High-power image discloses a low-grade mesenchymal component, vaguely resembling endometrial stroma, beneath non-neoplastic epithelium

Fig. 11.11  Low-grade Müllerian adenosarcoma featuring rigid cysts, some of which retain periglandular cuffs

Fig. 11.13  Low-grade Müllerian adenosarcoma. Non-neoplastic epithelial component with tubal metaplasia. Metaplastic epithelium is a common finding

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Fig. 11.14  Low-grade Müllerian adenosarcoma. A mitotic figure in the mesenchymal compartment. Historical criteria mandate at least 2 or 4 mitotic figures per 10 high power fields for an adenosarcoma diagnosis, but now more emphasis is placed on the architecture

Fig. 11.16  Low-grade Müllerian adenosarcoma. The first sections from this tumor displayed the appearance of an adenofibroma. No stromal cuffing or mitotic activity is noted. Additional sections were taken. (See Figs. 11.17 and 11.18).

Fig. 11.15  High-grade Müllerian adenosarcoma with stromal overgrowth. The high-grade sarcomatous component represented more than 50% of this tumor

Fig. 11.17  Low-grade Müllerian adenosarcoma. Further sectioning revealed a rigid cyst with a stromal cuff, characteristic of Müllerian adenosarcoma, illustrating that “adenofibroma” may be a focal finding. Extensive sectioning should be undertaken in this setting. Gland crowding is present. 

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11.3.5  Macroscopy The most common presentation is a polyp, usually attached to endometrium/lower uterine segment/upper endocervix by a wide base. Some polyps are sessile. The average size is 2 cm. The polyps can be bulging, lobulated, or bosselated, with firm/rubbery cut surfaces. When sessile, the polyps appear circumscribed at the interface between the polyp’s base and the myometrium or lower uterine segment stroma. Although some APAs contain microscopic foci of adenocarcinoma, the presence of myometrial invasion is exceptional.

11.3.6  Microscopy Fig. 11.18  Atypical hyperplasia within the adenosarcoma.

11.3 Atypical Polypoid Adenomyoma 11.3.1  Definition A polyp with myoid or myofibromatous stroma containing a proliferation of atypical endometrioid glands, lacking a surrounding rim of endometrial stroma and stromal condensation.

11.3.2  Synonyms

APA resembles endometrioid hyperplasia with variable nuclear atypia, set in a polyp with myoid or myofibromatous stroma. Fragmentation of the polyp leads to an appearance that simulates myometrial-invasive endometrioid carcinoma, hence the term “atypical.” To avoid overcalling myometrial invasion, it is a good practice never to diagnose myometrial invasion in polypectomy, biopsy, or curettage specimens. Familiarity with the entity usually leads to straightforward diagnosis. Some APAs exhibit architectural complexity and nuclear atypia that approaches or resembles FIGO grade 1 endometrioid carcinoma. Because most patients are young and the lesion is confined to a polyp, there is minimal risk of coincident myometrial invasive carcinoma or progression to myometrial invasive carcinoma. Some APAs are associated with adjacent, non-polypoid hyperplasia, including atypical hyperplasia.

APA

11.3.3  General Features Atypical polypoid adenomyoma disproportionately affects women in the fourth and fifth decades, with an average age of 35–40 years. These lesions frequently present in the lower uterine segment and may extend to involve the upper endocervix. Almost all patients are premenopausal, with a majority being nulligravid. A significant minority of patients have been diagnosed with APA during evaluation for infertility. Most patients present with vaginal bleeding.

11.3.4  Etiology Although it is uncertain, it is possible that these polyps arise from abnormalities in beta-catenin/wnt signaling.

Diagnostic Highlights

• APA is, essentially, endometrioid hyperplasia in myomatous stroma, forming a polyp. • It may resemble myometrial-invasive endometrioid adenocarcinoma in biopsy or curettings, which is a general reminder not to diagnose myometrial invasion unless it is unequivocally demonstrated in a hysterectomy specimen. • Patients can be managed conservatively. If a hysterectomy is performed, it is extraordinarily rare to encounter myometrial invasion.

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11.3.7  Differential Diagnosis

11.3.9  Case

• Myometrial-invasive adenocarcinoma. With the rarest exceptions, a diagnosis of myometrial-invasive carcinoma should be made only at hysterectomy; both APA and adenocarcinoma invading polyp stroma can resemble myometrial-­invasive adenocarcinoma on biopsy, polypectomy, or curettage. • Polypoid adenomyoma. These contain fewer glands than APAs and tend not to show gland crowding. The presence of appreciable endometrial stroma around the endometrioid glands favors adenomyoma. • Müllerian adenosarcoma. Most Müllerian adenosarcomas do not contain myoid stroma, facilitating diagnosis. APA lacks stromal cuffs around glands and phyllodes-like architecture.

A 35-year-old infertile woman presents to the reproductive endocrinologist, who finds a cervical polyp measuring approximately 2 cm (Figs. 11.19, 11.20, 11.21, and 11.22).

11.3.8  Prognosis The malignant potential of these polyps is very, very low; only several cases of invasive carcinoma are on record. No patient is reported to have died of disease. In most cases, APAs can be managed conservatively, with polypectomy, curettage, and hormonal therapy.

Fig. 11.19  Atypical polypoid adenomyoma. Irregular and crowded glands are found in a polyp with myoid stroma. A morule is present at center. This appearance is not at all diagnostic of myometrial-invasive carcinoma

Fig. 11.20  Atypical polypoid adenomyoma with prominent morules

Fig. 11.21  Sessile atypical polypoid adenomyoma with prominent morules. At the bottom is a rounded contour where the sessile polyp transitions to myometrium

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11.4.5  Macroscopy There are reports of both polypoid masses and deeply infiltrative tumors measuring, on average, 5  cm in greatest dimension.

11.4.6  Microscopy

Fig. 11.22  Atypical polypoid adenomyoma with complex atypical hyperplasia. Complex atypical hyperplasia can be found in atypical polypoid adenomyomas, as can well-differentiated endometrioid adenocarcinoma. To minimize the chance of mistaking this lesion for myometrial invasive adenocarcinoma, do not diagnose myometrial or cervical stromal invasion in a biopsy specimen or curetting

11.4 Mesonephric Carcinosarcoma 11.4.1  Definition A biphasic neoplasm, unassociated with human papillomavirus (HPV-independent), containing malignant mesonephric glandular and mesenchymal components.

11.4.2  Synonyms Malignant mixed mesonephric tumor (MMMT).

Mesonephric carcinosarcoma is usually epithelial-­ predominant, and the sarcomatous component may be homologous or heterologous. Occasional cases have mesonephric remnants at the periphery. The epithelial component represents mesonephric adenocarcinoma, which frequently displays a variety of different growth patterns. The most easily recognized and possibly the most common pattern displays small tubules with luminal eosinophilic secretions. Other configurations are glomeruloid, ductal, papillary, and retiform. (See Chap. 8.) Unlike the carcinomatous component of conventional carcinosarcomas, mesonephric adenocarcinomas only uncommonly or focally display overt nuclear atypia; more frequently, they feature uniform nuclei with powdery chromatin or chromatin clearing, with or without nuclear grooves. Spindle cell elements may be fused to the epithelial component or separated from it. Nuclei tend to be uniform. Some pathologists will diagnose “mesonephric carcinosarcoma” in the presence of adenocarcinoma with homologous spindle cells, whereas others would diagnose “mesonephric adenocarcinoma.” The presence of heterologous elements (most commonly rhabdomyoblastic or chondroid), which are found in perhaps half of mesonephric carcinosarcomas, is unequivocally in favor of carcinosarcoma diagnosis. Epithelial components of this tumor express PAX8 and GATA3 with or without TTF-1, in the absence of ER/PR expression.

11.4.3  General Features Most patients are perimenopausal or postmenopausal and present with vaginal bleeding. Direct extension or drop metastasis from carcinosarcoma originating in the corpus is far more common than primary cervical carcinosarcoma; mesonephric carcinosarcoma may be the only type of primary cervical carcinosarcoma.

11.4.4  Etiology Little is known about this very rare tumor.

Diagnostic Highlights

• Mesonephric adenocarcinoma with a neoplastic, usually spindle cell and frequently heterologous mesenchymal proliferation. • Mesonephric adenocarcinoma displays a variety of forms, including the typical small glandular pattern containing eosinophilic secretion; nuclei are usually bland and ovoid with chromatin clearing and/or nuclear grooves. • The mesenchymal component may be heterologous.

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11.4.7  Differential Diagnosis

11.4.9  Case

• Conventional carcinosarcoma. Biphasic tumors containing high-grade endometrioid, serous, or histologically ambiguous epithelial elements either do not arise in the cervix or they are extraordinarily rare. Such tumors, particularly when pleomorphic sarcomatous elements are present, likely originate in the uterine corpus or, rarely, in the uterine adnexa. • Mesonephric adenocarcinoma. As stated above, the classification of tumors with a mesonephric glandular constituent and a homologous spindle cell component is subject to difference of opinion, but it is advised to diagnose mesonephric carcinosarcoma when the homologous spindle cell component is highly atypical or heterologous elements are present. • Adenocarcinoma combined with neuroendocrine carcinoma. High-grade neuroendocrine carcinomas  of the cervix are not infrequently associated with HPV-associated adenocarcinomas, but the presence of high-grade neuroendocrine carcinoma in a mesonephric adenocarcinoma is case-reportable. Crush artifact and spindling of the neuroendocrine component may be misinterpreted as a sarcoma. Characteristic nuclear morphology, a very high mitotic index with abundant apoptosis, and immunohistochemical expression of neuroendocrine markers favor the presence of a high-grade neuroendocrine carcinoma. • Other endocervical adenocarcinomas. Mesonephric adenocarcinoma may resemble clear-cell, endometrioid, and serous carcinomas, which might complicate the diagnosis. Details can be found in Chap. 8.

A 67-year-old woman with a deeply infiltrative and polypoid mass involving the cervix (Figs.  11.23, 11.24, 11.25, and 11.26).

Fig. 11.23  The first sections taken (Figs. 11.23 and 11.24) show mesonephric adenocarcinoma. The small, round gland pattern is the most typical, although it is not required for diagnosis and is often mixed with other patterns.

11.4.8  Prognosis Firm conclusions cannot be drawn regarding whether mesonephric carcinosarcomas are more clinically aggressive than mesonephric adenocarcinomas, or whether clinical outcomes of mesonephric carcinosarcomas differ significantly from those of conventional carcinosarcomas. Several reported cases document recurrence/metastasis in locations (such as intestine and bone) that are unusual for both endocervical adenocarcinomas and conventional carcinosarcomas.

Fig. 11.24  Mesonephric adenocarcinoma with a nonspecific glandular pattern. The cells are low-cuboidal, retain some cytoplasm, and have nuclei that are similar to papillary thyroid carcinoma; they are “optically clear,” partly overlapping, and many have grooves

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11.5.3  General Features Most uterine leiomyosarcomas arise in the uterine corpus and some may secondarily extend into the cervix. It has been estimated that primary cervical leiomyosarcomas comprise approximately 15% of cervical sarcomas and 0.2–0.4% of all cervical malignancies. Affected patients are perimenopausal or postmenopausal and commonly present with vaginal bleeding and/or lower abdominal pain.

11.5.4  Etiology

Fig. 11.25  Mesonephric carcinosarcoma. Further sectioning of the mass reveals mesonephric carcinosarcoma with heterologous (cartilaginous) elements

Most uterine leiomyosarcomas are thought to arise de novo, but some literature supports the idea that occasional leiomyosarcomas arise from leiomyomas with bizarre nuclei (i.e., symplastic leiomyoma). Nothing is known about the molecular composition of cervical leiomyosarcomas specifically, but considerable data are available regarding the molecular underpinnings of leiomyosarcomas of the uterine corpus. Uterine leiomyosarcomas may contain mutations in p53, RB1, ATRX, DAXX, and rarely MED12, among others.

11.5.5  Macroscopy Cervical leiomyosarcomas may be very large and either prolapse into the cervical canal or infiltrate into cervical stroma with circumferential expansion. They usually present as tan, firm-to-fleshy tumors with hemorrhage and necrosis.

11.5.6  Microscopy

Fig. 11.26  Mesonephric carcinosarcoma. High-power magnification of mesonephric carcinosarcoma with cartilaginous elements

11.5 Leiomyosarcoma 11.5.1  Definition Malignant smooth muscle neoplasm.

11.5.2  Synonyms None.

Conventional (spindle), epithelioid, and myxoid types have been described, as in the uterine corpus. Conventional leiomyosarcomas are mostly composed of elongate cells with eosinophilic cytoplasm and atypical nuclei, sometimes with blunt ends, arranged in fascicles. The same criteria used to distinguish uterine corpus leiomyoma from leiomyosarcoma are employed in the cervix. The tumor must have two of the following three findings to qualify for a diagnosis of conventional leiomyosarcoma: moderate to severe nuclear atypia (usually diffusely distributed), coagulative tumor cell necrosis, and a mitotic count exceeding 9 mitotic figures per 10 high power fields. The very rare epithelioid leiomyosarcomas feature aggregated epithelioid cells with eosinophilic or clear cytoplasm, at least moderate nuclear atypia, and either tumor cell necrosis or more than 3 mitotic figures per 10 high power fields. Because the diagnostic criteria separating

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benign tumors from those of uncertain malignant potential high-grade endometrial stromal sarcomas are desmin differ between conventional and epithelioid leiomyosarconegative (although SMA expression can be encountered) mas, it is important to exclude cross-sectioning of fascicles and diffusely CD10 positive, with variable but diffuse in conventional leiomyosarcoma from truly epithelioid expression of cyclin D1. These high-grade stromal sarcotumors. mas more frequently display a pushing pattern of invasion Myxoid leiomyosarcomas are vanishingly rare, especially into stroma, whereas in myxoid leiomyosarcoma, destrucbecause many of these tumors have been recently re-­ tive invasion is more commonly encountered. classified as other tumor types. These tend to be paucicellu- • Inflammatory myofibroblastic tumor (IMT). This tumor of lar tumors with myxoid but not edematous stroma. Tumor low or uncertain malignant potential may resemble a concells are spindled, stellate, or ovoid. Diagnosis requires ventional smooth muscle tumor and/or one with myxoid exclusion of mimics (discussed below) and the presence of stroma. However, diffusely distributed, significant nuclear moderate nuclear atypia with either coagulative tumor cell atypia, necrosis, and a high mitotic index are very uncomnecrosis or more than 1 mitotic figure per 10 high power mon. Histologic distinguishing features include a usually fields. Examples that irregularly invade stroma are also likely mildly atypical proliferation of myofibroblasts with a to be myxoid leiomyosarcomas. myxoid stroma and a lymphocytic infiltrate. Smooth musSome sarcomas harbor both leiomyosarcomatous and pleocle actin (commonly) and desmin (less commonly) are morphic undifferentiated components, with the latter usually present, but in contrast to most cases of leiomyosarcoma, lacking desmin expression (see below); these are probably IMT expresses ALK, which is related to an ALK translobest diagnosed as de-differentiated leiomyosarcomas. cation. Other rare molecular abnormalities have been Immunohistochemistry for desmin has become important reported. Since the ALK translocation is targetable with in differentiating between smooth muscle tumors and their new therapies, it is important not only to consider this many mimics; desmin should be expressed multifocally or diagnosis, but also to confirm the presence of an ALK diffusely to confirm smooth muscle differentiation when the translocation, if ALK positive by immunohistochemistry, morphology is confounding and a diagnostic mimic is queswith fluorescence in situ hybridization (FISH) or RNA tioned. Many clinicians request ER and PR immunohistosequencing. chemistry for therapeutic prediction, and these results may • Undifferentiated sarcoma. Two types of undifferentiated also be prognostic, with ER/PR positive tumors possibly sarcomas have been reported: those with uniform but atyphaving a better prognosis than others. ical nuclei and those with overt nuclear pleomorphism. The former category is mostly composed of tumors now considered to be high-grade endometrial stromal sarcomas. Tumors in the latter category lack desmin expression Diagnostic Highlights but share many molecular genetic aberrations with leiomyosarcoma. The presence of a tumor focus resembling • Desmin-positive malignant spindle, epithelioid, or leiomyosarcoma with desmin expression would qualify myxoid smooth muscle neoplasm. for a diagnosis of de-differentiated leiomyosarcoma. • Entities in the differential should be excluded, par• Perivascular epithelioid cell tumor (PEComa), includticularly when the sarcoma is epithelioid or ing malignant PEComa. PEComas are epithelioid and/ myxoid. or spindle and epithelioid tumors, usually with myogenic differentiation, which accounts for their histologic overlap with smooth muscle tumors such as conven11.5.7  Differential Diagnosis tional and epithelioid leiomyosarcoma. The histology of PEComa is discussed subsequently in this chapter (Sect. • Leiomyoma, including leiomyomas with bizarre nuclei. 11.11), but in many cases, it overlaps to a certain degree The histologic criteria for distinguishing these tumors with that of leiomyoma and leiomyosarcoma. An attempt from leiomyosarcoma are discussed above. should be made to differentiate this tumor from atypical • Endometrial stromal sarcoma. Endometrial stromal sarleiomyoma and leiomyosarcoma, because the criteria comas are usually low-grade, so most would not resemble for distinguishing between benign and malignant examleiomyosarcoma. However, a molecularly defined, high-­ ples differ. Additionally, many PEComas harbor mutagrade subset (BCOR-translocated or with internal tandem tions in TSC1 or TSC2, which are thought to make some duplication) exhibits spindle cells and myxoid stroma, PEComas sensitive to mTOR pathway blockade. histologically very similar to myxoid leiomyosarcoma. Although it has been reported that H&E morphology, The distinction rests on immunohistochemical and molecalong with even focal expression of two melanocyticular results. Contrasted against leiomyosarcoma, BCOR associated immunohistochemical markers (usually

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HMB45 and Melan-A) can be used to ascertain a PEComa diagnosis, it is probably more informative to search for TSC1 or TSC2 mutations for a confident diagnosis, especially since many epithelioid leiomyosarcomas similarly express HMB45. • Fibroblastic sarcoma. These tumors might resemble conventional leiomyosarcoma because of the fascicles of atypical spindle cells, but they are desmin negative and display a storiform and/or herringbone arrangement of tumor cells more frequently than leiomyosarcoma. Two types have been described recently, one harboring an NTRK translocation and one harboring a PDGF-beta rearrangement, the former of which can be detected with NTRK immunohistochemistry (unfortunately not specific). The translocations can be detected with FISH or RNA sequencing. • Spindle cell melanoma. This tumor expresses S100 and SOX10 at least focally and lacks smooth muscle differentiation. In situ melanoma may be present. • Gastrointestinal stromal tumor. If this tumor secondarily involves the cervix, it could potentially be confused with leiomyosarcoma. Clinical history, lack of smooth muscle differentiation, and CD34, c-kit, and DOG1 immunohistochemical positivity support a diagnosis of gastrointestinal stromal tumor.

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2. A 45-year-old woman underwent a recent myomectomy that revealed a leiomyoma with bizarre nuclei and a hysterectomy was performed (Figs. 11.30 and 11.31).

Fig. 11.27  Leiomyosarcoma displaying spindled smooth muscle cells (conventional leiomyosarcoma) with striking nuclear atypia. Given this picture, either tumor cell necrosis or more than 9 mitotic figures per 10 high power fields is necessary to confirm the diagnosis.

11.5.8  Prognosis Very little is known about clinical outcomes for cervical leiomyosarcomas. Extrauterine disease, either locally or in distant sites, is the most important prognostic feature, extrapolating from uterine corpus leiomyosarcomas. Unfortunately, leiomyosarcomas apparently confined to the uterus are fatal in more than 50% of patients.

11.5.9  Cases 1. A 62-year-old woman who presented with pelvic pressure and was found to have a mass involving myometrium and cervical stroma (Figs. 11.27, 11.28, and 11.29).

Fig. 11.28  Conventional leiomyosarcoma with nuclear atypia and high mitotic counts.

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Fig. 11.29  Conventional leiomyosarcoma with nuclear atypia, high mitotic counts, and an atypical mitotic figure

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Fig. 11.31  Myxoid leiomyosarcoma, cytologic detail.

11.6 Endometrial/Endometrioid Stromal Sarcoma 11.6.1  Definition An invasive malignant tumor that resembles non-neoplastic endometrial stroma (i.e., conventional low-grade endometrial stromal sarcoma) or that contains a translocation known to be associated with endometrial stromal neoplasia.

11.6.2  Synonyms Stromal sarcoma; endolymphatic stromal myosis. Fig. 11.30  Myxoid leiomyosarcoma. This example was desmin positive and negative for ALK, CD10, BCOR, and cyclin D1, supporting this diagnosis. The differential diagnosis includes inflammatory myofibroblastic tumor (ALK+) and varieties of endometrial stromal sarcoma

11.6.3  General Features This tumor almost never arises as a cervical primary; most cases encountered in the cervix represent spread from a corpus primary. Affected patients are mostly perimenopausal.

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11.6.4  Etiology Tumors of the uterine corpus contain one of several chromosomal translocations, including t(7;17)(p15;q21), t(6;7) (p21;p15), t(6;10;10)(p21;q22;p11), t(10;17)(q22;p13), and t(1;6)(p34;p21), resulting in JAZF1–SUZ12, PHF1–JAZF1, EPC1–PHF1, YWHAE–FAM22, and MEAF6–PHF1 rearrangements, respectively. When present, these genetic alterations appear mutually exclusive. The t(7;17)(p15;q21) translocation resulting in JAZF1–SUZ12 gene fusion is by far the most common and most extensively studied genetic alteration in endometrial stromal tumors. Novel fusions continue to be reported.

11.6.5  Macroscopy Low-grade endometrial stromal sarcoma, the most common variety, displays soft and glistening yellow tumor nodules distributed irregularly in myometrium and/or cervical stroma. Extrauterine extension may be represented by tumor emboli or direct extension to the vessels of the broad ligament or ovarian hilum.

11.6.6  Microscopy Tongue-like invasion of the stroma, usually with conspicuous lymphovascular invasion, is typical. Cytologically, low-­ grade endometrial stromal sarcomas, the most commonly encountered type, usually resemble non-neoplastic endometrial stroma, including spiral-like arterioles and branching capillaries. Cells are ovoid, small, and lack appreciable cytoplasm and nuclear atypia. “Variant” patterns of low-grade endometrial stromal sarcoma are recognized. Tumors with fibroblastic, myxoid, and smooth muscle differentiation are the most common variants; less common are tumors with epithelioid cells and benign-appearing endometrioid glands. Regardless of the type of differentiation present, low-grade endometrial stromal sarcomas have low mitotic counts, with a mean of 4 mitotic figures per 10 high power fields. Previously, 10 mitotic figures per 10 high power fields was used as a diagnostic cut-off separating low-grade from high-­ grade endometrial stromal sarcoma, but now most high-­ grade sarcomas are defined by a combination of cytologic features, mitotic activity, and genotype. JAZF1 translocation is the most common genetic abnormality among the low-­ grade tumors.

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High-grade endometrial stromal sarcomas are heterogeneous from a morphologic and genetic perspective. The four subtypes that are best understood are YWHAE-translocated, BCOR-translocated, BCOR-internal tandem duplication (BCOR-ITD), and JAZF1-translocated. YWHAE tumors are usually biphasic, with hypocellular, bland, hypoproliferative fibromyxoid elements and a component containing solid and nested architecture with large, round cells with open chromatin and increased mitotic activity. The high-grade component is CD10 and ER/PR negative, with acquisition of BCOR and/or cyclin D1 by immunohistochemistry. The BCOR-­ translocated cases, as mentioned previously, resemble myxoid leiomyosarcoma with moderately atypical spindle cells in a myxoid stroma. These tumors are CD10 and SMA positive (but not desmin) with cyclin D1, and/or BCOR immunohistochemical expression. BCOR expression is paradoxically less often encountered than cyclin D1 labeling. BCOR-ITD cases may be biphasic, incorporating both the appearance of BCOR-translocated tumors and a histologically higher-grade component. Last are the poorly understood “de-­differentiated” high-grade endometrial stromal sarcomas, which arise from a low-grade tumor with JAZF1 translocation. This tumor can be recognized in the presence of a typical low-grade endometrial stromal sarcoma with acquisition of notable nuclear atypia and an increased mitotic count, or by presentation of such a high-grade tumor in a patient with a confirmed history of low-grade endometrial stromal sarcoma. Diagnostic Highlights

• Low-grade endometrioid/endometrial stromal sarcoma shows tongue-like invasion of myometrium/ stroma. Constituent cells are bland, ovoid, and featureless, arranged around spiral-like arterioles and branching capillaries. Several morphologic variations exist. • Low-grade endometrial stromal sarcomas are typically positive for CD10, ER, and PR. • High-grade endometrial stromal sarcoma has a variable appearance, which in many cases is associated with a particular gene fusion. • The immunophenotype of high-grade endometrial stromal sarcoma is variable and mostly dependent on the type of gene fusion present. • Low-grade endometrial stromal sarcomas with variant histology and high-grade endometrial stromal sarcomas need to be distinguished from histologic mimics. (See Differential diagnosis.)

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11.6.7  Differential Diagnosis • Endometrial stromal nodule. This tumor has a circumscribed contour without lymphovascular invasion, although tumor cells appear similar to those in low-grade endometrial stromal sarcomas. • Highly cellular leiomyoma. This tumor is usually circumscribed and contains thick-walled blood vessels and a characteristic cleft at its periphery, without myometrial/ stromal invasion. Cells are desmin positive and variably CD10 positive. • Intravenous leiomyomatosis. Like many endometrial stromal sarcomas, intravenous leiomyomatosis contains conspicuous tumor emboli. In contrast to endometrial stromal sarcoma, the tumor emboli resemble leiomyoma and its variants, including thick-walled blood vessels and clefting. Cells are desmin positive and variably CD10 positive. The tumor can be associated with an adjacent leiomyoma, including dissecting leiomyoma. Endometrial stromal neoplasia adjacent or admixed with the intravenous foci is lacking. • Smooth muscle tumor of uncertain malignant potential (STUMP) or “low-grade” leiomyosarcoma. Some endometrial stromal sarcomas with spindle cell growth, particularly those showing smooth muscle or fibroblastic differentiation, can be confused with an atypical smooth muscle tumor. Before considering a diagnosis of STUMP, these entities and others should be excluded by careful morphologic study, immunohistochemistry, and, if necessary, genetic analysis. • Myxoid leiomyosarcoma. As mentioned previously, myxoid leiomyosarcoma can mimic the histologic appearance of BCOR-translocated high-grade endometrial stromal sarcoma. Desmin expression without cyclin D1 or BCOR immunoreactivity favors a smooth muscle tumor, one of which is myxoid leiomyosarcoma. • Perivascular epithelioid cell tumor (PEComa). Epithelioid variants of low-grade endometrial stromal sarcoma and the high-grade component of YWHAE-translocated highgrade endometrial stromal sarcoma may bear passing resemblance to PEComa. Most PEComas show unequivocal expression of HMB45 and Melan-A in addition to characteristic molecular abnormalities. (See the discussion of PEComa, below [Sect. 11.11].) • Fibroblastic sarcoma. These tumors may closely resemble BCOR-translocated and BCOR-ITD endometrial stromal sarcomas, owing to spindled growth. They are associated with two different chromosomal translocations, involving PDGF-beta or NTRK, which are not found in endometrial stromal sarcoma. (See the discussion of fibroblastic sarcoma, below [Sect. 11.8].) • Inflammatory myofibroblastic tumor. This tumor may resemble endometrial stromal sarcoma with BCOR translocation, owing to the presence of spindle cells and myx-

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oid stroma in both lesions. Although there are quite a few distinguishing features, the most diagnostically reproducible is ALK expression with ALK translocation in inflammatory myofibroblastic tumor and a BCOR translocation in certain high-grade endometrial stromal sarcomas. • Gastrointestinal stromal tumor. When it secondarily involves the cervix, this tumor could potentially be confused with a spindled endometrial stromal sarcoma, including those with BCOR abnormality. Clinical history with CD34, c-kit, and DOG1 immunohistochemical positivity support a diagnosis of gastrointestinal stromal tumor. • Spindle cell melanoma. This tumor expresses S100 and SOX10 at least focally and lacks the characteristic translocations of endometrial stromal sarcoma. In situ melanoma may be present. • Solitary fibrous tumor. Like endometrial stromal sarcoma, this tumor may have ovoid-spindled, nondescript cells and a staghorn vasculature, but solitary fibrous tumor expresses CD34 and, more importantly, STAT6, which is diagnostically helpful.

11.6.8  Prognosis Although the prognosis of cervical stromal sarcomas has not been studied, one can extrapolate from the uterine corpus literature, where it appears that grade and stage are the most important prognostic indicators. Low-stage, lowgrade endometrial stromal sarcomas may recur in up to one third of cases. These recurrences can be managed with hormonal therapy with or without resection, but in general, the disease is indolent and overall survival significantly exceeds 10 years. High-stage, low-grade endometrial stromal sarcomas are, perhaps, more prone to recurrence than low-stage tumors, but when high-grade tumors are excluded, these are still very slow-growing tumors, metastases from which can be managed like the low-stage tumors. High-grade endometrial stromal sarcomas, more often than low-grade tumors, present with extrauterine disease and behave aggressively. Lymph node involvement may be present.

11.6.9  Cases 1. A 50-year-old woman underwent a supracervical hysterectomy and “completion surgery” (trachelectomy) (Figs. 11.32, 11.33, and 11.34). 2. This 48-year-old woman was found to have a mediastinal mass after reporting nonspecific respiratory symptoms. Work-up disclosed a large mass involving the corpus and cervix (Figs. 11.35 and 11.36). 3. A 45-year-old woman was diagnosed with myxoid leiomyosarcoma of the uterus (Figs. 11.37 and 11.38).

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Fig. 11.32  Low-grade endometrial stromal sarcoma. The sarcoma demonstrates a “tongue-like” pattern of invasion

Fig. 11.34  Low-grade endometrial stromal sarcoma, cytologic detail. Cells are bland and ovoid and contain scant cytoplasm with a low mitotic count. Note the prominent vasculature, consisting of spiral arterioles and delicate capillaries

Fig. 11.33  CD10-positive low-grade endometrial stromal sarcoma, illustrating balls of tumor infiltrating myometrium (CD10-negative)

Fig. 11.35  Low-grade endometrial stromal sarcoma, invading myometrium and vessels

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Fig. 11.36  High-grade endometrial stromal sarcoma. The cells are vaguely packeted and have large nuclei with open chromatin and mitotic activity. The nuclear size, chromatin, and mitotic count differ from conventional low-grade endometrial stromal neoplasia. These features suggest the presence of a rearrangement involving YWHAE, which was documented in this case

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Fig. 11.38  BCOR-rearranged high-grade endometrial stromal sarcoma, cytologic detail.

11.7 Undifferentiated Sarcoma 11.7.1  Definition A high-grade sarcoma that lacks obviously differentiating features.

11.7.2  Synonyms Undifferentiated sarcoma of uniform type; undifferentiated sarcoma of pleomorphic type; undifferentiated uterine sarcoma.

11.7.3  General Features Fig. 11.37  BCOR-rearranged high-grade endometrial stromal sarcoma. This is a myxoid neoplasm containing spindle cells. The patient experienced metastasis, and a biopsy specimen was found to be negative for desmin and positive for CD10; it was sent for FISH, which showed a rearrangement involving BCOR. The combination of features—myxoid stroma with spindle cells, the immunophenotype, and genotype—is diagnostic of a high-grade endometrial stromal sarcoma with BCOR rearrangement. The original diagnosis of myxoid leiomyosarcoma could not be verified.

This tumor almost never arises within the cervix; most cases encountered in the cervix represent spread from a corpus primary. Affected patients are mostly postmenopausal. Most undifferentiated sarcomas with uniform nuclei represent high-grade endometrial stromal sarcoma, whereas some pleomorphic sarcomas represent de-differentiated leiomyosarcoma. The remaining pleomorphic sarcomas are the subject of this section.

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11.7.4  Etiology Undifferentiated pleomorphic sarcomas contain mutations which can overlap with aggressive leiomyosarcomas, liposarcomas and osteosarcomas. •

11.7.5  Macroscopy • These tumors are not well described because they are very uncommon (particularly in the cervix) and subject to interobserver diagnostic variation. They are presumed to be large tumors with hemorrhage and necrosis.

11.7.6  Microscopy Pleomorphic spindle and epithelioid cells with a high mitotic count are typical. Foci representing low-grade endometrial stromal sarcoma and leiomyosarcoma should be absent, and other entities in the differential diagnosis should be excluded, as below. Desmin is preferentially negative. Many cases show mutation-type p53 staining, loss of ATRX by immunohistochemistry, and negative or weak-intensity staining for ER/PR.

Diagnostic Highlights

• Diagnosis of exclusion • Monomorphic examples should be studied to determine the presence of an endometrial stromal sarcoma–associated gene fusion. • Pleomorphic tumors should be extensively sampled to exclude carcinosarcoma and leiomyosarcoma.

11.7.7  Differential Diagnosis • Sarcomatous component of conventional carcinosarcoma or high-grade Müllerian adenosarcoma. The presence of epithelial elements should be excluded with careful morphologic review and liberal sectioning before considering a diagnosis of undifferentiated sarcoma. • Leiomyosarcoma. Both entities can contain pleomorphic cells, but leiomyosarcomas are desmin positive, in con-

•

• •

trast to most undifferentiated sarcomas. Remember that rare leiomyosarcomas (specifically de-differentiated leiomyosarcoma) can contain distinctive pleomorphic foci; they would still be categorized as leiomyosarcoma. Fibroblastic sarcoma. These are not commonly pleomorphic and are recognized by characteristic chromosomal translocations, as discussed in the next section. Malignant PEComa. Because some leiomyosarcomas and pleomorphic undifferentiated sarcomas can contain cells with melanocytic differentiation, accept only cases with strong HMB45 and Melan-A as either malignant PEComas or melanomas, the latter of which would also express SOX10 and S100. The presence of a mutation in TSC1 or TSC2 favors PEComa. High-grade endometrial stromal sarcoma. Only extremely rare endometrial stromal sarcomas contain pleomorphic cells. These can be recognized, theoretically, by their stromal sarcoma-like growth pattern and the presence of characteristic chromosomal translocations. Melanoma. This tumor expresses S100 and SOX10, at least focally. In situ melanoma may be present. Malignant solitary fibrous tumor. This tumor has ovoid-­ to-­ spindled nondescript cells with variable degrees of nuclear pleomorphism and a staghorn vasculature. Whereas most solitary fibrous tumors express STAT6, this may be muted or absent in malignant examples, especially when de-differentiation occurs. The presence of a chromosomal translocation involving STAT6 (NAB2-­STAT6) is diagnostically confirmatory.

11.7.8  Prognosis No data exist for cervical pleomorphic undifferentiated sarcomas, but tumors that arise in the corpus are highly aggressive, perhaps more aggressive than leiomyosarcoma.

11.7.9  Cases 1. A 70-year-old woman with a huge uterine mass, pelvic pain, and vaginal bleeding (Fig. 11.39). 2. A 42-year-old woman with a 7-cm uterine mass (Figs. 11.40 and 11.41).

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Fig. 11.39  Pleomorphic undifferentiated sarcoma. This sarcoma lacks differentiation on H&E stains and was negative for markers associated with particular tumor types (desmin, CD10, ER, PR, BCOR, cyclin D1). No epithelial component was identified, thereby excluding adenosarcoma and carcinosarcoma. A component of conventional leiomyosarcoma was not present, excluding a diagnosis of de-differentiated leiomyosarcoma. The tumor overexpressed p53

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Fig. 11.41  Uniform/monomorphic undifferentiated sarcoma with a high mitotic count

11.8 Fibroblastic Sarcoma 11.8.1  Definition Sarcoma demonstrating fibroblastic differentiation, containing one of two characteristic chromosomal translocations.

11.8.2  Synonyms Fibrosarcoma-like uterine sarcoma; Fibrosarcoma.

11.8.3  General Features These are rare and newly described entities. The NTRK-­ associated sarcomas (see below) preferentially affect young patients, often arise in the cervix, and occur at a median age of 30–35  years. In contrast, PDGF-beta cases affect perimenopausal and postmenopausal patients. Fig. 11.40 Uniform/monomorphic undifferentiated sarcoma. This tumor was negative for desmin, ER, PR, BCOR, and cyclin D1, and no epithelial component was identified. CD10 was positive. FISH analysis with probes recognizing JAZF1, PHF1, and YWHAE was negative for these stromal sarcoma-associated  rearrangements. Although negative FISH results do not exclude endometrial stromal sarcoma, they make that diagnosis less likely.

11.8.4  Etiology Chromosomal translocations involving PDGF-beta (COL1A1-PDGFB) or NTRK1 or NTRK3 (TPM3-NTRK1 or EML4-NTRK3). Some cases lack these rearrangements.

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11.8.5  Macroscopy Tumors appear polypoid and/or infiltrative, tan-yellow or white, and whorled, sometimes with necrosis. NTRK tumors have a median size of 3–4 cm, often located primarily in the cervix, whereas PDGF-beta–associated cases are larger, with a range of 6–12 cm.

•

•

11.8.6  Microscopy Both tumor types feature a malignant spindle cell proliferation resembling fibrosarcoma, with mild-to-moderate nuclear atypia and a variable mitotic count, growing in herringbone fascicles. NTRK cases may have a lymphocytic inflammatory infiltrate. The variant with PDGF-beta fusions also may have storiform growth that resembles dermatofibrosarcoma protuberans. These tumors are negative for desmin and ER/ • PR, and variably positive for CD34 and S100. NTRK-­ translocated tumors express pan-TRK and may be BCOR-­ positive with immunohistochemistry. As stated previously, NTRK/TRK immunohistochemistry is sensitive, but not specific. PDGF-beta immunohistochemistry can be positive in the PDGF-beta cases, but this immunohistochemical stain is difficult to optimize. Results should be confirmed with FISH or RNA sequencing. •

Diagnostic Highlights

• Morphology resembling fibrosarcoma or dermatofibrosarcoma protuberans • Desmin negative • Diagnosis should be confirmed by studies that reveal characteristic gene fusions and exclusion of other entities. (See Differential diagnosis.)

•

sarcoma–associated and BCOR fusions or BCOR internal tandem duplication solves this differential diagnosis. Spindle cell melanoma. This tumor expresses S100 and SOX10 at least focally and lacks the characteristic translocations of fibroblastic sarcoma. In situ melanoma may be present. Malignant peripheral nerve sheath tumor. The spindled nature of fibroblastic sarcomas overlaps with this entity. Only about nine tumors have been described in the cervix, under the names endocervical fibroblastic malignant peripheral nerve sheath tumor (i.e., neurofibrosarcoma), fibroblastic sarcoma with features of malignant peripheral nerve sheath tumor, or malignant schwannoma. Six of these tumors were described before the advent of genetic testing. Malignant peripheral nerve sheath tumors may have patchy S100 reactivity and loss of expression of H3K27me3, and they lack PDGF-beta and NTRK fusions. Monophasic synovial sarcoma. This tumor theoretically could involve the cervix secondarily. Herringbone architecture may be present, as in fibroblastic sarcoma, but the vasculature may differ (staghorn in synovial sarcoma). The tumor tends to express TLE1, cytokeratin, EMA, BCL2, and CD99. It has a characteristic chromosomal translocation, t(X;18)(p11;q11), involving genes SS18 and SSX1, SSX2, or SSX4. Gastrointestinal stromal tumor. Owing to spindled tumor cells and CD34 immunoreactivity, this tumor potentially could be confused with fibroblastic sarcoma, when it secondarily involves the cervix. The clinical history and c-kit and DOG1 immunohistochemical positivity support a diagnosis of gastrointestinal stromal tumor. Malignant solitary fibrous tumor. This tumor has ovoid-­to-­ spindled nondescript cells with variable degrees of nuclear pleomorphism and a staghorn vasculature. Whereas most solitary fibrous tumors express STAT6, this may be muted or absent in malignant examples, especially when de-differentiation occurs. The presence of a chromosomal translocation involving STAT6 is diagnostically confirmatory.

11.8.7  Differential Diagnosis 11.8.8  Prognosis • Smooth muscle tumors. Although fibroblastic sarcomas may express SMA, they are desmin negative, unlike smooth muscle tumors. Analysis for fibroblastic sarcoma–associated fusions solves this differential diagnosis. • Endometrial stromal tumors with BCOR abnormality. Although this tumor may appear similar to fibroblastic sarcoma, it is characteristically CD10-positive and negative for CD34, pan-TRK, and PDGF-beta. NTRK-­ associated sarcomas may be BCOR positive with immunohistochemistry, similar to BCOR-rearranged endometrial stromal sarcomas. Analysis for fibroblastic

Of 11 patients with NTRK-associated sarcomas, 6 are reported to have no evidence of disease, 4 experienced recurrence and are alive with disease, and 1 patient succumbed to disease. The number of PDGF-beta–related cases is insufficient for an informative summary of their clinical behavior. Confirming the presence of a rearrangement involving NTRK may provide patients with disease recurrence or progression an opportunity to be treated with agents that inhibit Trk. Similarly, it is possible that patients with PDGF-beta–associated tumors could potentially be treated with small molecular tyrosine kinase inhibitors in the setting of advanced disease.

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11.8.9  Cases 1. A 32-year-old woman complained of abdominal fullness and was found to have a 4-cm tumor centered in the cervix, a spindle cell neoplasm with a nonspecific appearance (Figs. 11.42 and 11.43). 2. A 58-year-old woman with a mass involving the uterus and, focally, the cervix (Figs. 11.44 and 11.45). 3. A 62-year-old woman with a large uterine mass (Fig. 11.46).

Fig. 11.44  Fibroblastic sarcoma. This example displays storiform architecture with moderately atypical spindle cells. The tumor was desmin-negative and was sent for RNA sequencing, revealing a COL1A1-PDGFB fusion, which has been described in rare fibroblastic sarcomas of the uterus and, interestingly, dermatofibrosarcoma protuberans and fibrosarcomas arising in that setting

Fig. 11.42  Fibroblastic sarcoma of cervix. A smooth muscle tumor was excluded by negative staining for desmin. RNA sequencing disclosed a TPM3-NTRK1 fusion, which is in favor of a diagnosis of NTRK-rearranged fibroblastic sarcoma. Should the patient experience recurrence, it is possible that she might respond to agents that target NTRK

Fig. 11.45  Fibroblastic sarcoma, cytologic detail

Fig. 11.43  Fibroblastic sarcoma of cervix, cytologic detail

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11.9.6  Microscopy

Fig. 11.46  Fibroblastic sarcoma. This example, reminiscent of malignant peripheral nerve sheath tumor or monophonic synovial sarcoma, was negative for desmin, but it was variably positive with CD34 and S100. RNA sequencing was negative for common fusions. These features have been described in “endocervical fibroblastic malignant peripheral nerve sheath tumor,” a nebulous concept

Rhabdoid sarcoma is thought to arise within the myometrium/cervical stroma, but colonization of the mucosa can be seen, simulating high-grade adenosarcoma with stromal overgrowth. Microscopically, this tumor resembles the large-­cell variant of small-cell hypercalcemic carcinoma of the ovary or undifferentiated carcinoma with rhabdoid cells. Rhabdoid sarcoma contains patternless sheets of cells with abundant eosinophilic cytoplasm and an eccentric, atypical nucleus, usually with a nucleolus (i.e., rhabdoid features). Intercellular dyshesion, myxoid stroma, and stromal sclerosis may be present. Lymphovascular invasion, necrosis, and infiltrative growth are common. Associated endometrial hyperplasia and carcinoma are not found. These sarcomas are negative for SMARCA4 (BRG1), claudin-4, PAX8, CD34, desmin, and S100 and are microsatellite-stable. Occasional cells may be positive for EMA and low-­ molecular-­ weight keratin. There is a SMARCA4 mutation, either germline or somatic, without mutations common to endometrioid carcinomas and related neoplasms.

11.9 Rhabdoid Sarcoma 11.9.1  Definition SMARCA4-deficient sarcoma with rhabdoid features.

11.9.2  Synonyms Malignant rhabdoid tumor of uterus; SMARCA4-deficient undifferentiated uterine sarcoma.

Diagnostic Highlights

• Sheet-like proliferation of rhabdoid tumor cells, sometimes growing in a pattern that resembles adenosarcoma, which should be excluded • SMARCA4 mutation with loss of expression • Endometrioid-associated genetic abnormalities (PTEN mutation, DNA mismatch repair deficiency) are not found.

11.9.3  General Features

11.9.7  Differential Diagnosis

These newly-described clinically-agressive tumors occur in young individuals with a median age of 25  years (range 2–58). In the past, they may have been classified as undifferentiated uterine sarcoma or undifferentiated carcinoma.

• Müllerian adenosarcoma. (Uterine sarcomas with adenosarcoma-­l ike growth) This differential diagnosis is discussed in Sect. 11.2, Müllerian Adenosarcoma. • Undifferentiated carcinoma. The histologic appearance can be identical and both tumors may have deleterious SMARCA4 mutations. Undifferentiated carcinomas, typically occurring in adulthood, tend to have a larger ­contribution of small cells with scant cytoplasm and can arise in the setting of endometrial hyperplasia or carcinoma. By definition, rhabdoid sarcoma does not have abnormalities common to endometrioid and undifferentiated carcinomas, such as microsatellite instability and PTEN mutation. It has also been reported that claudin-4 expression is found more commonly in undifferentiated carcinomas than in rhabdoid sarcomas, but this test likely has limited discriminatory value.

11.9.4  Etiology Inactivating mutations of SMARCA4 are present, either germline or somatic, without mutations common to endometrial carcinomas and related neoplasms.

11.9.5  Macroscopy Tumors tend to be large (at least 10  cm), tan-pink, and hemorrhagic.

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11.10.3  Etiology Uncertain, possibly a result of trans-differentiation from an underlying high-grade sarcoma such as leiomyosarcoma.

11.10.4  Macroscopy These are usually large tumors, frequently greater than 10  cm. Osteosarcomas tend to contain calcification and/or chondroid lobules.

11.10.5  Microscopy

These tumors are reported to be associated with a dismal prognosis.

These are usually pleomorphic tumors that resemble their counterparts in the soft tissues. Both botryoid and non-­ botryoid rhabdomyosarcomas can occur in adults. Of the non-botryoid sarcomas, some are embryonal-type (with or without anaplasia) or pleomorphic-type. Non-botryoid embryonal rhabdomyosarcomas tend to be stromal-invasive spindle cell tumors with primitive-appearing nuclei, a high mitotic count, and scattered, more mature rhabdomyoblasts that impart a moth-eaten appearance to the spindle cell proliferation. The infiltrative portion may be epitheliotrophic, with condensation of rhabdomyoblasts around pre-existing endocervical glands. Pleomorphic rhabdomyosarcomas have a nonspecific look, akin to malignant fibrous histiocytoma, but they are positive for desmin and myogenin/myoD1. Osteosarcomas may resemble osteoblastic, chondroblastic, or telangiectatic examples that are much more commonly encountered in the bones.

11.9.9  Case

11.10.6  Differential Diagnosis

A 38-year-old woman with vaginal bleeding and a 4-cm cervical mass (Fig. 11.47).

• Secondary involvement of cervix by a pelvic sarcoma. Imaging can usually distinguish between a uterine and extrauterine sarcoma. • Sarcomatous component of carcinosarcoma/adenosarcoma. Extensive sampling to exclude an epithelial component is necessary. Conventional carcinosarcomas are almost entirely centered in the uterine corpus and may extend secondarily to the cervix. • Other spindle cell sarcomas. Heterologous differentiation is sometimes overlooked when it is focal, so sampling and careful histologic examination are important.

Fig. 11.47  Rhabdoid sarcoma, featuring cells with abundant pink cytoplasm and eccentric, atypical nuclei with prominent nucleoli

• Undifferentiated sarcoma. This term should be used for histologically undifferentiated sarcomas that have intact SMARCA4 expression, unlike rhabdoid sarcomas. • Alveolar soft part sarcoma, rhabdomyosarcoma, PEComa, epithelioid smooth muscle tumors, and melanoma. All may bear passing resemblance to rhabdoid sarcoma, but the immunophenotypes and genotypes differ significantly.

11.9.8  Prognosis

11.10 Rhabdomyosarcoma and Osteosarcoma of Adulthood

11.10.1  Definition Adult sarcoma with heterologous differentiation.

11.10.2  Synonyms Rhabdomyosarcoma; osteosarcoma.

11.10.7  Prognosis These are thought to be very aggressive sarcomas, with the possible exception of botryoid embryonal rhabdomyosarcomas.

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Fig. 11.48 Botryoid embryonal rhabdomyosarcoma in an adult: grape-like tumor mass protruding from the uterine cervix. (Courtesy of Dr. Simona Stolnicu)

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Fig. 11.50  Adult sarcoma with heterologous differentiation (chondroand osteoblastic differentiation). Elements of leiomyosarcoma, carcinosarcoma, and adenosarcoma are not present

11.10.8  Case 1. A 76-year-old woman who complained of pelvic pressure and was found to have a 15-cm uterine mass (Figs. 11.48, 11.49, and 11.50).

11.11 P  erivascular Epithelioid Cell Tumor (PEComa) 11.11.1  Definition An epithelioid or mixed epithelioid–spindle cell tumor with myomelanocytic differentiation. Fig. 11.49  Adult sarcoma with heterologous differentiation (rhabdomyosarcoma). The rhabdomyosarcoma depicted here did not have a 11.11.2  botryoid component and arose in an adult patient. The spindle cell appearance may cause concern for leiomyosarcoma, but the “moth-­ PEComa. eaten” appearance caused by scattered, small, clear spaces is a clue to the correct diagnosis. Desmin and myogenin/myoD1 stains confirm the diagnosis. The presence of an epithelial component was excluded with extensive sectioning 11.11.3 

Synonym

General Features

As with most other mesenchymal tumors discussed in this chapter, PEComas arise more commonly in the uterine cor-

11  Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix

pus than in the cervix. Patients range in age from 25 to 61 years, with a median of 46 years. Most patients’ tumors are sporadically occurring, but PEComas that arise in the setting of tuberous sclerosis are also on record. Reported clinical presentations include vaginal bleeding, abdominal pain, a pelvic mass, and metastatic disease in a distant site. Like rhabdomyosarcomas and rare endometrial stromal sarcomas (but unlike most other sarcomas discussed in this chapter), malignant PEComas can metastasize to lymph nodes.

11.11.4  Etiology In one type of PEComa, mutations are present in TSC1 or TSC2 (more commonly), or a translocation involving RAD51B. In the second type, a TFE3 translocation [t(X;17) (p11;q25)] involving ASPSCR1-TFE3 is found.

11.11.5  Macroscopy The gross appearance may be nonspecific. Reported tumors have ranged in size from microscopic to almost 16 cm. Rare cases may be pigmented. Malignant examples may have hemorrhage and necrosis.

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The second PEComa variety, harboring a TFE3 translocation, is composed of large nests of clear-to-eosinophilic tumor cells surrounded by a conspicuous capillary vasculature. Its appearance may resemble clear-cell carcinoma of the kidney or the type of translocation-associated renal cell carcinoma with a TFE3 translocation. Scant melanin may be present. The immunophenotype of this PEComa type differs from that of the other type. TFE3-associated cases are negative for desmin, but are diffusely positive for HMB45 and TFE3 immunohistochemistry. PAX8 is negative. TFE3 immunohistochemical results should be validated with FISH or RNA sequencing.

Diagnostic Highlights

• There are two types of PEComas: –– Epithelioid +/− spindle cell tumors with SMA, HMB45, and Melan-A expression usually with TSC1/2 mutation and/or tuberous sclerosis syndrome. –– Renal cell carcinoma-like tumors with strong HMB45 expression and overexpression of TFE3. FISH or RNA sequencing should be used to confirm a TFE3 translocation.

11.11.6  Microscopy

11.11.7  Differential Diagnosis

The first of the two PEComa varieties, the TSC1/TSC2/ RAD51B PEComas, have solid architecture and tend to be epithelioid or mixed spindled and epithelioid tumors. The epithelioid cells may have a perivascular arrangement and/or nested and pseudo-alveolar architecture. Some examples show sclerotic stroma that entraps the epithelioid cells. Staghorn vasculature may be present. Epithelioid cells have clear-to-pink cytoplasm, frequently with cytoplasmic strands (spider cells). Spindle cells resemble smooth muscle cells. Rare cases have melanin deposition. Another rare finding is “PEComatosis,” typified by small aggregates of epithelioid cells in myometrium/stroma that are distinct from the tumor itself. The classic benign PEComa is small and lacks nuclear pleomorphism, necrosis, infiltrative edges, lymphovascular invasion, or a mitotic count that exceeds 1–2 mitotic figures per 50 high power fields. Criteria for malignancy vary, but generally, a malignant PEComa can be diagnosed in the presence of two or more of the above findings. Immunohistochemistry is an important part of the diagnostic workup. Most cases express smooth muscle markers HMB45, Melan-A, and cathepsin K.  A discussion of the utility of these markers can be found in the differential diagnosis section. It is best to confirm a diagnosis of malignant PEComa with sequencing to detect a mutation in TSC1, TSC2, or a translocation involving RAD51B.

• Lymphangioleiomyoma/leiomyomatosis. These proliferations have an immunophenotype that is similar to TSC1/ TSC2/RAD51B PEComas and may be associated with PEComa, but the morphology largely differs. Lymphangioleiomyomatosis is characterized by mulitple, usually small, packeted foci of bland smooth muscle cells with clear-to-eosinophilic cytoplasm arranged around lymphatic spaces and aggregates of lymphocytes. Lymphangioleiomyomatosis occasionally may be found along with PEComa. • Leiomyoma/leiomyosarcoma with epithelioid and/or spindle cell morphology. Smooth muscle tumors with epithelioid cells and/or clear cytoplasm may closely resemble PEComa. Histologic features favoring PEComa include the presence of staghorn vasculature,  sclerosis, spider cells, and melanin, but these findings are nonspecific when they are found only focally. Due to significant morphologic overlap, immunohistochemistry for a melanocyte-­ asssociated marker is usually performed. Both leiomyoma and leiomyosarcoma can contain scattered HMB45-positive cells, so focal expression of this marker is not helpful diagnostically. In general, PEComas express Melan-A more frequently than do smooth muscle tumors. If the staining is focal, it is recommended to pur-

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•

•

•

•

•

•

sue sequencing to find one of the characteristic mutations  or translocations. Compared with malignant PEComa, leiomyosarcoma more frequently has ATRX and RB1 mutations (and corresponding loss of expression for these markers using immunohistochemistry). P53 mutations can be seen in both malignant PEComas and smooth muscle tumors, but they are more common in leiomyosarcomas. Cathepsin K is commonly expressed in PEComas and variably in smooth muscle tumors, so this marker has limited utility. Alveolar soft part sarcoma. These may be indistinguishable from PEComa and share TFE3 overexpression with the TFE3 PEComas, owing to an almost identical gene fusion. Unlike PEComa, however, alveolar soft part sarcoma is negative for muscle and melanocytic markers. Undifferentiated sarcoma. These tumors and malignant PEComas may contain rare HMB45-positive cells, so a more comprehensive immunohistochemical workup (assessing for Melan-A, ATRX, and RB1) and/or sequencing should be performed. Melanoma. Obviously, both PEComa and melanoma express HMB45 and, frequently, Melan-A, but melanomas are far more likely to express S100 and SOX10. In situ melanoma may also be present. Sequencing can be performed to distinguish the two entities, if required. Rhabdoid sarcoma. This BRG-1–deficient sarcoma of the young contains epithelioid cells (frequently with a rhabdoid appearance), so it can mimic malignant PEComa, but the immunophenotypes differ. Clear cell carcinoma, Müllerian type. The TFE3-­ translocated tumors may resemble gynecologic clear cell carcinoma, but only to a limited degree. Unlike clear cell carcinoma, most cases of PEComa are found intramurally. Clear cell carcinomas are PAX8 positive, unlike PEComa, and lack a TFE3 translocation. Renal cell carcinoma. The TFE3-translocated PEComas may be indistinguishable from translocation-associated renal cell carcinomas with a TFE3 translocation. The renal cell carcinomas are PAX8 positive, whereas PEComas are negative.

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TFE3-translocated variant because this abnormality does not activate the mTOR pathway.

11.11.9  Cases 1. This 42-year-old woman with seizures (diagnosed with tuberous sclerosis in childhood) presented with vaginal bleeding (Figs. 11.51, 11.52, 11.53, 11.54, and 11.55). 2. A 50-year-old woman with pelvic pressure and a 4-cm uterine mass (Figs. 11.56, 11.57, and 11.58). 3. A 48-year-old woman with a 5-cm uterine mass (Figs. 11.59 and 11.60).

Fig. 11.51  Perivascular epithelioid cell tumor (PEComa). This focus of epithelioid cells invoked a differential diagnosis that included carcinoma and a mesenchymal tumor. EMA and AE1/3 cytokeratin were negative, suggesting that this is a mesenchymal tumor

11.11.8  Prognosis Most well-characterized PEComas are benign, according to the criteria presented above. Malignant tumors may behave aggressively, as evidenced in one study where patients with malignant PEComas had either died of disease or were alive with disease at the end of follow-up. The rare cases that are considered tumors of uncertain malignant potential (usually PEComas demonstrating only one feature of malignancy) are poorly understood. mTOR (mammalian target of rapamycin) pathway inhibitors have been used with varying success in recurrent, metastatic, or persistent malignant PEComas. This intervention is predicted to be unsuccessful in the

Fig. 11.52  Perivascular epithelioid cell tumor (PEComa) . Most of the patient’s tumor had this appearance. Tumor cells are vaguely nested and are large, with relatively abundant cytoplasm that is clear to light pink

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Fig. 11.53  Perivascular epithelioid cell tumor (PEComa), cytologic detail

Fig. 11.56  Sclerosing PEComa. Note collagenous bands that entrap epithelioid tumor cells

Fig. 11.54 HMB45-positive perivascular epithelioid cell tumor (PEComa) . Rare cells were also positive for Melan-A

Fig. 11.57  PEComa with features suggesting malignancy. Significant nuclear atypia is shown here. The tumor also had 3 mitotic figures per 50 high power fields and an infiltrative border

Fig. 11.55  Perivascular epithelioid cell tumor (PEComa) positive for cathepsin K

Fig. 11.58  PEComa with features suggesting malignancy

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11.12.3  General Features IMTs more commonly arise in the uterine corpus than in the cervix; only rare cervical cases have been reported. Affected patients range in age from 10 to 60 years.

11.12.4  Etiology

Fig. 11.59  TFE3-translocated PEComa. The tumor is composed of nests of epithelioid cells, separated by delicate vasculature, with clear cytoplasm. Such tumors frequently resemble TFE3-translocated renal cell carcinoma

In most cases, ALK rearrangements display the translocation t(2;5)(p23;q35), involving ALK and NPM; t(2;17)(p23;q23), involving ALK and CLTC; or t(2;19)(p23;p13.1), involving ALK and TPM4. Rare translocations involving the following genes also have been reported: ROS1, PDGFRB, RET, and NTRK1. It is uncertain whether cases with PDGFRB, RET, or NTRK1 translocations are, in reality, IMTs.

11.12.5  Macroscopy There is a wide range in reported tumor size, with a median of 5–6 cm. Most tumors are: tan, pink, or white. They may have a soft consistency, a whorled appearance, mucinous or myxoid features with pseudocyst formation, and (uncommonly) hemorrhage and necrosis.

11.12.6  Microscopy

Fig. 11.60  TFE3-translocated PEComa. Diffuse expression of TFE3 in tumor cell nuclei

11.12 Inflammatory Myofibroblastic Tumor 11.12.1  Definition A myofibroblastic neoplasm, usually with a chromosomal rearrangement involving ALK.

11.12.2  Synonym Inflammatory pseudotumor and IMT.

Most tumors have paucicellular, myxoid areas with or without pseudocysts and pools of myxoid material, as well as more cellular areas. The more cellular areas usually resemble fascicles of smooth muscle. A storiform pattern and a resemblance to nodular fasciitis (tissue culture-like appearance) can be encountered in both paucicellular and hypercellular areas. A lymphoplasmacytic infiltrate, which is typical, can be found in both the cellular and paucicellular areas. Nuclear atypia can be mild, moderate, or severe. Tumors frequently express SMA, desmin, and CD10; most express ALK1 with granular cytoplasmic labeling, with or without cytoplasmic or nuclear membrane accentuation. Aside from the very rare (ROS1) or diagnostically questionable cases reported to have PDGFRB, RET, or NTRK1 translocations, the characteristic ALK translocation should be found using FISH or RNA sequencing. Note that rare ALK-translocated cases may be negative with one or more testing modalities, so at least two modalities should be employed.

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Diagnostic Highlights

• Resembles leiomyoma, smooth muscle tumor of uncertain malignant potential with myxoid stroma, and myxoid leiomyosarcoma with lymphoid infiltrates. • Diagnosis should be confirmed with ALK immunohistochemistry +/− FISH or RNA sequencing for ALK translocations.

11.12.7  Differential Diagnosis

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tasize), IMTs generally should be regarded as tumors of low or uncertain malignant potential. Large size (more than 8  cm), presence of lymphovascular invasion, high mitotic count, and advanced patient age have been reported to be associated with an aggressive clinical course, but the number of cases studied is small. Therapies targeting ALK can be used in recurrent/metastatic cases.

11.12.9  Case A 47-year-old woman with vaginal bleeding who presented with a 3-cm uterine mass (Figs. 11.61, 11.62, and 11.63).

• Leiomyoma/leiomyosarcoma, including tumors with a myxoid matrix. Spindled cells with a smooth muscle appearance lead to morphologic overlap. One paper has described the tendency of IMTs to resemble smooth muscle tumors of low malignant potential. Histologic characteristics more commonly seen in IMT include a fasciitis-like appearance and notable lymphoplasmacytic infiltrates. Although ALK positivity has occasionally been reported in leiomyosarcomas, ALK positivity in the absence of abnormal p53 and p16 expression is more characteristic of IMT than of leiomyosarcoma. • Nodular fasciitis. IMT may contain areas resembling nodular fasciitis, so extensive sampling should be undertaken to recognize areas that are more common to IMT. Nodular fasciitis may harbor a translocation involving USP6 and usually measure less than 3 cm. Cervix is Fig. 11.61  Inflammatory myofibroblastic tumor (IMT). A dense lyman extremely rare disease site. phoplasmacytic infiltrate is found at the periphery of this bland-­ • Postoperative spindle cell nodule. The appearance of this appearing myofibroblastic tumor lesion and IMT may be identical, and many examples of this lesion have been reported to express ALK.  ALK-­ positive examples should probably be considered IMT. • Endometrial stromal sarcoma. Two types of endometrial stromal sarcoma could resemble IMT: low-grade endometrial stromal sarcoma with fibromyxoid features, and high-grade endometrial stromal sarcoma with BCOR abnormality. Although both of these express CD10, like IMT, they are desmin-negative and harbor translocations other than ALK.

11.12.8  Prognosis Of IMTs, 20–30% behave in a malignant fashion. Because it can be difficult or impossible to distinguish between benign and malignant examples (tumors destined to recur or metas-

Fig. 11.62  Inflammatory myofibroblastic tumor with myxoid stroma

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nuclei with large, conspicuous nucleoli. Nuclear pleomorphism and multinucleation can be encountered. Cells overexpress nuclear TFE3 and are negative for markers of smooth muscle and melanocytic differentiation.

Diagnostic Highlights

• Alveolar or solid aggregate cells with abundant pink cytoplasm containing crystals with PAS-­ diastase staining. • TFE3 overexpression without expression of myoid or melanocytic markers. The presence of a TFE3 translocation should be verified by FISH or RNA sequencing. Fig. 11.63  Inflammatory myofibroblastic tumor with diffuse expression of ALK

11.13.6  Differential Diagnosis

11.13 Alveolar Soft Part Sarcoma 11.13.1  Definition A sarcoma with packeted epithelioid cells that harbor a TFE3 translocation, without myoid or melanocytic differentiation.

11.13.2  General Features Only about one dozen cases have been reported. Patients with uterine tumors tend to be premenopausal, with a mean age of 30 years.

11.13.3  Etiology ASPSCR1-TFE3 fusion (deriving from an unbalanced translocation).

11.13.4  Macroscopy Tumors centered in the cervix have a mean size of 2–3 cm. They may be found beneath the epithelial surface, circumscribed and yellow in color.

11.13.5  Microscopy Most cases display a packeted/pseudoalveolar/nested or solid architecture. Constituent cells have abundant eosinophilic or, uncommonly, clear cytoplasm, containing crystals or coarse granules visible with PAS-diastase histochemistry. Tumor cells are polygonal, usually with cytoplasmic membrane accentuation, with central or eccentric round to oval

• PEComa. Alveolar soft part sarcoma may look identical to PEComa and shares a TFE3 fusion and immunohistochemical overexpression of TFE3 with TFE3 PEComas. PEComas express melanocytic-associated markers, unlike alveolar soft part sarcoma. • Epithelioid smooth muscle tumor. Epithelioid smooth muscle tumors may resemble alveolar soft part sarcoma, although architectural and cytoplasmic characteristics may differ. Unlike alveolar soft part sarcoma, epithelioid smooth muscle tumors are negative for TFE3 and lack the associated characteristic translocation. • Melanoma. Because melanoma may contain polygonal cells with eosinophilic cytoplasm and prominent nucleoli, its appearance can overlap that of alveolar soft part sarcoma. Unlike melanoma, alveolar soft part sarcomas lack melanocytic differentiation and contain the ASPSCR1-­ TFE3 fusion leading to TFE3 overexpression. • Rhabdomyosarcoma. There is only a passing resemblance to embryonal rhabdomyosarcoma, owing to abundant eosinophilic cytoplasm (found in maturing rhabdomyoblasts) and cytoplasmic inclusions (cross-striations in rhabdomyosarcoma; crystals and coarse granules in alveolar soft part sarcoma). Alveolar rhabdomyosarcoma and alveolar soft part sarcoma may closely resemble the other, but alveolar rhabdomyosarcoma almost never occurs in the cervix and is desmin-positive, like other rhabdomyosarcomas. Desmin and myogenin/myoD1 are negative in alveolar soft part sarcoma, and the characteristic alveolar soft part sarcoma translocations are lacking in rhabdomyosarcoma. • Rhabdoid sarcoma. This only vaguely resembles alveolar soft part sarcoma, although both occur in young individuals and feature polygonal cells that can have abundant eosinophilic cytoplasm. Rhabdoid sarcoma is characterized by a SMARCA4 mutation (somatic or germline) and lacks TFE3 overexpression and translocation.

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11.13.7  Prognosis Few data are available about clinical outcomes specifically for cervical tumors. Although the more typical alveolar soft part sarcomas that occur in the limbs and the head and neck are reported to be very aggressive tumors, with both early and late metastases (particularly to lung and brain), the rare cases of uterine alveolar soft part sarcoma appear to be significantly less aggressive, although follow-up intervals for reported cases are short.

11.13.8  Case A 39-year old woman who was incidentally found to have a 3-cm mass centered in the cervix (Figs.  11.64, 11.65, and 11.66).

Fig. 11.64  Alveolar soft part sarcoma. This tumor is composed of organoid, solid/alveolar nests of pink cells with abundant cytoplasm containing crystals (visible with PAS-diastase, not shown). Desmin, smooth muscle actin, HMB45, S100, and Melan-A were negative. FISH demonstrated a translocation involving TFE3

Fig. 11.65  Alveolar soft part sarcoma. In this area, tumor cells are arranged in small nests

Fig. 11.66  Alveolar soft part sarcoma, cytologic detail. Rare pleomorphic nuclei and multinucleation are present in a background of nuclear uniformity

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11.14 Primitive Neuroectodermal Tumors (Peripheral and Central Types) 11.14.1  Definition Peripheral primitive neuroectodermal tumor (PPNET) is Ewing sarcoma with its characteristic chromosomal translocations—t(11;22)(q24;q12) with an EWSR1-FLI1 fusion gene; t(2;22)(q33;q12) with an EWSR1-FEV fusion gene; t(7;22)(p22;q12) with an EWSR1-ETV1 fusion gene; t(17;22) (q12;q12) with an EWSR1-E1AF fusion gene; and t(21;22) (q22;q12) with a EWSR1-ERG fusion gene. Central-type primitive neuroectodermal tumors (CPNETs) encompass immature neuroectodermal tumors typical of histologically similar central nervous system tumors, lacking Ewing sarcoma-like chromosomal translocations.

11.14.2  Synonyms Ewing sarcoma (PPNET); Medulloblastoma/ependymoblastoma/neuroblastoma/glioblastoma (CPNET).

11.14.3  General Features These are very rare tumors and most reported cases do not distinguish between PPNET and CPNET. This limits our ability to characterize each tumor type separately, although the distinction between them is thought to be very important. Considering both PPNET and CPNET together, the median age at diagnosis is approximately 40 years, unlike PPNET/Ewing sarcoma of bone and soft tissues and central nervous system neuroectodermal tumors. Reported clinical presentations are vaginal bleeding and presence of a cervical mass. Some patients have localized disease, with or without parametrial extension, whereas others have presented with metastasis.

11.14.4  Etiology EWSR1 translocations are typical of Ewing sarcoma (PPNET). Some CPNETs in endometrium and ovary are associated with adenocarcinomas, suggesting transdifferentiation of the glandular neoplasm. Ovarian CPNETs also may arise from a high-grade immature teratoma.

11.14.5  Macroscopy The median size of reported PPNETs and CPNETs is approximately 5 cm. The tumor may be indistinct or obviously massforming, sometimes with hemorrhage and necrosis.

R. A. Soslow and M. Hameed

11.14.6  Microscopy PPNET: PPNET demonstrates all of the characteristics of Ewing sarcoma, including the typical appearance of monotonous, small, round cells; diffuse CD99; variable synaptophysin expression in most cases; and chromosomal translocations associated with Ewing sarcoma. CPNET: The morphology of this tumor type is highly variable because CPNETs comprise stroma-poor tumors (ependymoblastoma, medulloblastoma, and stroma-poor neuroblastoma), stroma-rich tumors (neuroblastoma and glioblastoma), and neuron-rich tumors (neuroblastoma). It is usual to find mixtures of the above elements, but it is not important or even feasible in many cases to distinguish between ependymoblastoma-like and medulloblastoma-like CPNETs, especially because of morphological overlap between these tumor subtypes. CPNETs, in general, should show glial fibrillary acidic protein (GFAP) and/or neurofilament expression. Neuronal tumors, particularly, are synaptophysin-­positive and express other markers indicating neuronal differentiation. Diffuse CD99 expression can be found in both PPNET and CPNET, limiting this marker’s usefulness for distinguishing between PPNET and CPNET. Chromosomal translocations associated with Ewing sarcoma are not found in CPNET.

11.14.7  Differential Diagnosis • Adenocarcinoma. The rosettes of CPNET can be mistaken for glands. Intracellular mucin and cytokeratin and epithelial membrane antigen (EMA) expression are much more characteristic of adenocarcinoma than of CPNET. Adenocarcinomas may express synaptophysin and chromogranin, but they very rarely have the appearance of a primitive tumor. Chromogranin and synaptophysin expression in an obviously gland-forming carcinoma probably has no significance. • Carcinosarcoma. The presence of epithelioid cells (usually neuronal) or epithelial-like structures (ribbons of primitive cells or rosettes and pseudo-rosettes) along with a small blue-cell component might lead to difficulties distinguishing between carcinosarcoma and PNET. Carcinosarcomas should demonstrate unequivocal and usually distinctive components of high-grade carcinoma and pleomorphic sarcoma, which are not seen in PNET. Because both carcinosarcomas and PNETs can contain rhabdomyoblasts, their presence does not inform the diagnosis. Rarely, morphologically typical carcinosarcomas (usually in endometrium) contain a PNET constituent, in which case the diagnosis is not pure PNET.

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Diagnostic Highlights

• PPNET is the gynecological equivalent of Ewing sarcoma and displays the same morphology and genotype. • CPNET resembles medulloblastoma, ependymoblastoma, neuroblastoma, and/or glioblastoma.

• High-grade neuroendocrine carcinoma, including small cell and large cell neuroendocrine carcinomas. This can be a challenging differential diagnosis, but it should be invoked only when the morphology of the primitive small round cells is very similar to that of small cell carcinoma or when large epithelioid cells are arranged in an organoid fashion, similar to large cell neuroendocrine carcinoma. Almost all of these tumors are synaptophysin-positive, limiting the role of this marker in this differential diagnosis. Convincing cytokeratin and/or TTF1 expression with loss of RB1 (found in most small cell carcinomas and some large cell neuroendocrine carcinomas) favors neuroendocrine carcinoma; GFAP and neurofilament expression, with or without neuron-specific markers, is more commonly observed in CPNETs. The presence of high-­risk HPV favors cervical high-grade neuroendocrine carcinoma, but this would not distinguish between PNET and high-grade neuroendocrine carcinomas secondarily involving the cervix. Not detecting high-risk HPV provides no diagnostic information. • Sarcoma, including rhabdomyosarcoma. The confusing and unfamiliar appearance of CPNET and the primitive small blue cells found in either CPNET or PPNET could lead to difficulties diagnosing PNET and sarcoma. The occasional presence of rhabdomyoblasts in CPNETs adds to these difficulties. The presence of a confirmed component of PNET, following the guidelines discussed above, invalidates a diagnosis of pure sarcoma. • Melanoma. The presence of atypical intraepithelial melanocytes and/or melanin and/or expression of S100 and SOX10 are characteristic of melanoma.

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11.14.9  Cases 1. A 57-year-old woman with a large uterine mass (Figs. 11.67 and 11.68). 2. A 59-year-old woman with a uterine carcinosarcoma (Figs. 11.69, 11.70, and 11.71).

Fig. 11.67  Peripheral primitive neuroectodermal tumor. This cytologically uniform and monotonous neoplasm was negative for desmin, cytokeratin, and leukocyte common antigen; it was diffusely CD99-­ positive. An EWS translocation was identified by FISH. Its fusion partner was FLI-1, supporting the diagnosis

11.14.8  Prognosis There are no studies including long-term follow-up of patients treated uniformly, so generalizations about prognosis are not appropriate. PPNETs, anecdotally, may be treated with the same regimen as Ewing sarcoma of bone and soft tissue. Neoadjuvant chemotherapy may have a role in treatment.

Fig. 11.68  Peripheral primitive neuroectodermal tumor, cytologic detail

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Fig. 11.69  Central-type primitive neuroectodermal tumor (CPNET) associated with a uterine carcinosarcoma. This example shows spindly, primitive-appearing tumor cells arranged in trabeculae. Rosettes are also present. Although this tumor was positive for CD99, which is nonspecific, it did not harbor an EWS translocation, arguing against PPNET. The tumor was positive for synaptophysin, GFAP, and neurofilament. Epithelial and sarcomatous components are not shown

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Fig. 11.71  Central-type primitive neuroectodermal tumor (CPNET). In this focus, the tumor demonstrated features of malignant glial and neuronal differentiation

11.15 Angiosarcoma 11.15.1  Definition Malignant vasoformative/endothelial tumor.

11.15.2  Synonyms None.

11.15.3  General Features

Fig. 11.70  Central-type primitive neuroectodermal tumor (CPNET), cytologic detail. Two rosettes are found at the center.

Angiosarcomas arise rarely in the uterine corpus, and they are extraordinarily rare in the cervix, with possibly only two reported cases. One well-described case involved a 43-year-­ old woman with a 5-cm endocervical tumor that filled the endocervical canal and endometrial cavity, and deeply invaded into the cervical wall.

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11.15.4  Etiology

11.15.8  Prognosis

In general, most cases are idiopathic. Some are attributable to ionizing radiation, vinyl chloride exposure, or chronic lymphedema. Factors that specifically predispose to cervical angiosarcoma are unknown.

Angiosarcoma is a very aggressive tumor type, with a high frequency of metastasis and death from disease.

11.15.5  Macroscopy

A 71-year-old woman was treated with ionizing radiation for rectal adenocarcinoma 8 years previously. A patch of bluish discoloration was found in her vagina, extending to the cervix (Figs. 11.72, 11.73, and 11.74).

These are usually described as hemorrhagic, spongy masses.

11.15.9  Case

11.15.6  Microscopy Most cases display obvious vasoformation with a range of nuclear atypia, but some tumors have predominantly solid architecture. In such cases, vasoformative elements are usually present at the periphery of the tumor. The vasoformative elements may contain irregular, ectatic vessels; large, cavernous or slit-like vascular spaces; and invasion through collagen bundles. The neoplastic endothelial cells may be flat, spindled, or epithelioid. The presence of red blood cells within poorly formed vessels is a diagnostic clue.

11.15.7  Differential Diagnosis • Sarcoma other than angiosarcoma. Densely cellular angiosarcomas with only subtle vessel formation can closely resemble spindle cell or undifferentiated sarcoma. Because undifferentiated sarcoma is a diagnosis of exclusion, it is advised to search the tumor’s periphery for vasoformation. Unlike other sarcomas, angiosarcoma coexpresses endothelial markers (CD31, ERG). • Carcinoma. This differential diagnosis involves tumors with epithelioid tumor cells. Finding neoplastic vascular formations is sufficient to distinguish between these tumor types. Caution is advised regarding the use of immunohistochemical markers associated with epithelial differentiation, as these are typically positive in both carcinoma and epithelioid angiosarcoma. Therefore, more weight should be placed on markers of endothelial differentiation. • Melanoma. Melanoma remains in the differential diagnosis because both tumors may contain epithelioid tumor cells. The presence of atypical intraepithelial melanocytes and/or melanin, and/or the expression of S100 and SOX10, are characteristic of melanoma. • Sarcomatous component of carcinosarcoma. Rare carcinosarcomas of the uterine corpus contain foci of angiosarcoma. In such cases, the presence of malignant epithelium confirms a diagnosis of carcinosarcoma.

Fig. 11.72  Angiosarcoma. The center of the tumor had solid architecture, with spindly cells and overt nuclear atypia. Vasoformative elements are present

Fig. 11.73  Angiosarcoma. Ectatic, neoplastic vessels

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R. A. Soslow and M. Hameed

11.16.6  Microscopy Uterine liposarcomas can have a differentiated appearance with abundant adipocytes (some of them lipoblasts), a myxoid appearance with lipoblasts, or a pleomorphic appearance. The limited work performed to understand the molecular biology of these tumors has generally failed to disclose molecular features specific to liposarcomas of the soft tissues. That being said, there is one report of a pleomorphic liposarcoma harboring nonspecific mutations that are common to both leiomyosarcoma and pleomorphic liposarcoma.

11.16.7  Differential Diagnosis Fig. 11.74  Angiosarcoma. Slit-like vessels with atypical endothelial cells are present at the periphery of this tumor.

• Lipoleiomyoma. Unlike liposarcoma, this tumor has the appearance of leiomyoma, with focal-to-extensive deposition of mature adipose tissue without lipoblasts.

11.16 Liposarcoma

11.16.8  Prognosis

11.16.1  Definition

Some deaths due to disease have been reported.

Sarcoma showing adipose differentiation, or a sarcoma that arises in the setting of a liposarcoma (i.e. de-differentiated liposarcoma).

11.16.9  Case

11.16.2  Synonyms

A 58-year-old woman with a 10-cm uterine mass that was both polypoid and infiltrative (Figs. 11.75, 11.76, and 11.77).

None.

11.16.3  General Features Only several cases of uterine liposarcoma have been reported in the literature. The average patient age is 54 years.

11.16.4  Etiology Some liposarcomas arise in association with lipoleiomyoma or lipoleiomyosarcoma.

11.16.5  Macroscopy They may be large tumors, up to 18.5 cm in size and have been reported to have well-circumscribed and pushing margins, with a gelatinous cut surface. Some are polypoid.

Fig. 11.75 Liposarcoma containing prominent lipoblasts, from a 58-year-old woman with a 10-cm uterine mass that was both polypoid and infiltrative

11  Mesenchymal and Mixed Epithelial–Stromal Malignant Tumors of the Cervix

281

Folpe AL.  MyoD1 and myogenin expression in human neoplasia: a review and update. Adv Anat Pathol. 2002;9:198–203. Li RF, Gupta M, McCluggage WG, Ronnett BM. Embryonal rhabdomyosarcoma (botryoid type) of the uterine corpus and cervix in adult women: report of a case series and review of the literature. Am J Surg Pathol. 2013;37:344–55. Minard-Colin V, Walterhouse D, Bisogno G, Martelli H, Anderson J, Rodeberg DA, et  al. International Society of Pediatric Oncology Sarcoma Committee, the Children’s Oncology Group, the Italian Cooperative Soft Tissue Sarcoma Group, and the European pediatric Soft tissue sarcoma Study Group. Localized vaginal/uterine rhabdomyosarcoma--results of a pooled analysis from four international cooperative groups. Pediatr Blood Cancer. 2018;65:e27096. Rudzinski ER, Anderson JR, Hawkins DS, Skapek SX, Parham DM, Teot LA. The World Health Organization classification of skeletal muscle tumors in pediatric rhabdomyosarcoma: a report from the Children’s oncology group. Arch Pathol Lab Med. 2015;139:1281–7.

Müllerian Adenosarcoma Fig. 11.76  Liposarcoma in association with leiomyosarcoma (see lower right). This tumor has been referred to as “lipoleiomyosarcoma”

Clement PB, Scully RE. Müllerian adenosarcomas of the uterus: a clinicopathologic analysis of 100 cases with a review of the literature. Hum Pathol. 1990;21:363–81. Gallardo A, Prat J.  Müllerian adenosarcoma: a clinicopathologic and immunohistochemical study of 55 cases challenging the existence of adenofibroma. Am J Surg Pathol. 2009;33:278–88. Jones MW, Lefkowitz M. Adenosarcoma of the uterine cervix: a clinicopathological study of 12 cases. Int J Gynecol Pathol. 1995;14:223–9. McCluggage WG. Müllerian adenosarcoma of the female genital tract. Adv Anat Pathol. 2010;17:122–9. Zaloudek CJ, Norris HJ. Adenofibroma and adenosarcoma of the uterus: a clinicopathologic study of 35 cases. Cancer. 1981;48:354–66.

Mesonephric Carcinosarcoma Bagué S, Rodríguez IM, Prat J. Malignant mesonephric tumors of the female genital tract: a clinicopathologic study of 9 cases. Am J Surg Pathol. 2004;28:601–7. Roma AA. Mesonephric carcinosarcoma involving uterine cervix and vagina: Report of 2 cases with immunohistochemical positivity For PAX2, PAX8, and GATA-3. Int J Gynecol Pathol. 2014;33:624–9. Fig. 11.77  Liposarcoma admixed with rhabdomyosarcoma.

Leiomyosarcoma

Suggested Reading Embryonal Rhabdomyosarcoma Cessna MH, Zhou H, Perkins SL, Tripp SR, Layfield L, Daines C, Coffin CM. Are myogenin and myoD1 expression specific for rhabdomyosarcoma? A study of 150 cases, with emphasis on spindle cell mimics. Am J Surg Pathol. 2001;25:1150–7. Daya DA, Scully RE.  Sarcoma botryoides of the uterine cervix in young women: a clinicopathological study of 13 cases. Gynecol Oncol. 1988;29:290–304. Dehner LP, Jarzembowski JA, Hill DA.  Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol. 2012;25:602–14. https://doi.org/10.1038/modpathol.2011.185. Ferguson SE, Gerald W, Barakat RR, Chi DS, Soslow RA.  Clinicopathologic features of rhabdomyosarcoma of gynecologic origin in adults. Am J Surg Pathol. 2007;31:382–9.

Fadare O.  Uncommon sarcomas of the uterine cervix: a review of selected entities. Diagn Pathol. 2006;1:30. Oliva E, Wilbur DC, Sebire NJ, Soslow RA.  Leiomyosarcoma. In: Tumors of the uterine corpus and trophoblastic diseases, AFIP atlas of tumor pathology, series 4. Arlington, VA: ARP Press; 2020a. p. 324–33.

Endometrial Stromal Tumors Cotzia P, Benayed R, Mullaney K, Oliva E, Felix A, Ferreira J, et al. Undifferentiated uterine sarcomas represent under-recognized high-grade endometrial stromal sarcomas. Am J Surg Pathol. 2019;43:662–9. Oliva E, Wilbur DC, Sebire NJ, Soslow RA.  Endometrial stromal tumors. In: Tumors of the uterine corpus and trophoblastic diseases, AFIP atlas of tumor pathology, series 4. Arlington, VA: ARP Press; 2020b. p. 229–70.

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Undifferentiated Sarcoma Binzer-Panchal A, Hardell E, Viklund B, Ghaderi M, Bosse T, Nucci MR, et  al. Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes. Clin Cancer Res. 2019;25:2155–65.

Fibroblastic Sarcoma

R. A. Soslow and M. Hameed Mills AM, Karamchandani JR, Vogel H, Longacre TA.  Endocervical fibroblastic malignant peripheral nerve sheath tumor (neurofibrosarcoma): report of a novel entity possibly related to endocervical CD34 fibrocytes. Am J Surg Pathol. 2011;35:404–12.

Liposarcoma McDonald AG, Dal Cin P, Ganguly A, Campbell S, Imai Y, Rosenberg AE, Oliva E.  Liposarcoma arising in uterine lipoleiomyoma: a report of 3 cases and review of the literature. Am J Surg Pathol. 2011;35:221–7. https://doi.org/10.1097/PAS.0b013e31820414f7. Schoolmeester JK, Stamatakos MD, Moyer AM, Park KJ, Fairbairn M, Fader AN.  Pleomorphic liposarcoma arising in a lipoleiomyosarcoma of the uterus: report of a case with genetic profiling by a next generation sequencing panel. Int J Gynecol Pathol. 2016;35:321–6.

Chiang S, Cotzia P, Hyman DM, Drilon A, Tap WD, Zhang L, et  al. NTRK fusions define a novel uterine sarcoma subtype with features of fibrosarcoma. Am J Surg Pathol. 2018;42:791–8. Chiang S, Oliva E. Recent developments in uterine mesenchymal neoplasms. Histopathology. 2013;62:124–37. Croce S, Hostein I, Longacre TA, Mills AM, Pérot G, Devouassoux-­ Shisheboran M, et  al. Uterine and vaginal sarcomas resembling fibrosarcoma: a clinicopathological and molecular analysis of 13 Recent Advances cases showing common NTRK-rearrangements and the description of a COL1A1-PDGFB fusion novel to uterine neoplasms. Mod Momeni-Boroujeni A, Chiang S. Uterine mesenchymal tumours: recent Pathol. 2019;32:1008–22. advances. Histopathology. 2020;76:64–75. Keel SB, Clement PB, Prat J, Young RH.  Malignant schwannoma of the uterine cervix: a study of three cases. Int J Gynecol Pathol. 1998;17:223–30.

Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)

12

Gulisa Turashvili

Contents 12.1 12.1.1 12.1.2 12.1.3 12.1.4 12.1.5 12.1.6 12.1.7

Melanocytic Tumors (Malignant Melanoma)   efinition  D Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Prognosis 

 284  284  285  285  285  285  287  288

12.2 12.2.1 12.2.1.1  12.2.1.2  12.2.1.3  12.2.1.4  12.2.1.5  12.2.1.6  12.2.1.7  12.2.2 12.2.2.1  12.2.2.2  12.2.2.3  12.2.2.4  12.2.2.5  12.2.2.6  12.2.3

Germ Cell Tumors   eratoma  T Definition  Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Prognosis  Yolk Sac Tumor  Definition  Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Choriocarcinoma 

 289  289  289  290  290  290  290  292  293  293  293  293  293  293  293  296  296

12.3 12.3.1 12.3.1.1  12.3.1.2  12.3.1.3  12.3.1.4  12.3.1.5  12.3.1.6  12.3.1.7  12.3.2 12.3.2.1  12.3.2.2  12.3.2.3  12.3.2.4  12.3.2.5  12.3.2.6 

Trophoblastic Tumors   horiocarcinoma  C Definition  Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Prognosis  Placental Site Trophoblastic Tumor  Definition  Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis 

 296  296  296  297  297  297  297  299  302  302  302  302  302  302  302  304

G. Turashvili (*) Department of Pathology and Laboratory Medicine, Mount Sinai Hospital and University of Toronto, Toronto, ON, Canada e-mail: [email protected] © Springer Nature Switzerland AG 2021 R. A. Soslow et al. (eds.), Atlas of Diagnostic Pathology of the Cervix, https://doi.org/10.1007/978-3-030-49954-9_12

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G. Turashvili 12.3.2.7  12.3.3 12.3.3.1  12.3.3.2  12.3.3.3  12.3.3.4  12.3.3.5  12.3.3.6  12.3.3.7 

Prognosis  Epithelioid Trophoblastic Tumor  Definition  Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Prognosis 

 306  306  306  306  306  306  306  309  309

12.4 12.4.1 12.4.2 12.4.3 12.4.4 12.4.5 12.4.6 12.4.7

Lymphoid Tumors   efinition  D Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Prognosis 

 309  309  309  309  310  310  315  317

12.5 12.5.1 12.5.2 12.5.3 12.5.4 12.5.5 12.5.6 12.5.7

Myeloid Tumors   efinition  D Synonyms  Etiology  Macroscopy  Microscopy  Differential Diagnosis  Prognosis 

 317  317  317  318  318  318  320  320

References 

12.1 Melanocytic Tumors (Malignant Melanoma) 12.1.1 Definition A malignant neoplasm composed of cells with melanocytic differentiation. The diagnosis of primary cervical malignant melanoma requires the demonstration of junctional activity in the epithelium in the absence of similar changes elsewhere in the body. The key features of malignant melanoma of the cervix are described in Table 12.1.

Table 12.1  Key features of cervical melanocytic tumors Clinical presentation     • Asymptomatic     • Abnormal cervical cytology     • Abnormal bleeding     • Cervical mass Macroscopy     • Single or multiple polypoid to fungating mass     • Pigmented mass     • Amelanotic mass     • Ulcerated mass     • Mean diameter 3 cm (range 0.3–9) Microscopy

 320

    • Diffuse, nested, trabecular and/or fascicular growth patterns     • Tumor cells with epithelioid, spindled, round, or clear cytoplasm; large, vesicular to hyperchromatic nuclei; prominent nucleoli; brisk mitoses, including atypical forms     • Rarely multinucleated giant cells     • Variable intracytoplasmic melanin pigment, from abundant to absent     • Junctional activity in 50% of cases     • Pagetoid growth     • Stromal desmoplastic reaction     • Morris and Taylor criteria for primary gynecologic melanoma [18]:         1. Melanin in benign epithelium         2. Junctional activity         3. Absence of melanoma elsewhere         4. Metastases according to the pattern of gynecologic tumor Immunohistochemistry     • Positive:         – S100 protein         – HMB-45         – Melan-A/MART-1         – MITF         – SOX10     • Negative:         – Cytokeratins         – Muscle markers (desmin, h-caldesmon, SMA) HMB-45 human melanoma black 45,  Melan-A/MART-1  melanoma antigen recognized by T cells, MITF microphthalmia transcription factor, SMA smooth muscle actin, SOX10 SRY-related HMG-box 10

12  Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)

12.1.2 Synonyms Invasive melanoma.

12.1.3 Etiology Primary cervical malignant melanoma has a melanocytic derivation. The proof of the presence of melanocytes in the cervical mucosa was first demonstrated in 3.5% of cervical biopsies in 1959 and further evidenced by diagnosing cervical melanocytic nevi [1–4]. Various hypotheses have been proposed for primary gynecologic melanomas, including its origin from Schwann cells, melanocyte migration from the neural crest, and melanocytic differentiation from the endocervical epithelium [2, 5–8]. No specific risk factors have been identified [9], but high levels of estrogen and association with human papillomavirus (HPV) infection and radiation therapy have been reported [10–12]. There are limited data on the distribution of mutations in primary cervical melanoma. However, non-vulvar gynecologic melanomas have been shown to harbor mutations in KIT and NRAS in approximately 30% of cases, while BRAF mutations are very rare.

12.1.4 Macroscopy Malignant melanoma can present as single or multiple pigmented, polypoid to fungating masses or (in approximately 45% of cases) as amelanotic masses mimicking a primary cervical neoplasm [13, 14]. Ulceration may be present [15]. The mean diameter is 3 cm (range 0.3–9). Pigmented lesions are usually dark (blue, blue-black, blue-red, black, black-­ brown) or sometimes reddish (red, violet-red, brown-red, brown) [13].

12.1.5 Microscopy Histologic features of primary cervical malignant melanoma are identical to cutaneous and mucosal melanoma. Diffuse, nested, trabecular, and/or fascicular growth patterns may be seen. Neoplastic cells exhibit epithelioid or spindled appearance, and rarely, round or clear cells. The nuclei are large, vesicular to hyperchromatic with prominent nucleoli and brisk mitotic activity, including atypical mitotic figures. Rarely multinucleated giant cells may be present. Melanin production can vary from abundant to focal or absent (Fig.  12.1). When present, melanin pigment granules are readily identified within the cytoplasm of tumor cells. In addition, approximately 50% of cases show junctional activity involving the overlying squamous epithelium. Pagetoid spread of tumor cells in the squamous epithelium may also be present. The tumor may invade the cervical mucosa with stromal desmoplastic reaction. Specific subtypes of primary cervical malignant melanoma, including a clear cell variant

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and a variant resembling a malignant peripheral nerve sheath tumor (MPNST), have been described [16, 17]. The four criteria proposed by Morris and Taylor for diagnosis of primary gynecological (vaginal) malignant melanoma include the presence of melanin in the benign epithelium, evidence of junctional activity, absence of melanoma elsewhere in the body, and the distribution of metastases that parallel the spread of squamous cell carcinoma [18]. These criteria may also be applied to cervical melanomas, but in many cases not all criteria are met; it can be difficult to establish definitively whether the melanoma is a primary or secondary lesion in the absence of cervical junctional changes. Clinical-pathologic correlation is essential in such cases. Immunohistochemically, the tumor cells are positive for S100 protein, HMB-45 (human melanoma black 45), melanA/MART-1 (melanoma antigen recognized by T cells), ­ SOX10 (SRY-related HMG-box 10)  and MITF (microphthalmia transcription factor); they are negative for cytokeratins and muscle markers. A combination of S100 (more sensitive) and HMB-45 (more specific) appears to lead to an accurate and reliable diagnosis in most cases [9, 13]. Ultrastructurally, the neoplastic cells contain intracytoplasmic pre-melanosomes and melanosomes. Cytologic features range from small, round, deceptively bland cells to pleomorphic, bizarre-shaped cells. Smear preparations usually show single cells with central or eccentric nuclei with coarse chromatin and prominent nucleoli, irregular nuclear membranes, high nuclear-cytoplasmic ratio, and finely granular or wispy cytoplasm with intracytoplasmic melanin pigment. Nuclear molding, multinucleation, and intranuclear inclusions are common. The background shows tumor diathesis [13, 19].

Diagnostic Highlights

• Diffuse, nested, trabecular and/or fascicular growth patterns • Tumor cells with epithelioid, spindled, round, or clear cytoplasm; large, vesicular to hyperchromatic nuclei; prominent nucleoli; brisk mitoses, including atypical forms • Rarely multinucleated giant cells • Variable intracytoplasmic melanin pigment, from abundant to absent • Junctional activity in 50% of cases • Pagetoid growth • Stromal desmoplastic reaction • Morris and Taylor criteria for primary gynecologic melanoma: 1. Melanin in benign epithelium 2. Junctional activity 3. Absence of melanoma elsewhere 4. Metastases according to the pattern of gynecologic tumor

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a

b

c

d

e

f

Fig. 12.1  Malignant melanoma. (a–e), Cervical biopsy with a nodular proliferation of high-grade neoplastic cells (H&E). There is epithelial ulceration (a, b). The tumor cells exhibit enlarged, irregular nuclei and prominent nucleoli (c–e). There is junctional activity in the squamous epithelium with atypical melanocytes and an atypical mitotic figure (d).

Intracytoplasmic melanin pigment is present (e). (f–h), Immunohistochemical stains show diffuse, strong staining for S100 (f) and melan-A/MART-1 (g), and focal, moderate staining for HMB-45 (h). The patient has no prior history of cutaneous or mucosal malignant melanoma

12  Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)

g

287

h

Fig. 12.1 (continued)

12.1.6 Differential Diagnosis In the absence of melanin pigment, diagnosis of primary cervical malignant melanoma may be difficult [9, 20–23]. Table  12.2 outlines the main differential diagnostic considerations: • Poorly differentiated squamous cell carcinoma shows at least focal keratin formation and/or intercellular bridges; may be associated with high-grade squamous intraepithelial lesion (HSIL); positive for high molecular weight keratin, p63, p40, and high-risk HPV subtypes; negative for melanocytic markers. • Poorly differentiated adenocarcinoma shows at least focal gland formation or intracytoplasmic mucin; may be associated with adenocarcinoma in situ  and HSIL; positive for low-molecular-weight keratin, CK7 (cytokeratin 7), and PAX8; negative for melanocytic markers. HPV-driven subtypes are also positive for high-risk HPV. • Leiomyosarcoma (epithelioid or spindle cell variants) is comprised of diffuse sheets or intersecting fascicles of epithelioid or spindle cells; positive for muscle markers

•

•

•

•

such as desmin, h-caldesmon, and SMA (smooth muscle actin); negative for melanocytic markers. Embryonal rhabdomyosarcoma shows a cellular subepithelial cambium layer with primitive  cells with variable  cytoplasmic cross-striations; positive for muscle markers; negative for melanocytic markers. MPNST shows densely cellular sweeping fascicles alternating with myxoid areas; rarely palisading, spindled to fusiform tumor cells with hyperchromatic and wavy nuclei, brisk mitoses, pale cytoplasm; necrosis, sometimes with melanin; variably positive for S100; negative for other melanocytic markers; may show loss of methylated H3K27. High-grade endometrial stromal sarcoma (YWHAE type) is comprised of high-grade round cells with nested or pseudoglandular patterns separated by thin-walled vessels; brisk mitoses; necrosis; variably positive, but usually negative for CD10, ER and PR (estrogen and progesterone receptors); negative for melanocytic markers. Metastatic malignant melanoma is characterized by absence of junctional activity; prior history of cutaneous or mucosal malignant melanoma elsewhere.

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Table 12.2  Differential diagnosis of malignant melanoma of the cervix Ancillary studies Positive S100, HMB-45, melan-A/ MART-1, SOX10, MITF

Metastatic malignant melanoma

History of melanoma elsewhere

Microscopy Melanin in benign cervical epithelium; junctional activity; diffuse, nested, trabecular, and/or fascicular growth; tumor cells with epithelioid, spindled, round, or clear cytoplasm; large, vesicular to hyperchromatic nuclei; prominent nucleoli; brisk mitoses Similar to primary melanoma, lacks junctional activity

Cervical poorly differentiated squamous cell carcinoma Cervical poorly differentiated adenocarcinoma Leiomyosarcoma, epithelioid or spindle cell

HSIL or invasive carcinoma

At least focal keratin formation and/or HMWK, p63, p40, intercellular bridges high-risk HPV

AIS, HSIL or invasive adenocarcinoma

At least focal gland formation or intracytoplasmic mucin

Primary malignant melanoma

Clinical history No melanoma elsewhere, metastases according to the pattern of gynecologic tumor

Sarcoma

Rhabdomyosarcoma, embryonal

Sarcoma

Malignant peripheral nerve sheath tumor (MPNST)

Neurofibromatosis type 1, neurofibroma, MPNST elsewhere

High-grade endometrial Uterine sarcoma stromal sarcoma (YWHAE type)

S100, HMB-45, melan-A/ MART-1, SOX10, MITF

LMWK, CK7, PAX8, high risk HPV in HPV-driven subtypes Diffuse sheets or intersecting fascicles Desmin, h-caldesmon, of epithelioid or spindle cells SMA, ±ER, PR, CD10, ±cytokeratins, EMA and HMB-45 in epithelioid subtype Cellular subepithelial cambium layer, Desmin, MSA, myogenin (specific), primitive cells, variable cytoplasmic myo-D1 (specific), cross striations myoglobin Variable S100 or SOX10 Densely cellular sweeping fascicles alternating with myxoid areas; rarely (not diffuse), cytokeratin in palisading, spindled to fusiform tumor tumors mostly with glandular differentiation cells with hyperchromatic and wavy nuclei, pale cytoplasm, brisk mitoses; geographic necrosis, ±melanin High-grade round cells with nested or BCOR, cyclin D1; variable CD10, ER, PR pseudo-glandular patterns separated by thin-walled vessels; brisk mitoses; necrosis

Negative Cytokeratins, desmin, h-caldesmon, SMA

Cytokeratins, desmin, h-caldesmon, SMA S100, HMB-45, melan-A/MART-1, SOX10, MITF S100, HMB-45, melan-A/MART-1, SOX10, MITF S100 protein, melan-A/MART-­ 1, SOX10, MITF

S100, HMB-45, melan-A/MART-1, SOX10, MITF, SMA HMB-45, melan-A/ MART-1, MITF, methylated H3K27

S100, HMB-45, melan-A/MART-1, MITF, SOX10, desmin, h-caldesmon

AIS adenocarcinoma in situ, CK7 cytokeratin 7, EMA epithelial membrane antigen, ER estrogen receptor, HMWK high molecular weight keratin, HPV human papillomavirus, HSIL high-grade squamous intraepithelial lesion, HMB-45 human melanoma black 45, LMWK low molecular weight keratin, MART-1 melanoma antigen recognized by T cells, MITF microphthalmia transcription factor, MPNST malignant peripheral nerve sheath tumor, MSA muscle specific actin, PAX8 paired box 8, PR progesterone receptor, SMA smooth muscle actin, SOX10 SRY-related HMG-box 10

12.1.7 Prognosis Primary cervical malignant melanoma is usually diagnosed at an advanced stage and has an extremely unfavorable prognosis, similar to that of melanomas of other gynecologic (vaginal, vulvar) and non-gynecologic (anal, oronasal, esophageal) mucosal sites [9]. Patients with cervical malignant melanoma tend to develop local relapse rather than distant metastases. The most common sites are vagina, vulva, and suture line [13]. The most important prognostic factors are tumor stage and tumor thickness. Additional important features include lymphovascular space invasion (LVSI), the presence of lymphocytes, and neovascularization [9]. Mutation status has not been shown to have prognostic sig-

nificance; however, patients with KIT (not uncommon) and BRAF (uncommon) mutations may be treated with targeted therapy. Survival analysis of 78 cases showed that most patients (87.5%) died within 3 years of diagnosis, and 5-year survival was only 10.7%. The mean overall survival was 22.9  months and the median was 12  months (range 0.1– 168). Furthermore, although 50% of patients were diagnosed at stage I, the 5-year survival rates were 18.8% for stage I, 11.1% for stage II, and 0% for stages III– IV. Treatment options include surgery alone and neoadjuvant, adjuvant, or palliative treatment with chemotherapy and/or radiation. Given the limited data, the optimal treatment strategy is unclear [9].

12  Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)

12.2 Germ Cell Tumors

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immature tissue (typically neuroepithelium) defines an immature teratoma. The key features of mature and immature teratomas of the cervix are described in Table 12.3.

12.2.1 Teratoma 12.2.1.1 Definition Mature cystic teratoma is a tumor composed of mature tissues derived from more than one germ layer. The presence of

Table 12.3  Key features of cervical germ cell tumors Clinical presentation

Macroscopy

Microscopy

Mature teratoma Asymptomatic Abnormal cervical cytology Abnormal bleeding Cervical mass Cystic or solid lesions with hair and sebaceous material

Immature teratoma Asymptomatic Abnormal cervical cytology Abnormal bleeding Cervical mass Variable amount of solid areas

Mature tissues of ectodermal, mesodermal, and endodermal derivation

Immature tissues, usually immature neuroepithelium Neuroepithelial tubules and rosettes lined by overlapping, hyperchromatic cells with brisk mitoses Cellular mitotically active glia Immature mesenchymal and endodermal elements (rare) Grading: a) 3-tiered: • 1 (immature elements in 3 LPF in any slide) b) 2-tiered: • Low-grade /grade 1 • High-grade/grade 2–3 Positive: GFAP, NSE, S100, SOX2, and glypican-3 in mature and immature neuroepithelium SALL4 in immature neuroepithelium, immature mesenchymal elements, mature and primitive enteric tissue OCT4 and PAX6 in immature neuroepithelium CD56 in mature neuroepithelium AFP in immature gastrointestinal-type glands or with hepatoid differentiation

Immunohistochemistry Not required

Yolk sac tumor Asymptomatic Abnormal cervical cytology Abnormal bleeding Cervical mass Polypoid mass Ulceration Friable, gray-white cut surface Hemorrhage and/or necrosis Mean size 5 cm (range 1–10) Multiple growth patterns including microcystic (most common), macrocystic, reticular, solid, papillary, polyvesicular vitelline Loose, myxoid to edematous stroma Schiller-Duval bodies in 50% Glandular or hepatoid differentiation (rare) Tumor cells with light eosinophilic to clear cytoplasm and primitive nuclei, often with prominent amphophilic nucleoli and brisk mitoses Intracytoplasmic hyaline bodies

Positive: SALL4 Glypican-3 AFP GATA3 LIN28 Variable CK7, EMA (usually focal), pan-­ cytokeratin, HNF1β, PAX8, CDX2, and TTF-1 Hep-Par1, albumin and CEA in hepatoid variant

AFP α-fetoprotein, CK7 cytokeratin 7, CDX2 caudal type homeobox 2, CEA carcinoembryonic antigen, EMA epithelial membrane antigen, GATA3 GATA binding protein 3, GFAP glial fibrillary acidic protein, Hep-Par1 hepatocyte paraffin 1, HNF1β hepatocyte nuclear 1β, LPF low power field, NSE neuron specific enolase, OCT4 octamer-binding transcription factor 4, PAX6 paired box 6, PAX8 paired box 8, SALL4 Sal-like protein 4, TTF-­ 1 thyroid transcription factor 1

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12.2.1.2 Synonyms Dermoid cyst. 12.2.1.3 Etiology Four possible origins of uterine and cervical mature cystic teratomas include displaced germinal cells, pluripotential stem cells, metaplasia, and residual fetal tissue [24]. 12.2.1.4 Macroscopy Cystic or solid lesions containing sebaceous material and hair. 12.2.1.5 Microscopy Mature cystic teratomas are composed of histologic structures of ectodermal, mesodermal, and endodermal derivation, most commonly skin and underlying cutaneous adnexal structures, as well as smooth and skeletal muscle and gastrointestinal or respiratory epithelium. Immature teratomas exhibit variable amounts of immature tissues, typically neuroepithelial tubules and rosettes lined by overlapping, hyperchromatic cells with numerous mitotic figures and apoptotic bodies (Fig.  12.2). Cellular, mitotically active glia and immature cartilage, adipose tissue, bone, and skeletal muscle may be present. Immature endodermal structures (hepatic, renal, gastrointestinal) are

Diagnostic Highlights

Mature cystic teratoma • Mature tissues of ectodermal, mesodermal, and endodermal derivation Immature teratoma • Immature tissues, most obviously, immature neuroepithelium • Neuroepithelial tubules and rosettes lined by overlapping, hyperchromatic cells with brisk mitoses • Cellular glia that can be mitotically active • Immature mesenchymal and endodermal elements (rare) • 3-tiered grading: –– 1 (immature elements in 3 LPF in any slide) • 2-tiered grading: –– Low-grade / grade 1 –– High-grade / grade 2–3

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less common. Based on the amount of immature neuroepithelial component, immature teratomas can be graded as grade 1 (immature elements in 3 low-­ power fields in any slide) [25], but a 2-tiered system is more commonly used (low-grade [grade 1] and high-grade [grades 2–3]) [26]. Immunohistochemically, GFAP (glial fibrillary acidic protein), NSE (neurospecific enolase), S100, SOX2, and glypican-3 are positive in both mature and immature neuroepithelium. SALL4 (Sal-like protein 4) is positive in immature neuroepithelium and mesenchymal elements, as well as mature and primitive enteric tissue. OCT4 (octamer-binding transcription factor 4) and PAX6 are positive in immature neuroepithelium, and CD56 is often positive in mature neuroepithelium. AFP (α-fetoprotein) may be positive in immature gastrointestinal-type glands. Cytologic features in mature teratoma include fragments of benign epithelial cells (squamous, respiratory, gastrointestinal), sometimes with fragments of mesenchymal tissue (nerve, cartilage, adipose tissue) in a background of cystic contents. Immature teratoma shows malignant primitive-­ appearing cells.

12  Other Tumors of the Cervix (Melanocytic, Germ Cell, Trophoblastic, Lymphoid, and Myeloid Tumors)

a

b

c

d

e

f

Fig. 12.2  Immature teratoma. (a–f), Total hysterectomy specimen with a low-grade immature teratoma (H&E). The tumor is composed predominantly of mature tissue elements such as skin and cutaneous appendages (a, b), cartilage, and small foci of immature neuroepithelium (b–f). The immature neuroepithelium is composed of tubules,

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rosettes and poorly defined clusters of overlapping, atypical, hyperchromatic cells with numerous mitotic figures and apoptotic bodies (c–f). The immature elements are seen in 95% [37–39]. Serum AFP levels are useful for monitoring therapy and for followup. Recurrence typically occurs within 2 years of treatment and carries a poor prognosis [38].

12.2.3 Choriocarcinoma Pure non-gestational choriocarcinoma is considered a primary germ cell neoplasm. Primary cervical non-gestational choriocarcinoma is extremely rare [40, 41] and displays morphologic and immunohistochemical features similar to those of gestational choriocarcinoma, as discussed in Sect. 12.3 below.

12.3 Trophoblastic Tumors 12.3.1 Choriocarcinoma 12.3.1.1 Definition Choriocarcinoma can be divided into gestational and non-­ gestational subtypes. Gestational choriocarcinoma is a malignant trophoblastic tumor consisting of a trimorphic proliferation of intermediate trophoblastic cells, syncytiotrophoblast and cytotrophoblast, in the absence of chorionic villi. Pure non-gestational choriocarcinoma is a germ cell neoplasm. In addition, choriocarcinomatous differentiation may occur in a variety of poorly differentiated somatic neoplasms of gynecologic or non-gynecologic origin [42, 43]. Thus, a malignant tumor with trophoblastic differentiation involving the uterine cervix may be a gestational or non-­gestational choriocarcinoma and may represent a primary tumor or a metastasis from other organs. The key features of gestational choriocarcinoma are described in Table 12.5.

Table 12.5  Key features of cervical trophoblastic tumors Clinical presentation

Macroscopy

Cell of origin

Placental site trophoblastic tumor Mean age 30–32 years (range 20–63) Vaginal bleeding or amenorrhea 2 weeks to 17 years from last pregnancy May follow normal pregnancy (most) or spontaneous abortion (16%)

Expansile endophytic or exophytic mass Infiltrative, poorly circumscribed solid mass Size 1–10 cm Solid and fleshy, white-tan to light yellow cut surface with focal hemorrhage and necrosis Mass may extend to serosa, broad ligament, or adnexa Much more common in uterine corpus Implantation site intermediate trophoblast

Epithelioid trophoblastic tumor Mean age 36 years (range 15–48) Vaginal bleeding or amenorrhea 1–25 years from last pregnancy May follow normal term pregnancy (67%), molar pregnancy (16%), or spontaneous abortion (16%) Possible precursor: Atypical placental site nodule

Choriocarcinoma Mean age 29–31 years (range 15–48) Vaginal bleeding A few months to 14 years from last pregnancy May follow molar pregnancy (50%), spontaneous abortion (25%), or normal term pregnancy (25%) Single or multiple bulky and Expansile endophytic or exophytic mass destructive, dark red masses with pushing borders Infiltrative or circumscribed Size 0.5–5 cm Hemorrhage and necrosis Solid or cystic Destructive growth in Hemorrhage and necrosis More common in uterine cervix and lower surrounding tissues More common in uterine uterine segment corpus

Chorionic-type intermediate trophoblast

Villous intermediate trophoblast, syncytiotrophoblast, and cytotrophoblast

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Table 12.5 (continued) Placental site trophoblastic tumor Central sheets and peripheral cords and nests of intermediate trophoblast cells Round to polygonal tumor cells with eosinophilic to clear cytoplasm and moderate to marked cytologic atypia Mitoses up to 6 per 10 high-power fields Rare multinucleated cells resembling syncytiotrophoblast Infiltrative borders with tumor cells separating myometrial smooth muscle fibers at tumor periphery Large nests of tumor cells replacing vascular walls Associated eosinophilic extracellular matrix Necrosis may be present Immunohistochemistry Positive: Diffusely positive for hPL, Mel-CAM, HSD3B1, CD10, pan-cytokeratin, CK18, EMA, GATA3, MUC4, HLA-G Focally positive for PLAP Positive β-hCG and inhibin-α in scattered multinucleated cells Ki-67 10–30% Negative: p63 SALL4 Microscopy

Epithelioid trophoblastic tumor Sheets, nests, and cords of intermediate trophoblast cells Rare syncytiotrophoblast Central small vessel Hyaline-like material May colonize cervical mucosal epithelium Mild to moderate cytologic atypia with prominent nucleoli Mitoses up to 9 per 10 high-power fields Decidualized stromal cells at tumor periphery Necrosis

Choriocarcinoma Trimorphic pattern with three types of trophoblast (villous intermediate trophoblast, syncytiotrophoblast, cytotrophoblast) Marked cytologic atypia Mitoses up to 22 per 10 high-power fields Extensive hemorrhage and necrosis No chorionic villi LVSI

Positive: Diffusely positive for p63, PLAP, pan-cytokeratin, CK18, EMA, inhibin-α, HLA-G, GATA3, H3D3B1, cyclin E, CD10, inhibin-α Variable hPL, Mel-CAM, β-hCG Ki-67 10–25% Negative: SALL4

Positive: β-hCG diffusely positive in syncytiotrophoblast, weakly and focally positive in cytotrophoblast or intermediate trophoblast Diffuse HSD3B1 in syncytiotrophoblast Mel-CAM, HLA-G, and MUC4 in intermediate trophoblast Diffuse keratin Variable hPL, SALL4, p63, inhibin-α Ki-67 > 90%

β-hCG β human chorionic gonadotropin, CK18 cytokeratin 18, EMA epithelial membrane antigen, GATA3 GATA binding protein 3, HLA-G human leukocyte antigen G, hPL human placental lactogen, LVSI lymphovascular space invasion, Mel-CAM melanoma cell adhesion molecule, MUC4 mucin 4, PLAP placental alkaline phosphatase, SALL4 Sal-like protein 4

12.3.1.2 Synonyms Chorioepithelioma, chorionepithelioma. 12.3.1.3 Etiology Gestational choriocarcinoma may arise due to progression of a complete or partial hydatidiform mole, or it may arise after a normal term pregnancy or an ectopic pregnancy [44, 45], with 50% of gestational choriocarcinomas occurring after complete hydatidiform mole, 25% after spontaneous abortion, and 25% after normal term pregnancy. The risk of developing choriocarcinoma is approximately 2% to 3% following a complete mole and 0.1% to 0.5% following a partial mole [46]. Non-gestational choriocarcinoma is likely to have the same origin as the other germ-cell tumors discussed above. 12.3.1.4 Macroscopy Single or multiple bulky and destructive dark red masses with hemorrhage and necrosis.

12.3.1.5 Microscopy Choriocarcinoma may be circumscribed but usually shows invasive and destructive growth in surrounding tissues. There is a trimorphic pattern consisting of all three types of trophoblast: large intermediate trophoblast with abundant amphophilic to eosinophilic cytoplasm, smaller cytotrophoblast, and multinucleated syncytiotrophoblast. There is conspicuous mitotic activity, up to 22 per 10 high-power fields. Extensive recent and remote hemorrhage and necrosis are seen (Fig. 12.4). LVSI is common. No residual chorionic villi are present. Immunohistochemically, β-hCG (β human chorionic gonadotropin) and HSD3B1 show diffuse staining in syncytiotrophoblast, with weak and focal expression of β-hCG in the cytotrophoblast or intermediate trophoblast cells. The intermediate trophoblast cells  are positive for Mel-CAM/CD146 (melanoma cell adhesion molecule), HLA-G (human leukocyte antigen G) and MUC4 (mucin 4). Keratin is diffusely positive, and hPL (human placental lactogen), SALL4, p63 and inhibin-α show variable staining. The Ki-67 labeling index is usually >90%. Cytologic features include clusters of syncytiotrophoblast and cytotrophoblast in a background of tumor diathesis.

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Diagnostic Highlights

• Trimorphic pattern with three types of trophoblast (villous intermediate trophoblast, syncytiotrophoblast, cytotrophoblast) • Marked cytologic atypia

• • • •

a

b

c

d

e

f

Fig. 12.4  Gestational choriocarcinoma. (a–h), Total hysterectomy specimen with a markedly atypical mass-forming lesion containing multiple foci of necrosis and hemorrhage and ulceration of the overlying squamous epithelium (H&E). The tumor is composed predominantly of medium-sized cytotrophoblast and intermediate trophoblast

Mitoses up to 22 per 10 high-power fields Extensive hemorrhage and necrosis No chorionic villi LVSI

and scattered large, multinucleated syncytiotrophoblast cells (b–h). Chorionic villi are not present. (i) An immunohistochemical stain for β-hCG shows strong, diffuse staining in both the syncytiotrophoblast (the most darkly stained cells) and cytotrophoblast cells

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g

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h

i

Fig. 12.4 (continued)

12.3.1.6 Differential Diagnosis Table 12.6 outlines the top differential diagnoses for trophoblastic tumors involving the cervix: •

•

•

•

• Normal immature trophoblast of early gestation in curettings lacks significant cytologic atypia, necrosis, or destructive growth; found in small quantities; chorionic villi may be seen on deeper sectioning. Epithelioid trophoblastic tumor is well-circumscribed; • Exaggerated placental site is usually an incidental microcomposed predominantly of nests or cords of chorionic-­ scopic finding composed of implantation-site trophoblastype intermediate trophoblast with only rare syncytiotrotic cells separated by hyalinized stroma and lacking phoblast; eosinophilic fibrinoid matrix; no diffuse β-hCG. mitotic activity; admixed with chorionic villi and fragPlacental site trophoblastic tumor is usually an infiltratments of decidua; absence of confluent masses (Fig. 12.5). ing mass; composed of confluent sheets or infiltrating Frequently associated with molar pregnancies. monomorphic implantation-site intermediate trophoblast; • Poorly differentiated carcinoma with trophoblastic differvariable necrosis; no diffuse β-hCG. entiation may show areas of more conventional Non-gestational choriocarcinoma shows identical procarcinoma. files to the patient’s benign tissue by DNA polymorphism • Poorly differentiated carcinoma with anaplastic features analysis or short tandem repeat genotyping [47, 48]. or giant cells lacks admixture of cytotrophoblast and synInvasive mole shows residual hydropic chorionic villi; cytiotrophoblast; positive for EMA; negative or weakly loss of p57 staining in cytotrophoblast and villous stromal positive for β-hCG. cells in complete mole.

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Table 12.6  Differential diagnosis of trophoblastic tumors involving the cervix

Epithelioid trophoblastic tumor

Placental site trophoblastic tumor

Clinical history Term pregnancy, complete or partial mole, spontaneous abortion, previous diagnosis of atypical placental site nodule, vaginal bleeding or amenorrhea Term pregnancy, spontaneous abortion, vaginal bleeding, or amenorrhea

Choriocarcinoma, gestational

Complete or partial hydatidiform mole, spontaneous abortion, or normal term pregnancy, vaginal bleeding

Choriocarcinoma, non-gestational

Ovarian germ cell tumor

Invasive mole

Complete or partial hydatidiform mole

Poorly differentiated Cervical cancer carcinoma with trophoblastic differentiation Poorly differentiated Cervical cancer carcinoma with anaplastic features or giant cells None Normal immature trophoblast of early gestation in curettings

Ancillary studies Positive Diffuse p63, PLAP, cytokeratin, EMA, inhibin-α, GATA3, H3D3B1, HLA-G, cyclin E, inhibin-α Focal hPL, Mel-CAM, β-hCG Ki-67 10–25% Diffuse hPL, Mel-CAM, Infiltrating, composed of confluent sheets or cytokeratin, EMA, infiltrating monomorphic implantation-site GATA3, MUC4, intermediate trophoblast; less extensive to no HSD3B1, HLA-G necrosis Focal PLAP β-hCG and inhibin-α in scattered multinucleated cells Ki-67 10–30% Biphasic tumor with three β-hCG diffuse in constituents: cytotrophoblast and intermediate syncytiotrophoblast, trophoblast surrounded by syncytiotrophoblast, weak and focal in with extensive necrosis and hemorrhage; DNA cytotrophoblast or polymorphism analysis or STR genotyping intermediate trophoblast showing different profiles between the tumor Diffuse hPL and and patient’s benign tissue HSD3B1 in syncytiotrophoblast Variable hPL, SALL4, p63, inhibin-α Ki-67 > 90% Morphology similar to gestational β-hCG diffuse in choriocarcinoma, but DNA polymorphism syncytiotrophoblast, analysis or STR genotyping shows identical weak and focal in profiles between the tumor and patient’s cytotrophoblast or benign tissue intermediate trophoblast Diffuse hPL and HSD3B1 in syncytiotrophoblast Variable hPL, SALL4, p63, inhibin-α Ki-67 > 90% Retained p57 in Residual chorionic villi; trophoblastic cytotrophoblast and proliferation in complete mole may villous stromal cells in predominate over villi partial mole

Microscopy Well circumscribed, composed of nests or cords of chorionic-type intermediate trophoblast with rare syncytiotrophoblast, eosinophilic fibrinoid matrix

Areas of more conventional carcinoma present, β-hCG no paternal genome by STR genotyping

Lacks admixture of cytotrophoblast and syncytiotrophoblast, no paternal genome by STR genotyping No significant cytologic atypia, necrosis, or destructive growth, small quantities, chorionic villi on deeper sectioning

EMA, diffuse p16 if associated with high-risk HPV, aberrant p53 p63

Negative SALL4

p63, SALL4

p16

p16

Loss of p57 in cytotrophoblast and villous stromal cells in complete mole PAX8, p63

β-hCG, PAX8, p63 β-hCG

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Table 12.6 (continued)

Exaggerated placental site

Placental site nodule

Atypical placental site nodule

Clinical history Microscopy Incidental, often found Implantation-site trophoblastic cells separated with molar pregnancies by hyalinized stroma and lacking mitotic activity, admixed with chorionic villi and fragments of decidua; absence of confluent masses Incidental Single or multiple well-circumscribed oval nodules or plaques,