WHO Classification of Urinary and Male Genital Tumours [8, 5 ed.] 9789283245124

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WHO Classification of Tumours • 5th Edition

i Urinary and Male I Genital Tumours

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WHO Classification of Tumours . 5th Edition

Urinary and Male Genital Tumours WHO Classification of Tumours Editorial Board

International Agency for Research on Cancer

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The WHO classification of urinary and male genital tumours presented in this book reflects the views of the WHO Classification of Tumours Editorial Board that convened via video conference 18-20 January 2021.

The WHO Classification of Tumours Editorial Board Expert members: Urinary and male genital tumours Amin, Mahul B.

Netto, George J.

University of Tennessee Health Science Center

University of Alabama at Birmingham

Memphis

Birmingham

Berney, Daniel Maurice

Barts Health NHS Trust

Raspollini, Maria Rosaria Histopathology and Molecular Diagnostics, University Hospital Careggi

London

Florence

Comperat, Eva Maria

Rubin, Mark A.

Sorbonne University, Hopital Tenon

Universitat Bern

Paris

Bern

Hartmann, Arndt Institute of Pathology

Tickoo, Satish K. Memorial Sloan Kettering Cancer Center

Erlangen

New York

Menon, Santosh

Turajlic, Samra Francis Crick Institute, Royal Marsden NHS Foundation Trust,

Tata Memorial Centre Mumbai

and Institute of Cancer Research London

For the complete list of all contributors and their affiliations, see pages 497-504.

The WHO Classification of Tumours Editorial Board (continued) Standing members Cree, Ian A. (Editorial Board Chair)

Moch, Holger*

International Agency for Research on Cancer

University of Zurich and University Hospital Zurich

Lyon

Zurich

Denton, Erika R.E.

Rous, Brian

Norfolk and Norwich University Hospitals NHS Foundation Trust

NHS Digital

Norwich

Fulbourn, Cambridge

Field, Andrew S.

Srigley, John R.*

St Vincent's Hospital Sydney

University of Toronto, Trillium Health Partners

Darlinghurst

Mississauga

Gill, Anthony J.*

Tan, Puay Hoon*

Royal North Shore Hospital

Singapore General Hospital

St Leonards

Singapore

Khoury, Joseph D.

Thompson, Lester D.R.

University of Texas MD Anderson Cancer Center

Head and Neck Pathology Consultations

Houston

Woodland Hills

Lax, Sigurd F.

Tsuzuki, Toyonori*

General Hospital Graz II, Medical University of Graz

Aichi Medical University Hospital

Graz

Nagakute

Lazar, Alexander J.

Washington, Mary K.

University of Texas MD Anderson Cancer Center

Vanderbilt University Medical Center

Houston

Nashville

Standing members marked with an asterisk also served as expert members for this volume.

For the complete list of all contributors and their affiliations, see pages 497-504.

WHO Classification of Tumours Urinary and Male Genital Tumours

Edited by

The WHO Classification of Tumours Editorial Board

IARC Editors

Ian A. Cree Gabrielle Goldman-L6vy

Dilani Lokuhetty B. Vishal Rao Valerie A. White

Epidemiology

Ariana Znaor

Project Assistant

Asiedua Asante

Assistants

Anne-Sophie Bres

Laura Brispot

Production Editor

Jessica Cox

Technical Editing

Julia Slone-Murphy

Principal Information Assistant

Alberto Machado

Information Assistant

Catarina Marques

Layout

Meaghan Fortune

Printed by

Omni book

74370 Argonay, France

Publisher

International Agency for Research on Cancer (IARC) 150 Cours Albert Thomas

69372 Lyon Cedex 08, France

Contents

List of abbreviations

xi

Foreword

xii

ICD-0 topographical coding

1

ICD-0 morphological coding

1

Tumours of the kidney Tumours of the urinary tract Tumours of the prostate

SMARCB1-deficient renal medullary carcinoma

Metanephric tumours Metanephric adenoma Metanephric adenofibroma Metanephric stromal tumour Mixed epithelial and stromal renal tumours Mixed epithelial and stromal tumour of the kidney

2 4 6

Paediatric cystic nephroma Renal mesenchymal tumours

Adult renal mesenchymal tumours Classic angiomyolipoma / PEComa of the kidney

7

Tumours of the seminal vesicle Tumours of the testis Tumours of the testicular adnexa Tumours of the penis and scrotum Neuroendocrine neoplasms Mesenchymal tumours

8 10 11 12 12

Haematolymphoid tumours Melanocytic lesions

14 15

TNM staging of urological tumours

16

Carcinomas of the penis

17

Adenocarcinomas of the prostate Germ cell tumours of the testis Renal cell carcinoma Carcinomas of the renal pelvis and ureter Carcinomas of the urinary bladder

18 20 22 23 24

Carcinomas of the urethra

25

1

Introduction to urinary and male genital tumours

27

2

Tumours of the kidney

31

potential Papillary renal tumours Renal papillary adenoma Papillary renal cell carcinoma Oncocytic and chromophobe renal tumours Oncocytoma of the kidney Chromophobe renal cell carcinoma Other oncocytic tumours of the kidney Collecting duct tumours Collecting duct carcinoma Other renal tumours Clear cell papillary renal cell tumour Mucinous tubular and spindle cell carcinoma Tubulocystic renal cell carcinoma Acquired cystic disease-associated renal cell

32

38 43 45 47 50 53 56

59

61 63 65

carcinoma Eosinophilic solid and cystic renal cell carcinoma Renal cell carcinoma NOS Molecularly defined renal carcinomas 7FE3-rearranged renal cell carcinomas TFEB-altered renal cell carcinomas ELOC (formerly 7CEB7)-mutated renal cell carcinoma

67 69 71

Fumarate hydratase-deficient renal cell carcinoma Succinate dehydrogenase-deficient renal cell carcinoma >4/.^-rearranged renal cell carcinomas

78

72 74 76

80 82

87 90 92

94 96

98

Epithelioid angiomyolipoma / epithelioid PEComa of

the kidney Renal haemangioblastoma Juxtaglomerular cell tumour Renomedullary interstitial cell tumour Paediatric renal mesenchymal tumours Ossifying renal tumour of infancy Congenital mesoblastic nephroma

102 105 107 109

Rhabdoid tumour of the kidney Clear cell sarcoma of the kidney

114 116

111 112

Embryonal neoplasms of the kidney Nephroblastic tumours Nephrogenic rests Cystic partially differentiated nephroblastoma

3 Renal cell tumours Introduction Clear cell renal tumours Clear cell renal cell carcinoma Multilocular cystic renal neoplasm of low malignant

84

119 121

Nephroblastoma Miscellaneous renal tumours Germ cell tumours of the kidney

129

Tumours of the urinary tract

131

Introduction Urothelial tumours

132

123

Non-invasive urothelial neoplasms

Urothelial papilloma Inverted urothelial papilloma Papillary urothelial neoplasm of low malignant potential

Non-invasive papillary urothelial carcinoma, lowgrade Non-invasive papillary urothelial carcinoma, high­ grade Urothelial carcinoma in situ Invasive urothelial neoplasms Invasive urothelial carcinoma Squamous cell neoplasms of the urinary tract Squamous papilloma of the urothelial tract Squamous cell carcinomas of the urinary tract Verrucous carcinoma of the bladder Pure squamous carcinoma of the urothelial tract Glandular neoplasms

Adenomas Villous adenoma Adenocarcinomas Adenocarcinoma NOS Urachal and diverticular neoplasms Urachal carcinoma Diverticular carcinoma Urethral neoplasms Urethral accessory gland carcinomas Litt怕 gland adenocarcinoma Skene gland adenocarcinoma Cowper gland adenocarcinoma

134 136

138

140 143 147 150

166

167 169

172 173

177 181

183 185 186

Tumours of Mullerian type Clear cell adenocarcinoma of the urinary tract

Endometrioid carcinoma of the urinary tract

4

Sertoli cell tumours Sertoli cell tumour

188

Large cell calcifying Sertoli cell tumour Granulosa cell tumours Adult granulosa cell tumour Juvenile granulosa cell tumour The fibroma thecoma family of tumours Tumours in the fibroma thecoma group

190

Tumours of the prostate

193

Introduction Epithelial tumours of the prostate Glandular neoplasms of the prostate

194

Prostatic cystadenoma High-grade prostatic intraepithelial neoplasia Intraductal carcinoma of the prostate

Mixed and other sex cord stromal tumours Mixed sex cord stromal tumour Signet ring stromal tumour Myoid gonadal stromal tumour Sex cord stromal tumour NOS

196 198 200

Prostatic acinar adenocarcinoma Prostatic ductal adenocarcinoma Treatment-related neuroendocrine prostatic carci­ noma Squamous neoplasms of the prostate Adenosquamous carcinoma of the prostate Squamous cell carcinoma of the prostate Adenoid cystic (basal cell) carcinoma of the prostate

203 220

223

7

5

225 227 229

231

235

Introduction Epithelial tumours Glandular neoplasms Cystadenoma

236

Adenocarcinoma Squamous neoplasms Squamous cell carcinoma

6

233

Tumours of the seminal vesicle

237 238

241

Tumours of the testis

243

Introduction Germ cell tumours derived from germ cell neoplasia in situ Non-invasive germ cell neoplasia Germ cell neoplasia in situ Specific forms of intratubular germ cell neoplasia Gonadoblastoma The germinoma family of tumours Seminoma Non-seminomatous germ cell tumours Embryonal carcinoma Yolk sac tumour, postpubertal-type Choriocarcinoma Placental site trophoblastic tumour Epithelioid trophoblastic tumour Cystic trophoblastic tumour Teratoma, postpubertal-type Teratoma with somatic-type malignancy Mixed germ cell tumours of the testis

244

Mixed germ cell tumours Germ cell tumours of unknown type

Regressed germ cell tumours Germ cell tumours unrelated to germ cell neoplasia in situ Spermatocytic tumour Teratoma, prepubertal-type Yolk sac tumour, prepubertal-type Testicular neuroendocrine tumour, prepubertal-type Mixed teratoma and yolk sac tumour, prepuber­ tal-type Sex cord stromal tumours of the testis Leydig cell tumour Leydig cell tumour

250 253 255

8

262 265 268 271 273 275 277 281

286

299

313 315 317 319

321

326 327 329 331 333 335 337 339 340

Adenoma Adenocarcinoma Paratesticular mesothelial tumours Adenomatoid tumour Well-differentiated papillary mesothelial tumour

341 342 343 346 348 351 352 354 356 358

Tumours of the penis and scrotum

361

Introduction

362

Differentiated penile intraepithelial neoplasia, HPV-independent 369 Invasive epithelial tumours of the penis and scrotum Invasive squamous epithelial tumours HPV-associated squamous cell carcinoma 372 HPV-independent squamous cell carcinoma 375 Squamous cell carcinoma NOS 378 Other epithelial tumours Penile adenosquamous and mucoepidermoid carci­ nomas 380

284

297

311

Benign and precursor squamous lesions Condyloma acuminatum 364 Squamous cell carcinoma precursors, HPV-associated Penile intraepithelial neoplasia, HPV-associated 366 Squamous cell carcinoma precursors, HPV-independent

258

288 291 293 295

307 309

Serous cystadenoma Serous tumour of borderline malignancy Serous cystadenocarcinoma Mucinous cystadenoma Mucinous borderline tumour Mucinous cystadenocarcinoma Endometrioid tumours Clear cell adenocarcinoma Brenner tumour Tumours of the collecting ducts and rete testis

Mesothelioma Tumours of the epididymis Cystadenoma Papillary cystadenoma Adenocarcinoma Squamous cell carcinoma Melanotic neuroectodermal tumour

240

Other tumours Mixed epithelial andstromal tumour

305

Introduction 322 Ovarian-type tumours of the collecting ducts and rete testis

Mesenchymal tumours unique to the prostate Stromal tumours of the prostate Prostatic stromal tumour of uncertain malignant

potential Prostatic stromal sarcoma

Tumours of the testicular adnexa

302

9

Extramammary Paget disease Other scrotal tumours Basal cell carcinoma of thescrotum

383

Neuroendocrine neoplasms

385

Introduction Neuroendocrine tumours Well-differentiated neuroendocrine tumour Neuroendocrine carcinomas Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma

381

386 387

389 392

Mixed neuroendocrine neoplasms Paragangliomas Paraganglioma

10 Mesenchymal tumours Introduction Fibroblastic and myofibroblastic tumours The angiofibroma family of tumours Solitary fibrous tumour Inflammatory myofibroblastic tumour Vascular tumours

394

13 Metastases in the genitourinary system

397

Introduction Metastasis to the urinary tract Metastasis to the kidney

401

Metastasis to the testis and paratestis

451 452 455 457 459

402 403 405 407

14 Genetic tumour syndromes of the urinary and male genital tracts

461

Introduction Von Hippel-Lindau syndrome

462 464

Birt-Hogg-Dube syndrome

466 469

Haemangioma Angiosarcoma Pericytic (perivascular) tumours Glomus tumour

409 412

414

Hereditary papillary renal carcinoma Hereditary leiomyomatosis and renal cell carcinoma syndrome Succinate dehydrogenase-deficient tumour syn­

Myointimoma Myopericytoma Extrarenal PEComa Smooth muscle tumours

416 418 419

dromes BAP1 tumour predisposition syndrome Hereditary phaeochromocytoma-paraganglioma

479

421

syndromes Tuberous sclerosis Genitourinary system and Lynch syndrome

481 484 487

Leiomyoma

471

474

Leiomyosarcoma Skeletal muscle tumours

423

Rhabdomyosarcoma

425

Hereditary tumour syndromes associated with homologous recombination pathway mutations Carney complex

490 492

427

Peutz-Jeghers syndrome

494

Tumours of uncertain differentiation Synovial sarcoma

Extrarenal rhabdoid tumour Desmoplastic small round cell tumour

11 Haematolymphoid tumours Introduction Mature B-cell lymphomas Extranodal marginal zone lymphoma of MALT Diffuse large B-cell lymphoma

Plasmacytoma Histiocytic tumours Juvenile xanthogranuloma

12 Melanocytic lesions Mucosal melanoma

429 431

Contributors

497

433

Declaration of interests

503

IARC/WHO Committee for ICD-0

504

Sources

505

References

511

Subject index

567

Previous volumes in the series

576

434 436 439 442 445

447 448

List of abbreviations

Al AIDS AJCC AR BCG vaccine cAMP CNS COG CT DNA EBV ER FISH FNA GG GUPS H&E HIV HPV HR HRR HVA IARC ICD-11 ICD-0 ig IGCCCG 旧SG ISUP ITD

artificial intelligence acquired immunodeficiency syndrome American Joint Committee on Cancer

androgen receptor bacillus Calmette-Guerin vaccine cyclic adenosine monophosphate central nervous system Children's Oncology Group

computed tomography deoxyribonucleic acid Epstein-Barr virus estrogen receptor fluorescence in situ hybridization

fine-needle aspiration WHO/ISUP grade group Genitourinary Pathology Society haematoxylin and eosin human immunodeficiency virus

human papillomavirus homologous recombination homologous recombination repair homovanillic acid International Agency for Research on Cancer International Classification of Diseases, 11th revision International Classification of Diseases for Oncology

immunoglobulin International Germ Cell Cancer Collaborative Group Intergroup Rhabdomyosarcoma Study Group International Society of Urological Pathology internal tandem duplication

MALT lymphoma MIM number MITF mpMRI MRI mRNA MSI N:C ratio ncRNA NOS NSE PAS staining PCR PET-CT PR RNA RPLND SEER Program

SIOP SNP TCGA TNM TPS TRUS TURBT UICC VI-RADS VMA WHO/ISUP grading

extranodal marginal zone lymphoma of mucosa-

associated lymphoid tissue Mendelian Inheritance in Man number melanogenesis-associated transcription factor multiparametric magnetic resonance imaging magnetic resonance imaging messenger ribonucleic acid microsatellite instability

nuclear-to-cytoplasmic ratio

non-coding RNA not otherwise specified neuron-specific enolase periodic acid-Schiff staining polymerase chain reaction positron emission tomography-computed tomography progesterone receptor ribonucleic acid retroperitoneal lymph node dissection Surveillance, Epidemiology, and End Results

Program International Society of Paediatric Oncology single-nucleotide polymorphism The Cancer Genome Atlas

tumour, node, metastasis The Paris System for reporting urinary cytopathology transrectal ultrasound transurethral resection of bladder tumour Union for International Cancer Control Vesical Imaging Reporting and Data System

vanillylmandelic acid

WHO Classification of Tumours / International Society of Urological Pathology (WHO/ISUP) grading

List of abbreviations

xi

Foreword The WHO Classification of Tumours, published as a series of books (also known as the WHO Blue Books) and now as a website (https://tumourclassification.iarc.who.int ), is an essential tool for standardizing diagnostic practice worldwide. It also serves as a vehicle for the translation of cancer research into practice. The diagnostic criteria and standards that make up the classification are underpinned by evidence evaluated and debated by experts in the field. About 200 authors and editors participate in the production of each book, and they give their time freely to this task. I am very grateful for their help; it is a remarkable team effort.

This volume, like the rest of the fifth edition, has been led by the WHO Classification of Tumours Editorial Board, composed of stand­ ing and expert members. The standing members, who have been nominated by pathology organizations, are the equivalent of the series editors of previous editions. The expert members for each volume, equivalent to the volume editors of previous editions, are selected on the basis of informed bibliometric analysis and advice from the standing members. The diagnostic process is increas­ ingly multidisciplinary, and we are delighted that several radiology and clinical experts have joined us to address specific needs. The most conspicuous change to the format of the books in the fifth edition is that tumour types common to multiple systems are dealt with together - so there are separate chapters on neuroendocrine neoplasms, mesenchymal tumours, haematolymphoid tumours, and melanocytic lesions. There is also a chapter on genetic tumour syndromes. Genetic disorders are of increasing impor­ tance to diagnosis in individual patients, and the study of these disorders has undoubtedly informed our understanding of tumour biology and behaviour over the past decade.

We have attempted to take a more systematic approach to the multifaceted nature of tumour classification; each tumour type is described on the basis of its localization, clinical features, epidemiology, etiology, pathogenesis, histopathology, diagnostic molecular pathology, staging, and prognosis and prediction. We have also included information on macroscopic appearance and cytology, as well as essential and desirable diagnostic criteria. This standardized, modular approach makes it easier for the books to be accessible online, but it also enables us to call attention to areas in which there is little information, and where serious gaps in our knowledge remain to be addressed. The organization of the WHO Blue Books content now follows the normal progression from benign to malignant - a break with the fourth edition, but one we hope will be welcome. The volumes are still organized by anatomical site (digestive system, breast, soft tissue and bone, etc.), and each tumour type is listed within a hierarchical taxonomic classification that follows the format below, which helps to structure the books in a systematic manner:

Site: e.g. tumours of the kidney Category: e.g. renal mesenchymal tumours

Family (class): e.g. paediatric renal mesenchymal tumours Type: e.g. congenital mesoblastic nephroma Subtype: e.g. cellular congenital mesoblastic nephroma The issue of whether a given tumour type represents a distinct entity rather than a subtype continues to exercise pathologists, and it is the topic of many publications in the literature. We continue to deal with this issue on a case-by-case basis, but we believe there are inherent rules that can be applied. For example, tumours in which multiple histological patterns contain shared truncal mutations are clearly of the same type, despite the differences in their appearance. Equally, genetic heterogeneity within the same tumour type may have implications for treatment. A small shift in terminology in the fifth edition is that the term "variant" in reference to a specific kind of tumour has been wholly superseded by "subtype", in an effort to more clearly differentiate this meaning from that of “variant" in reference to a genetic alteration.

xii

Foreword

Another important change in this edition of the WHO Classifica­ tion of Tumours series is the conversion of mitotic count from the traditional denominator of 10 HPF to a defined area expressed in mm2. This serves to standardize the true area over which mitoses are enumerated, because different microscopes have high-power fields of different sizes. This change will also be helpful for anyone reporting using digital systems. The approx­ imate number of fields per 1 mm2 based on the field diameter and its corresponding area is presented in Table A.

We are continually working to improve the consistency and standards within the classification. In addition to having moved to the International System of Units (SI) for all mitotic counts, we have standardized genomic nomenclature by using Human Genome Variation Society (HGVS) notation. We have also further standardized our use of units of length, adopting the convention used by the International Collaboration on Cancer Reporting (https://www.iccr-cancer.org ) and the UK Royal Col­ lege of Pathologists (https://www.rcpath.org/), so that the size of tumours is now given exclusively in millimetres (mm) rather than centimetres (cm). This is clearer, in our view, and avoids the use of decimal points - a common source of medical errors. The WHO Blue Books are much appreciated by pathologists and of increasing importance to practitioners of other clini­ cal disciplines involved in cancer management, as well as to researchers. The editorial board and I certainly hope that the series will continue to meet the need for standards in diagno­ sis and to facilitate the translation of diagnostic research into practice worldwide. It is particularly important that cancers continue to be classified and diagnosed according to the same standards internationally so that patients can benefit from mul­ ticentre clinical trials, as well as from the results of local trials conducted on different continents.

Dr Ian A. Cree

Head, WHO Classification of Tumours Programme International Agency for Research on Cancer

May 2022

Table A Approximate number of fields per 1 mm2 based on the field diameter and its corresponding area

Field diameter (mm)

Field area (mm2)

Approximate number of fields per 1 mm2

0.40

0.126

8

0.41

0.132

8

0.42

0.138

7

0.43

0.145

7

0.44

0.152

7

0.45

0.159

6

0.46

0.166

6

0.47

0.173

6

0.48

0.181

6

0.49

0.188

5

0.50

0.196

5

0.51

0.204

5

0.52

0.212

5

0.53

0.221

5

0.54

0.229

4

0.55

0.237

4

0.56

0.246

4

0.57

0.255

4

0.58

0.264

4

0.59

0.273

4

0.60

0.283

4

0.61

0.292

3

0.62

0.302

3

0.63

0.312

3

0.64

0.322

3

0.65

0.332

3

0.66

0.342

3

0.67

0.352

3

0.68

0.363

3

0.69

0.374

3

Foreword

xiii

ICD-0 topographical coding of urinary and male genital tumours The ICD-0 topography codes for the main anatomical sites covered in this volume are as follows (1053(:

C60 Penis C60.0 Prepuce C60.1 Glans penis 060.2 Body of penis C60.8 Overlapping lesion of penis

C60.9 Penis, NOS

C61 Prostate gland C61.9 Prostate gland

C62 Testis 062.0 Undescended testis C62.1 Descended testis C62.9 Testis, NOS

C63 Other and unspecified male genital organs C63.0 Epididymis 063.1 Spermatic cord C63.2 Scrotum, NOS C63.7 Other specified parts of male genital organs C63.8 Overlapping lesion of male genital organs C63.9 Male genital organs, NOS

C65 Renal pelvis C65.9 Renal pelvis

C66 Ureter C66.9 Ureter

C67 Bladder C67.0 Trigone of bladder

C67.1 Dome of bladder C67.2 Lateral wall of bladder C67.3 Anterior wall of bladder

C67.4 Posterior wall of bladder C67.5 Bladder neck C67.6 Ureteric orifice

C67.7 Urachus C67.8 Overlapping lesion of bladder C67.9 Bladder, NOS

C68 Other and unspecified urinary organs C68.0 Urethra

C68.1 Paraurethral gland C68.8 Overlapping lesion of urinary organs C68.9 Urinary system, NOS

C64 Kidney C64.9 Kidney, NOS

ICD-0 morphological coding: Introduction The ICD-0 coding system uses a topography (T) code and a morphology (M) code together, but these are presented in separate lists for ease of use. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carci­ noma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and 16 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. For various reasons, the ICD-0 morphology terms may not always be identical to the entity names used in the WHO classification, but they should be sufficiently similar to avoid confusion. The designation "NOS" ("not otherwise specified") is provided to make coding possible when subtypes exist but exact classification may not be possible in small biopsies or certain other scenarios. Therefore, it is usual to have "NOS" even when a more specific alternative term is listed in ICD-O.

ICD-0 coding of urinary and male genital tumours

1

ICD-0 coding of tumours of the kidney ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Renal cell tumours Clear cell renal tumours 8310/3 Clear cell renal cell carcinoma 8316/1 Multilocular cystic renal neoplasm of low malignant potential Papillary renal tumours

8260/0 8260/3

Papillary adenoma Papillary renal cell carcinoma1

Oncocytic and chromophobe renal tumours 8290/0 Oncocytoma 8317/3 Chromophobe cell renal carcinoma

Other oncocytic tumours of the kidney

Collecting duct tumours 8319/3

Collecting duct carcinoma

Other renal tumours 8323/1 Clear cell papillary renal cell turnout 8480/3 8316/3

Mucinous tubular and spindle cell carcinoma Tubulocystic renal cell carcinoma

8316/3 8311/3 8312/3

Acquired cystic disease-associated renal cell carcinoma Eosinophilic solid and cystic renal cell carcinoma Renal cell carcinoma, NOS

Molecularly defined renal carcinomas 8311/3 TFE3-rearranged renal cell carcinomas 8311/3 TFEB-altered renal cell carcinomas 8311/3 ELOC (formerly TCEB 7)-mutated renal cell carcinoma 8311/3 Fumarate hydratase-deficient renal cell carcinoma 8311/3 Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome-associated renal cell carcinoma 8311/3 Succinate dehydrogenase-deficient renal cell carcinoma 8311/3 ALKrearranged renal cell carcinomas 8510/3 Medullary carcinoma, NOS 8510/3 SMARCBI-deficient medullary-like renal cell carcinoma 8510/3 SMARCBI-deficient undifferentiated renal cell carcinoma, NOS 8510/3 SMARCBI-deficient dedifferentiated renal cell carcinomas of other specific subtypes

Metanephric tumours 8325/0 9013/0 8935/1

Metanephric adenoma Metanephric adenofibroma Metanephric stromal tumour

Mixed epithelial and stromal renal tumours 8959/0 8959/0 8959/0

2

Mixed epithelial and stromal tumour Adult cystic nephroma Paediatric cystic nephroma

ICD-0 coding of urinary and male genital tumours

ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented);

Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Renal mesenchymal tumours Adult renal mesenchymal tumours

8860/0 8860/0 8860/0 8860/1

Angiomyolipoma Oncocytic angiomyolipoma Angiomyolipoma with epithelial cysts Angiomyolipoma, epithelioid

9161/1

Haemangioblastoma

8361/0 8361/0 8361/0 8966/0

Juxtaglomerular tumour Functioning juxtaglomerular cell tumour Non-functioning juxtaglomerular cell tumour Renomedullary interstitial cell tumour

Paediatric renal mesenchymal tumours 8967/0 Ossifying renal tumour of infancy

8960/1 8960/1 8960/1 8960/1 8963/3 8964/3

Mesoblastic nephroma Classic congenital mesoblastic nephroma Cellular congenital mesoblastic nephroma Mixed congenital mesoblastic nephroma Malignant rhabdoid tumour of the kidney Clear cell sarcoma of kidney

Embryonal neoplasms of the kidney Nephroblastic tumours

Nephrogenic rests Perilobar nephrogenic rests

8959/1 8960/3

Intralobar nephrogenic rests Nephroblastomatosis Cystic partially differentiated nephroblastoma Nephroblastoma

Miscellaneous renal tumours Germ cell tumours of the kidney 9084/0

Prepubertal-type teratoma

9084/3 9071/3

Teratoma with carcinoid (neuroendocrine tumour) Yolk sac tumour, NOS

9085/3

Mixed teratoma-yolk sac tumour

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1457}. Behaviour is coded /0 for benign tumours; Z1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries.

This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions, n/a, not available (provisional entity). * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022.

十 Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

3

ICD-0 coding of tumours of the urinary tract ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Urothelial tumours Non-invasive urothelial neoplasms 8120/0 Urothelial papilloma 8121/0 8130/1

Urothelial papilloma, inverted Papillary urothelial neoplasm of low malignant potential

8130/1 8130/2 8130/2 8130/2 8130/2 8120/2

Inverted papillary urothelial neoplasm of low malignant potential Non-invasive papillary urothelialcarcinoma, low-grade Low-grade papillary urothelial carcinoma with an inverted growth pattern Non-invasive papillary urothelial carcinoma, high-grade Non-invasive high-grade papillary urothelial carcinoma with an inverted growth pattern Urothelial carcinoma in situ

Invasive urothelial neoplasms 8120/3 Invasive urothelial carcinoma 8120/3 Conventional urothelial carcinoma 8120/3 Urotheliaf carcinoma with squamous differentiation 8120/3 Urothelial carcinoma with glandular differentiation 8120/3 Urothelial carcinoma with trophoblastic differentiation 8120/3 Nested urothelial carcinoma 8120/3 Large nested urothelial carcinoma 8120/3 Tubular and microcystic urothelial carcinomas 8131/3 Micropapilfary urothelial carcinoma 8082/3 Lymphoepitheiioma-like urothelial carcinoma 8122/3 Plasmacytoid urothelial carcinoma'7 Giant cell urothelial carcinoma Lipid-rich urothelial carcinoma Clear cell (glycogen-rich) urothelial carcinoma Sarcomatoid urothelial carcinoma Poorly differentiated urothelial carcinoma

8031/3 8120/3 8120/3 8120/3 8020/3

Squamous cell neoplasms of the urinary tract 8052/0

Squamous papilloma

Squamous cell carcinomas of the urinary tract

8051/3 8070/3

Verrucous carcinoma Pure squamous carcinoma of the urothelial tract1

Glandular neoplasms

8263/0

Adenomas Villous adenoma Tubular adenoma Tubulovillous adenoma

8140/3 8144/3 8480/3 8323/3 8490/3 8140/2

Adenocarcinomas Adenocarcinoma, NOS Enteric adenocarcinoma Mucinous adenocarcinoma Mixed adenocarcinoma Signet-ring cell adenocarcinoma Adenocarcinoma in situ

8261/0 8211/0

4

ICD-0 coding of urinary and male genital tumours

ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Urachal and diverticular neoplasms 8010/3 8120/3

Urachal carcinoma Invasive urothelial carcinoma (code to site)

Urethral neoplasms Urethral accessory gland carcinomas 8140/3 8140/3 8140/3

Carcinoma of Littre glands Carcinoma of Skene glands Carcinoma of Cowper glands

Tumours of MOIIerian type 8310/3

Clear cell carcinoma

8380/3

Endometrioid carcinoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1457). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and 16 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. n/a, not available (provisional entity).

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022. f Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

5

ICD-0 coding of tumours of the prostate ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Epithelial tumours of the prostate Glandular neoplasms of the prostate

8440/0 8148/2

Cystadenoma Prostatic intraepithelial neoplasia, high-grade

8500/2 8140/3

Intraductal carcinoma Acinar adenocarcinoma

8490/3

Signet-ring cell-like acinar adenocarcinoma

8140/3 8572/3 8140/3 8500/3

Pleomorphic giant cell acinar adenocarcinoma Sarcomatoid acinar adenocarcinoma Prostatic intraepithelial neoplasia-like carcinoma Ductal adenocarcinoma

8574/3

Adenocarcinoma with neuroendocrine differentiation

Squamous neoplasms of the prostate 8560/3 8070/3 8147/3

Adenosquamous carcinoma Squamous cell carcinoma Adenoid cystic (basal cell) carcinoma1

Mesenchymal tumours unique to the prostate Stromal tumours of the prostate 8935/1 8935/3

Stromal tumour of uncertain malignant potential Stromal sarcoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) (1457). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

n/a, not available (provisional entity).

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022. t Labels marked with a dagger have undergone a change in terminology of a previous code.

6

ICD-0 coding of urinary and male genital tumours

ICD-0 coding of tumours of the seminal vesicle ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Epithelial tumours of the seminal vesicle Glandular neoplasms of the seminal vesicle 8440/0

Cystadenoma

8140/3

Adenocarcinoma

Squamous neoplasms of the seminal vesicle

8070/3

Squamous cell carcinoma

Other tumours of the seminal vesicle 8959/0

Mixed epithelial and stromal tumour

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2)

(1457). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. n/a, not available (provisional entity).

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022.

f Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

7

ICD-0 coding of tumours of the testis ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Germ cell tumours derived from germ cell neoplasia in situ Non-invasive germ cell neoplasia Germ cell neoplasia in situ Specific forms of intratubular germ cell neoplasia

9064/2

Intratubular seminoma Intratubular embryonal carcinoma Intratubular trophoblast

9061/2 9070/2 9061/2 9071/2 9080/2 9073/1

intratubular yolk sac tumour Intratubular teratoma Gonadoblastoma

The germinoma family of tumours 9061/3 Seminoma Seminoma with syncytiotrophoblastic cells 9061/3

Non-seminomatous germ cell tumours 9070/3 9071/3 9100/3 9104/3* 9105/3

9080/3 9084/3

Embryonal carcinoma Yolk sac tumour, postpubertal-type Choriocarcinoma Placental site trophoblastic tumour of the testis

Epithelioid trophoblastic tumour Cystic trophoblastic tumour Teratoma, postpubertal-type Teratoma with somatic-type malignancy

Mixed germ cell tumours of the testis 9085/3 Mixed germ cell tumours 9085/3 Polyembryoma 9085/3 Diffuse embryoma Germ cell tumours of unknown type Regressed germ cell tumours

9080/1

Germ cell tumours unrelated to germ cell neoplasia in situ 9063/3 9063/3 9084/0 9084/0 9084/0 9071/3 8240/3 9085/3

8

Spermatocytic tumour Spermatocytic tumour with sarcomatous differentiation Teratoma, prepubertal-type Dermoid cyst Epidermoid cyst Yolk sac tumour, prepubertal-type Well-differentiated neuroendocrine tumour (monodermal teratoma)

Mixed teratoma and yolk sac tumour, prepubertal-type

ICD-0 coding of urinary and male genital tumours

ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Sex cord stromal tumours of the testis Leydig cell tumour

8650/1 8650/3

Leydig cell tumour Malignant Leydig cell tumour

Sertoli cell tumours

8640/1

Sertoli cell tumour

8640/3 8642/1

Malignant Sertoli cell tumour Large cell calcifying Sertoli cell tumour

Granulosa cell tumours

8620/1

Adult granulosa cell tumour

8622/0

Juvenile granulosa cell tumour

The fibroma thecoma family of tumours 8600/0 Thecoma 8810/0

Fibroma

Mixed and other sex cord stromal tumours 8592/1 Mixed sex cord-stromal tumour 8590/0 Signet ring stromal tumour 8590/0 Myoid gonadal stromal tumour1

8590/1

Sex cord-stromal tumour, NOS

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1457}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

n/a, not available (provisional entity).

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022. + Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

9

ICD-0 coding of tumours of the testicular adnexa ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Ovarian-type tumours of the collecting ducts and rete testis 8441/0 8442/1 8441/3 8470/0 8472/1 8470/3

8380/1 8380/3 8310/3 9000/0

Serous cystadenoma, NOS Serous borderline tumour, NOS

Serous cystadenocarcinoma

Mucinous cystadenoma Mucinous borderline tumour Mucinous cystadenocarcinoma Endometrioid tumour, borderline Endometrioid adenocarcinoma Clear cell adenocarcinoma

Brenner tumour

Tumours of the collecting ducts and rete testis 8140/0 8140/3

Adenoma Adenocarcinoma

Paratesticular mesothelial tumours 9054/0 9052/0 9050/3 9052/3 9051/3 9053/3

Adenomatoid tumour Well-differentiated papillary mesothelial tumour

Mesothelioma Epithelioid mesothelioma Sarcomatoid mesothelioma Biphasic mesothelioma

Tumours of the epididymis 8440/0 8450/0 8140/3 8070/3 9363/0

Cystadenoma of the epididymis

Papillary cystadenoma Adenocarcinoma of the epididymis Squamous cell carcinoma Melanotic neuroectodermal tumour

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1457}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

n/a, not available (provisional entity). * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022. + Labels marked with a dagger have undergone a change in terminology of a previous code.

10

ICD-0 coding of urinary and male genital tumours

ICD-0 coding of tumours of the penis and scrotum ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Benign and precursor squamous lesions Condyloma acuminatum Squamous cell carcinoma precursors, HPV-associated

8077/2

High-grade squamous intraepithelial lesion

Squamous cell carcinoma precursors, HPV-independent 8071/2 Differentiated penile intraepithelial neoplasia

Invasive epithelial tumours of the penis and scrotum Invasive squamous epithelial tumours 8085/3 Squamous cell carcinoma, HPV-associated 8083/3 Basaloid squamous cell carcinoma 8054/3 8084/3 8082/3 8086/3

8086/3 8051/3 8052/3 8074/3 8070/3 Other epithelial 8560/3 8430/3 8542/3

Warty carcinoma Clear cell squamous ceil carcinoma Lymphoepithelial carcinoma Squamous cell carcinoma, HPV-independent Squamous cell carcinoma, usual type Verrucous carcinoma (including carcinoma cuniculatum) Papillary squamous cell carcinoma Sarcomatoid squamous cell carcinoma Squamous cell carcinoma, NOS

tumours Adenosquamous carcinoma

Mucoepidermoid carcinoma Paget disease, extramammary

Other scrotal tumours 8090/3

Basal cell carcinoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1457}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries.

This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

n/a, not available (provisional entity). * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022.

十 Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

11

ICD-0 coding of neuroendocrine neoplasms ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

ICD-O-3.2

Neuroendocrine tumours Neuroendocrine tumour, NOS

8240/3

8240/3 8249/3

Neuroendocrine tumour, grade 1 Neuroendocrine tumour, grade 2

Neuroendocrine carcinomas 8041/3 8013/3 8154/3 8045/3 8013/3

Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Mixed neuroendocrine-non-neuroendocrine neoplasm Combined small cell neuroendocrine carcinoma Combined large cell neuroendocrine carcinoma

Paragangliomas 8693/3

Extra-adrenal paraganglioma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2)

{1457}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. n/a, not available (provisional entity).

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022.

'Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of mesenchymal tumours ICD-O-3.2

(ICD-O-4.0)

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Fibroblastic and myofibroblastic tumours 9160/0 8825/0 8857/0 8815/0 8815/1 8815/1 8815/1 8815/3 8825/1

12

(91600/0) (88250/0) (88570/0) (88150/0) (88150/1)

(88150/3) (88251/1)

Cellular angiofibroma Myofibroblastoma Spindle cell / pleomorphic lipoma Solitary fibrous tumour, benign Solitary fibrous tumour, NOS Lipomatous solitary fibrous tumour Dedifferentiated (anaplastic) solitary fibrous tumour Solitary fibrous tumour, malignant Inflammatory myofibroblastic tumour

ICD-0 coding of urinary and male genital tumours

/

ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Vascular tumours 9120/0 9121/0

9131/0 9120/0 9125/0 9120/3

9120/3

Haemangioma, NOS

Cavernous haemangioma Capillary haemangioma Anastomosing haemangioma Epithelioid haemangioma Angiosarcoma

Epithelioid angiosarcoma

Pericytic (perivascular) tumours 8711/0 8712/0 8713/0 8711/1

Glomus tumour, NOS Glomangioma Glomangiomyoma Glomangiomatosis

8711/1 8711/3 9137/0 8824/0

Glomus tumour of uncertain malignant potential Malignant glomus tumour Myointimoma Myopericytoma

8714/0 8860/0 8714/3

PEComa, benign Sclerosing PEComa/angiomyolipoma Malignant PEComa

Smooth muscle tumours 8890/0

Leiomyoma, NOS

8897/1 8890/3 8890/3 8890/3

Smooth muscle tumour of uncertain malignant potential Leiomyosarcoma, NOS Superficial leiomyosarcoma Deep leiomyosarcoma

Skeletal muscle tumours 8910/3

Embryonal rhabdomyosarcoma, NOS

8920/3 8912/3

Alveolar rhabdomyosarcoma Spindle cell / sclerosing rhabdomyosarcoma

Tumours of uncertain differentiation 9040/3

9041/3 9043/3 9040/3 8963/3 8806/3

Synovial sarcoma, NOS Synovial sarcoma, monophasic

Synovial sarcoma, biphasic Synovial sarcoma, poorly differentiated Extrarenal rhabdoid tumour Desmoplastic small round cell tumour

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2)

(1457). Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

n/a, not available (provisional entity). * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022. * Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

13

ICD-0 coding of haematolymphoid tumours ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

Mature B-cell lymphomas 9699/3

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

9680/3

Diffuse large B-cell lymphoma, NOS

9734/3

Plasmacytoma, extramedullary

Histiocytic tumours 9749/1

Juvenile xanthogranuloma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2) {1457}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; Z2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.

n/a, not available (provisional entity). * Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022.

f Labels marked with a dagger have undergone a change in terminology of a previous code.

14

ICD-0 coding of urinary and male genital tumours

ICD-0 coding of melanocytic lesions ICD-O-3.2

ICD-0 label (subtypes are indicated in grey text, with the label indented); Please note that the WHO classification of tumour types is more readily reflected in the table of contents

8720/3 8746/3

Mucosal melanoma Mucosal lentiginous melanoma

8721/3

Nodular melanoma

These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2)

{1457}. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is

not generally used by cancer registries. This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions. n/a, not available (provisional entity).

* Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-0 at its meeting in Feb 2022.

f Labels marked with a dagger have undergone a change in terminology of a previous code.

ICD-0 coding of urinary and male genital tumours

15

TNM staging of urological tumours Urological Tumours Introductory Notes The following sites are included: • Penis

• • • • • •

Prostate Testis Kidney Renal pelvis and ureter Urinary bladder Urethra

Each site is described under the following headings: • Rules for classification with the procedures for assessing T, N, and M categories; additional methods may be used when they enhance the accuracy of appraisal before treatment

• Anatomical sites and subsites where appropriate • Definition of the regional lymph nodes • • • • •

Distant metastasis TNM clinical classification pTNM pathological classification G histopathological grading where applicable Stage

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition (429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

16

TNM staging of urological tumours

TNM staging of carcinomas of the penis Penis (ICD-0-3 060)

Rules for Classification

N - Regional Lymph Nodes

The classification applies only to carcinomas. There should be histological confirmation of the disease. The following are the procedures for assessing T, N, and M

NX NO N1 N2

Regional lymph nodes cannot be assessed No palpable or visibly enlarged inguinal lymph nodes Palpable mobile unilateral inguinal lymph node Palpable mobile multiple or bilateral inguinal lymph nodes

N3

Fixed inguinal nodal mass or pelvic lymphadenopathy

categories: T categories N categories M categories

Physical examination and endoscopy Physical examination and imaging Physical examination and imaging

Anatomical Subsites 1. 2. 3.

Prepuce (C60.0) Glans penis (C60.1) Body of penis (C60.2)

Regional Lymph Nodes The regional lymph nodes are the superficial and deep inguinal and the pelvic nodes.

TNM Clinical Classification T - Primary Tumour TX

Primary tumour cannot be assessed

TO Tis

No evidence of primary tumour Carcinoma in situ (penile intraepithelial neoplasia - PelN)

Ta T1

Non-invasive localized squamous cell carcinoma1 Tumour invades subepithelial connective tissue2 T1a

Tumour invades subepithelial connective tissue without lymphovascular invasion or perineural invasion and is not poorly differentiated

T1 b

T2

T3 T4

Tumour invades subepithelial connective tissue with lymphovascular invasion or perineural invasion or is poorly differentiated

Tumour invades corpus spongiosum with or without invasion of the urethra Tumour invades corpus cavernosum with or without invasion of the urethra Tumour invades other adjacent structures

unilateral or bilateral

M 一 Distant Metastasis MO M1

No distant metastasis Distant metastasis

pTNM Pathological Classification The pT categories correspond to the T categories. The pN categories are based upon biopsy, or surgical excision. pNX Regional lymph nodes cannot be assessed

pNO pN1 pN2

No regional lymph node metastasis Metastasis in one or two inguinal lymph nodes Metastasis in more than two unilateral inguinal nodes or

pN3

bilateral inguinal lymph nodes Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis

pM - Distant Metastasis* pM1

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories.

Stage Stage 0 Stage Stage Stage Stage Stage Stage

I IIA IIB IIIA IIIB IV

Tis Ta T1a T1btT2 T3 T1,T2,T3 T1,T2,T3 T4 Any T Any T

NO NO NO NO NO N1 N2 Any N N3 Any N

MO MO MO MO MO MO MO MO MO M1

Notes 1 Including verrucous carcinoma 2 Glans: Tumour invades lamina propria Foreskin: Tumour invades dermis, lamina propria or dartos fascia Shaft: Tumour invades connective tissue between epidermis and corpora and regardless of location

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition (429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

TNM staging of urological tumours

17

TNM staging of adenocarcinomas of the prostate Prostate (ICD-O-3C61.9)

Rules for Classification

N - Regional Lymph Nodes

The classification applies only to adenocarcinomas. Transitional

NX NO

Regional lymph nodes cannot be assessed No regional lymph node metastasis

N1

Regional lymph node metastasis

cell carcinoma of the prostate is classified as a urethral tumour (see p. 25). There should be histological confirmation of the

disease. The following are the procedures for assessing T, N, and M categories: Tcategories N categories M categories

Physical examination, imaging, endoscopy, biopsy, and biochemical tests Physical examination and imaging Physical examination, imaging, skeletal studies,

Note Metastasis no larger than 0.2 cm can be designated pNmi.

M - Distant Metastasis* MO M1

and biochemical tests

Regional Lymph Nodes The regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. Laterality does not affect the N

TNM Clinical Classification T 一 Primary Tumour

T2

T3

T4

M1b M1c

Bone(s) Other site(s)

Note * When more than one site of metastasis is present, the most advanced category is used. (p)M1c is the most advanced category.

classification.

TX TO T1

No distant metastasis Distant metastasis M1a Non-regional lymph node(s)

Primary tumour cannot be assessed No evidence of primary tumour Clinically inapparent tumour that is not palpable T1a Tumour incidental histological finding in 5% or less

T1b

of tissue resected Tumour incidental histological finding in more than

T1c

5% of tissue resected Tumour identified by needle biopsy (e.g. because

of elevated PSA) Tumour that is palpable and confined within prostate T2a Tumour involves one half of one lobe or less T2b Tumour involves more than half of one lobe, but

not both lobes T2c Tumour involves both lobes Tumour extends through the prostatic capsule* T3a Extraprostatic extension (unilateral or bilateral) including microscopic bladder neck involvement T3b Tumour invades seminal vesicle(s) Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphincter, rectum, levator muscles, and/or pelvic wall

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories. However, there is no pT1 category because there is insufficient

tissue to assess the highest pT category. There are no sub-cate­

gories of pT2.

pM - Distant Metastasis* pM1

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories.

G 一 Histopathological Grade Group12 GX

Grade cannot be assessed

Grade Group

Gleason Score

Gleason Pattern

1

《6

《3 + 3

2

7

3+4

3

7

4+3

4

8

4+4

5

9-10

4 +5, 5 +4, 5 + 5

Note * Invasion into the prostatic apex or into (but not beyond) the prostatic capsule is not classified as T3, but as T2.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

18

TNM staging of urological tumours

References

Stage* Stage Stage Stage Stage

I II III IV

T1,T2a T2b,T2c T3.T4 Any T Any T

NO NO NO N1 Any N

MO MO MO MO M1

Note

* The American Joint Committee on Cancer (AJCC) also publish a prognostic group for prostate tumours.

1

Epstein JI, Egevad L, Amin MB, et al. The 2014 International Society of Urological Pathology (ISUP) Consensus Conference on Gleason Grading of Prostatic Carcinoma: Definition of Grading Patterns and Proposal

for a New Grading System. Am J Surg Pathol 2016; 40:

2

244-252. Humphrey PA, Egevard L, Netto GL, et al. Acinar adenocarcinoma. In: WHO Classification of Tumours of the Urinary System and Male Genital Organs. Moch H, et al., eds. Lyon, France: IARC, 2016.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition (429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

TNM staging of urological tumours

19

TNM staging of germ cell tumours of the testis Testis (ICD-0-3 C62)

Rules for Classification

N - Regional Lymph Nodes

The classification applies only to germ cell tumours of the testis. There should be histological confirmation of the disease and

NX NO

division of cases by histological type. Histopathological grading

N1

is not applicable. The presence of elevated serum tumour markers, including alpha-fetoprotein (AFP), human chorionic gonadotropin (hCG), and lactate dehydrogenase (LDH), is frequent in this disease. Staging is based on the determination of the anatomic extent of disease and assessment of serum tumour markers. The following are the procedures for assessing N, M, and S

N2

N3

categories：

N categories M categories

Physical examination and imaging Physical examination, imaging, and biochemical

S categories

tests Serum tumour markers

Stages are subdivided based on the presence and degree of elevation of serum tumour markers. Serum tumour markers are obtained immediately after orchiectomy and, if elevated, should be performed serially after orchiectomy according to the normal decay for AFP (half-life 7 days) and hCG (half-life 3 days) to assess for serum tumour marker elevation. The S classification is based on the nadir value of hCG and AFP after orchiectomy. The serum level of LDH (but not its half-life levels) has prognostic value in patients with metastatic disease and is included for

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis with a lymph node mass 2 cm or less in greatest dimension or multiple lymph nodes, none more than 2 cm in greatest dimension Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension, or multiple

lymph nodes, any one mass more than 2 cm but not more than 5 cm in greatest dimension Metastasis with a lymph node mass more than 5 cm in greatest dimension

M - Distant Metastasis MO M1

No distant metastasis Distant metastasis M1a Non-regional lymph node(s) or lung metastasis

M1b

Distant metastasis other than non-regional lymph nodes and lung

pTNM Pathological Classification pT 一 Primary Tumour

Regional Lymph Nodes

Primary tumour cannot be assessed (see T - Primary Tumour) No evidence of primary tumour (e.g. histological scar in testis) Intratubular germ cell neoplasia (carcinoma in situ) Tumour limited to testis and epididymis without vascular/ lymphatic invasion; tumour may invade tunica albuginea

The regional lymph nodes are the abdominal para aortic (periaortic), preaortic, interaortocaval, precaval, paracaval,

pT2

but not tunica vaginalis* Tumour limited to testis and epididymis with vascular/

pT3

lymphatic invasion, or tumour extending through tunica albuginea with involvement of tunica vaginalis Tumour invades spermatic cord with or without vascular/

pT4

lymphatic invasion Tumour invades scrotum with or without vascular/lymphatic

pTX pTO

staging.

pTis pT1

retrocaval, and retroaortic nodes. Nodes along the spermatic vein should be considered regional. Laterality does not affect the N classification. The intrapelvic nodes and the inguinal nodes are considered regional after scrotal or inguinal surgery.

invasion

TNM Clinical Classification T - Primary Tumour Except for pTis and pT4, where radical orchiectomy is not always necessary for classification purposes, the extent of the primary tumour is classified after radical orchiectomy; see pT. In other circumstances, TX is used if no radical orchiectomy has been performed.

Note * The American Joint Committee on Cancer (AJCC) subdivides

T1 by T1a and T1b depending on size no greater than 3 cm or greater than 3 cm in greatest dimension.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

20

TNM staging of urological tumours

pN - Regional Lymph Nodes pNX pNO

Prognostic Group

Regional lymph nodes cannot be assessed No regional lymph node metastasis

pN1

Metastasis with a lymph node mass 2 cm or less in

pN2

greatest dimension and 5 or fewer positive nodes, none more than 2 cm in greatest dimension Metastasis with a lymph node mass more than 2 cm but

pN3

not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumour Metastasis with a lymph node mass more than 5 cm in

greatest dimension

0 I IA 旧

IS II IIA

Stage IIB Stage IIC Stage III Stage IIIA

pM - Distant Metastasis* pM1

Stage Stage Stage Stage Stage Stage Stage

Stage IIIB

Distant metastasis microscopically confirmed

Stage IIIC Note * pMO and pMX are not valid categories.

pTis pT1-4 pT1 pT2-4 Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX Any pT/TX

NO NO NO NO NO N1-3 N1 N1 N2 N2 N3 N3 Any N Any N Any N N1-3 Any N N1-3 Any N Any N

M0 M0 M0 M0 M0 MO MO MO MO MO MO MO M1a M1a M1a MO M1a MO M1a M1b

SO SX SO SO S1-3 SX SO S1 SO S1 SO S1 SX

so S1 S2 S2 S3 S3 Any S

S - Serum Tumour Markers SX

Serum marker studies not available or not performed

SO

Serum marker study levels within normal limits

LDH

hCG (mIU/mL)

AFP (ng/mL)

S1

< 1.5 x N

and < 5000

and 10 x N

or > 50 000

or > 10 000

Note N indicates the upper limit of normal for the LDH assay.

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {429,3242). © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

TNM staging of urological tumours

21

TNM staging of renal cell carcinoma Kidney (ICD-0-3 C64)

Rules for Classification

N - Regional Lymph Nodes

The classification applies only to renal cell carcinoma. There

NX NO N1

should be histological confirmation of the disease. The following are the procedures for assessing T, N, and M

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in regional lymph node(s)

categories: T categories N categories M categories

Physical examination and imaging Physical examination and imaging Physical examination and imaging

Regional Lymph Nodes The regional lymph nodes are the hilar, abdominal para-aortic, and paracaval nodes. Laterality does not affect the N categories.

M - Distant Metastasis MO

No distant metastasis

M1

Distant metastasis

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories.

pM - Distant Metastasis* pM1

TNM Clinical Classification T - Primary Tumour TX TO T1

T2

T3

Primary tumour cannot be assessed No evidence of primary tumour Tumour 7 cm or less in greatest dimension, limited to the

kidney T1a Tumour 4 cm or less T1b Tumour more than 4 cm but not more than 7 cm Tumour more than 7 cm in greatest dimension, limited to the kidney T2a Tumour more than 7 cm but not more than 10 cm T2b Tumour more than 10 cm, limited to the kidney Tumour extends into major veins or perinephric tissues

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories.

Stage Stage I Stage II Stage III Stage IV

T1 T2 T3 T1.T2.T3 T4 Any T

NO NO NO N1 Any N Any N

MO MO MO MO MO M1

but not into the ipsilateral adrenal gland and not beyond Gerota fascia

T4

T3a

Tumour extends into the renal vein or its segmental

T3b T3c

branches, or tumour invades the pelvicalyceal system or tumour invades perirenal and/or renal sinus fat (peripelvic) fat but not beyond Gerota fascia Tumour extends into vena cava below diaphragm Tumour extends into vena cava above the

diaphragm or invades the wall of the vena cava Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {429,3242). © 2017 IIICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

22

TNM staging of urological tumours

TNM staging of carcinomas of the renal pelvis and ureter Renal Pelvis and Ureter (ICD-O-3 C65, C66)

Rules for Classification

N - Regional Lymph Nodes

The classification applies to carcinomas. Papilloma is excluded. There should be histological or cytological confirmation of the

NX

Regional lymph nodes cannot be assessed

NO

No regional lymph node metastasis

disease. The following are the procedures for assessing T, N, and M

N1

Metastasis in a single lymph node 2 cm or less in greatest

categories:

N2

dimension Metastasis in a single lymph node more than 2 cm, or multiple lymph nodes

Tcategories N categories

Physical examination, imaging, and endoscopy Physical examination and imaging

M categories

Physical examination and imaging

M - Distant Metastasis MO M1

No distant metastasis Distant metastasis

Anatomical Sites 1. 2.

Renal pelvis (C65) Ureter (C66)

Regional Lymph Nodes The regional lymph nodes are the hilar, abdominal para-aortic, and paracaval nodes and, for ureter, intrapelvic nodes. Laterality does not affect the N classification.

TNM Clinical Classification T - Primary Tumour TX

Primary tumour cannot be assessed

TO

No evidence of primary tumour

Ta Tis

Non-invasive papillary carcinoma Carcinoma in situ

T1 T2 T3

Tumour invades subepithelial connective tissue Tumour invades muscularis (Renal pelvis) Tumour invades beyond muscularis into

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories.

pM - Distant Metastasis* pM1

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories.

Stage Stage Oa Stage Ois Stage I Stage II Stage III Stage IV

Any T Any T

NO NO NO NO NO NO N1.N2 Any N

MO MO MO MO MO MO MO M1

peripelvic fat or renal parenchyma (Ureter) Tumour invades beyond muscularis into T4

periureteric fat Tumour invades adjacent organs or through the kidney into

perinephric fat

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

TNM staging of urological tumours

23

TNM staging of carcinomas of the urinary bladder Urinary Bladder (ICD-O-3 C67)

Rules for Classification

N - Regional Lymph Nodes

The classification applies to carcinomas. Papilloma is excluded. There should be histological or cytological confirmation of the

NX NO N1

Regional lymph nodes cannot be assessed No regional lymph node metastasis Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral)

N2

Metastasis in multiple regional lymph nodes in the true pelvis (hypogastric, obturator, external iliac, or presacral) Metastasis in a common iliac lymph node(s)

disease. The following are the procedures for assessing T, N, and M categories:

T categories N categories M categories

Physical examination, imaging, and endoscopy Physical examination and imaging Physical examination and imaging

Regional Lymph Nodes

N3

M - Distant Metastasis MO M1

The regional lymph nodes are the nodes of the true pelvis, which essentially are the pelvic nodes below the bifurcation of the common iliac arteries. Laterality does not affect the

N classification.

No distant metastasis Distant metastasis M1a Non-regional lymph nodes M1 b Other distant metastasis

pTNM Pathological Classification The pT and pN categories correspond to the T and N categories.

TNM Clinical Classification T - Primary Tumour The suffix (m) should be added to the appropriate T category to

indicate multiple tumours. The suffix (is) may be added to any T to indicate presence of associated carcinoma in situ. TX Primary tumour cannot be assessed TO No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis T1 T2

Carcinoma in situ: 'flat tumour' Tumour invades subepithelial connective tissue Tumour invades muscularis propria T2a

Tumour invades superficial muscularis propria

T2b

(inner half) Tumour invades deep muscularis propria (outer

T3

half) Tumour invades perivesical tissue:

T4

T3a microscopically T3b macroscopically (extravesical mass) Tumour invades any of the following: prostate stroma,

pM 一 Distant Metastasis* pM1

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories.

Stage Stage Stage Stage Stage Stage

Oa Ois I II IIIA

Stage IIIB Stage IVA Stage IVB

Ta Tis T1 T2a,T2b T3a,T3b,T4a T1,T2,T3,T4a T1,T2,T3,T4a T4b Any T Any T

NO NO NO NO NO N1 N2.N3 Any N Any N Any N

seminal vesicles, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate stroma, seminal vesicles,

T4b

uterus or vagina Tumour invades pelvic wall or abdominal wall

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition (429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

24

TNM staging of urological tumours

TNM staging of carcinomas of the urethra Urethra (ICD-O-3C68.0, C61.9)

Rules for Classification

N 一 Regional Lymph Nodes

The classification applies to carcinomas of the urethra (ICD-0-3 C68.0) and transitional cell carcinomas of the prostate (ICD-0-3

NX

Regional lymph nodes cannot be assessed

NO N1 N2

No regional lymph node metastasis Metastasis in a single lymph node Metastasis in multiple lymph nodes

C61.9) and prostatic urethra. There should be histological or cytological confirmation of the disease. The following are the procedures for assessing T, N, and M categories：

M - Distant Metastasis

Tcategories

Physical examination, imaging, and endoscopy

N categories

Physical examination and imaging

M categories

Physical examination and imaging

MO M1

No distant metastasis Distant metastasis

pTNM Pathological Classification

Regional Lymph Nodes The regional lymph nodes are the inguinal and the pelvic nodes. Laterality does not affect the N classification.

TNM Clinical Classification T - Primary Tumour TX TO

Primary tumour cannot be assessed No evidence of primary tumour

Urethra (male and female) Ta Non-invasive papillary, polypoid, or verrucous carcinoma Tis T1 T2

Carcinoma in situ Tumour invades subepithelial connective tissue Tumour invades any of the following: corpus spongiosum,

T3

prostate, periurethral muscle Tumour invades any of the following: corpus cavernosum,

T4

beyond prostatic capsule, anterior vagina, bladder neck (extraprostatic extension) Tumour invades other adjacent organs (invasion of the

The pT and pN categories correspond to the T and N categories.

pM - Distant Metastasis* pM1

Distant metastasis microscopically confirmed

Note * pMO and pMX are not valid categories.

Stage Stage Oa Stage Ois Stage I Stage II Stage III

T1,T2

Stage IV Any T Any T

NO NO NO NO N1 N0.N1 N0.N1 N2 Any N

MO MO MO MO MO MO MO MO M1

bladder) Urothelial (transitional cell) carcinoma of the prostate

Tis T1

T2 T3

T4

Carcinoma in situ, involving the prostatic urethra, periurethral or prostatic ducts without stromal invasion Tumour invades subepithelial connective tissue (for tumours involving prostatic urethra only) Tumour invades any of the following: prostatic stroma, corpus spongiosum, periurethral muscle Tumour invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck (extraprostatic extension) Tumour invades other adjacent organs (invasion of the

bladder or rectum)

The information presented here has been excerpted from the 2017 TNM classification of malignant tumours, eighth edition {429,3242}. © 2017 UICC. A help desk for specific questions about the TNM classification is available at https://www.uicc.org/tnm-help-desk.

TNM staging of urological tumours

25

Introduction to urinary and male genital tumours Edited by: Moch H, Tickoo SK

Introduction to urinary and male genital tumours

This fifth-edition volume of the WHO Classification of Tumours series (the WHO Blue Books), devoted to tumours of the urinary and male genital tracts, is a complete revision of the fourth­ edition volume published in 2016 (2191). In the fourth-edition volume on urological tumours there were dramatic changes in tumour classification across all anatomical sites, which is not surprising considering that the third edition had been published some 12 years earlier (914). Although there is less change over­ all in this newest volume, considerable advances have been made since 2016 and, as appropriate, these have been incor­ porated herein. Many approaches to classification used in the earlier edition have been validated, and new advances have occurred. In recent years, precision medicine and targeted therapies, and their increased adoption in clinical practice, have had a major impact in the field by complementing the role of histo­ pathology in the prognostication and prediction of cancer. The application of molecular profiling has also made a substantial impact on tumour taxonomy and the classification of human malignancies, most notably observed in kidney cancer among the urological malignancies. Thus, while morphology remains the foundation for the taxonomy in this new volume, there is in addition a group of molecularly defined renal tumour entities. This also extends to independent molecular approaches to the classification of urothelial carcinoma (1308A,1603A(, which have provided a novel way of conceptualizing bladder cancer beyond the traditional low- and high-grade categories for noninvasive carcinomas. These approaches and the emerging role of immunotherapies for the management of select advanced malignancies are also likely to influence future paradigms of tumour taxonomy. The increasing emphasis on molecular classification under­ scores the importance of having appropriate ancillary tech­ nology in our pathology laboratories. High-quality immuno­ histochemistry and molecular testing have become crucial for accurate cancer diagnosis, prognosis, and prediction. This has important implications for low- and middle-income countries, where it may be difficult to get high-quality routine histology, let alone contemporary ancillary testing. Even in high-income countries, the availability of immunohistochemistry and molecu­ lar testing may be limited because of geographical, fiscal, and human resource issues. These facts have implications for the WHO Blue Books, because they are written for worldwide use. Therefore, major emphasis is placed on histopathological cri­ teria, and essential and desirable diagnostic criteria are listed within each entity section. Unlike for some anatomical sites (such as breast and lung) where predictive biomarker testing has become routine, and indeed critical for patient management, this has not been the case thus far for urological cancers. However, there is ongoing work related to the role of immunotherapies in advanced-stage bladder cancer and other urological tumours. Thus, the role of 28

Introduction to urinary and male genital tumours

Srigley JR Amin MB Gill AJ Turajlic S

testing for markers such as PDL1 is rapidly evolving and may assume increased importance. Additionally, alterations in DNA repair genes may be important in identifying patients, for instance those with castration-resistant prostate cancer, who should receive PARP inhibitor therapy or other novel treatments {794}. In keeping with other volumes in the fifth edition, tumour categories that are not unique to the genitourinary organs are handled in separate chapters after those dealing with the spe­ cific anatomical sites. For instance, neuroendocrine neoplasms, which can occur in many organ systems and in several ana­ tomical sites within a given organ system, are handled in a dedi­ cated chapter. The classification and terminology developed at the 2017 International Agency for Research on Cancer (IARC) neuroendocrine neoplasms consensus conference is used {2674}. Instead of having multiple separate sections about an entity such as small cell neuroendocrine carcinoma (SCNEC) in the kidney, bladder, upper urothelial tract, and prostate chap­ ters, there is a single section devoted to SCNEC within the neuroendocrine neoplasms chapter; however, a separate sec­ tion on treatment-related neuroendocrine carcinoma (NEC) has been included only in the prostate chapter, because this aspect is unique to that site. There are also chapters devoted specifically to mesenchy­ mal, haematolymphoid, melanocytic, and metastatic tumours, as well as a separate chapter on the diverse genetic syndromes relevant to the urinary and male genital tracts. In recent years, there have been some major unresolved controversies in urological pathology that have led to the state where two separate societies now represent the field. The edi­ torial leadership of the current volume has sought appropriate balance in assembling the authorship teams. These major controversies are in the field of prostate cancer and relate to intraductal carcinoma of the prostate and whether it should be included in the Gleason grading, as well as other nuances of grading and nomenclature. As much as possible, the current WHO classification of urinary and male genital tumours strives to use evidence in defining entities. A hierarchical approach to evidence is used, with the following categories listed in decreasing order of significance: systematic reviews, prospec­ tive controlled trials, retrospective cohort studies, series and case reports, and expert opinion. Understandably, for some topics, decisions are based solely on expert opinion because no other evidence exists expert opinion is still evidence, even if prone to bias. It is also important to remember that this vol­ ume represents a structured classification document for urinary and male genital tumours and not a comprehensive textbook or atlas of urological pathology. Therefore, some details on topics such as tumour grading and staging, and the complete morphological range for a given neoplastic entity, cannot be covered. In this volume, the anatomical sites are covered in the follow­ ing order: kidney, urinary tract, prostate gland, seminal vesicle,

一

testis, testicular adnexa, and penis and scrotum. Each chapter contains its own introduction, in which major changes and con­ troversies are outlined. Furthermore, some introductions cover topics and entities that do not have a dedicated section. In the following paragraphs, some highlights of the classification are presented. The adult renal tumour classification in the fourth edition was heavily based on the 2013 International Society of Urological Pathology (ISUP) Vancouver classification {3014). This taxon­ omy has evolved in the current iteration, with some new entities added, including eosinophilic, solid, and cystic renal cell carci­ noma; ELOC (formerly TCEB7)-mutated renal cell carcinoma; and SMARCB1 (INH)-deficient renal medullary carcinoma. The last two belong to a new subcategory of molecularly defined renal cell carcinomas. /A/-^-rearranged renal cell carcinoma (RCC), which was included in the emerging RCC category in the fourth edition, is now included as a recognized entity. Further­ more, hereditary leiomyomatosis and RCC syndrome-associ­ ated RCC is subsumed under the fumarate hydratase-deficient RCC category, which also includes some sporadic tumours. In the urothelial tract, the binary approach to morphological grading of papillary carcinoma is maintained, which reflects to a great extent the two major pathways of evolution of urothelial neoplasms. Furthermore, papillary urothelial neoplasm of low malignant potential is retained as a diagnostic category. In the invasive urothelial carcinoma category, there is focus on the importance of subtype histology, including aggressive sub­ types such as plasmacytoid and micropapillary urothelial car­ cinoma. Beyond morphology, there is increasing emphasis on the molecular classification of urothelial carcinoma, with several proposed omics schemes (2686,2185,1576). This approach may prove useful in stratifying prognosis in the morphologically defined low- and high-grade categories. The prostate section sees no dramatic changes in the classifi­ cation. However, there is a distinction (which may be somewhat arbitrary) between histological patterns of acinar adenocarci­ noma, such as atrophic, pseudohyperplastic, cystic, foamy gland, and mucinous, and special subtypes of acinar adenocar­ cinoma, which include prostatic intraepithelial neoplasia-like, plasmacytoid (signet ring-like), sarcomatoid, and pleomorphic giant cell adenocarcinoma. The subtypes have implications that relate to differential diagnosis and/or prognosis, whereas the patterns have no special prognostic significance beyond their associated Gleason grade but are important because they may simulate a benign histological pattern and may be under­ recognized as malignant. A succinct segment deals with Gleason grading and empha­ sizes the importance of providing the underlying Gleason grades and not relying entirely on the derivative grade groups (ISUP grades), which may be heterogeneous (i.e. grade group 4). Because a variety of names are used in the literature to indicate the grade grouping, it is suggested that the term "WHO grade" be used for the sake of simplicity and harmonization. This is also

consistent with the recommended WHO nomenclature used in this volume for bladder, kidney, and penile carcinoma grading. The issue of including (or excluding) intraductal carcinoma in the Gleason grade is controversial because the two socie­ ties representing urological pathology have different views on this matter. Additional studies are required to compare the two approaches from a prognostic perspective. In view of the lack of evidence supporting one position over the other, the deci­ sion as to which to use is left up to the pathologist working in a particular multidisciplinary environment. It is recognized that classic Gleason grading is an important independent prognostic factor that correlates with PSA level, clinical recurrence, and survival; however, Gleason grading has reproducibility issues, with only modest kappa scores. The fields of artificial intelligence (Al) and computational pathology hold great promise for improving both the effectiveness and reproducibility of grading, leading to their special mention in the current edition {3048,466}. The classification of testicular germ cell neoplasms (TGCNs) follows that in the fourth edition, using a combined pathogenetic and morphological approach. Tumours associated with germ cell neoplasia in situ are type 2 in the pathogenetic classification {2385}. These tumours constitute the majority of adult TGCNs, and they are separated from the less common prepubertaltype teratomas, yolk sac tumours and mixed teratoma-yolk sac tumours (type 1 TGCNs), and spermatocytic tumours (type 3 TGCNs). Penile squamous cell carcinomas and associated precursor lesions are classified into HPV-associated and HPV-independent categories, like the those used in the fourth-edition WHO classification. This approach reflects the different pathogenetic mechanisms underlying penile cancer and is in keeping with the classification of squamous tumours at other sites. The diverse morphological patterns of penile squamous cell carcinoma are grouped in appropriate pathogenetic categories, and (where indicated) an attempt has been made to simplify the morpho­ logical classification. For the first time in the history of the geni­ tourinary WHO Blue Book, a separate classification on tumours of the scrotum is included with a separate section on basal cell carcinoma of the scrotum. The histology of squamous cell carci­ noma and extramammary Paget disease of the scrotum follows the same paradigm as that of the penile counterparts, so the same terminology is adopted for these tumours. Overall, the new WHO classification of urinary and male geni­ tal tumours is presented in a uniform format using standardized subsections, and it is structured as a database that can be easily modified going forward. As new clinical, morphological, and molecular genetic data and information are synthesized, the database can be modified and updated to form the basis of future editions of the WHO classification. Additionally, this book is available as an online resource, complete with digital illustra­ tions, whole slide images, and relevant hyperlinks, permitting users to have an enriched real-time experience.

Introduction to urinary and male genital tumours

29

Tumours of the kidney Edited by: Amin MB, Gill AJ, Hartmann A, Lazar AJ, Moch H, Tickoo SK, Turajlic S

Renal cell tumours

Clear cell renal tumours Clear cell renal cell carcinoma Multilocular cystic renal neoplasm of low malignant potential Papillary renal tumours Renal papillary adenoma Papillary renal cell carcinoma Oncocytic and chromophobe renal tumours Oncocytoma of the kidney Chromophobe renal cell carcinoma Other oncocytic tumours of the kidney Collecting duct tumours Collecting duct carcinoma Other renal tumours Clear cell papillary renal cell tumour

Mucinous tubular and spindle cell carcinoma Tubulocystic renal cell carcinoma Acquired cystic disease-associated renal cell carcinoma Eosinophilic solid and cystic renal cell carcinoma Renal cell carcinoma NOS Molecularly defined renal carcinomas 7FE3-rearranged renal cell carcinomas TT^B-altered renal cell carcinomas ELOC (formerly TCEB /)-mutated renal cell carcinoma Fumarate hydratase-deficient renal cell carcinoma Succinate dehydrogenase-deficient renal cell carcinoma MK-reairanged renal cell carcinomas SMARCB1-deficient renal medullary carcinoma

Metanephric tumours Metanephric adenoma Metanephric adenofibroma Metanephric stromal tumour Mixed epithelial and stromal renal tumours Mixed epithelial and stromal tumour of the kidney Paediatric cystic nephroma Renal mesenchymal tumours Adult renal mesenchymal tumours Classic angiomyolipoma / PEComa of the kidney Epithelioid angiomyolipoma / epithelioid PEComa of the kidney Renal haemangioblastoma Juxtaglomerular cell tumour Renomedullary interstitial cell tumour Paediatric renal mesenchymal tumours Ossifying renal tumour of infancy Congenital mesoblastic nephroma Rhabdoid tumour of the kidney Clear cell sarcoma of the kidney Embryonal neoplasms of the kidney

Nephroblastic tumours Nephrogenic rests Cystic partially differentiated nephroblastoma Nephroblastoma Miscellaneous renal tumours Germ cell tumours of the kidney

Renal cell tumours: Introduction

Epidemiology The incidence and mortality rates of renal cell tumours have been increasing in many countries, across different levels of socioeconomic development (see Table 2.01).

Incidence Renal cell carcinoma (RCC) accounts for 2% of all cancers globally and is the cause of 2% of cancer deaths {2417}. In 2020, there were 271 249 new cases in men (age-standardized rate of 6.1 cases per 100 000 population) and 160 039 cases in women (age-standardized rate of 3.2 cases per 100 000 popu­ lation) (3070). The M:F ratio was 1.24:1 in 1990 and 1.58:1 in 2017 {245). Kidney cancer currently ranks as the seventh most common cancer in men and the tenth most common in women {3076}. The incidence is higher in high-income countries than in low-income countries, with the highest rates in Belarus (agestandardized rate of 16.8 cases per 100 000 population) in 2018, followed by Latvia, Lithuania, and the Czech Republic (994). Elevated rates of kidney cancer are also found in northern and eastern Europe, North America, and Australia. Low rates are reported in Africa and eastern Asia {245).

Mortality Globally, deaths from kidney cancer increased from 68 140 in 1990 to 138 530 in 2017 {245}, with those in male patients exceeding those in female patients： in 2017, the total number

Raspollini MR Amin MB Moch H Tan PH Turajlic S

of deaths was 89 620 in male patients and 48 910 in female patients (245). Kidney cancer is the 16th most common cause of death from cancer worldwide. The case fatality rate is lower in high-income countries (overall mortality-to-incidence ratio: 0.4) than in low- and middle-income countries (0.5). Only 3.1% of the cases were diagnosed in Africa, but 5.7% of the deaths occurred in this region {245}.

Etiology

Obesity Obesity is a risk factor for kidney cancer in both men and women {228,1913). There is an association between baseline body mass index and renal cancer risk, with increased risk when raised body mass index is documented at age 50. Weight gain of > 20 kg between the ages of 18 and 35 years or between the ages of 35 and 50 years is correlated with renal cancer risk (23(. The propor­ tion of all cases of renal cancer attributable to being overweight or obese has been estimated at about 40% in the USA and up to 40% in European countries {2653,2654). The mechanisms by which obesity influences renal carcinogenesis are unclear, with chronic inflammation in adipose tissue and immune dysregulation potentially promoting carcinogenesis (1843). Renal cell pro­ liferation may be caused by sex steroid hormones through direct endocrine receptor-mediated effects. Obesity associated with endocrine disorders, accompanied by decreased levels of sex hormone-binding globulin and progesterone, insulin resistance,

Age standardized (World) incidence rates, kidney, males, all ages

Fig. 2.01 Renal cancer. Estimated age-standardized global incidence rates (World), per 100 000 person-years, of renal cancer in 2020 among males (all ages).

32

Tumours of the kidney

and increased levels of growth factors such as IGF1, may be factors in renal carcinogenesis. No convincing association has been found between the ingestion of red and processed meat­ poultry, or seafood and the risk of RCC (1826,1827}.

Smoking Cigarette smoking is causally related to renal cancer. Meta­ analyses indicate that ever-smokers have a higher risk of renal

cancer than never-smokers (638,1427), with a dose-dependent increase in risk related to the number of cigarettes smoked per day, and that risk decreases in the 5-year period after smoking cessation. Epidemiological data on kidney cancer causation by smoking are often biased because cancer registries do not typi­ cally differentiate between RCCs and urothelial carcinomas of the renal pelvis, for which smoking is also a significant risk fac­ tor. In a study on smoking prevalence among 30 282 patients

Table2.01 Relative proportions of kidney cancer types3 recorded by population-based cancer registries by age and geogr叩hical region, cases diagnosed in 2001-2010bc Age group (years) Renal cancer type

0d

1-4

5-9

10-14

15-19

Wilms tumour (Vla1)

1812

8751

2813

462

181

Rhabdoid renal tumour (Vla2)

197

109

15

6

4

Kidney sarcomas (Vla3)

57

286

55

33

7

Renal cell carcinomas (Vlb)

13

69

155

306

564

Unspecified (Vic)

33

87

38

23

44

2112

9302

3076

830

800

Wilms tumour

85.8%

94.1%

91.4%

55.7%

22.6%

Rhabdoid renal tumour

9.3%

1.2%

0.5%

0.7%

0.5%

Kidney sarcomas

2.7%

3.1%

1.8%

4.0%

0.9%

Renal cell carcinomas

0.6%

0.7%

5.0%

36.9%

70.5%

Unspecified

1.6%

0.9%

1.2%

2.8%

5.5%

Total numbers of cases in each age group, all world regions combined

All malignant renal tumours

Cases as a percentage of all malignant renal tumours

Relative proportions of Wilms tumour and renal cell carcinomas (n = total number of renal cancer cases registered per region) North America (n = 5943)

Wilms tumour

82.9%

93.8%

90.8%

48.6%

18.4%

Renal cell carcinomas

0.8%

0.6%

6.1%

46.5%

78.4%

Wilms tumour

87.4%

95.1%

92.5%

60.7%

26.0%

Renal cell carcinomas

0.4%

0.5%

4.3%

34.0%

64.4%

Wilms tumour

90.2%

93.4%

90.6%

58.7%

40.0%

Renal cell carcinomas

0.6%

0.9%

2.1%

24.0%

48.6%

84.2%

91.0%

89.6%

57.5%

33.3%

1.2%

2.1%

5.5%

23.8%

52.4%

Wilms tumour

90.7%

95.7%

95.8%

83.9%

21.7%

Renal cell carcinomas

0.0%

0.1%

2.5%

9.7%

60.9%

Wilms tumour

86.3%

94.7%

96.1%

33.3%

36.4%

Renal cell carcinomas

0.0%

1.3%

1.3%

63.0%

54.5%

Europe (n = 5682)

Latin America and the Caribbean (n = 1174)

Asia (n=1734) Wilms tumour

Renal cell carcinomas Africa (n = 1157)

Oceania (n = 403)

aTumours classified in group VI (renal tumours) according to the International Classification of Childhood Cancer (ICCC), third edition, 2017 update (ICCC-3-2017) (3077). bNumbers derived from population-based cancer registry data submitted by International Incidence of Childhood Cancer 3 (IICC-3) contributors (3028}. cData extracted from sup­ plementary Table S3 of Nakata et al. (2020) (2282). dNumbers do not include the benign entity mesoblastic nephroma; this entity is reported by a collaborative effort of international childhood renal tumour study groups to account for 54% of all renal tumours diagnosed in the first month, 33% in the second, 16% in the third, and < 10% of all tumours diagnosed

in the fourth and subsequent months of life (3276}.

Tumours of the kidney

33

Age standardized (World) incidence rates, kidney, females, all ages

■ ■ ■■ ■■

2 5.4 32-5.4 2.0>3.2 13-2.0 0.88-1.3 4/_/ 90%) have occurred in male patients with a median age of 60 years {1261,1787,24511.

Etiology ELOC mutations almost exclusively involve VHL protein binding site residue Y79, resulting in non-binding with the VHL complex and consequent HIF1 a accumulation and overexpression {2824, 1261(.

Pathogenesis ELOC encodes elongin C, which is part of the VHL complex that ubiquitinates and thereby inactivates HIF1a. In these neo­ plasms, inactivation of ELOC by mutation accompanied by the loss of the other allele (typically by the loss of the entire chromo­ some 8) abrogates the function of elongin C; this is consistent with its role as a tumour suppressor gene {1261}. The loss of function of elongin C prevents the degradation of HIF1a and results in its accumulation {1261,870}.

Not relevant

Histopathology These neoplasms have a nodular appearance at low power, cre­ ated by thick transecting fibromuscular bands. The architecture 76

Tumours of the kidney

Diagnostic molecular pathology These neoplasms are defined by ELOC mutations.

Fig. 2.51 ELOC (TCEBf)-mutated renal cell carcinoma. A The neoplasm demonstrates a branching tubulopapillary architecture and prominent smooth muscle stroma. B The

neoplastic clear cells intermingle with smooth muscle bundles. C The ne叩lasm has a tubulopapillary architecture and clear cells. D The neoplastic cells have voluminous cytoplasm.

Essential and desirable diagnostic criteria

Prognosis and prediction

Essential: demonstration of ELOC mutation is required to defini­ tively diagnose this neoplasm.

The majority of these neoplasms have an indolent course. Recently, 2 patients were reported to develop disseminated dis­ ease, but their tumours demonstrated high nuclear grade (870).

Staging ELOC-mutated RCC is staged using guidelines for adult RCC.

Tumours of the kidney

77

Hes 0 Gill AJ Gupta S Jimenez RE Smith SC Trpkov K

Fumarate hydratase-deficient renal cell carcinoma

Definition

Subtype(s)

Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is characterized by pathogenic alterations in the FH gene, a mixed morphological pattern, and characteristic prominent eosinophilic nucleoli.

None

Localization Kidney cortex

ICD-0 coding

Clinical features

8311/3 Fumarate hydratase-deficient renal cell carcinoma 8311/3 Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome-associated renal cell carcinoma

Patients frequently present with flank pain and haematuria, and with large unilateral solitary tumours, often at an advanced stage and with distant metastases {1303,602}. FH-deficient RCCs have also been documented in a sporadic setting, with­ out the associated cutaneous and uterine leiomyomas usually found in HLRCC syndrome. The recognition of FH-deficient RCC is important because it should initiate genetic counselling for the patient's family.

ICD-11 coding 2C90.0 Renal cell carcinoma of kidney, except renal pelvis

Related terminology Acceptable (in familial cases): hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome-associated renal cell carcinoma.

Epidemiology The prevalence of FH-deficient RCC is unknown. It is more common in male patients than in female patients (M:F ratio:

Fig. 2.52 Fumarate hydratase-deficient renal cell carcinoma. A A multiplicity (typically 2 2) of admixed morphological patterns is typical. The most common is the papillary pattern; the papillae are often hyalinized and lack foamy cells. B This example has a sieve-like architectural pattern. C The cells show at least focal eosinophilic macronucleoli, often with perinuclear haloes.

Fig. 2.53 Fumarate hydratase-deficient renal cell carcinoma. A This example resembles succinate dehydrogenase-deficient renal cell carcinoma, but prominent nucleoli are not identified and the intracytoplasmic vacuoles that are typical for succinate dehydrogenase-deficient renal cell carcinoma are not seen. B This example shows solid and papillary architectural patterns.

78

Tumours of the kidney

Fig. 2.54 Fumarate hydratase-deficient renal cell carcinoma. A Fumarate hydratase immunohistochemistry in an example with a sieve-like architectural pattern. B Tumours with oncocytic morphology are immunohistochemically negative for fumarate hydratase. The retained positivity in non-tumour cells serves as an internal positive control. C Im­

munohistochemistry for 2-succinocysteine in an example with solid and papillary architectural patterns. Note the presence of nuclear and cytoplasmic staining.

1.9:1). About 15% of patients with HLRCC syndrome develop renal carcinomas (median patient age: 44 years) {3205,877, 2128,3180). A recent study of unclassified RCCs in children and young adults revealed that 12% (4 of 33 cases) were FHdeficient RCCs (median patient age: 18 years) (1869(.

Etiology FH-deficient RCCs are caused by germline or (in a subset) somatic mutations in the FHgene (chromosome 1q43) (65,1094, 2817}, FH-deficient RCC is the preferred terminology for renal carcinomas with compatible morphology, negative FH and/or positive 2-succinocysteine (2SC) staining, and/or pathogenic FH mutation in the tumour, when the clinical and family history of skin and uterine leiomyomas is uncertain and the genetic status is unknown (1303,2980,2359).

Pathogenesis Biallelic inactivation of FH, which encodes a Krebs cycle enzyme that converts fumarate to Lmaleate, triggers oncometabolic fumarate accumulation, favouring aerobic glycolysis, decreasing oxidative phosphorylation, and perturbing several downstream pathways {1898,2550,2377,3060,1094,2861}.

Negative immunohistochemical staining for FH in tumour cells, in the presence of positive FH staining in internal non-neo­ plastic cells, is highly specific for FH-deficient RCC but typically not sensitive. In contrast, aberrant staining for 2SC is highly sen­ sitive for FH-deficient RCC but less specific (602,3205,1803, 2980,2251,320}. A low threshold for immunohistochemistry screening for FH and/or 2SC is recommended in difficult-toclassify renal carcinoma (1303,2980,1803,604,2979}.

Cytology Clustering, voluminous cytoplasm, nuclear pleomorphism, and macronucleoli characterize cytology samples {2421(.

Diagnostic molecular pathology Genetic counselling and testing is strongly recommended because biallelic FH mutation/inactivation may be gemnline or somatic.

Essential and desirable diagnostic criteria

FH-deficient RCCs are typically solitary tumours. They are solid or solid and cystic.

Essential: demonstration of germline/somatic mutation of FH or immunohistochemical evidence of FH deficiency (FH loss and/or 2SC expression). Desirable: presence of multiple admixed architectural patterns with at least focal macronucleoli; clinical and/or family history of skin and uterine leiomyomas (if associated with HLRCC syndrome).

Histopathology

Staging

FH-deficient RCCs typically demonstrate multiple admixed morphological patterns {1303,2980,602,2251}. The most com­ mon pattern is papillary, followed by solid, tubulocystic, cribriform/sieve-like, and cystic (1303,1803,602). The finding of at least focal eosinophilic macronucleoli is a nonspecific but common feature {2251). Many such cases in the past have been described as "unclassified, high-grade renal carcinoma", "unclassified renal carcinoma with dominant papillary pattern", "tubulocystic carcinoma with dedifferentiated foci", "type 2 pap­ illary carcinoma", or "collecting duct carcinoma" {1303,2980, 2359}. The morphological spectrum was recently expanded to include cases with low-grade oncocytic morphology, remi­ niscent of succinate dehydrogenase-deficient RCCs, but with retained SDHB expression (2979,1803,1243).

Staging follows the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) stag­ ing systems.

Macroscopic appearance

Prognosis and prediction FH-deficient RCCs are often aggressive, but some tumours have a favourable prognosis despite nuclear atypia (1303, 3180,2135}. Therefore, histological grading is not appropriate for these tumours. After a mean follow-up of 27 months, 39% of patients had died of disease and 26% showed disease pro­ gression {3205}. For FH mutation carriers, recommended sur­ veillance includes annual abdominal MRI for detection, wide excision, and consideration of retroperitoneal lymph node dis­ section for new tumours {2128}.

Tumours of the kidney

79

Succinate dehydrogenase-deficient renal cell carcinoma

Hes 0 Gill AJ Jimenez RE Rao P Trpkov K

Definition

Localization

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a malignant renal epithelial tumour composed of bland cells with eosinophilic cytoplasm characterized by a loss of immunohistochemical expression of SDHB.

SDH-deficient RCCs arise in the renal parenchyma, only rarely with extension into fat, veins, or sinuses {1129).

ICD-0 coding 8311/3 Succinate dehydrogenase-deficient renal cell carci­ noma

ICD-11 coding 2C90.0 & XH8EN1 Renal cell carcinoma of kidney, except renal pelvis & Succinate dehydrogenase-deficient renal cell car­ cinoma

Clinical features Patients with SDH-deficient RCC may present with vague flank pain or metastasis. However, it is more commonly asymptomatic and identified as an incidental finding on imaging. A personal or family history of germline mutation in one of the SDH genes or associated syndromic neoplasms (SDH-deficient RCC, phaeochromocytoma-paraganglioma, SDH-deficient gastrointestinal stromal tumour, or pituitary adenoma) may be an important clue to the diagnosis but is often absent (1125,1124).

Epidemiology

Related terminology None

Subtype ⑥

SDH-deficient RCC accounts for < 0.05-0.2% of all renal carci­ nomas (1129). Presentation in young adulthood is usual (median age: 35 years; range: 14-76 years {1129,3457}. There is a slight male predominance (M:F ratio: 1.8:1) (1129,3457).

None

Fig. 2.55 Succinate dehydrogenase-deficient renal cell carcinoma. A The neoplastic cells are cuboidal with eosinophilic to bubbly pale cytoplasm. B Distinctive cytoplasmic inclusions containing eosinophilic or pale flocculent material. C High-grade transformation in direct continuity with more typical areas. D In this example, the neoplastic cells demonstrate weak diffuse cytoplasmic expression of SDHB. Because this lacks a mitochondrial (i.e. granular) pattern of cytoplasmic expression and contrasts markedly with the expression in the internal positive controls, this pattern is considered negative.

80

Tumours of the kidney

Etiology

一

The overwhelming majority of patients reported to date have been found to have pathogenic germline variants in one of the SDH genes most commonly SDHB, followed by SDHA and SDHC (1132,1131,1129,1130). SDHD mutation is rarely, if ever, associated with RCC (1129,1125}.

Pathogenesis

High-grade SDH-deficient RCCs or cases with other morphol­ ogies may be unrecognizable; in some cases, the high-grade foci may be admixed with foci of typical low-grade morphol­ ogy. Therefore, a low threshold for SDHB immunohistochemis­ try is recommended in any unusual or difficult-to-classify renal tumour, particularly one with eosinophilic cytoplasm or occurring in a young patient (2979,1129). Cases associated with SDHA mutation more commonly show other morphologies, often with a higher nuclear grade and demonstrating papillary, solid, cribri­ form, or desmoplastic architecture {3516,2412,1517,2086}.

Inactivation of any one of the SDH genes, usually due to germ­ line mutation with the addition of a somatic second hit, leads to dysfunction of the SDH complex, a key respiratory enzyme on the inner mitochondrial membrane that links the Krebs cycle and the electron transport chain (1125,1124). The subsequent accumulation of oncometabolites causes tumorigenesis by acti­ vating the pseudohypoxic pathway {2216).

The diagnosis is not normally made cytologically. SDHB immu­ nohistochemistry may be difficult to interpret on cell block prep­ arations {1125).

Macroscopic appearance

Diagnostic molecular pathology

The tumours are usually well circumscribed with a tan-brown to red cut surface. Although they are mostly solid, cystic change is not uncommon (1131,1129,3457). Multifocal or bilateral tumours are found in as many as 30% of cases at long-term follow-up (1129,3457).

The diagnosis of SDH-deficient RCC is considered an indica­ tion for genetic counselling and for testing for germline mutation in the SDH genes (most commonly SDHB, followed by SDHC, SDHA, and SDHD). Large-scale deletions are not uncommon and should be considered before SDH mutation is excluded. Immunohistochemistry can be useful to assess the pathogenic­ ity of genetic variants of uncertain significance. Germline patho­ genic variants in SDHA are both relatively common (estimated to occur in up to 0.3% of the population) (1711} and demon­ strate an extremely low lifetime penetrance (recently estimated as 1.7%) {319). Therefore, SDHA mutation identified by large panel sequencing commonly represents an incidental finding unrelated to renal neoplasia {1711,908}.

Histopathology The majority of SDH-deficient RCCs are well-circumscribed or lobulated and show distinctive morphological features at least focally, demonstrating sheets or compact nests of bland cells with eosinophilic cytoplasm. The eosinophilic cytoplasm, which may have a pale, bubbly appearance, lacks the fine homoge­ neous granularity of oncocytoma. The cells also lack prominent cell borders, like in chromophobe RCC. The tumours commonly contain microcysts filled with pale eosinophilic fluid {1131,1129, 3457), Normal renal tubules are frequently entrapped at the periphery. A characteristic but inconstant feature is the pres­ ence of cytoplasmic inclusions containing eosinophilic or pale flocculent material. Higher-grade transformation may occur, heralded by denser cytoplasm, increased nuclear atypia with prominent nucleoli, coagulative necrosis, and occasionally sar­ comatoid change. Other morphologies, sometimes with a pap­ illary or sarcomatoid architecture, are increasingly recognized {1131,1129}. Loss of immunohistochemical expression of SDHB is a prereq­ uisite for the diagnosis of SDH-deficient RCC. Care is required when performing and interpreting SDHB immunohistochemis­ try. An internal positive control displaying strong mitochondrial (i.e. granular and cytoplasmic) reactivity in non-neoplastic cells is always required before a stain is considered negative. Fur­ thermore, weak diffuse cytoplasmic expression of SDHB should also be considered negative if it contrasts the strong granular mitochondrial expression in internal positive controls. Tumours associated with biallelic inactivation of SDHA also show a loss of SDHA (as well as SDHB) expression, whereas tumours driven by SDHB, SDHC, or SDHD mutation show preserved SDHA expression (1711,908}. Although no other immunohistochemi­ cal stains are definitive, these tumours usually show negative staining for KIT (CD117) (scattered mast cells are typically highlighted), and they are frequently negative for cytokeratins including CK7 (1129,3457(. Fumarate hydratase expression is consistently preserved.

Cytology

Essential and desirable diagnostic criteria Essential： loss of expression of SDHB in the presence of an internal positive control in non-neoplastic cells; cases asso­ ciated with SDHA mutation also show loss of expression of SDHA. Desirable: typical morphology, characterized by bland cells with eosinophilic (but not oncocytic) cytoplasm and occasional cytoplasmic inclusions, is usually present at least focally, but other morphologies are increasingly being recognized.

Staging The Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) staging system is used.

Prognosis and prediction The majority of SDH-deficient RCCs demonstrate uniform lowgrade morphology and have a favourable prognosis, with a meta­ static rate of 11% on long-term follow-up (1129,3457}, However, in the presence of high-grade features (coagulative necrosis and sarcomatoid transformation), the risk of metastasis is as high as 70% (1129(. Late recurrences, as long as 30 years after primary excision, have been reported; however, some of these late metas­ tases may originate from unsampled metachronous tumours (1129,3457). Long-term follow-up with surveillance for other SDH-deficient neoplasms (i.e. paraganglioma, SDH-deficient gastrointestinal stromal tumour, and pituitary adenoma) is indi­ cated for cases associated with germline mutation {1125,3207).

Tumours of the kidney

81

/A/.^rearranged renal cell carcinomas

Definition

Subtype(s)

/ALK-rearranged renal cell carcinomas (RCCs) harbour chro­ mosome translocations resulting in gene fusions involving the anaplastic lymphoma kinase gene {ALK) at chromosome 2p23.

None

Argani P Inamura K Williamson SR

Localization Renal medulla

ICD-0 coding 8311/3 /ALK-rearranged renal cell carcinomas

Clinical features

ICD-11 coding 2C90.0 Renal cell carcinoma of kidney, except renal pelvis

There have been approximately 50 reported cases, with nearly equal sex distribution. The patients have been both children and adults (age range: 3-85 years).

Related terminology

Epidemiology

None

Insufficient data

Fig. 2.56 Renal cell carcinoma with VCL::ALKgene fusion. A The neoplastic cells demonstrate striking cytoplasmic vacuolization. B There are numerous sickled erythrocytes scattered among the vacuolated neoplastic cells.

Fig. 2.57 Renal cell carcinoma with EML4::ALK gene fusion. A The neoplastic cells form irregular glands and cribriform structures within an oedematous and desmoplastic

stroma. B The tumour has a striking desmoplastic reaction, and it infiltrates the native kidney.

82

Tumours of the kidney

Etiology Unknown

Pathogenesis ALK fusions convert the ALK receptor tyrosine kinase into novel fusion proteins that constitutively drive downstream growth­ promoting pathways (2975(.

Macroscopic appearance Most of the tumours reported have been small and organ-confined at presentation (pT1). Tumours have generally had a solid to solid-cystic appearance with a tan-grey and variegated cut surface, ranging in size from 30 to 70 mm.

Histopathology The 4 well-characterized cases with a VCL::ALK gene fusion are distinctive in that they have affected young patients with sickle cell trait and have a distinctive morphology. These neo­ plasms are typically well-circumscribed, and they may have chronic inflammation at their periphery. They are composed of polygonal neoplastic cells with abundant eosinophilic cyto­ plasm and often striking vacuolization {809,2030,29751 Sickle­ shaped erythrocytes are more readily seen in extravasated blood than in blood vessels. These neoplasms have been proposed to be the eighth sickle cell nephropathy {2975}. ALKrearranged RCCs with fusion partners other than VCL (e.g. TPM3, EML4, STRN, and HOOK1) are more heterogeneous (3050,3056,1769,490,1767). They may show cytoplasmic vacuolization but often have papillary or cribriform architec­ ture and mucinous stroma. Intracytoplasmic mucin, scattered psammoma bodies, and rhabdoid morphology may be seen. Variant morphology resembling metanephric adenoma or mucinous tubular and spindle cell carcinoma has also been reported {1767}. Immunohistochemistry for ALK protein is a useful screening test for /A/.^-rearranged RCC. SMARCB1 (also known as INI1, SNF5, or BAF47), which is typically lost in the renal medullary carcinomas that affect patients with sickle cell trait, is retained. TFE3 immunoreactivity is frequently seen using automated staining techniques but is usually negative in more standardized overnight incubation procedures, and TFE3 gene rearrange­ ments are not present. The melanocytic markers HMB45 and melan-A are negative.

Fig. 2.58 ALK translocation renal cell carcinoma. Break-apart FISH for the ALK gene shows most nuclei with one split signal (separate red and green probes) per nucleus and the second copy with a fused (normal) pattern for the 人LKgene.

Cytology Not relevant

Diagnostic molecular pathology Demonstration of ALK rearrangement is required in cases with positive ALK immunohistochemistry (1767,3398).

Essential and desirable diagnostic criteria Essential： documentation of ALK rearrangement by break-apart FISH, or demonstration of an ALKgene fusion by sequencing. Desirable: sickle cell trait.

Staging Staging follows the same Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) sys­ tems as used for other subtypes of RCC.

Prognosis and prediction Follow-up of patients with ALK-rearranged RCC is limited. Twenty-two patients have had no evidence of disease in limited follow-up. Three patients have died of disease, and 10 are alive with disease. Three patients with metastatic disease have had dramatic responses to a targeted ALK inhibitor, a non-toxic and potentially highly effective treatment for such patients (2418(.

Tumours of the kidney

83

SMARCB1-deficient renal medullary carcinoma

Argani P Agaimy A Colombo P Comperat EM Hartmann A

Montironi R OdaY Rao P Sirohi D

Definition Renal medullary carcinoma is a high-grade adenocarcinoma with SMARCB1 (INI1) deficiency, typically centred in the renal medulla and occurring mainly in patients with sickle cell trait.

ICD-0 coding 8510/3 Medullary carcinoma, NOS 8510/3 SMARCB1 -deficient medullary-like renal cell carcinoma 8510/3 SMARCBI-deficient undifferentiated renal cell carci­ noma, NOS 8510/3 SMARCBI-deficient dedifferentiated renal cell carcino­ mas of other specific subtypes

ICD-11 coding 2C90.Y & XH2YP5 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Medullary carcinoma, NOS

Related terminology

Fig. 2.59 Renal medullary carcinoma. The fleshy neoplasm has an irregular border

Acceptable: renal medullary carcinoma.

with the native kidney.

Subtype(s) SMARCBI-deficient medullary-like renal cell carcinoma; SMARCBI-deficient undifferentiated renal cell carcinoma NOS; SMARCBI-deficient dedifferentiated renal cell carcinomas of other specific subtypes

have not been documented in renal medullary carcinoma. Virtu­ ally all patients have symptoms at diagnosis, the most common being haematuria and flank or abdominal pain. Other common presenting symptoms are an abdominal mass, dysuria, and weight loss.

Localization

Epidemiology

SMARCB1 (INH)-deficient renal medullary carcinoma arises in any location of the renal cortex or medulla.

Age at diagnosis of SMARCBI-deficient renal medullary car­ cinoma ranges from childhood to the seventh decade of life {1434,32,1677,2621,3568). There is a male predominance (M:F ratio: 2:1). Most reported cases of renal medullary carcinoma have been in patients of African ancestry (3411), Almost all patients have

Clinical features There are no symptoms unique to this type of renal cell carci­ noma (RCC). Multifocality, bilaterality, and early age of onset

Fig. 2.60 Renal medullary carcinoma. A The neoplastic cells form cribriform, adenoid cystic-like structures within an oedematous desmoplastic stroma. A native renal tubule is present to the lower left. B The neoplasm invades into the renal pelvic urothelium, which leads to haematuria.

84

Tumours of the kidney

had sickle cell trait or haemoglobin SC disease, but a few have had sickle cell disease. A few patients have been reported to have tumours morphologically identical to renal medullary carcinoma but without any haemoglobinopathy {2350}. Such tumours have previously been termed "unclassified renal cell carcinoma with medullary phenotype" {134,2951}.

Etiology Among patients with renal medullary carcinoma (and in the gen­ eral population), there are many more individuals with sickle trait than with sickle cell disease. The two conditions confer a similar risk (about 1/40 000 over a 10-year period) of developing renal medullary carcinoma (2243,141).

Pathogenesis In renal medullary carcinomas, the hypoxic and hypertonic environment of the renal medulla, exacerbated by microvascular occlusion by sickle-shaped erythrocytes, may promote the DNA double-strand breaks that are prerequisites for the trans­ locations and deletions that inactivate SMARCB1 {2243(. About three quarters of these tumours occur in the right kidney; this predilection may be accounted for by the greater length of the right renal artery, which results in less blood flow and relative hypoxia in the right kidney.

Macroscopic appearance Renal medullary carcinomas are usually large and poorly cir­ cumscribed, ranging from 40 to 120 mm (mean: 70 mm). Smaller tumours are often centred in the renal medulla. The cut surface of the tumour is frequently tan or grey-white and often shows necrosis.

Histopathology Renal medullary carcinoma cells typically grow as infiltrating cords, nests, microcysts, sheets, and tubules. Round empty spaces from individual cell necrosis are common, and when numerous, they can impart a cribriform, adenoid cystic carci­ noma-like appearance. There is usually a pronounced myxoid desmoplastic reaction with a chronic inflammatory cell infiltrate. The carcinoma cells may show marked nuclear pleomorphism, and they may have vesicular chromatin, prominent nucleoli,

and eosinophilic cytoplasm, imparting a rhabdoid appearance. Mitotic figures are numerous. Sickle-shaped erythrocytes are very frequent, both in the vessels within the tumour and in nontumoural renal parenchyma. By immunohistochemistry, renal medullary carcinomas demonstrate loss of SMARCB1 (also known as INI1, SNF5, or BAF47) protein |609). Renal medullary carcinomas typically label diffusely for PAX8, broad spectrum cytokeratins, EMA, and vimentin (1908,1234). There is variable labelling for CK7, high-molecular-weight cytokeratin, CEA, and p53. OCT3/4 is strongly positive in about 50% of cases {2618}, which creates a potential diagnostic pitfail with metastatic germ cell tumours when young patients present with extensive retroperitoneal nodal involvement. Ultrastructurally, the carcinoma cells contain vesicles lined by long microvilli, prominent desmosomes, and condensed fibrillary electron-dense deposits. Intracytoplasmic glycogen or lipids are not prominent {3406). The main differential diagnostic considerations for renal med­ ullary carcinoma in children are the VCLMLK fusion RCCs that also occur in patients with sickle cell trait, and renal rhabdoid tumours that occur almost exclusively in very young patients (29). In adults, the differential diagnosis is mainly high-grade inva­ sive urothelial carcinoma or collecting duct carcinoma. Clinical evidence of sickle cell trait and young age at presentation are typical of renal medullary carcinoma, whereas the presence of in situ urothelial carcinoma or GATA3 positivity favour urothelial carcinoma. The differential diagnosis also includes other renal cancer subtypes with secondary SMARCB1 (INI1) deficiency (e.g. clear cell RCC with sarcomatoid differentiation, collecting duct carcinoma with secondary SMARCB1 loss (29}, or fumarate hydratase [FH]-deficient RCC with secondary SMARCB1 loss {30}). Secondary SMARCB1 deficiency does not constitute a dis­ tinct entity, and these tumours should be reported according to their underlying morphological or genetic (e.g. FH-deficient) sub­ type. Secondary SMARCB1 deficiency has been reported in only a few studies. It is more common among dedifferentiated and undifferentiated or sarcomatoid RCC, but such tumours are prob­ ably underreported because SMARCB1 is not evaluated in the majority of poorly differentiated and undifferentiated adult RCCs

Fig. 2.61 Renal medullary carcinoma. A The neoplastic cells form cords in a desmoplastic stroma. They frequently undergo necrosis. B Extravasated red blood cells within

the neoplasm demonstrate sickling.

Tumours of the kidney

85

Fig. 2.62 Undifferentiated SMARCB1-deficient renal cell carcinoma NOS. A Undifferentiated renal cell carcinoma with SMARCB1 (INI1) loss. Prominent neutrophilic infiltrates are seen frequently in these tumours. B The neoplastic cells demonstrate loss of SMARCB1 (INI1). The surrounding non-neoplastic stromal cells and entrapped native renal

tubules demonstrate appropriate nuclear immunoreactivity.

{32,1677,2621,3568}. A single case has been reported to be asso­ ciated with a SMARCB1 exon 4 mutation and the ASPSCR1::TFE3 fusion gene (3568). Another case showed VHL exon 1 mutation and chromosome 3 deletion {26211，One FH-deficient RCC (with verified FH mutation) had complete SMARCB1 loss but no detectable SMARCB1 (INI1) mutation by sequencing (30). Such examples support the contention that SMARCB1 loss in these cases probably represents a secondary event. Therefore, these tumours should be classified according to their primary tumour type as collecting duct carcinoma with secondary SMARCB1 loss {29}, FH-deficient RCC with secondary SMARCB1 loss (30), and unclassified RCC with secondary SMARCB1 loss. Some unclassified RCCs with a medullary phenotype show complete loss of SMARCB1 but no association with haemoglobinopathies. These tumours can be regarded as subtypes of SMARCB1-deficient RCC with medullary-like features or phe­ notype.

carcinoma, loss of SMARCB1 protein expression arises through concurrent hemizygous loss and translocation, or by homozy­ gous loss {1515}. Secondary SWI/SNF deficiency in non-medullary RCC is often associated with multiple other molecular alterations (1237].

Essential and desirable diagnostic criteria Essential: a high-grade infiltrating adenocarcinoma that is SMARCBI-deficient. Desirable: clinical/laboratory evidence of haemoglobinopathy (haemoglobin SC disease).

Staging Renal medullary carcinoma is staged according to the eighth edition of the Union for International Cancer Control (UICC) staging system.

Prognosis and prediction Cytology Not relevant

Diagnostic molecular pathology The most common genetic abnormality is inactivation of the SMAFICB1 gene at 22q11.23 by chromosome translocations or deletions {525}. SMARCB1 is commonly lost by mutation and deletion in rhabdoid tumour of the kidney. In medullary

86

Tumours of the kidney

Renal medullary carcinoma has a poor prognosis. More than 90% of patients present with metastases to lymph nodes or other sites (most frequently lung and liver) at the time of diagno­ sis (1434}. Patients with localized disease at presentation have only slightly improved survival. Overall, the median survival time is 8 months (968). There is little evidence that preopera­ tive chemotherapy will effect a significant difference in outcome {2242,2890}.

Metanephric adenoma

Definition

Argani P Cheng L Hartmann A Hirsch MS

初

Metanephric adenoma is a benign, highly cellular epithelial neo­ plasm composed of small, uniform, embryonic-appearing cells, usually with 8 Fmutations.

ICD-0 coding 8325/0 Metanephric adenoma

ICD-11 coding 2F35 & XH0JC7 Benign neoplasm of urinary organs & Metanephric adenoma

Related terminology None

Subtype(s) None

Localization Kidney

Clinical features Approximately 50% of cases are identified incidentally. Abdomi­ nal pain and haematuria are the most common presenting symptoms. Approximately 10% of patients have polycythaemia at presentation due to erythropoietin production by the neo­ plasm {1542,788).

Epidemiology More than 100 cases of metanephric adenoma have been reported. Patient ages have ranged from 5 to 83 years, but most patients are in their fifth or sixth decade of life. There is a distinct female predominance (M:F ratio: ~1:2) [1192).

Fig. 2.63 Metanephric adenoma. A well-circumscribed grey-white tumour.

Etiology Unknown

Pathogenesis The pathological spectrum of metanephric neoplasms includes pure epithelial neoplasms, termed metanephric adenoma; pure stromal neoplasms, termed metanephric stromal tumour; and composite stromal epithelial lesions, termed metanephric adenofibroma. Metanephric neoplasms are united by the com­ mon occurrence of 8R/AFp.V600E mutations, which elevate its

Fig. 2.64 Metanephric adenoma. A Small acini with cells characterized by scant cytoplasm, delicate chromatin, and absent mitoses. B The neoplasm is unencapsulated and directly abuts the native kidney to the right. The neoplasm is composed of cuboidal cells with primitive basophilic nuclei and minimal cytoplasm, forming small tubules. Mitotic activity is not evident.

Tumours of the kidney

87

Fig. 2.65 Metanephric adenoma. A Small acini with cells characterized by scant cytoplasm, delicate chromatin, and absent mitoses. B Metanephric adenoma with dystrophic calcification.

Fig. 2.66 Metanephric adenoma. A The stroma is oedematous and contains branching tubules and tubulopapillary structures that create a fingerprint-like appearance. B Me­ tanephric adenomas with more prominent papillary areas can be confused with low-grade papillary renal cell carcinoma. The more hyperchromatic nuclei and lack of stromal foam cells are clues to the diagnosis of metanephric adenoma.

kinase activity and constitutively activate ERK signalling, pro­ moting cellular survival |3481|.

Immunohistochemistry

Metanephric adenomas are typically unicentric, sizeable lesions; the mean diameter is 50-60 mm but they can reach 150 mm. They are solid and tan to grey, and they may be soft or firm. Degenerative cyst formation with haemorrhage and necro­ sis are not uncommon in larger tumours.

Metanephric adenomas usually demonstrate diffuse nuclear labelling for WT1 and cytoplasmic/membranous labelling for CD57. They are either negative or label in a patchy fashion for CK7； labelling is more intense in areas of elongated tubule formation. EMA and AMACR are typically negative (2247,1676, 2024,2365). Most (but not all) metanephric adenomas can be detected by immunohistochemistry for BRAF using the VE1 clone {2535}.

Histopathology

Differential diagnosis

Microscopically, metanephric adenomas usually lack pseudo­ capsules, but they are well-circumscribed. They are composed of embryonal epithelial cells with small round nuclei only slightly larger than those of lymphocytes. The cells are without promi­ nent nucleoli and have minimal cytoplasm. These primitive blue cells typically form small, crowded acini in a hyalinized, oedem­ atous, paucicellular stroma. Long, curved, branching tubules commonly impart a fingerprint-like appearance. Very tightly packed acini with overlapping nuclei create a solid appearance. Oedematous polypoid structures with microacini within their stroma and microcysts are occasionally found. Psammoma bodies are common and often abundant. Mitotic figures are usually absent or rare. Vascular invasion is not seen (788,1542).

The main differential diagnosis of metanephric adenoma is with the solid subtype of low-grade papillary renal cell carcinoma and epithelial-predominant nephroblastoma. Papillary renal cell car­ cinomas have slightly more vesicular chromatin and more abun­ dant cytoplasm than do metanephric adenomas. In contrast to metanephric adenomas, solid papillary renal cell carcinomas usually label diffusely for CK7 and EMA. WT1 is characteristically negative in papillary renal cell carcinoma (glomerular podocytes provide an excellent internal control for WT1 labelling) {1676, 2024,2365}. Papillary renal cell carcinomas almost always dem­ onstrate trisomy of chromosomes 7 and 17, which is not present in metanephric adenomas (453). Recently, metanephric-like tumours with ALK alteration have been reported.

Macroscopic appearance

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Tumours of the kidney

Fig. 2.67 Metanephric adenoma. A Smear shows dyscohesive clusters and a papillary pattern of atypical cells. The cells are ovoid, with scant cytoplasm and hyperchromatic nuclei. B Smear shows clusters of small, oval to round cells arranged in a microfollicular pattern. The tumour cells have scant cytoplasm, fine chromatin, and absent nucleoli.

Fig. 2.68 Metanephric adenoma. A WT1 immunohistochemistry. B CD57 immunohistochemistry. C The neoplasm shows diffuse cytoplasmic labelling for BRAF p.V600E by

immunohistochemistry using a mutation-specific antibody.

Epithelial-predominant nephroblastoma is typically distin­ guished from metanephric adenoma by the younger age of the patient, the presence of a pseudocapsule, elongate nuclei with small nucleoli, and abundant mitotic activity (162,788). Occa­ sional cases span the morphological spectrum of metanephric adenoma and nephroblastoma (2657)； however, most epithe­ lial-predominant nephroblastomas do not harbour BRAF muta­ tions (500), making their direct relationship to metanephric adenoma unlikely. However, a subset of epithelial-predominant nephroblastomas that have areas that overlap with metanephric adenoma do have BRAF mutations, supporting the notion of a relationship between this subset of nephroblastoma and metanephric adenoma (3481}.

Cytology Smears show clusters of tumour cells arranged in a nested, papillary, and microfollicular pattern. The tumour cells have round to oval hyperchromatic nuclei with fine chromatin and scant cytoplasm. Occasionally, psammoma bodies can be seen. Other features like nuclear atypia, cellular pleomorphism, necrosis, and mitoses are usually absent.

These tumours may show cytological features that mimic those of other malignant tumours; the differential diagnosis can be Wilms tumour or papillary renal cell carcinoma (371).

Diagnostic molecular pathology The p.V600E mutations of BRAF are present in approximately 90% of metanephric adenomas {500,646,3238}. Rare cases have BRAF p.V600D or BRAF p.K601L mutations. Two cases lacking BRAF mutations have demonstrated a t(9;15)(p24;q24) translocation resulting in a KANK1::NTRK3 gene fusion (553}.

Essential and desirable diagnostic criteria Essential: a primitive-appearing but mitotically inactive renal epithelial neoplasm that is WT1-positive. Desirable: 8R>4Fp.V600E mutations.

Staging Not relevant

Prognosis and prediction Metanephric adenomas are benign, although they may (rarely) coexist with nephroblastoma or papillary renal cell carcinoma.

Tumours of the kidney

89

Argani P Cheng L Hartmann A Hirsch MS

Metanephric adenofibroma

Definition

Pathogenesis

Metanephric adenofibroma is a rare biphasic neoplasm that combines a spindle cell component that is morphologically identical to metanephric stromal tumour with an epithelial component that is morphologically identical to metanephric adenoma.

p.V600E mutations have been present in all cases tested to date.

Macroscopic appearance

9013/0 Metanephric adenofibroma

Metanephric adenofibromas are typically solitary, tan, partially cystic masses with indistinct borders. The mean diameter is 40 mm. Many of these lesions have been centred in the renal pelvis, accounting for the presentation with haematuria.

ICD-11 coding

Histopathology

2F35 & XH7ZU2 Benign neoplasm of urinary organs & Metanephric adenofibroma

Metanephric adenofibromas arise in the kidney.

The relative amounts of the spindle cell and epithelial compo­ nents vary. The border of the tumour with the kidney is typically irregular and the spindle cell component entraps tubules and glomeruli. The stroma of metanephric adenofibroma frequently labels for CD34, like that of metanephric stromal tumour. The epithelial elements label similarly to those in metanephric ade­ noma. Composite cases have been reported in which epithelial mitotic activity, nephroblastoma, or papillary renal cell carci­ noma are associated with metanephric adenofibroma (207, 1081}.

Clinical features

Cytology

Patients with metanephric adenofibroma have presented with polycythaemia (in 4 of 14 cases) or haematuria (in 3 of 14 cases) {207,1328,3232,2536}.

Not relevant

ICD-0 coding

Related terminology Not recommended： nephrogenic adenofibroma.

Subtype(s) None

Localization

Epidemiology Fewer than 30 cases have been reported. Patient age ranges from 13 months to 36 years (median: 6.8 years) (207,1328).

Etiology Unknown

Diagnostic molecular pathology All metanephric adenofibromas tested to date have harboured BRAF p.V600E mutations that are characteristic of the other metanephric neoplasms, metanephric stromal tumour, and metanephric adenoma (180,2011). One composite metanephric adenofibroma-papillary renal cell carcinoma had the same BRAF p.V600E mutation in both the adenoma and carcinoma components {561}.

Fig. 2.69 Metanephric adenofibroma. A The bland spindle cell stromal component is at the bottom, and the primitive but mitotically inactive epithelial component is at the top right. Note the unencapsulated border with the native kidney at the top of the image. B The metanephric stromal tumour component (left) is composed of bland spindle cells, and the metanephric adenoma component (right) is composed of primitive but mitotically inactive tubules. C The majority of this biphasic neoplasm is a stromal neoplasm identical

to metanephric stromal tumour, but an epithelial nodule that is identical to metanephric adenoma is present at the top. Note the unencapsulated border with the native kidney at the top of the image.

90

Tumours of the kidney

Fig. 2.70 Metanephric adenofibroma. A The metanephric stromal tumour component (right) is composed of bland spindle cells, and the metanephric adenoma component (left)

is composed of primitive but mitotically inactive tubules. B The bland spindle cell stromal component is on the left, and the primitive but mitotically inactive epithelial component is on the right.

Essential and desirable diagnostic criteria

Prognosis and prediction

Essential: a biphasic neoplasm with features of both metanephric stromal tumour and metanephric adenoma. Desirable: B/?/4Fp.V600E mutations.

Uncomplicated metanephric adenofibroma is benign. The vast majority of patients with composite tumours having an aggres­ sive component (nephroblastoma or papillary renal cell carci­ noma) have presented with low-stage disease and have been cured by surgery alone (207).

Staging Not relevant

Tumours of the kidney

91

Argani P Cheng L Hartmann A Hirsch MS

Metanephric stromal tumour

Definition Metanephric stromal tumour is a renal stromal neoplasm com­ posed of moderately cellular spindle cells identical to the stro­ mal component of metanephric adenofibrorria.

ICD-0 coding 8935/1 Metanephric stromal tumour

ICD-11 coding 2F35 & XH4N88 Benign neoplasm of urinary organs & Metanephric stromal tumour

Related terminology None

Subtype ⑥ None

Localization Renal medulla

Clinical features The typical presentation is that of an abdominal mass. A few patients have presented with manifestations of extrarenal vas­ culopathy such as hypertension or haemorrhage. The mean age at diagnosis is 24 months. Rare adult cases have been described (374,579), as has a case in a patient with neurofi­ bromatosis type 1 (2083(. See Table 2.07.

Fig. 2.71 Metanephric stromal tumour. This is a fibrous neoplasm centred in the me­ dulla of this bivalved kidney. Note the scalloped border with the native kidney.

Pathogenesis

Epidemiology Metanephric stromal tumour is approximately one-tenth as common as congenital mesoblastic nephroma (167).

Most metanephric stromal tumours harbour BRAF p.V600E mutations (180).

Macroscopic appearance

Etiology

Metanephric stromal tumours are typically tan, lobulated fibrous masses centred in the renal medulla. The mean diameter is

Unknown

Table 2.07 Metanephric stromal tumour versus congenital mesoblastic nephroma and clear cell sarcoma of the kidney

Metanephric stromal tumour

Classic congenital mesoblastic nephroma

Cellular congenital mesoblastic nephroma

Clear cell sarcoma of the

Age

Mean: 2 years; rare adult cases

< 3 years

< 3 years

Mean: 3 years; rare adult cases

Border with kidney

Scalloped

Highly infiltrative

Pushing

Morphology

Bland spindle cell neoplasm; onion skinning, angiodysplasia, juxtaglomerular cell hyperplasia

Fascicles of bland spindled cells identical to infantile fibromatosis

Sheets of mitotically active spindle cells identical to infantile fibrosarcoma

Immunohistochemistry

CD34+

Genetics

92

8RAF p.V600E mutations

Tumours of the kidney

kidney

Subtly permeative, entraps single nephrons

Regular branching capillary vasculature; cord cells with open chromatin; multiple variant patterns

BCOR+ EGFH internal tandem duplication (ITD)

E7V6::NTRK3 fusion

BCOR internal tandem duplication, YWHAE::NUTM2B fusion, or BCOR :CC/VB3 fusion

Fig. 2.72 Metanephric stromal tumour. Neoplastic spindle cells encircle entrapped

native tubules in a concentric fashion, yielding an onion-skin pattern.

Fig. 2.73 Metanephric stromal tumour. Glomeruli entrapped within a metanephric stromal tumour frequently demonstrate florid juxtaglomerular cell hyperplasia. This

may result in hyperreninism.

50 mm. Approximately half of cases are grossly cystic, and one sixth are multifocal {167).

Histopathology Metanephric stromal tumours are subtly infiltrative neoplasms composed of spindle-shaped to stellate cells with thin, hyperchromatic nuclei. Epithelioid stromal cells are not rare but typi­ cally are focal. Metanephric stromal tumours characteristically surround and entrap renal tubules and blood vessels to form concentric (onion-skin) rings or collarettes around these struc­ tures in a myxoid background. Most neoplasms induce angiodysplasia of entrapped arterioles, which involves epithelioid transformation of medial smooth muscle and myxoid change. One quarter of metanephric stromal tumours induce juxtaglo­ merular cell hyperplasia within entrapped glomeruli, which may occasionally lead to hypertension associated with hyperreninism. One fifth of metanephric stromal tumours demonstrate heterologous differentiation in the form of glia or cartilage. Most metanephric stromal tumours are mitotically inactive, but cellu­ lar foci may have multiple mitotic figures in a given high-power field. Although metanephric stromal tumours may involve the renal sinus and nerves, as well as undermine the renal pelvic urothelium (suburothelial pads), vascular invasion is absent {167}.

Fig. 2.74 Metanephric stromal tumour. Arterioles within and occasionally outside a metanephric stromal tumour frequently demonstrate angiodysplasia. The majority of this arterial wall is markedly thickened, having undergone myxoid degeneration. The normally spindled smooth muscle cells have become epithelioid. These vessels can

rupture, leading to haemorrhage.

Unlike cellular congenital mesoblastic nephromas, metanephric stromal tumours lack the ETV6::NTRK3 gene fusion (171).

Immunohistochemistry Metanephric stromal tumours are typically immunoreactive for CD34. Desmin, cytokeratins, PAX8, and S100 are negative, although heterologous glial areas label for GFAP and S100.

Cytology

Essential and desirable diagnostic criteria Essential： a spindle cell neoplasm that shows concentric peri­ tubular growth. Desirable： BRAF p.V600E mutations; angiodysplasia; juxtaglo­ merular cell hyperplasia.

Not relevant

Staging

Diagnostic molecular pathology Most metanephric stromal tumours harbour BRAF p.V600E mutations {180}. This mutation is not found in clear cell sarcoma of the kidney, congenital mesoblastic nephroma, or ossifying renal tumour of infancy, so its presence may support the diag­ nosis of metanephric stromal tumour in difficult cases (180).

Not relevant

Prognosis and prediction Metanephric stromal tumours are benign. Rare patients have experienced haemorrhage from extrarenal angiodysplasia apparently induced by metanephric stromal tumour {167}.

Tumours of the kidney

93

Mixed epithelial and stromal tumour of the kidney

Williamson SR Calid A

Definition This tumour type encompasses mixed epithelial and stromal tumour (MEST) and adult cystic nephroma, which are biphasic renal tumours composed of epithelial cysts lined by benign epi­ thelium (usually of renal cell type) and a proliferation of cytologically benign-appearing spindle-shaped cells.

ICD-0 coding 8959/0 Mixed epithelial and stromal tumour 8959/0 Adult cystic nephroma

ICD-11 coding 2C90.Y & XH0533 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Mixed epithelial and stromal tumour

Related terminology Acceptable: renal epithelial and stromal tumour. Not recommended: cystic hamartoma of renal pelvis; leiomyomatous renal hamartoma.

Fig. 2.75 Mixed epithelial and stromal tumour. A gross specimen containing mixed epithelial and stromal tumour shows a white-tan fibrous mass with scattered cysts that involves the renal medulla and renal pelvis.

Subtype(s) Adult cystic nephroma

Localization These are unilateral tumours, usually arising in the renal medulla {3227,2151}.

symptoms are present, haematuria and abdominal pain are the most common. On radiological studies, cystic nephroma is commonly a Bosniak III lesion, and as many as 70% of MESTs have a solid enhancing component {1789(.

Epidemiology

Clinical features Adult cystic nephromas and MESTs frequently occur in middleaged women (M:F ratio: 1:7) (498,499}. For the rare tumours that occur in men, there is often a history of hormone therapy (3227,28,2151}. Both tumours are mainly asymptomatic. When

Fig. 2.76 Mixed epithelial and stromal tumour. A cyst (left) is lined by flattened epi­ thelial cells and surrounded by spindle cell stroma (centre) resembling ovarian stroma.

94

Tumours of the kidney

These are rare tumours that occur overwhelmingly in women.

Etiology Hormonal imbalance or other hormonal factors have been hypothesized as potential etiological factors.

Fig. 2.77 Mixed epithelial and stromal tumour. A solid area demonstrates ovarian-like stroma containing numerous tubules with flattened lining, resembling thyroid tubules.

Pathogenesis One pathogenetic theory is that the presence of periductal fetal mesenchyme around the epithelial component in the kidney (in the renal medulla) becomes sensitive to female hormone stimulation and undergoes proliferation (28). Gene expression profiling has demonstrated that MEST and cystic nephroma are different from other renal epithelial tumours )3628], The epithe­ lial and stromal components both appear to be clonal {1748}. Abnormalities of chromosomes 8, 11, and 17 are lacking, unlike in congenital cellular mesoblastic nephroma {2527}. DICER1 mutation has not been found in MEST or adult cystic nephroma (3308), supporting the notion that these are unrelated to paedi­ atric cystic nephroma.

Macroscopic appearance MESTs and cystic nephromas are well-demarcated and typi­ cally unencapsulated tumours. Cystic nephromas are entirely cystic, whereas MESTs are solid and cystic or entirely solid. The solid areas have a white and firm cut surface {498,499).

Fig. 2.78 Mixed epithelial and stromal tumour. Spindle-shaped cells within glandular structures create a phyllodes tumour-like appearance.

Histopathology Adult cystic nephromas are entirely cystic, whereas MESTs contain a variable solid component {1512,149,3227,3628). Cys­ tic nephromas and MESTs both show variably sized cysts and glands separated by stroma. The epithelium lining the cysts in cystic nephroma is usually flat, cuboidal, or hobnail-shaped; rarely, cells with clear cyto­ plasm have been observed (498). The septal stroma is of vari­ able thickness, usually thin, and consists of fibrous tissue rang­ ing from hypocellular to hypercellular, sometimes resembling ovarian stroma. Stromal calcifications are common. Stromal luteinization and nodules of hyalinized stroma with sharp con­ tours resembling ovarian corpora albicantia can occur (2151, 3227,498). Scattered mitoses are seldom encountered, but atypia and necrosis are lacking. The epithelial component in MEST is variable in architecture and in cell type. The glands are usually scattered in the stroma or closely clustered. Small cysts containing eosinophilic material reminiscent of thyroid follicles, complex branching tubules, phyllodes-type architecture, and papillary structures have been reported (499,3227). The epithelium can be flat, cuboidal, or hobnail-shaped, but also urothelial, ciliated, or with clear or eosinophilic cytoplasm. Mucinous goblet cells and endometri­ oid differentiation have been described {2151,3535}. The septal stroma consists of fibrous tissue ranging from hypocellular to hypercellular. Smooth muscle stroma and fat are common. Myxoid and oedematous changes can occur {3227, 499). Scattered mitoses are seldom encountered, but there is no atypia or necrosis. Malignant transformation can rarely occur, usually manifesting as sarcomas arising from the stroma (3084,1766,3081,2126,1560,3055).

Cytology Cytological diagnosis may be difficult because aspiration specimens may contain occasional groups of cohesive renal epithelial cells, raising the differential diagnosis of renal cell car­ cinoma {811}.

Diagnostic molecular pathology Molecular pathology is rarely necessary for diagnostic pur­ poses. If the distinction from paediatric cystic nephroma is nec­ essary, an absence of DICER1 mutation may be helpful (3308}. Renal synovial sarcoma may have entrapped cystic tubules, mimicking MEST (2851,170,1598), in which case an absence of SS18 rearrangement may be helpful.

Essential and desirable diagnostic criteria

Cystic nephroma Essential: a multilocular cystic tumour made up of cysts lined by flat, cuboidal, or hobnail-shaped cells and separated by thin septa with benign-appearing spindle-shaped cells. Desirable: immunohistochemical labelling for PR and/or ER and frequently for inhibin {498}.

MEST Essential: a complex solid and cystic tumour composed of varied epithelial elements embedded in a variably cellular heterogeneous spindle-shaped cell stroma. Desirable: immunohistochemical labelling for PR and/or ER but not for cathepsin K (499).

Staging

Immunohistochemistry The stromal component is typically positive for actin, desmin, CD10, ER, and PR {3227,28,3628,498,499) and frequently the luteinized stromal cells express inhibin and calretinin {3227,471, 498,499}. Cathepsin K is negative. The epithelial component is PAX2/8-positive (1598(. Immunohistochemistry is helpful in the exclusion of renal synovial sarcoma, clear cell papillary tumour, and tubulocystic renal cell carcinoma.

Not applicable

Prognosis and prediction Tumours with typical features are benign; however, putative malignant transformation of MEST (typically with sarcomatous morphology) has been described, in which behaviour has been aggressive (1560,2278,3055,3081,3084}.

Tumours of the kidney

95

Argani P Calio A Chang KTE de Krijger RR Vujanic GM

Paediatric cystic nephroma

Definition Paediatric cystic nephroma is an exclusively cystic neoplasm with DICEFI1 mutations, in which the septa contain only fibrous tissue and differentiated tubules.

ICD-0 coding 8959/0 Paediatric cystic nephroma

ICD-11 coding 2F35 & XH7TJ0 Benign neoplasm of urinary organs & Paediatric cystic nephroma

Related terminology None Fig. 2.79 Cystic nephroma. The lesion is entirely cystic, and the cysts mould the

Subtype(s)

septa.

None

Localization

DICER1 syndrome includes susceptibility to pleuropulmonary blastoma, Sertoli-Leydig cell tumour, and other neoplasms.

Paediatric cystic nephroma is localized to the kidney.

Pathogenesis Clinical features The typical presentation is that of an abdominal mass. The purely cystic nature of the lesion may be evident on imaging studies.

Epidemiology Paediatric cystic nephroma occurs slightly more commonly in boys than in girls. Most patients are aged < 24 months.

DICER1 mutations specific to paediatric cystic nephroma have not been found in cystic partially differentiated nephroblastoma (890} or lesions known as adult cystic nephroma (1868), sup­ porting its distinctive nature. Mouse models with conditional ablation of DICER1 in ureteric bud epithelium during develop­ ment show cystic masses of the kidney that resemble cystic nephroma (2267).

Macroscopic appearance

Etiology Approximately 90% of paediatric cystic nephromas harbour DICER1 mutations; most (two thirds) of these are associated with a germline mutation. Familial cystic nephroma (829} associated with germline DICEFI1 mutations (2964,243} may be bilateral.

Paediatric cystic nephromas have a median diameter of approximately 90 mm (1983,547,3279( and a median weight of approximately 500 g (491). They are usually well circumscribed and consist entirely of cysts of variable size; the septa are thin and there are no expansile, solid nodules to alter the rounded

Fig. 2.80 Cystic nephroma. A The septa are typically thin and composed of bland fibrous tissue. B Although mature tubules and chronic inflammation may be present, no primitive nephroblastic elements are present within the septa.

96

Tumours of the kidney

contour of the cysts (912(. Lesions frequently herniate into the renal pelvis.

Diagnostic molecular pathology

Histopathology

Essential and desirable diagnostic criteria

Most paediatric cystic nephromas are well demarcated micro­ scopically by a fibrous pseudocapsule (491), but a minority lack a pseudocapsule, either partially or completely. They are com­ posed entirely of septated cysts lined by flattened, cuboidal, or hobnail epithelium, or they are denuded. The septa contain fibrous tissue with focal cellular condensations and well-dif­ ferentiated tubules. The stroma labels for ER like many other cystic renal lesions. The presence of immature nephroblastic elements excludes the diagnosis of paediatric cystic nephroma and indicates cystic partially differentiated nephroblastoma {1555}. The lesions known as adult cystic nephromas belong to the mixed epithelial and stromal tumour family; unlike paediatric cystic nephroma, they typically contain ropy collagen and label for inhibin (1868).

Essential: paediatric cystic nephromas must lack solid nodules on gross or microscopic examination; septa may contain mature tubules but no primitive blastemal elements. Desirable: the presence of DICER1 mutations is supportive but not required.

Cytology

Demonstration of DICEP 1 mutation is helpful in some cases.

Staging Not relevant

Prognosis and prediction Paediatric cystic nephroma is treated with surgery only, usu­ ally by complete nephrectomy or (in selected cases) by par­ tial nephrectomy (3279}. Its prognosis is excellent, with 100% event-free and overall survival (1971). Very rare cases of cys­ tic nephroma transformation into DICER1 sarcoma have been described, but the risk is regarded as very low (890|.

Not relevant

Tumours of the kidney

97

Classic angiomyolipoma / PEComa of the kidney

Definition

Related terminology

Angiomyolipoma is a benign mesenchymal tumour composed of variable proportions of adipose tissue, spindle and epithelioid smooth muscle cells, and thick-walled blood vessels.

None

HesO Calio A Martignoni G Raspollini MR

Subtype(s) Oncocytic angiomyolipoma; angiomyolipoma with epithelial cysts

ICD-0 coding 8860/0 Angiomyolipoma 8860/0 Oncocytic angiomyolipoma 8860/0 Angiomyolipoma with epithelial cysts

ICD-11 coding 2F35 & XH4CC6 Benign neoplasm of urinary organs & Perivas­ cular epithelioid tumour, benign 2C90.Y & XH4CC6 Other specified malignant neoplasms of kidney, except renal pelvis & Perivascular epithelioid tumour, malignant

Localization Angiomyolipomas mainly arise in the cortex or medulla of the kidney; they may be multifocal (3102}. Less frequently, angio­ myolipomas may originate from retroperitoneal soft tissue (2413} with or without contact with the renal parenchyma. Angiomyoli­ poma may be found in regional lymph nodes.

Clinical features Most cases are asymptomatic and diagnosed incidentally dur­ ing imaging, which is increasingly used {1054(. The high fat content present in most angiomyolipomas allows preoperative

Fig. 2.81 Classic angiomyolipoma / PEComa of the kidney. A Classic angiomyolipoma. Gross section with all three components: lipomatous, vascular, and smooth muscle tissue. B Gross picture of an angiomyolipoma with a prominent smooth muscle component, without a fat component, and with a white, firm, and whorled cut surface. C Classic angiomyolipoma, gross view. Predominantly lipomatous angiomyolipoma resembling normal fatty retroperitoneal tissue. D An enlarged kidney with multiple cysts and angiomyo­ lipomas in a patient with TSC2/PKD1 contiguous gene syndrome.

98

Tumours of the kidney

diagnosis by ultrasonography and/or CT. When the smooth mus­ cle component is predominant, or in cases of prominent cystic changes, distinguishing an angiomyolipoma from an epithelial neoplasm by imaging may be a challenge {1531}, and evalua­ tion by biopsy may be useful {2035}. Angiomyolipoma is usually sporadic; however, in a minority of cases it may be identified in patients with tuberous sclerosis. Tuberous sclerosis-associ­ ated angiomyolipomas are diagnosed at a younger age (even in childhood); they may be larger than their sporadic counterparts, bilateral, and associated with renal cysts or combined with poly­ cystic kidney disease (2987(. Larger angiomyolipomas are more likely than smaller ones to grow, and they frequently require sur­ gery, angioembolization procedures, or mTOR inhibitor therapy to avoid life-threatening haemorrhage into the retroperitoneum (Wunderlich syndrome) {3027}. Renal cell carcinomas (RCCs) have been uncommonly reported in association with tuberous sclerosis-associated angiomyolipomas {3027}. Female patients with tuberous sclerosis-associated angiomyolipomas are also frequently affected by lymphangioleiomyomatosis, a progres­ sive pulmonary cystic disease (386,3567}. Fat-poor angio­ myolipoma is usually challenging for preoperative diagnostics; however, combining clinical features and unenhanced CT and MRI features can result in relatively high specificity, according to some recent studies {1530,3472,3473}.

Epidemiology Angiomyolipomas account for approximately 1% of surgically removed renal tumours. For the majority of children with tuber­ ous sclerosis, renal angiolipomas account for 10-20% of their tumours (967,2608), with a peak of diagnosis usually in the third and fourth decades of life and no sex predominance. Eighty to ninety per cent of angiomyolipomas are sporadic, and these mostly occur in women and in older people {3027}. A bimodal age distribution (30-50 years and > 70 years) has been observed in an autopsy series (503|.

Etiology Angiomyolipoma was previously hypothesized to be a hamar­ toma and not a true neoplasm, but a clonal origin has now been confirmed {1186). Molecular, immunohistochemical, and ultrastructural examinations have indicated that the cell of origin for angiomyolipoma is the perivascular epithelioid cell (1601,2044,1383,1030}; however, an origin from renal proximal tubule cells has recently been suggested {1158}. In addition, the mechanism of hormonal modulation may explain the high rates of growth in angiomyolipomas > 30 mm in female patients {1675}, enlargement of angiomyolipomas after ovarian stimula­ tion therapy (3410), and the frequent PR immunoreactivity in angiomyolipomas {1332}.

Pathogenesis This tumour belongs to a family of lesions characterized by the proliferation of perivascular epithelioid cells (2044,1030}. The biallelic inactivation of TSC2 or (less commonly) TSC1 has been found in as many as 94% of angiomyolipomas, and it represents the primary driver genetic event for the development of this tumour. Inactivation of TSC2or TSC1 includes point muta­ tions, small indels, large genomic deletions, and copy-neutral loss of heterozygosity (1334,2588,1118,2085,2596}. The last of these is more common in patients with tuberous sclerosis,

whereas small mutations are more frequent in patients without this syndrome. Furthermore, it has been demonstrated that multiple tumours from one patient with tuberous sclerosis have independent clonal origin due to different second-hit mutations in TSC2 or TSC1. TSC1 and TSC2 are tumour suppressor genes. TSC1 is located on chromosome 9q34; it consists of 23 exons, and it encodes hamartin (3303). The TSC2 gene on chromosome 16p13 contains 41 exons encoding tuberin {962). Hamartin and tuberin interact with each other and with a third protein, TBC1D7, forming a cytoplasmic complex that reduces the level of RHEB-GTP inhibition of mTOR {2302,2543). mTOR has a crucial role in the regulation of cell growth and proliferation. Mutation in one of the TSC genes causes dysfunction of the protein complex, which results in altered activation of mTOR and leads to the phosphorylation and activation of S6K1 and the ribosomal subunit protein S6. mTOR is a component of two functional complexes: mTOR complex 1 (mTORCI) and mTOR complex 2 (mTORC2). mTORCI (mTOR associated with RPTOR and mLST8) induces cell growth and gluco­ neogenesis, regulates mitochondrial biogenesis, and inhibits autophagy. mTORC2 (mTOR associated with RICTOR, mSIN1, and mLST8), although less understood, seems to be critical for actin cytoskeletal reorganization and mechanotransduction in certain cell types. mTORCI can be pharmacologically inhibited by rapamycin, whereas mTORC2 is not sensitive to the effects of this drug (2302,2543,1311).

Macroscopic appearance Angiomyolipomas are mostly solitary, but multiple or large tumours bulging in the perirenal fat may occur. Usually, angiomyolipomas are solid, well-demarcated (but not encapsulated) masses from the adjacent kidney. The colour of the cut surface ranges from yellow (lipoma-like) to white firm or whorled when the smooth muscle component is prominent. Uncommonly, prominent cystic or pseudocystic changes may be present {1859,787,1014,495).

Histopathology Angiomyolipomas are characterized by a variable mixture of mature adipose tissue, thick-walled and poorly organized blood vessels, and smooth muscle (classic triphasic pattern). Classic angiomyolipoma can be designated as "lipoma-like" or 'leio­ myoma-like", according to the prevalence of adipose or spindle smooth muscle components. The smooth muscle cells are radi­ ally organized around vessels, forming sunburst-like structures {1859}. Angiomyolipomas located subcapsularly may be com­ posed entirely of smooth muscle cells. These have been called capsulomas, and they resemble leiomyomas both grossly and histologically (503(. Cells associated with thin-walled, branching vessels with a pattern similar to that of lymphangioleiomyoma are another variation of the smooth muscle component. Leiomyomatous cells are mostly spindled, but they may be rounded and epithelioid. Such epithelioid cells may uncommonly show prominent nuclear atypia, which should raise the suspicion of malignancy. The lipomatous component consists of mature adi­ pose tissue, but it may contain vacuolated adipocytes with scal­ loped nuclei resembling lipoblasts. Such findings, particularly in cases with extensive adipocytic differentiation, may mimic a liposarcoma (3580).

Tumours of the kidney

99

Fig. 2.82 Classic angiomyolipoma / PEComa of the kidney. A-E Classic angiomyolipoma. A This tumour is composed of smooth muscle tissue with numerous thick-walled ves­ sels and a sharp expansive border with the surrounding lipomatous tissue. B Low-power view showing well-demarcated, smooth muscle-rich classic angiomyolipoma within the renal cortex. C This example is smooth muscle-rich, without a lipomatous component. D Predominantly smooth muscle with an abortive thick-walled vessel in the upper-left cor­ ner. E Classic angiomyolipoma composed of adipose tissue, smooth muscle cells, and thick-walled blood vessels. F Angiomyolipoma with epithelial cysts. High-magnification view. Note the hobnail cells lining the cysts, and the compact cambium-like layer of stromal cells underneath.

The blood vessels are thick-walled and lack the normal elas­ tic fibres of arteries, which explains their frequent rupture and haemorrhage. Angiomyolipomas with a prominent vascular component may mimic a vascular malformation. The border between angiomyolipoma and the renal paren­ chyma is sharp, although renal tubules may be entrapped at the periphery (1859,787,1014,495}. Angiomyolipoma with epithelial cysts (AMLEC) is an unusual and rare subtype of angiomyolipoma characterized by a mixed solid and cystic architecture, with the cysts lined by cuboidal to hobnail epithelial cells and, underneath, a compact, cambium­ like layer of stromal cells. The solid areas of AMLEC show a smooth muscle-predominant angiomyolipoma associated with thickened and irregular blood vessels (787,1014,196,2165, 2719}. Oncocytoma-like angiomyolipoma is an extremely rare sub­ type consisting of homogeneous sheets of polygonal cells with eosinophilic cytoplasm. The correct histological diagnosis of

this entity is important because cases of oncocytoma coex­ isting with angiomyolipoma have been reported and tuberous sclerosis-associated oncocytomas have been detected more frequently than in the general population {1522). AMLEC and oncocytoma-like angiomyolipoma may be spo­ radic or associated with tuberous sclerosis (787,1014,196,2165, 2719,2040,3017}. Small mesenchymal nodules (microscopic angiomyolipoma or microhamartoina) have sometimes been observed in kidneys bearing angiomyolipomas. They are composed of smooth mus­ cle cells and/or adipose tissue without blood vessels {650}. Intraglomerular lesions have been observed within the glo­ merular capillary tuft in both sporadic and tuberous sclero­ sis-associated cases and in patients with polycystic kidney disease (TSC2/PKD1 contiguous gene syndrome) (1646,2036, 2270). They are characterized by minute nodules composed of epithelioid smooth muscle cells occasionally intermixed with fat cells.

Fig. 2.83 Classic angiomyolipoma. A Melan-A immunohistochemistry (red substrate detection). B Predominantly leiomyomatous classic angiomyolipoma with strong melan-A positivity (DAB system). C Patchy HMB45 staining, in particular around the blood vessels.

100

Tumours of the kidney

Immunohistochemistry Angiomyolipoma shows a coexpression of melanocytic markers (HMB45, melan-A, and MITF), cathepsin K, and smooth muscle markers (SMA and calponin). CD68, S100, ER, PR, and desmin may also be positive, whereas epithelial markers are always negative {1565,1859,2476,3580,2035}. In AMLEC, the epithelial lining of the cysts is positive for cytokeratin, PAX2, and PAX8, while the compact subepithelial cambium-like layer of stromal cells is positive for HMB45, melan-A, cathepsin K, CD10, ER, and PR. In addition, the solid extracystic component with the morphology of a smooth muscie-predominant angiomyolipoma is positive for HMB45, cath­ epsin K, ER, PR, SMA, and desmin (906,494}. Ultrastructurally, angiomyolipomas have spindle cells with features of smooth muscle cells - some with lipid droplets, indicating transition forms between smooth muscle cells and adipocytes, others with intracytoplasmic membrane-bound dense bodies, crystals, and granules linked to renin and premelanosomes )1383,2248,3421).

called a microhamartoma.

Differential diagnosis

Essential and desirable diagnostic criteria

Diagnosis is straightforward when dealing with classic angio­ myolipoma. However, diagnosis can be challenging for other patterns. Immunohistochemistry can be helpful to properly identify these, for instance to differentiate lipoma-like and leio­ myoma-like angiomyolipoma from lipoma/liposarcoma and leiomyoma/leiomyosarcoma, which are rare (almost anecdotal) in the renal parenchyma. A large exophytic mass focally attached to the external surface of the kidney can mimic liposarcoma on imaging and morphologically. Careful consideration of HMB45positive perivascular epithelioid cells may solve the diagnostic challenge {2467,495}. AMLEC can be misdiagnosed as mixed epithelial and stro­ mal tumour, and less frequently as multilocular cystic renal neo­ plasm of low malignant potential; however, the characteristic immunophenotype is diagnostic. Oncocytoma-like angiomyolipoma should be differenti­ ated from all the oncocytic renal tumours (oncocytomas, the eosinophilic subtype of chromophobe RCC, eosinophilic and solid cystic RCC, and TFEB-altered RCC). Staining for HMB45, melan-A, and cathepsin K, in addition to negativity for cy to kera­ tin and PAX8, allows the diagnosis of oncocytoma-like angio­ myolipoma. The same immunohistochemical markers are useful for the differential diagnosis with eosinophilic and solid cystic RCC; however, cathepsin K can be positive in both lesions (2040,2035).

Essential: presence of thick-walled vessels; presence of a myoid and/or lipoid component in variable proportion; positivity for melanocytic markers (melan-A, HMB45); for AMLEC: pres­ ence of a cystic component and a cambium-like layer of stro­ mal cells expressing HMB45 and melan-A; for oncocytoma­ like angiomyolipoma: expression of melanocytic markers and absence of epithelial markers. Desirable: for AMLEC: positivity for cathepsin K, CD10, ER, and PR； immunohistochemistry may be helpful in cases with unu­ sual histology or for small biopsies.

Cytology Not clinically relevant

Fig. 2.84 Microhamartoma. A small nodule with some features of angiomyolipoma is

Staging Not clinically relevant

Prognosis and prediction Classic angiomyolipomas are benign. They are rarely associ­ ated with complications causing morbidity and mortality due to haemorrhage into the retroperitoneum, or with renal failure in patients who have tuberous sclerosis with renal cysts and multiple angiomyolipomas (2353,2840}. However, worrisome features may (rarely) be observed, such as the invasion of intraparenchymal and renal veins, but these should not be misin­ terpreted as evidence of malignancy. Multifocality and regional lymph node involvement can also occur, representing a multifo­ cal growth pattern rather than a metastasis {3102). Only a few cases of sarcoma developing in sporadic angiomyolipoma have been reported; 2 patients had pulmonary metastases and 1 had hepatic metastases (659,1001,2045).

Diagnostic molecular pathology Not clinically relevant

Tumours of the kidney

101

Epithelioid angiomyolipoma/ epithelioid PEComa of the kidney

Hes 0 Calio A Martignoni G Raspollini MR

Definition Epithelioid angiomyolipoma (EAML) is a rare variation of angiomyolipoma that consists of at least 80% epithelioid cells.

ICD-0 coding 8860/1 Angiomyolipoma, epithelioid

ICD-11 coding 2F35 & XH0QR3 Benign neoplasm of urinary organs & Angio­ myolipoma, epithelioid 2B5F.2 & XH0QR3 Sarcoma, not elsewhere classified of other specified sites & Angiomyolipoma, epithelioid

Related terminology

Fig. 2.85 Epithelioid angiomyolipoma. Epithelioid angiomyolipoma on gross section

Acceptable: pure epithelioid PEComa of the kidney.

shows a solid structure and beige colour.

Subtype(s)

Epidemiology

None

Localization

The mean patient age is 50 years (range: 30-80 years) and there is no sex predilection. EAMLs represent 4.6% of all resected angiomyolipomas {1316).

Kidney, with possible extrarenal extension and involvement of renal veins

Etiology

Clinical features Most reports on EAML indicate that it is radiologically, clinically, and grossly similar to renal cell carcinoma {2995}; however, combining unenhanced CT and MRI features can result in rela­ tively high specificity {3216A|.

EAML has been described in patients with tuberous sclerosis, as well as in patients with TSC2/PKD1 contiguous gene syn­ drome {2039,2475,2036).

Pathogenesis TSC2 mutation has been reported in sporadic EAMLs (2039, 2426}.

Fig. 2.86 Epithelioid angiomyolipoma. A Core biopsy can be helpful in establishing a preoperative diagnosis. B Epithelioid angiomyolipoma with epithelioid and plump spindle

cells in diffuse growth. Note the multinucleated cells.

102

Tumours of the kidney

Fig. 2.87 Epithelioid angiomyolipoma. A High-magnification view of epithelioid and plump spindle cells in diffuse growth. Note the relatively uniform epithelioid cells with clear to granular, feathery eosinophilic cytoplasm. B Epithelioid angiomyolipoma with a carcinoma-like pattern characterized by large eosinophilic cells with atypical nuclei and prominent nucleoli arranged as nests.

Macroscopic appearance Usually, large tumours with an infiltrative pattern and a hetero­ geneous appearance are the most frequent gross finding. The colour ranges from grey-tan to brown. Haemorrhagic areas and necrosis may be observed. Extrarenal extension into the renal vein and/or vena cava and regional lymph node involvement may occur. However, not all cases of EAML with lymph node involvement represent metastatic disease (432,2306).

Histopathology EAML displays two different patterns. The first, a carcinoma-like pattern, is characterized by nests of atypical large eosinophilic cells, resembling ganglion cells, with prominent nucleoli and intranuclear inclusions (ganglion cell-like appearance). The nests are separated by thin, vessel-rich septa. Most tumours have few mitoses. The second pattern, epithelioid and plump spindle cells in dif­ fuse growth, consists of sheets of voluminous cells and spindle cells with moderate atypia and pale cytoplasm. Mitotic activ­ ity as well as intranuclear inclusions are uncommon or lacking. Multinucleated giant cells, lipomatous foci, and inconspicuous thick-walled vessels may be present in both morphological pat­ terns {432,2306,408}.

Immunohistochemistry EAMLs express melanocytic markers (HMB45, melan-A, and MITF), cathepsin K, CD68 (as recognized by PGM1), and (vari­ ably) smooth muscle markers {2039,2475,3580,2035,911,977}. The most common challenging differential diagnoses are clear cell renal cell carcinoma and urothelial carcinoma with exten­ sive sarcomatoid differentiation. Immunolabelling for cathep­ sin K, HMB45, and melan-A is helpful. This immunophenotype overlaps with TFES-rearranged or 7FE8-altered renal cell carci­ noma, but PAX8 and CD68 (PGM1) are reliable tools for distin­ guishing between them {977}. Parvalbumin is negative, unlike in other perivascular epithelioid cell-related tumours (494}.

Cytology Not clinically relevant Fig. 2.88 Epithelioid angiomyolipoma. A Strong and diffuse expression of cathepsin

K. B Granular cytoplasmic expression of HMB45.

Tumours of the kidney

103

Diagnostic molecular pathology Rarely, TFE3 gene rearrangement has been described in EAMLs (the partner gene is usually SFPQ [PSF]) (165,2358, 190}. However, most EAMLs with TFE3 immunopositivity do not show TFE3 rearrangement {165).

Essential and desirable diagnostic criteria Essential: a carcinoma-like appearance and/or epithelioid and plump spindle cells in a diffuse growth pattern showing posi­ tivity for melanocytic markers and cathepsin K; > 80% of the tumour cells should be epithelioid cells.

Staging Not applicable

Prognosis and prediction EAML can be malignant {2823,432,2306,1316). However, the differences in aggressiveness reported in the literature (rang­ ing from 5% to 66%, including local recurrence and metastasis) may be related to case selection in the studies.

104

Tumours of the kidney

Two studies have stratified EAMLs on a pathological or ciinicopathological basis and suggested the criteria for malignancy. The presence of > 70% atypical epithelioid cells, > 1 mitosis/ mm2 (> 2 mitoses/10 HPF of 0.2 mm2), atypical mitotic figures, and necrosis has been correlated with prognosis in a series of 40 atypical angiomyolipomas characterized by an epithelioid component making up 5-90% of the tumour {432}. The presence of tuberous sclerosis and/or concurrent angiomyolipoma, tumour size > 70 mm, a carcinoma-like pattern, inva­ sion of the perinephric fat and/or renal vein, and necrosis were found to be associated with disease progression, recurrence, metastasis, or death due to disease in a series of 41 cases of EAML characterized by an epithelioid component of > 95%. A prognostic parameter-based risk stratification model divides tumours into three categories: low risk (0-1 parameter), inter­ mediate risk (2-3 parameters), and high risk (> 4 parameters) {2306}. Risk of disease progression among these groups was 15%, 64%, and 100%, respectively; for patients with > 3 adverse parameters, 80% had disease progression (2306}.

Cheville J Thway K Wick MR Zhou M

Renal haemangioblastoma

Definition

Etiology

Renal haemangioblastoma is similar to haemangioblastoma of the CNS and composed of capillaries and stromal cells. Unlike CNS tumours, renal haemangioblastomas are not associated with von Hippel-Lindau syndrome.

There is no known etiology. The tumours are not associated with von Hippel-Lindau syndrome {2259}.

Pathogenesis Unknown

ICD-0 coding 9161/1 Haemangioblastoma

Macroscopic appearance

2F98 & XH6810 Neoplasms of unknown behaviour of urinary organs & Haemangioblastoma

The tumours range from 120 to 680 mm in greatest dimension (3373). They are encapsulated, they may be red-brown, grey, and/or yellow, and some tumours show areas of haemorrhage {3549,3367,3496,1911}.

Related terminology

Histopathology

None

The tumours are well circumscribed, and they are composed of sheets of cells with round to oval nuclei and clear to slightly eosinophilic cytoplasm. The clear cytoplasm may be vacuo­ lated as a result of lipid accumulation. Additionally, cytoplasmic eosinophilic globules may be present. There may be mild cyto­ logical atypia with scattered larger cells, but diffuse atypia is not present. Rhabdoid features have been described (2343,3549). The neoplastic cells are associated with a network of arborizing thin-walled capillaries. Mitotic activity is very low. Necrosis has been reported in a minority of cases.

ICD-11 coding

Subtype ⑥ None

Localization Any renal location

Clinical features Renal haemangioblastomas have been reported only in adults (patient age range: 29-71 years). Most patients are asymptom­ atic, but haematuria and abdominal/back pain have occurred. Imaging characteristics cannot distinguish renal haemangio­ blastomas from renal epithelial tumours (3373(.

Epidemiology Fewer than 15 cases have been reported. Tumours occur in adults and there is an equal sex distribution. No predisposing conditions have been identified (3373,2259).

Immunohistochemistry Immunohistochemical findings show staining for PAX8, a-inhibin, NSE, S100, and vimentin {3611,1757,1365). CAIX and partial CD10 membrane staining has been reported (1757). There may be focal EMA and cytokeratin staining, but cytokeratins are usually negative, as are chromogranin, synaptophysin, and melanocytic markers other than S100.

Fig. 2.89 Renal haemangioblastoma. A The tumour comprises sheets of ovoid cells that are traversed by an arborizing network of delicate vessels, many of which are ec-

tatic. B The tumour cells have pale to eosinophilic cytoplasm and small pale vacuoles. Occasional pleomorphic nuclei are present.

Tumours of the kidney

105

浜，EK比

见匕打*•

£.5.奁 Fig. 2.90 Renal haemangioblastoma. The tumour cells are positive for a-inhibin (A) and PAX8 (B).

Cytology Not relevant

Desirable: immunophenotyping shows positivity for PAX8, S100, and a-inhibin, and usually negativity for keratin.

Diagnostic molecular pathology

Staging

There are no diagnostic molecular abnormalities. These tumours lack alterations of VHL.

Most tumours are pT1 or (rarely) pT2, with an absence of renal sinus, perinephric fat, and renal vein invasion. Regional lymph node involvement is not reported.

Essential and desirable diagnostic criteria Essential: cells with round to oval nuclei with clear to slightly eosinophilic cytoplasm set in a background of arborizing cap­ illaries.

106

Tumours of the kidney

Prognosis and prediction No tumours have been reported to recur or metastasize (2343).

Juxtaglomerular cell tumour

Sirohi D Cunha IW Gupta S

Definition

Pathogenesis

Juxtaglomerular cell tumours are rare renin-secreting mesen­ chymal tumours derived from the modified smooth muscle cells in the wall of the afferent arteriole of the juxtaglomerular appa­ ratus.

Limited studies have evaluated genetic abnormalities in juxtaglomerular cell tumours. Reported alterations include gains on chromosome 10 and losses of chromosomes 9 and X. Aneuploid karyotype and complex genotypes have been reported in tumours with aggressive features histologically (1761,414,519}.

ICD-0 coding 8361/0 Juxtaglomerular tumour 8361/0 Functioning juxtaglomerular cell tumour 8361/0 Non-functioning juxtaglomerular cell tumour

ICD-11 coding

Macroscopic appearance Juxtaglomerular cell tumours are small, cortical-based renal tumours with a mean size of approximately 28 mm {3624}. Tumours as small as 2 mm have been described and a rare malignant tumour of 150 mm has been reported (900,1358(. The

2F35 & XH6M13 Benign neoplasm of urinary organs & Juxtaglo­ merular tumour

Related terminology Acceptable: reninoma.

Subtype(s) Functioning juxtaglomerular cell tumour; juxtaglomerular cell tumour {885,2108|

non-functioning

Localization Renal cortex

Clinical features Patients with juxtaglomerular cell tumours present with severe hypertension, hyperaldosteronism, and hypokalaemia due to tumour renin secretion (699,700). Other clinical signs and symptoms are due to hypertension and include headaches, dizziness, polyuria, proteinuria, and retinopathy. Hypertension may be present for several years before the diagnosis and its severity is not correlated with tumour size. Unlike patients with primary hyperaldosteronism, patients with renin-secreting juxtaglomerular cell tumours present with a normal aldosteroneto-renin ratio {3359}. In most cases, there is a renal mass with hypertension, elevated plasma renin activity, and hypokalaemia that all typically resolve after surgical resection. Rarely, non­ functioning tumours with normal blood pressure and serum potassium levels have been described {885,1312).

Fig. 2.91 Juxtaglomerular cell tumour. The tumour is composed of small bland round to polygonal cells arranged around blood vessels.

Epidemiology Juxtaglomerular cell tumours are rare tumours of young adults. Approximately 100 cases have been reported, mostly as case reports or small series. They typically occur in the second to fourth decade of life, with an age range of 6-72 years (1518, 3368}, and there is a female predilection.

Etiology Unknown Fig. 2.92 Juxtaglomerular cell tumour. Renin immunohistochemistry shows diffuse positivity.

Tumours of the kidney

107

Immunohistochemistry Immunophenotypically, these tumours exhibit diffuse granular cytoplasmic renin positivity. However, it must be noted that rare to focal renin expression has been documented for other renal tumour types including glomus tumours of the kidney [3171, 2950}. These tumours are characterized by PAS-positive, dia­ stase-resistant cytoplasmic granules (3624}. In addition, they show positivity for CD34 and vimentin, with variable reactivity for KIT (CD117) and SMA. They are negative for cytokeratins, PAX8, renal cell carcinoma, chromogranin, synaptophysin, HMB45, and desmin (1698,3624}. Ultrastructural analysis dem­ onstrates characteristic rhomboid-shaped protogranule crys­ tals, abundant rough endoplasmic reticulum, prominent Golgi complexes, and membrane-bound electron-dense renin gran­ ules (2650,1758).

Cytology Not relevant

Diagnostic molecular pathology Fig. 2.93 Juxtaglomerular cell tumour. Rhomboid shaped renin crystals are charac­ teristic of juxtaglomerular cell tumours on ultrastructural analysis.

Not relevant

Essential and desirable diagnostic criteria majority of these tumours are well circumscribed, fully or par­ tially encapsulated, and yellow to grey-tan in colour, and they can have small areas of haemorrhage or cysts (3624).

Histopathology Histologically, these tumours are composed of round to poly­ gonal or spindle-shaped monomorphic cells with indistinct cell borders, pale to eosinophilic cytoplasm, and central small nuclei arranged in solid sheets or lobules with prominent vasculature. Mild to moderate atypia can be present, but mitoses are uncom­ mon. Small foci of necrosis may be present. Hyalinized ves­ sels, various patterns (haemangiopericytoma-like, microcystic, and papillary), intratumoural mast cells, tumour giant cells, and entrapped renal tubules at the periphery have been described (2048,1758,1761,3624,3143}. Rare cases with capsular and angioinvasion have been reported {900,1256}.

108

Tumours of the kidney

Essential: round to polygonal or spindle-shaped monomorphic cells with indistinct cell borders and diffuse positivity for renin and CD34. Desirable： clinical and ultrastructural criteria in addition to the histological and immunophenotypic features.

Staging Not relevant

Prognosis and prediction The majority of juxtaglomerular cell tumours are benign (1518). Rare vascular invasion has been reported, manifesting either as metastases or as multicentric synchronous disease. Large size, necrosis, and increased mitoses are considered atypical features that may warrant close follow-up (900,747,3624}.

Renomedullary interstitial cell tumour

Williamson SR Calid A Cheng L

Definition Renomedullary interstitial cell tumour is a benign neoplasm composed of cells resembling those of the renomedullary interstitium.

ICD-0 coding 8966/0 Renomedullary interstitial cell tumour

ICD-11 coding 2F35 & XH3470 Benign neoplasm of urinary organs & Renomed­ ullary interstitial cell tumour

Related terminology Acceptable: medullary fibroma.

Subtype(s) None

Fig. 2.94 Renomedullary interstitial cell tumour. The characteristic gross appearance is a small, white-tan nodule (arrow) in the renal medulla, usually < 6 mm.

Localization Tumours occur approximately equally in both kidneys, over­ whelmingly within the body of the renal medulla, and rarely in the renal papilla or corticomedullary junction {504}.

Clinical features The vast majority of renomedullary interstitial cell tumours are < 6 mm and found incidentally at pathological examination of the kidney for a larger neoplasm, or at autopsy. However, rare tumours have manifested as clinically evident masses, some­ times causing renal obstruction (2360,1997,765,981,297}.

Epidemiology Renomedullary interstitial cell tumours occur predominantly in adults.

Etiology The exact etiology of this lesion is unknown. It was earlier pos­ tulated to be related to systemic hypertension, but more recent studies have not found any conclusive evidence of an associa­ tion with hypertension (504}.

Pathogenesis Unknown

Macroscopic appearance The prototypical appearance of renomedullary interstitial cell tumour is a round to oval whitish nodule in the renal medulla, rarely larger than 6 mm.

Histopathology Renomedullary interstitial cell tumour is composed of elongated spindle-shaped to stellate cells with bland nuclei and scant cytoplasm. The density ranges from hypocellular with prominent

Fig. 2.95 Renomedullary interstitial cell tumour. A A small, circumscribed nodule of spindle-shaped cells is present within the renal medulla. B This lesion is relatively cellular and contains entrapped cystic tubules.

Tumours of the kidney

109

collagen to more cellular {504}. Eosinophilic, rope-like strands of collagen are sometimes present within the lesion; initially, these were thought to be amyloid (3641}, but more recent stud­ ies have found them to be consistently negative for Congo red stain (1966,504). Entrapped renal tubules are common, and sometimes these are dilated.

Diagnostic molecular pathology

Immunohistochemistry

Staging

The immunohistochemical staining characteristics are nonspe­ cific with weak to moderate labelling for SMA and calponin, negative or weak CD34, and usually weak ER and PR (1966(. The ultrastructural characteristics are thought to resemble the normal renomedullary interstitial cells (1850).

Not applicable

Cytology Not clinically relevant

110

Tumours of the kidney

Not relevant

Essential and desirable diagnostic criteria Essential: a round or oval spindle cell nodule in the renal medulla, lacking cytological atypia, usually < 6 mm in size.

Prognosis and prediction Renomedullary interstitial cell tumour is a benign tumour. Malig­ nant behaviour or transformation has not been described.

Ossifying renal tumour of infancy

Chang KTE Calid A de Krijger RR Tsuzuki T

4 cvJ C J C ccr c

Definition

Macroscopic appearance

Ossifying renal tumour of infancy (ORTI) is an intracalyceal tumour composed of a combination of osteoid, osteoblastic, and spindle cells.

Tumours are well circumscribed and measure 10-60 mm in diameter. Almost all tumours show signs of calcification on imaging studies, and this is reflected in the gross appearance.

ICD-0 coding

Histopathology

8967/0 Ossifying renal tumour of infancy

None

ORTIs are composed of two cell types: osteoblast-like cells that are located between and around areas of osteoid, and a spindle cell (blastema-like) component, mostly at the periphery of the tumour (3004). Osteoblast-like cells and spindle cells are both bland, without features of malignancy. Immunohistochemistry shows that the osteoblast-like cells are almost always positive for EMA and vimentin {1210}. SATB2 and WT1 have also been reported to be positive (1210,3268).

Subtype ⑥

Cytology

None

Not relevant

Localization

Diagnostic molecular pathology

Renal pelvis

Five cases of ORTI with clonal trisomy 4 have now been reported (in two different papers), so clonal trisomy 4 seems a relevant and recurrent molecular abnormality {1904,1210).

ICD-11 coding 2F35 & XH3SR2 Benign neoplasm of urinary organs & Ossify­ ing renal tumour

Related terminology

Clinical features ORTI has no specific clinical presentation, but most patients present with gross haematuria and a calcified mass protruding into the renal pelvis on imaging (3004,1831}. No association with any other renal tumour type or syndrome has been published.

Essential and desirable diagnostic criteria Essentia/: the typical histological combination of osteoid, osteo­ blastic cells, and spindle cells.

Epidemiology

Staging

These tumours are extremely rare, with only about 25 cases published in the literature. There is a clear male predominance (M:F ratio: 7:1), and patients are aged between 6 days and 2.5 years (1210,1259).

All tumours are limited to the kidney and regarded as benign lesions. No particular staging protocol applies.

Etiology Unknown

Prognosis and prediction This is a benign tumour for which conservative surgical man­ agement is sufficient. Outcome has been uniformly favourable (3004,1473).

Pathogenesis Unknown

Fig. 2.96 Ossifying renal tumour of infancy. A Calcified part with osteoblastic cells. B Spindle cell component. C Tumour within the renal calyx.

Tumours of the kidney

111

Congenital mesoblastic nephroma

Argani P Calio A Chang KTE Cunha IW de Krijger RR Vujanic GM

Definition

Etiology

Congenital mesoblastic nephromas (CMNs) are low-grade fibroblastic neoplasms of the infantile renal sinus.

There are neither environmental nor hereditary genetic risk fac­ tors.

ICD-0 coding

Pathogenesis

8960/1 8960/1 8960/1 8960/1

Mesoblastic nephroma Classic congenital mesoblastic nephroma Cellular congenital mesoblastic nephroma Mixed congenital mesoblastic nephroma

ICD-11 coding 2C90.Y & XH10F1 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Mesoblastic nephroma

Related terminology None

Subtype ⑥ Classic congenital mesoblastic nephroma; cellular congenital mesoblastic nephroma; mixed congenital mesoblastic nephroma

Localization CMNs by definition arise in the renal sinus. Cases are always unifocal and unilateral.

Clinical features The typical presentation is that of an abdominal mass (in 75% of cases). Hypertension due to hyperreninism (in 20%) and haematuria (in 10%) are less common. Approximately 15% of cases are diagnosed prenatally owing to polyhydramnios {1167}.

In > 70% of cases, cellular CMNs harbour a t(12;15)(p13;q25) translocation, which results in a fusion of the ETV6 and NTRK3 genes. NTRK3 is a receptor tyrosine kinase. The fusion gene is a constitutively active tyrosine kinase that promotes cellular growth via multiple downstream pathways {1073}. Other variant fusions, such as EML4::NTRK3 (657), have also been identified. The ETV6::NTRK3 gene fusion in cellular CMN was first iden­ tified in infantile fibrosarcoma, but it is not present in classic CMN or its analogue, infantile fibromatosis (1689,1688,2742). Thus, cellular CMN and infantile fibrosarcoma are identical neo­ plasms. The molecular spectrum of cellular CMN and infantile fibrosarcoma has recently been expanded to include genetic alterations outside of the canonical fusion, includ­ ing BRAFand NTRK1 gene fusions {3613,1591,3423|. Classic CMNs harbour an EGFR internal tandem duplica­ tion (ITD) that is predicted to activate EGFR signalling {3423, 3613,1836). Mixed CMNs more frequently demonstrate EGFR ITD than the ETV6::NTRK3 gene fusion, suggesting that most of them represent classic CMN with foci of increased cellularity )171,143,926,3338), similarly to composite fibromatosis/fibrosarcoma of soft tissue (172). Classic CMNs are typically diploid, whereas cellular CMNs frequently demonstrate aneuploidy of chromosomes 11, 8, and 17 {1722,2516,2742}.

Macroscopic appearance

Epidemiology CMNs account for 2% of paediatric renal tumours. CMN is the most common congenital renal neoplasm, and 90% of cases occur in the first year of life {1167}.

Classic CMNs have a firm, whorled texture, whereas cellular CMNs are larger and more typically soft, cystic, and haemor­ rhagic.

Fig. 2.97 Congenital mesoblastic nephroma. A Classic type. Fascicles of fibroblastic cells resembling fibromatosis dissect apart islands of native nephrons. B Cellular type. The neoplasm features poorly defined fascicles, high cellularity, and abundant mitotic activity. C Mixed type. The left half is identical to the cellular type and the right half is identical to the classic type.

112

Tumours of the kidney

Histopathology

Diagnostic molecular pathology

Classic CMN (accounting for 24% of all cases of CMN) is morphologically identical to infantile fibromatosis of the renal sinus {384(. Tumours are composed of interlacing fascicles of fibroblastic cells with thin, tapered nuclei; pink cytoplasm; low mitotic activity; and abundant collagen deposition. The tumour dissects and entraps islands of renal parenchyma. Islands of cartilage are often found. Cellular CMN (66% of cases) is mor­ phologically identical to infantile fibrosarcoma. These tumours have a pushing border, and they are composed of poorly formed fascicles that give way to sheet-like growth patterns. The tumours have a high mitotic count and frequently feature necrosis. Mixed CMN (10% of cases) has features of both clas­ sic and cellular CMN (176).

The ETV6::NTRK3 gene fusion is characteristic of cellular CMN, whereas EGFR ITD is characteristic of classic CMN {3338,171, 2742,1688,3423}.

Immunohistochemistry CMNs are often immunoreactive for actin, with infrequent desmin labelling; CD34 is non-reactive. Although pan-TRK and cyclin D1 are often positive in CMN, both are also positive in its main differential diagnostic consideration, clear cell sarcoma of the kidney, which limits their utility (1592). Diffuse nuclear label­ ling for BCOR, which is characteristic of clear cell sarcoma of the kidney, is not found in CMN and thus is discriminatory (183, 175}, Ultrastructurally, CMNs have features of myofibroblasts or fibroblasts.

Essential and desirable diagnostic criteria Essential: an infantile fibroblastic neoplasm with the typical mor­ phology described above, in a child aged < 3 years. Desirable: molecular confirmation can be helpful in some cases.

Staging Not relevant

Prognosis and prediction When completely excised, CMN is associated with an excel­ lent prognosis. Recurrence occurs in 5% of patients, and it is mainly related to the completeness of resection. Children with cellular CMN, children aged > 3 months, and children with stage III disease have more recurrences {1067}. All recurrences have occurred within 12 months of diagnosis, and half of them resulted in patient death {1504,1320,3346,1067,943,1167). Causes of recurrence divide almost equally between diseaserelated and treatment-related. All documented haematogenous metastases have resulted from cellular CMN. Relapsed cases are responsive to chemotherapy if resection is not possible {2079,1916}.

Cytology Not relevant

Tumours of the kidney

113

de Krijger RR Argani P Calio A

Rhabdoid tumour of the kidney

Definition Rhabdoid tumour of the kidney is composed of sheets of cells that have eccentric pleomorphic nuclei with prominent nucleoli and characteristic intracytoplasmic inclusions, complemented by a loss of SMARCB1 (INI1) immunostaining and SMARCB1 genetic abnormalities.

ICD-0 coding 8963/3 Malignant rhabdoid tumour of the kidney

ICD-11 coding 2C90.Y & XH3RF3 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Malignant rhabdoid tumour

Related terminology Acceptable: malignant rhabdoid tumour; atypical teratoid rhab­ doid tumour; rhabdoid tumour predisposition syndrome.

Subtype(s) None

Fig. 2.98 Rhabdoid tumour of the kidney. T1-weighted MRI of a 6-month-old boy with

a renal tumour.

patients diagnosed before the age of 2 years. Although congenital cases have been described, it is rare to find rhabdoid tumour of the kidney in children aged > 3 years (3420(. Synchronous intra­ cranial tumours (either metastases or synchronous atypical teratoid/rhabdoid tumours) are found in 10-15% of patients {3020}.

Localization Kidney parenchyma

Clinical features Patients may present with hypercalcaemia, fever, haematuria, and/or an abdominal mass. Some tumours produce PTHrelated protein or PGE2. Rhabdoid tumours of the kidney show lobulated architecture on imaging, with hypointense to isoin­ tense signal on T1 and isointense to hyperintense signal on T2, and with frequent curvilinear calcifications (in 70% of cases) and subcapsular fluid collections {3020}.

Epidemiology Rhabdoid tumours of the kidney account for approximately 2% of paediatric renal tumours. They occur in infants and young chil­ dren, with a mean/median patient age of 1 year and with 80% of

Etiology Biallelic inactivation of the SMARCB1 gene (also known as BAF47, SNF5, or INI1), located on chromosome 22q11.23, is the almost universal hallmark of rhabdoid tumour of the kidney. Another feature is the presence of extrarenal rhabdoid tumours, including atypical teratoid/rhabdoid tumour of the brain. Inac­ tivation may occur through mutation, segmental chromosomal deletion, or whole-chromosome loss (loss of heterozygosity). SMARCB1 mutations may occur in the germline in up to one third of patients. If so, they are affected by familial rhabdoid tumour predisposition syndrome type 1, which increases the risk of synchronous or metachronous rhabdoid tumour in various loca­ tions, or of other tumours including schwannomas, meningio­ mas, and malignant peripheral nerve sheath tumours. A small proportion (< 5%) of patients with rhabdoid tumour of the kidney

Fig. 2.99 Rhabdoid tumour of the kidney. A Diffuse growth pattern of tumour cells. B High-power view showing the typical cellular aspect with prominent nucleoli and cytoplas­ mic inclusions in some cells. C Section highlighting the diffuse growth and the typical cellular aspect with prominent nucleoli and cytoplasmic inclusions.

114

Tumours of the kidney

Fig. 2.100 Rhabdoid tumour of the kidney. A Lack of SMARCB1 (INI1) immunostaining in tumour cells. SMARCB1 staining is retained in normal cells and serves as an internal positive control. B Tumour cells lack SMARCB1 (INI1) immunostaining, whereas it is retained in normal cells.

have biallelic inactivation of SMARCA4, another component of the SWI/SNF complex, instead of SMARCB1 inactivation. If this occurs in the germline, these patients have familial rhabdoid tumour predisposition syndrome type 2 (2474).

Pathogenesis Because rhabdoid tumour of the kidney and other rhabdoid tumours are genetically silent tumours almost exclusively char­ acterized by SMARCB1 or SMAFICA4 inactivation, deregulation of the SWI/SNF chromatin remodelling complex is thought to lead to carcinogenesis by its epigenetic effect on promoter and enhancer regions of other genes.

Macroscopic appearance These are large, highly infiltrative tumours with a haemorrhagic and necrotic appearance.

expression in all other cells {2474}. Other than by loss of SMARCB1 (INI1) immunostaining, rhabdoid tumour of the kidney and indeed all rhabdoid tumours have a diverse pattern of immunoreactivity, including multiple keratins and vimentin, but also SMA, synaptophysin, and GFAP. Nonspecific polyphenotypic patterns for other antibodies may occur due to trapping of antibodies in hyaline inclusions such as EMA and pancytokeratin. Importantly, over half of rhabdoid tumours show CD99 expression, which may add to the morphological confusion with Ewing sarcoma. Although differ­ ential diagnoses are limited in cases with typical morphology and immunohistochemistry, cellular mesoblastic nephroma, plump cell pattern, and clear cell sarcoma of the kidney may be consid­ ered. Several renal cell carcinoma morphologies, including clear cell renal cell carcinoma and renal medullary carcinoma, may show rhabdoid morphology with or without SMARCB1 (INI) loss.

Cytology

Histopathology Rhabdoid tumour of the kidney is composed of loosely cohe­ sive sheets of large, non-cohesive cells with large vesicular nuclei and one or more prominent eosinophilic nucleoli, grow­ ing in a diffuse infiltrative pattern. Many (but not all) rhabdoid tumours of the kidney have foci with cells containing character­ istic eosinophilic intracytoplasmic inclusions. Mitoses, atypical mitoses, and necrosis are frequent. Not all tumours are entirely composed of these typical cells and careful analysis for typical areas is important. In fact, biopsies may completely lack the characteristic features of rhabdoid cells, so additional immuno­ histochemistry is important. Rhabdoid tumour of the kidney, like other rhabdoid tumours, may have different architectural growth patterns, such as solid, sclerosing, cystic, cord-like, myxoid, or myxohyaline. In addition, the cellular composition may vary and show clear cells, spindle cells, or epithelioid cells. Although it may be suspected on the basis of morphology, SMARCB1 (INI1) immunostaining is important to confirm the diagnosis of rhabdoid tumour of the kidney. SMARCB1 (INI1) is universally present in all cells, and therefore normal cells represent an inter­ nal positive control for this method (1558}. It should be noted that a limited spectrum of other tumours may also show a loss of SMARCB1 (INI1) staining; of these, renal medullary carcinoma is the most relevant in the differential diagnosis of renal tumours.

Not relevant

Diagnostic molecular pathology Mutation analysis by next-generation sequencing techniques will show SMARCB1 or SMARCA4 mutations. This should be complemented with other techniques aiming to demonstrate the loss of the other allele, such as SNP arrays. Patients with mutations should be referred to clinical genetics for germline analysis and counselling.

Essential and desirable diagnostic criteria Essential： typical rhabdoid morphology, supported by absent SMARCB1 (INI1) immunostaining; alternative diagnoses should be excluded (see Histopathology). Desirable: demonstration of biallelic SMARCB1 or SMARCA4 loss.

Staging No separate staging system exists for renal rhabdoid tumour, but the staging system from the International Society of Paedi­ atric Oncology (SIOP) 2016 UMBRELLA protocol or from the Children's Oncology Group (COG) may be used. Most patients present with advanced-stage tumours; only 6-21% present with stage I tumours {3173,3278}.

Prognosis and prediction

Immunohistochemistry For rhabdoid tumour of the kidney with SMARCA4 inactiva­ tion, SMARCA4 (BRG1) immunohistochemistry may be used; this shows a loss of nuclear staining in tumour cells and normal

Rhabdoid tumours of the kidney have a uniformly dismal progno­ sis, with reported 5-year overall survival rates ranging from < 15% to 25%. Younger age and presence of metastases at diagnosis are adverse prognostic factors for survival {3173,3278). Tumours of the kidney

115

Chang KTE Calio A de Krijger RR

Clear cell sarcoma of the kidney

Definition Clear cell sarcoma of the kidney (CCSK) is a rare malignant renal tumour of childhood characterized histologically by vari­ ably clear tumour cells and distinctive arborizing fibrovascular septa, and molecularly by BC mutations or YI/VHAE::NUTM2 gene fusion.

。"

ICD-0 coding 8964/3 Clear cell sarcoma of kidney

ICD-11 coding 2C90.Y & XH0765 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Clear cell sarcoma of kidney

Related terminology Not recommended: bone-metastasizing renal tumour of child­ hood (2034}. Fig. 2.101 Clear cell sarcoma of the kidney. Grossly, this tumour is a well-circum­

Subtype(s)

scribed fleshy mass.

None

Localization

Etiology

CCSK arises in the kidney and is often centred in the renal medulla. Bilateral CCSK has not been reported.

There are no known risk factors. CCSK is a sporadic tumour. There have been no reports of familial CCSK.

Clinical features

Pathogenesis

The affected child may have nonspecific features of abdominal distension, pain, a palpable abdominal mass, or gross haematuria.

CCSK is characterized by one of three mutations: (1) an in-frame internal tandem duplication (ITD) affecting a segment within exon 15 of the BCOR gene (3240),⑵ YWHAE:NUTM2 gene fusion (2371}, or (3) BCOR::CCNB3 gene fusion {3484}. The specific mechanisms of molecular pathogenesis are currently unknown. The three mutations result in oncogenic upregula­ tion of BCOR, which is a component of non-canonical PRC1.1 {1102).

Epidemiology CCSK constitutes 3-5% of malignant renal tumours in childhood and ranks a distant second after nephroblastoma. The M:F ratio is 2:1. The mean age at diagnosis is 3 years (3005(.

Fig. 2.102 Clear cell sarcoma of the kidney. A Classic areas feature ovoid tumour cells with variably clear nuclei and cytoplasm. Note the delicate branching vasculature. B Cel­ lular areas feature overlapping of the nuclei.

116

Tumours of the kidney

e

5 Q E 8

Fig. 2.103 Clear cell sarcoma of the kidney. A Myxoid areas show increased extracellular matrix. Cyst formation is possible. B Epithelioid areas feature tumour cells arranged as tubules or trabeculae.

Fig. 2.104 Clear cell sarcoma of the kidney. A Palisading areas resemble Verocay bodies of schwannomas. B Spindled areas feature fascicular groups of elongated tumour cells, resembling a spindle cell sarcoma. C Anaplasia may rarely occur in clear cell sarcoma of the kidney. It is defined as for nephroblastoma.

Macroscopic appearance CCSK often manifests as a solitary large renal tumour with its epicentre at the renal medulla. The cut surface is pale tan-grey and fleshy; mucoid to cystic areas may be present.

Histopathology CCSK has various histological patterns (184}. The classic pattern is most common and usually present at least focally. This features plump ovoid tumour cells demarcated into broad trabeculae or nests by distinctive arborizing fibrovascular septa. Tumour cells have barely perceptible cytoplasm and monomorphic nuclei

with dispersed chromatin and indistinct nucleoli. The nuclei and cytoplasm often have a clear appearance, from which this tumour derives its name. The cellular pattern has similar tumour cells, more closely packed, with frequent nuclear overlapping. The myxoid pattern features increased mucopolysaccharide matrix that may form mucoid pools and cysts. The sclerosing pattern features hyalinized collagen that may resemble oste­ oid. The epithelioid pattern has tumour cells aligned in acini or elongated trabeculae mimicking epithelial structures, as may be seen in nephroblastoma. The palisading pattern features nuclear palisading that resembles Verocay bodies of schwannomas. The

Fig. 2.105 Clear cell sarcoma of the kidney. Tumour cell nuclei are strongly and diffusely positive forcyclin D1 (A) and BCOR (B). Note that vascular endothelial cells are negative.

Tumours of the kidney

117

spindled pattern has elongated tumour cells resembling spin­ dle cell sarcomas. Rare tumours have anaplasia defined in the same way as for nephroblastomas. Posttreatment relapses may resemble myxoma or fibromatosis histologically.

Immunohistochemistry Immunoreactivity for both cyclin D1 and BCOR in a diffuse nuclear staining pattern provides robust support for the diag­ nosis of CCSK (3484,1511,2175). However, cyclin D1, although sensitive, is not perfectly specific; and BCOR is neither per­ fectly sensitive nor specific. Other positive markers include vimentin, p75-NGFR, BCL2, TLE1, and SATB2 (1633,209|. CCSK is negative for CD34, S100, desmin, cytokeratins, and EMA (1924). CCSK with BC0R::CCNB3 gene fusion expresses cyclin B3 {2066}.

Essential and desirable diagnostic criteria Essential: characteristic histomorphology of ovoid tumour cells with nuclear and/or cytoplasmic clearing at least focally, dis­ tinctive arborizing fibrovascular septa, and immunoreactivity for cyclin D1 and BCOR. Desirable: features for cases with atypical histomorphology or immunophenotype include molecular identification of BCOR exon 15 ITD or of YWH4E:NUTM2 or 8COR::CCNB3 gene fusion.

Staging Staging uses either the International Society of Paediatric Oncology (SIOP) or the Children's Oncology Group (COG) stag­ ing systems, like for nephroblastomas.

Prognosis and prediction

Cytology Not relevant

Diagnostic molecular pathology Three characteristic mutations of CCSK are (in decreasing order of frequency) BCOR exon 15 ITD, H4/H4E::NUTM2 gene fusion, and BCOR..CCNB3 gene fusion. These three mutations are mutually exclusive.

118

Tumours of the kidney

CCSK has 5-year event-free and overall survival rates of 65-85% and 75-90%, respectively, with intensive multiagent chemotherapy and radiation therapy (1166). Approximately 16% of patients relapse (1165). Relapse may be late {184}, CCSK may metastasize to unusual sites such as bone, orbit, and brain. The clinical course is not predicted by histological pattern or mutation findings.

Nephrogenic rests

Definition Nephrogenic rests are abnormally persistent foci of embryonal cells (after 36 weeks of gestation) that are potentially capable of developing into nephroblastoma.

Argani P Calio A Chang KTE de Krijger RR Vujanic GM

Table2.08 Features distinguishing perilobar from intralobar rests

Perilobar rests

Intralobar rests

Position in lobe

Peripheral

Random

Margins

Sharp, demarcated

Irregular, intermingling

Blastema, tubules

Stroma, blastema, tubules

Stroma scant or sclerotic

Stroma often predominates

Usually multifocal

Often unifocal

ICD-0 coding None

Composition

ICD-11 coding

Distribution

None

Related terminology None

Subtype(s) Perilobar nephrogenic rests; intralobar nephrogenic rests; nephroblastomatosis (the presence of diffuse or multifocal nephrogenic rests)

Localization

with nephroblastoma, but in virtually all patients with bilateral nephroblastoma {305,304,306.1329}. Perilobar nephrogenic rests (PLNRs) are nearly absent in the Asian population {1060). PLNRs are associated with hemihypertrophy and overgrowth syndromes such as Beckwith-Wiedemann syndrome. Intralobar nephrogenic rests (ILNRs) are associated with Denys-Drash syndrome (Wilms tumour, pseudohermaphroditism, glomeru­ lopathy, and renal failure) and WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies, and a range of developmental delays) {427,1060}.

Nephrogenic rests are localized to the kidney.

Etiology Clinical features Usually, nephrogenic rests do not themselves cause symptoms except for cases of hyperplastic nephroblastomatosis, in which an abdominal mass may be noted. A spherical, exophytic mass on imaging favours nephroblastoma over nephrogenic rest, but it is not definitive (2804}.

PLNRs reflect abnormal renal development late during gesta­ tion, so they are usually located at the periphery of the renal lobe, which develops last. ILNRs reflect abnormal renal devel­ opment earlier during gestation, so they are typically located in the central areas of the lobe.

Pathogenesis

Epidemiology Nephrogenic rests are found in approximately 1% of term infant autopsies. Overall, they are identified in 25-40% of patients

Many of the genetic alterations identified in nephroblastoma have also been found in nephrogenic rests, such as WT1 loss in ILNR and /GF2 overexpression in PLNR {576}.

Fig. 2.106 Nephrogenic rest. A Perilobar rest. Well-demarcated, lens-shaped subc即sular collections of primitive blastemal and tubular cells. B Intralobar rest. Poorly defined proliferation of embryonal cells that intermingles with the native kidney.

Tumours of the kidney

119

Fig.2.107 Nephrogenic rest. A Perilobar rest. Hyperplastic areas commonly show mitotic activity. B Intralobar rest. Adipose tissue is a common component in intralobar rests, along with primitive nephroblastic epithelial tissue.

Macroscopic appearance Nephrogenic rests may appear paler than the surrounding nor­ mal kidney, but most are microscopic findings that are grossly unapparent. Hyperplastic nephrogenic rests (see Histopathol­ ogy, below) may form clinically and grossly evident nodules.

Histopathology Nephrogenic rests can be found adjacent to nephroblastoma or in the surrounding renal parenchyma. The two subtypes, PLNR and ILNR (see Table 2.08, p. 119), may be further subclassified into incipient or dormant, regressing or sclerosing, obsolescent, adenomatous, or hyperplastic nephrogenic rests {306,305,168). PLNRs are usually well demarcated and located at the corti­ cal subcapsular surface of the kidney, but they may also be identified deep within the renal parenchyma. Untreated cases have no capsule and contain blastemal and epithelial ele­ ments, whereas stroma is sparse or sclerotic. Rarely, PLNRs form a thick band (crust) that replaces the renal cortex, result­ ing in massive renal enlargement (diffuse hyperplastic perilobar nephroblastomatosis) {2500|. Hyperplasia may produce large masses of blastemal and primitive tubular cells that can exhibit active growth and numerous mitotic figures, and a section or small biopsy from the interior of a hyperplastic nephrogenic rest may be indistinguishable from nephroblastoma. Two features help make this distinction. First, hyperplasia involving all or most cells of a rest tends to preserve its original lens shape, unlike nephroblastomas, which tend to be spherical. Second, hyper­ plastic nephrogenic rests remain unencapsulated whereas nephroblastomas are encapsulated {306,305,168}. In contrast to PLNRs, ILNRs are typically located in the cen­ tral areas of the lobe. They are often single or not numerous, poorly demarcated, and mainly composed of stromal and epi­ thelial elements. Often, ILNRs also occur within the renal sinus, including in the walls of the pelvicalyceal system and ureter.

120

Tumours of the kidney

Hyperplastic ILNRs are also easily mistaken for nephroblas­ toma. Two features help make this distinction. First, the permea­ tive border of the ILNR contrasts with the encapsulated border of nephroblastoma. Second, the histological composition pro­ vides a clue; skeletal muscle is uncommon in ILNRs but com­ mon in nephroblastoma, whereas fat is uncommon in nephro­ blastoma and commonly in found in ILNRs (306,305).

Cytology Not relevant

Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: for PLNR: well-delineated proliferation of nephro­ blastic elements, usually located in the renal cortex or at the tumour periphery, typically composed of blastema and epi­ thelium； for ILNR: infiltrative proliferation of nephroblastic ele­ ments, usually located deeper in the kidney, mingling with the renal parenchyma, often composed of stroma.

Staging Not relevant

Prognosis and prediction The presence of nephrogenic rests (particularly PLNR in chil­ dren aged < 1 year) indicates an increased risk of developing contralateral nephroblastoma {708}. Diffuse hyperplastic perilo­ bar nephroblastomatosis is associated with a high risk of devel­ oping multiple nephroblastomas as well as anaplastic nephro­ blastomas (2500,1068,168). Prompt therapy can minimize the amount of native kidney that requires excision (nephron-sparing approach), thereby maximizing the preservation of renal function.

。

Cystic partially differentiated nephroblastoma

Argani P Cali A Chang KTE de Krijger RR Pritchard-Jones K Vujanic GM

■ CM5 Q 2

。

Definition Cystic partially differentiated nephroblastoma (CPDN) is a multilocular, exclusively cystic renal neoplasm of very young chil­ dren, containing nephroblastomatous tissue.

ICD-0 coding 8959/1 Cystic partially differentiated nephroblastoma

ICD-11 coding 2C90.Y & XH1JB4 Other specified malignant neoplasms of kidney, except renal pelvis & Cystic partially differentiated nephroblastoma

Related terminology

Fig. 2.108 Cystic partially differentiated nephroblastoma. The lesion is entirely cystic,

None

and the cysts mould the septa.

Subtype(s) None

Localization CPDN arises in the kidney. There are exceptionally rare cases of bilateral CPDN (3044,1755).

Clinical features The typical presentation is that of an abdominal mass. The purely cystic nature of the lesion may be evident on imaging studies.

Epidemiology More than 100 patients with CPDN have been reported in the literature, with a male predominance. Patients usually present before the age of 2 years {3296}.

Fig. 2.109 Cystic partially differentiated nephroblastoma. Primitive nephroblastic ele­

ments are locally present within the septa.

Histopathology

Unknown

CPDNs are composed entirely of septated cysts (445,912, 1555}. The cysts are lined with flattened, cuboidal, or hobnail epithelium, or they are denuded. The septa are variably cellu­ lar and contain undifferentiated and differentiated mesenchyme (often skeletal muscle, occasionally cartilage or fat), islands of blastema, and nephroblastomatous epithelial elements {912). Focally, the septal elements may protrude into the cysts in microscopic papillary folds. The epithelial components con­ sist mainly of mature and immature tubules and small papillae resembling immature glomeruli (912,1555}.

Macroscopic appearance

Cytology

CPDNs often are large (particularly considering the patients' young age), reaching diameters as great as 190 mm (mean： 100 mm). They are well circumscribed and consist entirely of cysts of variable size; the septa are thin and there are no expan­ sile, solid nodules to alter the rounded contour of the cysts {3296,912,1555}.

Not relevant

Etiology CPDN is considered part of the nephroblastoma spectrum. Pae­ diatric cystic nephroma used to be considered related to CPDN, but recent genetic studies have shown that cystic nephroma harbours DICER1 mutations whereas CPDN does not, indicat­ ing that these two morphologically similar lesions are unrelated (890).

Pathogenesis

Diagnostic molecular pathology No specific molecular abnormalities have been reported for these tumours.

Tumours of the kidney

121

Essential and desirable diagnostic criteria

Prognosis and prediction

Essential: CPDN must lack solid nodules on gross or micro­ scopic examination; septa contain (undifferentiated) mesen­ chyme, as well as blastemal and immature epithelial elements.

Surgery is almost always curative {1971,369(. Patients with stage I disease are cured by surgery without adjuvant chemo­ therapy {369}. Rare recurrences have been reported as a com­ plication of incomplete resection {1555} or tumour rupture {248}.

Staging Not relevant

122

Tumours of the kidney

Nephroblastoma

Argani P Calio A Chang KTE de Krijger RR Pritchard-Jones K Vujanic GM

Definition Nephroblastoma is a malignant embryonal neoplasm derived from nephrogenic blastemal cells that replicates the histology of developing kidneys and often shows divergent patterns of differentiation.

ICD-0 coding 8960/3 Nephroblastoma

ICD-11 coding 2C90.Y & XH5QN3 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Nephroblastoma, NOS

Related terminology Acceptable: Wilms tumour.

Subtype(s)

Fig. 2.110 Nephroblastoma. The neoplasm is well delineated and fleshy, with small

None

yellow areas of necrosis. A multinodular internal structure is typical.

Localization

Box2.01 Revised International Society of Paediatric Oncology (SIOP) working clas­

Most nephroblastomas are unicentric. However, multicentric masses in a single kidney and bilateral primary lesions have been observed in 7% and 5% of cases, respectively (708}. Rarely, nephroblastoma occurs in extrarenal sites (13,2393).

sification of nephroblastoma

For pretreated cases: I. Low-risk tumours

Cystic partially differentiated nephroblastoma

Clinical features Nephroblastomas most commonly come to clinical attention as an abdominal mass detected by the patient's parents. Abdomi­ nal pain, haematuria, hypertension, and anaemia are found in 20-30% of patients (783}. On imaging, nephroblastoma typically manifests as a solid mass of heterogeneous appearance, dis­ torting the renal parenchyma and collecting system (3414,1960). The majority of nephroblastomas are treated using therapeutic protocols created either by the International Society of Paediatric Oncology (SIOP) or by the Children's Oncology Group (COG). The SIOP protocols generally advocate preoperative therapy foltowed by surgical removal. Pretherapeutic tumour biopsy for diagnosis is advocated only in specific circumstances (age > 7 years, unusual clinical or radiological features) that make nephroblastoma less likely {1487}. For children aged < 6 months (when identification of congenital mesoblastic nephroma is com­ mon) or children with completely cystic neoplasms on imaging, immediate surgical excision without biopsy is recommended. Otherwise, chemotherapy is administered without previous biopsy. Preoperative chemotherapy allows for tumour shrinkage before resection, resulting in fewer intraoperative ruptures and more favourable stage distribution (more stage l-ll tumours). Postoperative chemotherapy is then determined by histologi­ cal evidence of responsiveness to therapy, as indicated in the SIOP classification {3350} (see Box 2.01). COG (including its predecessor, the National Wilms Tumour Study Group) advo­ cates primary resection of tumours, followed by therapy that is

Completely necrotic nephroblastoma

II. Intermediate-risk tumours Nephroblastoma - epithelial type Nephroblastoma 一 stromal type Nephroblastoma-mixed type

Nephroblastoma - regressive type Nephroblastoma-focal an 叩 lasia III. High-risk tumours

Nephroblastoma - blastemal type Nephroblastoma - diffuse anaplasia For primary nephrectomy cases: I. Low-risk tumours

Cystic partially differentiated nephroblastoma

II. Intermediate-risk tumours Non-anaplastic nephroblastoma and its variants

Nephroblastoma-focal anaplasia

III. High-risk tumours Nephroblastoma-diffuse anaplasia

determined by the tumour's histology and stage. This permits diagnosis of untreated tumours and enables their stratification according to biological parameters. Although the SIOP and COG protocols have different approaches, they have produced similar outcomes (2498,3349}. Tumours of the kidney

123

Table2.09 Frequency of paediatric renal malignancies Estimated relative frequency

Neoplasm

75-80%

Nephroblastoma (non-anaplastic) Nephroblastoma (anaplastic)

J/o

4%

Congenital mesoblastic nephroma

X%

Clear cell sarcoma of the kidney

2%

Rhabdoid tumour Renal cell carcinoma

J%

Miscellaneous (neuroblastoma, Ewing sarcoma, synovial sarcoma, angiomyolipoma, lymphoma, other rare neoplasms)

1-2%

Epidemiology Nephroblastoma affects approximately 1:8000 children (426). Tumours occur with equal frequency in both kidneys and there is overall a slight female predominance (M:F ratio: 0.9:1) {2282}. The mean age at diagnosis for male and female patients is 37 months and 43 months, respectively, and 98% of cases occur in individuals aged < 10 years, although presentation in adult­ hood does occur {425,783,2868,2181}. Nephroblastoma occurs at relatively stable frequencies around the world, so environmen­ tal factors do not appear to play a major role in its development. The incidence varies among different racial groups, which sug­ gests a genetic predisposition. In the USA, nephroblastoma is more common among Black people than White people, and least frequent among people of eastern Asian descent {2282(. The estimated relative frequencies of various paediatric renal malignancies are listed in Table 2.09.

Etiology The majority of patients with nephroblastoma are non-syndromic. In 10-15% of patients it develops in association with syndromes and congenital anomalies (see Table 2.10) (2866,

Table2.10 Conditions associated with nephroblastoma

Risk of nephroblastoma

■』 Syndrome

High (> 20%)

WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies, and a range of developmental delays)

Denys-Drash syndrome Beckwith-Wiedemann syndrome Moderate (5-20%)

Simpson-Golabi-Behmel syndrome

Frasier syndrome

Bloom syndrome

Li-Fraumeni syndrome DICER1 syndrome Isolated hemihypertrophy

Cutaneous naevi, haemangiomas Low(< 5%)

Trisomy 18

KlippekTrenaunay syndrome

Neurofibromatosis

Renal or genital malformations

1418,648,3190}. In 1-2% of cases it is familial {2757}, with many underlying genes. Three syndromes pose a moderate to high risk of nephroblastoma: WAGR syndrome (Wilms tumour, aniridia, genitourinary anomalies, and a range of developmen­ tal delays), Denys-Drash syndrome (pseudohermaphroditism, nephropathy, and Wilms tumour), and Beckwith-Wiedemann syndrome (macrosomia, macroglossia, abdominal wall defect, and renal abnormalities). WAGR syndrome is caused by a germline deletion involving chromosome band 11p13, where the WT1 gene is located (encoding a zinc finger transcription factor that plays a pivotal role in renal and gonadal develop­ ment), and it imparts a 45-60% chance of developing nephro­ blastoma (1016,1377}. Denys-Drash syndrome is characterized by germline point mutations in the WT1 gene, and it carries a 90% chance of developing nephroblastoma. Nephroblasto­ mas in patients with WAGR and Denys-Drash syndromes typi­ cally show a loss of the normal WT1 allele, consistent with its role as a tumour suppressor gene. A second nephroblastoma locus, implicated in Beckwith-Wiedemann syndrome, maps to 11p15, where multiple imprinted candidate genes reside, includ­ ing IGF2, CDKN1C (also known as P57 or KIP2), and KCNQ1 (KVLQT1). The risk of nephroblastoma is approximately 20% but varies according to epigenotype {1977}. Other syndromes carry a lower risk of developing nephroblastoma, including SimpsonGolabi-Behmel and Frasier syndromes (5-20%), and Bloom, Li-Fraumeni, and DICER1 syndromes (< 5%). Dysregulation of IGF2 expression (via methylation or copy­ number alterations) is found in approximately 70% of sporadic nephroblastomas, making it the most common genetic alteration in these tumours. /GE2-dysregulated nephroblastomas often arise from perilobar nephrogenic rests and have blastema) and epithelial-predominant histology. The WT1 gene is mutated in approximately 20% of sporadic nephroblastomas. kl/H-mutated nephroblastomas often arise from intralobar nephrogenic rests and have stromal-predominant histology. Unlike IVH-wildtype nephroblastomas, H/H-mutated tumours frequently harbour CTNNB1 mutations and almost all show p-catenin pathway activation {I860}. Inactivation of a tumour suppressor gene on the X chromosome, AMER1 (WTX), has been demonstrated in one third of nephroblastomas {2676}. Mutations in the SIX1/SIX2 pathway and the DROSHA/DGCR8 microRNA microprocessor complex have been found in high-risk blastemal nephroblasto­ mas (3422,3365}.

Perlman syndrome Sotos syndrome Cerebral gigantism

124

Tumours of the kidney

Pathogenesis Three main pathways are implicated in nephroblastoma devel­ opment: IGF2 overexpression (in 70% of cases), dysregulated

Fig. 2.111 Nephroblastoma. A Classic triphasic growth pattern, of blastemal cells, stromal cells, and epithelial differentiation including tubules and primitive glomeruli. B The stromal component commonly shows rhabdomyoblastic differentiation. C Diffuse blastemal pattern demonstrating undifferentiated small blue round cell tumour pattern. D Dif­ fuse blastemal pattern demonstrating intrarenal vascular invasion. E Anaplastic nephroblastoma. Blastemal and stromal neoplasm with enlarged, hyperchromatic nuclei and multipolar mitotic figures.

WNT signalling (encompassing WT1, AMER1 [WTX], and CTNNB1 mutations) (in 30%), and microRNA processing altera­ tions (in 20%). Late events that promote progression or chem­ oresistance include 1p/16q loss, 1q gain, and TP53 mutations. The genetic profile is diverse, with over 40 genes found to be somatically mutated in nephroblastoma (3190).

Macroscopic appearance Nephroblastomas are usually solitary, rounded, multinodular masses, sharply demarcated from the adjacent renal paren­ chyma by a peritumoural fibrous pseudocapsule. The cut sur­ face of untreated tumours is most commonly pale grey or tan and has a soft consistency, although it may be firm and whorled if a large fraction of the lesion is composed of mature stromal elements. Tumours treated with preoperative chemotherapy usually show areas of necrosis, and they can even be com­ pletely necrotic. Cysts may be prominent.

Histopathology Nephroblastomas characteristically contain undifferentiated blastemal cells, as well as cells differentiating to various degrees and in different proportions towards epithelial and stromal lineages. Triphasic patterns are the most characteris­ tic, but biphasic and monophasic lesions are often observed. Most of these components represent stages in normal or abnormal nephrogenesis, but heterologous, non-renal ele­ ments also occur.

Blastemal cells are small, closely packed, mitotically active, rounded or oval cells with scant cytoplasm. Nuclei are character­ istically overlapping, with evenly distributed, slightly coarse chro­ matin and small nucleoli. Several distinctive blastemal patterns have been described. The diffuse blastemal pattern is charac­ terized by sheets of blastemal cells that aggressively invade the kidney, and it often comes to clinical attention at an advanced stage. Other blastemal patterns are more cohesive. The nodular and serpentine blastemal patterns demonstrate round or undu­ lating, sharply defined cords or nests of blastemal cells set in a loose fibromyxoid stroma. Most nephroblastomas contain an epithelial component; early tubular forms mimic primitive rosette­ like structures, but most contain easily recognizable tubular or glomerular elements that recapitulate various stages of normal nephrogenesis. Most tubular elements have a columnar shape and are mitotically active, but some foci can be cuboidal and have less mitotic activity, mimicking metanephric adenoma. Het­ erologous epithelial differentiation most commonly consists of mucinous and squamous epithelium. Stromal patterns include smooth muscle and fibroblastic differentiation. Skeletal muscle is the most common heterologous stromal cell type and may consti­ tute large fields of the tumour. Other types of heterologous stromal differentiation include adipose tissue, cartilage, bone, ganglion cells, and neuroglial tissue. The histology and clinical features of nephroblastoma may be determined by the type of nephrogenic rest from which it arose. Stromal components often predominate in nephroblastomas associated with intralobar nephrogenic rests Tumours of the kidney

125

Box 2.02 Histological criteria for anaplasia

Focal an叩lasia A clearly defined focus of anaplasia within the primary tumour. It may be circumscribed and its perimeter completely examined (this may require mapping of anaplastic foci that extend to the edge of tissue sections). If more than one focus is present, each has to be small enough to be contained on a single microscopic side

Anaplasia must be confined to the renal parenchyma An叩lasia must not be present within vascular spaces

Absence of severe nuclear pleom。甲hism and hyperchromasia (marked/severe nuclear unrest) in a non-anaplastic tumour

One or two foci of anaplasia, none > 15 mm (SIOP trials) Diffuse anaplasia

Non-localized (multifocal) anaplasia An叩lasia beyond the tumour capsule

Rg. 2.112 Anaplastic nephroblastoma. Blastemal and stromal neoplasm with en­ larged, hyperchromatic nuclei (best evident in the stroma) and multipolar mitotic figures.

Anaplastic cells in intrarenal vessels, extrarenal vessels, renal sinus, extracapsular invasive sites, or metastatic deposits

An叩lasia that is focal, but with nuclear atypia approaching the criteria for anaplasia (marked nuclear unrest) present elsewhere in the tumour

(which typically affect young infants), whereas blastemal and epithelial components predominate in nephroblastomas associ­ ated with perilobar nephrogenic rests (which commonly affect older children). Descriptive terms such as ufetal rhabdomyomatous nephroblastoma", Hbotryoid nephroblastoma", and "teratoid nephroblastoma" add no independent prognostic information and describe patterns but not distinctive entities {3351,856} Approximately 5-8% of nephroblastomas demonstrate anaplasia, defined as cells with huge hyperchromatic nuclei, associated with multipolar mitotic figures. The enlarged nuclei should be at least three times larger than non-anaplastic nuclei in the surrounding cells. The combination of nucleomegaly and hyperchromasia reflects the increased DNA content of the poly­ ploid anaplastic cells. Atypical mitotic figures must be large, with each arm being larger than a normal metaphase plate. It is important to distinguish multipolar mitotic figures from minor mitotic abnormalities resulting from lagging of chromosomes on the anaphase spindle or uneven separation of a metaphase plate. The latter can occasionally produce an X- or Y-shaped mitotic figure, but the total length of the X or Y structure is simi­ lar to that of normal metaphase. Anaplasia is frequently missed

or overdiagnosed because the above criteria are not followed {882,2498}. Anaplasia is rare during the first 2 years of life, but it increases in prevalence to > 15% after 4 years of age. Anaplasia is sub­ classified as focal and diffuse anaplasia; these subclassifica­ tions have an important impact on treatment and prognosis (see Box 2.01, p. 123) (882,3347}. Criteria for focal anaplasia are listed in Box 2.02. In gen­ eral, focal anaplasia must be intrarenal and well demarcated. SIOP criteria further limit the definition to one or two foci, none > 15 mm in size. Anaplasia identified on biopsy, in perirenal or extrarenal sites, or in blood vessels, or anaplasia than cannot be proved to be focal, is considered diffuse. Focal anaplasia has an outcome similar to that associated with non-anaplastic nephroblastoma in SIOP trials (3348} and a prognosis between

Rg. 2.113 Focally anaplastic nephroblastoma. p53 immunohistochemistry highlights the focally anaplastic area.

Hg. 2.114 Nephroblastoma. WT1 immunohistochemistry labels blastemal cells and primitive tubules, but not stromal cells or better-formed tubules.

126

Tumours of the kidney

Anaplasia not clearly demarcated from non-anaplastic tumour Anaplasia present in a biopsy or other incomplete tumour sample

SIOP, International Society of Paediatric Oncology.

that of favourable histology and diffuse anaplasia in National Wilms Tumor Study (NWTS) / COG studies {882}. Chemotherapy-induced changes include necrosis, xan­ thomatous histiocytic foci, haemosiderin deposits, and fibrosis. Chemotherapy may also induce maturation of blastemal, epi­ thelial, and stromal components, with striated muscle differen­ tiation being the most frequent. Remarkable responsiveness to chemotherapy has resulted in complete necrosis in some tumours; such cases are considered low risk by the SIOP cri­ teria and receive minimal treatment after surgery {377}. In con­ trast, tumours that contain a large amount of blastema despite therapy, or those that demonstrate anaplasia, have a worse prognosis and increased requirement for therapy. Other cat­ egories (epithelial, stromal, regressive, or mixed subtype) are considered of intermediate risk {3347}.

Immunohistochemistry The diversity of cell lines and degrees of differentiation in nephroblastoma imparts a correspondingly varied immuno­ histochemical profile. Blastemal cells may or may not label for cytokeratin, and they typically show focal labelling for desmin with negative results for other muscle markers. Various differ­ entiating cell lines will give results according to their patterns of differentiation. Immunoreactivity for WT1 (seen in 〜80% of cases) is typically limited to the blastema and epithelial compo­ nents of nephroblastoma, with the stroma being negative. Although the typical triphasic nephroblastoma is usually not a difficult diagnosis, monophasic nephroblastomas can be

mistaken for a variety of neoplasms. Pure epithelial nephroblas­ tomas can be confused with metanephric adenoma as well as type 1 papillary renal cell carcinoma. WT1 immunoreactivity helps exclude papillary renal cell carcinoma, but it is consist­ ently found in metanephric adenoma. Pure blastemal nephro­ blastomas raise the broad differential diagnosis of small round cell tumours, particularly neuroblastomas and rhabdoid tumour in young patients and Ewing sarcoma in older children or young adults. The absence of membranous CD99 immunoreactivity or nuclear PHOX2B immunoreactivity, as well as intact SMARCB1 (INI1) labelling, can help exclude these possibilities. Pure stro­ mal nephroblastomas can be confused with clear cell sarcoma of the kidney, congenital mesoblastic nephroma, or synovial sarcoma {2378}. This difficulty can be magnified by preopera­ tive chemotherapy, which often selectively kills the blastemal and epithelial cells of nephroblastoma and leaves the stromal component behind. A paediatric renal neoplasm containing skeletal muscle can be assumed to be a nephroblastoma until proved otherwise.

Cytology Nephroblastoma cannot be distinguished from a hyperplastic nephrogenic rest by cytology.

Diagnostic molecular pathology The genetic heterogeneity of nephroblastoma explains the absence of a specific diagnostic genetic marker. However, ana­ plasia is closely correlated with the presence of 7P53 mutations,

Table2.11 Staging of paediatric renal tumours: Children's Oncology Group (COG) and International Society of Paediatric Oncology (SIOP)

Stage

Definition

I

COG

Limited to kidney and completely resected; renal capsule is intact

Renal sinus soft tissue may be minimally infiltrated, without any involvement of the sinus vessels; the tumour may protrude into the pelvic

system without infiltrating the wall of the ureter Intrarenal vessels may be involved

SI0Pa

As COG, but no infiltration of the renal sinus soft tissues is permitted; limited to kidney or surrounded with fibrous pseudocapsule if outside the normal contours of the kidney; presence of necrotic tumour or chemotherapy-induced changes in the renal sinus or soft tissue outside the

kidney does not upstage the tumour in the posttherapy kidney

II

COG & SIOP

Tumour infiltrates beyond the kidney but is completely resected Tumour penetration of renal capsule or infiltration of soft tissues and vessels within the renal sinus (including the intrarenal extension of the

sinus); tumour infiltrates adjacent organs or vena cava but is completely resected III

COG & SIOP

Gross or microscopic residual tumour confined to abdomen. Includes cases with any of the following:

(A) Involvement of specimen margins grossly or microscopically (B) Tumour in abdominal lymph nodes (C) Any peritoneal contamination by direct tumour growth, tumour implants, or spillage into peritoneum before or during surgery (D) Residual tumour in abdomen

(E) Tumour removed non-contiguously (piecemeal resection)

COG

Tumour was surgically biopsied before preoperative chemotherapy (including FNA)

SIOP

The presence of necrotic tumour or chemotherapy-induced changes in a lymph node should be regarded as stage III

IV

COG & SIOP

Haematogenous metastases or lymph node metastasis outside the abdominopelvic region

V

COG & SIOP

Bilateral renal involvement at diagnosis; the tumours in each kidney should be s叩arately substaged in these cases

aFNA or percutaneous core needle (Tru-Cut) biopsy does not upstage the tumour, but the size of the needle gauge should be mentioned to the pathologist. The presence of ne­ crotic tumour or chemotherapy-induced change in the renal sinus and/or within the perirenal fat should not be regarded as a reason for upstaging a tumour providing it is completely excised and does not reach the resection margins. Infiltration of the adrenal gland does not upstage a tumour if the external capsule of the adrenal gland is intact. Liver: tumour might be attached to the liver capsule, and this should not be regarded as infiltration of the adjacent organ; only if clear infiltration of the liver parenchyma is present should the

tumour be regarded as stage III.

Tumours of the kidney

127

whereas non-anaplastic nephroblastomas virtually never har­ bour TP53 mutations, which the majority of anaplastic nephro­ blastomas do {273}. Furthermore, microdissection experiments have demonstrated that TP53 mutations are usually restricted to the anaplastic portions of nephroblastomas with focal anaplasia (272}. Because an apoptotic pathway induced by chemother­ apy depends on functional p53t the association of TP53 muta­ tions with resistance to chemotherapy that is the hallmark of anaplastic nephroblastoma makes sense. Recent studies show that TP53 mutation status may better stratify risk in patients with diffuse anaplasia (2053}. A subset of epithelial-predominant nephroblastomas in children and adults harbour BRAF p.V600E mutations; these neoplasms characteristically have highly differentiated foci that resemble metanephric adenomas. These tumours can be effectively treated with targeted therapy (3481). Another subset of epithelial nephroblastomas of favourable prognosis in very young children are associated with germline and somatic muta­ tions in the TRIM28 gene (1266(.

Essential and desirable diagnostic criteria Essential: an abdominal solid and heterogeneous mass; mul­ tiple components (stromal, blastemal, epithelial) present on histology; in monophasic neoplasms, immunohistochemistry and/or molecular testing may be needed to exclude mimics.

Staging Nephroblastomas generally have a restricted pattern of metas­ tasis： most commonly regional lymph nodes, lungs, and liver. Metastases usually occur within 2 years of diagnosis. Other metastatic sites (e.g. bone or brain) or a prolonged interval to metastasis are unusual and in such cases other diagnoses should be considered.

128

Tumours of the kidney

The most widely accepted staging systems for nephroblasto­ mas are the SIOP and COG staging systems, which have some differences (see Table 2.11, p. 127). Both systems rely on the identification of renal capsule penetration, involvement of the renal sinus, positive surgical margins, and positive regional lymph nodes. Although bilateral nephroblastomas are desig­ nated as stage V, their treatment and prognosis are determined by the local stage of the most advanced tumour and by the presence or absence of diffuse anaplasia.

Prognosis and prediction Most nephroblastomas of low stage have favourable histol­ ogy and are associated with an excellent prognosis. The most important unfavourable factors are high stage and the presence of anaplasia (882}. The majority of blastemal tumours are exqui­ sitely sensitive to therapy. However, tumours that demonstrate extensive blastemal cells after preoperative chemotherapy are associated with a poor response to therapy and reduced sur­ vival {307,377,3277). In SIOP protocols, blastemal type nephro­ blastomas are classified as high risk, and they are treated more aggressively. Genetic studies that subclassify nephroblastomas into distinctive groups may potentially substratify risk {2865, 1074,883). Nephroblastomas demonstrating a loss of heterozygosity for both chromosomes 1p and 16q have been shown to have a poor prognosis and may trigger more intensive chemotherapy in the COG protocols (1208). SIOP does not include biological markers for risk and treatment stratification {883}. The recent SIOP and COG studies have found that gain of chromosome 1q is associated with a poor prognosis and it will be used in the coming COG protocol, whereas SIOP will study this marker pro­ spectively {558,1184).

Germ cell tumours of the kidney

Definition Germ cell tumours of the kidney are usually prepubertal-type teratomas or (exceptionally) yolk sac tumours (YSTs) or mixed teratoma-YST arising within the kidney parenchyma.

Srigley JR

Primary type 2 germ cell tumours may occur in extragonadal sites such as the mediastinum and CNS, but they have not been described in the kidney.

Macroscopic appearance ICD-0 coding 9084/0 Prepubertal-type teratoma 9084/3 Teratoma with carcinoid (neuroendocrine tumour) 9071/3 Yolk sac tumour, NOS 9085/3 Mixed teratoma-yolk sac tumour

The gross appearances of renal germ cell tumours are like those described in other anatomical sites. Teratomas are usu­ ally cystic, but they may have solid areas. Sometimes hair and sebaceous material is present and areas of calcification with cartilage and bone may be identified (1450}. The rare renal YSTs are solid, sometimes yellow, and haemorrhagic (1750,1889).

ICD-11 coding 2C90.Y & XH83G5 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Teratoma, NOS 2C90.Y & XH09W7 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Yolk sac tumour

Related terminology Acceptable: germ cell tumour, type 1.

Subtype ⑥ Teratoma with carcinoid (neuroendocrine tumour); mixed teratoma-yolk sac tumour

Localization Kidney, including horseshoe kidney

Clinical features Patients may present symptomatically with abdominal pain or a palpable mass, or without symptoms on imaging studies {1450, 3607). Patients with associated carcinoid/neuroendocrine tumours have not displayed clinical features of the carcinoid syndrome (195).

Histopathology Teratomas display a wide range of patterns reflecting ectoder­ mal, endodermal, and mesenchymal differentiation. Squamous, transitional, and various types of glandular epithelium can be seen along with neural tissue, smooth muscle, cartilage, and bone {1450(. In most cases, the tissues have a mature appear­ ance, but immature elements have also been described (1450, 3607}. Teratomas may be associated with carcinoid (welldifferentiated neuroendocrine) tumours {195,3066(. It is also possible that pure carcinoid tumours of the kidney may have a teratomatous origin. Primary YST of the kidney has an appear­ ance like its gonadal counterpart {1750,1889). A rare mixed tumour with both teratomatous and yolk sac patterns has been described {1912). In making a diagnosis of primary renal germ cell tumour, it is important to rule out metastasis or direct extension from a retroperitoneal neoplasm. Wilms tumour with teratoid differ­ entiation is another consideration. If a trophoblastic tumour is

Epidemiology Primary germ cell tumours are rare, with < 25 cases reported. In a review of 17 patients (10 male, 7 female), ages ranged from 1 month to 65 years {1450}. Paediatric examples may be congenital {2193(. Teratomas may occur in horseshoe kidneys (2193,3066} and in association with renal dysplasia {2406(.

Etiology See Teratoma, prepubertal-type (p. 291) and Yolk sac tumour, prepubertal-type (p. 293).

Pathogenesis During embryogenesis, the developing renal structures are closely related to the genital ridges and it is postulated that migrating primordial germ cells may be displaced in nephro­ genic precursor tissue (1546(. See also Teratoma, prepubertal-type (p. 291) and Yolk sac tumour, prepubertal-type (p. 293).

Fig.2.115 Renal germ cell tumour. A renal teratoma with an associated well-differen­ tiated neuroendocrine tumour (carcinoid).

Tumours of the kidney

129

encountered in the kidney, it probably represents metastasis from a gonadal or gestational trophoblastic primary {2392}. Rarely, trophoblastic differentiation is present in upper tract urothelial carcinoma (1181}.

Essential and desirable diagnostic criteria Essential: kidney epicentre; no other primary site; prepubertaltype germ cell pattern, usually teratoma.

Staging

Cytology

Not applicable

Not relevant

Prognosis and prediction Diagnostic molecular pathology Germ cell tumours of the kidney lack chromosome 12p abnor­ malities. See also Teratoma, prepubertal-type (p. 291) and Yolk sac tumour, prepubertal-type (p. 293).

130

Tumours of the kidney

Follow-up data on renal teratomas are limited, but with surgical excision, recurrence of mature teratoma is unlikely. If immature teratomatous or yolk sac elements are present, prognosis is less predictable (3607,1912,1750}.

IFF!:

Tumours of the urinary tract Edited by: Comperat EM, Netto GJ, Tsuzuki T

Urothelial tumours Non-invasive urothelial neoplasms Urothelial papilloma Inverted urothelial papilloma Papillary urothelial neoplasm of low malignant potential Non-invasive papillary urothelial carcinoma, low-grade Non-invasive papillary urothelial carcinoma, high-grade Urothelial carcinoma in situ Invasive urothelial neoplasms Invasive urothelial carcinoma Squamous cell neoplasms of the urinary tract Squamous papilloma of the urothelial tract Squamous cell carcinomas of the urinary tract Verrucous carcinoma of the bladder Pure squamous carcinoma of the urothelial tract

Glandular neoplasms

Adenomas Villous adenoma Adenocarcinomas Adenocarcinoma NOS

Urachal and diverticular neoplasms Urachal carcinoma Diverticular carcinoma Urethral neoplasms Urethral accessory gland carcinomas

Litt伯 gland adenocarcinoma Skene gland adenocarcinoma Cowper gland adenocarcinoma

Tumours of Mullerian type Clear cell adenocarcinoma of the urinary tract Endometrioid carcinoma of the urinary tract

Tumours of the urinary tract: Introduction

In the fifth-edition WHO classification of urinary and male geni­ tal tumours, histological characteristics remain the gold stan­ dard for classifying and diagnosing urothelial tract tumours. There is a large and growing body of literature on the compre­ hensive molecular classification of urothelial tumours in terms of the mutation landscape and transcriptomic and proteomic sig­ natures that have translational relevance to better classification, prognosis, and selection of efficacious therapeutic targets. We highlight some of these developments in the sections below, but more data are needed to enable the consistent application of these developments in routine pathology practice or for patient management. The three-tiered classification for the morphological grading of papillary neoplasms (low malignant potential, low-grade, and high-grade) is maintained, aside from the rare urothelial papillo­ mas. First proposed in 1998, this system has been promulgated by WHO in the third, fourth, and now fifth series. This classifica­ tion system closely reflects the two major molecular pathways of evolution of urothelial neoplasms and is based on the level of architectural and cytological disorder {950}, which has been proved to be clinically relevant (3089). Classification systems continue to evolve as large amounts of clinicopathological evidence emerge, with refinements and/or enhancements based on molecular advances. We believe there is room for such work in urothelial tumours for better manage­ ment stratification, but until then, for the fifth edition, we have tried to address the issue of intratumoural heterogeneity that has resulted in a diagnostic conundrum (and probably grade migration), leading to the reporting of more high-grade tumours. This conundrum is due in large part to heterogeneity of grade in many bladder tumours, and a lack of clearly enunciated criteria, resulting in variable application of these criteria and poor inter­ observer reproducibility. Heterogeneity of grade occurs in as many as one third of non-invasive papillary urothelial carcino­ mas, and it influences the outcome {621,1149,2854,2643). For this edition, we propose criteria for reporting papillary tumours as high-grade as long as the high-grade component represents > 5% of the tumour (2643). Moreover, tumours with < 5% high­ grade component should be reported as "low-grade with < 5% high-grade component*' {2643}. Such a pragmatic approach to reporting should help achieve more consistent grading of tumours with grade heterogeneity and allow further data to be obtained in large, appropriately powered, prospectively designed studies using consistent criteria. Future advances may also be substantially impacted by the use of deep learning and artificial intelligence (Al) (1499,3013,641}, and potentially with immunohistochemical and molecular markers included within classification systems or used as guides to further refine morphological criteria for greater clinical utility. WHO encour­ ages multidisciplinary international collaboration in this area. Urine cytology is an important management tool for patients with bladder cancer. In this edition, we have promulgated the 132

Tumours of the urinary tract

Raspollini MR Amin MB Hartmann A Moch H Srigley JR

use of The Paris System (TPS) for cytological diagnosis, which has been widely adopted because it is very helpful in clinical management, focusing on the diagnosis of high-grade cytology, which is well suited to accurate diagnoses and has high clini­ cal relevance. Accurate staging for bladder cancer is critical, although the pathological approach using transurethral resec­ tion of the bladder tumour (TURBT) provides limited information. The Vesical Imaging Reporting and Data System (VI-RADS) using mpMRI demonstrates the potential to diagnose patho­ logical T stage (2432,3485,815). Using TURBT and VI-RADS in conjunction is expected to improve bladder cancer staging. We also shed light on the nomenclature of tumours with inverted histology for non-invasive papillary urothelial carci­ noma, papillary urothelial neoplasm of low malignant potential, and urothelial papilloma class groups {128,1367,136,1222}. The diagnosis of inverted papilloma is reserved for almost exclu­ sively inverted lesions and has its own section; however, for each of the other types (papillary urothelial neoplasm of low malignant potential, and low-grade and high-grade non-inva­ sive carcinomas), we have made reference to inverted lesions within sections that refer to the vastly more common exophytic tumours. An exclusive inverted histology is very rare, although when it is relatively prominent, there may be merit to including the descriptor of 11 inverted" to acknowledge its presence, dif­ ferentiating such tumours from invasive tumours and indicating that they may correlate with a less typical exophytic papillary cystoscopy. In the invasive urothelial carcinoma category, the updates relate to advances in the understanding of the molecular underpinnings of invasive cancer based on comprehensive omics profiling {2953,642,768,2686,1576,2185). The impact of molecular characterization is on prognostication and, more importantly, will be in the selection of treatment approaches in a neoadjuvant to adjuvant setting in the future. The updated nomenclature of subtype histology is provided and avoids the term "variant" for histology, which is still frequently used in the lit­ erature on such tumour types {2223,2213,3096). This approach is consistent with the terminology used in other volumes in the fifth-edition WHO classification, in which the term "variant" is more commonly used to denote genomic alterations. The term "urothelial dysplasia" is greatly debated, and pathologists continue to disagree on its use. Moreover, the lack of agreement and poor reproducibility in the diagnosis of urothelial dysplasia is well known, and it is largely because the disease is difficult to study in clinical cohorts, given the compounding aspects of multifocality, issues with reproduc­ ibility in diagnosis, and the need for long clinical follow-up. The definition of "dysplasia" in the urinary tract is not a synonym of 'Intraepithelial neoplasia" and, like in the fourth edition, we retain its definition as a lesion that encompasses changes thought to be preneoplastic in nature but that cytologically fall short of the diagnosis of "carcinoma in situ". The diagnostic

term is preserved, but instead of devoting an entire section to it (like in the previous edition), reference is made to it in Urothelial carcinoma in situ (p. 147) for use in the diagnostic context when lesions fall short of the diagnosis. Flat urothelial hyperplasia has been observed in association with a variety of conditions {1935} and is believed to be benign {1935,2794}. However, chromosome 9 alteration and a clonal relationship have been reported (1366,2344,3295}. Previously, lesions that were considered to be precursors of low-grade non-invasive papillary carcinoma were designated as "papillary urothelial hyperplasia" or "urothelial proliferation with undetermined malignant potential". Such lesions have a tented architectural appearance, with short, non-branching papillae covered by mildly atypical urothelium that has cytologi­ cal features similar to those of low-grade non-invasive papillary carcinoma. In this fifth-edition WHO classification, such lesions are no longer recognized as a unique entity; rather, they are considered early low-grade non-invasive papillary carcinoma or an extension of such tumours.

Refinements to the fourth-edition WHO classification concern the lineages of differentiation. Following these changes, in the fifth edition, the descriptions of each tumour type in the urinary tract are presented in order from benign to malignant. The chap­ ters are split by tumour lineages of differentiation occurring in different urinary tract organs. Note that the classification order for urinary tract tumours mainly follows lineages of differentia­ tion. Therefore, tumours with similar morphological patterns are described in different chapters. Histological findings useful for the diagnosis and staging of rare tumours (e.g. neoplasia aris­ ing from urachal remnants, diverticula, and urethral accessory glands) are described in the sections on urachal and diverticu­ lar neoplasms and urethral neoplasms. There are no specific chapters for urothelial tumours of the upper urinary tract, urethra, or prostate; information about urothelial tumours and other divergent histology is the same as in the urinary bladder and is included in Invasive urothelial car­ cinoma (p. 150).

Tumours of the urinary tract

133

Raspollini MR Cho YM He HY Humphrey PA Williamson SR

Urothelial papilloma

Definition

Etiology

Urothelial papilloma is a solitary exophytic papillary neoplasm composed of slender fibrovascular cores covered by urothelium of normal thickness with normal cytological features.

Unknown

ICD-0 coding 8120/0 Urothelial papilloma

coding 2F35 & XH5M82 Benign neoplasm of urinary organs & Urothe­ lial papilloma, NOS

Pathogenesis Recent whole-exome and targeted next-generation sequenc­ ing analyses have demonstrated that papillomas are primar­ ily driven by activation of the RAS/ERK pathway. Oncogenic HRAS and KRAS mutations are present in almost all lesions. The benign nature of these tumours is attributed to an absence of other coexisting genetic alterations (e.g. those in the TERT promoter, in TP53, and in chromatin-modifying genes) that are common in urothelial carcinomas (1467).

Related terminology None

Macroscopic appearance

Subtype(s) None

The papillary lesion is usually solitary and ranges in size from 2 to 28 mm {2096). Multifocal lesions, and lesions > 30 mm, are rare.

Localization

Histopathology

Papillomas occur most commonly in the bladder, especially in the trigone region (2096). Rare cases have been reported in the ureter {2599}.

Urothelial papilloma is characterized by delicate papillae and exophytic growth with a fibrovascular core lined by normal­ appearing urothelium of normal thickness and cellularity (< 7 cell layers). Papillary fronds may show branching without fusion. Cells are perpendicularly oriented and maintain nuclear polarity. Surface umbrella cells can be inconspicuous, contain slightly enlarged nuclei or vacuolated cytoplasm, or at times display a hobnail appearance with abundant eosinophilic cyto­ plasm or mucinous metaplasia. Mitotic figures are absent or rare and confined to the basal cell layer. Like in normal urothelium, papilloma shows CK20-positive staining in umbrella cells only. CD44 staining is limited to the basal cells. Caution is advised when making this diagnosis in patients with a history of urothe­ lial carcinoma; in such cases, the entire lesion should be exam­ ined {844,2096,1992,1467).

Clinical features Symptoms include microscopic or gross haematuria. Urothelial papilloma can occur at any age (range: 8-87 years), but mainly in the fifth decade of life, and there is a male predominance (784,1992,2096,57). This diagnosis is rare in patients with a his­ tory of urothelial carcinoma.

Epidemiology Using restrictive diagnostic criteria, the incidence is very low, accounting for < 4% of non-invasive urothelial neoplasms (2096).

Fig. 3.01 Urothelial papilloma. A Exophytic slender papillary structures with minimal branching and urothelial lining of normal thickness. B Note the vacuolated umbrella cells.

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Tumours of the urinary tract

Fig. 3.02 Urothelial papilloma. A Exophytic slender papillary structures with minimal branching and urothelial lining of normal thickness. B At higher power, the urothelial lining is of normal thickness, with cuboidal umbrella cells with slightly enlarged nuclei and occasional vacuoles.

The differential diagnosis includes polypoid/papillary cystitis, a lesion seen in association with inflammatory conditions and characterized by a broad, oedematous stromal core that blends into the underlying lamina propria and is covered by reactive benign urothelium (1793}.

with extreme caution. In this setting, tumour molecular profiling could help determine whether the tumour represents a recur­ rence of the prior non-muscle-invasive bladder cancer or a new, clonally unrelated, papilloma {1467).

Essential and desirable diagnostic criteria

Cytology Cytological diagnosis of urothelial papilloma in urinary samples is of limited value. The Paris System (TPS) acknowledges the inability of cytology to reliably detect low-grade urothelial neo­ plasms. Papilloma is therefore placed in the low-grade urothelial neoplasm category, which also encompasses papillary urothe­ lial neoplasm of low malignant potential and low-grade urothelial carcinoma {2720).

Essential: examination of the entire lesion; presence of a solitary exophytic papillary neoplasm; slender fibrovascular cores covered by urothelium of normal thickness with normal cyto­ logical features.

Staging Not clinically relevant

Prognosis and prediction Diagnostic molecular pathology Molecular diagnostics are not required for the diagnosis of urothelial papilloma. In patients with a history of prior non-muscle-invasive bladder cancer, the diagnosis of urothelial papilloma should be made

Urothelial papilloma is characterized by a benign clinical course with a very low recurrence rate. Progression is exceedingly rare (< 1%) in de novo lesions (1992}. The treatment is complete tran­ surethral resection.

Tumours of the urinary tract

135

Raspollini MR Cho YM He HY Humphrey PA Williamson SR

Inverted urothelial papilloma

Definition

Etiology

Inverted urothelial papilloma is a benign neoplasm with an endophytic pushing growth pattern into the lamina propria, composed of a complex trabecular and anastomosing prolifera­ tion of sheets of urothelial cells.

Unknown

Pathogenesis

ICD-11 coding

Like their exophytic counterparts, inverted papillomas are driven by early alterations in the RAS/ERK pathway. Oncogenic mutations in HRAS and KRAS are present in almost all lesions {2082,1467(. Their benign biological behaviour is ascribed to an absence of other genomic and epigenomic alterations that are encountered in malignant urothelial neoplasms.

2F35 & XH5A08 Benign neoplasm of urinary organs & Urothelial papilloma, inverted

Macroscopic appearance

ICD-0 coding 8121/0 Urothelial papilloma, inverted

Related terminology None

Cystoscopically, inverted papillomas manifest as raised lesions with a smooth surface. At times they may display a polypoid appearance. They are mostly solitary, but multiple tumours may occur. Size ranges from 1 to 30 mm (mean: 12 mm) {2523}.

Subtype(s) Histopathology

None

Localization Inverted papilloma arises in the bladder, mainly in the bladder neck and trigone, and less commonly in the renal pelvis, ureter, and urethra {3073,1974).

Clinical features Most patients present with haematuria and, less commonly, dysuria and irritative voiding symptoms. Flank pain is reported in upper urinary tract lesions {3073,1974}.

Epidemiology Inverted papilloma represents < 1% of urothelial neoplasms. It can occur at any age, from childhood to old age, but most cases occur in the fifth and sixth decades of life. There is a male predominance (M:F ratio: 5.8-7.3:1) {3073,2523).

Inverted papillomas are characterized by anastomosing urothe­ lial cords of normal thickness (5-10 cells) and preserved polar­ ity, growing in an endophytic pattern from the normal overlying urothelium, invaginating into the lamina propria. The periphery of the trabeculae are lined by a palisaded darker basal layer, in contrast to the streaming architecture of the centrally located urothelial cells. The periphery of the lesion is sharply delineated. The lesional cells lack cytological atypia, and mitotic figures are rare and limited to the basal layer. Lesions composed of thicker cords or nodular endophytic structures should raise the differential diagnosis of an inverted papillary urothelial neoplasm of low malignant potential or an inverted urothelial carcinoma. Only minimal exophytic papillary surface component is accepted for the diagnosis of inverted papilloma. Severe nuclear atypia, the presence of atypi­ cal mitoses, and an infiltrative invasive border into the lamina

Fig. 3.03 Inverted urothelial papilloma. A Cystoscopy showing a sessile polypoid mass with a smooth surface. B Endophytic urothelial growth covered with normal urothelium.

136

Tumours of the urinary tract

Fig. 3.04 Inverted urothelial papilloma. A Endophytic urothelial growth from the overlying urothelium. B Thin, anastomosing, uniform trabeculae with peripheral palisading.

Fig. 3.05 Inverted urothelial papilloma. A Focal degenerative cytological atypia without associated mitotic activity. B Anastomosing uniform sheets with focal microcyst forma­

tion.

propria are not in line with the diagnosis of an inverted pap­ illoma and should point to the diagnosis of invasive urothelial carcinoma with inverted growth (2466). Occasional lesions contain luminal structures filled with colloidal material, some lined by cells with foamy vacuolated cytoplasm or by columnar mucin-secreting cells (1012(. Focal non-keratinizing squamous metaplasia (1011}, degenerative cytological atypia (443(, and a cribriform adenoid cystic-like appearance are rarely encountered {3103), as is the presence of granular eosinophilic cells with Paneth cell neuroendocrine features {3062}.

differential diagnosis of malignant urothelial neoplasms with inverted growth, the unique molecular profile mentioned in Pathogenesis above is helpful {2082,1467}. Inverted papilloma is CK20-negative and shows low p53 expression and a low Ki-67 proliferation index {1367}.

Essential and desirable diagnostic criteria Essential: trabecular, anastomosing, proliferating cords of urothelial cells of normal thickness with an endophytic growth pattern; no cytological atypia; minimal surface exophytic growth.

Cytology

Staging

Urine cytology is non-contributory to the diagnosis.

Not clinically relevant

Diagnostic molecular pathology

Prognosis and prediction

Molecular diagnostic assays are not required for the diagno­ sis of inverted urothelial papilloma. In cases that may raise the

Inverted papilloma is a benign lesion. The recurrence rate is 1-2% (3073|. Treatment is transurethral resection.

Tumours of the urinary tract

137

Williamson SR Cheng L McKenney JK Pan CC

Papillary urothelial neoplasm of low malignant potential

Raspollini MR Samaratunga H Yilmaz A

Papillary urothelial neoplasm of low malignant potential (PUNLMP) is a urothelial neoplasm with papillary fibrovascular struc­ tures lined by thickened urothelium or increased cellularity, with mild cytological atypia.

lower than that of low-grade papillary urothelial carcinoma {620, 1381). Although it is less common in children and young adults, PUNLMP can also occur in these age groups, in whom it makes up a much larger proportion (40-50%) of urothelial neoplasms {2782,3443,694,68,1013}.

ICD-0 coding

Etiology

8130/1 Papillary urothelial neoplasm of low malignant potential 8130/1 Inverted papillary urothelial neoplasm of low malignant potential

In older patients, the etiology of PUNLMP is presumed to resemble that of bladder cancer in general; however, there may be alternative pathways to its development in young patients, who have had fewer years of exposure to carcinogens {3466}.

Definition

ICD-11 coding 2F78 & XH5UU5 Neoplasms of uncertain behaviour of urinary organs & Papillary urothelial neoplasm of low malignant potential

Related terminology None

Pathogenesis The pathogenesis of PUNLMP is not as well delineated as that of bladder cancer; however, like low-grade urothelial carcinoma, mutations of the TERT promoter and FGFR3 have been reported (3366,2699,618). Telomeres are overall longer (less shortened) in PUNLMP than in urothelial carcinoma; however, there is sub­ stantial overlap between individual cases (1483}.

Subtype ⑥ Inverted papillary urothelial neoplasm of low malignant poten­ tial

Localization PUNLMP occurs overwhelmingly in the urinary bladder, but it can occur at other sites in the urinary tract (957}.

Macroscopic appearance Cystoscopically, PUNLMP typically appears as an exophytic papillary neoplasm, like other urinary bladder papillary lesions. Although there is no size cut-off point for this diagnosis, lesions are generally small and single (136,1931,950}.

Histopathology

Clinical features Patients typically present with haematuria or other lower urinary tract symptoms, prompting cystoscopic evaluation. There is no history of urothelial carcinoma {136,1931,950).

Epidemiology Like other urothelial neoplasms, PUNLMP has a strong male predominance and tends to occur in adults, usually in the sixth or seventh decade of life. The age at development is slightly

Fig. 3.06 Papillary urothelial neoplasm of low malignant potential. A Papillary cores shows thickened urothelium without cytological atypia lining papillary structures.

138

Tumours of the urinary tract

PUNLMP represents a urothelial neoplasm with branching pap­ illary structures lined by thickened urothelium. In contrast to normal urothelium, the cells are monotonous, with mild cellular and nuclear enlargement and without variation in nuclear size, shape, or chromatin pattern (950). An inverted growth pattern has been increasingly recognized and "inverted PUNLMP" is considered an acceptable diagnostic category for tumours that do not meet the architectural criteria of inverted papilloma yet have insufficient cytological atypia to warrant a diagnosis of

inverted urothelial carcinoma (2070,136). Immunohistochemistry for CK20 or p53 is of little assistance in making the diagnosis.

Desirable: small and single lesion on cystoscopy.

Staging Cytology Diagnosis of low-grade urothelial neoplasms is generally difficult in urine cytology specimens, and patients with biopsy diagno­ ses of PUNLMP have had urine cytology frequently interpreted as negative {754}. The Paris System (TPS) acknowledges the inability of cytology to reliably detect low-grade urothelial neo­ plasms. In TPS, PUNLMP is therefore placed in the low-grade urothelial neoplasm category, which also encompasses lowgrade urothelial carcinoma {2720).

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: no history of urothelial carcinoma; fibrovascular papil­ lary structures lined by urothelium that is thickened or shows increased cellularity; mild cytological atypia.

PUNLMP is a non-invasive neoplasm and therefore considered stage pTa in the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) staging sys­ tems.

Prognosis and prediction Although there may be interobserver variability in diagnosis (2258,2387,1547,3555), several studies have found PUNLMP to have lower rates of recurrence and progression than those of carcinoma, warranting its distinction as a particularly low-risk tumour {694,2070,113,506,1342,1381,2522,2793}. Risk of recur­ rence of PUNLMP appears to be higher in patients with multi­ ple tumours (1381). PUNLMP with inverted growth is less well characterized but also appears to have rare recurrence (2070}. The presence of TERT promoter mutation in PUNLMP may be associated with a higher recurrence rate |3366}.

Tumours of the urinary tract

139

Williamson SR Hansel DE Kaushal S Lopez-Beltran A Pan CC Raspollini MR

Non-invasive papillary urothelial carcinoma, low-grade

Definition

Localization

Low-grade, non-invasive papillary urothelial carcinoma is a malignant urothelial neoplasm characterized by papillary struc­ tures that are confined within the basement membrane and lined by urothelial cells with mild architectural disorder and nuclear atypia.

Low-grade, non-invasive papillary urothelial carcinoma can occur throughout the urinary tract (urinary bladder, renal pelvis, ureter, urethra), but it is most common in the urinary bladder.

ICD-0 coding 8130/2 Non-invasive papillary urothelial carcinoma, low-grade 8130/2 Low-grade papillary urothelial carcinoma with an inverted growth pattern

ICD-11 coding 2C91.0 & XH12F0 Urothelial carcinoma of renal pelvis & Papil­ lary urothelial carcinoma, non-invasive 2C92.0 & XH12F0 Urothelial carcinoma of ureter & Papillary urothelial carcinoma, non-invasive 2C94.2 & XH12F0 Urothelial carcinoma of bladder & Papillary urothelial carcinoma, non-invasive 2C93.2 & XH12F0 Urothelial carcinoma of urethra or paraure­ thral gland & Papillary urothelial carcinoma, non-invasive 2C95.2 & XH12F0 Urothelial carcinoma involving overlapping sites of urinary organs & Papillary urothelial carcinoma, noninvasive

Related terminology Not recommended: non-invasive low-grade papillary transi­ tional cell carcinoma.

Clinical features Presenting signs and symptoms include haematuria (micro­ scopic or macroscopic). Depending on its location, the tumour can lead to lower urinary tract symptoms (e.g. frequency, urgency, dysuria) or obstructive upper-tract mass effect presen­ tation. Low-grade, non-invasive papillary carcinoma is known for frequent recurrence and a low likelihood of progression to invasive cancer (2390,1931)

Epidemiology Low-grade, non-invasive papillary urothelial carcinoma has a male predominance and tends to occur at a mean age of > 60 years {1381); however, development in young patients is also possible.

Etiology Bladder cancer in general is associated with exposure to sev­ eral carcinogens, including cigarette smoking and various chemicals (e.g. aristolochic acid) {1439,1844(. Specific risk fac­ tors for low-grade, non-invasive papillary carcinomas are dif­ ficult to dissect from the risk factors for bladder cancer as a whole, including those for high-grade and invasive tumours.

Pathogenesis

Subtype(s) Low-grade papillary urothelial carcinoma with an inverted growth pattern

Low-grade, non-invasive papillary urothelial carcinomas are, for the most part, thought to develop via a different pathway to that of their high-grade counterparts. Mutations and oncogenic

Fig. 3.07 Non-invasive papillary urothelial carcinoma, low-grade. A Papillae are lined by urothelium with minor cytological and architectural disorder. B Papillae are lined by thickened urothelium with mild cytological atypia and minimal architectural disorder.

140

Tumours of the urinary tract

Fig. 3.08 Non-invasive papillary urothelial carcinoma, low-grade. A Thickened and fused papillary structures are lined by mildly atypical urothelial cells. B High-magnification view shows papillary cores lined by thickened urothelium with mild cytological atypia and no marked pleomorphism.

fusions of FGFR3 are thought to be key elements of this pathway (1502,3452,3404). Mutations of the TERT promoter are common in as many as 70-80% of low-grade tumours and tend to be more common in tumours that also have FGFFI3 alterations (96, 1672,618,2423). A key pathway altered in low-grade tumours is the MARK pathway. Frequent mutations in HRAS {2991,853,903,410,3608} and mutations in PIK3CA, PTEN, STAG2, and TSC1 can also be encountered {2991,903,2725,2545,1946}. Although low-grade tumours undergo less frequent progression to invasive carci­ noma than do high-grade tumours, crossover to the high-grade invasive pathway is thought to be due most often to CDKN2A deletion or TP53 or RB1 loss {53). Loss of part of chromosome 9 is described both in low-grade and in high-grade tumours, as well as in urothelial hyperplasia (489,2113}.

Macroscopic appearance Cystoscopic examination typically demonstrates an exophytic papillary tumour (single or multiple and variable in size) (2390). The appearance may be more translucent in low-grade tumours than in their high-grade counterparts. Tumours with an inverted growth pattern may appear predominantly endophytic or nodu­ lar.

Histopathology Low-grade, non-invasive papillary urothelial carcinoma typically is composed of thin fibrovascular cores lined by urothelial cells of variable thickness. There may be branching or fusion of the papillary structures. Although there is a lack of marked variation in nuclear size at low magnification, intermediate to high magni­ fication shows overall mild nuclear enlargement, scattered cells with nuclear hyperchromasia, mild loss of nuclear polarity, and mild variation in nuclear size {950}. Occasional mitotic figures can be present away from the basal layer. Although the mitotic count is significantly lower in low-grade papillary urothelial carcinoma than in high-grade tumours, a definite cut-off point is not recognized, and the grade should not be determined by mitotic count alone. In cases with an inverted growth pat­ tern, the inverted nests are usually thickened and display a similar degree of nuclear atypia to that of low-grade exophytic

Fig. 3.09 Non-invasive papillary urothelial carcinoma, low-grade, with inverted growth pattern. Complex interconnecting inverted growth of thick cords and nodules of

urothelial cells into the lamina propria with only mild nuclear atypia.

non-invasive papillary urothelial carcinoma. These features con­ trast with the uniform, thin, interconnecting structures of inverted papilloma {1931,950,136}. Immunohistochemistry for E-cadherin, p53, Ki-67, and CK20 has been studied but is of limited assistance in making the diag­ nosis.

Cytology Diagnosis of low-grade neoplasms is challenging in urine cytol­ ogy specimens because of the similarity of low-grade tumour cells to benign urothelial cells. If fibrovascular cores lined by urothelial cells without high-grade atypia are identified in cytol­ ogy specimens, a diagnosis of low-grade urothelial neoplasm is assigned according to The Paris System (TPS) {2720}.

Diagnostic molecular pathology Molecular pathology has no clinically significant role at present in the diagnosis of low-grade, non-invasive papillary Tumours of the urinary tract

141

urothelial carcinomas in surgical pathology (3404). Mutations of the TERT promoter are now increasingly recognized in both low-grade and high-grade tumours and could be used as a diagnostic adjunct (96,1672,618,2423}; however, such testing remains infrequently used in diagnostic practice at present {3404}. Several molecular assays have been proposed as adjuncts to urine cytology for the screening, diagnosis, and surveillance of non-invasive urothelial carcinoma. These include protein-based and multitarget FISH assays for ploidy. Their routine use has been generally infrequent (237,1936,3633,3404). More recently, DNA sequencing-based assays, targeting some of the abovementioned genetic alterations that are associated with lowgrade urothelial carcinoma, have shown promising results that await further validation {594,2988,2954,2955,901,3012,2698, 924,96,1672,618,2423). Various molecular markers have been assessed for their utility in helping to predict recurrence and progression in non-invasive papillary carcinomas. These include FGFR3 and PIK3CA muta­ tions as predictors of a lower risk of recurrence, and loss of PTENas being associated with a higher risk {61,3298,2547,903, 1946,710). However, none of these markers is currently recom­ mended for routine use (3404).

142

Tumours of the urinary tract

Essential and desirable diagnostic criteria Essential: fibrovascular papillary cores or expanded and inverted nests, lined by urothelial cells with (at most) mild cytological atypia and architectural disorder； absence of marked nuclear size variation and hyperchromasia; no evi­ dence of lamina propria invasion. Note: Caution should be exercised in the diagnosis of low-grade lesions if incompletely resected, particularly in the upper uri­ nary tract.

Staging In the absence of invasive carcinoma, low-grade papillary urothelial carcinoma is stage category pTa in the American Joint Committee on Cancer (AJCC) and Union for International Can­ cer Control (UICC) systems.

Prognosis and prediction Overall, low-grade papillary urothelial carcinoma has about a 50% rate of recurrence and a 10-20% rate of grade and/or stage pro­ gression (1942,1342,616,2012). Although these rates are higher than those of papillary urothelial neoplasm of low malignant poten­ tial, the rate of progression to invasion is lower than that of high­ grade tumours.

Non-invasive papillary urothelial carcinoma, high-grade

Cheng L Kaushal S Matoso A Raspollini MR Williamson SR

Definition

Localization

High-grade, non-invasive papillary urothelial carcinoma is a malignant urothelial neoplasm characterized by papillary struc­ tures lined by urothelial cells with marked architectural and cytological disorder. The neoplastic cells are confined within the basement membrane.

High-grade, non-invasive papillary urothelial carcinomas can occur anywhere along the urothelial surface in the urinary tract, most commonly in the posterior wall of the urinary bladder {1844}.

Clinical features ICD-0 coding 8130/2 Non-invasive papillary urothelial carcinoma, high-grade 8130/2 Non-invasive high-grade papillary urothelial carcinoma with an inverted growth pattern

The most frequent presenting symptom is microscopic or mac­ roscopic haematuria. Other common clinical presentations include urinary frequency, urgency, and irritative voiding symp­ toms (615).

ICD-11 coding

Epidemiology

2C91.0 & XH12F0 Urothelial carcinoma of renal pelvis & Papil­ lary urothelial carcinoma, non-invasive 2C92.0 & XH12F0 Urothelial carcinoma of ureter & Papillary urothelial carcinoma, non-invasive 2C94.2 & XH12F0 Urothelial carcinoma of bladder & Papillary urothelial carcinoma, non-invasive 2C93.2 & XH12F0 Urothelial carcinoma of urethra or paraure­ thral gland & Papillary urothelial carcinoma, non-invasive 2C95.2 & XH12F0 Urothelial carcinoma involving overlapping sites of urinary organs & Papillary urothelial carcinoma, noninvasive

Non-invasive papillary urothelial carcinomas account for 70-85% of initial bladder cancer diagnoses (237,3297). The mean age at diagnosis is 70 years and the M:F ratio is 3:1 {959}. Women tend to have a higher risk of recurrence and of progres­ sion to invasive disease (959,1687,1162}.

Related terminology Not recommended: non-invasive high-grade transitional cell carcinoma.

Etiology High-grade, non-invasive papillary urothelial carcinoma has a similar etiology to that of its invasive counterpart (see Invasive urothelial carcinoma, p. 150). Cigarette smoking, environmen­ tal factors (including exposure to chemicals such as aromatic amines and arsenic), dietary factors, and iatrogenic factors have all been linked to bladder cancer development (1203, 1505,1507,1301,2520}.

Pathogenesis

Subtype⑥ Non-invasive high-grade papillary urothelial carcinoma with an inverted growth pattern

High-grade, non-invasive papillary urothelial carcinoma is a pre­ cursor lesion of most invasive urothelial carcinomas. Approxi­ mately 70-80% of non-invasive urothelial carcinomas of the bladder have somatic TERT promoter mutations, which occur

Fig. 3.10 Non-invasive papillary urothelial carcinoma, high-grade. A Note the disordered architecture and nuclear pleomorphism with nuclear hyperchromasia. B High-magni­ fication view illustrating the marked nuclear pleomorphism, high N:C ratio, and loss of polarity.

Tumours of the urinary tract

143

Fig. 3.11 Non-invasive papillary urothelial carcinoma, high-grade. Nuclear pleomor­ phism is evident.

early in carcinogenesis (96,1672,618,2423). Additional com­ mon alterations include FGFR3 mutations, amplifications, and fusions, as well as mutations in the TP53gene and in genes that control p53, including CDKN2A (p16) (624,2370}. The CDKN2A locus is on chromosome 9, and allelic loss of chromosome 9 is another common finding in high-grade, non-invasive urothelial carcinomas (2370,2940,488,1625}. A more detailed discussion on pathogenesis is presented in Invasive urothelial carcinoma (p. 150)."

Macroscopic appearance On cystoscopy, the lesions are most commonly exophytic, can be either single or multiple, have a hyperaemic appearance, and are less translucent than low-grade tumours (1679}, A small proportion of cases show a predominant endophytic growth pattern (615}.

Histopathology High-grade, non-invasive papillary urothelial carcinomas dis­ play marked architectural and cytological disorder. The majority are exophytic tumours composed of papillae that are more com­ plex than those in low-grade tumours, with fusion and frequent

branching. Nonetheless, the cytological features - not the archi­ tectural pattern - determine the high-grade nature of the lesion. Tumour cells lining the papillae show disorderly orientation with loss of polarity. They display irregular and pleomorphic nuclei that are readily apparent at low to intermediate magnification. Significant nuclear size variation, nuclear hyperchromasia, prominent irregular nucleoli, and irregular nuclear contours are evident features. Frequent mitoses including irregular forms are usually noted. Nuclear anaplasia can be occasionally encoun­ tered {615). Architecturally, a subset of high-grade non-invasive papillary urothelial carcinoma can display a component with an inverted growth pattern. In tumours that are exclusively inverted, the designation of "papillary urothelial carcinoma with an inverted growth pattern" may be used (1938). The inverted tumour com­ ponent is characterized by the invagination of broad sheets or thick trabeculae of neoplastic urothelium pushing into the lamina propria but not the muscularis propria. In tumours with prominent endophytic growth, ruling out lamina propria invasion can be challenging; the non-invasive nature of such tumours is established by the preservation of a regular smooth stromalepithelial interface and the absence of features associated with lamina propria invasion, such as stromal retraction artefact and desmoplasia. By immunohistochemistry, tumour cells are most frequently positive for GATA3, p63, CK20, or CK5/6. CD44 is often lost, and proliferation (e.g. Ki-67 index) is usually increased. How­ ever, grading is based purely on morphology, and none of these ancillary markers are needed to establish a lesion as high-grade in nature so their use for that purpose is discouraged {50,137, 844). Heterogeneity in grade is characteristic of non-invasive pap­ illary urothelial carcinoma. It occurs in as many as one third of tumours and may impact outcome {621,1149,2854,2643}. Currently, an arbitrary but generally accepted approach is to grade a lesion based on its highest grade component: a lesion is designated as high-grade as long as that component repre­ sents > 5% of the tumour {2072}. Tumours with < 5% high-grade component may have a prognosis that is closer to low-grade tumours and should be reported descriptively ("low-grade with < 5% high-grade component"). This approach to reporting may

Fig. 3.12 Non-invasive papillary urothelial carcinoma, high-grade. A Micropapillary pattern. Note the secondary structures; micropapillary tufts. B Villoglandular pattern. The papillary structures have acquired a villous morphology with focal columnar cell lining.

144

Tumours of the urinary tract

。

coJ o Q e q

Fig.3.13 Non-invasive papillary urothelial carcinoma, high-grade, with inverted growth pattern. A The inverted growth pattern is characterized by the endophytic growth of sheets and nodules into the lamina propria. The smooth stromal epithelial interface is the key to establishing the non-invasive nature of the tumour. B High-magnification view of the endophytic growth of urothelial nodules into the lamina propria. Note the smooth stromal epithelial interface and absence of stromal desmoplasia or retraction artefact.

aid in risk stratification and help guide the management of such heterogeneous lesions, although further studies are required (419,235,1149,2643(. Finally, non-invasive papillary urothelial carcinoma can exhibit a range of distinct histological patterns. These include noninvasive micropapillary urothelial carcinoma and urothelial car­ cinoma with villoglandular or glandular differentiation, among others (119,1881,2808}.

and multitarget FISH assays for ploidy, with variable (generally modest) adoption and acceptance in practice guidelines {237, 1936,3633}. More recently, DNA sequencing-based assays targeting the above-mentioned genetic alterations involved in high-grade urothelial carcinoma pathogenesis have shown

Cytology Examination of voided urine for exfoliated cancer cells has a high sensitivity and specificity for the screening, diagnosis, and monitoring of high-grade urothelial carcinomas {237}. Urine cytology, in conjunction with cystoscopy, is one of the most effi­ cient methods for the detection and surveillance of non-invasive urothelial carcinomas (3515). Its accuracy has improved further since the implementation of The Paris System (TPS) for report­ ing urinary cytology (2720,276). TPS criteria for establishing the diagnosis of high-grade urothelial carcinoma include the iden­ tification of a minimum of 5-10 well-preserved urothelial cells with an N:C ratio of > 0.7, moderate to severe hyperchromasia, coarse chromatin, and irregular nuclear membrane {276). The system is discussed in further detail in Invasive urothelial carci­ noma (p. 150).

Diagnostic molecular pathology Diagnostic molecular assays are not routinely used during the surgical pathology workup of high-grade, non-invasive urothe­ lial carcinoma. There have been innumerable studies evaluating molecular and genetic markers for their potential as prognostic markers, but despite remarkable progress made in the molecu­ lar classification of bladder cancer, the 2019 International Soci­ ety of Urological Pathology (ISUP) Consultation Conference on Molecular Pathology of Urogenital Cancers concluded that, as yet, there are no molecular or genetic markers with sufficient evidence to support their routine use in surgical pathology prac­ tice (3404}. Several urine-based molecular assays have been developed as adjunct tools for the screening, diagnosis, and surveillance of non-invasive urothelial carcinoma. These include protein-based

Fig. 3.14 High-grade non-invasive papillary urothelial carcinoma, urine cytolo­ gy. A,B Smears showing urothelial cells with a high N:C ratio, hyperchromatic nuclei, and an irregular nuclear membrane.

Tumours of the urinary tract

145

Fig. 3.15 Non-invasive papillary urothelial carcinoma, high-grade. A,B Cytology.

is based on the highest-grade component representing > 5% of the tumour.

Staging Staging is based on the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) sys­ tems and these tumours are classified as pTa urothelial carci­ nomas.

Prognosis and prediction

Fig. 3.16 Non-invasive papillary urothelial carcinoma, high-grade. Cytology of a stage Ta tumour.

promising results that await further validation for routine use (594,2988,2954,2955,901,3012,2698,924}.

Essential and desirable diagnostic criteria Essential: papillary structures or sheets of urothelium with marked cytoarchitectural disorder; regular and smooth stro­ mal-epithelial interface and absence of stromal reaction con­ firming the non-invasive nature of the tumour; the diagnosis

146

Tumours of the urinary tract

For high-grade, non-invasive papillary carcinoma, the rates of recurrence and progression to invasive disease are approxi­ mately 60% and 25%, respectively {1161,616,1980,3089, 3302}. Categories of risk and models for predicting various outcomes in non-muscle-invasive urothelial carcinoma have been developed by several professional urology societies in North America and Europe (237,3006,573,236). In general, these are based on the assessment of the following param­ eters: number of tumours, tumour diameter, previous recur­ rence rate, pathological stage (pTa versus pT1), presence of concomitant urothelial carcinoma in situ, and histological grade. This highlights the importance of incorporating all these pathological parameters into reporting guidelines for speci­ mens obtained from the urinary bladder.

Urothelial carcinoma in situ

Williamson SR Magi-Galluzzi C Matoso A Montironi R Raspollini MR

Definition Urothelial carcinoma in situ (CIS) is a flat neoplastic proliferation of high-grade malignant urothelial cells of variable thickness without papillary formation. Urothelial dysplasia, an infrequently diagnosed and poorly reproducible category, encompasses changes that are thought to be neoplastic in nature but cytologically fall short of the diagnosis of CIS.

ICD-0 coding 8120/2 Urothelial carcinoma in situ

ICD-11 coding 2C91.0 & XH5GH8 Urothelial carcinoma of renal pelvis & Urothelial carcinoma in situ 2C92.0 & XH5GH8 Urothelial carcinoma of ureter & Urothelial carcinoma in situ 2C94.2 & XH5GH8 Urothelial carcinoma of bladder & Urothelial carcinoma in situ 2C93.2 & XH5GH8 Urothelial carcinoma of urethra or paraure­ thral gland & Urothelial carcinoma in situ 2C95.2 & XH5GH8 Urothelial carcinoma involving overlapping sites of urinary organs & Urothelial carcinoma in situ

Fig. 3.17 Urothelial carcinoma in situ. Dysplasia of the urothelium.

usually is multifocal and at times is diffuse. In such cases, exten­ sion into the distal ureter and prostatic urethra is not uncommon {540,984,1715,2517,2909}.

Related terminology

Clinical features

Not recommended: high-grade flat intraurothelial neoplasia; high-grade dysplasia; low-grade dysplasia.

None

Patients with de novo CIS can present with microscopic or mac­ roscopic haematuria, or with irritative symptoms that include dysuria, urinary frequency, and urinary urgency. Urothelial CIS may also be asymptomatic and thus detected incidentally dur­ ing surveillance for prior urothelial carcinoma (611,540).

Localization

Epidemiology

Urothelial CIS can occur throughout the urinary tract. The uri­ nary bladder is the most common location of involvement, which

De novo urothelial CIS makes up only a small fraction (esti­ mated at 1-3%) of all urothelial malignancies (540}. Much more

Subtype(s)

Fig. 3.18 Urothelial carcinoma in situ. A This example is predominantly denuded; however, the residual epithelial cells have hyperchromatic nuclei with a high N:C ratio and a plasmacytoid appearance. B High-magnification view shows urothelial cells with high-grade cytological atypia.

Tumours of the urinary tract

147

Macroscopic appearance Cystoscopically, CIS can manifest as erythematous mucosal patches that may be raised, granular, or velvety. At times, the lesion is difficult to identify {611,3468). Several novel cystoscopic techniques (e.g. blue-light cystoscopy) have been pro­ posed to aid the detection of CIS (2481).

Histopathology

Fig.3.19 Urothelial carcinoma in situ. Most of the urothelium has been replaced by high-grade malignant cells; however, a layer of benign cells is preserved at the base of the epithelium.

commonly, CIS is found synchronously with or subsequently to high-grade papillary or invasive urothelial carcinoma; in such cases it is sometimes referred to as secondary CIS. The rates of concurrent CIS are as high as 50-60% among patients with T1 or higher-stage bladder cancer {540).

Etiology See Invasive urothelial carcinoma (p. 150).

Pathogenesis Urothelial CIS is considered part of the high-grade pathway of bladder cancer development, with frequent molecular altera­ tions of the TERT promoter, TP53 and related genes, genes encoding chromatin-modifying proteins (ARID1A and KDM6A), DNA damage repair genes {BRCA2 and ATM), and PI3K and MAPK pathway genes (1093,1306,1672). See Invasive urothelial carcinoma (p. 150) for a detailed discussion of molecular altera­ tions in bladder cancer.

Urothelial CIS is characterized by the presence of cells that usually have large pleomorphic nuclei with hyperchromasia, an irregular chromatin pattern, and irregular contours (2094}. These nuclear features are usually identifiable on low to intermediate magnification. Loss of nuclear polarity and irregular crowding is frequently present. The nuclear and architectural features of CIS contrast with those of reactive urothelial atypia, in which nuclear enlargement is milder, chromatin pattern and nuclear contour remain regular, and polarization is preserved for the most part. In CIS, the neoplastic cells need not occupy the full thickness of the mucosa. The presence of unequivocally malignant iso­ lated cells interspersed within benign urothelium (i.e. pagetoid spread) or of cells undermining the overlying benign urothelial layer cells is sufficient for the diagnosis. Although mitotic figures are often present, including atypical forms, they may be absent and are not required for the diagnosis {3468|. Several morphological patterns of CIS have been described. These include the large cell and small cell patterns (charac­ terized by abundant or scant cytoplasm, respectively, with no indication of neuroendocrine differentiation in the latter), the plasmacytoid pattern (characterized by eccentric eosinophilic cytoplasm), and the denuding cystitis / clinging CIS pattern (predominantly denuded epithelium with rare malignant cells). These patterns are of purely morphological value to help rec­ ognize CIS; there is no evidence at this time that they carry any clinical or prognostic implications (2809,693,2094). Rare examples of urothelial CIS with in situ glandular differentiation (adenocarcinoma in situ) have been reported {564,1939,3538}. Immunohistochemistry often shows abnormal full-thickness labelling for CK20 (normally limited to umbrella cells), an abnor­ mal immunohistochemical expression pattern for p53 (diffuse and strong, or entirely negative / null), and decreased label­ ling for CD44 (basal only or absent, in contrast to full-thickness

Fig. 3.20 Urothelial carcinoma in situ. A The large cell pattern of carcinoma in situ contains large cells with voluminous cytoplasm, usually eosinophilic. B This example spreads in a pagetoid fashion through metaplastic keratinized squamous epithelium of the lateral bladder wall.

148

Tumours of the urinary tract

Fig. 3.21 Carcinoma in situ. A Carcinoma in situ with numerous mitoses. B This example shows multiple glandular lumina and apically polarized cytoplasm, consistent with adenocarcinoma in situ or carcinoma in situ with glandular differentiation.

labelling in reactive urothelium) (2098,2319,286). Other (less established) markers that have been suggested to help confirm a diagnosis of CIS include Ki-67, AMACR, and ERBB2, p16, CK5/6, andCD138 (2093). However, none of these markers is entirely sensitive or specific, especially in equivocal lesions where the differential diagnosis of reactive urothelial atypia is most challenging {191]. Therefore, routine use of immunohistochemistry is not necessary. Urothelial dysplasia shows cytological atypia that is thought to be neoplastic in nature but not definitive for the diagnosis of CIS. Although sometimes this terminology is necessary, some authors have emphasized that there is a lack of reproducible criteria to distinguish urothelial dysplasia from atypia of uncer­ tain significance, undermining the accuracy and utility of the diagnosis of dysplasia (2093).

Essential and desirable diagnostic criteria

Urothelial CIS Essential: high-grade malignant urothelial cells with markedly atypical nuclear features (recognizable at low to intermediate magnification) with no papillary formation.

Urothelial dysplasia Essential: cytological atypia that is interpreted as neoplastic in nature but not definitive for the diagnosis of CIS.

Staging Urothelial CIS is staged as pTis by the Union for International Cancer Control (UICC) and the American Joint Committee on Cancer (AJCC).

Prognosis and prediction

Cytology Given the loss of cohesion in urothelial CIS cells, urine cytology offers a valuable tool for detecting CIS regardless of its location in the urinary tract. Cytological findings of CIS are indistinguish­ able from those of other lesions in The Paris System (TPS) cate­ gory of high-grade urothelial carcinoma {277,2463,3337,2720}. See the Cytology subsection in Invasive urothelial carcinoma (p. 150) for illustrations and more details.

Diagnostic molecular pathology Molecular pathology is not required for the diagnosis of CIS. FISH using the UroVysion probe set against chromosomes 3, 7, 17, and 9p21 has been suggested as an adjunct to CIS diagno­ sis in urine specimens {459,3337}, and other non-invasive blad­ der cancer markers have been studied for potential use (3141).

Patients with non-muscle-invasive bladder cancer and CIS are classified as high risk, and they have a high risk of recurrence and progression to invasive bladder cancer. The diagnosis of CIS requires treatment with intravesical therapy. Poor prognostic factors in urothelial CIS include failure of BCG therapy and the presence of multifocal disease (611). Radical cystectomy has been recommended, but promising novel immunotherapeutic agents (e.g. pembrolizumab) and biological modifier agents are being investigated for use in BCG-refractory cases )3500,1419, 554,391}. The biological behaviour of dysplasia is under debate. Some studies have suggested that it is associated with a significant risk of progression (610}. The inconsistent reports are most likely related to the poor reproducibility of the diagnostic criteria for urothelial dysplasia (2093}. Further studies are required.

Tumours of the urinary tract

149

Williamson SR Al-Ahmadie HA Cheng L Downes MR Lopez-Beltran A McKenney JK

Invasive urothelial carcinoma

Definition Invasive urothelial carcinoma is a malignant epithelial neoplasm with invasion, arising from the urothelial lining of the urinary tract.

ICD-0 coding 8120/3 Invasive urothelial carcinoma 8120/3 Conventional urothelial carcinoma 8120/3 Urothelial carcinoma with squamous differentiation 8120/3 Urothelial carcinoma with glandular differentiation 8120/3 Urothelial carcinoma with trophoblastic differentiation 8120/3 Nested urothelial carcinoma 8120/3 Large nested urothelial carcinoma 8120/3 Tubular and microcystic urothelial carcinomas 8131/3 Micropapillary urothelial carcinoma 8082/3 Lymphoepithelioma-like urothelial carcinoma 8122/3 Plasmacytoid urothelial carcinoma 8031/3 Giant cell urothelial carcinoma 8120/3 Lipid-rich urothelial carcinoma 8120/3 Clear cell (glycogen-rich) urothelial carcinoma 8120/3 Sarcomatoid urothelial carcinoma 8020/3 Poorly differentiated urothelial carcinoma

ICD-11 coding 2C91.0 & XH8EH1 Urothelial carcinoma of renal pelvis & Transi­ tional cell carcinoma, NOS

Fig. 3.22 Bladder cancer. A pT1 bladder cancer in the left lateral wall showing an uninterrupted thickened low-signal line (arrow) demonstrating non-muscle-invasive bladder cancer on T2-weighted MRI. B Contrast-enhanced MRI shows preserved muscle layer and continuous enhancement of the submucosal layer at the base of the tumour (arrows). C Diffusion-weighted MRI demonstrates high-signal bladder cancer and the preserved low-signal bladder wall. The inchworm sign (arrow) is depicted, suggesting superficial bladder cancer (VI-RADS 2). D Apparent diffusion coefficient MRI demonstrates low-signal bladder cancer and preserved high-signal bladder wall (arrow). The overall assigned VI-RADS score was 2.

150

Tumours of the urinary tract

Narumi Y Panebianco V Paner GP Raspollini MR Ro JY Wojcik EM

2C92.0 & XH8EH1 Urothelial carcinoma of ureter & Transitional cell carcinoma, NOS 2C94.2 & XH8EH1 Urothelial carcinoma of bladder & Transi­ tional cell carcinoma, NOS 2C93.2 & XH8EH1 Urothelial carcinoma of urethra or paraure­ thral gland & Transitional cell carcinoma, NOS 2C95.2 & XH8EH1 Urothelial carcinoma involving overlapping sites of urinary organs & Transitional cell carcinoma, NOS Please note: The term "transitional" is no longer recommended, and ICD-11 will be updated.

Related terminology Not recommended: infiltrating transitional cell carcinoma.

Subtype(s) Urothelial carcinoma is notable for its many histological sub­ types, listed in Table 3.01.

Localization Invasive urothelial carcinoma occurs throughout the urinary tract. The vast majority of cases originate in the urinary blad­ der. Upper urinary tract tumours account for 5-10% of cases. Synchronous or metachronous multifocal tumours are not infre­ quent (1187,2732,3001).

Fig. 3.23 Bladder cancer. A pT2 bladder cancer in the right lateral wall showing an interrupted low-signal line and perivesical adipose tissue invasion (arrow) demon­ strating muscle-invasive bladder cancer on T2-weighted MRI. B Contrast-enhanced MRI shows interrupted muscle layer and invasion of perivesical adipose tissue (ar­ row). C Diffusion-weighted MRI demonstrates high-signal bladder cancer with inva­ sion of the bladder wall and adipose tissue (arrow). 0 Apparent diffusion coefficient MRI demonstrates low-signal bladder cancer and invasion of the bladder wall and adipose tissue (arrow). The overall assigned VI-RADS score was 5.

Table3.01

Urothelial carcinoma subtypes and their essential and desirable diagnostic criteria

Subtype

Essential diagnostic criteria

Conventional urothelial carcinoma

Invasive carcinoma with evidence of urothelial origin

Urothelial carcinoma with squamous differentiation

Conventional urothelial carcinoma with transition to squamous differentiation, including intercellular bridges or keratinization

Coexisting CIS and/or papillary urothelial carcinoma; no morphologically similar tumour in another organ

Urothelial carcinoma with

Conventional urothelial carcinoma with transition to glandular

glandular differentiation

formation (叩ical cytoplasm and glandular lumina)

Coexisting CIS and/or papillary urothelial carcinoma; no morphologically similar tumour in another organ

Urothelial carcinoma with

Conventional urothelial carcinoma with admixed

trophoblastic differentiation

syncytiotrophoblastic cells

Coexisting CIS and/or papillary urothelial carcinoma; increased serum level of p-hCG; positive hCG immunohistochemistry

Nested urothelial carcinoma

Nests of bland cells (superficial portion) or atypical cells (deep portion) in myxoid, focally desmoplastic, or non-reactive stroma

Coexisting CIS and/or papillary/conventional urothelial carcinoma; invasion to the muscularis propria

Tubular and microcystic

Cysts, macrocysts, or large tubular structures in non-reactive or

urothelial carcinomas

myxoid stroma

Coexisting CIS and/or papillary/conventional urothelial carcinoma; negative immunohistochemistry for markers of prostate cancer (in a man) or relevant gynaecological tumour

Desirable diagnostic criteria Coexisting CIS and/or papiillary urothelial carcinoma; no morphologically similar tumour in another organ

(in a woman) Coexisting CIS and/or papillary/conventional urothelial

Micropapillary urothelial carcinoma

Invasive carcinoma with multiple cell clusters with micropapillary features in cleft-like or lacunar spaces

carcinoma; no morphologically similar tumour in another organ (such as a gynaecological tumour); positive ERBB2 immunohistochemistry; negativity for markers of non-bladder

origin Lymphoepithelioma-like

urothelial carcinoma

Invasive carcinoma composed of a syncytial arrangement of cytokeratin-positive cells in a polymorphic inflammatory infiltrate

Plasmacytoid urothelial carcinoma

Invasive carcinoma composed of single cells, dispersed or in a linear arrangement; absence of extracellular mucin

Giant cell urothelial carcinoma

Invasive carcinoma composed of pleomorphic giant cells

Lipid-rich urothelial carcinoma

Clear cell (glycogen-rich)

urothelial carcinoma

Sarcomatoid urothelial carcinoma

Urothelial carcinoma, poorly differentiated

Coexisting CIS and/or papillary/conventional urothelial carcinoma Coexisting CIS and/or papillary/conventional urothelial carcinoma; no morphologically similar tumour in another organ; positive immunohistochemistry for cytokeratin; absence of membranous E-cadherin labelling; negative immunohistochemistry for markers of non-bladder origin

Coexisting CIS and/or papillary/conventional urothelial carcinoma; positive cytokeratin immunohistochemistry

Invasive carcinoma composed of lipoblast-like, cytokeratin-

Coexisting CIS and/or papillary/conventional urothelial

positive cells

carcinoma

Invasive carcinoma composed of nests or sheets of clear cells with well-defined cell membranes and voluminous optically clear

Coexisting CIS and/or papillary/conventional urothelial carcinoma; no morphologically similar tumour in another organ (such as renal cell carcinoma); positive for urothelial markers

cytoplasm

Coexisting CIS and/or papillary/conventional urothelial

Tumour cells that are moiphologically indistinguishable from sarcoma cells

carcinoma; positive immunohistochemistry for urothelial or

Invasive carcinoma with evidence of urothelial origin by immunohistochemistry

Coexisting CIS and/or papillary/conventional urothelial carcinoma; no morphologically similar tumour in another organ

epithelial markers

CIS, carcinoma in situ.

Clinical features Typical presenting signs and symptoms include microscopic or macroscopic haematuria, urinary urgency, urinary frequency, nocturia, or dysuria {279}. Women may have a delay in diagnosis due to a presumptive diagnosis of a urinary tract infection {1330}. Location impacts presentation, with upper tract urothelial carci­ nomas leading to obstructive symptoms related to mass effect. When urothelial carcinomas occur in the bladder, most patients (as many as 70-85%) present with non-muscle-invasive blad­ der cancer, a designation that collectively encompasses Tis, pTa, and pT1 bladder cancers. Non-muscle-invasive bladder cancer has a typical clinical course of multiple recurrences leading to stage progression to muscle-invasive bladder can­ cer in a subset (10-20%) of cases (237,3297,2206). Advanced disease can manifest as weight loss or bone pain. Metastases

most often involve regional lymph nodes, liver, lung, and bone (3111,3362]. Diagnosis and staging of urothelial carcinoma is typically achieved by cystoscopy, urine cytology examination, transurethral biopsy, and transurethral resection (TURBT).

Imaging CT may be used to identify extraluminal tumour spread and lymph node staging. CT urography is superior to excretory urography for the detection of upper urinary tract cancer (1529|. To assess muscle invasion, mpMRI (including diffusionweighted and dynamic contrast-enhanced imaging) in addition to T2-weighted imaging is preferred, because these methods enable the differentiation of submucosal (or lamina propria) tis­ sue from the muscularis propria. The Vesical Imaging Reporting and Data System (VI-RADS) using mpMRI proposes a five-point Tumours of the urinary tract

151

Estimated age-standardized incidence rates (World) in 2020, bladder, females, all ages

All rights reserved. Th« designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, dty or area or of its authorities, or concerning the delimitation of its frontiers or boundanes. Dotted and dashed lines on maps represent approximate borderlines for which there may not yet be full agreement.

Data source: GLOBOCAN 2020 Graph production: IARC (http://gen wre fr/today) World Health Organization

(耕 World Health yl*/ Organization

© International Agenry for Research on Cancer 2021

Fig. 3.24 Bladder cancer. Estimated age-standardized global incidence rates (ASRs; World), per 100 000 person-years, of bladder cancer in 2020 among females (all ages).

scale for staging, which suggests the likelihood of the bladder cancer invading the detrusor muscle and extravesical space. T2-weighted images are defined as first-pass images, and diffusion-weighted and dynamic contrast-enhanced images are defined as dominant images (2432(. The diagnostic per­ formance of this system was found to be good by systematic review and meta-analysis (3485,815}. Use of this system allows selected patients to avoid unnecessary second tumour resec­ tion (1562,814).

The most common type of bladder cancer is urothelial carci­ noma, which accounts for > 90% of all bladder cancers in highincome countries; it is far more common than pure squamous cell carcinoma (SCC) or pure adenocarcinoma. Only 5-10% of urothelial carcinomas originate in the upper urinary tract (renal pelvis and/or ureter). The annual incidence of upper urinary tract carcinomas in high-income countries is 1-2 cases per 100 000 population, but the incidence rate is much higher in populations exposed to aristolochic acid (1406, 1782,3001,2733) (see Etiology, below).

Epidemiology Bladder cancer is the 10th most common cancer worldwide, with an estimated 573 278 new cases in 2020, representing 3% of all cancers. It is the 13th most common cause of cancerrelated mortality, with an estimated 212 536 deaths worldwide in 2020 {1455). Bladder cancer incidence and mortality differ significantly among global regions, with higher rates reported in southern European, North American, and northern African countries than elsewhere {154}. In general, bladder cancer is about six times as common in high-income countries as in low- and middle­ income nations. As such, 55% of all bladder cancers and 43% of bladder cancer deaths occur in one fifth of the world's popu­ lation living in countries with a very high Human Development Index (HDI). The incidence and mortality rate of bladder cancer is four times as high in men as in women, making it the sixth most com­ mon cancer and the ninth leading cause of death in men (421, 2766,2934}. Most patients are diagnosed in the seventh dec­ ade or later; however, the tumour can affect younger patients, including (in rare cases) children.

152

Tumours of the urinary tract

Etiology

Inherited Urothelial carcinoma can occur in the context of Lynch syn­ drome, an autosomal dominant hereditary condition resulting from DNA mismatch repair deficiency. In this setting, it tends to involve the upper urinary tract, making it the third most frequent Lynch syndrome-associated malignancy {2734,1153). Further­ more, a slightly increased risk of urinary bladder urothelial car­ cinoma is also associated with Lynch syndrome, especially with MSH2 germline mutations {2960}. Costello syndrome, a rare genetic condition caused by germ­ line HRAS mutations, is another inherited disease associated with an increased risk of bladder cancer, which notably devel­ ops in adolescence and early adulthood (1195).

Dietary and herbal medicine exposure Aristolochic acid is a carcinogenic and nephrotoxic nitrophen­ anthrene carboxylic acid produced by Aristolochia plants. An etiological link between upper tract urothelial carcinoma and aristolochic acid exposure through ingestion of Aristolochiabased herbal medicines or contaminated wheat grains has

Estimated age-standardized incidence rates (World) in 2020, bladder, males, all ages

All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Qncer concerning the legal status of any country, territory, dty or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate borderlines for

Data source: GLOBOCAN 2020 Graph production: IARC (http://geotarc.fr/today)

which there may not yet be full agreement.

World Health Organization

World Health Organization © International Agency for Research on Cancer 2021

Fig. 3.25 Bladder cancer. Estimated age-standardized global incidence rates (ASRs; World), per 100 000 person-years, of bladder cancer in 2020 among males (all ages).

been established in several populations, including those living in Taiwan and the Balkan regions (1203,1506,593,1782,1204, 1406,1514,683}.

Radiation and medication Radiation exposure (external beam therapy and brachytherapy) for the treatment of cancer (e.g. prostate cancer and uterine cervix cancer) increases the subsequent risk of bladder can­ cers, including tumours of non-urothelial histology {2224,1230}. This is supported by findings from studies of patients treated for ankylosing spondylitis and by findings among survivors of the atomic bomb detonations in Japan {1440}. Chlornaphazine, used in several countries in the past as a chemotherapeutic agent for treatment of Hodgkin lymphoma and polycythaemia vera, was found to increase the risk of inva­ sive carcinoma and papillary carcinoma of the bladder (1439}. Cyclophosphamide is an antineoplastic agent used in the treatment of lymphomas, soft tissue and osteogenic sarcomas, and other tumours. Case-control studies of survivors of these cancers have demonstrated an association of cyclophospha­ mide therapy with the subsequent development of bladder can­ cer (1439). Phenacetin, an over-the-counter analgesic used during the nineteenth and twentieth centuries and since banned in many countries, has been documented to increase the risk of renal pelvis and ureter cancers {1439}.

chronic inflammatory response to Schistosoma eggs residing within the bladder wall is thought to induce squamous meta­ plasia, hyperplasia, and ultimately carcinoma. Mechanistic

Table3.02 Occupational agents and exposure circumstances classified by the IARC Monographs Programme (https://monographs.iarc.who.int/ ) that have sufficient evi­ dence of human carcinogenicity for the bladder Agent or mixture

Main industry, use, or exposure source

4-Aminobiphenyl

Rubber antioxidant (in the past), dye intermediate, cigarette smoke

compounds

Glass, metals, pesticides, contaminated drinking-water

Benzidine

Azo dye reagent base

Arsenic and inorganic arsenic

2-Naphthylamine

Opium consumption

Rubber antioxidant and dye intermediate (in

the past), cigarette smoke Smoking, ingestion

Tobacco smoking ortf)o-Toluidine

X-radiation, y-radiation, neutron radiation

Intermediate in synthesis of herbicides, dyes, pigments, and synthetic rubber chemicals

Medical, nuclear

Exposure circumstance Aluminium production

Infections and chronic irritation

Auramine production

Schistosoma haematobium infection, endemic in the Middle East and on the African continent, is associated with increased rates of squamous and urothelial carcinoma of bladder. The

Magenta production

Painting (occupational exposure) Rubber-manufacturing industry

Tumours of the urinary tract

153

amines in cigarette smoke cause the formation of DNA adducts that in turn induce DNA mutations. Polymorphisms in GSTM1 and CYP1A1 modify one*s ability to detoxify these carcinogens and hence are determinants of risk (730}.

studies suggest that a skewed immune microenvironment and host epigenomic alterations play a role in this process (1468|. Patients with neurogenic bladder are also at increased risk of bladder cancer (194,2246}. This is thought to be related to urine stagnation and a response to reconstructive surgery, augmen­ tation, and long-term indwelling catheters. Likewise, congenital bladder exstrophy is a risk factor for bladder cancers, including those with non-urothelial histology {2968}. The main occupational, environmental, and other exposures of everyday life that have been found to cause bladder cancer are listed in Table 3.02 (p. 153).

Opium The smoking or ingestion of raw or minimally processed forms of opium has recently been identified as carcinogenic to the bladder, in studies conducted throughout the Islamic Repub­ lic of Iran. Opium is consumed in a minimally processed form by nearly 4 million people worldwide, primarily in countries of south-eastern Asia and the Middle East {1438}.

Tobacco smoke

Occupational and environmental exposure

Smoking (especially cigarette smoking) has long been recog­ nized as a risk factor for urothelial carcinoma, contributing to more than half of all cases {995). The duration of smoking his­ tory is relevant, and the risk reduces after cessation. Aromatic

MSigl

■ APOBEC-High

MSIg2

□ APOBEC-Low

MSig3

□ APOBEC-No

Exposure to benzidine-based dyes (or dyes that metabolize to benzidine), aromatic amines, and arsenic increases the risk of developing bladder cancer. Exposure can be through

MSig4

Neoantigen (1st quartile) Neoantigen (2nd quartile)

MSi9 Cluster

Neoantigen (3rd quartile) APOBECmutLoad Neoantigen (4th quartile)

Neoantigen Load

C>T_CpG

■ APOBEC-a

ERCC2

□

POLE

APOBEC-b T1,2&Node-・

Papillary

T3,4 & Node-S

Female

Node*

Male

■

Non-PapillaryD

Combined.Tx Histology

Gender

NA

Squamous

TPS3(48%) KMT2D(28%) KDMM (26%) ARID1A(25%) PIK3CA (22%) KMTX(18%) RB1 (17%) EP300(15%) FQFR3(14%) S7AG2(14%) ATM (14%) ran (12%) ELF3(12%) CREBBP(12%) ERBB2(12%) SPUN1 (12%) KMT2A(11K) ERBB3(10%) ERCCi(9K) CDKN1A (9%)

E2F3.amp(12%) PPARQ.amp(6%) MDM2.・mp(6%) CDKN2A.del (22%) FGFR3.fusion (2%) PPARG.fusion (3%)

Mutation burden o) u > A J n s

Mutational process

—Low (134/74) —Mid (134/56) —High (138/48)

Le

APOBEC mutation load

Neoantigen load

p=151E I

，*s M

uoJJOdol

O..8 O..6 O..4 O..2 0..0

'中讪“

，

a. MSigl (28/5) — MSig3 (99/39) MSig2 (220/112) —MSig4(5&21)

p = 9.0-10'5 0

B

50

100

150

Time (months)

0

50

100

Time (months)

150

0

50

100

Time (months)

150

0

50

100

150

Time (months)

Fig. 3.26 Mutation, copy-number alteration, and mutation signature landscape of invasive urothelial carcinoma. A Genomic landscape for 412 primary, muscle-invasive urothe­ lial carcinomas. Top to bottom: synonymous and non-synonymous somatic mutation rates, mutation signature (Msig) cluster, APOBEC mutation load, and neoantigen load by quartile; significantly mutated genes (2 7% of tumours); copy-number alterations and fusions for selected genes. B Kaplan-Meier plots for overall survival. Left to right: overall mutation burden (single-nucleotide variants); mutation signature clusters (Msig1-4); APOBEC-mediated mutation load; neoantigen load {2686}.

154

Tumours of the urinary tract

effect, providing a favourable environment for the development of urothelial carcinoma through a monoclonal or oligoclonal process associated with shared ancestral mutations, as well as many novel and unique mutations in multifocal disease {3152, 973}. Molecular genetic studies comparing synchronous or metachronous bladder and upper tract urothelial carcinoma tumours in the same individual have supported the clonal relatedness of at least a subset of urothelial neoplasms, pointing to seeding as a possible mechanism (3285,226}. Urothelial carcinoma develops through unique molecular pathways that parallel histopathological classification. Low-

inhalation or ingestion. Arsenic exposure may occur through the consumption of contaminated drinking-water, as seen in certain geographical regions {2293}. Occupational exposures in the production of aluminium, auramine, magenta, and rubber, as well as occupational exposure as a painter, are all associated with a risk of developing bladder cancer. Chemical exposures act synergistically with smoking to increase risk through epige­ netic DNA methylation (730}.

Pathogenesis

Copy-number alterations and mutation landscape

grade papillary carcinoma recurs frequently but progresses infrequently, whereas high-grade papillary carcinoma and carcinoma in situ (CIS) are associated with higher rates of

The lining of the bladder harbours multiple mutational clones that can be detected in diseased as well as healthy urothelium (1815,1866,3152). The rich mutation landscape creates a field

mRNA Clusters mRNA Clusters TCGA 2014 Luminal Female Luminal-infiltrated Papillary Basal-squamous Squamous Neuronal Luminal-papillary Neuroendocrine Lymphocytes TP53 mut TCGA 2014 RB1 mut ■ Cluster I FGFR3 alterations ■ Cluster II miR-200a7p ■ Cluster III miR-200b-3p ■ Cluster IV miR-99a-5p miR-100-5p GATA3 protein EGFR protein CDH1 protein HER2 protein KRT20 PPARG FOXA1 GATA3 Luminal markers SNX31 UPK1A UPK2 FGFR3 PGM5 DES C7 ECM and smooth muscle SFRP4 COMP SGCD

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ZEB2 SNAI1 TWIST1 EMT and Claudin markers CDH2 CLDN3 CLDN4 CLDN7 CD44 KRT6A Basal markers KRT5 KRT14 COL17A1 DSC3 GSDMC TGM1 Squamous markers PI3 TP63 CD274 PDCD1LG2 IDO1 Immune markers CXCL11 L1CAM SAA1 MSI1 PLEKHG4B GNG4 PEG10 Neuronal-differentiation RND2 APLP1 S0X2 TUBB2B CRTAC1* CTSE* Down-regulated in CIS* PADI3* Up-regulated In CIS** MSN** NR3C1** SHH Sonic Hedgehog BMP5

mRNA & microRNA expression - Log2(fold change) Protein expresion - z score

Fig. 3.27 Invasive urothelial carcinoma. mRNA expression subtypes. Top, left to right: five mRNA expression subtypes: luminal-papillary, luminal-infiltrated, luminal, basalsquamous, and neuronal. Covariates: four previously reported TCGA subtypes; selected clinical covariates and key genetic alterations; normalized expression for microRNAs and proteins for selected genes. Samples within the three luminal subtypes, the basal-squamous subtype, and the neuronal subtype are ordered by luminal, basal, and neuroen­ docrine signature scores, respectively. TCGA, The Cancer Genome Atlas.

Tumours of the urinary tract

155

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Luminal papillary (LumP) • Lum^^papillary

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■ Luminaljaapillary ■ Luminal ■ LuminaIJnfiltrated Basal_squamous ■ Neuronal CIT-Curie |MC1 ■ MC2 ■ MC3 MC4 MC5 |MC6 ■ MC7

Lund ■ UroA-Prog UroC ■ Uro-lnf | UroB |GU ■ GU-Inf | Ba/Sq-Inf | Ba/Sq ■ Mes-like ■ Sc/NE-like

Fig. 3.28 Consensus molecular classification of muscle-invasive urothelial carcinoma. A Clustered network of the six-consensus-class solution based on a reanalysis of 1750 transcriptomes originally classified according to six different input molecular subtypes. The circles inside each clique represent input subtypes from each consensus matched by colour. Circle size is proportional to the number of samples assigned to the subtype. B Input subtypes repartitioned among each consensus class. C Relationship between subtyping results from the six input classification schemes. Samples are ordered by predicted consensus classes. Ba/Sq, basal/squamous; LumNS, luminal non-specified; LumP, luminal-papillary; LumU, luminal-unstable; MDA, MD Anderson Cancer Center; TCGA, The Cancer Genome Atlas; UNC, University of North Carolina {1576}.

progression and are believed to be the precursor lesions for muscle-invasive bladder cancer (568). The two pathways have overlapping mutation spectra but marked differences in the prevalence of certain genetic alterations {1215,2528}. Comprehensive genomic analysis identified significant chro­ mosomal copy-number alterations, including those at the arm level, as well as focal amplifications and deletions {510,2686}. The most common focal deletions have been detected in the tumour suppressor genes CDKN2A, RB1, NCORL and PTEN. The most common focal amplifications include known oncogenes such as E2F3, PPARG, CCND1, CCNE1, MYC, and MDM2, as well as genes not previously implicated in bladder cancer, such as YWHAZ, NECTIN4〈PVRL4), BCL2L1, and ZNF703.

156

Tumours of the urinary tract

Bladder cancer characteristically harbours a high rate of somatic mutations, consistent with a carcinogen-induced eti­ ology {1812,2686). Its mutation signatures are dominated by APOBEC mutagenesis, identified in nearly two thirds of mus­ cle-invasive bladder cancer studied by The Cancer Genome Atlas (TCGA) group {2686}. The cytidine deaminase enzymes active in this process are primarily responsible for innate immu­ nity against retroviruses and retrotransposons. Another muta­ tion signature is associated with ERCC2, a DNA helicase gene central to the nucleotide excision repair mechanism of DNA damage repair (1657,3270). Many recurrent somatic muta­ tions detected in urothelial carcinoma are in genes involved in multiple cell functions and canonical pathways. These include cell cycle regulation (TP53, RB1, CDKN2A, CDKN1A),

chromatin modification (ARID1A, KDM6A, KMT2D, KMT2C, KMT2A, EP300, CREBBP), receptor tyrosine kinase/RAS signalling (FGFR3, ERBB2, ERBB3, KRAS, HRAS), the PI3K/ AKT pathway (PIK3CA, TSC1), and other functions (STAG2, ATM, FAT1, FBXW7, etc.) {510,2686,1661,1479}. Mutations in the TERT promoter region are the most common alterations in urothelial carcinoma; they occur in all grades and stages of the disease, and across the spectrum of morphological subtypes, but not in benign conditions {1647,1466,1672,3267, 3618}. These mutations create novel consensus binding sites for ETS family transcription factors, leading to upregulated telomerase expression and increased telomere activity, pro­ viding a tumour growth and survival advantage. In urothelial carcinoma, tumours with TERT promoter mutations tend to occur in older patients and have a higher mutation and copy­ number alteration burden (1466}. Integrated analyses revealed recurrent patterns of mutual exclusivity (e.g. TP53 and MDM2; TP53 and CDKN2A; RB1 and CDKN2A： FGFR3 and RB1) or co-occurrence (e.g. TP53 and RB1; FGFR3 and CDKN2A) (2686,1479}. The presence of these alterations has clinical significance. The efficacy of targeting oncogenic FGFR3 alterations (muta­ tion, amplification, and fusion) has recently been demon­ strated in patients with advanced and metastatic urothelial carcinoma harbouring these alterations, and it has resulted in the approval of novel anti-FGFR agents (2420,2480(. However, targeting other genes that are frequently mutated in urothelial carcinoma (e.g. ERBB2、ERBB3, and PIK3CA) has not been as efficacious, probably because of genetic heterogeneity and the subclonal nature of such alterations in urothelial car­ cinoma (1432). Alterations in ERCC2 and other DNA damage repair genes have been associated with response to cisplatin­ based chemotherapy (and to some extent immune checkpoint blockade and radiation therapy). Such alterations are currently being explored as potential biomarkers for selecting patients for neoadjuvant cisplatin-based chemotherapy, mutation pro­ filing of invasive tumour samples, and a subsequent thorough clinical assessment for response with the option of offering a bladder-preserving approach in responsive tumours {3270, 1480). The detection of TERT promoter mutation in early-stage and low-grade disease suggests that it is an early genetic event in the development of urothelial carcinoma {1672,2528). Moreover, TERT promoter mutation can also be detected from urine sam­ ples, highlighting its role as a potential biomarker for the noninvasive detection of urothelial neoplasia (3012,924).

Expression profiling and molecular taxonomy Urothelial carcinoma can be classified into multiple molecular subtypes based on RNA and immunohistochemical expression profiling. Many terms have been proposed for different subtypes according to different classification schemes, but significant overlap exists among them {2953,642,768,2686,1576,2185). Cluster analysis enabled the grouping of invasive urothelial car­ cinoma into two major subtypes, luminal and basal, with further subdivisions within the luminal subtype. These subtypes dif­ fered in their relative expression of markers of basal-squamous differentiation (e.g. CK5, CK6, CK14, CD44, desmocollins, and desmogleins) and markers of urothelial (luminal) differentiation (e.g. CK20, uroplakins, FGFR3, FOXA1, GATA3, and PPARG).

Fig. 3.29 Bladder specimen with sarcomatoid urothelial carcinoma. Macroscopic ap­ pearance of sarcomatoid urothelial carcinoma infiltrating and expanding the bladder wall.

They also differed in their mutation profile and tumour immune microenvironment. In addition, a small subset of tumours were enriched for neuronal/neuroendocrine markers, the majority (but not all) of which exhibited neuroendocrine histomorphological features. Details on these classification schemes can be reviewed in the 2016 TOGA bladder cancer report (2686} and in the consensus molecular classification report that incorporated analyses from previously published studies and 1750 muscleinvasive bladder cancer transcriptomes {1576(.

Macroscopic appearance Invasive urothelial carcinoma can have a variety of gross appearances. These include papillary, sessile, polypoid, nodu­ lar, and ulcerative morphology. Carcinomas can be unifocal or multifocal, with the latter at times displaying a mixed gross mor­ phology. Concurrent CIS has a flat erythematous appearance. The presence and level of invasion should be assessed during macroscopic examination and confirmed microscopically. Prior transurethral resection and neoadjuvant therapy may distort the typical macroscopic appearance of the tumour, leaving areas of scarring or ulceration.

Histopathology Invasive urothelial carcinoma is remarkable for its diversity of morphological appearances (1938}. A single lesion can display an admixture of conventional urothelial and various well-defined histological subtypes, together with areas of divergent differen­ tiation along other epithelial lineages (e.g. squamous, glandular, and small cell neuroendocrine). Specific subtypes of urothelial carcinoma (see below) are important to recognize, given that they may resemble other non-urothelial tumours, have a decep­ tively benign appearance, or carry a unique prognostic or thera­ peutic implication {1934,122}. It is not unusual for tumours to dis­ play a mixture of conventional urothelial carcinoma, histological subtypes, and/or divergent differentiation components. A listing of the various components, and an attempt to quantify them, is required in such cases. Architecturally, conventional urothelial carcinomas present as variably sized nests, sheets, trabeculae, cords, and individual Tumours of the urinary tract

157

Fig. 3.30 Invasive urothelial carcinoma. A Early invasion in urothelial carcinoma is characterized by eosinophilic nests of cells with retraction spaces in the lamina pro­

pria. B Conventional invasive urothelial carcinoma invades the muscularis propria.

cells. Occasional tumours may show a stratified architecture with an attempt to recapitulate normal urothelium, but most tumours lack resemblance to normal urothelium. The presence of one or more surface non-invasive papillary or CIS precursor lesions is helpful in recognizing the primary nature of the inva­ sive tumour if subsequent surface colonization is a considera­ tion (such as local extension from colorectal adenocarcinoma) {3467}. Immunohistochemical markers supporting a urothelial lineage include p63, GATA3, and high-molecular-weight cytokeratins {137}. Although a high rate of expression of each of these three markers is frequent, this immunophenotype overlaps substan­ tially with that of SCC. If direct involvement by HPV-associated SCC of uterine cervical or anal origin is a consideration, stud­ ies to detect HPV (such as chromogenic in situ hybridization or molecular testing) can be helpful in establishing the diagnosis. Of note, p16 expression is frequent in urothelial carcinoma, mak­ ing it of limited utility in this context (137}. Urothelial carcinoma frequently coexpresses CK7 and CK20. However, labelling for both markers is not always present {137). Divergent intestinaltype glandular differentiation overlaps substantially with that seen in enteric primary adenocarcinoma. Definitive distinc­ tion between the two types of neoplasm is not possible using morphological or immunohistochemical approaches (both can

be positive for CDX2 and/or CK20) (137,3467). Although an absence of nuclear staining for p-catenin has been suggested as favouring bladder primary adenocarcinoma, the differential is best resolved on clinical grounds and by imaging studies (137,3467).

Grading Cytologically, invasive urothelial neoplastic cells display high­ grade features. This is characterized by their frequent striking nuclear pleomorphism and hyperchromasia. Nuclear contours are irregular and often angulated. Mitotic figures can be numer­ ous, with occasional abnormal forms. The tumour cells usually contain pale to eosinophilic cytoplasm in moderate to abundant quantities, imparting a squamous appearance that should be distinguished from true divergent squamous differentiation (intercellular bridges and keratinization) (1076}. Less frequently, the cytoplasm is scant and amphophilic. Although the above­ described nuclear features are present in most invasive tumours and are graded as high-grade, rare low-grade invasive urothelial carcinomas lacking marked nuclear atypia are recognized. No standardized criteria have been established for designating an invasive urothelial carcinoma as low-grade, but some authors have suggested that such low-grade tumours may pursue a more favourable outcome. Therefore, every invasive urothelial

Fig. 3.31 Urothelial carcinoma with trophoblastic differentiation. Tumour with syncytiotrophoblastic cells (A), which are highlighted using p-hCG immunohistochemistry (B).

158

Tumours of the urinary tract

carcinoma must be graded (2325,136}. Histological subtypes of urothelial carcinoma and those with divergent differentiation are all considered high-grade tumours (see below).

Urothelial carcinoma with divergent differentiation Urothelial carcinoma with squamous differentiation Squamous differentiation is characterized by a transition from

conventional morphology to squamous morphology, as evi­ denced by intercellular bridges or keratinization. This is the most common form of divergent differentiation in most series, accounting for as many as 30-40% of cases {1893,1665,1944, 3408}. Although there is a tendency for more locally advanced disease to show squamous histology, stage by stage it has not been found to be associated with worse cancer-specific sur­ vival (1665,3408}. As alluded to above (see Pathogenesis), a basal-squamous molecular subtype of urothelial carcinoma is now recognized by its genomic expression signature. Tumours in this molecular cluster tend to display squamous morphologi­ cal features.

papillary architecture are set in cleft-like spaces.

Urothelial carcinoma with glandular differentiation Glandular differentiation is often considered the second most common form of divergent differentiation after squamous, with as many as 18% of tumours showing this differentiation in one study (1665,3408,1893). True glandular differentiation should be distinguished from the not uncommon occurrence of gland­ like luminal spaces in otherwise conventional urothelial carci­ noma. The divergent glandular differentiation is often of intes­ tinal type, akin to colorectal adenocarcinoma. As mentioned above, immunohistochemistry is of little value in establishing a primary bladder origin for an intestinal-type adenocarcinoma; the presence of a bona fide conventional urothelial carcinoma component can help establish the primary bladder origin. Like tumours with squamous differentiation, there is some evidence that tumours with glandular differentiation often come to clinical attention at an advanced stage; however, glandular differentia­ tion does not influence prognosis once stage is accounted for (1665,3408|.

Fig. 3.33 Nested urothelial carcinoma. Cytologically bland nests of urothelial cells

Fig. 3.32 Micropapillary urothelial carcinoma. Invasive tumour clusters with a micro-

intermingle between normal structures without any stromal response.

Urothelial carcinoma with trophoblastic differentiation In urothelial carcinoma with trophoblastic differentiation, a com­ ponent of trophoblastic cells (including syncytiotrophoblastic and cytotrophoblastic cells) is present (2580). Rarely, these tumours can be indistinguishable from choriocarcinoma {2580, 1181,2634). Serum elevation of p-hCG is usually observed. However, a considerable proportion of patients with metastatic urothelial carcinoma without apparent trophoblastic histology also have p-hCG elevation, which has been used by some as a marker for monitoring response to therapy (850,892,1451). Urothelial carcinoma with Mullerian differentiation Urothelial carcinoma with Mullerian differentiation (clear cell adenocarcinoma) is discussed in Clear cell adenocarcinoma of the urinary tract (p. 188) {25,2366,1206,1337,3175,563,3632}.

Histological subtypes of urothelial carcinoma Micropapillary urothelial carcinoma Micropapillary urothelial carcinoma is defined by the presence of small clusters of tumour cells without fibrovascular cores, often surrounded by lacunae resembling vascular invasion. The

presence of multiple clusters within the same lacuna is typical. The tumour cells have peripherally oriented nuclei and occa­ sional cytoplasmic vacuoles distorting the nuclear contour (ring forms) {132,2807), Lymphovascular invasion is common and CIS is present in more than half of all micropapillary carcinomas (2107,696]. Adherence to this compilation of morphological fea­ tures will assure accuracy and reproducibility of the diagnosis (2807). Overexpression and or amplification of ERBB2 is more frequent in micropapillary carcinoma and could offer a target for therapy {634,2814,3642,311}. Micropapillary urothelial carci­ noma is an aggressive subtype. Radical cystectomy could be a consideration in patients with non-muscle-invasive bladder cancer with a substantial micropapillary component (3471,1573, 348}.

Nested urothelial carcinoma The nested subtype of urothelial carcinoma has a deceivingly bland histology that belies its aggressive biological behav­ iour (similar to that of conventional urothelial carcinoma). It is characterized by a proliferation of small round to ovoid nests

Tumours of the urinary tract

159

nests can be a challenge in superficial biopsies. Clues to this diagnosis include the confluence of multiple nests and the irregular infiltrative base of the lesion that usually involves the muscularis propria. Increased cytological atypia in the deeper aspect of the tumour can be encountered (3407,2257,896,1888, 1382,315}. Identification of TERT promoter mutation can help in difficult TURBT cases (see the Diagnostic molecular pathol­ ogy subsecim, below). Nested carcinoma is often pure, but it can be mixed with other urothelial carcinoma subtypes. Nested carcinoma shares the usual immunophenotype of conventional urothelial carcinoma.

Fig. 3.34 Microcystic urothelial carcinoma. Relatively bland cystic structures infiltrate a non-reactive stroma.

Large nested urothelial carcinoma Large nested urothelial carcinoma is a rare subtype composed of medium to large nests whose borders vary from rounded and circumscribed to a stromal-tumour interface with a more irregu­ lar, ragged appearance. This pattern is distinguished from an inverted growth pattern of non-invasive urothelial carcinoma, and from expanded von Brunn nests, by the presence of mus­ cular propria invasion, irregularly infiltrating nests, or stromal reaction. Despite the bland cytological features of the large nested subtype, 70% of patients present with pT2 tumours, and 58% have extravesical disease (> pT3 and/or > pN1). One fifth of patients endure recurrences or metastases, and 24% died of disease in one series (726,695,315,1894,3442).

Tubular and microcystic urothelial carcinomas These two subtypes are thought to be closely related to their nested counterpart, in which cytologically bland cells line small tubular or microcystic distended structures (2000,1943). Like the nested subtype, deep irregular infiltration including the involvement of the muscularis propria is a clue to the malignant nature of this proliferation and helps distinguish it from cystitis cystica. Urothelial markers, such as GATA3 or p63, are typically positive (2434).

Fig. 3.35 Plasmacytoid urothelial carcinoma. Invasive carcinoma comprising dis­ persed, dyscohesive cells with eccentrically placed high-grade nuclei imparting a plasmacytoid appearance. Intracytoplasmic vacuoles can be seen.

of urothelial cells with limited cytological atypia, mimicking von Brunn nests (315,896,1382,1894,2257,3339,3407}. Differ­ entiating this subtype from a benign proliferation of von Brunn

Plasmacytoid urothelial carcinoma Plasmacytoid urothelial carcinoma is an aggressive subtype, characterized by single infiltrating cells with or without cyto­ plasmic lumina or vacuoles. As a result, tumour cells can be overlooked as plasma cells or other inflammatory cells. At times they may also resemble signet-ring carcinoma cells, but notably they lack the extracellular mucin found in signet-ring adenocarcinomas (2767,3651(. The discohesive tumour cells

Fig. 3.36 Sarcomatoid urothelial carcinoma. A Spindle-shaped tumour cells with occasional epithelioid appearance and marked nuclear atypia. B Tumour cells acquire a spindle-shaped, occasionally epithelioid appearance, with marked nuclear atypia. C There is a transition from carcinoma (upper right) to malignant spindle-shaped cells resem­ bling those of a sarcoma.

160

Tumours of the urinary tract

Fig. 3.37 Lipid-rich urothelial carcinoma. A An invasive carcinoma composed of lipid-containing vacuolated cells imparting a lipoblast-like appearance. B Higher-magnification view.

can spread extensively along tissue planes and peritoneal surfaces. Special attention to the frequent positive surgical margins in areas that are not grossly evident, such as the soft tissue around ureters, is warranted during frozen section evalu­ ation {2503,1564,1938}. Plasmacytoid carcinoma is character­ ized by somatic mutations of CDH1 (leading to frequent loss of E-cadherin expression), akin to lobular breast carcinoma and signet ring gastric cancer (62}. The plasma cell marker CD138 may be positive, which can be misleading as it is also expressed in epithelial neoplasms. Plasmacytoid carcinoma typically labels for urothelial markers such as p63 or GATA3. Expression of the latter is shared with metastatic lobular breast carcinoma, which presents a differential diagnostic challenge. Markers such as ER, PR, and mammaglobin are of utility in such cases {2503,396,2434}.

components has been suggested to impart a more adverse behaviour {3486,137,2806,622}. The survival of patients with sarcomatoid urothelial carcinoma is particularly poor, with a reported 5-year cancer-specific survival of 28% and a median overall survival of 14 months (3380). Immunohistochemical expression of markers of urothelial differentiation such as p63, GATA3, and high-molecular-weight cytokeratin, albeit focal, can be supportive of the diagnosis (137,2806,622}. Benign rriyofibroblastic proliferations such as postoperative spindle cell nod­ ule and inflammatory myofibroblastic tumours can mimic sarco­ matoid carcinoma given their frequent expression of cytokeratin and occasional brisk mitotic activity {3440,1293(. The lack of expression of urothelial markers (e.g. p63 and GATA3) and pos­ itivity for ALK (present in as many as two thirds of inflammatory myofibroblastic tumours) can be helpful {3440,1293).

Sarcomatoid urothelial carcinoma The sarcomatoid urothelial carcinoma subtype is characterized by the presence of areas of the neoplasm that are indistinguish­ able from sarcoma. Conventional urothelial, squamous, glan­ dular, or small cell neuroendocrine carcinoma (SCNEC) com­ ponents are frequently admixed. Morphological features vary from the nondescript spindle cell pattern to those of an undif­ ferentiated pleomorphic sarcoma. Heterologous components include osteosarcoma, chondrosarcoma, rhabdomyosarcoma, and angiosarcoma. The presence of one or more heterologous

Lipid-rich urothelial carcinoma Lipid-rich urothelial carcinoma contains lipoblast-like cells with one or more cytoplasmic vacuoles indenting their nuclei (1932, 1853,310}. The lipid nature of the vacuolar content has been confirmed by electron microscopy and histochemical staining {1932,399). The lipid-rich subtype is usually admixed with con­ ventional urothelial carcinoma and other subtypes. Epithelial immunohistochemical markers are frequently positive. A poor 5-year survival outcome (42%) was found in the largest reported multi-institutional series (1932}.

Fig. 3.38 Lymphoepithelioma-like urothelial carcinoma. A Sheets of CK7-positive pleomorphic cells with a syncytial arrangement. B Rich lymphocytic infiltrate (CD45-positive) highlighted in lymphoepithelioma-like urothelial carcinoma. C Invasive carcinoma composed of sheets of pleomorphic cells with a syncytial arrangement admixed with a rich lymphocytic infiltrate.

Tumours of the urinary tract

161

Fig. 3.39 Clear cell (glycogen-rich) urothelial carcinoma. A Sheets of clear cells have well-defined cell membranes and abundant optically clear cytoplasm. B Cells have clear cytoplasm, reminiscent of renal cell carcinoma.

Lymphoepithelioma-like urothelial carcinoma Lymphoepithelioma-like urothelial carcinoma (LELC) is a rare subtype composed of sheets and clusters of undifferentiated cells with poorly defined cytoplasmic borders imparting a typi­ cal syncytial appearance. The tumour cells contain large pleo­ morphic nuclei with prominent nucleoli, and they are associated with a dense infiltrate of (predominantly) lymphocytes, plasma cells, and other inflammatory cells {3651). LELC of the bladder has morphological similarities to nasopharyngeal lymphoepithelioma and occasionally oropharyngeal carcinoma, but it differs from both by its lack of any association with EBV or HPV {3470). Tumours with pure or predominant (> 50%) LELC features have been suggested by some (but not all) authors to be associated with better overall survival than those in which LELC is admixed with conventional and other subtypes {3558,3470,133,3104). Immunohistochemistry for cytokeratin and urothelial markers highlights the epithelial cells and helps distinguish LELC from high-grade lymphomas (3470,2434}, A recent study showed that LELC tumours are enriched for basal-squamous molecular subtype markers and for PDL1 expression. These findings are consistent with the known sensitivity of LELC tumours to chemo­ therapy and support the potential of immune checkpoint inhibi­ tors as a therapeutic option {2022).

Clear cell (glycogen-rich) urothelial carcinoma Clear cell (glycogen-rich) urothelial carcinoma is typified by an accumulation of glycogen within tumour cells, resulting in a clear cell appearance (1716,1998). The immunohistochemi­ cal profile is similar to that of conventional urothelial carcinoma and can help distinguish this subtype from metastasis from a clear cell renal cell carcinoma (2434). Clear cell (glycogen-rich) urothelial carcinoma should be distinguished from clear cell adenocarcinoma (see Clear cell adenocarcinoma of the uri­ nary tract, p. 188), which is generally considered to have more aggressive behaviour. Giant cell urothelial carcinoma Giant cell urothelial carcinoma is a very rare subtype that is often accompanied by conventional urothelial carcinoma. Like its lung counterpart, bizarre pleomorphic giant tumour cells are typical of this subtype and should be distinguished from tro­ phoblastic and osteoclast-like giant cells. Immunohistochemi­ cal positivity for epithelial and urothelial markers is present in at

162

Tumours of the urinary tract

least some of the bizarre tumour cells. The behaviour of this rare subtype is highly aggressive {1933,2787,2789}.

Poorly differentiated urothelial carcinoma The poorly differentiated urothelial carcinoma subtype encom­ passes carcinomas lacking morphological features that point to a urothelial origin. Immunohistochemistry is necessary to establish epithelial differentiation in such tumours. Undiffer­ entiated carcinoma with osteoclastic giant cells, resembling a giant cell tumour of bone, is the best-described member of this subtype {296}. This extremely rare tumour is usually composed of a mixture of mononuclear carcinoma cells (often positive for epithelial markers), host histiocytes, and multinucleated oste­ oclast-like giant cells (positive for histiocytic markers such as CD68). A conventional urothelial carcinoma component or CIS when present would aid in confirming the diagnosis of poorly differentiated urothelial carcinoma. The behaviour appears to be aggressive, although data on this are scant.

Cytology Historically, urine cytology has been an efficient, non-invasive method of detecting de novo or recurrent bladder cancer. Its accuracy has improved substantially since the implementation of The Paris System (TPS) for reporting cytology (2720(, summa­ rized in Table 3.03. TPS acknowledges the inability of cytology to reliably detect low-grade urothelial neoplasms and, in considera­ tion of their benign behaviour, TPS has introduced a new diag­ nostic category, low-grade urothelial neoplasm, which encom­ passes papilloma, papillary urothelial neoplasm of low malignant potential, and low-grade urothelial carcinoma. Therefore, TPS pri­ oritizes the identification of morphological diagnostic criteria for the detection of high-grade urothelial carcinoma (HGUC). These criteria are defined in Table 3.03. Based on the presence of these findings, the risk of high-grade malignancy increases relative to the diagnostic category of the sample. The cytological findings of HGUC are indistinguishable from those of urothelial CIS (i.e. staging cannot be achieved by cytol­ ogy). In general, urine specimens with HGUC are cellular with numerous cells displaying a set of characteristic nuclear diag­ nostic features, including an N:C ratio > 0.7, hyperchromasia, irregular clumpy chromatin, and irregular contours. Although a high N:C ratio carries the most significance, given the mor­ phological heterogeneity of HGUC subtypes, not all identifiable

Table 3.03 Summary of The Paris System (TPS) for reporting urinary cytopathology

Diagnostic category

Diagnostic criteria (non*superficial urothelial cells)

Example

urothelial carcinoma

ROHM

0-5%

0-15%

See Fig. 3.40B

70-90%

8-24%

See Fig. 3.40C

5-15%

2453%

See Fig. 3.40D

0.5-3%

59-94%

See Fig. 3.40E

3-7%

76-100%

See Fig. 3.40F

0.1-3%

(M4%

Voided urine: volume > 30 mL

See Fig. 3.40A for an example

Instrumented urine: cellularity

of an inadequate (acellular) specimen

Adequacy

Negative for high-grade

Frequency

Benign urothelial, glandular, and squamous cells; benign tissue fragments; changes due to instrumentation, lithiasis, polyomavirus, therapy Required: N:C ratio > 0.5 and one of:

Atypical urothelial cells

・ Hyperchromasia ・ Irregular clumpy chromatin , Irregular nuclear contours

Required: N:C ratio > 0.7, hyperchromasia, and one of:

Suspicious for high-grade urothelial carcinoma

・ Irregular clumpy chromatin ・ Irregular nuclear contours Required: cellularity (> 5 cells) and:

• N:C ratio >0.7 Positive for high-grade urothelial carcinoma

• Hyperchromasia • Irregular clumpy chromatin

• Irregular nuclear contours Low-grade urothelial neoplasm

Required: fibrovascular cores and absence of nuclear atypia

ROHM, risk of high-grade malignancy.

Fig. 3.40 The Paris System (TPS) for reporting urinary cytopathology: examples. A Acellular (and therefore inadequate) specimen due to gel. B Negative for high-grade urothelial carcinoma. C Atypical urothelial cells. D Suspicious for high-grade urothelial carcinoma. E Positive for high-grade urothelial carcinoma. F Low-grade urothelial neoplasm.

cells will have an N:C ratio > 0.7. Some subtypes, such as plasmacytoid or micropapillary urothelial carcinoma, may contain cells with relatively bland nuclear features. Moreover, HGUC with divergent squamous differentiation will contain numer­ ous cells with a low N:C ratio. Similarly, a small percentage of HGUCs can contain cells with hypochromatic nuclei. However, cells with hyperchromatic nuclei are usually admixed and the

presence of other features of HGUC will help establish the diag­ nosis in such samples.

Diagnostic molecular pathology TERT promoter mutations are the most common genetic altera­ tion in urothelial carcinoma across all grades, stages, and histological subtypes, and as such they can be utilized as a Tumours of the urinary tract

163

reliable molecular diagnostic biomarker in some clinical set­ tings. The presence of TERT promoter mutations can be used to distinguish deceptively bland malignant processes (e.g. the nested subtype of urothelial carcinoma) from benign prolifera­ tive conditions (e.g. proliferative cystitis; florid von Brunn nests; and urothelial papilloma, both exophytic and inverted) {3618, 1672,2528,1466,1467,98,3126}. It can also be used to establish a urothelial origin of tumours with morphological features that are ambiguous or not organ-specific (e.g. small cell carcinoma of the lung vs bladder vs prostate or other organs; plasmacytoid urothelial carcinoma vs mammary lobular carcinoma or diffuse gastric cancer； primary lung non-keratinizing SCC vs metastatic urothelial carcinoma) (572,2573,2487,3615}. Moreover, as pre­ viously mentioned, TERT promoter mutations can be detected from urine samples, making it a promising biomarker for the detection of urothelial neoplasia using non-invasive urine liquid biopsy assays (3012,924}. In advanced urothelial carcinoma, evaluation of FGFR3 alterations can determine eligibility for treatment with anti-FGFR agents (2420,1949). Likewise, assessment of mutations in EFICC2 and other DNA damage repair genes may help stratify patients that are most likely to benefit from cisplatin-based chemotherapy (3270,1480). Assessment of PDL1 expression in tumour and host immune cells in urothelial carcinoma, tumour mutation burden, and microsatellite instability / mismatch repair deficiency are cur­ rently used as predictors of response to immune checkpoint inhibitor therapy for bladder cancer and urinary tract urothelial carcinoma (1368,3192,2640(.

urothelium, and the presence of the vascular plexus in the lam­ ina propria are helpful clues (2441). Histoanatomical variations also exist within the bladder wall and the typically superficial presence of the muscularis propria at the trigone and ureteric insertion may complicate staging at these sites. Studies have confirmed the prognostic significance of pT2a and pT2b divided by the depth of invasion of the muscularis propria {3165,1117,2999} The outer muscularis propria and perivesical soft tissue boundary is irregular, and awareness of such irregularity in cystectomy specimens can enhance the accuracy of staging pT2b and pT3a tumours {140). Although a poorer outcome is observed with pT3b tumours, staging relies substantially on gross assessment of perivesical tissue involve­ ment {3166,3000,2862}. Prostatic stromal invasion is considered pT4a only if it is con­ tiguous with bladder transmural invasion (2464,1692); other­ wise, it should be staged as a separate tumour focus originating in the prostatic urethra. The studies on the prognostic differ­ ences of pT4a tumours by sex-specific organ involvement have conflicting results, so maintaining a single category appears to be the optimal approach at present {1180,232,2071(. Both the total number of resected lymph nodes and the num­ ber of positive nodes should be documented. Studies have also pointed to the value of documenting extracapsular nodal exten­ sion (2490). Tumours of the upper urinary tract and urethra are staged according to their site-specific TNM systems, as elaborated by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) {2443}.

Essential and desirable diagnostic criteria

Prognosis and prediction

See Table 3.01 (p. 151).

Staging Bladder cancer is staged using the TNM system [2443,2440, 1988,1078}. The pT categories are determined by the depth of invasion into the layers of the bladder wall and extension into adjacent structures. There is a consensus that assessing the extent of lamina propria invasion in transurethral resection specimens has prog­ nostic value. Several approaches have been proposed for pT1 subcategorization. It can be based on micrometric measure­ ments (microscopic vs extensive invasion) or on histoanatomical landmarks such as the muscularis mucosae and the vascular plexus of the lamina propria, to produce a two- or three-tiered pT1 subcategorization (2625,690,1042,574,3299,1409,345,1841}. Higher subcategories correlate with recurrence and stage pro­ gression {1603), Although some studies have suggested that the micrometric-based pT1 approach may be more feasible and better predict outcome, there remains a need for well-designed prospective studies with head-to-head comparisons of the vari­ ous methods (2440). In the meantime, pathologists are strongly encouraged to convey the extent of lamina propria invasion using any of the proposed approaches. Awareness of the occasionally hyperplastic appearance of the muscularis mucosae layer is important to prevent overstag­ ing of urothelial carcinoma. In TURBT, a lack of orientation of the curettings may preclude the distinction of the hyperplastic muscularis mucosae from true muscularis propria. The num­ ber and orientation of muscle bundles, their relationship to the 164

Tumours of the urinary tract

Clinicopathological features Tumour stage is a critical factor in determining patient out­ come, but this should be considered in light of several clinical and pathological features to inform prognosis and guide case management. Further prognostic stratification can be achieved using stage subcategorization. Several approaches for pT1 stage have been proposed (see Staging, above). Although none of these approaches is currently adopted by the TNM sys­ tem, it is strongly recommended that the level or extent of pT1 disease be conveyed in TURBT pathology reports at this time {1603). Established subcategorization of pT2 and pT3 stages at cystectomy correlates with outcome. Tumour grade is an important prognostic feature, with the two-tiered 2004 WHO system (which recognizes low- and high-grade urothelial carcinomas) being by far the most com­ monly employed grading system. Grading is a key component of pathology reports in urothelial carcinoma across sites and stages as adopted by several professional urology and pathol­ ogy societies {698,237,685}. Risk categories and models for predicting various outcomes in non-muscle-invasive urothelial carcinoma (pTa-T1) have been developed by urology societies in North America and Europe {237,3006,573,236). High grade, pT1 stage, tumour size > 30 mm, multifocality, and association with CIS are features of the high-risk category. In contrast, lesions that are low-grade, pTa stage, solitary, < 30 mm in size, and without associated CIS are deemed low-risk tumours. The risk category assigned will dictate the management strategy {237}. Additional adverse prognostic factors in Ta/T1 cases include disease recurrence,

presence of lymphovascular space invasion, and aggressive histological subtypes {2027}. CIS progresses to muscle-invasive carcinoma within 5 years in about 50% of cases in the absence of therapy {1786). The presence of multifocal CIS, CIS in the prostatic urethra, and non-response to intravesical therapy are adverse indicators (2992). The overwhelming majority of muscle-invasive bladder cancers (pT2-T4) are high-grade (3160,136}. The outcome in pT2-T4 cases is influenced not just by pathological stage at cystectomy but also by the presence of aggressive subtypes (particularly micropapillary, plasmacytoid, and sarcomatoid subtypes), nodal status, lymphovascular space invasion, response to neoadjuvant therapy, and timing of surgery {3480, 2213}. Furthermore, the survival benefit of neoadjuvant therapy in urothelial carcinoma subtypes has recently been called into question (3577). Lymph node dissection at cystectomy is associated with a survival benefit irrespective of pN status {448}; however, an increased number of positive lymph nodes, node density, and extracapsular extension are considered adverse features {2490}. Lymphovascular space invasion in the absence of nodal metastases at cystectomy portends a worse oncological outcome {2901(. Positive ureteric and urethral margins are risk factors for disease recurrence in the upper tract and urethra (520(. Finally, hospital and surgeon volume are both recog­ nized as determinants of patient outcome after cystectomy {449). Recently, there has been increasing recognition of the role that inflammation and the host immune response play in determining patient prognosis in multiple cancers. In invasive urothelial carcinoma, the inflammatory milieu is made up of T cells, myeloid-derived suppressor cells, tumour-associated macrophages, cytokines, and various chemokines (2307). The role inflammation plays may vary during carcinogenesis, from an early tumour promoter to later representing the host immune response as a mechanism of tumour containment {723}. The presence of increased tumour immune cells in TURBT speci­ mens has been associated with better outcome after intravesi­ cal therapy (1604}, as well as after cystectomy )1369(. Multiple clinical trials demonstrated improved progression-free and overall survival with immune checkpoint inhibitors in patients with tumours with high PDL1 expression, leading to the imple­ mentation of PDL1 as a predictive biomarker. Multiple immune checkpoint inhibitor agents are available, each with a match­ ing PDL1 antibody, platform, and scoring algorithm. Many

studies have looked at concordance across these antibodies to harmonize assays (1368,3192,2640). The assessment of immune components and novel immuno-oncology biomarkers is an active and very promising area of research. Molecular features The recently published consensus molecular classification of muscle-invasive bladder cancer {1576) encompasses data from six independent muscle-invasive classification systems and has identified six molecular clusters with different prog­ nostic outcomes: luminal-papillary (identified in 24% of cases

of muscle-invasive bladder cancer), luminal non-specified (8%), luminal-unstable (15%,) stroma-rich (15%), basal-squamous (35%), and neuroendocrine-like (3%). The neuroendocrinelike, basal-squamous, and luminal-unstable subtypes were associated with worse overall survival. Furthermore, these clus­ ters were enriched with certain histological features, immune microenvironments, and gene signatures. TP53 mutations were frequent in the neuroendocrine-like (100%), basal-squamous (61%), and luminal-unstable (76%) groups. FGFR3 mutations were most notable in the luminal-papillary subtype (33%). Overall, the luminal-unstable group had the most genomic alterations. The identification of APOBEC-mediated mutation signatures, neoantigen burdens, and mutation burden in the TCGA analysis {2686} also demonstrated an association with prognosis such that APOBEC3 signatures, increased mutation burden, and neoantigen load correlated with improved 5-year survival. In addition to prognosis, the role of molecular subtypes as predictors of therapeutic response is under active investiga­ tion {1576,2686}. Attempts to improve upon the prognostic power and repro­ ducibility of the current histology-based grading by incorporat­ ing molecular markers (e.g. Ki-67 [M 1] and FGFR3 status) have been made by some authors, but the methods have not been widely adopted in routine clinical use {3300,3301). A plethora of novel prognostic and predictive biomarkers are rapidly emerging. They include long ncRNAs, microRNA, epi­ genetic changes, DNA damage repair defects (2125,3556), proteomic signatures {1656), and a variety of tumour immune microenvironment markers {2125,3284}. Many of these mark­ ers are also being investigated in blood and urine samples (liquid biopsy) assessing circulating proteins, RNA, and cellfree DNA in patients with bladder cancer. These hold great promise, particularly in the metastatic setting, allowing the identification of mutations that may be amenable to targeted therapy (39,3305,2317}.

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Squamous papilloma of the urothelial tract

Gordetsky JB Hansel DE Menon S

Definition Squamous papilloma of the urothelial tract is a benign neoplasm arising from the urothelial mucosa, showing a papillary growth covered by keratinizing squamous neoplasm.

ICD-0 coding 8052/0 Squamous papilloma

ICD-11 coding 2F35 & XH50T2 Benign neoplasm of urinary organs & Squa­ mous cell papilloma, NOS

Related terminology None

Subtype(s) None

Localization Squamous papillomas are localized in the bladder and urethra.

Clinical features Squamous papillomas generally occur in elderly people. Patients may be asymptomatic or present with gross haematu­ ria, urinary frequency, urgency, or dysuria {2167}.

Fig. 3.41 Squamous papilloma. A pedunculated squamous papilloma with a fibrovas-

cular core covered by keratinizing epithelium.

squamous epithelium. The neoplastic cells are positive for p63 and negative for CK7 and CK20. Ki-67 expression is limited to the basal cells, and p53 shows wildtype expression {2167,614}.

Cytology

Epidemiology

Not relevant

Insufficient data

Diagnostic molecular pathology

Etiology Squamous papillomas occur in patients of various ages (range: 27-84 years; median: 62 years) The M:F ratio is 3:2 {614,1225}.

Squamous papilloma usually shows a diploid pattern with unde­ tectable or minimal nuclear p53 accumulation. EGFR protein expression has been reported {1225}.

Essential and desirable diagnostic criteria

Pathogenesis The pathogenesis of squamous papilloma is unknown. It is not related to HPV infection {614}.

Essential: a papillary growth with fibrovascular cores lined by squamous epithelium; squamous mucosa shows no architec­ tural or cytological atypia. Desirable: negative for HPV infection.

Macroscopic appearance These tumours appear as exophytic, tan-white lesions that arise from the urothelium. On endoscopic examination, they can be clinically suspicious for malignancy {2167}.

Staging Not applicable

Prognosis and prediction Histopathology Squamous papilloma consists of papillary projections con­ taining fibrovascular cores covered by benign, keratinizing

166

Tumours of the urinary tract

These are benign lesions that typically resolve with complete endoscopic resection and have infrequent recurrence {614, 1225(.

Verrucous carcinoma of the bladder

Gordetsky JB Hansel DE Tomlins SA

Definition Verrucous carcinoma is a subtype of exophytic squamous cell carcinoma with multiple filiform projections covered by welldifferentiated squamous epithelium, with an invasive front with a pushing margin.

ICD-0 coding 8051/3 Verrucous carcinoma

ICD-11 coding 2C9Y & XH5PM0 Other specified malignant neoplasms of uri­ nary tract & Verrucous carcinoma, NOS

Related terminology None

Fig. 3.42 Verrucous carcinoma. A well-differentiated verrucous carcinoma with exo­

phytic growth.

Subtype(s) None

Localization Most cases of verrucous carcinoma occur in the bladder (2456, 1394).

Clinical features Patients often present with haematuria, dysuria, urinary fre­ quency, or obstructive symptoms {2456,1857,1378}. Urinary excretion of cellular debris has also been reported {1996}.

Epidemiology Verrucous carcinoma most commonly occurs in areas where schistosomiasis is endemic (1996,2456), although it has also been reported in patients from other areas (614). It is seen more frequently in men, often in the fifth decade of life {2456,1996}.

Etiology Verrucous carcinoma of the bladder is most often seen in the setting of schistosomiasis, with a reported incidence of 5000 cases per 100 000 person-years in endemic areas {927, 2456}. Rare sporadic cases from areas without endemic schis­ tosomiasis have been reported (1857,614).

Pathogenesis Most verrucous carcinoma occurs in patients with schistoso­ miasis (927), although a few cases unrelated to schistosomiasis have also been reported {1225). HPV infection is not associated with carcinogenesis {1225,1857).

Macroscopic appearance Grossly, these tumours appear as exophytic, fungating lesions that are typically solitary.

Fig.3.43 Verrucous carcinoma. Papillary proliferation of squamous epithelium com­ posed of well-differentiated cells with a pushing tumour border.

Histopathology These tumours have the same histological features as those that arise in other areas of the body, including warty gross fea­ tures, large hyperkeratotic papillae, and acanthosis with mini­ mal cytological atypia. They have a broad, pushing, invasive front, with tongue-like downward projections. Mitoses are rare. This is different from the classic small, irregular invasive tumour nests with paradoxical maturation seen in typical squamous cell carcinoma of the bladder {2456,1394}. The diagnosis of verrucous carcinoma requires examination of the entire lesion to rule out the presence of conventional inva­ sive squamous carcinomas.

Tumours of the urinary tract

167

Focal cytoplasmic and membranous positivity for EGFR and TGF-a have been reported (3224), as has increased p53 expression {614).

Staging Staging is based on the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM system. Most cases are categorized as stage I.

Cytology Not available

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: a warty mass on gross examination; histology shows verrucous or papillary growth, minimal nuclear and architec­ tural atypia, and rounded and pushing deep borders.

168

Tumours of the urinary tract

Prognosis and prediction Verrucous carcinoma has classically been considered a clini­ cally indolent tumour. Most cases have been reported to have an excellent clinical prognosis. Rarely, it may be locally aggres­ sive; extravesical extension and transformation to invasive squamous cell carcinoma have been reported {934,1996).

Pure squamous carcinoma of the urothelial tract

Definition Pure squamous carcinoma of the urothelial tract is a malignant neoplasm arising from the urothelium, showing a pure squa­ mous phenotype on histology.

Gordetsky JB Gakis G Hansel DE Menon S Osunkoya AO Tomlins SA

The M:F ratio for squamous carcinoma is lower than that for urothelial carcinoma {1776,1171}. By contrast, a study from Egypt has shown that there is a higher prevalence of Schis­ tosoma infection in male patients with bladder cancer than in female patients with bladder cancer {1776}.

ICD-0 coding 8070/3 Pure squamous carcinoma of the urothelial tract

ICD-11 coding 2C94.1 Squamous cell carcinoma of bladder

Related terminology None

Subtype(s) None

Localization Squamous carcinomas may arise anywhere in the bladder as solitary or multiple lesions (solitary lesions are most common), with a mean tumour size of 38-56 mm (1171,1780). In a study of non-Sc/7/stosoma-associated squamous carcinoma, there was a slight predilection for the trigone and lateral walls [2751(, whereas Schistosoma-associaied squamous carcinoma may favour the involvement of the lateral walls (928).

Clinical features Patients with squamous carcinoma often present with gross haematuria, urinary frequency, urgency, urinary obstruction, or dysuria. Most patients present at an advanced clinical stage, with as many as one quarter of patients showing metastasis at presentation {1780). Although squamous carcinoma has worse clinical outcomes than conventional urothelial carcinoma [2863, 847,2067}, stage-matched analyses have shown no differences in cancer-specific survival (2700,1481,1117).

Epidemiology Pure squamous carcinoma is the second most common histo­ logical type of bladder cancer, but it is rare, making up about 5% of bladder cancers in high-income countries (935}, By con­ trast, squamous carcinoma accounts for an estimated 20.8% of bladder cancers in sub-Saharan Africa, according to a study using microscopically verified cases from cancer registries (2458); it accounts for 33.7% of bladder cancers in Sudan and Egypt {1104,1776), and 17% in Yemen (112). The higher inci­ dence in these regions is due to infection with the Schistosoma parasite, especially S. haematobium, which is endemic in subSaharan Africa, Sudan, Egypt, and Yemen (2778(. In Egypt, infection is seen in 37-48% of the population {1117], although efforts to reduce and treat waterborne infection have resulted in a decreasing contribution of Schistosoma infection to bladder cancer (3579,2778,2777).

Etiology Squamous carcinoma of the bladder in high-income countries arises from processes that contribute to urinary stasis and ongoing chronic inflammation in the bladder. Indwelling cath­ eter use for a duration of > 10 years has been identified as a risk factor for the development of squamous carcinoma of the bladder. Recently, clean intermittent self-catheterization has been suggested as a potential risk factor (833,2017,541,2469). Longstanding bladder stones have also been implicated in the development of bladder squamous carcinoma {2017). Smoking is a significant risk factor {2017,1171}, with one study reporting a relative risk of 6.1 for those who smoke > 40 cigarettes/day (1578}. Recurrent urinary tract infection has been shown to predispose people to bladder squamous carcinoma {2563,1579}. Similarly, patients with a neurogenic bladder are predisposed to squamous carcinoma because of the risk of recurrent urinary tract infection and the use of indwelling cath­ eters {3437}. In endemic regions, schistosomiasis has been reported as the major cause of squamous carcinoma of the bladder (927, 411,935,1117). Three pathogenic species cause disease in humans, namely S. haematobium, S. mansoni, and S. japonicum. The parasites reside in the pelvic and mesenteric venous plexus and the deposition of Schistosoma eggs in the lamina propria and muscularis propria of the urinary bladder evokes a severe inflammatory response and fibrosis, which predisposes patients to squamous carcinoma of the bladder {2230}.

Pathogenesis Chronic inflammation with ongoing mucosal injury is an impor­ tant contributor to carcinogenesis in squamous carcinoma (2017}. The mechanisms by which this occurs may be related to reactive oxygen and nitrogen species generated by inflam­ matory cells, which leads to subsequent DNA damage (2157, 2778}. Although the exact mechanism is unknown, urothelial to squamous metaplasia (with subsequent development of dyspla­ sia) probably precedes the development of invasive carcinoma {2157,672,2230}. However, several precursor lesions have been described as affecting the surface urothelium in the squamous carcinoma setting {1780}. Some chromosomal abnormalities identified in urothelial car­ cinoma have also been documented in squamous carcinoma, including trisomy 7, monosomy 9, and rearrangements of chro­ mosomes 3, 8, 10, 13, and 17 {970}. In addition, deletions on chromosome 9p and loss of the CDKN2A tumour suppressor gene have been identified in squamous carcinoma (1163). A Tumours of the urinary tract

169

Macroscopic appearance Grossly, these tumours can appear as solid, polypoid, nodular, or ulcerative lesions. They are typically bulky, solitary lesions that occupy a large area of the bladder, which is probably related to their presentation at a late stage. Large tumours are often associated with necrosis {935}.

Histopathology

Fig. 3.44 Squamous carcinoma of the bladder. Malignant squamous cell clusters in­ vading the lamina propria of the bladder.

Fig. 3.45 Squamous carcinoma of the bladder. A moderately differentiated tumour associated with Schistosoma infection. Note the Schistosoma egg in the centre.

high frequency of p53 mutations has been reported in squa­ mous carcinoma, with the type and position of mutations distinct from those of urothelial carcinoma {1163,3402). TEFIT promoter mutations have also been shown to be prevalent in squamous carcinoma of the bladder {724}. Frequent losses of chromosomes 17p and 18p have been demonstrated to be more frequent in schistosomiasis-asso­ ciated squamous carcinoma than in conventional squamous carcinoma (2260}. Ib4 signalling may play a critical role in schistosomiasis-associated squamous carcinoma pathogen­ esis (2077). With rare exceptions, most studies have demonstrated that HPV has very little to no contribution to the pathogenesis of squamous carcinoma of the bladder {2857,1171,689}. There is no association between p16 overexpression and the presence of HPV in squamous carcinoma of the bladder, and p16 should not be used as a surrogate marker for HPV in this setting (1171,689).

170

Tumours of the urinary tract

Squamous carcinoma of the bladder has a similar morphol­ ogy to that of squamous cell carcinomas seen elsewhere in the body. Invasive carcinoma nests are rounded to irregular, although more poorly differentiated squamous carcinomas may show cords or single cells. Carcinoma cells vary in their degree of atypia from well-differentiated cells with keratin for­ mation, abundant eosinophilic cytoplasm, and intercellular bridges to poorly differentiated cells with marked atypia and an absence of keratin. Squamous carcinoma of the bladder is graded as "well differentiated", '"moderately differentiated", or "poorly differentiated", based on the degree of differentiation (keratinization) and nuclear pleomorphism {986,1537}, although there is no generally accepted grading system (2751). Several variations in morphology exist that can confound the diagnosis, including a bizarre giant cell formation and clear cell squamous morphology, among others [1780). In the setting of Schisto­ soma infection, eggs are seen in a background of marked chronic inflammation, including foreign body-type giant cells, lymphoplasmacytic infiltrate, and abundant eosinophils (935). Some eggs may be calcified. Schistosoma-assoc\ated squa­ mous carcinoma has been reported to be better differentiated than its non-Sc/i/stosoma-associated counterpart {935(. In situ lesions are often present and can include squamous carcinoma in situ, glandular carcinoma in situ, and urothelial carcinoma in situ. Verrucous squamous hyperplasia, which shows repeti­ tive upward tenting of the urothelium with prominent squamous metaplasia and keratinization, is a known precursor lesion to squamous carcinoma and has been reported in some cases (1225). Rarely, condylomas have been found associated with invasive squamous carcinoma (1780,2796,1225); in this setting, the condylomas are often extensive. Immunohistochemistry is rarely helpful, but positivity for CK5, CK6, CK14, desmocollin-2, desmoglein-3, and MAC387, as well as negativity for GATA3, FOXA1, uroplakin-2, and uroplakin-3 have been described (2686,1313,1415).

Cytology The hallmark is the presence of dysplastic squamous cells showing nuclear enlargement and hyperchromasia along with nuclear membrane irregularity and coarse chromatin. Anucleated squames and necrotic debris are often seen. Because of the squamous differentiation, the N:C ratio can be lower than that in classic urothelial carcinoma. Urine cytology cannot dif­ ferentiate squamous carcinoma from urothelial carcinoma with squamous differentiation {2720|.

Diagnostic molecular pathology The BTA TRAK quantitative bladder tumour antigen test and the detection of TERT promoter mutations are potentially useful non-invasive molecular diagnostic tests for squamous carci­ noma in the urine {2245,724}. Urine proteomic testing has also

been used in the setting of schistosomiasis-associated squa­ mous carcinoma of the bladder (329).

Essential and desirable diagnostic criteria Essential: a lesion exclusively composed of invasive squamous carcinoma characterized by overt keratinization and/or the presence of intercellular bridges; exclusion of metastatic or invasive squamous cell carcinoma from other organs.

Staging Staging is based on the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) sys­ tems.

Prognosis and prediction Squamous carcinoma of the bladder is thought to have a worse prognosis than conventional urothelial carcinoma, perhaps because squamous carcinomas often manifest at a higher clinical stage (27,847,1915,2067,1780(. The standard of care remains radical cystectomy for muscle-invasive cases, with the option of neoadjuvant chemotherapy and possibly neoadjuvant immunotherapy (although this is still debated in the

, ■

literature) (2721,2301,2067,5). Prognostic indicators include TNM stage, age at diagnosis, surgical approach, tumour size, lymphovascular invasion, perineural invasion, and margin sta-

I

tus {5,3599).

Tumours of the urinary tract

171

、

Villous adenoma

Osunkoya AO Gaisa NT McKenney JK

Definition Villous adenoma is a rare benign neoplasm that is morphologi­ cally indistinguishable from its colonic counterpart.

ICD-0 coding 8261/0 Villous adenoma 8211/0 Tubular adenoma 8263/0 Tubulovillous adenoma

ICD-11 coding 2F35 & XH90D6 Benign neoplasm of urinary organs & Villous adenoma, NOS

Related terminology Acceptable: villous tumour.

Subtype(s)

Fig. 3.46 Villous adenoma of the bladder. Villous adenoma is characterized by elon­ gated villous structures lined by epithelium with focal intestinal metaplasia, nuclear pleomorphism, and hyperchromasia. Tubular areas are also present focally.

Villous adenoma; tubular adenoma; tubulovillous adenoma

Localization The bladder and urachus are the most common sites for vil­ lous adenoma, but it may also occur throughout the urinary tract (2869,3075).

Clinical features Patients present with haematuria and/or irritative symptoms {617}. Mucusuria is rare (913(.

cases have prototypical low-grade dysplasia, but associated high-grade dysplasia, carcinoma in situ, and invasive adeno­ carcinoma may occur (this last feature is found in as many as 35% of cases) {617,2869,144}, Hence, a careful examination of the whole lesion is required before making the diagnosis. The adjacent urothelial mucosa often shows cystitis glandularis and intestinal or squamous metaplasia. Immunohistochemically, an enteric phenotype is common, with frequent reactivity for both CK20 and CDX2. GATA3, PSA, and PAP are typically negative, but P501S and PSMA may be expressed {1795}.

Epidemiology Tumours occur in adults with a mean age of 62 years (range: 23-94 years), and there is a slight male predominance (617, 2869}.

Cytology In urine cytology specimens, villous adenoma is composed of glandular cells and columnar mucin-filled goblet cells arranged along the basement membrane (1470).

Etiology The etiology is unknown; however, there is an association with intestinal metaplasia in a subset of cases, and augmentation cystoplasty may be a risk factor {617,2869,836}.

Diagnostic molecular pathology Mutations associated with APC, PRKDC, ROS1, ATM, and KMT2D have been described in a subset of cases of villous adenoma and intestinal metaplasia of the bladder and urachus {2537}.

Pathogenesis Although not extensively studied, mutations in APC, PRKDC, ROS1, ATM, and KMT2D have been described (2537).

Macroscopic appearance Cystoscopically, these tumours have an exophytic papillary appearance indistinguishable from that of papillary urothelial neoplasia {617}.

Essential and desirable diagnostic criteria Essential: classic histopathological features (described above) and no focus of invasion should be identified in a pure villous adenoma; the whole lesion must be examined before making the diagnosis.

Staging Not applicable

Histopathology Histologically, villous adenoma is identical to its colorectal counterpart. They commonly have villoglandular fronds lined by a pseudostratified columnar epithelial layer. However, a tubular architecture has also been described {617,2869,1582}. Most 172

Tumours of the urinary tract

Prognosis and prediction Prognosis is excellent for pure villous adenoma after complete excision. However, a subset of cases are precursor lesions that subsequently progress to adenocarcinoma (617,2869,2093).

Guo CC Aron M Lopez-Beltran A Paner GP ReisH

Adenocarcinoma NOS

Definition Adenocarcinoma not otherwise specified (NOS) arising from the urothelium is a malignant neoplasm showing a pure glandu­ lar phenotype on histology.

ICD-0 coding 8140/3 Adenocarcinoma, NOS 8144/3 Enteric adenocarcinoma 8480/3 Mucinous adenocarcinoma 8323/3 Mixed adenocarcinoma 8490/3 Signet-ring cell adenocarcinoma 8140/2 Adenocarcinoma in situ

ICD-11 coding 2C94.0 Adenocarcinoma of bladder 2C93.0 Adenocarcinoma of urethra or paraurethral gland 2C95.0 Adenocarcinoma involving overlapping sites of urinary organs

Related terminology Not recommended: columnar carcinoma; mucin-producing urothelial-type adenocarcinoma.

Subtype ⑥ Enteric adenocarcinoma; mucinous adenocarcinoma; mixed adenocarcinoma; signet-ring cell adenocarcinoma; adenocar­ cinoma in situ

Localization The tumours usually arise anywhere in the urinary organs, blad­ der, renal pelvis, ureter, or urethra (1193,2741,2273,3085,1292).

Fig.3.47 Adenocarcinoma in situ of the urinary bladder. Enteric-type malignant

glands growing on the bladder mucosal surface.

Etiology The etiology is largely unknown. Common risk factors include bladder exstrophy, augmentation, chronic irritation, urinary obstruction, and non-functional bladder {3576}. The risk of ade­ nocarcinoma is high in patients with bladder exstrophy, ranging from 4.1% to 7.1% {2088,300}. Infection with Schistosoma hae­ matobium is the most important risk factor for bladder adeno­ carcinoma in areas with endemic schistosomiasis (also known as bilharzia), although adenocarcinoma is less common than squamous cell carcinoma in these areas {238}. Pelvic lipomato­ sis is also considered a risk factor for bladder adenocarcinoma (1172). Potential etiological factors of urethral adenocarcinoma include chronic inflammation due to stricture, diverticula, and infections. An association with chronic exposure to arsenic has also been reported (3213,3148,2349).

Clinical features Haematuria occurs in approximately 90% of patients {1193). Irri­ tative bladder symptoms, such as dysuria, nocturia, frequency, and pain, are seen in some patients (1193,758). Mucusuria may occur, but it is uncommon. In advanced urethral cases, acute urinary retention may appear {1292,2121).

Epidemiology Adenocarcinoma is uncommon in the urinary tract, account­ ing for 0.5-2% of all malignant bladder tumours {1193,2741, 1975} and 0.7% of those of the upper urinary tract (848} in high-income countries. Because of its rarity, the incidence of adenocarcinoma of the urethra is not clear. It is more common in countries with endemic schistosomiasis, where nearly 10% of all bladder cancers are adenocarcinomas (1117). It affects adults, with peak incidence in the seventh decade of life. Adenocarci­ noma of the urinary tract has a male predominance (M:F ratio: 〜2-3:1) (1193,2741,848,2273).

Pathogenesis It has been postulated that bladder and upper urinary tract adenocarcinoma may result from malignant transformation of intestinal metaplasia in the urothelial mucosa (2903,3509, 3631,3187,1292}. Recent studies demonstrate that intestinal metaplasia can harbour potentially oncogenic genetic vari­ ants, suggesting that it might represent a cancer precursor or a marker of increased cancer risk in a subset of cases {19,2069}. However, this theory is disputed (2971,712). A long-term follow­ up study of patients with intestinal metaplasia did not show the development of bladder adenocarcinoma (712}. Nonetheless, a subset of cases of intestinal metaplasia with high-grade dys­ plasia are frequently associated with invasive adenocarcinoma, warranting clinical follow-up {1170}. Some experts think that bladder adenocarcinoma may also arise through the divergent differentiation of urothelial carcinoma. Glandular differentia­ tion is frequently seen (in as many as 18% of bladder urothe­ lial carcinomas) (3408}, and adenocarcinoma may represent a complete divergent differentiation from urothelial carcinoma to Tumours of the urinary tract

173

Fig. 3.48 Adenocarcinoma of the urethra. A Adenocarcinoma of the prostatic urethra. Tumour glands (upper part of image) and benign prostate glands (lower part of im­ age). B The tumour is composed of atypical glandular structures with nuclear pleomorphism and loss of nuclear polarity.

pure adenocarcinoma. EGFR amplification was identified in a comprehensive genomic analysis of a urethral adenocarcinoma from one patient; this was supported by immunohistochemistry showing EGFR protein overexpression in this case and in six additional cases (457|.

Fig. 3.49 Primary adenocarcinoma of the urinary bladder NOS. Note the atypical glandular proliferation with high-grade nuclear atypia.

Bladder adenocarcinomas and urothelial carcinomas demon­ strate distinct molecular alterations. A number of cancer genes, including TP53, KRAS, PIK3CA, CTNNB1, APC, TERT, FBXW7, IDH2, and RB1, are mutated in bladder adenocarcinoma {2740}. Other frequently mutated genes include ARID1A, BRAF, PTEN, and SMAD4 (2069). The most frequently mutated genes are TP53 in the enteric subtype and KRAS in the mucinous sub­ type (2537(. Interestingly, the genetic alterations in bladder adenocarcinoma overlap substantially with those in colorectal adenocarcinoma. KRAS mutations are present in a small subset (11.5%) of bladder adenocarcinomas, whereas they are absent in urothelial carcinoma with glandular differentiation (74}. Muta­ tions in the TERT promoter are seen in 17-28.5% of bladder adenocarcinomas {725,2069}, but the frequency is significantly lower than that in urothelial carcinomas (60-80%) (96,3494). Unlike lung adenocarcinoma, bladder adenocarcinoma lacks EGFR mutations and ALK rearrangements (75(. Bladder adenocarcinoma has a significantly lower level of total mutation burden than bladder urothelial carcinoma and squamous cell carcinoma (2300(. It usually shows intact expression of DNA mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6) and lacks the expression of PDL1 (2069, 1540). Expression of cell proliferation markers, such as Ki-67 and PCNA, may be associated with local recurrence and dis­ tant metastasis [2411}. There are few molecular data on upper urinary tract and ure­ thral adenocarcinomas because of their rarity.

Macroscopic appearance Grossly, the tumours often appear as single, sessile, nodular tumours that cannot be reliably distinguished from urothelial carcinomas. The mucosal surface may become ulcerated, and cut surfaces sometimes display a gelatinous appearance because of abundant mucin {758,1292,755}.

Histopathology Fig. 3.50 Primary adenocarcinoma of the urinary bladder, signet-ring cell subtype. The tumour is characterized by infiltrative tumour cells with a large intracellular mucin vacuole and an indented nucleus.

174

Tumours of the urinary tract

Adenocarcinoma of the urinary tract shows several distinct histological subtypes, including enteric (or colonic), mucinous (or colloid), signet-ring cell, and NOS, as well as mixed (1193,

848,2402,2121). The enteric subtype is composed of intestinaltype glands with pseudostratified columnar cells and nuclear atypia, resembling colorectal adenocarcinoma. Villoglandular structures and epithelium-lined microcysts filled with mucin are also seen. It may produce a variable amount of intracellular or extracellular mucin, and necrosis is common. The mucinous subtype produces abundant extracellular mucin, frequently dis­ secting the stroma and resulting in single or small clusters of tumour cells floating in mucin pools. Extracellular mucin usu­ ally constitutes > 50% of the tumour volume. The signet-ring cell subtype is characterized by diffusely infiltrative tumour cells with a prominent intracellular mucin vacuole that displaces the nucleus to the periphery. It may produce linitis plastica of the bladder (2557,1194). Adenocarcinoma NOS shows a nondescriptive glandular growth pattern. Tumours with more than one growth pattern are classified as the mixed subtype. Occa­ sionally, hepatoid morphology can be detected {2943,1941). Grading for adenocarcinoma of the urinary tract is usually based on the degree of differentiation and cytological features including nuclear pleomorphism, categorized as well differenti­ ated, moderately differentiated, or poorly differentiated {3467}, although there is no generally accepted grading system for uri­ nary tract adenocarcinoma. Adenocarcinoma in situ may be found in the urinary tract mucosa alone or in combination with invasive adenocarci­ noma (564,2171,3538,3219}. The superficial lesion may show papillary, glandular, cribriform, or flat patterns. Nuclear atypia is prominent, and mitoses are frequent. These mixed lesions

are interpreted as urothelial carcinoma with glandular differen­ tiation. Adenocarcinoma in situ shows a close association with specific histological patterns of urothelial carcinoma, including small cell carcinoma and micropapillary patterns {3538(. The immunohistochemical profile of adenocarcinoma of the urinary tract resembles that of colonic adenocarcinoma (2620, 2626,3631,1292,2402}. Adenocarcinoma of the urinary tract is usually positive for CK20, villin, and CDX2. It also shows invari­ able positivity for CK7. GATA3 positivity can be seen in some cases, especially those with signet-ring cell features (931,435, 3631,1292,2402}. Nuclear expression of p-catenin in bladder primary adenocarcinoma is less frequent than that in metastatic adenocarcinoma from the coIorectum )3376,435,2069}.

Differential diagnosis Metastatic adenocarcinomas from adjacent organs (e.g. pros­ tate, coIorectum, and gynaecological tract) must be ruled out, because they are more common than primary adenocarcino­ mas in the urinary tract (290,758,988,1273).

Cytology Urine cytology can detect bladder adenocarcinoma (271(. Malignant cells will display glandular differentiation, and they can be single or form small three-dimensional cell clusters. Cells will often have prominent nucleoli and vacuolated cyto­ plasm. Because urothelial carcinomas can have glandular dif­ ferentiation, it may be impossible to be certain of the tumour origin from cytology.

Fig. 3.51 Adenocarcinoma NOS. A-C Mucinous (columnar) carcinoma of the urethra. A A superficial glandular lesion is visible and mucin lakes dissect the stroma. B Note the tumour cell clusters floating in mucinous lakes. C Note the signet-ring cell-like morphology. D Primary adenocarcinoma of the urinary bladder, mucinous subtype. Note the tumour cells floating in a pool of extracellular mucin.

Tumours of the urinary tract

175

Fig. 3.52 Mucinous (columnar) carcinoma of the urethra. A,B Signet-ring cell-like morphology is present.

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: a malignant tumour arising from the urothelial epithe­ lium showing an exclusively glandular phenotype. Desirable: no urothelial carcinoma or urothelial carcinoma in situ in the tumour; transition to urethral surface glandular changes such as urethritis cystica et glandularis, adenoma, or adeno­ carcinoma in situ; exclusion of adenocarcinoma spreading from adjacent organs such as the prostate, colorectum, and gynaecological tract; special staining for cytoplasmic mucins (e.g. using PAS, Alcian blue, etc.).

Staging Cancer stage according to the TNM staging system is the most important prognostic factor for bladder adenocarcinoma (2290,3537). Most patients with adenocarcinoma present at an advanced stage with muscle-invasive disease and beyond (pT2 or T3).

Prognosis and prediction Bladder and upper urinary tract adenocarcinoma is usu­ ally treated with radical cystectomy or nephroureterectomy

176

Tumours of the urinary tract

followed by chemotherapy or radiotherapy according to the extent of disease {779,2273,848}. The overall prognosis for pri­ mary adenocarcinoma is poor because of advanced stage at diagnosis. Disease-specific survival rates at 2, 5, and 10 years for bladder adenocarcinoma are 62%, 47%, and 40%, respec­ tively {2290}. The disease-specific survival rate at 6 years for bladder adenocarcinoma is 40% {848}. Overall survival rates at 3 and 5 years for upper urinary tract adenocarcinoma are 30% and 24% )2273}. In multivariate analyses, independent prog­ nostic factors include sex, cancer stage, tumour location, and histological subtype (2290,2047,2273,848). Female patients have a significantly better outcome than male patients, and urachal adenocarcinoma confers a survival advantage over non-urachal locations. Signet cell carcinoma is associated with the worst survival outcome among the histological subtypes (2290,1527). Almost 60% of patients with urethral adenocarcinoma present with advanced stage IV disease. The location of the tumour within the urethra is also an important prognostic factor; distal (anterior) urethral adenocarcinoma has a better prognosis than proximal (posterior) urethral adenocarcinoma (67% and 21% survival at 5 years, respectively). Metastases may involve ingui­ nal nodes when present. An overall survival of < 30% at 5 years has been reported (1292,2121,2273).

ReisH Cunha IW Gopalan A Paner GP

Urachal carcinoma

Definition

Epidemiology

Urachal carcinoma is a malignant epithelial tumour that arises from urachal remnants. It is a diagnosis of exclusion.

Urachal carcinoma is rare, with an estimated incidence of < 1 case per 1 million person-years. It usually occurs in the fifth or sixth decade of life but with a wide age range, and the M:F ratio is {2534,450,3092,1252,2274,687). Most ura­ chal carcinomas are non-cystic adenocarcinomas and fewer are cystic tumours {135,2437}. Rarer non-glandular carcinoma types include urothelial, squamous, and neuroendocrine carci­ nomas (NECs) {2435,2639}.

ICD-0 coding 8010/3 Urachal carcinoma

ICD-11 coding 2C9Y & XH74S1 Other specified malignant neoplasms of uri­ nary tract & Adenocarcinoma, NOS 2C9Y & XH8EH1 Other specified malignant neoplasms of uri­ nary tract & Transitional cell carcinoma, NOS 2C9Y & XH0945 Other specified malignant neoplasms of uri­ nary tract & Squamous cell carcinoma, NOS

Related terminology None

Subtype(s) See Box 3.01.

Localization Urachal carcinoma most commonly arises from the bladder dome, and rarely from the anterior wall along the midline or superiorly to the umbilicus (1169).

Clinical features

Fig. 3.53 Urachal carcinoma. CT showing a calcified mucinous urachal adenocarci­

noma (arrow) growing into the urinary bladder.

There are no specific early symptoms. Haematuria is the most common symptom, followed by abdominal pain, dysuria, and mucusuria. Nonspecific urinary tract symptoms can occur. CT often shows calcifications, especially in mucinous urachal can­ cer (3092}.

Box 3.01 Malignant epithelial neoplasms of the urachus Adenocarcinoma Non-cystic

Enteric (intestinal) Mucinous (colloid)

Signet-ring cell NOS

Mixed Cystic

Mucinous cystic tumour of low malignant potential Mucinous cystadenocarcinoma

Urothelial carcinoma Squamous cell carcinoma Neuroendocrine carcinoma (NEC)

Mixed carcinoma

Fig. 3.54 Urachal carcinoma. A Resection specimen of a mucinous urachal adeno­ carcinoma with partial cystectomy of the bladder dome (arrow), tumour (asterisk), me­ dian umbilical ligament (+) and umbilicus (>). B Cut surface of a mucinous urachal adenocarcinoma (asterisk) with ulceration of the bladder dome (arrow) and sharp/cystic demarcation as well as calcifications.

Tumours of the urinary tract

177

Fig. 3.55 Urachal carcinoma. Urachal adenocarcinoma NOS showing an indistinct malignant glandular architecture.

Etiology Urachal carcinoma arises from urachal remnants (2905).

Pathogenesis Although the predisposing factors are unclear, the transitional epithelium lining the urachal remnant can undergo glandular metaplasia, which might predispose to adenocarcinoma (309, 3234,2853(. Urothelial carcinomas may be associated with similar risks to those of their bladder counterparts because of the communication of the urachal remnants with the bladder surface {1277,2435}. No familial clustering has been described.

Macroscopic appearance Non-cystic adenocarcinomas are usually firm white or grey infil­ trative tumours. Cystadenocarcinomas show cystic lumina that frequently contain abundant mucin. The non-glandular carcino­ mas may show cystic, cavitary, or solid infiltrative growth (135, 2435}.

Histopathology Enteric non-cystic adenocarcinoma is morphologically indis­ tinguishable from colorectal adenocarcinoma, with glandular and cribriform architecture, nuclear pseudostratification, and necrosis. The mucinous subtype shows a predominance of

Fig. 3.56 Urachal carcinoma. Intestinal-type urachal adenocarcinoma showing glan­ dular architecture, pseudostratified malignant epithelia, and cellular debris.

extracellular mucin pools. It may have copious mucin (colloid type) dissecting the stroma and occasionally may show single or small clusters of signet-ring cells floating in the mucin pools. The signet-ring cell subtype is reserved for tumours with sig­ net-ring cells exhibiting permeative stromal growth that can be extensive. Non-cystic adenocarcinomas not readily classifiable as enteric or mucinous/signet-ring cell subtype are categorized as NOS. An admixture of different morphologies may occur (mixed subtype) (2437,855,1169(. Cystadenocarcinoma forms a histological spectrum with benign mucinous cystadenoma, the latter lined by a single layer of mucinous columnar epithelium lacking atypia (135, 2437}. Mucinous cystic tumour of low malignant potential shows areas of mild epithelial proliferation, including flat, tufted, pseudopapillary, villous, or tubulovillous patterns; mild to moderate atypia; and rare mitoses. Intraepithelial carci­ noma may arise from mucinous cystic tumour of low malignant potential and is characterized by marked epithelial stratifica­ tion and unequivocal malignant cytological features. Mucinous cystadenocarcinoma can be microinvasive (the stromal inva­ sion component being < 2 mm and < 5% of the tumour) or frankly invasive. The different non-glandular carcinomas show a morphology similar to that of their bladder counterparts {2435}. Urothelial carcinoma may also show intraluminal papillary architectures

Fig. 3.57 Urachal carcinoma. A Mucinous urachal adenocarcinoma showing abundant extracellular mucin, a malignant mucinous epithelial lining, and some free-floating tu­ mour cell formations. B Signet-ring cell subtype of urachal adenocarcinoma.

178

Tumours of the urinary tract

"Urothelial"

“Colorectal"

・ Missense ■ Truncating

■ Inframe

I Amplification

Enteric

. Promoter | Deletion

I

| j Mucinous

Mix

Fig. 3.58 Urachal carcinoma. Genomic alterations in bladder tumours with the glandular phenotype. BAC, bladder adenocarcinoma; UCg, urothelial carcinoma with glandular differentiation; UAC, urachal adenocarcinoma; *Only hotspots analysed {2069(.

and divergent histology. NECs may exhibit small cell carcinoma or large cell carcinoma morphologies {3369}. Residual benign urachal remnants can be seen intermingled with the carcinoma and may harbour early non-invasive lesions in urothelial carci­ noma {2435,1277}. Non-cystic adenocarcinomas are usually positive for CDX2 and CK20; 50% are positive for CK7; and nuclear p-catenin staining, positivity for AMACR (P504S), and PTEN loss are rare events. CD15 and CEA are usually positive, whereas GATA3 is not expressed {2439,2639,2277}.

Cytology Urine cytology has limited diagnostic value for urachal adeno­ carcinoma (3092).

Diagnostic molecular pathology Although not routinely used for diagnosis, molecular profiling might aid in the differential diagnostic process. Non-cystic urachal adenocarcinoma shows a distinct molecular phenotype that lies between the profiles of urothe­ lial bladder cancer and colorectal adenocarcinoma, with more

Table3.04 Diagnostic criteria for urachal carcinoma Non-cystic urachal adenocarcinoma8

1. Tumour in the dome or elsewhere in the midline of the bladder

Non-glandular urachal carcinomab

1. Tumour in the bladder dome or anterior wall and/or midline supravesical to the umbilicus

2. Sharp demarcation between tumour and surface urothelium

2. Tumour epicentre away from the bladder surface

3. Tumour epicentre in the muscularis propria or perivesical soft tissues with intact/ ulcerated overlying urothelium; surface colonization may be present

the genitourinary tract

4. Absence of extensive cystitis cystica et glandularis (particularly with any dysplasia) in the bladder 5. Absence of urothelial carcinoma in situ elsewhere in the bladder

6. Absence of a primary adenocarcinoma in another organ

3. No primary tumour of similar morphology elsewhere, except urothelial carcinoma in

4. Close relationship with urachal remnant structures 5. If no urachal remnant structure is identifiable, the tumour does not involve the

intact bladder surface

6. If no urachal remnant structure is identifiable and the tumour involves the bladder surface: for urothelial carcinoma only, cavitary or cystic tumour with intraluminal papillary structures; for all non-glandular urachal carcinomas, presence of reverse

invasive front 'Modified from {3444,1536,1169,855,2437}. 'Diagnosis requires criteria 1-3 and any one of criteria 4-6 {2435}.

Tumours of the urinary tract

179

similarities to the latter (2641,2069}. Urachal adenocarcinomas are enriched in TP53 mutations and often show activation of the MAPK and PI3K pathways, with pathogenic alterations mostly in RAS (KRAS > NRAS), and fewer in PIK3CA, BRAF, and NF1 (1828,715,1283,2194,684,2945}. Modest TGF-p and WNT path­ way activation is present in all three tumour types with low to moderate alteration frequencies in SMAD4, CTNNB1 (encod­ ing p-catenin), and APC, this last gene being more commonly mutated in colorectal adenocarcinomas {715,2277|. Micro­ satellite instability, DNA mismatch repair deficiency, and POLE mutations are less frequent in urachal adenocarcinomas and associated with a higher tumour mutation burden {2642,1602, 2639,2949,2069}, which tends to be low in the other two tumour types {2945}. TEFIT promoter mutations are very rare in urachal adenocarcinomas (3146,2069(. Alterations in the chromatin remodelling genes and in FGFR3, PTEN, and RB1 are present but rare in all three tumour types, whereas the copy-number alteration profiles differ {2069). Very limited molecular data are available for non-glandular urachal carcinomas {2642).

Essential and desirable diagnostic criteria Essential: a carcinoma arising from urachal remnants. Desirable: a carcinoma located in the bladder dome or ante­ rior wall, and/or in the midline supravesical to the umbilicus; a sharp demarcation between the carcinoma and surface urothelium, or a carcinoma epicentre away from the bladder surface; possibility of metastasis from other sites ruled out. See also Table 3.04 (p. 179).

Staging The most widely used system is the Sheldon system from 1984 (see Box 3.02). Other proposed systems are the simplified Mayo system and the Ontario system. Use of the TNM system for bladder cancer has been adopted by some, but it is not pri­ marily designed for tumours with epicentres outside the urinary bladder {2905,213,2534,855}.

180

Tumours of the urinary tract

Box 3.02 The Sheldon staging system (1984) (2905}

I

Carcinoma confined to the urachal mucosa

II

Carcinoma confined to the urachus

III

Local carcinoma extension

IIIA

Into the bladder

IIIB

Into the abdominal wall

IIIC

Into the peritoneum

HID

Into other viscera

IV

Metastasis

IVA

To lymph nodes

IVB

To distant sites

Prognosis and prediction Metastases are common and mostly detected in the bones, lungs, liver, (non-regional) lymph nodes, and peritoneum. Mul­ tisite metastatic disease and local recurrence are common {213,855,2534}. The mean 5-year survival rate is approximately 50%, better than that of stage-matched adenocarcinomas or urothelial carcinomas of the urinary bladder (769,3488,2534). Independent parameters of adverse prognosis are Sheldon tumour stage > IIIB, Mayo stage > II, tumour-positive surgical margins, and the presence of lymph node metastases or distant metastases {450,855,1655,213}. Cystic urachal adenocarcinomas have a more favourable prognosis and are more commonly detected as a tumorous mass with a higher risk of pseudomyxoma peritonei (135). No routinely used predictive molecular markers are presently available. In advanced disease, chemotherapy based on regi­ mens from colorectal adenocarcinomas seems to be advanta­ geous (3092,1270,2931). Rare targeted treatment approaches have been reported {684,1602,1921).

Diverticular carcinoma

ReisH Cunha IW Gopalan A Paner GP

Definition Diverticular carcinoma is a carcinoma that is located in a diver­ ticulum in the urinary tract.

ICD-0 coding 8120/3 Invasive urothelial carcinoma (code to site)

ICD-11 coding GC01.2 & XH74S1 Diverticulum of bladder & Adenocarcinoma, NOS GC01.2 & XH8EH1 Diverticulum of bladder & Transitional cell carcinoma, NOS GC01.2 & XH0945 Diverticulum of bladder & Squamous cell carcinoma, NOS

Related terminology

Fig. 3.59 Diverticular carcinoma. A A urinary bladder diverticulum with carcino­ ma. B Cross-sections of urinary bladder diverticulum with carcinoma with perivesical fat involvement.

Not recommended: intradiverticular carcinoma.

Subtype ⑥ None

Localization Most types and subtypes of carcinomas of the urinary tract can occur in diverticula (3361). Common locations are the lateral urinary bladder walls close to the ureteric orifices and the dome {3361,1446,1709}.

Clinical features Clinical features are similar to those of non-diverticular carcino­ mas in the urinary tract. Cystoscopy, urine cytology, ultrasonog­ raphy, and cross-sectional imaging studies often establish the diagnosis. A narrow or concealed diverticular orifice might limit the sensitivity of cystoscopy (3361).

Epidemiology Diverticular carcinomas are rare, estimated to account for < 1% (range: 0.8-10.8%) of urinary bladder tumours {3361,2122,260, 774,2158}. Most patients present in the sixth decade of life and most cases occur in men (3361(.

Etiology Risk factors for diverticular carcinomas are similar to those of other carcinomas in the urinary tract. The presence of a urinary bladder diverticulum indicates a higher risk of subsequent blad­ der cancer development (3105,469,978,3361). When diverticu­ lar and bladder tumours are present simultaneously, tumours are more commonly found within the diverticulum {1446,260}.

Pathogenesis Urinary bladder cancer risk may be increased through uri­ nary stasis in diverticula, prolonging the effect of carcinogens and potentially leading to increased inflammation, recurrent

Fig. 3.60 Diverticular carcinoma. A Urothelial tumour with glandular differentiation in the diverticulum without detrusor muscle invasion (+) and in the neighbouring bladder with detrusor muscle invasion (asterisk). B Urothelial tumour with glandular differen­ tiation in the diverticulum, with a hypertrophic muscularis mucosae layer (asterisk) directly under the diverticular urothelium.

Tumours of the urinary tract

181

infections, calculi, and metaplastic and dysplastic changes {2065,3623,3361,858,1709,1446,3105}, No specific molecular pathology has been described.

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Diverticular carcinomas can be single or multiple. Tumour size varies, and they can weigh as much as 14 kg {3361,2109}.

Essential: a carcinoma arising from or mainly located in a diver­ ticulum; morphological criteria of non-diverticular carcinomas of the urinary tract also apply for diverticular carcinomas.

Histopathology

Staging

The histopathology of diverticular carcinomas resembles that of other carcinomas in the urinary tract. The most common type is urothelial carcinoma. Other tumour types seem to be more frequent in diverticula than in the main urinary bladder {3105, 2920,3616,1446,1709). Diverticula do not have a detrusor mus­ cle layer, but they often have a hypertrophic layer of muscularis mucosae |3616}.

The TNM system is used for diverticular carcinomas. How­ ever, as diverticula lack detrusor muscle, pT2 stage cannot be assigned. Upstaging from a transurethral resection specimen to radical cystectomy is common {1446).

Macroscopic appearance

Cytology Urine cytology is useful in diagnosis and follow-up, mostly in high-grade disease. A narrow diverticular orifice might limit cytological test sensitivity (3361).

182

Tumours of the urinary tract

Prognosis and prediction The prognostic significance of tumour stages for diverticular carcinomas compared with those for cancers of the main blad­ der are under debate (1155,2314).

Littre gland adenocarcinoma of the urethra

Hes 0 Brimo F Cheng L Raspollini MR

co I d fflq

岳

Etiology

Littrd gland adenocarcinoma is a tumour originating in the periurethral glands of the penile urethra.

Unknown

ICD-0 coding

。

。

Definition

Pathogenesis Unknown

8140/3 Carcinoma of Littr glands

ICD-11 coding 2C93.0 & XH22Z8 Adenocarcinoma of urethra or paraurethral gland & Carcinoma of Skene, Cowper, and LittrQ glands

Related terminology

Macroscopic appearance Various macroscopic appearances have been described, rang­ ing from flattened urethral mucosa to friable haemorrhagic tumorous masses in the urethra to deep ulceration on the sur­ face of the shaft of the penis with firm induration of the surround­ ing soft tissues (878,2761,2624).

Not recommended: urethral accessory gland adenocarcinoma.

Histopathology

Subtype ⑥ None

Localization Tumours are localized in the penile urethra {878,2761,2624}.

Adenocarcinoma with papillary or tubulopapillary architecture. Cells are columnar with voluminous cytoplasm and mucinous vacuoles. Nuclei are large and oval without marked pleomor­ phism. Information about the immunohistochemical profile is very limited. Neoplastic cells are positive for CK7 and negative for PSA (878,2761,2624(.

Clinical features The main clinical symptoms are bloody or mucous urethral discharge, haematospermia, haematuria, and a palpable mass. Tumours of the Littrd glands of the distal urethra causing mucous secretion may be detected early (878,2761,2624).

Cytology

Epidemiology

Diagnostic molecular pathology

Extremely rare tumours have been documented in the literature, with a broad patient age range (30-66 years) {878,2761,2624).

Not relevant

Urethral secretions have shown cells with fine chromatin and dense cytoplasm with secretory granules containing mucin {2624).

Fig. 3.61 Littre gland adenocarcinoma. A High-power view showing carcinoma (right) and normal Littre gland (left). B Adenocarcinoma with tubulopapillary architecture, with atypical glands composed of columnar mucinous cells.

Tumours of the urinary tract

183

Essential and desirable diagnostic criteria

Staging

Essential: the diagnosis of Littre gland adenocarcinoma is one of exclusion, so clinical and radiological correlation is required; urothelial carcinoma with extensive glandular differ­ entiation, adenocarcinoma of the bladder and prostate, ade­ nocarcinoma with urethral extension, or colonic metastatic adenocarcinoma should be considered within the differential diagnosis; absence of neoplastic changes in urethral epithe­ lial layer. Desirable: dysplasia or in situ changes within the remaining Lit­ tre gland.

The eighth edition of the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM system can be applied.

184

Tumours of the urinary tract

。

Prognosis and prediction Very limited information about the prognosis and biological behaviour of Littr gland adenocarcinoma exists in the litera­ ture. Prognosis is related to stage. No recurrences or distant metastases after complete resection have been documented {878,2761,2624}.

Skene gland adenocarcinoma of the urethra

HesO Brimo F Cheng L Raspollini MR

Definition Skene gland adenocarcinoma is a malignant tumour arising in female urethral accessory glands.

ICD-0 coding 8140/3 Carcinoma of Skene glands

ICD-11 coding

。

2C93.0 & XH22Z8 Adenocarcinoma of urethra or paraurethral gland & Carcinoma of Skene, Cowper, and Littr glands

Related terminology Acceptable: urethral accessory gland adenocarcinoma.

Subtype(s) None

Localization Tumours are localized mainly in the distal urethra and arise from Skene glands, which are homologous to the male prostate. The presence of a tumoural mass in the anterior vaginal wall and bladder neck have been also documented {3582,1845,3191].

Clinical features Patients may present with gross haematuria or urinary urgency, or they may be asymptomatic. Serum PSA level may be ele­ vated (3191(.

Fig. 3.62 Skene gland adenocarcinoma. A Skene gland adenocarcinoma resembles acinar prostatic adenocarcinoma in its morphology and in its immunohistochemical profile. B Strong diffuse positivity with PSA.

PSA, PAP, and NKX3-1, as well as for AMACR and P501S {3239, 3191,3582,2261,1845}.

Epidemiology Skene gland adenocarcinoma is an extremely rare tumour. It occurs in women, mostly those in menopause, with patient age ranging from 46 to 91 years (3191,2261,1845,2966,3155).

Cytology Not clinically relevant

Diagnostic molecular pathology

Etiology

Not clinically relevant

Unknown

Essential and desirable diagnostic criteria

Pathogenesis Mutation and loss of heterozygosity of the PTENgene have been detected in one case (1845(. No further information is available.

Macroscopic appearance Skene gland adenocarcinomas are flat to polypoid tumours measuring 10-35 mm in the largest dimension {84,2553,3191, 1845}.

Histopathology Overall architecture and cytological features are very similar to those of acinar prostatic adenocarcinomas. Tumours are arranged in a tubular or cribriform pattern (with pseudostrati­ fication in the latter), although solid areas, a single-file pattern, and even intestinal-like morphology have been documented. Neoplastic cells are positive for classic prostatic markers like

Essential: a tumour with acinar to cribriform architecture and usually columnar epithelium; tumour morphology almost iden­ tical to that of prostatic acinar adenocarcinoma. Desirable: a positive reaction with prostatic immunohistochemi ­ cal markers (e.g. PSA, NKX3-1).

Staging The eighth-edition American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM system can be applied.

Prognosis and prediction Very few cases have been reported. One case has metastasized to inguinal nodes (2966}. Cases with increased PSA serum level and with decreased PSA after surgical excision of the lesion, can then be followed up by the serum level of PSA {1712,879,1775}. Tumours of the urinary tract

185

Hes 0 Brimo F Cheng L Raspollini MR

Cowper gland adenocarcinoma of the urethra

Definition Cowper gland adenocarcinoma is a tumour of the periurethral bulbomembranous glands, with features of adenoid cystic car­ cinoma of the salivary glands.

ICD-0 coding 8140/3 Carcinoma of Cowper glands

ICD-11 coding 2C93.0 & XH22Z8 Adenocarcinoma of urethra or paraurethral gland & Carcinoma of Skene, Cowper, and Littr6 glands

Related terminology Not recommended: urethral accessory gland adenocarcinoma; adenoid cystic carcinoma of the Cowper gland.

Subtype(s) None Fig. 3.63 Cowper gland adenocarcinoma. Invasion of Cowper gland adenocarcinoma

Localization

into fatty tissue around the urethra.

Cowper gland adenocarcinoma is localized in the bulbomembranous urethra with infiltrative growth to surrounding tissues (3604(.

Epidemiology

Clinical features Cowper gland adenocarcinoma usually manifests as perianal or perirectal pain/discomfort, and/or urinary retention. Physical examination usually shows a hard, fixed mass in the infraprostatic area {532,2967,3604,1360,2262}.

Cowper gland adenocarcinoma is an extremely rare tumour. It affects men in the fifth to seventh decades of life {532,2967, 3604,1360,2262).

Etiology Unknown

Flg. 3.64 Cowper gland adenocarcinoma. A Tumour with tubular and cribriform patterns growing around a thick-walled vessel. B Perineural and intraneural spread is common in Cowper gland adenocarcinoma.

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Tumours of the urinary tract

Pathogenesis

Cytology

The presence of MYB::NFIB fusion, which has been described in adenoid cystic carcinoma of the salivary glands and breast, has also been reported in Cowper gland adenocarcinoma of the urethra (2262).

Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Macroscopic appearance

Essential and desirable diagnostic criteria

Tumours are firm, lobulated, whitish-tan to yellow masses (3604}.

Essential: a tumour with adenoid cystic carcinoma morphology; the tumour's relationship to the Cowper glands should be confirmed by clinical and radiological correlation; negativity for prostatic immunohistochemical markers. Desirable: confirmation of MYB..NFIB fusion.

Histopathology Tumours have cribriform, trabecular, and solid patterns. Neo­ plastic cells have a bland appearance, with dark nuclei forming gland-like structures and rarely true tubules. Glandular/glandlike structures often contain mucoid material. Perineural spread is frequent. Immunohistochemistry for CK7 and high-molecularweight cytokeratin is positive. Prostatic markers (PSA, PAP), CEA, S100, and SMA are negative (1360,3604). The diagnosis of a tumour arising from accessory paraure­ thral glands of the bulbomembranous urethra is challenging because most patients present with an advanced-stage tumour that frequently destroys the glandular tissues. The differential diagnosis includes urothelial carcinoma with extensive glandular differentiation, prostatic ductal adenocarci­ noma, and basal cell carcinoma of the prostate.

Staging The eighth-edition American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) TNM system can be applied.

Prognosis and prediction Most patients present at an advanced stage and need addi­ tional treatment after surgery. Metastatic spread has been documented in the lung in one case and in the liver in another case (1360,2262).

Tumours of the urinary tract

187

Brimo F Aron M Cheng L HesO Raspollini MR

Clear cell adenocarcinoma of the urinary tract

Definition

Subtype(s)

Clear cell adenocarcinoma is an adenocarcinoma with cellu­ lar atypia; clear and eosinophilic cytoplasm; and tubulocystic, papillary, and solid growth patterns. It is thought to be of Mul­ lerian origin.

None

Localization

2C9Y & XH6L02 Other specified malignant neoplasms of uri­ nary tract & Clear cell adenocarcinoma, NOS

Clear cell adenocarcinomas are mostly seen in the urethra, but they also occur in the bladder. They are frequently associated with Mullerianosis. Rare cases invading the prostate, peripro­ static tissue, or renal pelvis have been described (1206,2465, 3632). Clear cell adenocarcinomas may originate from a Mulle­ rian duct cyst (2338} or a urethral diverticulum in the female and male (periprostatic) embryological remnants or prostatic utricle {2198,2362,1206}.

Related terminology

Clinical features

Acceptable: Mullerian-type tumour, clear cell type; clear cell adenocarcinoma. Not recommended: mesonephric carcinoma; mesonephroma.

The tumour shows a female predominance (M:F ratio: 1:4.6), with patient age ranging from 8 to 93 years. Patients typically present with haematuria or urinary symptoms. Frequently, the

ICD-0 coding 8310/3 Clear cell carcinoma

ICD-11 coding

Flg. 3.65 Clear cell adenocarcinoma of the bladder. A Tubules arranged back to back and solid areas lined by cells showing abundant eosinophilic cytoplasm, large pleomorphic nuclei, and prominent nucleoli. Background myxoid stroma is common. B Sheets of neoplastic cells with abundant eosinophilic to clear cytoplasm, large pleomorphic nuclei, and prominent nucleoli. Numerous mitotic figures are present.

Fig. 3.66 Clear cell adenocarcinoma of the bladder. A Tubules and microcysts lined by cells with scant to abundant clear cytoplasm and moderately atypical nuclei. B Tubules and papillae lined by mostly clear cells with large pleomorphic nuclei, irregular nuclear membranes, and prominent nucleoli.

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Tumours of the urinary tract

tumour is at an advanced stage at diagnosis, with nodal and distant metastases {3632}.

Epidemiology This is a relatively rare tumour, with about 250 cases reported in the English-language literature {1206).

Etiology The histogenesis of clear cell adenocarcinoma is debated; hypotheses include origins from the urothelium, pre-existing Mullerian precursors, or mesonephric remnants (Wolffian ducts). Urothelial origin is supported by the occasional pres­ ence of a neoplastic urothelial component {78,263,3065} and similar chromosomal abnormalities to those observed in urothe­ lial carcinoma using UroVysion FISH and X-chromosome inac­ tivation pattern analysis (3074}. A Mullerian origin is supported by the female predominance, similarities with tumours arising in the female genital tract {1884,3309), and occasional asso­ ciation with endometriosis (including malignant transformation of endometriosis of the bladder) (88,2020}. Rarely, there is an association with prostatic utricle cysts and paraurethral glands in the female urethra (1337,2020,2366,1781,1206}.

Pathogenesis Data on the pathogenesis of clear cell adenocarcinoma are limited. Targeted exon sequencing of 4 clear cell adenocar­ cinomas demonstrated the presence of a pathogenic variant of PIK3CA in 3 cases; 2 of those 3 cases also had a KRAS pathogenic variant (1884}. Next-generation sequencing analy­ sis of one case showed novel gene fusion candidates including ANKFfD28::FNDC3B, focal copy-number loss at the SMAD4 and AFHD2\oc\, and 38 somatic mutations including in the ATM and ALK genes (2116).

Fig. 3.67 Clear cell adenocarcinoma of the bladder. Solid areas (left) of highly atypi­ cal cells merging with tubules (right) showing a nephrogenic adenoma-like growth pat­ tern with a low degree of atypia. Superficial biopsies of similar cases may raise the

differential diagnosis of nephrogenic adenoma.

muscularis propria, hyperchromasia, and p53 staining are dis­ tinguishing features consistent with clear cell adenocarcinoma {1122,1206,1337}.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria

Clear cell adenocarcinoma forms a solitary polypoid or papil­ lary, rarely ulcerative, mass with a mean size of 40 mm (2366).

Essential: a combination of solid, tubulocystic, and papillary growth patterns; hobnail cells with eosinophilic or clear cyto­ plasm. Desirable: positivity for PAX8; negativity for urothelial markers.

Histopathology

Staging

The tumour displays papillary, tubulocystic, and/or solid growth patterns. The papillary fibrovascular cores may show hyalinization. Myxoid stromal reaction is common. The cells are flat, cuboidal. and hobnail, with clear, glycogen-rich, or eosino­ philic cytoplasm. Cytological atypia is moderate to severe, with variable mitotic activity and necrosis. Tumours with relatively bland cytological features resembling nephrogenic adenoma have been described (1337}. An associated urothelial carci­ noma component or adjacent endometriotic foci may rarely be present (3074}. The cells are usually positive for CK7, CA125, PAX8, AMACR, HNFip, p53, and napsin A. CK20 staining is variable (430,3074, 1122}. They are negative for GATA3, p63, 34pE12, PSA, ER, PR, and WT1 {1122,1206}. PAX8 positivity and urothelial marker negativity differentiate clear cell adenocarcinoma from the clear cell (glycogen-rich) pattern of urothelial carcinoma. The histological and immuno­ histochemical overlap with nephrogenic adenoma can be dif­ ficult. Mitotic activity, invasive growth with involvement of the

Staging is based on the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) sys­ tems and is similar to that of urothelial tumours in the bladder and urethra. A histology-based urethral carcinoma staging system has been proposed for female urethral carcinomas, which pro­ vides better prognostic stratification than the AJCC system (202).

Macroscopic appearance

Prognosis and prediction Clear cell adenocarcinoma has been considered an aggressive tumour, with a 5-year survival rate of 40% for urethral or bladder clear cell adenocarcinoma (2465,3632). However, the clinical course is stage-driven, with patients presenting at an advanced stage more often than those with urothelial carcinoma. A stageby-stage comparison of bladder tumours did not show sig­ nificant differences between clear cell adenocarcinoma and urothelial carcinoma {2465,3632,1206}. Advanced stage and poor prognosis are reported for clear cell adenocarcinomas in prostatic locations, whereas low-stage exophytic tumours are associated with good outcomes (1206).

Tumours of the urinary tract

189

Raspollini MR Cheng L HesO

Endometrioid carcinoma of the urinary tract

Definition Endometrioid carcinoma is an adenocarcinoma of Mullerian ori­ gin with glands resembling normal endometrium.

ICD-0 coding 8380/3 Endometrioid carcinoma

ICD-11 coding 2C94.Y & XH0SD2 Other specified malignant neoplasms of bladder & Endometrioid adenocarcinoma, NOS 2C92.Y & XH0SD2 Other specified malignant neoplasms of ure­ ter & Endometrioid adenocarcinoma, NOS

Related terminology Acceptable: Mullerian-type tumour, endometrioid type.

Subtype(s) None

Localization Cases of endometrioid carcinoma of the urinary tract have been described in the bladder, mainly in the posterior wall or in the trigone, and in the ureter (1524,1089}.

Clinical features Intermittent or painless haematuria {88,1747,92,1089}, frequent urination, and micturition pain during the menstrual period {3120} have been observed for patients with an endometrioid carcinoma in the bladder. Pelvic pain and recurrent cystitis (2779) or unilateral hydronephrosis {1524} have been reported for cases in the ureter.

Fig. 3.68 Endometrioid carcinoma of the ureter. The tumour is relatively well differ­ entiated, with a crowded glandular pattern and back-to-back glands, showing basal nuclei.

Epidemiology Endometrioid carcinoma is an exceptionally rare tumour in the genitourinary system that occurs in middle-aged and elderly women and is associated with endometriosis or Mullerianosis (281). Malignancy arising in the background of endometriosis may occur in upto 1% of women with endometriosis. The urinary bladder is involved in < 1% of cases of extraovarian endome­ triosis (887). Endometrioid carcinoma in the genitourinary tract organs arises where endometriosis is more common (e.g. for

Fig. 3.69 Endometrioid carcinoma. A This example is moderately differentiated, with greater glandular architectural atypia and loss of nuclear polarity. B ER positivity in endometrioid carcinoma of the bladder.

190

Tumours of the urinary tract

cases in the bladder, endometrioid carcinoma arises from the posterior wall). The uncommon endometrioid carcinomas of the ureter have been observed with a disseminate pelvic endome­ triosis, which may be correlated to surgical manipulation (1524, 3037).

Etiology Tumours arise in patients with endometriosis or Mullerianosis of the genitourinary organs or from disseminated pelvic endome­ triosis )1089,1524,3120}

Like in uterine endometrioid carcinoma, tumour cells show strong immunoreactivity for estrogen and progesterone; tumours stain positively for CAM5.2, CK7, and EMA, and vari­ ably for CA125, PAX8, and PAX2. The differential diagnosis includes urothelial carcinoma with glandular differentiation (endometrioid carcinoma does not show areas of typical urothelial carcinoma or intestinal metapla­ sia), urachal adenocarcinoma (endometrioid carcinoma does not arise in the dome of the bladder or in the anterior wall), and metastases (there is no extravesical primary tumour in endome­ trioid carcinoma).

Pathogenesis Extraovarian endometriosis is potentially capable of malignant transformation, and endometrioid carcinoma in the genitouri­ nary organs is related to the transition to malignancy of Mullerianosis (1089} and endometriosis (3120.2779). In addition, the malignant transformation of endometriotic foci may be cor­ related with additional risk factors such as unopposed estrogen hormone replacement therapy (2556,1524).

Cytology

Macroscopic appearance

Essential and desirable diagnostic criteria

Gross findings show a solid tumour in the vesical wall. Smaller tumours are located close to the serosa; larger tumours, which arise in the bladder wall, may protrude into the vesical lumen. Multiple cystic spaces can be associated to solid areas. The endometrioid carcinoma arising from periurethral endo­ metriosis manifests as a pelvic mass encasing the ureter.

Essential: infiltrating malignant glands with endometrioid dif­ ferentiation; histological findings of endometriosis or previous history of endometriosis. Desirable: presence of the benign urothelial lining covering most of the luminal surface, if not ulcerated; demonstration of a continuum between the malignant glands and benign endometriosis.

Cytology is not clinically relevant for endometrioid carcinoma of the urinary tract. Urine cytology has been negative in one case (3120).

Diagnostic molecular pathology Not clinically relevant

Histopathology Endometrioid carcinoma of the urinary tract shows morphologi­ cal similarities to its uterine counterpart. It is characterized by a glandular pattern and back-to-back glands, with grades based on different degrees of differentiation (low, moderate, and high) and nuclear pleomorphism. The glands are lined by large columnar cells with eosinophilic and granular cytoplasm, vesic­ ular nuclei, and prominent nucleoli. Foci of clear cell change {92}, squamous nests {2779}, basaloid differentiation (1524], or hobnail cells {88} have been described. A key feature for the diagnosis is the coexistence of foci of malignant endometriotic glands and endometriosis with benign glands and endometrial stroma.

Staging The eighth-edition TNM staging system of the American Joint Committee on Cancer (AJCC) has been created for blad­ der urothelial carcinoma and is also used for other epithelial tumours of the bladder. Endometrioid carcinomas arise in deep the muscularis propria near to the serosa of the bladder and in the periureteric endometriotic foci; consequently, the disease stage is T2-T3.

Prognosis and prediction The prognosis for endometrioid carcinoma is predicted by pathological stage.

Tumours of the urinary tract

191

Tumours of the prostate Edited by: Amin MB, Kench JG, Rubin MA, Srigley JR, Tsuzuki T

Epithelial tumours of the prostate Glandular neoplasms of the prostate Prostatic cystadenoma High-grade prostatic intraepithelial neoplasia

Intraductal carcinoma of the prostate Prostatic acinar adenocarcinoma Prostatic ductal adenocarcinoma Treatment-related neuroendocrine prostatic carcinoma Squamous neoplasms of the prostate Adenosquamous carcinoma of the prostate Squamous cell carcinoma of the prostate Adenoid cystic (basal cell) carcinoma of the prostate

Mesenchymal tumours unique to the prostate Stromal tumours of the prostate Prostatic stromal tumour of uncertain malignant potential Prostatic stromal sarcoma

Tumours of the prostate: Introduction

In this chapter, we present an overview of recent advances in our understanding of the etiology, pathogenesis, and molecular underpinnings of prostate cancer development and progres­ sion. Equal emphasis is placed on detailing the continuous refinements in the classification, grading, and prognostica­ tion of this, the most prevalent cancer in men. Promising novel therapeutic targets, radiological imaging solutions, and appli­ cations of computational digital pathology are also described. The computational pathology approach brings the potential for greater accuracy and interobserver reproducibility in the diag­ nosis and grading of prostate cancer. In keeping with the terminology scheme that is now in use across the volumes of the fifth edition of the WHO Classifica­ tion of Tumours, we adopted the designation of "subtypes" to replace "variants" for distinct clinical or morphological catego­ ries within a tumour type (e.g. subtypes of acinar adenocar­ cinoma that are morphologically distinct and have prognostic significance). The term "variant" is reserved for genomic rather than morphological alterations. In another change aligned with the structure of the fifth-edition series, neuroendocrine, mesenchymal, haematolymphoid, mel­ anocytic, metastatic, and genetic syndrome-related tumours are each discussed in separate chapters, consolidating these topics across various genitourinary organs. The only exceptions are mesenchymal tumours that are thought to originate from the prostate stromal cell proper, and treatment-related neuroendo ­ crine prostatic carcinoma. These remain present as individual sections in the prostate chapter, given their distinct features at the biological and clinical level. In particular, treatment-related neuroendocrine carcinomas (NECs) of the prostate continue to present steep management challenges and exert a heavy mor­ tality toll in castration-resistant prostate cancer. Unlike in the previous edition, the section on urothelial car­ cinoma of the prostate and prostatic urethra is now integrated into Chapter 3: Tumours of the urinary tract. However, the cur­ rent edition maintains the previously adopted approach to stag­ ing urothelial carcinoma that invades prostate stroma, which depends on whether the tumour originated in the urethra (pT2) or there is contiguous direct invasion from a transmural bladder primary (pT4); this is highlighted in Invasive urothelial carcinoma (p. 150) to bring attention to the contrasting outcome of the two categories of spread (1180,232,2071). As discussed in Prostatic acinar adenocarcinoma (p. 203), among hereditary tumour syndromes, those associated with homologous recombination repair defects and Lynch syndrome are of particular importance in the setting of prostate adenocar­ cinoma. This is primarily due to recent revelations that gernnline or somatic alterations in DNA repair genes (e.g. BRCA1, BRCA2, ATM, CHEK2, FANCI, PALB2, MSH2) are present in as many as 20% of aggressive primary and metastatic prostatic carcino­ mas {2689,198,2574,2056,3498,2593,3334,2660}. Advanced prostate cancers harbouring homologous recombination repair 194

Tumours of the prostate

Netto GJ Amin MB Kench JG

defects are likely to respond to inhibition of poly (ADP-ribose) polymerase (PARP), whereas patients with DNA mismatch repair-deficient cancers are poised to be offered immune checkpoint inhibitors {1138,1214,48}. Morphological correlates of prostate carcinoma (e.g. intraductal carcinoma, cribriform histology) that are more likely to harbour genetic defects of DNA repair are being increasingly elucidated in high-risk adenocarci­ noma. Detailing the impact of the above advances has led to a substantial expansion of the text on pathogenesis and molecu­ lar diagnostics in prostatic acinar adenocarcinoma. As is the case in any volume on cutting-edge advances, delving into conceptually controversial topics including those on evolving nomenclatures - is unavoidable, and this chapter is no exception. For instance, entities like low-grade prostatic intraepithelial neoplasia and the cribriform subtype of high­ grade prostatic intraepithelial neoplasia (HGPIN) are no longer regarded as distinct entities. The former lost its entity status because it was impossible to recognize histologically (with any degree of reproducibility) as a lesion distinct from benign glandular hyperplasia of the prostate. The latter may represent a group of intraductal proliferations that border on intraductal carcinoma of the prostate (IDC-P) {948}. As discussed in Intra­ ductal carcinoma of the prostate (p. 200), this group of lesions is increasingly referred to as atypical intraductal proliferation, which encompasses a spectrum of intraductal proliferations that are architecturally and/or cytologically more complex than HGPIN but fall short of IDC-R Although a consensus on the best terminology for this group of lesions has yet to be reached (919,948,3314), the limited literature on the topic has so far sug­ gested that they have clinical and molecular features in line with being a short step away from IDC-P (1354,2895,1251). In recent years, studies on the molecular changes and clini­ cal implications of IDC-P have gained considerable momen­ tum. Therefore, the section on IDC-P has been substantially expanded in this fifth edition. We were keen to put front and centre the fact that current biological and clinical evidence strongly supports the notion that IDC-P represents two distinct entities. Only a small minority of IDC-P lesions are now thought to be truly in situ in nature, originating by progression from the HGPIN precursor. The majority of IDC-P lesions are formed as late events in tumour progression where high-grade invasive prostate cancer spreads into (colonizes) non-neoplastic pros­ tate ducts/acini. Accumulating genomic data strongly support this origin (by intraductal spread) of most IDC-Ps from pre­ existing invasive cancer rather than by progression from HGPIN (349,791,407,653,1950). There is a general consensus that identifying IDC-P in patients with invasive prostate cancer has a negative prognostic impact, and that it is important to report its presence given the clini­ cal management implications {3291,948}. However, whether to incorporate IDC-P areas in the calculation of the assigned Glea­ son score remains a major controversy. This has resulted in an

一

unfortunate divergence in practice guidelines among leading professional societies {948,3291,3315]. The hope is that such divergence will be resolved as more evidence accumulates, but at present these features should be described when present. The presence of IDC-P and/or cribriform architecture (pat­ tern 4) has been shown by some to be associated with a higher incidence of inherited germline alterations in DNA repair genes (specifically those involved in homologous recombination repair and mismatch repair). This has triggered some professional cancer organizations to recommend germline genetic testing in all patients with prostate cancer harbouring these lesions (2834,2197). It remains to be seen whether such an aggressive (and expensive) approach will stand the test of time. In this edition, we contemplated the notion of transitioning ductal adenocarcinoma into a subtype of acinar adenocarci­ noma rather than maintaining it as a separate type of prostate cancer. The discussion was primarily driven by the fact that, in the majority of cases, ductal adenocarcinoma is admixed with acinar adenocarcinoma. Furthermore, the preponder­ ance of evidence shows ductal adenocarcinoma to be clonally

related to the coexisting acinar cancer, given the shared ERG rearrangements and other genomic alterations {1955,1134). However, occasional studies have pointed to a discordant molecular origin {2212,2858,3332}. Ultimately, given its distinc­ tive clinical behaviour and at times unique metastatic pattern, we elected to maintain ductal adenocarcinoma as a separate type at this time (see Prostatic ductal adenocarcinoma, p. 220), while awaiting further data bolstering the argument for future integration as a subtype of acinar cancer. Basal cell carcinoma of the prostate is genetically and mor­ phologically a type of adenoid cystic carcinoma occurring in the prostate, and the name can cause confusion with the skin tumour, which is much more common. As a result, we have taken the decision to rename this entity as "adenoid cystic (basal cell) carcinoma of the prostate" to make the difference clear to all. Finally, prostatic intraepithelial neoplasia-like adenocarci­ noma has been moved to the chapter on acinar adenocarci­ noma because of its behaviour and recently described genetic changes, which are different from those of ductal adenocarci­ noma {3123,2470,1621}.

Tumours of the prostate

195

Srigley JR Tsuzuki T

Prostatic cystadenoma

Definition

Epidemiology

Cystadenoma of the prostate is a benign epithelial neoplasm composed of multiple macroscopic cysts lined by bland pros­ tatic secretory and basal cells and separated by fibrous or fibromuscular stroma.

About 30 cases have been reported in patients in their third to ninth decades of life {234,2281).

Etiology Unknown

ICD-0 coding 8440/0 Cystadenoma

Pathogenesis Unknown

ICD-11 coding 2F34 & XH5RJ2 Benign neoplasm of male genital organs & Cystadenoma, NOS

Macroscopic appearance

None

Cystadenomas may be intraprostatic, periprostatic but attached to the prostate by a pedicle, or entirely separate. Masses are large (70-450 mm) and have smooth and/or bosselated outer surfaces. The cut aspect is multilocular, with cysts (usually < 20 mm in diameter) separated by grey-white fibrous septa. The cysts often contain yellow or brown serous fluid and some­ times inspissated semi-solid material (2010,643,2468,2438}.

Localization

Histopathology

Prostate gland, retrovesical space, retroperitoneum

Cysts are lined by a dual layer consisting of low columnar or atrophic secretory cells and flattened outer basal cells. Focal bland papillae may be seen. Cysts are surrounded by prostatic fibromuscular or fibrotic stroma, which may be hyalinized and show chronic inflammation. Squamous metaplasia may be seen in the lining epithelium (2438(. No marked epithelial atypia is present. By immunohistochemistry, the lining epithelium stains for PSA, PAP, and other prostate lineage-specific markers. Basal cells are decorated with high-molecular-weight cytokera­ tin and p63 {2010,643,2468,2438}. Rarely, both high-grade prostatic intraepithelial neoplasia and acinar adenocarcinoma have been described as occurring in prostatic cystadenomas {94,1832}, Prostatic ductal adenocar­ cinoma can rarely present as a large multilocular mass resem­ bling cystadenoma; however, prominent intracystic papillary growth and cytological atypia have been noted in cystadeno­ carcinoma {2438).

Related terminology Acceptable： giant multilocular cystadenoma.

Subtype(s)

Clinical features Patients may present with obstructive urinary symptoms, con­ stipation, abdominal distention, and pain. Imaging studies often show large multiseptate masses involving the prostate gland and/or retrovesical space. Serum PSA is commonly elevated, and biopsies (if performed) are often non-diagnostic {234,2281}.

Cytology Insufficient data

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria

Fig. 4.01 Prostatic cystadenocarcinoma. Cystadenocarcinoma showing multiple cys­ tic loculations, with focal intracystic papillae. Non-cystic conventional adenocarcinoma (grade group 5) is present adjacent to the multiple loculations.

196

Tumours of the prostate

Essential: a large multiloculated cystic mass in or around the prostate gland; cysts lined by bland prostatic secretory and basal cells; no marked cytological atypia; septa with fibro­ muscular or fibrous stroma. Desirable: immunohistochemistry to confirm prostatic epithelial origin (if the differential diagnosis includes a seminal vesicle lesion).

Staging Not relevant

Prognosis and prediction The therapy of choice is complete surgical excision, which may involve local resection, prostatectomy, or (rarely) pelvic exen­ teration (2281). Cases behave in a benign fashion; however, incomplete removal may result in tumour recurrence {2010, 2752,2281}.

寸成

Ideqo

Tumours of the prostate

197

High-grade prostatic intraepithelial neoplasia

Netto GJ Humphrey PA Magi-Galluzzi C NesiG van der Kwast TH Zhao M

Definition

Pathogenesis

High-grade prostatic intraepithelial neoplasia (HGPIN) is a pro­ liferation of atypical secretory cells within prostatic glands. It is thought to be the earliest histologically recognizable precursor of invasive adenocarcinoma of the prostate.

None

There is some evidence pointing to glandular epithelial cell injury by dietary carcinogens, estrogens, or oxidants as trig­ gers of a chronic inflammatory milieu that sets the stage for the development of prostate cancer precursors. Faced with persistent oxidative stress, the epithelial cells mount a genome damage defence and cell survival response by activating the expression of a- and -class glutathione S-transferases, COX-2, and other mediators (2304,3289). Ultimately, this is followed by epigenetic silencing of hundreds of genes, including the crucial caretaker gene GSTP1, that persists throughout cancer pro­ gression {438}. As a result, HGPIN shares many of the somatic genetic and epigenetic alterations that are exhibited by prostate cancer {401}. These include, among others, critical shortening of telomeres {2112}, the presence of MYC amplifications in as many as half of all HGPIN lesions {2587,1478), TMPRSS2::ERG fusion in 20-30% (3606,2227}, and the loss of the tumour sup­ pressor gene PTEN in 23% (3557}. Other genetic changes in HGPIN include loss of heterozygosity at chromosomes 6 and 8 and gain of chromosomes 7, 8, 10, and 12 (942,1509,2586).

Localization

Macroscopic appearance

HGPIN is most frequently located in the peripheral zone of the prostate gland, but rarely it can be found in the central and tran­ sition zones {1100}.

HGPIN is not identifiable at the macroscopic level.

ICD-0 coding 8148/2 Prostatic intraepithelial neoplasia, high-grade

ICD-11 coding 2E67.5 High-grade intraepithelial lesion of prostate

Related terminology Acceptable: prostatic intraepithelial neoplasia. Not recommended: low-grade prostatic intraepithelial neopla­ sia; grade 1, 2, or 3 prostatic intraepithelial neoplasia; carci­ noma in situ.

Subtype(s)

Clinical features HGPIN is incidentally detected in histological samples obtained during the workup for prostate carcinoma. Isolated HGPIN does not lead to clinical manifestations (2211}.

兀

Histopathology HGPIN is characterized by an atypical proliferation of the secre­ tory epithelial cells that line pre-existing ductal and acinar pros­ tate gland structures. The surrounding basal layers remain dis­ cernible, albeit frequently with fewer basal cells. HGPIN lesions are identifiable on low to intermediate magnification given their

Epidemiology Overall, the mean reported incidence of HGPIN in prostate biopsy studies is 9% (range: 4-16%) (401,3149). The incidence increases with age and varies by race and geographical region. Autopsy series have confirmed the development of HGPIN in young men in their third and fourth decades of life (in 9% and 20% of the patients studied, respectively) (2772). Population­ based studies point to the highest incidence being in AfricanAmerican men and the lowest in Asian men {2771}.

Etiology The variation in the incidence of prostate cancer and its pre­ cursor HGPIN among populations and geographical regions has long indicated that differences in ethnic genetic determi­ nants as well as environmental factors are etiological factors. Although the higher incidence of the disease in African Ameri­ cans is probably genetically based {3590|, the alteration in risk upon migration in each ethnic group strongly suggests environ­ mental, dietary, and lifestyle factors (e.g. obesity and a lack of physical activity) as contributing determinants of risk {2304(.

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Tumours of the prostate

Fig. 4.02 High-grade prostatic intraepithelial neoplasia with adjacent normal glands. Tufted and micropapillary patterns. Secretory cells show nuclear stratification and prominent nucleoli; basal cells are retained.

(hobnail) patterns, as well as HGPIN with squamous differentia­ tion (401,671,2136,169}. The existence of a cribriform pattern of HGPIN is now contro­ versial and its diagnosis is not recommended on needle biopsy {948), As discussed in Intraductal carcinoma of the prostate (p. 200), some authors have recently proposed that intraductal proliferations that overlap with lesions previously categorized as cribriform HGPIN but that do not reach the threshold for IDC-P should be assigned to a newly suggested category, vari­ ably referred to as "atypical cribriform proliferation", “atypical intraductal proliferation", and "atypical intraductal proliferation suspicious for IDC-P". These represent intraductal precursor lesions that fall short of meeting the architectural and cytologi­ cal criteria required for the diagnosis of IDC-P (919,948,3314}.

Immunohistochemistry

Fig. 4.03 Inverted high-grade prostatic intraepithelial neoplasia. This example dem­

onstrates nuclei that are polarized towards the lumen.

Confirmation of the presence of basal cells by immunostaining for high-molecular-weight cytokeratin and/or p63 may occasionally help to distinguish outpouchings of HGPIN from adjacent microscopic foci of adenocarcinoma. Furthermore, immunostaining for basal cells may help distinguish prostatic intraepithelial neoplasia-like adenocarcinoma and the foamy gland and pseudohyperplastic patterns of prostatic adenocar­ cinoma from HGPIN (2983,328,1423,1268}.

Cytology Not relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: crowded, stratified atypical secretory cells in pre­ existing normal-sized or expanded glands; enlarged, hyper­ chromatic, and sometimes pleomorphic nuclei; prominent nucleoli; basal layer present but often discontinuous.

Staging Fig. 4.04 Prostatic intraepithelial neoplasia with small-cell changes. A lesion with centrally located solid sheets of dark small-cell populations punctuated by rosette

Not relevant

formations.

Prognosis and prediction

usually darker tinctorial appearance. This is imparted by the increased density of the multilayered, enlarged, hyperchromatic nuclei and the more amphophilic cytoplasm of HGPIN cells as compared with cells of normal or hyperplastic glands (2103}. The presence of conspicuous nucleoli is a key requirement for the diagnosis of HGPIN (3340). Absence of necrosis, marked nuclear pleomorphism, and brisk mitotic activity are features that distinguish HGPIN from intraductal carcinoma (see Intra­ ductal carcinoma of the prostate, p. 200). Three main histologi­ cal patterns of HGPIN are recognized: tufting, micropapillary, and flat {2103,400); however, designating HGPIN patterns in routine practice is of no clinical significance and should there­ fore be avoided. Additional morphological patterns of HGPIN that are encountered less frequently include the small cell, vacuolated (signet ring-like), foamy, mucinous, and inverted

As a precursor lesion, HGPIN alone does not require therapy. Identification of HGPIN on needle biopsy workup for prostate cancer has long been recognized as a predictor of associated invasive adenocarcinoma {953,3340}. The likelihood of finding cancer on subsequent biopsy in men with an initially identified isolated HGPIN lesion has fallen significantly in populations with rigorous PSA screening programmes. Currently, the risk associ­ ated with the presence of a single focus of HGPIN equates to that of patients with no identifiable HGPIN (19% vs 21%, respec­ tively) {953,3340}. In contrast, a larger extent of isolated HGPIN has maintained its significance as a predictor of a subsequent diagnosis of cancer, with the presence of multifocal HGPIN almost doubling the risk of cancer (30-40%). Accordingly, only patients with an initial biopsy set containing multiple foci of HGPIN are currently advised to undergo a repeat biopsy during the following year {3016,2137,2310,3340}.

Tumours of the prostate

199

Intraductal carcinoma of the prostate

Zhou M Egevad L Fine SW Leite KRM

Lotan TL Netto GJ Varma M

Definition

Pathogenesis

Intraductal carcinoma of the prostate (IDC-P) is a neoplastic epi­ thelial proliferation involving pre-existing, generally expanded, duct-acinar structures and characterized by architectural and cytological atypia beyond what is acceptable for high-grade prostatic intraepithelial neoplasia (HGPIN). It is typically associ­ ated with high-grade and high-stage prostate carcinoma but in rare cases may represent a precursor lesion.

IDC-P is a neoplastic epithelial proliferation that is located within native prostatic ducts and acini, which may represent two bio­ logically distinct entities. In the vast majority of cases, IDC-P is associated with invasive high-grade carcinoma and consid­ ered a late colonization-type event in the evolution of prostatic acinar carcinoma (1224,2105,676). In a small subset of cases, IDC-P is seen in the absence of invasive prostate cancer and may represent a carcinoma in situ that exhibits much greater architectural and/or cytological atypia than HGPIN. Studies support IDC-P as being distinct from HGPIN and as showing overlap with profiles of high-grade invasive prostate cancer. Early studies found that IDC-P and Gleason pattern 4/5 prostate cancer show a similar high frequency of genomic instability (as determined by loss of heterozygosity and comparative genomic hybridization) to that of Gleason pattern 3 prostate cancer and HGPIN (349,791). More recent studies have shown that prostate cancer with IDC-P and/or invasive cribriform cancer is associated with a higher percentage of genomic alteration than prostate cancer without these patterns {407,653}. Specific somatic copy-number alterations known to be associated with aggressive prostate cancer that have been observed in IDC-P studies include loss of PTEN, CDH1, and BCAR1, and gain of MYC {407}. Expression of SCHLAP1, a long non-coding RNA associated with a poor prognosis in prostate cancer, has been observed at > 3 times the frequency in prostate cancer with an IDC-P / invasive cribriform pattern {653}. Mutations in SPOP and TP53 as well as in the transcription factor gene FOXA1 are more frequent in cases with IDC-P or invasive cribriform cancer than in cases without these findings (407). ERG rearrangement is present in the majority of cases of IDC-P {1275), and loss of PTEN expression may be identified in as many as -85% of cases, with the latter uncommonly seen in HGPIN {1950). Rarely, IDC-P is found without concomitant invasive prostate cancer or adjacent to Gleason 6 prostate cancer, raising the possibility that IDC-P may represent an in situ-type lesion pre­ ceding the development of invasive prostate cancer (2688,678, 1641}. Discordance in either ERG or PTEN expression between IDC-P and concomitant Gleason score 6 carcinomas has been noted, and this suggests that IDC-P is unlikely to be a precur­ sor of low-grade invasive carcinoma {1641}. Others dispute the existence of a true in situ IDC-P {2788) because there are no reliable morphological features to distinguish between IDC-P with or without associated invasive prostate cancer. In prostate biopsies, the absence of concomitant invasive prostate cancer generally represents undersampling; follow-up radical prosta­ tectomy specimens, when completely sampled, have virtually never displayed IDC-P alone. ERG gene fusion, PTEN genomic alterations, and loss of PTEN protein expression may be helpful for diagnosis in selected patients. Biallelic BRCA2 loss is significantly associ­ ated with IDC-P (1961).

ICD-0 coding 8500/2 Intraductal carcinoma

ICD-11 coding 2E67.5 & XH1H31 Carcinoma in situ of prostate & Intraductal carcinoma, non-infiltrating, NOS

Related terminology Not recommended: low-grade intraductal carcinoma; carci­ noma in situ.

Subtype ⑥ None

Localization Most commonly in the peripheral zone together with high-grade and high-volume prostate cancer

Clinical features Patients may present with symptoms and laboratory findings related to high-grade and high-volume invasive prostate can­ cer.

Epidemiology IDC-P is seen in 15.4-31.1% of routinely processed radical pros­ tatectomies (2183,2893,1612,2673,2560}. In the vast majority of cases, IDC-P is associated with invasive prostate cancer. Its incidence depends on the Gleason grade and volume of the concomitant prostate cancer, and on disease risk categories (1612,2673,2560}. IDC-P without concomitant invasive cancer is an exceedingly rare finding in radical prostatectomies {678, 1641}. In prospective series, IDC-P has been identified in 2.8% of prostate biopsies {3415} and in 14% of biopsies with invasive prostate cancer (2673,2560}. Isolated IDC-P without invasive prostate cancer has been reported in 0.06-0.26% of prostate biopsies (1224,2688,3415).

Etiology The etiology of IDC-P is the same as that of prostate adenocar­ cinoma. Biallelic BFICA2 loss has been associated with IDC-P and primary prostate tumours, but the association of prostatic carcinomas with germline BRCA2 mutations remains controver­ sial (1961,11381，

、

200

Tumours of the prostate

Macroscopic appearance Not relevant

Histopathology IDC-P is a complex, generally expansile proliferation of neo­ plastic cells within native ducts and acini, which displays at least partial preservation of the basal cell layer. Architectur­ ally, the best agreed upon criterion for IDC-P is solid or dense cribriform growth {1224,2105,676). A dense cribriform pattern has been defined as one with more solid than luminal areas, i.e. > 50% of the gland comprising epithelial cells relative to luminal spaces {948}. Comedonecrosis is strongly associated with IDC-P (1009,1981} and may be used as a diagnostic cri­ terion (1224,2105,676}. Whether intraductal proliferations with loose cribriform and/or micropapillary architecture can be diag­ nosed as IDC-P is a matter of debate, with many considering only lumen-spanning proliferations (solid, dense, or loose crib­ riform) for the diagnosis of IDC-P and others including micropapillary proliferations only in the context of marked cytological atypia. IDC-P has been variably associated with pleomorphic and/or hyperchromatic cells with moderate to marked enlarge­ ment and associated mitoses and apoptotic bodies. However, whether this degree of cytological atypia is required for diagno­ sis is more controversial (1224,2105,676(. The most widely used criteria among current publications accept solid/dense cribriform architecture alone as diagnostic of IDC-P and require marked cytological atypia (+/- comedo­ necrosis) for the diagnosis of IDC-P with less complexity, i.e. a loose cribriform/micropapillary architecture (1224}. These crite­ ria were developed in a biopsy series in which IDC-P was found

and its presence was the determinant of definitive therapy even in the absence of a concomitant invasive component. From a differential diagnosis standpoint, it is most crucial particularly in biopsies - to distinguish IDC-P from HGPIN, as their clinical associations are drastically different. For atypical lesions that do not meet the criteria for IDC-P, the term "atypical intraductal proliferation" is preferred. Furthermore, it is recom­ mended that lesions formerly considered cribriform HGPIN be included in the atypical intraductal proliferation category. It is important to note that cribriform architecture may occasionally be seen in normal prostatic glands, especially from the central zone, and in prostatic hyperplasia. However, cytological atypia is lacking in these situations {3313}. Solid patterns of IDC-P may mimic intraductal spread of urothelial carcinoma; in difficult cases, prostate-specific and urothelial markers can aid in their distinction. The ductal subtype of prostate cancer, characterized by papillary/cribriform-papillary architecture and pseudostratified columnar epithelium, is readily distinguished from usual IDC-P in which the intraductal proliferation closely resembles that of complex acinar prostatic carcinoma. Uncommonly, ductal prostate cancer may grow in an intraductal fashion {948|, a phenomenon that has been incompletely described and for which standard terminology does not currently exist. Basal cell marker immunohistochemistry is recommended for prostate biopsies displaying isolated IDC-P without concomi­ tant invasive prostate cancer {3291,948}. A current controversy is whether to perform immunohistochemical stains in biopsies containing invasive prostate cancer and cribriform/solid lesions that may represent IDC-P, when this determination impacts the assigned prostate cancer grade (948). Immunohistochemistry

Fig. 4.05 Intraductal carcinoma of the prostate. A Core biopsy showing solid cribriform glands. B Surrounding basal cells are highlighted by high-molecular-weight cytokeratin and p63 immunostaining. AMACR is positive in cancer cells. C High-power view of panel A. D High-power view of panel B.

Fig. 4.06 Intraductal carcinoma of the prostate. A Comedonecrosis in dense cribriform glands. Corpora amylacea are present in several glands, suggestive of involvement of pre-existing benign glands. B There is partial involvement of a benign gland. C An example with markedly pleomorphic nuclei.

Tumours of the prostate

201

is not considered necessary in cases where the distinction between IDC-P and invasive prostate cancer will not change the assigned prostate cancer grade (3291,948). There is wide agreement that when IDC-P is identified on prostate biopsy without concomitant invasive cancer it should not be graded, but rather a comment should detail the usual association of IDC-P with aggressive prostate cancer. There is also agreement that when IDC-P is observed in the setting of invasive prostate cancer, its presence should be noted. How­ ever, whether the architectural pattern of the IDC-P should addi­ tionally be incorporated into prostate cancer grading remains controversial at this time, owing to insufficient data {3315,2977}.

Cytology Not relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: expansile epithelial proliferation in the pre-existing duct-acinar system; lumen-spanning solid, cribriform, and/or comedo patterns; loose cribriform or micropapillary patterns with enlarged pleomorphic nuclei; residual basal cells. Desirable: immunohistochemistry demonstrating at least partial basal cell retention.

202

Tumours of the prostate

Staging Staging is based on the associated invasive prostate cancer.

Prognosis and prediction Current recommendations include the reporting of IDC-P because it has been associated with adverse pathological findings and clinical outcomes in both needle biopsy and radical prostatec­ tomy studies. In radical prostatectomies, IDC-P correlates with a higher grade, larger tumour volume, and greater probability of extraprostatic extension, seminal vesicle invasion, and pelvic lymph node metastasis. It has also been strongly associated with biochemical recurrence, progression-free survival, and cancer­ specific mortality after radical prostatectomy {871,1668,2182, 2347,916,3518}. In biopsy specimens, IDC-P is typically seen with high-grade, high-volume prostate cancer, and it is associ­ ated with adverse radical prostatectomy findings and clinical out­ comes {3415,2673,2560). IDC-P diagnosed in prostate biopsies has also been strongly associated with early biochemical recur­ rence, cancer-specific survival, survival in patients with distant metastasis at presentation, and metastatic failure after radiation therapy in intermediate- and high-risk prostate cancer {1611, 3280,2765,3196}. Although germline BRCA2 testing has been recommended formally by the National Comprehensive Cancer Network (NCCN) and the Philadelphia Prostate Cancer Consen­ sus Conference, it remains a controversial topic {1961,1138}.

Prostatic acinar adenocarcinoma

Definition Acinar adenocarcinoma is a malignant epithelial neoplasm originating in the prostate and showing secretory differentiation, without a substantial component of any other type of prostatic cancer. Basal cells are typically not present.

ICD-0 coding 8140/3 Acinar adenocarcinoma 8490/3 Signet-ring cell-like acinar adenocarcinoma 8140/3 Pleomorphic giant cell acinar adenocarcinoma 8572/3 Sarcomatoid acinar adenocarcinoma 8140/3 Prostatic intraepithelial neoplasia-like carcinoma

ICD-11 coding 2C82.0 & XH4PB1 Adenocarcinoma of prostate & Acinar ade­ nocarcinoma of prostate

Related terminology None

Subtype(s) Signet ring-like cell acinar adenocarcinoma; pleomorphic giant cell acinar adenocarcinoma; sarcomatoid acinar adenocarci­ noma； prostatic intraepithelial neoplasia (PIN)-like carcinoma In addition, there are some special morphological patterns: atrophic, pseudohyperplastic, microcystic, foamy gland, and mucinous (colloid) (see Histopathology, below).

Localization Most acinar adenocarcinomas arise in the peripheral zone of the prostate, predominantly posteriorly or posterolaterally (2104, 613,1189}. A smaller number of adenocarcinomas are located anteriorly, arising either in the anterior peripheral zone or in the transition zone {63}. Morphometric studies of radical prostatec­ tomy specimens have shown that acinar adenocarcinoma is multifocal in 68-90% cases, with an average of 2-3 separate tumour nodules in each {1254,3478,206}.

Clinical features PSA is a serine protease present in prostatic epithelium and seminal fluid (10,1878). The vast majority of acinar adenocarci­ nomas of the prostate produce PSA (1033), although as many as 13% of high-grade cancers are completely negative for PSA by immunohistochemistry {952}. The discovery that PSA can be measured in serum {11} led to the use of elevated serum PSA as a test for the early detection of prostate cancer (552). Despite suboptimal sensitivity and specificity, PSA testing is widely used for the screening of prostate cancer {1651,2533,1420). Serum PSA is also useful for monitoring recurrences and disease pro­ gression after treatment with curative intent. However, the major­ ity of men with a rising serum PSA level after prostatectomy do

Kench JG Berney DM De Marzo A Egevad L Kristiansen G

Litjens GJS Magi-Galluzzi C Netto GJ Yang XJ

not develop distant metastases {2564}. Several PSA derivatives, including PSA density, doubling time, and velocity, have been proposed over the years with the aim of improving the specific­ ity of serum PSA screening. These have demonstrated limited improvements in some studies, as have similar investigations of free PSA and its isoforms (551,3330,1389,1816}. A variety of uri­ nary assays for biomarkers, such as TMPFISS2：-.ERG fusion and AMACR, have also been advocated (1858,3031,1429}. Many prostate cancers are asymptomatic at diagnosis and detected because of an elevation of serum PSA (1690}. Oth­ ers are detected incidentally in men undergoing transurethral resection for benign prostatic hyperplasia. Lower urinary tract symptoms may be present in men diagnosed with prostate can­ cer, but they do not seem to be associated with prostate can­ cer risk {567,2837,1041}. Haematuria is an unusual presenting symptom of prostate cancer {3064}. Men with erectile dysfunc­ tion are more often diagnosed with prostate cancer than are those with normal potency {1271,1890). Metastases are detected at diagnosis in 5-13% of prostate cancer cases {2932,3151}. The predominant site of distant metastasis is the skeleton (accounting for 88.7% of cases of metastatic disease) {1412}, and bone metastases of prostate cancer are usually osteoblastic (1626}. Osteoblasts are acti­ vated by growth factors, and bone absorption is decreased by PSA (1476). Bone metastases in prostate cancer are a major cause of declining quality of life due to persistent pain and pathological fractures {1978(. In autopsies of men who died of prostate cancer, the most common distant metastatic sites were bone (75-90%), lung (46-58%), liver (25-42%), pleura (21%), and adrenal glands (13-31%) {2375,461}.

Imaging For the primary diagnosis of prostate cancer, transrectal ultra­ sound (TRUS) and mpMRI are the key modalities. Historically, TRUS was most commonly used as a guide for systematic biopsies (2722); however, in recent years, mpMRI has been recommended for initial imaging )1609,3281). mpMRI allows for a reduction of the total number of biopsy procedures and has a higher sensitivity for clinically significant cancers (Gleason score >3 + 3) both in biopsy-naive men and after an initial negative biopsy (1818,2736,897). In jurisdictions where MRI resources are scarce, ultrasound-guided systematic 10- to 14-core sam­ pling is the initial diagnostic approach. TRUS-guided biopsies and mpMRI are currently only indicated for men with a clinical suspicion of prostate cancer. The current recommended protocol for mpMRI includes T2-weighted imaging, T1-weighted dynamic contrast-enhanced imaging with a gadolinium-based agent, and diffusion-weighted imaging {274,275}. T2-weighted imaging allows the assessment of anatomical details, dynamic contrast-enhanced imaging allows the assessment of tissue vascularization, and diffusionweighted imaging-derived measures correlate with cellular Tumours of the prostate

203

Estimated age-standardized incidence rates (World) in 2020, prostate, males, all ages

AU rights reserved. The designations employed and the presentation of the material In this publication do not impty the expression of any opinion whatsoever on the part of the World Health Organization / International Agency for Research on Cancer concerning the legal status of any country, territory, cky or area or of i 160 prostate cancer risk-associated SNPs have been reproducibly identified {2856}. While individually imparting only a small increase in risk, these appear to have a cumulative effect such that the polygenic risk score may help in clinically identify­ ing men at high risk {3511,1138(.

Etiology

Race/ancestry

Risk factors

The incidence and mortality rates for prostate cancer are higher in Black men than in White men of European descent. The highest mortaHty occurs in African-Caribbean men and men of middle and southern African descent, while the lowest occurs in men in eastern and south-central Asia (2502,2981). The reasons for the disparity by race/ancestry are multifacto­ rial and include unequal access to prostate cancer screening, detection, and treatment. In addition, biological differences have been identified among tumours from people of various

SNPl 4UNMMPtrwlM(t.»

Fig. 4.08 Prostate cancer. Etiological factors implicated in prostate cancer develop­ ment. Chronic inflammation triggered by environmental and lifestyle exposures leads to persistent prostate epithelial cell damage. Inherited genetic predisposition also plays a determining factor in promoting oncogenesis. PIA, proliferative inflammatory

Established risk factors for prostate cancer include advancing age, family history, genetics, and race (2502). The widespread adoption of PSA screening and its impact on early diagnosis has profoundly affected studies on disease etiology {2502, 2484). Therefore, recent work has focused largely on studying exposures related to aggressive localized and lethal metastatic disease {1428}.

ETV1 Fusion/over-expression ■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ SPOP mutation FOXA1 mutation IDH1 mutation CHD1 CNA SPOPLCNA SPINK 1 over-expression KDM6A mutation KMT2A mutation KMT2C mutation KMT2D mutation Gleason score Himi ■■■ fliailBIO SI I II ■ IIBIIIIIH M II IMS I ■■■■■■■■■,■ Purity estimates ■MM Leukocyte fraction estimates

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Tumors (n=333)

Normals (n=19)

Wildtype Fusion Over-expression Mutation Heterozygous loss Homozygous deletion

FOXA1 IDH1

ii on smii i

scNAdustere wearasi DNA methylation dusters ■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■■ ■ ■■

Genetic alterations

SPOP

MM Mi

Beta value

iCIuster

Methylation

CL1 ■ CL2 ■ CL3

■ CL1 CL2 ■ CL3 ■ CL4

■

Purity estimate 0.17

0.98

Leukocyte fraction

SCNA Quiet a Some ■ More

Fig. 4.09 Prostate cancer. The molecular taxonomy of primary prostate cancer. Mutually exclusive somatic DNA alterations define key molecular subtypes of prostate cancer (511). CNA, copy-number alteration; SCNA, somatic copy-number alteration.

Tumours of the prostate

205

racial and ethnic groups. Prostate cancers in Black men con­ tain fewer TMPRSS2■:.ERG fusions {2713,3182,3570,1699} and PTEN deletions {3182,3570,1699,1496) and a higher incidence of SPOP mutations {3570,1699} than do those in men of Euro­ pean descent. Furthermore, germline variants in the region of chromosome 8q24, which contains loci linked to prostate can­ cer through the modulation of MYC expression (772), have also been linked to a greater susceptibility to prostate cancer in men of African ancestry {3360}.

Environmental and modifiable risk factors Environmental and lifestyle factors play an important role in prostate cancer initiation and progression. Determining which exposures are most important is complex, but managing modifi­ able risk factors has the potential to impact disease-preventive strategies {2502,2484}.

Obesity, diet, and other lifestyle factors Obesity has been linked to prostate cancer, with some studies suggesting a link to lethal disease (2502} and a higher risk of biochemical recurrence after prostatectomy (1556). Diets high in saturated and animal fats have been implicated in prostate cancer progression. In contrast, a higher intake of tomatoes and cooked vegetables containing lycopene and a low intake of carbohydrates are associated with a lower risk of aggressive prostate cancer (2502,2484). Dietary red and charred meats have been linked to an increased risk of prostate cancer in American men {2484,2628}. Cooking meats at high tempera­ tures results in the production of heterocyclic amines such as 2-amino-1-methyl-6-phenylimidazo[4,5-d]pyridine (PhIP). In animal studies, PhIP leads to the formation of DNA adducts and genomic changes {1691}, with the formation of intraductal high-grade prostate lesions {2921}. PhIP also leads to the development of inflammation in the prostate (397,2279}. Some studies support a link between heterocyclic amines and pros­ tate cancer, but quantifying this exposure is very difficult (313). A number of studies have indicated that even moderate physi­ cal activity is associated with a lower risk of dying from prostate cancer {2502,2484}. Also, although tobacco smoking is not generally considered to increase the risk of prostate cancer, a number of large studies have documented more prostate can­ cer-specific deaths in tobacco smokers than in non-smokers {2502,2484}.

Pathogenesis

Role of chronic inflammation and infection Chronic inflammation is highly frequent in benign tissue regions of the prostate. Whether infection and/or inflammation involving the prostate is causative for prostate cancer remains unclear and under active investigation. The prostatic epithelium in the vicin­ ity of inflammation is frequently atrophic yet highly proliferative compared with nearby non-inflamed luminal epithelium {2884}. These regions are termed "proliferative inflammatory atrophy" and have been considered risk factor lesions for prostatic car­ cinogenesis; at times, they merge with and potentially transition into high-grade prostatic intraepithelial neoplasia (HGPIN), or more rarely directly into small adenocarcinoma lesions (2585, 2283,3390}. A subset of the latter have the somatic GSTP1 hypermethylation seen in HGPIN and carcinoma (2283). Stud­ ies attempting to establish pathogenetic links between chronic 206

Tumours of the prostate

inflammation, microbial agents (including sexually transmitted infections), atrophy, and prostate carcinogenesis are ongoing {2884,2919,1773,2883,1910,215,2031}.

Somatic alterations driving disease initiation and progression Recent large-scale genomic studies including The Cancer Genome Atlas (TCGA) study have further elucidated the molec­ ular landscape of somatic DNA alterations in prostate cancer (511,2689,3371,199,3545,205,2744). Activation of MYC over­ expression, shortening of telomeres, inactivation of GSTP1 and other genes by CpG island hypermethylation, and gene fusions involving ETS transcription factors (e.g. TMPRSS2::ERG) are among the most common molecular alterations associated with prostate cancer initiation (3186). Androgen-driven ETS factors are key oncogenic drivers in 25-50% of prostate cancer cases (3172}. Half of the remaining cases of acinar adenocarcinoma of the prostate are driven by somatic mutations involving FLU, SPOP, FOXA1, or IDH1 that are mutually exclusive with ETS rearrangements and with each other. Gain of 8q24 (including MYC), loss of PTEN, inactivation of TP53, and additional muta­ tions and hypermethylation events are linked to disease pro­ gression. Somatic copy-number alterations are common in pri­ mary and metastatic prostate cancer. The accumulation of such alterations is associated with a worse outcome, suggesting that genetic instability is a key driver of prostate cancer progression {3128,1355}. In metastatic prostate cancer, the disease is nearly univer­ sally sensitive initially to androgen deprivation or AR blockade, yet most cases will ultimately progress to castration-resistant prostate cancer (CRPC). This transition is associated with AR gene amplification, mutation, or rearrangement, and/or with the activation of AR splice variants (151,1871), indicating that AR remains a key driver of late-stage disease. In a small subset, castration resistance is the result of transdifferentiation into an AR-negative phenotype, with some of these cases showing a spectrum of neuroendocrine differentiation including small cell neuroendocrine carcinoma (SCNEC) (2670,1620} (see Chap­ ter 9: Neuroendocrine neoplasms). Finally, as many as 20% of metastatic prostatic carcinomas appear to harbour germline or somatic alterations in DNA repair genes involved in homolo­ gous recombination repair (HRR), mismatch repair, and others (e.g. BRCA1, BRCA2, ATM, CHEK2, FANCI, PALB2, MSH2) {2689,199,2574,2056,3498,2593,3334,2660}. HRR defects can render prostate cancer susceptible to poly (ADP-ribose) polymerase (PARP) inhibition, and mismatch repair defects may render it sensitive to immune checkpoint inhibitors; these observations prompted the current guideline recommendations for germline and/or somatic testing for DNA repair defects in men with aggressive primary tumours and in men presenting with metastatic prostate cancer (1138,1214,48).

Macroscopic appearance Clinically diagnosed prostate cancer is most commonly located in the peripheral zone (in 79.2-90.9% of cases) (1461,655} followed by the transition zone (8.5-19.4%) (3133,1461,770), whereas only 0.3-2.5% of cancers originate in the central zone {677,770}. Unlike most cancers of other organs, prostate cancer is often not apparent macroscopically. Cancers were clearly visible in 41%, 52%, and 92% of cases in published series,

Fig. 4.10 Acinar adenocarcinoma. A Prostate cancer in the peripheral zone with tan cut surface (lower right). B Prostate cancer in the peripheral zone with white cut surface

(lower right). C Prostate cancer in the transition zone with orange cut surface (叩per left).

depending on the examination technique and how advanced the tumours were {1264,2656,1896}. Visible cancers are solid, firm, and poorly circumscribed {1896}. Tumours of the periph­ eral zone are most often tan or white in unfixed specimens (67.9%), and transition zone cancers are commonly yellow or orange (80.7%) {1896}. Transition zone cancers are less often visible (39.2%) than peripheral zone cancers (63.0%), possibly because they commonly grow within a pre-existing nodularity of prostatic hyperplasia (1896).

Histopathology The diagnosis of prostate cancer is usually initially established by histopathological examination of prostate needle biopsy samples and is based on a combination of architectural and cytological features {1991,1421). A similar combination of histo­ logical features is also applicable to the identification of acinar adenocarcinoma in radical prostatectomy and transurethral resection specimens, although some patterns (e.g. infiltrative growth) are easier to assess in larger specimens. Several diag­ nostic criteria and supportive features have been advocated, but few of them are absolutely specific. The microscopic criteria used to establish a diagnosis of prostatic carcinoma can be subdivided into major and minor {3153). Major criteria include an infiltrative growth pattern, an absence of basal cells, and nuclear atypia {1421). The infiltrative growth pattern typically consists of small atypical glands scattered between larger, more complex, and frequently paler benign glands. The pres­ ence of crowded glands in a linear arrangement spanning the width of the biopsy core should raise concern for malignancy. Single cells, cells arranged in cords, and fused and cribriform glands are less common patterns of invasion that are character­ istic of high-grade prostatic carcinoma. Prominent nucleoli are a common finding in prostate cancer; nuclear enlargement is often a helpful criterion, but its diagnostic value is not as high as that of the presence of prominent nucleoli. In challenging cases, the absence of basal cells may be confirmed by immunohisto­ chemical stains for basal cell markers such as high-molecularweight cytokeratins (34pE12, CK5) or p63 (1991,1421}. Minor criteria include amphophilic cytoplasm, nuclear hyperchroma­ sia, intraluminal amorphous eosinophilic material, intraluminal crystalloids, blue-tinged mucinous secretions, close proximity to high-grade prostatic intraepithelial neoplasia, and periacinar retraction clefting {3316). Corpora amylacea, atrophic glands,

substantial inflammation, and atypical glands merging with benign glands are features against the diagnosis of prostatic acinar adenocarcinoma. Only a few features are pathognomonic of prostate cancer: perineural invasion, glomerulations, and mucinous fibroplasia (collagenous micronodules) {945,246). Because these features are not common in needle biopsy cores with limited prostate cancer, their diagnostic value is limited in this setting. To be able to use perineural invasion as a diagnostic feature of cancer, the atypical prostatic glands should encircle the nerve or display intraneural invasion, because benign prostatic glands can indent nerves. Glomerulation consists of glands with an intra­ luminal tuft attached to only one point of the gland, reminiscent of a renal glomerulus {3316,2414). Mucinous fibroplasia is char­ acterized by very delicate, loose fibrous tissue with an ingrowth of fibroblasts {406). Seminal vesicle invasion and extraprostatic extension are diagnostic features of prostate cancer, although they are uncommon on core needle biopsy.

Unusual histological patterns Some patterns of prostate cancers, including atrophic, foamy gland, microcystic, and pseudohyperplastic, can be misdiag­ nosed as benign conditions because of their benign-appearing histological features {3524}.

Atrophic pattern adenocarcinoma, including adenocarcinoma with aberrant p63 positivity Some acinar adenocarcinomas show marked cytoplasmic vol­ ume loss mimicking benign atrophy. These changes may occur sporadically and are found in as many as 16% of radical pros­ tatectomy specimens {1569), although lower rates have been reported in other series {917|. When present, atrophic features are usually mixed with more typical areas of acinar adenocarci­ noma. Atrophic changes may also be seen after androgen abla­ tion or radiotherapy (2661). AMACR immunostaining is negative in 30% of atrophic pattern adenocarcinomas, so paying attention to the atypical architecture and nuclear features, as well as the absence of basal cells on immunochemistry, helps to prevent underdiagnosis (980). Such tumours are typically composed of single separate glands with an infiltrative pattern; they are usu­ ally assigned Gleason pattern 3. Some atrophic carcinomas show aberrant positivity for p63 and these may be molecularly distinct {3106,3181}. The concordance between atrophy and Tumours of the prostate

207

p63-positive prostatic adenocarcinomas is not complete. Aware­ ness of this pitfail and utilization of a high-molecular-weight keratin stain may help prevent a false negative diagnosis. p63-positive acinar adenocarcinoma has no proven prognostic significance.

behaviour is not noted to be different from that of other patterns of well-differentiated and Gleason pattern 3 tumours. HOXB13 p.G84E-related familial prostate cancers often show pseudohy­ perplastic features {2978}.

Pseudohyperplastic adenocarcinoma Acinar adenocarcinomas with a pseudohyperplastic pattern mimic epithelial hyperplasia of the prostate. In prostatectomy specimens there is nearly always an associated acinar adeno­ carcinoma; however, in core biopsies, as much as 90% of the adenocarcinoma may be pseudohyperplastic (1424). Differen­ tiation from benign hyperplasia is aided by the identification of glandular crowding, nuclear enlargement, macronucleoli, intraluminal crystalloids, and amorphous debris. Immunohis­ tochemistry highlights the complete loss of basal cells (193), and AMACR positivity is detected in 70-83% of cases (3627). Metastases and perineural invasion have been described in pseudohyperplastic adenocarcinoma {1424,2983} and its

Microcystic adenocarcinoma The microcystic pattern is characterized by dilated malignant glands, on average 10 times the size of acini in typical aci­ nar adenocarcinoma. Microcystic adenocarcinoma is usually admixed with areas of more typical acinar carcinoma and has been recognized in 11% of radical prostatectomy specimens {3541}. It may resemble benign cystic atrophy and although it is assigned Gleason pattern 3, higher-grade carcinoma may be seen in other areas. Foamy gland adenocarcinoma Foamy gland adenocarcinoma shows abundant xanthoma­ tous cytoplasm and often has pyknotic nuclei lacking the

Fig. 4.11 Prostatic acinar adenocarcinoma. A Small malignant glands infiltrating between larger benign glands in a needle core biopsy. B The same case shows strong AMACR (red) positivity in the small infiltrating glands. The basal cells in the adjacent benign glands are highlighted in the triple stain (p63 and high-molecular-weight cy­ tokeratin; brown). C Prostate cancer with prominent nucleoli and amphophilic cytoplasm. D Prostate cancer glands with intraluminal amorphous eosinophilic material and crystalloids. E Wispy, blue-tinged intraluminal mucin in prostate cancer. F This example shows marked retraction artefact. G Acinar adenocarcinoma with perineural invasion. Adenocarcinoma glands circumferentially encircling a nerve. H Acinar adenocarcinoma with glomerulation. The glomerulation consists of a prostatic gland with a cribriform tuft attached to only one edge of the gland, resulting in a structure resembling a glomerulus. I Acinar adenocarcinoma with mucinous fibroplasia. Mucinous fibroplasia (or collagen­ ous micronodule) is characterized by delicate loose eosinophilic fibrous tissue with an ingrowth of fibroblasts that impinge on glandular lumina.

208

Tumours of the prostate

Fig. 4.12 Acinar adenocarcinoma. A Atrophic pattern of acinar adenocarcinoma with malignant glands showing cytoplasmic volume loss, mimicking benign atrophy. B p63positive adenocarcinoma with typical atrophic pattern morphology. C Diffuse aberrant staining for p63. D Pseudohyperplastic pattern of adenocarcinoma with papillary infold­ ings, luminal undulation, and branching resembling benign prostatic hyperplasia. E Microcystic pattern of adenocarcinoma with dilated malignant glands. F Foamy gland pattern of adenocarcinoma with abundant xanthomatous cytoplasm. G Foamy gland adenocarcinoma with small dark nuclei. H Prostatic mucinous adenocarcinoma. Gleason pattern 3 adenocarcinoma composed of discrete glands with abundant extraluminal mucin. I Prostatic mucinous adenocarcinoma. Gleason pattern 4 adenocarcinoma composed of cribriform glands with extraluminal mucin.

characteristic macronucleoli of typical acinar adenocarcinoma {2303}. For these reasons it may be mistaken for benign glands or even macrophages. It is seen (usually in combination with typical acinar adenocarcinoma) in 17% of needle biopsy cases and a similar percentage of radical prostatectomy specimens (3403}. The foamy appearance is caused by the presence of numerous intracytoplasmic vesicles, which lack lipid or neu­ tral mucin {3189}. Most foamy gland carcinomas are Gleason score 6 or 7, although Gleason score 8-10 carcinomas have been reported. AMACR overexpression is seen in > 90% of cases {1696,3403}. Foamy gland adenocarcinoma carries a similar prognosis to that of typical acinar adenocarcinoma of the same grade after radical prostatectomy (1417).

Mucinous adenocarcinoma Mucinous (colloid) adenocarcinoma is defined as a primary prostatic acinar carcinoma with > 25% of the tumour composed of glands with extraluminal mucin, so the diagnosis can be made only in excision specimens {2401). Tumours where the

extraluminal mucinous component represents < 25% of the lesion are referred to as prostatic adenocarcinoma with muci­ nous features. The prognosis of mucinous adenocarcinoma appears to be similar to, or in some cases better than, that of non-mucinous prostate cancers of a similar grade, when treated by radical prostatectomy (2791,1791,2401}. Patients with muci­ nous adenocarcinoma have similar cancer-specific survival and overall survival to matched individuals with typical prostate aci­ nar adenocarcinoma {3609). The majority of mucinous prostatic adenocarcinomas and prostatic adenocarcinomas with muci­ nous features retain PTEN expression {344}.

Subtypes Signet-ring cell-like adenocarcinoma Signet-ring morphology is defined by intracytoplasmic vacu­ oles that displace the compressed nucleus to the periphery of the cell (2683}. Prostatic signet-ring cells are generally mucin­ negative, which is why the term ''signet-ring cell-like" is often used {3401,1768}. This subtype is very rare in its pure form. Tumours of the prostate

209

Fig. 4.13 Acinar adenocarcinoma. A Signet-ring cell-like adenocarcinoma. This subtype of acinar adenocarcinoma shows numerous malignant cells with cytoplasmic vacuoles compressing the nucleus. This example is Gleason score 5 + 5 = 10. B Sarcomatoid carcinoma comprising pleomorphic spindle cells. C Prostatic intraepithelial neoplasia

(PIN)-like carcinoma. This subtype of acinar adenocarcinoma comprises large, discrete glands with flat or tufted pseudostratified epithelium. Like in this case, the nuclei are often

elongated, resembling those in ductal adenocarcinoma. D Prostatic intraepithelial neoplasia (PIN)-like carcinoma. Triple immunohistochemistry cocktail of p63, high-molecularweight cytokeratin, and AMACR demonstrating the absence of basal cells in the malignant glands.

The presence of signet ring-like cells accounting for > 25% of tumour cells is considered diagnostic; in consecutive series, this is found in about 2% of cases. Intracytoplasmic vacuola­ tion may occur in any Gleason pattern, but it is more commonly associated with higher Gleason patterns and therefore usually has a poor prognosis {436,1055,3178). Very rarely, true signet­ ring adenocarcinomas of the gastrointestinal tract metastasize to the prostate {2454}.

Sarcomatoid carcinoma Sarcomatoid dedifferentiation of prostate carcinoma is exceed­ ingly rare {2294,905} and most commonly occurs during the development of high-grade adenocarcinoma, especially after irradiation {1286,1410}. The sarcomatous tumour component may appear as homogeneous spindle cell sarcoma, but it may also contain areas of heterologous leiomyomatous, angiosarcomatous, chondroid, or osseous differentiation. The prognosis is generally dismal despite therapy (2032,1286). The differential diagnosis encompasses prostatic stromal sarcoma and solitary fibrous tumour, but also gastrointestinal stromal tumour and other sarcomas secondarily involving the prostate (249,2092}. Demonstration of a TMPRSS2::ERG translocation by FISH may be diagnostically useful to confirm the tumour's prostatic origin.

On immunohistochemistry, AR expression may be lost and PSA is usually negative (2693,81,2785,2659). Pleomorphic giant cell adenocarcinoma Pleomorphic giant cell adenocarcinoma is a rare and clinically highly aggressive subtype described in relatively small series (< 30 patients) or as case reports (1937,2459,1799,82,1953,81}. Morphologically, it is defined by the presence of extreme nuclear atypia and pleomorphism, with characteristic bizarre multinucleated and mononuclear giant cells, usually with abundant cyto­ plasm. There are often atypical mitoses. The overall histological appearance is variable: in some cases, the giant cell adenocar­ cinoma component is present focally (~5% of the tumour) along­ side usual high-grade acinar adenocarcinoma, whereas in oth­ ers, the giant cell component predominates (> 70%). It may occur mixed with ductal adenocarcinoma or other rare morphological subtypes or patterns (e.g. squamous, sarcomatoid, and neuroen­ docrine). Many cases arise after prior androgen deprivation or radiation therapy. Most cases are positive (at least focally) for one or more prostate-restricted markers such as PSA, P501S, NKX31, HOXB13, and AR (1799,82,1953). Molecularly, they are char­ acterized by relatively infrequent ERG rearrangements, a high prevalence of PTEN loss, and TP53 mutations (1953,81). Also,

Fig. 4.14 Pleomorphic giant cell adenocarcinoma of the prostate. This is from a recent case of a lymph node metastasis accompanying a radical prostatectomy, which was also metastatic to the penis at the time of surgery. Morphologically, it is a very high-grade carcinoma and contains a high degree of nuclear pleomorphism and many bizarre giant cells (A). Immunophenotypically, many of the tumour cells (including giant cells) were positive for PSA, and the lesion was diffusely positive for NKX3-1 (B) and AR.

210

Tumours of the prostate

there are frequent biallelic pathogenic mutations in homologous DNA repair genes or mismatch repair genes (1953).

contrasts with the usual molecular profile of both acinar and ductal adenocarcinoma, highlighting its distinctiveness {1621).

PIN-like carcinoma Prostatic intraepithelial neoplasia (PIN)-like carcinoma is uncommon and a mimic of HGPIN. This subtype is character­ ized by large, discrete glands with a flat or tufted architecture; the glands are often lined by pseudostratified epithelium dis­ playing elongated hyperchromatic nuclei, which resembles that of ductal adenocarcinoma (1268,3123). In other cases of PINlike carcinoma the neoplastic epithelium is cuboidal, with round nuclei that are more typical of acinar adenocarcinoma (1268}. This subtype can be distinguished from HGPIN by the crowd­ ing of the glands and the lack of basal cells, and from ductal adenocarcinoma by the absence of true papillae with fibrovascular cores, cribriform glands, and necrosis. It has a generally favourable prognosis and is assigned Gleason score 3 + 3 = 6 (3123,2470(. A recent molecular study found frequent activating mutations in the RAF/RAS pathway in PIN-like carcinoma, which

Tumour invasion and spread Prostatic adenocarcinoma spreads outside the prostate by direct invasion into adjacent organs and tissues, by lymphatic spread to lymph node groups, or by haematogenous spread to distant organs. Extraprostatic extension is identified histo­ logically by the direct invasion of periprostatic fat or beyond the plane of fat, or by the involvement of dorsolateral nerve bun­ dles, or by the carcinoma bulging beyond the normal prostatic contour (3445,1993}. Diagnosis of seminal vesicle invasion requires involvement of its muscular wall, with only the extrapro­ static portion of the seminal vesicles being considered positive (339). Invasion of the seminal vesicles can occur directly from the prostate, via the extraprostatic tissues or discontinuously as a metastasis {2361,360(. Direct involvement of the urinary bladder, pelvic soft tissue, and rectum may occur in advanced cancers (290,412,1794(.

Fig. 4.15 Acinar adenocarcinoma. A,B Gleason score 2 + 2 = 4 adenocarcinoma showing circumscription and rounded contours of the tumour nodule (A) and displaying promi­ nent nucleoli, straight luminal borders, intraluminal amorphous eosinophilic secretion, and crystalloids (B). C Gleason pattern 3 with individual well-formed glands. D Gleason pattern 4 cancer comprising poorly formed glands. E Gleason pattern 4 carcinoma consisting of small cribriform glands. F Gleason pattern 4 adenocarcinoma composed of large cribriform glands. G Gleason pattern 5 adenocarcinoma comprising large sheets of cribriform and solid carcinoma with comedonecrosis. H Gleason pattern 5 adenocarci­ noma showing single cells, cords, and nests infiltrating between benign glands with minimal glandular differentiation. I Gleason pattern 5 adenocarcinoma with single cells and cords displaying minimal glandular differentiation infiltrating between benign glands.

Tumours of the prostate

211

Prostate cancer spreads via the lymphatics to regional lymph nodes and shows a propensity to metastasize haematogenously to bone. When nodal disease is present it most commonly involves the external iliac, internal iliac, obturator, and presacral lymph nodes {1486,1321}. Advanced cancers can spread to vis­ ceral sites, including liver, lungs, and brain {1084(.

Immunohistochemistry Immunohistochemistry can be used to enhance the diagnostic accuracy of prostate biopsies or to identify metastatic prostate cancer in other organs (952). A panel of markers is usually rec­ ommended; however, it should be noted that the pathological

Flg.4.16 Acinar adenocarcinoma. ing. C ERG is positive. Table4.01

A

diagnosis of prostatic adenocarcinoma is primarily based on histological features. A number of prostate-specific markers can be used to deter­ mine whether a carcinoma originates from the prostate. Among them, PSA is best known; however, NKX3-1 has much better sensitivity and specificity for prostatic adenocarcinoma {1245, 654}. ERG is positive in < 50% of cases of prostatic adeno­ carcinoma (835,437} and in an even lower proportion in Asian populations (3052,3620); its low sensitivity limits its usefulness in prostate biopsies. AMACR has been widely used for the diag­ nosis of prostate cancer on core needle biopsies because of its higher expression in adenocarcinoma than in benign epithelium

PSA staining in signet-ring cell-like carcinoma. Note the strongly positive staining in benign glands (left).

B

PSMA-positive immunostain­

Diagnostic immunohistochemical markers of prostatic adenocarcinoma

Antibody (marker)

Prostatic secretory cells

Prostatic basal cells

Prostatic adenocarcinoma

Staining pattern

Utility and comment

NKX3-1 (1245,654}

Positive

Positive (weak)

Positive

Nuclear

Best for determining prostatic origin

PSA

Positive

Negative

Positive

Cytoplasmic

PSMA {255}

Positive

Negative

Positive

Cytoplasmic

P501S {1571,2911}

Positive

Negative

Positive

Cytoplasmic

PAP {95}

Positive

Negative

Positive

Cytoplasmic

Negative, or cytoplasmic fine

Negative

Positive

AMACR (1520,2745,1521}

granules

Cytoplasmic, coarse granules

Decreased in high-grade carcinoma

Positive in colorectal carcinoma, renal cell papillary carcinoma, etc.

p63 {2896,3630,2891}

Negative

Positive

Negative

Nuclear

p63 and HMWCKs often used with AMACR as a triple stain

HMWCKs (34PE12) (2896,3630,2891)

Negative

Positive

Negative

Cytoplasmic

p63 and HMWCKs often used with AMACR as a triple stain

ERG {835,437,3052}

Negative

Negative

Nuclear

Low sensitivity, positive in endothelium

Positive

Positive (weak)

Positive

Nuclear

Not specific for prostate

Negative or very weakly positive

Positive (weak)

Variable

Nuclear

Proliferative activity

Chromogranin, synaptophysin, NSE

Negative

Scattered positivity in neuroendocrine cells

Variable, usually focal

Cytoplasmic

To identify neuroendocrine differentiation

MUC6(1852}

Negative

Negative

Negative

Cytoplasmic

Positive in seminal vesicle / ejaculatory duct

AR

Ki-67

HMWCKs, high-molecular-weight cytokeratins (CK5 and CK6).

212

Tumours of the prostate

Positive (in< 50% of cases)

in the prostate {1520,2745,1521}. However, AMACR has limited value in identifying metastatic prostate cancer because other carcinomas (e.g. colonic adenocarcinoma, papillary renal cell carcinoma) can also be positive for AMACR. Basal cell markers (p63, high-molecular-weight cytokeratin) are usually absent in invasive prostatic adenocarcinoma {2896,3630). An antibody cocktail including AMACR, p63, and high-molecular-weight cytokeratin (triple stain) is often used on prostate biopsies, par­ ticularly for a small focus of abnormal cells {2891(. Such triple immunostains can also be used in the diagnosis of prostatic intraductal carcinoma (1224,2687} and p63-positive prostatic carcinoma {2403}. The diagnostic immunohistochemical markers of prostatic adenocarcinoma are summarized in Table 4.01.

Grading The Gleason grading system forms the basis for prostate cancer grading worldwide. It has been modified on several occasions over the past 50 years, most recently after the International Society of Urological Pathology (ISUP) consensus conferences in 2005, 2014, and 2019 and the 2019 white paper by the Geni­ tourinary Pathology Society (GUPS) (946,951,3291,948). Vali­ dation studies that followed the 2005 and 2014 modifications demonstrated that the Gleason score remains an independent predictor of biochemical recurrence, metastasis, and prostate cancer-specific mortality (955,822,3011,331,1819,1197). In essence, the Gleason system assigns values ranging from 1 (most differentiated) to 5 (least differentiated) to the various architectural patterns of prostate cancer. The primary (i.e. the most prevalent) and secondary grade patterns are added together to derive a Gleason score, usually expressed as a sum (e.g. 3 + 4 = 7 or 4 + 5 = 9). When only one grade pattern is present, its value is doubled to give the Gleason score (Table 4.02 and Table 4.03). Nuclear and cytoplasmic features are not factored into Gleason grading of prostate cancer. The 2005 ISUP consensus conference introduced a number of key changes to reflect evolving diagnostic prac­ tice. In particular, patterns 1 and 2 are no longer assigned to core needle biopsy specimens and are rarely used in radical prostatectomy specimens, leaving an effective range of 6-10 for Gleason scores. Moreover, since 2005, the Gleason score

for core needle biopsies is derived by adding the primary pat­ tern to the highest remaining grade pattern, unlike in prosta­ tectomy specimens where the score is generally derived from the sum of the primary and second most prevalent patterns (946). However, in some radical prostatectomy specimens the prostate cancer may consist of more than two Gleason patterns, with the highest grade (pattern 5) representing the smallest volume, referred to as a tertiary high-grade pattern. In this situation, if the tertiary grade pattern constitutes > 5% of the tumour volume it becomes the secondary pattern in Gleason scoring {2191,949,948,3291}. Although the 5% cut­ off point is somewhat arbitrary, higher tertiary-pattern volumes are associated with a worse prognosis {1465,395,268,2825, 1611(. If there is a higher-grade component constituting < 5% of the tumour, it may be dealt with differently in the 2019 ISUP and GUPS systems, depending on the grading scenario (see Table 4.03, p. 214, and Table 4.04, p. 215). Some authors have advocated for more quantitative grading, recognizing that the amount of high-grade (pattern 4 or 5) tumour strongly corre­ lates with outcome (3019,921,2826). At the 2014 ISUP conference the concept of grade groups (GG1-GG5) was endorsed. This system is also referred to as "ISUP grade" or simply "WHO Classification of Tumours grade (WHO grade)", in part to distinguish it from the other grade grouping systems used in various studies before 2013. These grade groups correspond to Gleason scores but have some advantages with respect to the communication of results to patients, clinicians, and researchers; for instance, Gleason score 3 + 3 = 6 cancers are assigned GG1 to highlight their generally favourable prognosis, whereas 3 + 4 = 7 cancers (GG2) are placed in a separate grade group to 4 + 3 = 7 can­ cers (GG3) to emphasize the higher risk of recurrence associ­ ated with the latter (2525,951). The 2019 grading changes proposed by ISUP and GUPS are yet to be fully validated, and there are also some specific differences between the recommendations from the two bod­ ies that cannot be resolved on the basis of currently available published evidence (Table 4.04, p. 215) {3291,948,2977). Both organizations advocate reporting an estimate of the percent­ age of pattern 4 cancer present in prostate biopsies with Glea­ son score 7 (GG2 or GG3), as well as the presence of invasive

Table4.02 Gleason grade patterns (after the ISUP 2005 and 2014 modifications (946,951))

Gleason

pattern 1 and 2

Key morphological features

Discrete regular glands; circumscribed, rounded nodules

Discrete glands with marked variation in size and shape; infiltration between 3

non-neoplastic acini

Comments

Not used for needle biopsy specimens; very rarely used in grading radical

prostatectomy specimens

No longer includes cribriform or glomeruloid glands after the ISUP 2005 and 2014 consensus conferences

Includes pseudohyperplastic, atrophic, and microcystic patterns 4

Fused microacinar glands, poorly formed glands without well-defined lumina, cribriform glands, or glomeruloid glands Minimal glandular differentiation, comprising solid sheets, cords, small solid cylinders, or single cells

5

OR

Most (but not all) comedocarcinomas are now recognized as IDC-P

{1981,1009)

Solid, cribriform or papillary structures with central necrosis (comedocarcinoma) IDC-P, intraductal carcinoma of the prostate; ISUP, International Society of Urological Pathology.

Tumours of the prostate

213

,

■
5% tumour): 5

Second most prevalent (secondary): 3

OR

4

5+3=8

Most prevalent (primary): 5

Second most prevalent (secondary): 3 One, two, or three grade patterns present:

One, two, or three grade patterns present: Most prevalent (primary): 4 Highest additional grade pattern (secondary): 5

4+5=9 5+4=9

5 + 5 = 10

OR

5

Most prevalent (primary): 5 Highest additional grade pattern (secondary): 4 OR Only pattern 5 present

Most prevalent (primary): 4

Second most prevalent (secondary): 5* OR

Most prevalent (primary): 4 Third most prevalent (> 5% tumour): 5

OR

Most prevalent (primary): 5 Second most prevalent (secondary): 4

OR Only pattern 5 present

GG, grade group; ISUP, International Society of Urological Pathology. 'For core needle biopsies with multiple specimens there is uncertainty about whether the highest specimen score or the global (overall) Gleason score is superior in predicting the radical prostatectomy score and clinical outcome. ISUP recommends reporting a separate Gleason score for each biopsy site. Global scores should be assigned for each MRItargeted lesion {3291,948}. bMost radical prostatectomy specimens show multifocal carcinoma (3478}, and ISUP recommends that the Gleason scores of the largest, highest-grade, and highest-stage nodules are recorded. cISUP2019 recommendations would allow assignment of a minor Gleason pattern 4or5ina3 + 3 = 6 (GG1) carcinoma provided that the pattern 4 or 5 represents s 5% of the tumour volume. Genitourinary Pathology Society (GUPS) 2020 defines a minor tertiary pattern as requiring the presence of three different

patterns, and confines its use to GG2 or GG3 cancers. Thus, in the GUPS system, a carcinoma with 96% pattern 3 and 4% pattern 4 would be scored as 3 + 4 = 7. dMinor tertiary grade patterns should be mentioned in the report. However, if tertiary pattern 5 constitutes > 5% of the tumour volume it becomes the secondary pattern in the Gleason score (i.e. either 3 + 5 = 8 or 4 + 5 = 9). eA cancer scored as 4 + 4 = 8 (GG4) can have a minor component of Gleason pattern 5 (s 5% pattern 5 and >95% pattern 4) under ISUP 2019

recommendations. In contrast, according to the GUPS guidelines, such a tumour would be scored 4 + 5 = 9 (GG5).

214

Tumours of the prostate

Table4.04 Key differences between ISUP 2019 and GUPS 2019 recommendations on Gleason grading Issue

ISUP 2019 (3291}

GUPS 2019 (948}

Supporting evidence

Overall evidence for or against inclusion is inconclusive; positions were based largely on consensus opinion

Whether to include IDC-P

Yes, incorporate into Gleason

No, do not incorporate into

admixed with invasion

score

Gleason score

Often cannot reliably identify IDC-P without using IHC to identify basal cells; therefore, historical and

Cases where the presence of IDC-P would alter the Gleason score represent a small subset of these cohorts and any effect of inclusion

Few studies have been specifically designed to address the questions of whether to include IDC-P in Gleason

on outcome predictions would not be

One 2020 study showed that incorporating IDC-P made

apparent

minimal difference to Gleason score assignment in biopsy

cancer in Gleason scoring3

contemporary outcome data are based on incorporation of IDC-P

score / grade group and what its relationship is to

outcome (1612,3290)

and prostatectomy cohorts {2673}; another smaller 2020 study showed that it did change in Gleason score in a significant minority (23%) of biopsy cases {627}

Avoids need for widespread IHC

whenever cribriform glands or comedocarcinoma is present

Can be mitigated by performing IHC to identify IDC-P only if the result

Few studies address the question of how frequently IHC is required in diagnostic practice for the identification of

would change the Gleason score

IDC-P {1085,627,2673} Most comedocarcinomas (Gleason pattern 5) represent IDC-P, once IHC is performed for basal cells (1981,1009}

Limited data on how these differences might affect other recommendations, e.g. quantification of percentage of Gleason pattern 4 in Gleason score 7 cases (1085,2673)

Precursor-like IDC-P associated with

Recognition of minor/ tertiary Gleason patterns in radical prostatectomy cases with Gleason scores of 3 + 3 = 6 and 4 + 4 = 8

Could lead to incorporation of precursor-like IDC-P into the Gleason

Few published cases of precursor-like IDC-P {678,2688,2183,1640}

invasive carcinoma is so rare that its potential incorporation into Gleason

score, thereby including an in situ

score is not a major issue

component in the grade

Yes: if a higher grade component represents < 5%b of tumour volume

No: by GUPS definition, minor tertiary pattern 5 does not exist in

Mixed evidence, data not conclusive; complicated by different grading definitions, relatively small case

it is not included in the Gleason score but reported as a minor high­ grade pattern

these grading scenarios

numbers, different endpoints Specific ISUP scoring scenarios:

•3 + 3 = 6 with minor pattern 4(8 (3391(. The SCNEC component shows nuclear p53 staining in most cases, thyroid transcription factor 1 (TTF1) positivity in about half of cases, and AR positivity in a subset; PSA and PAP are typically negative in the SCNEC component (411. t-NEPC is probably a separate clinical entity that has a spec­ trum of histological features including pure neuroendocrine morphology (most commonly small cell carcinoma) and mixed tumours with a poorly differentiated adenocarcinoma compo­ nent (2226). The histology and the immunohistochemical stain­ ing pattern of t-NEPC are similar to those of primary prostatic SCNEC. t-NEPC can show pronounced heterogeneity, ranging from adenocarcinoma to small-cell areas within the same meta­ static deposit. Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: prostatic carcinoma with neuroendocrine differentia­ tion, pure or admixed with generally high-grade adenocar­ cinoma; confirmatory immunohistochemical stains (synapto­ physin, chromogranin); history of antiandrogen therapy. Staging The eighth-edition Union for International Cancer Control (UICC) staging system is used. Prognosis and prediction In more than half of the patients in whom it develops, t-NEPC develops within 24 months of androgen-deprivation therapy and the median survival time after transdifferentiation to t-NEPC is only 7 months {3377}. Pure small cell carcinoma is associ­ ated with a worse overall survival than tumours with a mixed histology (8.9 months from t-NEPC diagnosis vs 26.1 months, respectively; P< 0.001) {701}.

Adenosquamous carcinoma of the prostate

Definition Adenosquamous carcinoma of the prostate is defined by the presence of both glandular and squamous components. ICD-0 coding 8560/3 Adenosquamous carcinoma

ICD-11 coding 2C82.Y & XH7873 Other specified malignant neoplasms of prostate & Adenosquamous carcinoma Related terminology Acceptable: prostatic carcinoma with adenosquamous differen­ tiation.

Subtype(s) None Localization Prostate

Clinical features Most patients present with urinary obstructive symptoms and increased urinary frequency. As many as 72% have had a prior diagnosis of prostate adenocarcinoma, for which they were often treated by hormone and/or radiation therapy; 29% of patients present without a history of adenocarcinoma (2461). As many as 20% of patients present with metastatic disease {3379). Serum PSA levels can be elevated or normal.

Fig. 4.23 Adenosquamous cell carcinoma of the prostate. This example shows a dis­ tinct squamous component with a transition to the glandular component.

Parwani AV Humphrey PA Montironi R van Leenders GJLH

Epidemiology Adenosquamous carcinoma represents 0.003% of all prostate cancers {436). It is less commonly seen than pure squamous cell carcinoma of the prostate. Median reported ages vary from 67 to 74 years {3379,436}. The tumour arises either de novo or after radiation and/or hormone therapy (2461). Etiology Most patients have a history of conventional prostatic adenocar­ cinoma for which they were treated by radiation and/or hormone therapy {2461). Pathogenesis The molecular background is comparable to that of conven­ tional acinar adenocarcinoma, with TMPRSS2::ERG fusions, PTEN deletions, and SPOP mutations (81,876). In reported E/?G-rearranged cases, immunohistochemical staining was strongly positive in the glandular component but weak to negative in the squamous component (81). One adenosquamous carcinoma with FAM131A::BRAF fusion has been reported (81).

Macroscopic appearance Not well established Histopathology Adenosquamous carcinoma is composed of both glandular (acinar) and squamous components. Most cases show vary­ ing proportions of the squamous component admixed with the glandular component. In most cases, the acinar component is grade group 2 or higher. The squamous component can range from 5% to 95%, and it can show a wide range of differentia­ tion as well as mild to severe cytological atypia (2461}. Nuclei in the squamous component are larger and more pleomorphic than in the glandular component. The glandular or squamous component can be distinct or show transitions from one to the other. Transitions of both components are frequently observed. A third component, sarcomatous, is observed in 20-57% of cases (2461,81). The glandular component expresses PSA or other prostate markers such as PAP; the squamous component is positive for basal cell markers while being mostly negative for PSA {2461}. There are only scant data on NKX3-1 {876). The most important differential diagnosis is urothelial car­ cinoma with divergent differentiation, from which adenosqua­ mous carcinoma can be distinguished by the morphology and immunohistochemical profile of the non-squamous component as well as by consideration of the clinical history and radiologi­ cal appearance.

Cytology Not relevant

Tumours of the prostate

225

Diagnostic molecular pathology Molecular investigation (for TMPRSS2::ERGfusions, P7EA/dele­ tions, and SPOP mutations) may be helpful in selected cases.

Staging The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM classification is used.

Essential and desirable diagnostic criteria Essential: presence of both malignant glandular and squamous components.

Prognosis and prediction Adenosquamous carcinoma is a rare and aggressive disease, with 20-31% of men presenting with metastasis, and with 5-year cancer-specific survival rates of 30% {3379,436).

226

Tumours of the prostate

Squamous cell carcinoma of the prostate

Gordetsky JB Algaba F Kench JG Parwani AV

Definition Prostatic squamous cell carcinoma (SCC) is a rare type of pros­ tate cancer with squamous histology, defined by keratinization, keratin pearls, and intercellular bridges. ICD-0 coding 8070/3 Squamous cell carcinoma

ICD-11 coding 2C82.Y & XH0945 Other specified malignant neoplasms of prostate & Squamous cell carcinoma, NOS

Related terminology None

Subtype(s) None

Localization Prostate

Clinical features SCC of the prostate gland most often arises in elderly patients with a history of hormone or radiation therapy, typically for prostatic adenocarcinoma (1422,2461,2196}. Patients typically present with urinary obstruction, dysuria, haematuria, or bone pain from metastatic disease {1422,2461,1577). Pelvic lymph node metastases and osteolytic bone metastases are common. Serum PSA levels are usually not elevated. Radical prostatec­ tomy or cystoprostatectomy is performed for organ-confined or locally advanced disease. There is no standard approach to metastatic disease; the use of chemotherapy and radiation therapy has been described in the. literature, with questionable efficacy being reported (2252,1577). Epidemiology The prognosis is poor, with a short survival time after diagnosis and no definitive treatment {1422,2461). SCC of the prostate is extremely rare {1422,2461,2196,2265}. Most cases in the litera­ ture have been in patients who were > 70 years old.

Etiology In most reported cases, there is an association with previous hormone or radiation therapy for prostatic adenocarcinoma {2461,2265(. Pathogenesis Studies in the literature and the sequence of disease progres­ sion suggest that treatment of adenocarcinoma precedes the development of SCC of the prostate {1779,1577,210,1825}. Lager et al. suggested that SCC of the prostate may arise because of adverse stimuli affecting the columnar cells, resulting in a

Fig. 4.24 Squamous cell carcinoma of the prostate. Infiltration of the stroma by a nest of squamous epithelium, with some cells showing keratinization.

loss of secretion of PSA and/or PAP with a concomitant gain in expression of keratin (1779}. It has been speculated that SCC can arise from the pluripotent stem cells of the prostate gland or from squamous metaplasia of acini and prostatic ducts {2196, 210}. Another hypothesis is that it might be a cellular transdif­ ferentiation of acinar prostatic adenocarcinoma after cancer therapy such as androgen-deprivation therapy or radiation {210,2600,416,876}. There are limited molecular data available because of the rarity of these tumours. However, several recent case reports, which applied next-generation sequencing-based technolo­ gies to 4 cases of locally recurrent and metastatic prostatic SCC, demonstrated TMPRSS2::ERG fusion in 3 of the tumours (1798,876,1804). The remaining case harboured an SPOPmuta­ tion, which can also lead to ERG activation at the posttranslational level {876}. In contrast to the morphological features of SCC, which are nonspecific with respect to the site of origin, the presence of a TMP白SS2.:ERG fusion essentially confirms the

prostatic origin of the carcinoma. Also typical of acinar prostatic adenocarcinoma was the loss of PTEN in 3 cases, and a PTEN mutation was identified in the remaining case (1798,876,1804}.

Macroscopic appearance Grossly, these tumours are yellow-white, firm, and often exten­ sive, replacing most of the normal prostatic tissue. Compression of the prostatic urethra and invasion into the urinary bladder and other adjacent organs has been reported (1422}. Histopathology The microscopic findings are similar to those observed in SCCs at other sites. Features include squamous architecture with keratinization and/or intercellular bridges and cellular anaplasia.

Tumours of the prostate

227

There should be no glandular elements. Prostatic adenocar­ cinoma with squamous differentiation, local extension of blad­ der carcinoma with squamous differentiation, and metastatic SCC should be excluded (1050,2236,2007,1323,1}. Gleason grading / grade groups are not applicable; these tumours can be graded as well differentiated, moderately differentiated, or poorly differentiated, based on the degree of keratinization and cellular atypia. Tumours lack expression of PSA, PAP, and PSMA, and the show positivity for p63, 340E12, CK5/6, and CK14 (2252,2461), AMACR can be positive {210(.

Cytology Not relevant Diagnostic molecular pathology Not relevant Essential and desirable diagnostic criteria Essential: squamous architecture with keratinization and/or intercellular bridges; cellular anaplasia; absence of glandular

228

Tumours of the prostate

differentiation; exclusion of prostatic adenocarcinoma with squamous differentiation, local invasion by bladder carci­ noma with squamous features, and metastatic SCC.

Staging The American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC) classification applies to prostatic SCC {2443}. Prognosis and prediction SCC of the prostate is an aggressive disease with a poor prog­ nosis. These tumours are often detected at the time of transure­ thral resection subsequent to urinary obstruction and patients have advanced disease at presentation (210,1577,2252}. The average survival period is usually short, ranging from 6 to 24 months in the literature, with no known prognostic factors {2461,1422,1577(.

Adenoid cystic (basal cell) carcinoma of the prostate

Definition Adenoid cystic (basal cell) carcinoma of the prostate is a malig­ nant neoplasm thought to be derived from prostatic basal cells.

ICD-0 coding 8147/3 Adenoid cystic (basal cell) carcinoma ICD-11 coding 2C82.Y & XH4ZC3 Other specified malignant neoplasms of prostate & Basal cell carcinoma of the prostate Related terminology Acceptable: adenoid cystic carcinoma; adenoid basal cell car­ cinoma; basal cell carcinoma of the prostate; adenoid cystic carcinoma (solid pattern).

Subtype(s) None

Localization Prostate Clinical features Patients often have urinary obstruction; diagnosis is most com­ monly made on transurethral resection specimens, less often on biopsy. Serum PSA is normal {1443,85,46} unless there is a concomitant acinar carcinoma, which is found in a minority of cases {1443,85,2095,2941}. Epidemiology The reported patient age range is 42-93 years (1443,85,2913, 2095}.

McKenney JK Iczkowski KA Parwani AV van Leenders GJLH

Etiology Unknown Pathogenesis A subset of cases are associated with MYB::NFIB fusion {1986, 363).

Macroscopic appearance Not well established Histopathology Most cases show varying proportions of (1) the adenoid cys­ tic / cribriform pattern with inspissated secretions and (2) the basaloid pattern with small solid nests of basal cells. Less often, cords of cells or small tubules lined by a hyaline rim are seen. The stroma may be desmoplastic. Mitotic activity and Ki-67 proliferation index vary widely. Five criteria support the differ­ ential diagnosis from florid basal cell hyperplasia: cytoarchitectural atypia, invasive pattern into the stroma and between normal prostate acini, perineural invasion, necrosis (seen in a few cases), and extraprostatic extension. Basal cell markers often label the outermost layer(s) of basal cell carcinoma, sparing the adluminal cells. Conversely, CK7 labels only adluminal cells {1443). PSA is expressed in a minor­ ity of cases. Labelling in neoplastic cells is negative to weak for AMACR and AR (2913,85,2941). ERG is negative (2941}. Strong BCL2 positivity and elevated Ki-67 have been proposed to have utility in the distinction of basal cell carcinoma from florid basal cell hyperplasia (3531). Like adenoid cystic carcinomas in other organs, 12 of 13 adenoid cystic carcinomas from the prostate were found to overexpress ERBB2(HER2) strongly at the mRNA level, whereas acinar adenocarcinomas were negative {1444).

Fig. 4.25 Basal cell carcinoma. A This non-adenoid cystic-like pattern has irregular anastomosing sheets of basaloid neoplastic cells. B Strong nuclear p63 immunoreactivity is characteristic. PSA is commonly negative.

Tumours of the prostate

229

ERBB2 protein expression was also positive, although some studies have shown contrary findings {1020). Adenoid cystic (basal cell) carcinoma of the prostate should be distinguished from urothelial carcinoma, high-grade acinar adenocarcinoma, and neuroendocrine carcinoma (NEC), as well as from metastatic adenoid cystic carcinoma from a pri­ mary elsewhere (including the Cowper glands). Cytology Insufficient data

Diagnostic molecular pathology By FISH, 17-47% of adenoid cystic (basal cell) carcinomas of the prostate harbour the MYB::NFIB fusion, a similar rate to that seen in their salivary gland counterparts (1986,363). Most fusion-positive cases (57%) had adenoid cystic-like morphol­ ogy, whereas 93% of fusion-negative cases did not have ade­ noid cystic-like features. The fusion is not found in benign basal cell proliferations {1986). TMPRSS2::ERG fusions have not been identified (2941).

230

Tumours of the prostate

Essential and desirable diagnostic criteria Essential: basal cell morphology and immunophenotype; identi­ fication of malignant features (cytoarchitectural atypia, infiltra­ tion of non-neoplastic prostate, perineural invasion, necrosis); exclusion of metastatic adenoid cystic carcinoma from a pri­ mary elsewhere, including the Cowper glands.

Staging The eighth edition of the Union for International Cancer Control (UICC) TNM system is used for staging. Prognosis and prediction Extraprostatic extension of adenoid cystic (basal cell) carci­ noma of the prostate at radical prostatectomy has been reported in 44-71% of cases {1986,85}. Distant metastasis occurred in 14-29% of patients, half of whom died from the disease (1443, 85,2095}. Thus, adenoid cystic (basal cell) carcinoma of the prostate is a potentially aggressive neoplasm requiring ablative therapy.

Prostatic stromal tumour of uncertain malignant potential

Definition Prostatic stromal tumour of uncertain malignant potential is a mesenchymal tumour that arises from the specialized prostatic stroma and has uncertain clinical behaviour.

ICD-0 coding 8935/1 Stromal tumour of uncertain malignant potential

ICD-11 coding 2F77 & XH8747 Neoplasms of uncertain behaviour of male gen­ ital organs & Stromal tumour of uncertain malignant potential Related terminology Not recommended: atypical stromal hyperplasia; stromal hyper­ plasia with atypia; phyllodes tumour; phyllodes-type atypical stromal hyperplasia; cystic epithelial-stromal tumour.

Zhou M Fine SW Pan CC Tavora F

Subtype ⑥ None

Localization Prostate gland, transition zone, and peripheral zone Clinical features The clinical, laboratory, and imaging findings are nonspecific. Patients typically present with lower urinary tract obstruction, and less commonly with a palpable mass, haematuria, haematospermia, or rectal fullness {1339,1099,2908,404}. Epidemiology Prostatic stromal tumour of uncertain malignant potential is rare. The median age of patients with this tumour is 57.5 years (range: 25-86 years) - older than patients with prostatic stromal sar­ coma {1339,1099,2908,404). It was diagnosed in 0.43% of a prostatectomy and transurethral resection cohort (2199}.

Etiology The etiology of prostatic stromal tumour of uncertain malignant potential is unknown. There are no known predisposing condi­ tions.

Fig. 4.26 Prostatic stromal tumour of uncertain malignant potential. Axial T2-weighted MRI of the prostate shows an encapsulated solid mass with cystic components.

Pathogenesis Although some consider the term "prostatic stromal tumour of uncertain malignant potential" to encompass benign prostatic hyperplasia with atypia and other mesenchymal tumours {402}, recent array comparative genomic hybridization and wholeexome sequencing studies demonstrated recurrent losses of chromosomes 13, 14, and 1p, supporting the concept of pros­ tate stromal tumours as a distinctive neoplastic entity {2427, 2429(. Macroscopic appearance Prostatic stromal tumours of uncertain malignant potential are whitish-tan and solid or partially cystic, with smooth-walled cysts filled with bloody, mucinous, or clear fluid. Tumours range from incidental microscopic lesions to masses as large as 150 mm. Extensive sampling is required after needle biopsy detection to determine extent and tumour grade.

Fig. 4.27 Prostatic stromal tumour of uncertain malignant potential. Cut surface showing lobular growth with whitish 叩pearance.

Histopathology Prostatic stromal tumours of uncertain malignant potential have five histological patterns, and tumours can exhibit a mixture of these patterns {1288,402}. The most common pattern is hypercellular stromal cells with scattered atypical but degenerativelooking nuclei admixed with benign prostatic glands. Another pattern exhibits hypercellular bland fusiform stromal cells with eosinophilic cytoplasm admixed with benign glands. The phyl­ lodes pattern is distinctive, with a leaf-like arrangement and variably cellular fibrous stroma covered by benign-looking Tumours of the prostate

231

Fig. 4.28 Prostatic stromal tumour of uncertain malignant potential. A Phyllodes pattern. B Hypercellular bland spindle cells.

prostatic epithelium. The myxoid pattern has a myxoid stroma containing bland stromal cells, often without glands. The epi­ thelioid stromal pattern is newly described and shows mildly increased stromal cellularity with round nuclei {2763}. The glands within the stromal tumours are benign and can exhibit crowding and complexity, as well as various other proliferative changes, including adenosis, squamous and urothelial meta­ plasia, basal cell hyperplasia, clear cell cribriform hyperplasia, and high-grade prostatic intraepithelial neoplasia (2268). Stromal tumours are positive for vimentin and PR, variably positive for CD34, SMA, and desmin, and they uncommonly express ER. KIT, S100, and STAT6 are negative (1099,3514}.

Differential diagnosis Prostatic stromal tumour of uncertain malignant potential can be differentiated from florid benign prostatic hyperplasia by the extensive growth of atypical stromal cells and by the absence of the nodularity and thick-walled vessels found in the latter. How­ ever, the distinction may be difficult in small specimens. The key to the correct diagnosis is the high degree of hypercellularity and eosinophilic cytoplasm often seen in the stromal tumours. The distinction from low-grade prostatic stromal sarcoma is critical. Necrosis, increased mitosis, increased atypical mitotic figures, marked hypercellularity, and nuclear pleomorphism of a non-degenerative nature are features of stromal sarcomas. Other spindle cell tumours may rarely involve the prostate and must be excluded; these include solitary fibrous tumour, inflam­ matory myofibroblastic tumour, smooth muscle tumours, rhab­ domyosarcoma, gastrointestinal stromal tumour, sarcomatoid carcinoma, and seminal vesicle tumours {1288,402). Finding

232

Tumours of the prostate

prototypical morphological and immunohistochemical features is critical to the correct diagnosis. Cytology Insufficient data Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: extensive growth of atypical stromal cells without fea­ tures of benign prostatic hyperplasia (i.e. nodularity and thick­ walled vessels); exclusion of other mesenchymal tumours. Desirable: one or a combination of the following five histological patterns: (1) hypercellular atypical stromal cells with a degen­ erative appearance, (2) hypercellular bland fusiform stromal cells, (3) phyllodes pattern, (4) myxoid stroma containing bland stromal cells, (5) epithelioid stromal pattern.

Staging Not relevant Prognosis and prediction The clinical behaviour is unpredictable. Most prostatic stromal tumours of uncertain malignant potential are not aggressive. They recur after resection in approximately 15% of cases (1339,2908(, and in two cohorts they were found to coexist with prostatic stro­ mal sarcoma in 14% and 21.7% of cases (1339,2908). The his­ tological features of these stromal tumours do not correlate with clinical behaviour or with concurrent prostatic stromal sarcoma.

Prostatic stromal sarcoma

Zhou M Fine SW Pan CC Tavora F

Definition Prostatic stromal sarcoma is a malignant mesenchymal tumour that arises from the specialized prostatic stroma.

ICD-0 coding 8935/3 Stromal sarcoma

ICD-11 coding 2C82.Y & XH49Y5 Other specified malignant neoplasms of prostate & Stromal sarcoma, NOS

Related terminology Not recommended: cystosarcoma phyllodes.

Hg.4.29 Prostatic stromal sarcoma. Cystoprostatectomy specimen showing unre­ markable bladder mucosa along with a large globular prostatic mass. Cut surface shows a well-circumscribed, grey-white, firm tumour with a whorled and lobulated appearance.

Localization Prostate, transition zone, and peripheral zone

51.5 years (range: 25-86 years) (1339,1099,2908}, and approxi­ mately 50% are aged < 50 years. The clinical, laboratory, and imaging findings are nonspecific. Patients present with lower urinary tract obstruction, and less commonly with a palpable mass, haematuria, haematospermia, or rectal fullness.

Clinical features Patients are slightly younger than those afflicted by stromal tumours of uncertain malignant potential, with a mean age of

Epidemiology Prostatic stromal sarcomas are rare, accounting for < 0.1% of prostatic cancers.

Subtype(s) None

Fig. 4.30 Prostatic stromal sarcoma. A Vague storiform growth. B Malignant spindle cells in diffuse sheets and interlacing fascicles. C Prostatic acini surrounded by malignant spindle cells. A few cells with bizarre nuclei are seen. D Pleomorphic nuclei and increased mitoses.

Tumours of the prostate

233

Fig. 4.31 Prostatic stromal sarcoma. A Diffuse and strong immunohistochemical positivity for CD34. B Diffuse and strong immunohistochemical positivity for desmin. C Tu­ mour cells are positive for PR by immunohistochemistry.

Etiology The etiology of prostatic stromal sarcomas is unknown. There are no known predisposing conditions.

and uncommonly express ER and PR (1099,3514). Epithelial markers such as pancytokeratin are rarely positive.

Pathogenesis In two cohorts, prostatic stromal sarcomas coexisted with prostatic stromal tumour of uncertain malignant potential in 14% and 21.7% of cases {1339,2908(. Molecular studies have shown similar alterations in the two tumour types (including deletions of chromosomes 13 and 14), and a higher mutation burden and more disorganized aberrations in stromal sarcomas (2427,2429}, suggesting a relationship between the two. However, there have been no convincing reports of progression from prostatic stro­ mal tumour of uncertain malignant potential to stromal sarcoma. MED12 mutations, which have been found in prostatic carci­ noma and breast phyllodes tumours, have not been detected in prostatic specialized stromal tumours (2429}. A next-gener­ ation sequencing study of 11 prostatic stromal sarcomas and 14 prostatic stromal tumours of uncertain malignant potential demonstrated that these tumours are molecularly heteroge­ neous with largely non-recurrent alterations. Some tumours harbour genetic aberrations seen in specific mesenchymal tumours arising in other anatomical sites {18}.

The distinction between prostatic stromal sarcoma and stromal tumour of uncertain malignant potential is discussed in Prostatic stromal tumour of uncertain malignant potential (p. 231). Sar­ comatoid prostate cancer may not have recognizable epithe­ lial differentiation in rare cases. These tumours usually occur in patients with a history of prostate cancer and treatment with radiation or hormonal ablation, and the sarcomatoid compo­ nent shows at least focal expression of pancytokeratin {2092}. Postirradiation sarcoma may be difficult to distinguish from a high-grade stromal sarcoma, and a history of radiation therapy to the pelvis should raise the possibility of the former. Other malignant mesenchymal tumours, such as leiomyosarcoma and rhabdomyosarcoma, should be excluded. Finding prototypical morphological and immunohistochemical features is key to the correct diagnosis.

Differential diagnosis

Macroscopic appearance Prostatic stromal sarcomas range from 20 to 180 mm and are grey, white, tan, or yellow in colour. The masses are firm or fleshy. Cystic changes and haemorrhage may be seen.

Histopathology Stromal sarcomas may be circumscribed, or they may infiltrate between benign prostate glands. They exhibit diffuse stromal growth with variable patterns, including storiform, epithelioid, fibrosarcomatous, leaf-like, and phyllodes-type (malignant phyl­ lodes tumour), or they can be patternless. Tumour cells often exhibit hypercellularity, cytological atypia, increased mitoses, and atypical mitosis. Necrosis may also be seen (1099,1339, 2908}. Stromal sarcomas are positive for vimentin and variably posi­ tive for CD34. They are usually negative for SMA and desmin

234

Tumours of the prostate

Cytology Insufficient data Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: diffuse stromal growth with hypercellularity, cyto­ logical atypia, increased or atypical mitosis, and necrosis; sarcomatoid prostate cancer and other sarcomas should be excluded. Desirable: immunohistochemistry positive for CD34 and PR.

Staging Staging of prostatic stromal sarcoma follows the TNM staging system for soft tissue tumours. Prognosis and prediction Stromal sarcoma has the potential to act aggressively and metastasize to distant sites such as bone and lung.

5 Tumours of the seminal vesicle Edited by: Srigley JR, Tsuzuki T

Epithelial tumours Glandular neoplasms Cystadenoma Adenocarcinoma Squamous neoplasms Squamous cell carcinoma Other tumours Mixed epithelial and stromaL.tumour

Tumours of the seminal vesicle: Introduction

The seminal vesicles are derived from the Wolffian duct, and, like other derivatives such as the epididymis and vas deferens, they are relatively resistant to neoplastic transformation. Sec­ ondary tumours affect seminal vesicles considerably more often than do primary tumours, with direct spread from adenocarci­ noma of the prostate being the usual source. Prostatic carci­ noma involving the seminal vesicle is prognostically significant to such an extent that it has a specific pT category (pT3b) in the Union for International Cancer Control (UICC) and Ameri­ can Joint Committee on Cancer (AJCC) TNM staging system {127}. Both bladder and colorectal carcinoma may also directly invade seminal vesicles. Bladder carcinoma normally invades the seminal vesicle stroma and glands but in rare instances may spread in an in situ fashion from the urethra along the ejacula­ tory ducts to involve the seminal vesicle {2679,2453}. Primary neoplasms of the seminal vesicle are pathological curiosities {3563|. Epithelial tumours include both cystadenoma and carcinomas, the commonest being adenocarcinoma. Squamous and undifferentiated carcinomas may also originate in the seminal vesicle. Rarely, benign and malignant mesen­ chymal tumours occur in the seminal vesicles (see Chapter 10: Mesenchymal tumours). In this chapter, cystadenoma, adenocarcinoma, and squa­ mous carcinoma are covered in individual sections. Additionally, there is a section on mixed epithelial-stromal tumours originat­ ing in the seminal vesicle. The exceedingly rare fibroadenomas

236

Tumours of the seminal vesicle

Srigley JR

and adenomyomas of the seminal vesicle have overlapping fea­ tures with the mixed tumours. All the entities mentioned above can be diagnostically challenging because of their rarity and potential confusion with other local tumours. Origin within the seminal vesicle may be difficult to establish, especially with large tumours. Furthermore, to establish a diagnosis of primary carcinoma of the seminal vesicle, it is important to rule out sec­ ondary malignancies such as local spread from a prostatic or bladder carcinoma. Immunohistochemical studies can be help­ ful to diagnose primary seminal vesicle cancer: tumours are usually positive for PAX8, CEA, CK7, and CA125, and negative for prostate and urothelial lineage biomarkers {952,137,2561}. In addition to rare neoplasms, there are several tumour-like lesions and histological mimics that affect seminal vesicles {3563}. These include developmental and acquired cysts, hamartomas, hyperplastic conditions, nodular calcification, and amyloidosis. One notable and common histological feature that may cause problems in prostate needle biopsies is epithelial atypia (1753,729). When a seminal vesicle displays a small aci­ nar (adenotic) pattern along with epithelial atypia, a diagnosis of prostatic adenocarcinoma may be mistakenly made. Helpful diagnostic features in favour of a seminal vesicle origin include the spotty nature of the atypia, the presence of cytoplasmic lipochrome pigment, marked hyperchromasia, and intranuclear cytoplasmic inclusions. In difficult cases, immunohistochemis­ try for prostatic markers is helpful.

Cystadenoma of the seminal vesicle

Cheng L Egevad L

Definition Cystadenoma of the seminal vesicle is a rare benign epithelial tumour composed of variably sized cysts lined by bland cuboidal cells. ICD-0 coding 8440/0 Cystadenoma ICD-11 coding 2F34 & XH5RJ2 Benign neoplasm of male genital organs & Cystadenoma, NOS

Related terminology None Subtype(s) None

Localization The lesion is confined within the seminal vesicles. Clinical features The most common clinical presentation is obstructive urinary symptoms. Some patients may present with an asymptomatic mass (1947).

Epidemiology Fewer than two dozen cases of cystadenoma of the seminal vesicles have been documented since Soule and Dockerty first used the term "cystadenoma" to describe a "pathological curiosity" in 1951 {1821,1947,288,2816,1494,2331,204,3007,2076). Patient age ranges from 23 to 66 years. Etiology Unknown

Fig. 5.01 Cystadenoma of the seminal vesicle. A Large cyst lined by cuboidal cells without atypia. B The single layer of epithelium lining this cyst is folded and forms papillary structures.

Pathogenesis Unknown

Cytology Not relevant

Macroscopic appearance The cystic to solid mass can be as large as 150 mm in diameter (1947,1494). The cut surface is tan-white with cysts of variable size.

Diagnostic molecular pathology Not relevant

Histopathology Glandular spaces of varying sizes are lined by cuboidal cells without atypia. The glands are arranged in a lobular pattern and form branching lumina and cysts in a scant stroma. The cystic spaces often contain granular intraluminal secretions. Epithe­ lial cells are positive for cytokeratin and negative for PSA, PAP, and calretinin {1947,288}. Focal luminal AMACR positivity can be seen {1494). Stromal cells are weakly positive for SMA and negative forSIOO.

Essential and desirable diagnostic criteria Essential: seminal vesicle location; variably sized cysts; bland cuboidal epithelium. Staging Not relevant

Prognosis and prediction Local excision is curative (1494}.

Tumours of the seminal vesicle

237

Adenocarcinoma of the seminal vesicle

冷

Definition Adenocarcinomas of the seminal vesicle are malignant gland­ forming tumours originating from seminal vesicle epithelium. Diagnosis requires clinicopathological exclusion of secondary carcinomas.

Subtype(s) None

ICD-0 coding 8140/3 Adenocarcinoma

Clinical features Approximately 60 cases of primary adenocarcinoma of the seminal vesicles have been reported (2355,322,3145,351, 352,920,2561). Patients often present with urinary obstruction and haematuria, and rarely with haematospermia (3145,925). Ultrasonography, PET-CT, and MRI may be helpful to define the extent of the lesion and exclude local spread from tumours in adjacent organs (2292).

ICD-11 coding 2C84 & XH74S1 Malignant neoplasms of other specified male genital organs & Adenocarcinoma, NOS Related terminology None

Localization Seminal vesicles, but may invade adjacent structures

Epidemiology These are rare tumours that mainly occur in men aged 40-70 years (2355,322,3145,351,352,920,2561}. The mean age at diagnosis is 62 years (range: 19-90 years). Etiology Unknown

Pathogenesis The tumour originates from the epithelium of the seminal vesi­ cle, which is a Wolffian duct derivative. Seminal vesicle intraepi­ thelial neoplasia has been proposed as a putative precursor {2210}.

Fig. 5.02 Primary adenocarcinoma of the seminal vesicle. The tumour displays a pap­ illary growth pattern.

Fig. 5.03 Primary adenocarcinoma of the seminal vesicle. Goblet cells and mucin depo­ sitions can be seen. Prominent retraction artefacts are also present (lower-right corner).

238

Tumours of the seminal vesicle

Macroscopic appearance Seminal vesicle adenocarcinoma often occurs as a large cystic or solid mass (30-50 mm in diameter), and it may be bilateral {507}.

Histopathology The tumours have a glandular differentiation, often with trabecu­ lar and papillary growth patterns. There may be a papillary clear cell pattern with occasional hobnail tumour cells. Goblet cells and mucin secretion may be seen. The seminal vesicle epithe­ lium stains positively for PAX2, PAX8, 340E12, and p63, and negatively for AMACR, PSA, PAP, NKX3-1, and P501S (920, 3174,2541}. The tumour cells are positive for PAX8, CK7, CEA, and CA125, and negative for PSA, PAP, AR, p63, GATA3, WT1, calretinin, and CDX2 (925,3159,2394}. CK20 is either positive or negative {3159}. AMACR stains are focally positive (2561} or negative {351}, Identification of mucin production is helpful as well (322}. The diagnosis of this entity is complicated by the frequent invasion of adenocarcinomas from surrounding organs, most often the prostate and less often the bladder or rectum {920, 925}. Such invasion must be excluded {764}.

Cytology Not relevant

Staging Not relevant

Diagnostic molecular pathology Not relevant

Prognosis and prediction The prognosis is poor, with survival usually < 3 years from diagnosis (3634). Complete surgical resection together with chemotherapy can occasionally offer a cure (352,507,1784, 1219,3548). Penile and lung metastases have been reported {3159}. Some tumours may be responsive to adjuvant hormone treatments (322,3145,1219,790). Serum CA125 level may be a useful biomarker for disease recurrence.

Essential and desirable diagnostic criteria Essential: seminal vesicle location (or for large tumours, seminal vesicle epicentre); adenocarcinoma, often with papillary-glan­ dular and trabecular growth patterns; exclusion of metastasis and local spread clinically and pathologically; supportive immunohistochemistry (see above).

Squamous cell carcinoma of the seminal vesicle

Cheng L Egevad L

Definition Primary squamous cell carcinoma of the seminal vesicle is a rare epithelial malignancy showing squamous differentiation in the absence of gland formation and mucin secretion.

ICD-0 coding 8070/3 Squamous cell carcinoma

ICD-11 coding 2C8Z & XH0945 Malignant neoplasms of male genital organs, unspecified & Squamous cell carcinoma, NOS Related terminology None

Subtype(s) None Localization Seminal vesicles, with left and right involved equally

Clinical features The most frequent presenting symptom is gross haematuria {979,1667,3113,3521,3381,3094}. Other common symptoms include haematospermia, dysuria, and bladder outlet obstruc­ tion, while serum PSA is normal {3521,3381}. One tumour arose in an acquired cyst in a patient with a history of gonorrhoea {3521(, and another patient had Zinner syndrome {1667(. Epidemiology Six cases have been reported (979,1667,3113,3521,3381,3094), all of them from eastern Asia (China, Japan, and the Repub­ lic of Korea). The mean age at diagnosis is 52 years (range: 26-69 years).

Etiology Unknown Pathogenesis Squamous cell carcinoma of the seminal vesicle often has a heavily inflamed background. In one case, sporadic p53 protein accumulation without evident gene mutations was apparent in both squamous metaplastic epithelium and carcinoma, sug­ gesting a possible relationship to inflammatory change {3521}.

Macroscopic appearance The reported cases were unilateral cystic and solid masses with tan to white cut surfaces. They measured 40-110 mm in largest diameter.

240

Tumours of the seminal vesicle

Fig. 5.04 Primary squamous cell carcinoma of the seminal vesicle. Typical appear­ ances with central keratinization within larger nests of tumour cells.

Histopathology Keratinizing squamous cell carcinoma has cystic spaces of var­ iable size. The tumour is often associated with marked chronic inflammation, and foci of squamous metaplasia are seen. The tumour cells are positive for p63 and CK5/6, and negative for CK7, CK20, PSA, and CEA.

Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: seminal vesicle epicentre; squamous morphology with keratinization; exclusion of local spread or metastasis from other sites (322,764}. Staging Not relevant Prognosis and prediction The prognosis is generally poor (979,1667,3113,3521,3381, 3094}. In one patient, rectal metastasis occurred 7 months after resection despite chemotherapy, leading to death {3381}. Another patient developed pelvic metastasis 28 months after surgery and died 6 months later {3113}.

Mixed epithelial and stromal tumour of the seminal vesicle

霍瞿"

Definition Mixed epithelial and stromal tumours (MESTs) of the seminal vesicles are biphasic tumours with stromal and benign epithelial components. ICD-0 coding 8959/0 Mixed epithelial and stromal tumour

ICD-11 coding 2F34 & XH0533 Benign neoplasm of male genital organs & Mixed epithelial and stromal tumour Related terminology Not recommended: cystic epithelial-stromal tumour; fibro­ adenoma; adenomyoma; mesonephric hamartoma; Mullerian adenosarcoma-like tumour; phyllodes tumour; cystosarcoma phyllodes.

Subtype ⑥ None

Localization Seminal vesicles

Clinical features Patients often present with obstructive lower urinary tract symp­ toms, haematospermia, fever, or abdominal pain (284). A mass above the prostate may be incidentally detected by digital rectal examination or by contrast-enhanced CT. Epidemiology Twelve cases of MESTs of the seminal vesicle have been reported with sufficient histopathological description {284,7,971, 1397,1639,1810,2054,2075,2205,2636,2994,3158}. The mean age at diagnosis was 54 years (range: 39-82 years). The aver­ age tumour size was 67 mm (range: 5-160 mm).

Etiology Unknown Pathogenesis Unknown

Fig. 5.05 Mixed epithelial and stromal tumour of the seminal vesicle. The tumour is well circumscribed with variably sized cysts. The cysts contain eosinophilic secretions. There are abundant stromal elements. Inset: gross appearance.

columnar or cuboidal epithelial cells with occasional hobnail­ ing, papillary infolding, or tufting. In contrast to cystadenoma of the seminal vesicle, the stromal component of MEST is more pronounced and often hypercellular. The stroma may condense around distorted glandular spaces lined by cuboidal epithelium. Rare tumours may display stromal atypia and mitotic activity and behave in a malignant manner (7,971,2075}. The stromal cells stain positively for ER, PR, vimentin, desmin, SMA, h-caldesmon, and CD34. Immunostaining for inhibin, S100, and KIT (CD117) is negative. Epithelial cells are positive for CK7, and negative for CK20, PSA, and PAP (2636(. Cytology Not relevant

Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: origin in the seminal vesicle; biphasic tumour with both epithelial cells and spindled stromal cells; exclusion of stromal tumours and sarcomas of the prostate incorporating epithelial elements. Desirable: stromal cells positive for ER and PR.

Macroscopic appearance The tumour is a well-circumscribed, solid and cystic, tan to white mass centred in the seminal vesicle. It is occasionally spongiform with cyst formations.

Staging Not relevant

Histopathology The tumour is composed of both stromal and benign epithe­ lial components {2636). Variably sized cysts are lined with

Prognosis and prediction Occasional patients with MEST have been reported to develop local recurrence or metastasis (7,971,2075).

Tumours of the seminal vesicle

241

6 Tumours of the testis Edited by: Berney DM, Tickoo SK

Germ cell tumours derived from germ cell neoplasia in situ Non-invasive germ cell neoplasia Germ cell neoplasia in situ Specific forms of intratubular germ cell neoplasia Gonadoblastoma The germinoma family of tumours Seminoma Nonrseminomatous germ cell.tumours___ Embryonal carcinoma Yolk sac tumour, postpubertal-type Choriocarcinoma Placental site trophoblastic tumour Epithelioid trophoblastic tumour Cystic trophoblastic tumour Teratoma, postpubertal-type Teratoma with somatic-type malignancy Mixed germ cell tumours of the testis Mixed germ cell tumours Germ cell tumours of unknown type Regressed germ cell tumours Germ cell tumours unrelated to germ cell neoplasia in situ Spermatocytic tumour Teratoma, prepubertal-type Yolk sac tumour, prepubertal-type Testicular neuroendocrine tumour, prepubertal-type Mixed teratoma and yolk sac tumour, prepubertal-type

Sex cord stromal tumours of the testis Leydig cell tumour Leydig cell tumour Sertoli cell tumours Sertoli cell tumour Large cell calcifying Sertoli cell tumour Granulosa cell tumours Adult granulosa cell tumour___ Juvenile granulosa cell tumour The fibroma thecoma family of tumours Tumours in the fibroma thecoma group Mixed and other sex cord stromal tumours M仪ed sex cord stromal tumour Signet ring stromal tumour Myoid gonadal stromal tumour Sex cord stromal tumour NOS

Tumours of the testis: Introduction

The complexity and range of histology that can be seen in tes­ ticular tumours surpasses all other areas of human pathology, and this is reflected in this latest edition of the WHO classifica ­ tion. More than 90% of testicular tumours are of germ cell ori­ gin. Germ cell tumours may be highly aggressive or benign, with relatively subtle morphological differences affecting their classification and behaviour. Approximately 50% of germ cell tumours are seminomas, and the vast majority of the remain­ der are either pure forms of other subtypes or mixed germ cell tumours usually referred to as Mnon-seminomatous germ cell tumours*' (NSGCTs) (776,2221(. Seminomas and NSGCTs show differences in biological behaviour, and their precise classifica ­ tion has a profound effect on patient care. The rarity of testicular neoplasia compounds many of these issues, and misclassifica­ tion remains problematic {2584,831,2899(.

Germ cell tumours Epidemiology Approximately 75 000 new cases of testicular cancer were diag­ nosed worldwide in 2020, and there were 9300 deaths due to dis­ ease {1456}. Although the overall incidence of germ cell tumours is low, the majority of these patients are young men, mostly aged between 15 and 45 years. The age-standardized incidence rate worldwide is 1.8 cases per 100 000 person-years, but there are

Tickoo SK Al-Ahmadie HA Daugaard G Looijenga LHJ Raspollini MR

marked geographical variations; the highest incidence rates are in western Europe (9.3/100 000), northern Europe (7.5/100 000), and Australia and New Zealand (7.0/100 000) (1456|. Variation between different ethnic groups is also apparent, with higher rates in White populations than in people of other ethnicities. The only non-White population with a comparably high incidence is Maori New Zealanders {1035,3451). The incidence of testicu­ lar germ cell tumours (TGCTs) showed a progressive increase during the 20th century. There has been evidence of recent stabilization {3644}, although mathematical models predict that the incidence in Europe will continue to grow over the period of 2010-2035, particularly in historically low-risk countries (espe­ cially those in eastern Europe) {3644}. TGCTs are also reported to occur more commonly among higher socioeconomic groups (2084} and in patients with Marfan syndrome {851,418}, Down syndrome {418), and dysplastic naevus syndrome (2936). The median patient age at diagnosis is 37 years for seminomas and 30 years for NSGCTs {776,2221}.

Etiology and pathogenesis The vast majority of TGCTs are associated with germ cell neoplasia in situ (GCNIS), which is believed to represent transformed embryonic germ cells arrested at the gonocyte stage {1284}. The etiology of other (non-GCNIS-related) germ

Estimated age-standardized incidence rates (World) in 2020, testis, males, all ages

Fig. 6.01 Tumours of the testis. Estimated age-standardized incidence rates (ASRs; World), per 100 000 person-years, of testicular cancer in 2020 among males (all ages).

244

Tumours of the testis

cell tumours is less certain. The development of GCNIS may involve aberrant activation of the KITLG/KIT pathway (2622) and overexpression of embryonic transcription factors such as NANOG and OCT4 (POU5F1), which leads to the suppression of apoptosis, an increase in proliferation, and the accumula­ tion of mutations in gonocytes (1284). Invasive TGCT, but not GCNIS, consistently shows gain of chromosome 12p (typically isochromosome 12p) {2407}. Although many candidate genes are present in this region of chromosome 12p (such as KITLG, NANOG, KRAS, BCAT1, and CCND2), no specific genes have been implicated in the progression to invasive TGCT. Distinct gene expression through epigenetic regulation, including DNA methylation, may result in the formation of the different histologi­ cal subtypes {1719(. A comprehensive multiomic (DNA methylation, DNA copy number, mRNA, microRNA, and protein) analysis of 137 TGCTs by The Cancer Genome Atlas (TCGA) identified significant dif­ ferences between seminomas and NSGCTs {2907}. The overall mutation burden in TGCTs is lower (0.5 mutations per Mb) than most adult-type tumours {3131,1957,2907). Recurrent somatic mutations are not common and are detected more often in seminomas than in NSGCT. These include activating mutations in KRAS, KIT, NRAS, and PIK3CA {2907,3131,241,2297,1900). TGCTs show a low frequency of somatic TP53 mutation (1957, 2907,3131) compared with extragonadal germ cell tumours, particularly those associated with resistance to platinum ther­ apy {241}. A subset of TGCTs is associated with somatic WNT/pcatenin pathway mutations (1957). Both TGCT and GCNIS cells are typically aneuploid, with hypertriploid to subtetraploid karyotypes. Highly recurrent ampli­ fications and reciprocal deletions (reciprocal loss of heterozy­ gosity) at the chromosome arm level are a common feature of TGCTs {3063,3131,2907}, supporting a model of whole-genome duplication followed by chromosome arm deletions {1051). The TCGA analysis reported specific patterns of chromosome arm loss after whole-genome duplication for NSGCTs (fewer copies of chromosomes 19q, 15, 22, 19p, 10q, 8p, 2q, and 8q) and for seminomas (fewer copies of 11q, which was inferred to be an early event) |2907}. In the same TCGA analysis, there was also at least one isochromosome 12p in 114 of 131 tumours (87%). TGCTs harbour recurrent focal amplifications containing the entire genes of KIT, KRAS, and MDM2 (2090,2089,2231,2297}, which occur with similar frequency in seminomas and NSGCTs. Seminomas with increased copies of KRAS (chromosome 12) were more likely to have wildtype KIT {2907}. By phylogenetic analysis and mutation multiplicity calculation, it was estimated that somatic KIT mutations occur before whole-genome dupli­ cation, whereas KR/AS mutations are later events occurring after whole-genome duplication (3131,2907}. Recurrent focal dele­ tions were identified in the chromosomal fragile sites GRID2, ATOH1, JARID2, WWOX, NEGR1, PDE4D, and PRKN (PARK2) that were observed almost exclusively in NSGCTs {2907}. In addition to the enrichment of KIT mutations in semino­ mas, KIT mRNA and protein are also highly expressed in these tumours. Although this is true regardless of KIT mutation status, KIT expression levels are higher in K/rmutant tumours than in K/rwildtype tumours. Interestingly, compared with NSGCTs, even seminomas without a KIT mutation or KIT focal amplifica­ tion have a higher expression of KIT mRNA and protein. Sup­ porting evidence for the role of KIT activation in seminomas is

Fig. 6.02 Testicular germ cell tumours. Simplified organogram of the relationships between testicular germ cell tumours. GCNIS, germ cell neoplasia in situ; YST, yolk sac tumour.

that gene signatures downstream of KIT signalling (including genes involved in the AKT, PI3K, RAS/MAPK, and JAK/STAT pathways) are highly expressed in seminomas, regardless of KIT or KRAS mutation status (2907}. In another study, there was a positive association between KRAS and KIT mutations {2055). Distinct patterns of global DNA methylation have been identi­ fied for different histological subtypes. The majority of canonical CpG sites in seminomas are completely unmethylated, contrib­ uting to the overall low global methylation observed in semi­ nomas 12969,2311,2907}. In contrast, embryonal carcinoma is associated with extensive methylation at non-canonical cyto­ sine sites (e.g. CpA, CpT, CpC), which further correlates with the amount of embryonal carcinoma component in mixed NSGCTs {2907}. Epigenetic silencing of the important tumour suppres­ sors BRCA1, MGMT, RASSF1 (RASSF1A), and RAD51C has been reported exclusively in NSGCTs (1719,2051,1387,2907}. The silencing of BRCA1 and RAD51C highlights the potential role of homologous repair deficiency in TGCTs (1957}. The TCGA analysis confirmed prior reports of the presence of distinct microRNA profiles between seminomas and NSGCTs and identified additional findings. For example, the miR-519 genomic cluster on 19q13.42 is significantly overexpressed in embryonal carcinoma compared with seminoma and other NSGCTs. miR-371a-3p is highly overexpressed in seminomas, embryonal carcinomas, and mixed NSGCTs, but minimally expressed in teratomas (865,864). This microRNA has been proposed as a serum biomarker for monitoring disease status in patients with germ cell tumours {2711,239,3091). On the other hand, miR-375 is highly expressed in teratoma and yolk sac tumour (YST), but not in seminoma or embryonal carcinoma (2907). By comparing genomic profiles of matched primary and metastatic germ cell tumours enriched for resistance to cispl­ atin therapy, a high discordance rate of somatic mutations was identified between the primary and metastatic samples (68% of all somatic mutations were discordant) {625). In the same study, genome duplication was common and highly concordant

Tumours of the testis

245

Fig. 6.03 Organogram of germ cell tumours. Relationships between families of germ cell tumours of the testis. GCNIS, germ cell neoplasia in situ.

between primary and metastatic samples, but only 25% of primary-metastatic pairs had > 50% concordance at the level of DNA copy-number alterations. Most mutations arose after copy-number alterations at the respective loci in both primary and metastatic samples, and oncogenic mutations were more likely to occur earlier than variants of unknown significance. p53 pathway alterations had the highest degree of concordance in primary and metastatic specimens, consistent with their asso­ ciation with resistance to cisplatin therapy {241}. Overview of the revised histological classification The WHO histological classification is now used globally for germ cell tumours. In 2016, this classification was substantially modified. The term for the preneoplastic lesion for the vast majority of germ cell tumours was changed to Mgerm cell neo­ plasia in situ1' from a range of previous terminologies including "carcinoma in situ", "intratubular germ cell neoplasia, unclassi­ fied", and "testicular intraepithelial neoplasia" {337}. Based on their pathogenesis, tumours were divided into a larger group

derived from GCNIS and a smaller group with no preinvasive entity. Prepubertal-type tumours (including some teratomas, some YSTs, and spermatocytic tumour) are classified as nonGCNIS-derived germ cell tumours. The classification is based on a proposal (2383} encompassing types of germ cell tumours arising at any site. Only three of these types occur in the testis. An overview of these types in the ovary and testis is shown in Table 6.01. This fifth-edition WHO classification has retained all these changes, with a few important additions. The entity known in the fourth edition as "primitive neuroecto­ dermal tumour'* (PNET) may arise as secondary somatic-type malignancy in NSGCTs, particularly in association with teratoma or YST (1987). Neuroectodermal differentiation is also frequently seen in postpubertal-type teratomas. In the fifth-edition WHO classification of CNS tumours, the overarching term "PNET" has been replaced by the specific terms for embryonic tumours of different subtypes. Also, because PNET was traditionally regarded to be akin to Ewing sarcoma, usage of this terminology has caused some confusion among treating clinicians. Germ

Table 6.01 The types of germ cell tumour of the ovary and testis (adapted from {2899})

Germ cell tumour type

Description

1

Testis: prepubertal-type teratoma and prepubertal yolk sac tumour

2

Testis: postpubertal-type teratoma, seminoma, and other non-seminomatous (malignant) germ cell tumours

3

Testis: spermatocytic tumour

4

Ovarian dermoid cyst (also known as benign cystic teratoma); may include some immature teratomas

5

Gestational trophoblastic neoplasia

6

Somatic tumours showing transdifferentiation to elements with characteristic germ cell features

Ovary: may form a subset of some ovarian teratomas and yolk sac tumours

Ovary: dysgerminoma and other malignant ovarian tumours (yolk sac, embryonal carcinoma) and possibly immature teratomas of the ovary

Ovary: no counterpart exists

246

Tumours of the testis

cell tumour-associated PNET is more similar to CNS-related embryonic tumours than to Ewing sarcoma {3246}. Because of the existence of embryonal carcinoma as a distinct tumour among germ cell tumours, substituting "embryonic tumour** for “PNET" in the testis may cause misunderstanding. Therefore, the term "embryonic-type neuroectodermal tumour" is used in this edition. Similarly, ''primitive neuroectodermn as a compo­ nent of postpubertal-type teratoma is replaced by "embryonictype neuroectoderm". In keeping with other volumes, we have changed "testicular carcinoid'* to Htesticular neuroendocrine tumourM. It is now appar­ ent that most (but not all) neuroendocrine tumours (NETs) in the testis arise from prepubertal-type teratomas. Most are not asso­ ciated with GCNIS, and many prepubertal-type teratomas show small NETs associated with them. We have therefore added prepubertal-type NET to the list of non-GCNIS-associated tumours, although the diagnosis of GCNIS-associated NET is still possible under the category of "teratoma with somatic-type malignancy” Clinical management The clinical management of germ cell tumours is highly depen­ dent on their classification. Among the GCNIS-related tumours, NSGCTs are more aggressive and often include multiple lines of differentiation. Mixed seminomatous and non-seminomatous germ cell tumours are managed as non-seminomas. Apart from tumour type, clinical stage and postorchiectomy serum marker levels are also vital for clinical decisions. Non-metastatic tumours are clinical stage I, those with metastasis to nearby (subdiaphragmatic/abdominal or pelvic) lymph nodes are stage II, and metastasis above the diaphragm or systemic metastasis is clinical stage III {127}. Serum tumour markers for guiding management include AFP, hCG, and LDH {2173.1842}. Serum levels of tumour markers are included in the staging sys­ tem as an "S" stage. These postorchiectomy values are used to stratify risk and select treatment. Elevated AFP and hCG are markers of a YST component and a trophoblastic component, respectively; their elevation after orchiectomy (taking into con­ sideration their half-lives) indicates the presence of these com­ ponents at metastatic sites. However, the false positive rate with LDH is high. About 30% of patients with pure seminomas show p-hCG elevations due to syncytiotrophoblastic cells, although levels rarely exceed 500 IU/L. The pre-orchiectomy marker levels, while important for pathologists to know, are not used for staging purposes. Pre-orchiectomy elevated serum levels of AFP or p-hCG may indicate the need for further sampling from orchiectomies in discordant cases. Other circulating tumour markers, including microRNA, have been proposed as novel biomarkers, but they are not yet in clinical use (103,864). At diagnosis, 80% of patients with seminoma and approxi­ mately 60% with non-seminoma have clinical stage I disease. During follow-up, about 18% of patients on surveillance with stage I seminoma and one third of those with NSGCTs will relapse (3185,776}. Therefore, approximately half of patients will at some point receive treatment for metastatic disease (776, 2221). Risk factors are debated, but for the recurrence of semi­ noma they include rete testis stromal invasion and large primary tumour size. For NSGCTs, the presence of dominant embryonal carcinoma and lymphovascular invasion are regarded by most as risk factors for the presence or subsequent development of

metastases (2832,393,3195,2831}. There is no definitive cut-off value for tumour size; however, larger tumours appear to con­ fer a higher risk of recurrence as a continuous variable {1384}. About 4% of patients with pure primary (testicular) seminomas relapse with non-seminomas. Although adjuvant treatment undoubtedly reduces recurrence risk substantially, there is continuing debate about which clinical stage I seminomas and NSGCTs should receive therapy, and about the use of risk factors to decide this. Patients with seminoma without any identified risk factors have an extremely low risk of recurrence, and disease-free sur­ vival after 15 years is > 99% in men with clinical stage I semino­ mas followed on a surveillance programme (2221). The use of adjuvant chemotherapy or radiotherapy is debated, and a focus on morbidity and late effects (e.g. the risk of metastasis) has made the continued use of adjuvant radiotherapy less attrac­ tive (1384}. Adjuvant carboplatin reduces the risk of relapse by about 60%, but it provides a number-needed-to-treat value in the range of 15-20 patients to prevent one relapse (1384). According to the original International Germ Cell Cancer Col­ laborative Group (IGCCCG) system, metastatic seminoma is split into "good prognosis" or "intermediate prognosis*' catego­ ries based on the presence or absence of liver, bone, or brain metastases (1459}. The standard treatment for clinical stage II or III seminoma is chemotherapy, except in cases with limited spread to the retroperitoneum, for which radiation therapy is considered to be an option. Five-year disease-specific sur­ vival and overall survival are about 95% and 93%, respectively, for patients with seminomas belonging to the good prognosis group by the IGCCCG criteria {1645). In a recent update of the original IGCCCG scheme, an LDH level of > 2.5 times the upper level of normal further refines the classification and iden­ tifies men with intermediate-risk seminoma in the absence of extrapulmonary metastases. No pure seminomas are regarded as poor prognosis tumours by IGCCCG. For NSGCTs, surveil­ lance is often the clinical option for stage I disease, although retroperitoneal lymph node dissection (RPLND) or one cycle of platinum-based chemotherapy (BEP) may be used, particularly in patients with risk factors for metastasis. The presence of a prominent embryonal carcinoma component correlates with an increased probability of lymphovascular invasion and metasta­ sis {2831,989,776,373}. The presence and proportion of YST in the primary testis site is associated with a lower incidence of lymphovascular invasion (although there is chemoresistance at metastatic sites). Choriocarcinoma components are associ­ ated with a higher incidence of non-nodal metastasis. Teratoma in a primary tumour often correlates with residual teratoma in postchemotherapy RPLND specimens. It has also been shown that the presence of mature (but not immature) teratoma in the primary sites correlates best with the poorest long-term survival (1064}. Patients with low clinical stage II disease may also be offered RPLND or BEP, whereas those with higher stage II or stage III disease are offered multiple (three or four) cycles of multiagent platinum-based therapy, depending on whether they are in the good, intermediate, or poor prognosis IGCCCG category (242). Tumour spread The sites of retroperitoneal lymph node metastasis from tes­ ticular tumours show very consistent patterns (primary landing

Tumours of the testis

247

Table 6.02 A comparison of the TNM staging systems in the eighth-edition Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) classifications

Pathological feature

UICC eighth edition

Rete testis invasion

pT1

pH

No size criteria used

30 mm used as a cut-off point (between pHaand pT1b), for seminoma only

Size of tumour

AJCC eighth edition

Epididymal invasion

PT1

PT2

Tunica vaginalis invasion

PT2

PT2

PT2

PT2

Vascular invasion

Soft tissue invasion Cord invasion

Not considered

PT2

pT3 but no definition given

pT3 with criteria on level of invasion above the insertion of the tunica vaginalis

zones) based on whether the primary tumour is on the right or left side. Right-sided tumours most commonly metastasize to the inter-aortocaval lymph nodes followed by the precaval and paracaval lymph nodes, whereas left-sided tumours most com­ monly spread to the para-aortic and preaortic lymph nodes. Contralateral involvement occurs more commonly with rightsided primary tumours, especially with higher-stage tumours. Unlike right-sided tumours, early left-sided tumours may pro­ duce occasional suprahilar nodal metastases (3116).

Staging Traditionally, the American Joint Committee on Cancer (AJCC) and/or Union for International Cancer Control (UICC) staging systems have been used worldwide for the staging of testicular tumours, and both systems have been identical until recently. In the eighth edition of the AJCC system, some substantial changes were introduced (see Table 6.02). The pT1 stage was divided into pT1a and pT1b for seminomas depending on their size, with a threshold of 30 mm. Tumours invading hilar soft tissue and/or the epididymis were upstaged to pT2 from pT1. Discontinuous involvement of spermatic cord soft tissue (usu­ ally from lymphovascular invasion) was upgraded to pM1 from pT3. However, most of the evidence on which these changes are based is retrospective. Consequently, UICC has decided to continue with the seventh edition of the AJCC staging system. Nevertheless, recent evidence seems to support many of the AJCC decisions {3195,2831,2832}. The International Collaboration on Cancer Reporting (ICCR) has adopted the AJCC system in its datasets (332}, but the National Comprehensive Cancer Network (NCCN) has not wholeheartedly accepted the eighth-edition AJCC staging sys­ tem and has recommended considering stage I seminoma as either low risk or high risk, without definitive size criteria. As a compromise and acknowledging that nearly all cases of germ cell tumour with epididymal invasion will show soft tissue inva­ sion, the UK Royal College of Pathologists has recommended use of the AJCC criteria where the UICC criteria are currently undefined {330}.

Sex cord stromal tumours Sex cord stromal tumours (SCSTs) constitute < 5% of all testicu­ lar tumours. Of these, Leydig cell tumours constitute about 75%, and Sertoli cell tumours are the next most common {3572,15}. Thus, an overwhelming majority of SCSTs are relatively pure sex 248

Tumours of the testis

cord tumours. However, a small proportion include a stromal component, either in pure form or in combination with sex cord elements. Sex cord elements are usually positive for steroidproducing immunohistochemical cell markers (e.g. inhibin, SF1), and the presence of stromal elements is easily confirmed by a reticulin stain that shows the framework surrounding individual tumour cells. Two new entities have been introduced in this classification. The striking signet ring stromal tumour, while possibly part of the morphological spectrum of Sertoli cell tumours, is distinct enough to warrant inclusion as a separate entity. Confusion with metastatic signet ring tumours is possible and therefore deserves attention. Myoid gonadal stromal tumour appears to show both morphological and immunohistochemical differ­ ences from other sex cord tumours. In this fifth edition of the WHO classification, one important change is the discussion of sertoliform cystadenoma, now included under Sertoli cell tumours. The tumour almost exclusively occupies the rete testis tubules {2425}. The rationale behind the classification of sertoliform cystadenoma under sex cord stromal (Sertoli cell) tumours is their close histological and immunohis­ tochemical overlap {2138,2944}. Unless a clear immunohisto­ chemical and molecular distinction is shown, it is suggested that sertoliform cystadenoma should be removed from its classifica­ tion within testicular adnexal tumours. Sertoliform cystadenomas are of unknown origin, and although there is speculation that they arise from cells at the junction of seminiferous tubules and rete testis that retain the capability of differentiating towards sex cord stromal cells {2944}, they are indistinguishable from Sertoli cell tumours on morphology and immunohistochemistry. Note that intratubular large cell hyalinizing Sertoli cell tumour is only included in the chapter on genetic tumour syndromes. It is only seen in Peutz-Jeghers syndrome, so this approach avoids repetition. Large cell calcifying Sertoli cell tumour is seen both sporadically and associated with Carney complex, so it retains a place in both sections. There is also separation of mixed/undifferentiated SCST into separate categories of "mixed SCST” and "SCST, NOSM, related to the fact that in the mixed category, the Sertoli cell, Leydig cell, and granulosa cell components are recognizable, whereas in the undifferentiated category, these components are not mor­ phologically clear. One of the major issues among testicular SCST has been the prediction of clinical behaviour. The vast majority of SCSTs

are indolent, but metastasis may occur even in relatively bland tumours, most commonly to the retroperitoneal lymph nodes, similarly to TGCTs. Because of the lack of effective chemo­ therapy and radiation treatment options, SCST metastasis often results in adverse outcome and death. For this reason, RPLND even in the absence of metastasis is believed by some to be appropriate (2938). Despite the generally accepted notion that the only reliable criterion for malignancy is metastasis (3572), attempts at predicting aggressive clinical behaviour in nonmetastatic tumours has resulted in histopathological criteria predictive of metastatic potential for SCSTs. Such parameters include tumour size, necrosis, nuclear atypia, angiolymphatic invasion, invasive/infiltrative margins, and mitotic count. Note that for mitotic counts, the use of HPFs has been removed in the fifth edition and replaced by square millimetres, because of inaccuracy due to differences in field diameters {731}. Unfortu­ nately, previous publications have not specified field diameters, so the implementation of mitotic counts per square millimetre as an assessment of malignancy in SCSTs will involve further work. Owing to mostly small cohorts with a limited number of events, there is still some debate about how best to treat patients with testicular SCST. It has been advocated that orchiectomy alone is sufficient in cases with none of the above-mentioned aggres­ sive features (492,987). Given the lack of available effective therapies after metastasis, others suggest that only those with­ out any high-risk features {492} or at the most with only one high-risk feature (2938} should be placed under observation without RPLND after orchiectomy. Early retroperitoneal lymph

node dissection is favoured by many for patients with two or more high-risk features or with clinical stage Ila disease {492, 2938,15|. Another clinically very relevant issue among testicular SCST is clinical bilaterality. SCSTs by themselves are quite rare, and bilaterality is even rarer (described in 5-10% cases). A tumour that morphologically resembles a Leydig cell tumour, with the clinical impression of bilateral tumours, always requires the exclusion of a biochemical etiology, particularly for congenital adrenal hyperplasia (2285,3260}. Although there are morpho­ logical differences between genuine Leydig cell tumours and tumours of the adrenogenital syndrome, sometimes the differ­ ences might be subtle. Therefore, in bilateral SCST, particularly Leydig tumours, biochemical investigations must be under­ taken {3397}. Otherwise, the clinical consequences can be sig­ nificant: radical orchiectomy versus pharmacological manage­ ment (214). Finally, there is new literature on mixed germ cell / sex cord tumours. Variants in gonadoblastoma morphology have recently been described (1583). Also, there is continued evidence for non-gonadoblastoma mixed germ cell / sex cord tumours. A recent report outlines 8 cases of a sex cord component resem­ bling adult-type granulosa cell tumour and spermatocytic tumour (2153). One tumour was extratesticular. The highly unu­ sual nature of these tumours defies easy classification. It is still suggested that these are probably collision tumours of some kind (2379(, and they may be of import, but their formal clas­ sification will await further work.

Tumours of the testis

249

Germ cell neoplasia in situ

Berney DM Looijenga LHJ Moch H Srigley JR

Definition Germ cell neoplasia in situ (GCNIS) is a common precursor of all seminomas and most adult non-seminomatous germ cell tumours of the testis. It consists of neoplastic gonocytes with latent totipotent (naive) developmental potential, located in the spermatogonial niche of seminiferous tubules.

ICD-0 coding 9064/2 Germ cell neoplasia in situ

ICD-11 coding 2C80.2 & XH8AD3 Intratubular germ cell neoplasia, unclassi­ fied & Intratubular malignant germ cells Related terminology Not recommended: carcinoma in situ of the testis; intratubular germ cell neoplasia, unclassified; testicular intraepithelial neoplasia.

Subtype(s) GCNIS contains trophoblastic giant cells in about 20% of cases {336).

Localization GCNIS occurs within the seminiferous tubules of the postpubertal testis. In disorders/differences of sex development it may be found in the prepubertal testis. Clinical features Adults with isolated GCNIS are usually symptomless or present with mild testicular pain and relatively small testes (6-12 mL) (341,1295,2391,2746). GCNIS is bilateral in 4-5% of cases {3341,863}. About 80% of cases show a heterogeneous ultra­ sound pattern, sometimes due to microlithiasis {1380,797,938).

Fig. 6.04 Germ cell neoplasia in situ. Seminiferous tubules, most showing germ cell neoplasia in situ arranged as atypical gonocytes in the spermatogonial niche.

Epidemiology See Tumours of the testis: Introduction (p. 244).

Etiology See Tumours of the testis: Introduction (p. 244).

Fig. 6.05 Germ cell neoplasia in situ (GCNIS). A Immunochemistry for OCT4 showing strong nuclear positivity of GCNIS cells. B Immunochemistry for PLAP. GCNIS cells are seen largely in the spermatogonial niche. Note the PLAP-positive smooth muscle. C Immunochemistry for KIT (CD117) showing membranous positivity in GCNIS cells.

250

Tumours of the testis

Table 6.03 Immunohistochemical profile of the most common germ cell tumours3 derived from germ cell neoplasia in situ

Marker

Seminomab

Embryonal carcinoma

OCT3/4

+N

+N

SALL4

+N

+N

PLAP

+ CM

-

KIT

+ CM

Yblk sac tumour

-

-

-

(few cases +)

+N

-

SOX2

-

+

+ CM

-

-

-

-

cyto+++

SOX17

D2-40

Choriocarcinoma6

-

+

+

+

CD30

-

+M

-

-

AFP

-

-

+

-

GPC3

-

-

+

(SCs: + C)

-

-

AE1/AE3

hCG

(uncommonly: dot-like)

hPL

-

-

p63

-

-

GDF3

-

GATA3

-

Inhibin

-

-

-

syncy+++ syncy +++

一 may be + -

cyto + syncy +++

cyto +

int + cyto+++

cyto +++ syncy+++ cyto syncy +++

C, cytoplasmic; GPC3, glypican-3; M, membranous; N, nuclear; SCs, syncytiotrophoblastic cells. 'Teratoma is not included in the table; the use of stains should be related to tissue type components. bSeminoma with SCs shows SCs that stain positive for hCG. Choriocarcinoma with mononucleated trophoblasts (cytotrophoblasts [cyto] and intermediate trophoblasts [int]) and multinucleated syncytiotrophoblasts (syncy).

Pathogenesis See Tumours of the testis: Introduction (p. 244).

Macroscopic appearance GCNIS cannot be identified on macroscopy. Histopathology GCNIS consists of atypical cells resembling gonocytes with ample clear cytoplasm and large (10-11 pm) angulated nuclei with usually one nucleolus and coarse chromatin; the cells are typically located in the niche of spermatogonia, in one layer resembling a string of beads. This pattern may be recognized at low power; however, reliable diagnosis of GCNIS requires immu­ nohistochemistry {3273}. GCNIS is usually a dispersed, patchy process whereby the number of affected tubules may vary from few to all (341,863,3272}. It is virtually always present in the tes­ ticular parenchyma surrounding adult germ cell tumours {1489, 159,1806). Isolated GCNIS may be found in the workup of male infertility (2956) and in contralateral biopsies in cases of a clini­ cally unilateral adult germ cell tumour (863(. In the testis, it can be the only neoplastic manifestation of a burnt-out adult germ cell tumour, which most often comes to clinical attention with retroperitoneal metastases {2383,1037,2099,3022}.

Often the GCNIS cells are stacked in more layers and float in the lumen of the seminiferous tubules. Seminiferous tubules with GCNIS may contain trophoblastic giant cells in as many as 20% of cases, virtually always in combination with seminoma with trophoblastic giant cells {336}. GCNIS can spread in a pagetoid manner into neighbouring normal tubules, entrapping and replacing spermatogonia, whereby spermatogenesis is disturbed. Pagetoid spread of GCNIS cells into the rete testis is common. It follows the plane between the rete epithelium and the basement membrane, and it can be so extensive that clusters of GCNIS cells cause polypoid bulging of the rete epi­ thelium. The tumour cells in the rete are in situ, and they do not worsen prognosis {3328}. Floating GCNIS cells can colo­ nize remote tubules and be released in seminal fluid. Testicular parenchyma surrounding GCNIS may show normal morphology or changes of testicular dysgenesis: clusters of maldeveloped tubules with undifferentiated Sertoli cells, Sertoli cell-only pat­ tern, intratubular microliths, and occasionally branching tubules (1372,3119). In parenchyma adjacent to seminoma, infiltrates of lymphocytes are invariably present, particularly around and in GCNIS tubules. They cause tubular atrophy and fibrosis [2382, 1431) comparable to the fibrosis of burnt-out seminoma.

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251

Immunohistochemistry The immunoprofiles of gonocytes, GCNIS, and seminoma are similar (2603,2671}. The protein markers absent in normal spermatogonia include PLAP {472}, OCT4 {1928,2604,1548, 798}, SOX17 {799}, AP-2y {1373}, NANOG {1370,1304,2308}, LIN28A {3438,1136(, and podoplanin {2997}. KIT {2607), which is expressed in spermatogonia {382,356}, is useful because it is overexpressed in GCNIS and seminoma {2089}. Enzyme reactivity of alkaline phosphatase has been utilized to diagnose GCNIS on frozen sections {3041} during operations, to assist testis-sparing surgery. Immunoreactions may vary depending on the fixatives used and the origin of the antibodies. How­ ever, heterogeneity of expression may also be due to genuine maturation-dependent variations (2606,1551,2179). The overall DNA epigenetic profile of GCNIS is hypomethylation (3436, 2311,1732,1731), which is also found at the histone level {104}. The genome-wide transcriptomes of GCNIS and gonocytes are nearly identical, and in addition to the markers listed above, they include numerous other embryonic and germ cell-specific genes (101,2996}. See also Table 6.03 (p. 251).

Differential diagnosis In the infantile and prepubertal testis, GCNIS should be distin­ guished from gonocytes with normal and delayed maturation, and from pre-GCNIS; in the postpubertal testis, it should be distinguished from arrested spermatogonia, intratubular semi­ noma, and intratubular non-seminoma. The morphological cri­ teria have been described above. Crucially, a reliable diagnosis of GCNIS requires immunohistochemistry (3273(.

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Tumours of the testis

Extensive pagetoid involvement of the rete testis may lead to the erroneous diagnosis of a non-seminoma combining tera­ toma (simulated by rete epithelium) and seminoma. Absence of GCNIS in a postpubertal testis with a pure tera­ toma must raise suspicion of a prepubertal-type teratoma {3597, 782}.

Cytology GCNIS may be detected in ejaculate by immunocytology (2127, 1371,3274,102}. Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: neoplastic gonocytes located in the spermatogonial niche of seminiferous tubules in a string-of-beads arrange­ ment. Desirable: positive immunohistochemistry for a range of markers including OCT4, KIT, PLAP, SOX17, NANOG, and podoplanin. Staging By definition, GCNIS is staged as pTis {3328}. Prognosis and prediction Reportedly, about 90% of GCNIS cases will progress to an overt testicular germ cell tumour within 7 years (3341). In some cases this interval may be as long as 15-20 years (861|.

Specific forms of intratubular germ cell neoplasia

Definition These are intratubular forms of germ cell neoplasia other than germ cell neoplasia in situ (GCNIS).

Berney DM Looijenga LHJ MochH Srigley JR

Histopathology

Intratubular seminoma

ICD-0 coding 9061/2 Intratubular seminoma 9070/2 Intratubular embryonal carcinoma 9061/2 Intratubular trophoblast 9071/2 Intratubular yolk sac tumour 9080/2 Intratubular teratoma

When GCNIS cells fill the lumina of seminiferous tubules, dis­ placing Sertoli cells, this results in intratubular seminoma. It typi­ cally expands the tubules. Like invasive seminoma, it contains lymphocytes. The tubules are often also surrounded by lympho­ cytic infiltrates. Intratubular seminoma is found in about 30% of seminomas and 15% of non-seminomatous tumours. The cells show an identical immunophenotype to that of seminoma (posi­ tive for OCT4, PLAP, and KIT) (2382,1806,335).

ICD-11 coding 2C80.2 & XH8AD3 Intratubular germ cell neoplasia, unclassi­ fied & Intratubular malignant germ cells

Intratubular embryonal carcinoma often shows central necro­ sis and calcification. Cells are far more pleomorphic than in

Intratubular embryonal carcinoma

Related terminology None

Subtype(s) Intratubular seminoma; intratubular embryonal carcinoma; intra­ tubular trophoblast; intratubular yolk sac tumour; intratubular teratoma

Localization Intratubular germ cell tumour types other than GCNIS are occasionally seen adjacent to invasive adult germ cell tumours. Exceptionally rarely, they are seen without invasive disease. Clinical features Because intratubular germ cell neoplasia only exceptionally occurs without invasive tumours, there are no specific clinical features.

Fig. 6.06 Intratubular embryonal carcinoma and germ cell neoplasia in situ. KIT (CD117) staining in germ cell neoplasia in situ (left) and pleomorphic intratubular cells of intratubular embryonal carcinoma (right).

Epidemiology Insufficient data

Etiology See Tumours of the testis: Introduction (p. 244). Pathogenesis It has not been proved definitively whether these intratubular neoplasms are an intermediate stage between GCNIS and inva­ sive germ cell tumour or merely spread of the invasive tumour down pre-existing tubules.

Macroscopic appearance The macroscopic appearance is not relevant because these tumours are never seen in pure form. Fig. 6.07 Intratubular seminoma. Seminiferous tubules are enlarged and filled with cells identical to invasive seminoma. Sertoli cells are not seen. This area was adjacent to an invasive seminoma.

Tumours of the testis

253

GCNIS. Differentiation into other components only starts upon invasion (2383,2838). It is confined to the parenchyma sur­ rounding non-seminomatous tumours and occurs in about 15% of cases (2382,1806}. It is most frequently associated with small tumours, suggesting that larger tumours overgrow and obscure their intratubular precursor (2382}. Intratubular embryonal carci­ noma is positive for CD30, although immature Sertoli cells may also be falsely positive (334). Immature Sertoli cells are also positive for OCT4 but negative for KIT.

Fig. 6.08 Intratubular germ cell neoplasia. Seminiferous tubule with a syncytiotrophoblastic cell.

Intratubular trophoblast Occasionally, syncytiotrophoblastic cells are seen within tubules. This is mainly associated with seminomas and occurs in 15% of germ cell tumours {336). Intratubular yolk sac tumour and intra­ tubular teratoma have been reported with extreme rarity (1108). Cytology Not relevant

Diagnostic molecular pathology Not relevant Essential and desirable diagnostic criteria Essentia/: intratubular germ cell elements with appropriate his­ tological patterns. Desirable: immunohistochemical confirmation with appropriate markers.

Staging Intratubular disease is by definition in situ (Tis), but it is almost inevitably associated with invasive disease.

Fig. 6.09 Embryonal carcinoma. Intratubular spread of embryonal carcinoma with central comedonecrosis.

254

Tumours of the testis

Prognosis and prediction Nearly all examples are associated with invasive germ cell neo­ plasms, on which the prognosis and prediction should be based.

Gonadoblastoma

Reyes-Mugica M Cheng L Idrees MT Kao OS Moch H Roth LM

Definition Gonadoblastoma is an in situ form of malignant germ cell tumour consisting of germ cell neoplasia in situ (GCNIS), seminoma, or dysgerminoma cells, and incompletely differentiated sex cord cells reminiscent of Sertoli or granulosa cells.

ICD-0 coding 9073/1 Gonadoblastoma ICD-11 coding 2C73.Y & XH0K61 Other specified malignant neoplasms of the ovary & Gonadoblastoma 2F76 & XH0K61 Neoplasms of uncertain behaviour of female genital organs & Gonadoblastoma 2F77 & XH0K61 Neoplasms of uncertain behaviour of male genital organs & Gonadoblastoma Related terminology Not recommended: dysgenetic gonadoma.

Subtype(s) None

Localization Gonads

Clinical features Most patients present as neonates with ambiguous genitalia in the setting of a disorder of sex development (DSD) {703,1402, 3254), althcxjgh occasional patients do not present until their fourth decade of life {2867}. Approximately half of all cases of gonadoblastoma appear in virilized female patients, 30% in non­ virilized female patients, and 20% in male patients with hypo­ spadias and an empty scrotum (2867,3326}. A common initial presentation in young women is primary amenorrhoea {3254}. Advanced presentations usually feature an abdominal mass. Epidemiology Although gonadoblastomas are almost always associated with DSDs {2327,2328,2727}, a subset occur in patients with no apparent DSD and a normal peripheral blood karyotype {2728). As many as 60% of dysgenetic gonads develop gonadoblas ­ toma {2867,1402,703,3254}. Frequent entities associated with gonadoblastoma include 46,XY pure gonadal dysgenesis (bilat­ eral streak gonads), mixed gonadal dysgenesis, ovotesticular disorder of sex development, Turner syndrome (see below), and androgen insensitivity syndrome (2327,2328). Gonadoblastoma is bilateral in 30-40% of cases {2867,3254,326}.

Etiology Mutations (many hereditary) leading to DSDs cause gonado­ blastoma (1471,2001,2898}. DSDs are caused by abnormalities

Fig. 6.10 Gonadoblastoma in a dysgenetic gonad. Dysgenetic testis from a 4-year-old girl with a disorder of sex development and 45,X/46,XY mosaicism in which a gona­ doblastoma is starting to develop. A Note the dysplastic testicular cords/tubules and an early focus of gonadoblastoma in the centre left. B Closer view of the developing gonadoblastoma. Note the basement membrane hyaline deposits and nests of two cellular populations (germ cells and sex cord cells).

in genes implicated in the 46,XY developmental pathway, including SRY, SOX9, WT1, and NR5A1 (SF1) {702,703,1925}. Multiple genes may be affected in a single patient (1345}. An essential etiological element is the presence of the GBY region of the Y chromosome, including the candidate gene encoding testis-specific Y-encoded protein (TSPY1) {3215,1809). Abnor­ malities in this pathway result in immature sex cord cells instead of normal Sertoli cells. This undervirilized environment causes

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255

Fig. 6.11 Gonadoblastoma. A Low-power view. A gonadoblastoma in a streak gonad shows the characteristic small nests in a cellular stroma. This case shows extensive calci­ fications, some with a mulberry-like configuration. B High-power view. The three components can be seen: germ cells, most resembling those of germ cell neoplasia in situ; sex cord cells; and round deposits of basement membrane matrix. A dissecting pattern is at the top, mimicking a focus of invasive germinoma.

the delayed development of the embryonic germ cells, allow­ ing coexpression of embryonal and early differentiation genes, particularly POU5F1 (which encodes OCT3/4) and TSPY1 (705, 1636}. This, combined with enhanced KIT/KITLG signalling (3040), promotes the neoplastic transformation of germ cells into GCNIS-like cells. Concurrent GCNIS and gonadoblastoma have been reported within a single gonad, indicating an underlying DSD {1344,1870). Patients with germline or somatic mutations in WT1 (Denys-Drash and Frasier syndromes) or SRY (Swyer syndrome) feature dysgenetic gonads and gonadoblastomas (1247). As many as 35% of patients with Turner syndrome who have Y chromosome material (which may be cryptic) develop gonadoblastomas (3593,728}, as do about 5% of patients with androgen insensitivity syndrome )1411,1516}.

Pathogenesis Most patients with gonadoblastoma feature a female pheno­ type. However, their gonads carry Y chromosome material and show either a dysgenetic/dysplastic testicular histology (20%) or a streak gonad appearance (20%) (2867). Because the genetic male developmental pathway is faulty, or androgen effects are deficient, SOX9 expression is insufficient to support the nor­ mal formation of seminiferous cords and Sertoli cells, leading to a predominance of FOXL2 {1343,463} and causing a delay in germ cell maturation, with expression of OCT3/4 and TSPY,

which combined with KIT/KITLG signalling seems to promote neoplastic transformation. Macroscopic appearance Gonadoblastomas range from soft to firm; they are brown, yel­ low, or grey in appearance, and they can reach 80 mm in size. They often show multifocal calcification. If they progress to invasive germ cell tumours, they show soft, grey nodules (3254, 2727). Histopathology Like all blastomas, gonadoblastoma recapitulates the develop­ mental process of its organ of origin. Gonadoblastomas feature round nests and cords composed of germ cells, small sex cord cells, and globoid deposits of hyaline basement membrane material in variable proportions. The germ cells have large nuclei, one or more prominent nucleoli, and pale/clear cytoplasm. Many resemble GCNIS or seminoma/dysgerminoma cells; oth­ ers appear as spermatogonia. Mitotic figures can be seen. The sex cord cells show angulated, sometimes grooved, nuclei; they are similar to Sertoli cells and may also show Charcot-Bdttcher crystals {1469,2729}. The germ cells are scattered between the sex cord cells, which may form palisades at the periphery of nests, rosettes around the basement membrane deposits, or circular arrays around the germ cells. The basement membrane

Fig. 6.12 Gonadoblastoma. A Germ cells of gonadoblastoma showing nuclei positive for OCT3/4. B Germ cells of gonadoblastoma showing membranous staining of PLAP. C Sex cord cells of gonadoblastoma showing positive staining of inhibin. D Sex cord cells of gonadoblastoma showing positive nuclear staining of SOX9.

256

Tumours of the testis

Fig. 6.13 Gonadoblastoma. A Gonadoblastoma nest with germ cells of variable appearance, from spermatogonia*like cells to cells resembling those of germ cell neoplasia in situ / seminoma / dysgerminoma, as well as incompletely differentiated sex cord cells and round hyaline material. The surrounding spindle cell gonadal stroma contains Leydig-like or lutein-like cells. B An immunostain for PLAP strongly highlights germ cells.

material frequently develops laminated calcifications, resem­ bling psammoma bodies, with occasional coalescence to form mulberry-like structures. Rarely, calcifications can be so exten­ sive as to obliterate the cellular detail (burnt-out or regressed gonadoblastoma). Scattered Leydig-like cells may be present in adjacent gonadal stroma. The morphological features of undifferentiated gonadal tissue overlap with what Scully called "dissecting gonadoblastoma*', which should be distinguished from the classic gonadoblas ­ toma and is present in approximately 75% of cases. In these areas the neoplastic cells adopt a cord-like pattern {1583(.

Immunohistochemistry The immunophenotype includes PLAP, KIT (CD117), and podoplanin staining in the germ cells; inhibin, nuclear SOX9 (weak), and FOXL2 (strong) in the sex cord cells; and inhibin plus calretinin in the Leydig-like cells. Gonadoblastoma is a precursor of invasive germ cell tumours. Depending on the degree of development in the dysgenetic gonad, the lesion may develop into a GCNIS or gonadoblastoma. Infiltration by the neoplastic germ cells into the surrounding stroma may result in any of the usual types of germ cell tumour, most frequently seminoma/ dysgerminoma.

Differential diagnosis In fetuses and neonates the differential includes the lesion known as fetal gonadoblastoid testicular dysplasia (3009,1425, 2330(. In postpubertal patients, Sertoli cell nodules colonized by GCNIS should be excluded. Immunohistochemistry facili­ tates their distinction, because Sertoli cell nodules are negative for FOXL2 and strongly positive for SOX9 (1588}. Gonadoblas­ toma seems to originate from surviving OCT3/4-positive germ cells within undifferentiated gonadal tissue (704} present in dysgenetic gonads, which may precede the development of fully recognizable gonadoblastoma. The existence of testicular mixed germ cell-sex cord stromal tumour has been challenged;

some consider it a distinct neoplasm (2730), but mostly it is considered as a sex cord stromal tumour with entrapped germ cells {3252). Recently, it has been suggested that the germ cell component might be related to spermatocytic tumour, with mul­ tiple aneuploidies (2153}. The germ cells are SALL4-positive but OCT4-negative {2153}. These tumours almost always show indolent behaviour.

Cytology Not relevant Diagnostic molecular pathology FISH analysis may be useful to demonstrate the Y chromosome in tissues or other materials (urine) of phenotypically female patients (326) (see also Pathogenesis and Etiology, above).

Essential and desirable diagnostic criteria Essential: nested to corded arrangement of germ cells (similar to GCNIS/seminoma) and small sex cord cells with deposits of basement membrane material. Desirable: frequent background of a DSD; typical immunophe­ notype (in selected cases); marker positivity for germ cell and sex cord stromal tumours can be helpful. Staging Gonadoblastoma is an in situ malignancy. It is staged as pTis using the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM system. Prognosis and prediction Given the potential for gonadoblastoma to transform into an invasive germ cell tumour, gonadectomy is recommended in all cases. Surgical excision and bilateral gonadectomy result in cure of the tumour and prevention of contralateral gonado­ blastoma. In cases that have progressed to an invasive tumour, staging and prognosis vary accordingly.

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Seminoma

I drees MT Daugaard G Looijenga LHJ Raspollini MR Verrill C Yilmaz A

Definition Seminoma is a malignant germ cell tumour arising from cells analogous to the primordial germ cells / gonocytes present dur­ ing early embryonic development. The tumour is composed of cells with ample clear cytoplasm, well-defined cell boundaries, angulated or irregular nuclei, and prominent nucleoli.

ICD-0 coding 9061/3 Seminoma 9061/3 Seminoma with syncytiotrophoblastic cells ICD-11 coding 2C80.2 & XH9FM4 Germ cell tumour of testis & Seminoma, NOS

Related terminology None

Subtype(s) Seminoma with syncytiotrophoblastic cells Localization Seminomas arise primarily from the testis. They are morphologi­ cally and immunohistochemically identical to dysgerminomas and germinomas arising in the ovary and in extragonadal sites including the mediastinum, dysgenetic gonads, and pineal gland. Clinical features Seminoma is the most common testicular germ cell tumour and constitutes > 50% of all the testicular germ cell tumours; it occurs predominantly in postpubertal men (1723,3344}. Although seminoma is generally considered a disease of young men with an average age of 37-41 years {1723), a considerable proportion of tumours can be seen in men aged > 50 years {3144}. It is rare in men aged > 70 years {338}. Seminomas occur rarely in children, with a major proportion occurring in patients with an intersex disorder (2506,1622). Seminomas typically occur 5-10 years later than non-seminomatous germ cell tumours (1049,3344}, which explains the higher incidence the older age group. Seminoma has similar epidemiology and etiological factors to those of all germ cell tumours derived from germ cell neoplasia in situ (GCNIS). However, certain associa­ tions have been described, including cryptorchidism (1267(, immunodeficiency disorders (e.g. AIDS) [1837,3474}, some types of HLA (2367,866}, and very tall stature {3086}. There is a slight right-sided tendency, and about 2% of seminomas occur bilaterally, mostly asynchronously. The most common pre­ sentation is a self-identified mass sometimes associated with vague pain and discomfort in the testis, groin, or lower abdo­ men. Only 10% of the patients present with acute pain (2220|. Symptoms related to retroperitoneal metastasis, including

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Tumours of the testis

Fig. 6.14 Seminoma. A The tumour bulges above the cut surface. It is a greyish tan, nodular, well-circumscribed lesion with focal haemorrhage. B Formalin-fixed speci­ men showing a seminoma bulging above the cut surface: a white, solid, and lobulated tumour.

lower back pain, may be the first presentation in < 3% of the individuals {2582,2324}. The usual mode of seminoma metas­ tasis is via the lymphatics to several groups of retroperitoneal lymph nodes, with later spread to the mediastinal and cervical (particularly left supraclavicular) lymph nodes. Rarely, the pri­ mary presentation is the involvement of other organs, including lungs, bone {422}, gastrointestinal tract, and neural tissue, with or without retroperitoneal spread {2220}. Interestingly, patients who present with metastatic disease usually have smaller tumours than those without metastasis, and this may relate to primary tumour regression. Very rarely seen paraneoplastic syndromes include polycythaemia (1566,2648), hypercalcaemia {756), exophthalmos {2018,3129(, autoimmune haemolytic anaemia {1973J, limbic or brainstem encephalopathy {321,477, 3476}, and membranous glomerulonephritis (2848(.

Tumour markers Syncytiotrophoblast cells are frequently seen in pure seminoma, and 10-20% of patients have elevated serum hCG (2682,2756). hCG level is not usually > 1000 mIU/mL, but rare examples of markedly elevated levels exist and probably relate to the pro­ portion of syncytiotrophoblast cells in the seminoma (367,1036). Elevated serum lactate dehydrogenase is seen in as many as 80% of advanced-stage seminomas {1036). Serum AFP levels are not usually elevated, although one small study reported sig­ nificantly elevated AFP levels in patients with pure seminomas {2295}; this may be due to undersampling of small areas of yolk sac tumour (YST), now known to be a mimic of seminoma in its solid pattern (1584}. Epidemiology See Tumours of the testis: Introduction (p. 244). Etiology See Tumours of the testis: Introduction (p. 244).

Pathogenesis See Tumours of the testis: Introduction (p. 244).

Macroscopic appearance Most seminomas are solid tumours and manifest as an expan­ sile enlargement of the testis. There is tremendous variability in tumour size, with the mean close to 50 mm {1723}. Almost half of the tumours replace the testicular parenchyma entirely but without rupturing the tunica vaginalis {3144}. The majority of seminomas are solid, lobulated to multinodular, relatively

homogeneous nodules, often cream-coloured to tan, or pale yellow to pink, that on sectioning bulge above the surrounding normal parenchyma. The consistency is usually soft and fleshy, but less commonly it may be firm to hard. Inadequate fixation frequently results in liquefaction, which leads to challenging morphology and artefactual spread. Approximately 10% of testes with seminomas are normal or small, and a similar pro­ portion of tumours involve paratesticular structures through the hilar soft tissue; direct extension beyond the tunica vaginalis is exceptionally rare {3144,2233}. Grossly invisible tumours often are associated with scarring or burnt-out tumours, and their tex­ ture is firm to fibrous {254}. Also, tumours that are small or have predominant intertubular growth may not be grossly discernible (1327}. Tumour necrosis and haemorrhage are common, but extensive necrosis is mostly seen in larger tumours. Petechial haemorrhages may indicate clusters of syncytiotrophoblast cells.

Histopathology The most prevalent growth pattern is a diffuse sheet-like arrangement with interspersed variably sized fibrous septa, which imparts a nested to nodular appearance to the tumour at high magnification. The fibrous septa are associated with a mild to extensive lymphocytic infiltrate that may vary consider­ ably in different areas of the tumour. Prominent fibrous tissue or expanded fibrous bands may separate tumour cells into small clusters, cord-like to trabecular appearances, or single cells within the hyalinized stroma. A solid or hollow tubule pattern is uncommonly visualized. Tubules, microcysts, and irregularly arranged vague tubular structures often contain light-coloured

Fig. 6.15 Seminoma. A Classic seminoma. Sheets of tumour cells with lymphocytic infiltrates and fibrous septa. B Exuberant lymphocytic infiltrate predominates over the seminoma cells. C Tumour cells with cytological features of distinct cytoplasmic membranes, clear cytoplasm, and nuclei with prominent nucleoli. Lymphoid infiltrate is present. D Sheets of seminoma cells showing the nuclear detail. Angulated cells and prominent, often smudged, nucleoli are seen.

Fig. 6.16 Seminoma. A A prominent granulomatous reaction is often observed. B Occasional syncytiotrophoblasts are usually seen dispersed among seminoma cells. C hCG immunostaining highlights the syncytiotrophoblasts.

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259

Fig. 6.17 Seminoma. A Seminoma, pseudoglandular. Central cellular degeneration creates spaces imparting a pseudoglandular appearance. B Seminoma, signet-ring cells. Many cells show vacuolation of the cytoplasm, with nuclei pushed to the side, creating a signet-ring cell appearance. C Seminoma, peritubular. Groups of invasive seminoma cells closely embracing the tubules (a very rare pattern). D OCT3/4 immunohistochemistry highlights the intertubular seminoma cells. E Seminoma infiltrating the rete tes­ tis. F Intertubular seminoma. In this example, intertubular seminoma cells are nestled in Leydig cell nests set between atrophic seminiferous tubules, one with intratubular seminoma. G Seminoma infiltrating the rete testis in a pagetoid pattern. The seminoma cells are positive for OCT4.

Fig. 6.18 Seminoma and germ cell neoplasia in situ. Germ cell neoplasia in situ adja­ cent to invasive seminoma.

oedema fluid {3259}. When the tubular pattern predominates, the tumour subtype is often referred to as pseudoglandular. An intertubular pattern may exist in many tumours, especially in the periphery of the dominant nodule; however, occasionally, the entire invasive tumour exists in this fashion, without forming a discernible mass, and is amenable to being missed {1327}. One consistent finding is that there is almost always lymphocytic infiltrate in areas of the invasive tumour as well as the GCNIS. Seminoma cells are round to polygonal and characteristically have clear to pale or lightly eosinophilic granular cytoplasm and well-delineated cytoplasmic membranes. Areas with cells con­ taining amphophilic to eosinophilic cytoplasm may be seen, but a predominance of these cells is rare. Sometimes cells appear plasmacytoid with eccentric nuclei but without a perinuclear hot.

260

Tumours of the testis

The tumour cells are relatively uniform, measuring up to 25 pm in diameter; the nuclei are large and central or slightly eccentric, with granular chromatin, usually one or more prominent nucleoli, and an irregularly thickened nuclear membrane. The nuclear membranes are often angulated and have squared-off nuclear contours. The cells are evenly spaced without overlapping, and in well-fixed tumours the cell outlines are easily observed. The clear cytoplasm is due to the presence of a large amount of glycogen, which can be highlighted by a PAS stain as granular deposits digestible by diastases. A spectrum of more unusual morphological patterns may be observed, including corded, microcystic, tubular-like (3244, 3586), and signet-ring cell (3258}. These patterns are usually only focally present in otherwise typical tumours. A variably prominent lymphocytic infiltrate occurs in almost all cases and a granulomatous reaction occurs in more than half (2232,2233). Granulomatous inflammation mostly occurs in small clusters of epithelioid cells, but a few Langerhans-type giant cells may be observed. Occasionally, the tumour may be entirely masked by an exuberant granulomatous reaction and may mimic granu­ lomatous orchitis. Approximately 10-20% of tumours contain syncytiotrophoblasts in varying proportions (2234,3342). Syncytiotrophoblasts are multinucleated, with the nuclei sometimes arranged in mulberry-like clusters, and often show intracytoplasmic lacunae containing red cells. When clustered, they are often associated with small foci of haemorrhage. These cells may be highlighted by hCG or cytokeratin immunostaining. Occasion­ ally, tumour cells appear smudgy, show crush artefact, and may even appear spindled. Artefactual displacement of tumour cells may produce false vascular invasion and can be avoided by early fixation and meticulous handling of the specimen at gross­ ing. GCNIS can be found in the residual seminiferous tubules in > 85-90% of cases (674,2382). Pagetoid extension of GCNIS

to the rete testis and rete testis invasion have been reported in a few studies (3195,983,3547}. Intratubular expansion of semi­ noma cells is occasionally seen, and it may show a pagetoid extension to the rete testis. A pleomorphic pattern of semi­ noma has been described as anaplastic or atypical seminoma because of the greater degree of pleomorphism and increased mitotic activity. However, several studies have not convincingly demonstrated that these behave differently from other semino­ mas (3648,3082,3343,1500,1714}. Necrosis is present in about half of seminomas but can be extensive in up to 10% of cases.

interspersed between intact cells, especially in air-dried smears {253,521). The cells have round to oval nuclei with fine chromatin and one or more prominent nucleoli {54,1356). The nuclei may appear squared off because of irregular or flattened nuclear membranes. A moderate amount of cytoplasm with prominent vacuoles containing glycogen is present (54}. The cytoplasmic boundaries are visible {1356}. Lymphocytic infiltrate, plasma cells, and epithelioid histiocytes may be present {54,1356,521}. Diagnostic molecular pathology See Tumours of the testis: Introduction (p. 244).

Immunohistochemistry Antigen expression in seminomas is similar to that of fetal gonocytes and includes OCT3/4 (nuclear) {1548,1928), SALL4 (nuclear) (516}, PLAP (cytoplasmic membrane) {473,1492, 2323}, KIT (cytoplasmic membrane) (1482,1808,1807,1851}, and SOX17 (nuclear) {378,2335}. Podoplanin is also expressed (cytoplasmic membrane) (1807,3566). Cytokeratin AE1/AE3 immunoreactivity is typically negative; if positive, it is dot-1 ike (632,2323}. CD30, AFP, and EMA are negative {3253(.

Differential diagnosis Embryonal carcinoma is a common differential diagnosis because a solid pattern may be confused with seminoma. Fea­ tures that help in differentiating it from seminoma are poorly defined cell boundaries; overlapping, pleomorphic, and hyperchromatic nuclei; and no fibrous septa or lymphocytic infiltra­ tion. OCT4 is expressed in both tumours, but KIT, podoplanin, and SOX17 are expressed in seminoma whereas CD30, SOX2, and cytokeratin AE1/AE3 are expressed embryonal carcinoma. Solid yolk sac tumour may pose a diagnostic challenge; how­ ever, it is almost always associated with other more common patterns, less prominent lymphocytic infiltrate, and an absence of fibrous septa. Yolk sac tumours are positive for AFP, glypican-3 (GPC3), and cytokeratin AE1/AE3, and they are negative for OCT3/4. Occasionally, syncytiotrophoblast cell clusters are present, imparting an appearance similar to that of choriocarci­ noma; however, the absence of mononucleated trophoblastic cells helps rule out choriocarcinoma. Spermatocytic tumour can be distinguished from seminoma by its three distinct cell types as well as its lack of inflammatory infiltration, fibrous septa, and GCNIS. Occasionally, malignant Sertoli cell tumours {1326} may be mistaken for seminoma. The cells of Sertoli cell tumours are usually smaller than those in seminomas, their nuclei are less pleomorphic and display a low mitotic count, and there is no GCNIS. Negative germ cell markers and positive sex cord stromal markers provide an easy diagnosis of Sertoli cell tumour. Diffuse large B-cell lymphomas may occur in the testis; these usually show prominent intertubular growth and irregular nuclear membranes, and they lack GCNIS. Negative germ cell markers and immunoreactivity for lymphoid markers resolves this differential. Cytology FNA smears display dyscohesive cell groups, flattened sheets, and single cells (54,1356,521}. The cytoplasm is delicate, and a characteristic tigroid pattern is usually seen because of frag­ mented cytoplasmic components containing glycogen that are

Essential and desirable diagnostic criteria Essential: characteristic tumour cells with abundant clear cyto­ plasm, well-defined cell boundaries, and uniform nuclei con­ taining prominent nucleoli. Desirable: immunohistochemical confirmation in selected cases (e.g. OCT4, podoplanin [D2-40]); presence of GCNIS.

Staging Staging is according to the eighth-edition Union for International Cancer Control (UICC) and American Joint Committee on Can­ cer (AJCC) TNM system (see Tumours of the testis: Introduction, p. 244). Prognosis and prediction Patients with stage I seminoma are followed mainly on surveil­ lance programmes; about 20% will have a relapse in the follow­ up period. The treatment for these patients is either radiation therapy or chemotherapy, depending on the spread of the disease. Disease-specific survival after 15 years is > 99% in patients initially diagnosed with stage I disease {2221}. Predic­ tors of relapse on surveillance include larger primary tumour size, stromal rete testis invasion, epididymal involvement, and possibly vascular invasion (2221,3399,656). These factors are also associated with higher stage at presentation {3195,2832}. This provides a rationale for adjuvant chemotherapy for selected stage I tumours in some centres. In 1997 the International Germ Cell Cancer Collaborative Group (IGCCCG) published a classification for metastatic germ cell tumours that became the accepted international standard (1459). According to this original IGCCCG classification, meta­ static seminoma is split into good or intermediate prognosis categories based on the presence or absence of liver, bone, or brain metastases. A recent update of the IGCCCG classification showed 5-year overall survival probabilities of 95% and 88% for patients diag­ nosed with metastatic disease and belonging to the good and intermediate prognostic group, respectively (350). The updated version identified LDH level as the most significant prognostic factor for good-risk patients, with a cut-off point of 2.5 times the upper level of normal. Patients in the IGCCCG good-risk group whose LDH level was > 2.5 times the upper level of normal had similar progression-free and overall survival to those of patients in the intermediate-risk group. The LDH cut-off point further refines this classification and enables the identification of men with intermediate-risk seminoma in the absence of extrapulmonary metastases.

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Verrill C Idrees MT Looijenga LHJ Yilmaz A

Embryonal carcinoma

Definition Embryonal carcinoma is a malignant germ cell tumour com­ posed of primitive large and pleomorphic epithelioid cells reca­ pitulating the early stages of embryonic development.

ICD-0 coding 9070/3 Embryonal carcinoma ICD-11 coding 2C80.2 & XH8MB9 Germ cell tumour of testis & Embryonal car­ cinoma, NOS Related terminology Not recommended: malignant teratoma, undifferentiated.

Subtype(s) None Localization Embryonal carcinoma occurs in the testis and at metastatic sites. Clinical features Embryonal carcinoma is the second most prevalent germ cell tumour of the testis (after seminoma), accounting for approxi­ mately 4-16% of cases in pure form {1914,1589). It is the most common predominant component of mixed germ cell tumour, as well as the most frequent component (seen in 82.5% of cases) (1914,1589(. The majority (80%) of cases occur in people aged 15-34 years, with a peak incidence at 30 years (10 years ear­ lier than for seminoma); cases in patients aged < 14 years or > 55 years are rare {3345}. The proportion of patients present­ ing with this aggressive subtype who have stage ll/lll disease ranges from 35% (for those with mixed carcinoma that includes

Fig. 6.19 Embryonal carcinoma. Solid tumour with cysts and haemorrhage.

embryonal carcinoma) to 57-74% (for those with pure embryo­ nal carcinoma) {1723,3345}. Elevated serum AFP and p-hCG are not usually associated with embryonal carcinoma, and their presence in an apparently pure embryonal carcinoma should trigger further sampling. However, syncytiotrophoblastic giant cells can be seen, result­ ing in raised p-hCG. LDH can also be raised. For pure embryo­ nal carcinoma, serum tumour markers are of little use in tracking disease progression, but promising microRNA markers, espe­ cially miR-371a-3p, may become available in the future {239}.

Epidemiology See Tumours of the testis: Introduction (p. 244). Etiology See Tumours of the testis: Introduction (p. 244).

Pathogenesis See Tumours of the testis: Introduction (p. 244). Macroscopic appearance Grossly, there can be a variegated appearance, with tumours ranging from solid and white or tan in colour to showing cysts,

Fig. 6.20 Embryonal carcinoma. A Solid pattern with packed highly pleomorphic cells. B Glandular pattern.

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haemorrhage, and/or necrosis (1914). Embryonal carcinoma can be very small (< 10 mm) yet still show disease progression {2830}. In non-seminomatous germ cell tumours, tumour size > 60 mm is associated with metastatic disease at presentation (2831}, but separate evidence for pure embryonal carcinoma is lacking. Widespread sampling is advisable.

Histopathology The key diagnostic feature is the cell type: large pleomorphic, epithelioid cells with vesicular nuclei containing macronucleoli (one or more), mitotic figures, and dense amphophilic cyto­ plasm. Nuclei frequently overlap and there is often a syncytial appearance without well-defined cell borders. The most common patterns (often more than one present) are solid (55%), glandular (17%), and papillary (11%); less com­ mon are nested, micropapillary, anastomosing glandular, sieve­ like glandular, pseudopapillary, and blastocyst-like {1589). Smudged and degenerate embryonal carcinoma cells can be present at the tumour periphery (applique appearance). Extensive necrosis or dense acute/chronic inflammation can cause diagnostic difficulties. Granulomatous inflammation rep­ resents a pitfail in the distinction from seminoma. There are two types of stroma in embryonal carcinoma - nonneoplastic (bland spindle cells in a collagen-rich background) and neoplastic (cellular mesenchyme with atypia and mitotic figures) - and both can be present. Some consider neoplastic stroma as a teratomatous element, but many do not and con­ sider it a part of embryonal carcinoma. The spindle cell compo­ nent, if considered to be a part of embryonal carcinoma, should be perithelial in distribution. When the cellular spindle cell com­ ponent is more diffuse in arrangement, the tumour represents teratoma. Immunohistochemistry Embryonal carcinoma can show prominent spread within semi­ niferous tubules. The distinction between intratubular spread and lymphovascular invasion may require immunohistochemis­ try (CD34 for basement membranes of tubules, CD31 for blood vessel endothelia, and D2-40 for lymphatic vessel endothelia). Intratubular embryonal carcinoma may undergo comedonecro­ sis with calcification, which can be seen in regressed embryo­ nal carcinoma. Embryonal carcinomas consistently express CD30 (mem­ brane), OCT3/4 (nuclear), SALL4, and AE1/AE3. CD30 may be lost in metastases, but OCT3/4 is maintained in lymph node metastases after chemotherapy (3072). Differential diagnosis Distinction from choriocarcinoma: Syncytiotrophoblastic giant cells are frequently seen in embryonal carcinoma (in 46% of cases) (1589} and this can be mistaken for choriocarcinoma. p-hCG is seen in the syncytiotrophoblasts in both entities, but it is mostly negative in the cytotrophoblast of choriocarcinoma. OCT3/4 staining in embryonal carcinoma, and its absence in the cytotrophoblast of choriocarcinoma, is the most useful dis­ tinguishing feature. Distinction from seminoma: Some embryonal carcinomas (11%) show a seminoma-like pattern, which is a pitfall. AE1/AE3 and CD30 staining is diffuse/strong in embryonal carcinoma, but AE1/AE3 is patchy/weak in seminoma and CD30 should

Fig. 6.21 Embryonal carcinoma. A Papillary pattern with thick and thin papillae. Some areas resemble yolk sac tumour, but the larger cell size supports this be­ ing embryonal carcinoma; immunohistochemistry can be performed for confirma­ tion. B High-power view showing highly pleomorphic cells with mitoses and necrosis.

be negative or only very focally positive. PLAP, D2-40, and KIT (CD117) are diffusely positive in seminoma but should be negative (or can be patchy) in embryonal carcinoma. OCT3/4 is consistently expressed in seminoma and embryonal carcinoma and thus does not help in the distinction. SOX2 is a specific marker for embryonal carcinoma, staining 96% of embryonal carcinomas and < 1% of seminomas (3253}. Distinction from yolk sac tumour (YST): Embryonal carcinoma may show YST-like features - pseudoendodermal sinuses (resembling Schiller-Duval bodies), columnar cells, secretorytype subnuclear vacuoles, or papillary architecture — but embry­ onal carcinoma cells are larger. OCT3/4 is positive in embryonal carcinoma and negative in YST, whereas glypican-3 (GPC3) and AFP are positive (diffuse/patchy) in YST and negative in embryonal carcinoma. Distinction from teratoma: Columnar cell morphology can mimic teratoma, but teratomas lack nuclear pleomorphism and will stain negative for OCT3/4.

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Fig. 6.22 Embryonal carcinoma. A Vascular invasion. B Small nests of embryonal carcinoma among widespread necrosis. Syncytiotrophoblastic giant cells are seen (right). C Solid pattern showing neoplastic stroma with atypia and mitoses (left) and non-neoplastic stroma (upper right).

Essential and desirable diagnostic criteria Essential: large epithelioid cells; pleomorphic vesicular nuclei with 21 macronucleolus; dense amphophilic cytoplasm; over­ lapping nuclei; syncytial appearance; presence of one of the common (solid, glandular, papillary) or less common docu­ mented growth patterns. Desirable: immunohistochemical confirmation in selected cases (e.g. OCT4, CD30, cytokeratin); presence of germ cell neopla­ sia in situ. Staging Staging follows the 2018 Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) clas­ sification.

Fig. 6.23 Embryonal carcinoma. Immunohistochemistry for CD30 showing strong membranous staining in embryonal carcinoma.

Cytology Not relevant Diagnostic molecular pathology Diagnostic molecular pathology is usually not required. Isoch­ romosome 12p or overrepresentation of chromosome 12p may be helpful in selected scenarios such as distinguishing between somatic carcinoma and embryonal carcinoma in metastasis {1047}.

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Tumours of the testis

Prognosis and prediction Lymphovascular invasion and percentage of embryonal carci­ noma are predictive of high stage, and of progression in stage I disease, but there is no agreement on whether to quantify embryonal carcinoma as a continuous or dichotomous vari­ able, with various cut-off points (50-100%) having been used in studies {989,776,3547}. In practice, > 50% is often used clini­ cally {2831). The presence of any embryonal carcinoma and of > 50% embryonal carcinoma had similar predictive power for metastasis in a meta-analysis (373). Interestingly, one study showed that pure embryonal carcinoma was associated with a lower risk of disease relapse at 5 years than embryonal car­ cinoma in a mixed germ cell tumour {893}. Other factors such as local staging, tumour size, and rete invasion have also been shown to predict metastatic spread {2831}. The presence of embryonal carcinoma and lymphovascular invasion can trigger adjuvant chemotherapy in stage I disease.

Yolk sac tumour, postpubertal-type

Definition Postpubertal-type yolk sac tumour (YST) is a malignant germ cell tumour that forms structures of the embryonic yolk sac, allantois, and extraembryonic mesenchyme. ICD-0 coding 9071/3 Yolk sac tumour, postpubertal-type

ICD-11 coding 2C80.Y & XH15X1 Other specified malignant neoplasms of tes­ tis & Yolk sac tumour, postpubertal-type

Related terminology Acceptable: endodermal sinus tumour.

Subtype(s) None

KaoCS Idrees MT Verrill C

of testicular germ cell tumours across two series (1723,3344}. Most patients are aged 15-40 years, but rare cases in elderly people have been reported {2524,3025}. A testicular mass is the most common presentation, and there is a strong correlation between the presence of YST and elevated serum levels of AFP (typically hundreds to thousands of ng/mL) {3101). Epidemiology See Tumours of the testis: Introduction (p. 244). Etiology See Tumours of the testis: Introduction (p. 244).

Pathogenesis See Tumours of the testis: Introduction (p. 244).

Localization See Tumours of the testis: Introduction (p. 244).

Macroscopic appearance Tumours are usually solid to partially cystic, with a greyish white to tan cut surface that may have a myxoid appearance. Haem­ orrhage and necrosis, occasionally extensive, may be present.

Clinical features Postpubertal YST occurs commonly as a component of mixed germ cell tumour (44% {3099}) and is associated with germ cell neoplasia in situ. The pure form is rare, accounting for < 1%

Histopathology A variety of patterns may be seen, often in combination. The most common features seen in many patterns are: (1) the pres­ ence of intracytoplasmic and/or extracellular hyaline globules

Fig. 6.24 Yolk sac tumour, postpubertal-type. A Solid pattern with sheets of tumour cells that have clear cytoplasm and scattered hyaline globules. Note the lack of lymphocytes and fibrous septa compared with seminoma. B Solid pattern with a blastematous appearance. C Papillary pattern with basement membrane deposits (parietal differentiation) within the papillae. D Sarcomatoid pattern showing stellate and spindled tumour cells in a myxoid stroma. The tumour cells are focally arranged in ringlets within the stro­ ma. E Sarcomatoid pattern of postpubertal yolk sac tumour containing epithelioid cells with round, plump nuclei in a fibrous background. F Parietal pattern of postpubertal yolk sac tumour with large amounts of basement membrane material (parietal differentiation). G Polyvesicular vitelline pattern showing vesicles with eccentric constrictions (figureof-eight 叩pearance) and lined by flat tumour cells in a loose fibrous stroma.

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Fig. 6.25 Yolk sac tumour, postpubertal-type. A Solid yolk sac tumour with intense staining for glypican-3 (GPC3). B Microcystic/reticular yolk sac tumour (upper-left corner) adjacent to solid yolk sac tumour (right), illustrating how the intensity of GPC3 staining is typically weaker in the solid pattern. C AFP can be completely negative in solid yolk sac tumour. D AE1/AE3 immunoreactivity in a solid yolk sac tumour.

and (2) parietal differentiation in the form of irregular, often band-like, intercellular basement membrane deposits. The various patterns are described below in approximate order of decreasing frequency.

Myxoid pattern Closely related to the microcystic/reticular pattern, the myxoid pattern consists of sparse tumour cells dispersed as stellate and (occasionally) epithelioid cells in a myxomatous stroma that is often prominently vascular.

Microcystic/reticular pattern Vacuolated cells form a honeycomb-like meshwork, or several flattened tumour cells form ringlets enclosing spaces that often contain mucoid material.

Macrocystic pattern Large irregular spaces develop as an apparent consequence of coalescence of microcysts or due to oedema. The surrounding pattern, therefore, is often microcystic.

Solid pattern Sheets of polygonal tumour cells, typically with abundant pale or clear cytoplasm, form nodules. The cells may have prominent cytoplasmic membranes, similar to those of seminoma cells, but they usually lack a lymphocytic infiltrate and fibrous septa; the nuclei are also more pleomorphic than in seminoma. Rarely, the cytoplasm may be scant and resemble blastema.

Glandular/alveolar pattern A range of tumour cell arrangements may be seen, from simple tubular structures to complex and interconnecting glands. Subnuclear vacuoles may be present, similar to those in secretory phase endometrium. The glands often display enteric features (including immunoreactivity). Unlike teratomatous glands, they lack a surrounding smooth muscle component. Hg.6.26 Yolk sac tumour. Vascular invasion.

Endodermal sinus/pehvascular pattern This pattern consists of a fibrovascular core with a peripheral mantle of cuboidal tumour cells, surrounded by a cystic space. This is sometimes referred to as Schiller-Duval or glomeruloid bodies and is considered a hallmark of YST, although it is present in only a minority (-25%) of cases {1488}.

Hepatoid pattern Polygonal cells with abundant eosinophilic cytoplasm and vesicular nuclei with large nucleoli, resembling hepatocytes, make up this pattern. They may form trabeculae and solid nests, but they only rarely produce bile. These tumours are strongly immunoreactive for AFP and other hepatocellular markers.

Papillary pattern Slender fibrovascular papillae have a peripheral arrange­ ment of a single layer of tumour cells that often show a hob­ nail morphology and project into tissue spaces. Alternatively, Fig. 6.27 Yolk sac tumour. Microcytic pattern.

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Tumours of the testis

Fig. 6.28 Yolk sac tumour, postpubertal-type. A Hepatoid yolk sac tumour. B Glandular yolk sac tumour. The glandular pattern is more common in late recurrences.

pseudopapillary formation may result when epithelium piles up and lacks stromal support.

Sarcomatoid / spindle cell pattern This pattern usually appears as a progression of the myxoid pattern, wherein the spindled/stellate cells dispersed in the stroma are increased in number and density; epithelioid cells are less common but may (rarely) predominate. Myxomatous and microcystic foci are often present nearby.

Parietal pattern A large number of dense eosinophilic basement membrane deposits surround individual or small groups of tumour cells.

Polyvesicular vitelline pattern This pattern almost always occurs with other patterns and con­ tains vesicles, sometimes with luminal constructions (figure-ofeight shape), that are lined by flattened to columnar cells in a myxoid or fibrous stroma.

Immunophenotype AFP is frequently positive but may lack sensitivity {1490,2323, 2235}. Solid areas are more frequently AFP-negative (in 40% of cases) {1584}, whereas hepatoid foci are often intensely positive. GPC3 is more sensitive than AFP, often with more diffuse stain­ ing (3653,2405}, but it is less specific. KIT (CD117) positivity is a potential pitfall and may be variably positive (in 60% of cases of solid YST) (1584). SALL4 and pankeratins are diffusely positive (2323,517}, although CK7 is often negative or only focally reac­ tive {767}, as is EMA (2323}. All YSTs showed nuclear positivity for HNFip in one study (2731}. CDX2 and GATA3 are frequently positive )2731,2399}, the latter with negativity in hepatoid, glan­ dular, and solid foci )2731,2399,2855}. Cytology YST often forms tight, rounded clusters of epithelium in aspirated specimens {55,253}, which are sometimes covered by a layer of flattened tumour cells {253}. Their association with a loosely cohesive spindle cell component, often in a metachromatic back­ ground, is a characteristic feature. The nuclei are often ovoid, with irregular nuclear membranes, coarse chromatin, and one or

more nucleoli {55). The distinctive Schiller-Duval bodies are not typically apparent in cytological preparations, but when found, they consist of tumour cells coating thin-walled, branching ves­ sels with occasional bulbous protrusions of attached epithelium, an appearance that has been likened to a balloon animal (3525). Diagnostic molecular pathology Molecular pathology is usually not required for diagnosis. Isoch­ romosome 12p or 12p overrepresentation may be helpful in dis­ tinguishing postpubertal-type YSTs from prepubertal-type YSTs (such as in cases that lack background germ cell neoplasia in situ) (542,2380,3286).

Essential and desirable diagnostic criteria Essential: the presence of patterns described above, in com­ bination. Desirable: positivity for SALL4, AFP, and GPC3; negativity for OCT3/4 and CD30; presence of Schiller-Duval bodies, hya­ line bodies, and/or germ cell neoplasia in situ. Staging Staging follows the 2018 Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) clas­ sification.

Prognosis and prediction The prognostic significance of postpubertal-type YST is difficult to evaluate because it most often occurs with other forms of germ cell tumour, and most studies do not discriminate between patients with or without this component. Metastatic YST is asso­ ciated with a worse outcome than metastatic non-seminomatous germ cell tumours of other types (1920}; its prognostic significance may therefore vary depending on whether or not it has disseminated, probably because of its higher chemoresistance. A study supporting this viewpoint documented a much higher frequency of YST elements at autopsy during the chemo­ therapeutic era than in the pre-chemotherapeutic era (2340}. Therefore, the histological patterns of YST disproportionately found in chemoresistant cases and late recurrences (glandular predominant, hepatoid, parietal, and sarcomatoid) (2150} may be adverse findings, although this remains unproved.

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267

Choriocarcinoma

Idrees MT Kao CS Paner GP Verrill C

Definition Choriocarcinoma is a malignant germ cell tumour that differenti­ ates to resemble the trophoblastic cells of the extraembryonic chorion, including cytotrophoblasts, intermediate trophoblasts, and syncytiotrophoblasts. ICD-0 coding 9100/3 Choriocarcinoma ICD-11 coding 2C80.2 & XH8PK7 Germ cell tumour of testis & Choriocarci­ noma, NOS Related terminology Not recommended: malignant teratoma; trophoblastic epithe­ lioma; chorio(n)epithelioma.

Subtype(s) None Localization Testis, mediastinum

Clinical features Choriocarcinoma is found in 6.4-17.8% of mixed germ cell tumours and is a pure tumour in only 0.3% of testicular germ cell tumours {1723,2225,2232,116}. Choriocarcinoma is the predominant component in about 1% of all mixed germ cell tumours. Approximately 40% of choriocarcinomas in men occur in the testis, with the remainder occurring at other sites includ­ ing the mediastinum, liver, lung, and gastrointestinal tract. Other than those occurring in the testis, mediastinum, and midline brain, the tumours arise from carcinoma differentiating into trophoblastic neoplasia by a process of neometaplasia. Chorio­ carcinoma occurs during the second and third decades of life (1331,2232,2450,116} and has never been reported in prepu­ bertal boys. Patients most frequently present with disseminated metastasis (often involving the lungs, brain, and liver {2886}), which is characterized by extensive vascularity. Presentation with metastatic disease can include haemoptysis, an abdomi­ nal mass, neurological dysfunction, anaemia, hypotension, or (rarely) a cutaneous nodule. Serum hCG is remarkably elevated and is often > 50 000 IU/L (116). Because of the structural simi­ larity of hCG to LH and TSH, high levels may cause gynaecomastia (in -10% of cases) and thyrotoxicosis (less commonly). Some patients may develop a choriocarcinoma syndrome leading to sudden decompensation; this is characterized by multiorgan haemorrhage due to visceral metastases and is associated with extremely high levels of hCG, often exceeding 100 000 IU/L {2091,2450(.

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Fig. 6.29 Mixed germ cell tumour with choriocarcinoma. Well-circumscribed tumour with prominent haemorrhagic areas.

Epidemiology See Tumours of the testis: Introduction (p. 244).

Etiology See Tumours of the testis: Introduction (p. 244). Pathogenesis EGFR overexpression and EGFR copy-number gain and ampli­ fication have been reported; however, mutations in EGFiR exons 18-24, which occur in many other tumours and are targeted by EGFR inhibitor treatment, have not been observed in chorio­ carcinoma (2184J. See also Tumours of the testis: Introduction (P- 244).

Macroscopic appearance Often, choriocarcinoma is not observed as a markedly expan­ sile neoplasm because of the smaller size of these tumours compared with other germ cell tumours. The cut surface of most choriocarcinomas appears nodular with extensive haemorrhage and necrotic areas. The periphery of the necrotic or haemor­ rhagic nodule(s) is rimmed by the solid greyish tan tumour. Cystic degeneration is usually present. Often, patients with established metastasis will not show any tumour in the testis to be confirmed, only a scar at microscopy (2284,936(. Choriocar­ cinoma manifests as confluent haemorrhage with necrosis and cystic areas in mixed germ cell tumours.

Histopathology Microscopically, pure choriocarcinomas appear remarkably haemorrhagic and necrotic. The viable areas show a character­ istic mixture of mononucleated trophoblasts (cytotrophoblasts and intermediate trophoblasts) and multinucleated syncy­ tiotrophoblasts, producing a biphasic appearance. The cystic haemorrhagic spaces (blood lakes) are lined by aggregates of

mononucleated trophoblasts capped by syncytiotrophoblasts that are often protruding into the cystic spaces, thus imparting an appearance of early placental villous growth that typically lacks stromal cores. The mononucleated trophoblasts consist of small cytotrophoblasts with some medium-sized and (fewer) large intermediate trophoblasts, which may represent a mixture of phenotypically similar implantation site or chorion laevetype intermediate trophoblasts. The cytotrophoblasts contain a moderate amount of clear to eosinophilic cytoplasm and show prominent cell boundaries. The nuclei are slightly irregular, con­ tain multiple prominent nucleoli, and display numerous mitotic figures. The syncytiotrophoblasts are large and have deeply eosino­ philic cytoplasm (which often contains lacunae with erythro­ cytes) and one or multiple nuclei (which are often dark and smudgy). The syncytiotrophoblasts may also have spindled or elongated configurations situated at the tumour periphery or subtly percolating within the mononucleated trophoblastic cells. Occasionally, syncytiotrophoblasts are seen floating within the blood-filled spaces. They are usually associated with thin­ walled capillaries, and they are mitotically inactive. Vascular invasion with clusters of both cell types is common (116(. Leydig cell hyperplasia is often seen in adjacent normal parenchyma, due to elevated hCG levels.

Some tumours may show a predominant population of cyto­ trophoblasts in a sheet-like syncytial pattern with very few or absent syncytiotrophoblasts. This has been described as a pat­ tern of choriocarcinoma; however, such terminology is discour­ aged because no difference in prognosis has been observed between this and the classic morphology {3261}. It may be a diagnostic pitfail and care is required to distinguish this pattern from other germ cell tumours.

Immunohistochemistry Trophoblast-associated markers such as hCG and hPL are expressed mainly by the syncytiotrophoblasts {2323,116}, but a few cytotrophoblasts are also positive. The syncytiotrophoblasts also express inhibin, GATA3, and glypican-3 (GPC3) {2080, 3653). The cytotrophoblasts express SALL4, GDF3, p63, and GATA3 (258,517,1168,116}. The intermediate trophoblasts may weakly label for hPL (116}. Pregnancy-specific pi-glycoprotein 1 (PSG1, previously known as SP1), PLAP, CEA, EMA, wildtype p53, and cytokeratins (including CK7, CK8, CK18, and CK19) may show variable reactivity {2015,2323,1892,667}.

Differential diagnosis The differential diagnosis includes other germ cell tumours and other trophoblastic tumours, including placental site

Fig. 6.30 Choriocarcinoma. A Haemorrhage and cyst formation with viable tumour showing capping of cytotrophoblasts with syncytiotrophoblasts. B Haemorrhagic tumour with a biphasic population of cells composed of mononucleated cytotrophoblasts and multinucleated syncytiotrophoblasts.

Fig. 6.31 Choriocarcinoma. A Pleomorphic tumour cells with clear cytoplasm. B Clusters of syncytiotrophoblasts lying within vascular spaces. Prominent cytoplasmic vacuola­ tion and lacunae with red blood cells are present. C Monophasic appearance with an abundance of cytotrophoblasts and only rare syncytiotrophoblasts.

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Cytology Cytology preparations show an admixture of syncytiotropho­ blasts and cytotrophoblasts in a necrotic and haemorrhagic background (2583,837,51). In the absence of a prominent syncytiotrophoblast component, it may be challenging to establish a definitive diagnosis; in such cases, immunocytochemistry is required for the diagnosis. Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: a characteristic biphasic pattern containing cyto­ trophoblastic cells and syncytiotrophoblasts. Desirable: trophoblastic immunohistochemical markers (e.g. hCG, hPL, GATA3, and GDF3) for the distinction of choriocar­ cinoma from other germ cell tumours; presence of germ cell neoplasia in situ. Fig. 6.32 Choriocarcinoma. GATA3 nuclear positivity in trophoblastic cells.

trophoblastic tumour (PSTT) and cystic trophoblastic tumour. The differential diagnosis with other germ cell tumours is dis­ cussed in their respective sections. Often embryonal carcinoma and seminoma display syncytiotrophoblasts admixed with the tumour cells; when this is associated with elevated hCG, it may present a diagnostic challenge. In the absence of a biphasic and characteristic haemorrhagic appearance, a diagnosis of choriocarcinoma cannot be entertained, and the tumour should be diagnosed as the respective germ cell tumour with syncytio­ trophoblasts. In comparison to non-choriocarcinomatous trophoblastic tumours, choriocarcinoma cells are remarkably pleomorphic and occur in sheets embedded in a haemorrhagic background. Necrosis, degeneration, high mitotic activity, and cystic changes are frequently observed. The tumour cells exhibit diffuse hCG reactivity. Epithelioid trophoblastic tumours have a distinct squamoid appearance, apoptotic hyaline cellular debris, and no vascular invasion; in contrast, PSTTs show a sheet-like pattern, vascular invasion, and prominent fibrinoid change in the ves­ sels. p63 and hPL are the most important immunohistochemis ­ try markers for distinguishing between epithelioid trophoblastic tumours and PSTTs: epithelioid trophoblastic tumours show diffuse reactivity for p63 and are negative for hPL, whereas PSTTs are negative for p63 but show hPL expression. Cystic trophoblastic tumours are characteristically cystic, showing squamoid-appearing cells with smudged nuclei and intracel­ lular lacunae with low proliferation.

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Staging Staging follows the eighth-edition Union for International Can­ cer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM system. Prognosis and prediction Choriocarcinoma is the most aggressive form of germ cell tumour, with a proclivity for early haematogenous spread, high stage at presentation, and haemorrhagic complications (289,1331,1510, 116}. It generally metastasizes to the lungs, liver, gastrointesti­ nal tract, brain, spleen, and adrenals (2232,2450,116). Elevated serum hCG, particularly > 50 000 IU/L, is predictive of an unfa­ vourable treatment response (1895,1918}. hCG can be secreted by other germ cell tumours, including seminoma with syncytio­ trophoblasts, although usually at lower levels than are seen with choriocarcinoma. A small amount of hCG is produced by normal functioning testes and prostate gland. Serum levels are typically < 5 mIU/mL in healthy men (324}. Pure and predominant (> 50%) choriocarcinomas appear to have a similarly poor outcome (116|. Small amounts of choriocarcinoma (< 5%) do not impact the prognosis in mixed germ cell tumours. When treated with com­ bination chemotherapy, patients with choriocarcinoma have a 3-year survival rate of only 21% (116(. The outcome may not be uniformly fatal with standard chemotherapy for distant metastasis confined to the lungs or after complete resection of the residual mass and with high-dose chemotherapy with stem cell support (638,1829,2450,116,1918}. A small amount of choriocarcinoma in clinical stage I disease can be managed by surveillance (1308).

Placental site trophoblastic tumour

Idrees MT KaoCS Paner GP Verrill C

Definition Placental site trophoblastic tumour (PSTT) of the testis is a malignant trophoblastic neoplasm with morphological features similar to those of its predominantly uterine counterpart, which is considered to be derived from implantation site intermediate trophoblasts. ICD-0 coding 9104/3 Placental site trophoblastic tumour of the testis

ICD-11 coding 2C80.Y & XH1RM5 Other specified malignant neoplasms of tes­ tis & Placental site trophoblastic tumour Related terminology None

Subtype(s) None

Localization Testis

Fig. 6.33 Placental site trophoblastic tumour. Pleomorphic trophoblastic cells in a fi­ brinoid background with prominent vascular invasion. The tumour shows a cohesive growth pattern with areas of cells growing in small clusters and singly.

Clinical features Only 7 cases of testicular PSTT have been described, in patients aged 16 months to 61 years (median age: 33 years) {1447,2511,1849,2630,3079,3261,357). Five arose in the testis and the remaining two reported were at metastatic sites. Four of the testicular PSTTs arose as a component of mixed germ cell tumours, and the remaining case was a pure PSTT. Two tumours reported in metastatic sites were in patients who had previously received chemotherapy (3079,3261). Serum hCG may be elevated in patients with PSTT. The corresponding primary testicular tumour may demonstrate trophoblastic differ­ entiation (choriocarcinoma) in metastatic PSTT. One PSTT has also been reported in a mediastinal germ cell tumour {3435}. Epidemiology Insufficient data

Etiology See Tumours of the testis: Introduction (p. 244).

Fig. 6.34 Placental site trophoblastic tumour. Hyperchromatic, pleomorphic, often multinucleated tumour cells invading the vessels, with the almost complete destruction of the vessel wall.

See Tumours of the testis: Introduction (p. 244).

Macroscopic appearance No characteristic findings are known.

Histopathology PSTT consists of mononucleated implantation-type intermedi­ ate trophoblastic cells, as well as infiltrative single or loosely

cohesive cells with abundant eosinophilic or focally vacuolated cytoplasm, with irregular nuclei, often appearing smudged. PSTT distinctively invades into the muscular walls of vessels, with partial or complete replacement usually associated with fibrinoid change. PSTT expresses HSD3B1, inhibin, GATA3, and CK18, and it is specifically positive for hPL {1447}. Inhibin reactivity is patchy, while hCG is focally positive. p63 is negative Tumours of the testis

271

in PSTT (2915,1447|, and this is helpful in the differentiation from epithelioid trophoblastic tumour, in which p63 is positive. The Ki-67 index ranges between 10% and 50%.

Cytology None reported Diagnostic molecular pathology Not relevant Essential and desirable diagnostic criteria Essential: mononucleated trophoblastic cells in diffuse sheets; infiltrative pattern with prominent vascular invasion; tumour cells are positive for hPL and negative for p63.

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Staging The eighth-edition TNM staging system is used. Prognosis and prediction Data regarding the behaviour of PSTT are limited. The avail­ able follow-up on three of four testicular tumours showed that two patients were alive after 3 and 8 years, and one patient developed metastasis 1 month after orchiectomy {2511,3261, 2630), One of two metastatic tumours had follow-up; the patient developed three recurrences over 27 months of follow-up.

Epithelioid trophoblastic tumour

Definition Epithelioid trophoblastic tumour (ETT) is a malignant tropho­ blastic neoplasm with morphological features analogous to those of its predominantly uterine counterpart, which is con­ sidered to be derived from chorionic-type intermediate tropho­ blasts.

ICD-0 coding 9105/3 Epithelioid trophoblastic tumour ICD-11 coding 2C80.Y & XH8FW3 Other specified malignant neoplasms of tes­ tis & Trophoblastic tumour, epithelioid

Related terminology None Subtype(s) None

Localization ETTs occur in the testis and as metastatic germ cell tumours.

Clinical features Only 5 ETTs have been described in men (91,1447). The first case was in a para-aortic lymph node in a 39-year-old man who had undergone a prior orchiectomy for mixed germ cell tumour. In the only case series (4 cases), the patient age range was 19-43 years. Two tumours arose in testicular mixed germ cell tumours and two were metastases to the chest wall and precaval nodes {1447).日evated hCG levels and choriocarcinoma in primary testicular germ cell tumour were identified in 3 of the 5 cases. The metastases and recurrence occurred 2-11 years after orchiectomy despite chemotherapy. In metastases, all ETTs were associated with teratoma. The ETT component was

I drees MT KaoCS Paner GP Verrill C

minor (~5%) in 3 of the 4 cases in the series. In the fourth case, the ETT component made up 95% of a chest wall mass. In 1 patient, ETT was identified only in the first and third recur­ rences. Epidemiology See Tumours of the testis: Introduction (p. 244).

Etiology See Tumours of the testis: Introduction (p. 244).

Pathogenesis The exact pathogenesis of ETT is not clear; however, it has been suggested that the tumour arises within a mixed germ cell tumour after reprogramming in the differentiation of the neoplastic cytotrophoblasts (stem cells) to produce ETT {2914}. Alternatively, it is possible that chemotherapy contributes to the differentiation of choriocarcinoma into ETT, which is more refractory to chemotherapy owing to its low proliferation activ­ ity. Consequently, the ETT cells survive after the destruction of choriocarcinoma (2914,3245). Macroscopic appearance No macroscopic features have been described. Histopathology Epithelioid trophoblastic tumours consist of cohesive nests of squamoid-appearing cells with abundant pink cytoplasm. The majority of the cells are mononucleated; however, multinucle­ ated cells may be seen dispersed among mononucleated cells. The tumour may comprise sheets of cells, cells in clusters, and single cells. The nuclei are pleomorphic and hyperchromatic with variably prominent nucleoli. The cytoplasmic membranes are well delineated but lack intercellular bridges. The cells may contain intracytoplasmic vacuoles of variable size and often

Fig. 6.35 Epithelioid trophoblastic tumour. A Cohesive groups of squamoid cells with areas of necrosis and 叩optosis. B The squamoid tumour cells are pleomorphic and often multinucleated; the nuclei contain prominent nucleoli. The cells contain hyaline globules and show prominent apoptosis and necrosis. Mitotic figures are easily identified. C p63 expression in trophoblastic tumour cells suggests chorion laeve-type intermediate trophoblastic cells.

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contain fibrinoid cellular debris. The deeply stained eosino­ philic fibrinoid material may be present around the tumour and vessels. Cystic degeneration was present in one tumour, and isolated cells may be necrotic. Mitotic activity varies in differ­ ent areas. The stroma is usually hyalinized to fibrinoid, and all tumours contain lymphocytic infiltrate predominantly around the cell clusters.

Immunohistochemistry ETTs are positive for inhibin, GATA3, p63, and PLAP. The tumour cells usually express hCG (2915). hPL staining is characteristi­ cally focal, unlike in placental site trophoblastic tumour. Ki-67 index ranges from 10% to 25% {1148,1447,2915}.

Cytology Not described

Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: squamoid-appearing, mostly mononucleated tropho­ blastic cells with a variable amount of fibrinoid material sur­ rounding the tumour clusters and vessels. Desirable: positive staining for p63; Ki-67 index > 10%. Staging The eighth edition of the TNM staging system is used.

Differential diagnosis The morphological and immunohistochemical characteristics of the trophoblastic cells of ETT are similar to those of intermediate trophoblasts in the chorion laeve region (the smooth part of the placental chorion). The differential diagnosis includes chorio­ carcinoma and other trophoblastic tumours (e.g. placental site trophoblastic tumour and cystic trophoblastic tumour).

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Prognosis and prediction Because of the limited number of cases, it has not yet been pos­ sible to determine the behaviour of these tumours; however, the current evidence suggests that these may be less aggressive than choriocarcinoma {1447).

Cystic trophoblastic tumour

Definition Cystic trophoblastic tumour (CTT) is a putatively transformed trophoblastic neoplasm mostly seen in metastatic sites after chemotherapy for germ cell tumours that may have a concomi­ tant or prior choriocarcinoma component. ICD-0 coding None

ICD-11 coding 2C80.Y Other specified malignant neoplasms of testis Related terminology None

Subtype(s) None

Idrees MT Kao CS Paner GP Verrill C

Localization Primarily retroperitoneal lymph node germ cell metastasis; less commonly testis and other germ cell tumour metastatic sites Clinical features CTT was first described in retroperitoneal lymph node dissec­ tions after chemotherapy {3247}. However, it is now known that these tumours can occur as part of primary testicular mixed germ cell tumours, and they are occasionally seen in visceral and non-regional lymph node germ cell tumour metastases {1159}. Less commonly, these tumours have been described in germ cell tumour patients without chemotherapy {3387). The most common association with chemotherapy may be explained by a greater number of resections examined after chemotherapy. However, it can be speculated that the regres­ sive phenotype of this tumour may have been a consequence of the effect of chemotherapy on germ cell tumours, especially choriocarcinoma. The patient age ranged from 15 to 43 years in two larger series (3247,1159). To date, CTT has not been

Fig. 6.36 Cystic trophoblastic tumour. A Multiple interconnected cysts lined by trophoblastic cells. The cysts are often filled with eosinophilic material or blood. B The tropho­ blast cells lining the cysts have abundant eosinophilic cytoplasm with large clear vacuoles. The nuclei appear smudged and degenerating. The cell boundaries are well demar­ cated. C Cystic structure lined by trophoblastic cells with extensive vacuolization (lacunae). D The cysts are often compressed and surrounded by fibrinoid material. The cells have large vacuoles that coalesce to form lacunae. Hyaline material is usually present within and outside the cells. Often, a cord-like arrangement of trophoblastic cells is seen within the fibrinoid material. E Multinucleation, hyperchromasia, and nuclear atypia are common findings.

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described in women who have received treatment for tropho­ blastic malignancies; however, similar lesions may have been described using different terminology {1963}. Epidemiology Because of the rarity of this tumour, the epidemiological factors are not apparent.

Etiology CTTs arise as a result of the effect of chemotherapy on germ cell tumours and the spontaneous regression of choriocarcinoma.

Pathogenesis The pathogenesis of CTT is not entirely understood. Regres­ sion of choriocarcinoma under the effect of chemotherapy was introduced as the hypothesis for the pathogenesis of this lesion, but untreated patients without choriocarcinoma may have CTT in the testis. It has been proposed that testicular CTT represents a form of regressed choriocarcinoma or a late morphological phase in the maturation of choriocarcinoma to teratoma, which essentially explains its presence at other sites as well {1159(. It is possible that the regression of more aggressive tropho­ blastic cell types (whether due to chemotherapy or spontane­ ous regression) may have favoured the proliferation of the less aggressive trophoblastic cell type that constitutes this tumour {1447}. Macroscopic appearance CTT is admixed commonly with teratoma and less commonly with other germ cell tumours, and it occurs in small propor­ tions; for these reasons, characteristic gross features cannot be ascribed to it.

Histopathology CTT is composed of squamoid-appearing, predominantly mon­ onucleated intermediate trophoblasts lining the cyst wall {3247, 1159}. The cyst may vary in size and shape and often appears collapsed among other germ cell tumour components. The cells display smudged nuclei with abundant eosinophilic cytoplasm, suggesting a degenerative phenotype. Cytoplasmic lacunae

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(vacuoles) are present in a variable proportion of cells. Small solid clusters of cells and single cells may also be seen adjacent to the larger cysts. The cyst may contain eosinophilic secretion or fibrinoid material. The cytoplasmic lacunae may coalesce to create variably sized spaces. Mitoses are rarely seen.

Immunohistochemistry CTTs are diffusely positive for GATA3. Inhibin, p63, and hCG are variably positive {1159}.

Differential diagnosis The primary differential diagnoses for CTT are other tropho­ blastic tumours and teratoma. CTT is often underdiagnosed because it may be intricately admixed with other teratoma com­ ponents. Choriocarcinoma is distinctly biphasic, haemorrhagic, and pleomorphic, and it displays brisk mitotic activity. Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: cysts lined by squamoid-appearing cells with smudged, irregular nuclei; abundant eosinophilic cytoplasm with intracytoplasmic lacunae and associated fibrinoid material. Desirable: immunohistochemistry may be supportive in selected cases. Staging CTT is staged using the TNM system. Prognosis and prediction When identified at metastatic sites, the clinical course of CTT is comparable with that of metastatic teratoma, indicating no fur­ ther therapy {3247}. When present with other germ cell tumours, the prognosis depends on the type and proportion of the spe­ cific germ cell tumour component.

Teratoma, postpubertal-type

Idrees MT Tickoo SK

ICD-0 coding 9080/3 Teratoma, postpubertal-type

elevated, especially AFP, which helps to differentiate a postpubertal teratoma from a yolk sac tumour. At imaging, teratomas appear as well-circumscribed and complex masses. Cartilage, calcification, fibrosis, and scar formation result in echogenic foci, manifesting as variable shad­ owing patterns. Predominant cystic changes indicate a terato­ matous component. Tumour spread is via the lymphatics. Like other germ cell tumours, teratomas spread first to the retroperitoneal lymph nodes; later, mediastinal and visceral metastasis can be seen.

ICD-11 coding 2C80.4 Malignant teratoma of testis

Epidemiology See Tumours of the testis: Introduction (p. 244).

Related terminology Not recommended: mature teratoma; immature teratoma.

Etiology See Tumours of the testis: Introduction (p. 244).

Subtype(s) None

Pathogenesis See Tumours of the testis: Introduction (p. 244).

Localization Testis

Macroscopic appearance The tumours are firm and nodular; the tunica appears bulged and stretched over the nodules. The cut sections show tremen­ dous heterogeneity due to the presence of several tissue types and usually appear solid and cystic. The solid areas are firm to soft to myxoid and whitish-tan to translucent. The cysts are filled with serous, mucoid, or keratinous material. Cartilage, bone, and pigmented areas may be identified grossly.

Definition Postpubertal-type teratoma is a malignant germ cell tumour derived from germ cell neoplasia in situ (GCNIS) and com­ posed of several tissue types arising from one or more germ lay­ ers (endoderm, mesoderm, and ectoderm). Well-differentiated, mature somatic-type tissues or immature, embryonic-type tis­ sues may comprise the morphological spectrum.

Clinical features Postpubertal teratoma typically occurs in young men within the same age range as other germ cell tumours. In children, post­ pubertal teratomas can occur in disorders of sex development, and it is important to distinguish these cases from prepubertaltype teratoma in younger age groups to address management differences properly. Most postpubertal teratomas occur as a component of mixed germ cell tumours and are identified in 47-50% of these cases {3344}. Only 27-7.0% occur as pure teratomas {2235}. A firm, irregular scrotal mass is the most common presentation. Occasionally, metastasis (usually in the retroperitoneum) may be the presenting finding, where it may occur along with other germ cell tumours. It is also possible that only other germ cell components are identified in metastasis with pure teratoma in the testis {2582}. Serum markers may be

Histopathology Typically several tissues can be observed, including epithelial, mesenchymal, and neural tissue. The most common tissue types with an organoid appearance are skin with append­ ages, respiratory tract, gastrointestinal tract, and genitourinary tract; however, organoid arrangements are seen less often in postpubertal-type teratoma than in prepubertal-type teratoma. Cysts lined by glandular and squamous epithelium are com­ mon and sometimes prevalent. The gland may be complex and

Fig. 6.37 Teratoma, postpubertal-type. A Mixed teratomatous elements with embryonic-type neuroectodermal components. B This example shows mature cartilage and an embryonal-type neuroectodermal component. C This example shows several mature tissue types, including squamous epithelium, mature cartilage, glandular epithelium, adi­ pose tissue, and myofibroblastic stroma. D Cartilage and glandular tissue are seen in this teratoma. The cartilage appears hypercellular and shows prominent cellular atypia.

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Fig. 6.38 Teratoma, postpubertal-type. A Glandular 叩ithelium showing goblet cells. The surrounding spindle cell stroma is predominantly aggregating around the glands. B A single gland is surrounded by highly cellular spindle cell stroma in a myxoid matrix. C Mature glandular elements with mild nuclear atypia and pleomorphism. Note the syncytiotrophoblast with intracytoplasmic red blood cells and the spindle cell stroma displaying variable cellularity. D Periglandular stromal cuffing. Both mesenchymal and epithelial components show nuclear atypia. E Glandular tissue, fibrous stroma, and adipose tissue (high-power view).

cribriforming. Neuroectodermal tissue, non-cystic glands, and mesenchymal tissues such as adipose tissue and cartilage are usually present. A varying degree of cytological atypia is often observed in most of the tissues. Mature glandular tissue may show high-grade dysplasia or carcinoma in situ, and cartilage may show chondrosarcoma features. The stromal elements may show atypical spindle cell proliferation and often imma­ ture, mitotically active, cellular stroma cuffing the glands. The mesenchymal stroma may show fibroblastic, myofibroblastic, smooth muscle, and even skeletal muscle differentiation. Inter­ vening collagenous and fibrocollagenous areas are common. The vascularity varies from a few vessels to occasional exuber­ ant vascularization displaying anastomosing vascular channels with varying degrees of endothelial atypia. Fetal or embryonictype tissue from ectodermal, endodermal, and/or mesenchymal tissues may be seen. Immature neuroectodermal structures resembling those of the early embryonic CNS are particularly common. Neural, glial, or neuroglial tissue may be seen and usually accompanies the embryonal-type neuroectodermal tis­ sue, suggesting differentiation. Rarely, nephroblastoma-like epi­ thelium is seen. Embryonic rhabdomyoblastic and mature fetal type skeletal muscle can be seen.

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Occasionally, the teratomatous tissue (especially in metasta­ ses) is associated with extensive rhabdomyoblastic differentia­ tion, which lacks anaplasia and shows mature rhabdomyocytes without robust mitotic activity, barring the diagnosis of rhabdo­ myosarcoma {670). Syncytiotrophoblasts may be seen scat­ tered among different elements. Note that rarely, mesenchymal components in the form of spindle cell proliferation may be the only teratomatous component present in a mixed germ cell tumour. This finding should be reported as postpubertal-type teratoma along with the other germ cell tumour components. Teratoma may invade paratesticular tissue and may rarely show intratesticular and extratesticular vascular invasion. The uninvolved testis parenchyma usually shows dysgenetic changes constituting testicular atrophy, including sclerotic tubules and impaired spermatogenesis. Microlithiasis may be seen in adjacent sclerotic tubules. As many as 90% of terato­ mas have GCNIS in uninvolved seminiferous tubules. In mixed germ cell tumours, teratoma is most commonly observed in combination with yolk sac tumour or embryonal carcinoma (2225}. In postchemotherapy resections, teratoma is the most prevalent tumour type either alone or in combination with other germ cell tumour components.

Fig. 6.39 Teratoma, postpubertal-type. A Glandular and mesenchymal component with prominent rhabdomyomatous differentiation. B Rhabdomyomatous differentiation.

Immunohistochemistry The different tissue types express tissue-specific markers. The glandular elements of a teratoma are positive for EMA (1442(. AFP expression can be seen in up to 36% of glandular compo­ nents. hCG may highlight syncytiotrophoblastic cells. PLAP is also demonstrable in glandular structures {2235}. Several other immunohistochemical markers, including a1-antitrypsin, CEA, ferritin, and PLAP, are seen in glandular tissue (1491,473,2014, 3236). SOX2, SALL4, SOX17, CDX2, GATA3, and p53 can be seen in different components (1168,517,2162,2335,2399,2161, 904). Cytology The cytological findings depend on the type of tissue the tera­ toma comprises. Cytomorphological heterogeneity and the presence of mature tissue elements suggest teratoma. Special­ ized tissues such as cartilage, pancreas, thyroid, neural/glial tissue, and skin indicate the presence of teratoma. Because of limited tissue sampling, other germ cell tumour components cannot be ruled out by cytological evaluation.

Diagnostic molecular pathology Postpubertal-type teratoma is hypotriploid, as are the fully differentiated tumour cells found in residual teratomas after chemotherapy {93,2200,2381,1151). Isochromosome 12p and 12p overrepresentation can be observed in the majority of tumours using cytogenetic and FISH studies (2695,2878,543, 3358). In cases where testicular postpubertal-type teratomas coexist with other germ cell tumour components, the postpubertal-type teratomas (in the testis and metastasis) exhibit similar genetic changes to those of other germ cell tumour components (1549, 1634,3287). Postchemotherapy teratoma exhibits aneuploid DNA and lower chromosome numbers than primary teratoma {2381,1927,2877,543,544}. In cases in which the testicular primary has teratoma ele­ ments, postchemotherapy lymph node metastases typically also contain teratoma. In both testicular primary and postch­ emotherapy lymph node specimens, the stromal cells adjacent to teratoma often have concordant genetic alterations to the teratoma, indicating that the stroma is germ cell-derived and not just reactive fibrosis {623,415,1927).

Fig. 6.40 Teratoma, postpubertal-type. A Glandular tissue, fibrous stroma, and adipose tissue (low-power view). B Cartilage tissue showing hypercellularity and chondrocyte atypia. C Squamous epithelial and glandular tissue, fibrous stroma, adipose tissue, and glial proliferation (lower right).

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Essential and desirable diagnostic criteria Essential: several tissue types derived from any of the germ layers (ectoderm, mesoderm, or endoderm); the tissue types may range from mature and completely differentiated to immature and undifferentiated. Desirable: the presence of dysgenetic changes and GCNIS in residual seminiferous tubules; isochromosome 12p and 12p overrepresentation in the tumour components. Staging Teratomas are staged in the same way as germ cell tumours derived from GCNIS. Prognosis and prediction In large referral studies, the presence of teratoma in a testicular germ cell tumour was seen to decrease the chance of occult metastasis (1107,3479,1062}. Pure teratoma is commonly identi­ fied in metastases after chemotherapy for non-seminomatous germ cell tumours, which often contain teratomatous elements in the testis {1917}. About 20-46% of patients with pure postpubertal teratomas have metastases at presentation (1838,875,2939|. Cytological atypia or immaturity in any of the teratoma element does not affect prognosis, unless it is expanded to produce a pure expansile nodule > 5 mm, which is to be considered as somatic-type malignancy arising in a teratoma (3249). Because the tissues of which postpubertal teratoma consists commonly show cytological atypia and immaturity, the recommendation is not to report it to avoid confusion with somatic-type malignancy. In patients with clinical stage I teratoma, the risk of metastasis in

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retroperitoneal lymphadenectomies is 16.7% (1838). About 37% of referred patients with pure teratoma present with metastases {1838}. Teratoma is the most common component in treated germ cell tumours. The sole teratoma component in metastases generally confers a better prognosis than residual, postchemo­ therapy non-teratomatous germ cell tumours {3118}. Teratoma metastases are typically synchronous (in 20-46% of cases); they are metachronous only in about 13% of cases {1838, 875,2939). A higher metastatic rate (close to 66%) has been reported for teratomas associated with a regressed (burnt-out) germ cell tumour. Teratomas, even pure teratomas, may exhibit metastases of any type of germ cell tumour (1039,1493,2389, 2598,3035}. The majority of late recurrences (> 2 years after a complete initial response to chemotherapy) contain teratoma. Postpubertal-type teratomas are resistant to chemotherapy and radiotherapy, and surgical removal is the only curative modality (1919). About half of the residual tumours removed at postch­ emotherapy surgery contain teratoma {537}. If teratoma is the sole component, the prognosis is better: no further chemotherapy is required and disease-free survival approaches 95% {1038,3650,1917,888(. The presence of other germ cell tumour components in the late recurrence setting is prognostically worse (2150,888}. In postchemotherapy lymph nodes, the finding of mature rhabdomyocytes with abundant eosinophilic cytoplasm (lacking mitotic activity and without a primitive cellular component) is associated with a favourable prognosis. It must be differentiated from metastatic rhabdomyo­ sarcoma as a component of a somatic malignancy arising in a teratoma {670}.

Teratoma with somatic-type malignancy

Idrees MT Boormans JL Colecchia M Looijenga LHJ

Definition A teratoma with somatic-type malignancy is a teratoma that develops a distinct component that resembles a somatic-type malignant neoplasm (e.g. sarcoma, carcinoma), as seen in other organs and tissues. ICD-0 coding 9084/3 Teratoma with somatic-type malignancy

ICD-11 coding 2C80.4 & XH33E8 Malignant teratoma of testis & Teratoma with malignant transformation Related terminology Not recommended: teratoma with malignant transformation; teratoma with a secondary malignant component.

Subtype(s) None

Localization Testis, retroperitoneum, metastatic sites, and mediastinum Clinical features Somatic-type malignancies occur in 2.5-8.0% of testicular germ cell tumours {538,45,682,3248}, virtually only in postpubertal patients (ranging in age from 15 to 68 years) {682,1987,2237). Most patients have teratomatous germ cell tumours (682,2237, 2665}; however, a recent study suggested that many somatictype sarcomas actually arise from yolk sac tumours {1404, 1856}. The somatic-type malignancies associated with teratoma most commonly occur in retroperitoneal lymph nodes seen in resections after cisplatin-based chemotherapy; they occur less commonly in primary testicular germ cell tumour and at other

Fig. 6.41 Somatic-type malignancy. Embryonic-type neuroectodermal tumour arising within a testis, exhibiting involvement of hilar and adnexal structures.

metastatic sites (45,1987}. The interval from the diagnosis of a germ cell tumour to the onset of a somatic-type malignancy varies widely; some malignancies are seen in the primary site and others occur > 30 years later {86}. Carcinomas develop late in the course of disease (median: 108 months from germ cell tumour diagnosis), whereas sarcomas develop earlier (median: 20 months) {2665}. Epidemiology See Tumours of the testis: Introduction (p. 244). Etiology See Tumours of the testis: Introduction (p. 244). Pathogenesis See Tumours of the testis: Introduction (p. 244).

Fig. 6.42 Rhabdomyosarcoma. A Embryonal-type rhabdomyosarcoma showing pleomorphic spindle cells and differentiated rhabdomyoblasts. B High-power view showing rhabdomyoblasts and pleomorphic spindle cells.

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281

Fig. 6.43 Embryonic-type neuroectodermal tumour. Embryonic-type neuroectoder­ mal tumour showing hyperchromatic cells in rosettes.

Macroscopic appearance There are no distinct features ascribed to somatic-type malig­ nancies. The sarcomas may appear as solid, whitish-grey to tan, firm, nodular masses; however, in the presence of teratoma it is not possible to distinguish them with certainty.

Histopathology Depending on the type of malignancy, the tumours may display expansile or infiltrative growth patterns. To declare a tumour as a somatic-type malignancy, the tumours should exhibit a pure population of atypical mesenchymal or epithelial cells and occupy at least one low-power field (x4 objective, 5 mm in diameter) {3248}. However, the tumour may be separated by foci of teratoma and other germ cell tumour components, and less stringent criteria may be applied because the overall amount of tumour may exceed 5 mm in contiguous sections. Teratoma often displays marked atypia, consists of somewhat organoid admixtures of varied elements, and is often mixed with other germ cell tumour components. Radiation and chemotherapy may also induce atypical changes in both neoplastic and sup­ portive cells, but treatment-induced atypia is usually diffuse and lacks the requisite nodular or infiltrative growth of a single type of atypical cell population (780). Sarcomas are more common than carcinomas and often appear early in the course of the

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disease. It is of utmost importance that these malignancies be differentiated from teratoma because their presence dramati­ cally impacts prognosis and overall survival. Rhabdomyosarcoma is the most commonly identified sarcoma in postchemotherapy resections {1226,2004,2237,1987}. It rep­ resents more than half of all sarcomas (2004,1226}. The majority of these are embryonal rhabdomyosarcoma, whereas alveolar and pleomorphic subtypes occur occasionally. Approximately 50% of patients were disease-free after a median follow-up of 75 months (682,1226,2237). Leiomyosarcoma, angiosarcoma, and other sarcomas are infrequently reported {1226,2004). Embryonic-type neuroectodermal tumour (formerly primi­ tive neuroectodermal tumour',) is another relatively common somatic-type malignancy for which WHO has adopted new ter­ minology {42,2149}. These tumours represent an overgrowth of embryonic-type neuroectodermal tissue that is commonly seen in teratomas and often categorized as an immature neuroec­ todermal component. They resemble CNS embryonal tumours and lack the chromosome 22 translocation seen in peripheral primitive neuroectodermal tumours (Ewing sarcoma) {3246(. The change in terminology was necessary because these tumours are often referred to as "central-type primitive neuroec­ todermal tumours”; however, the current WHO classification for the CNS does not contain this term because these and similar primitive tumours were classified under the category of embryo­ nal tumours in the 2016 WHO classification. This change pro­ vides alignment with CNS terminology and will help avoid the misinterpretation of this tumour as Ewing sarcoma, which has vastly different therapeutic implications. Embryonic-type neuro­ ectodermal tumours often show glial differentiation, more com­ monly in postchemotherapy instances. If the predominant glial component is present, it is pertinent to classify it as glioma or glioblastoma multiforme if it displays anaplastic features. GFAP, S100, and SOX11 are positive in the tumour cells {1989}. Rarely, nephroblastoma may develop in a teratoma {2148( or occur in pure form (1135) in metastasis. Most carcinomas are adenocarcinomas (usually NOS) {1987). Squamous cell, neuroendocrine, and poorly differentiated car­ cinomas have also been found in teratomas {682,1987,2237(. Rarely, two types of secondary somatic-type malignancies develop simultaneously (691,2386}. Somatic-type malignancies demonstrate immunohistochemical features similar to those of

their counterparts in other organs. They generally lose immu­ noreactivity for PLAP, OCT3/4, and AFP, but they may maintain various degrees of positivity for SALL4 {1987(. Although most neuroendocrine tumours (NETs) develop from prepubertal-type teratomas, some are associated with germ cell neoplasia in situ and isochromosome 12p and therefore arise from postpubertaltype teratomas (3J.

Cytology Cytomorphological features in metastasis may help in determin­ ing the presence of epithelial or sarcomatous malignancy. Diagnostic molecular pathology Isochromosome 12p and overrepresentation of 12p has been demonstrated in most somatic-type malignancies (1749, 2237,1448). Chromosomal rearrangements analogous to their counterparts in other locations have also been shown (2237}. Iwo thirds of somatic-type malignancies have patterns of loss of heterozygosity identical to those of their matched teratomas, and the remaining ones showed additional allelic losses (1634, 1749).

Fig. 6.46 Squamous cell carcinoma. Well-differentiated squamous cell carcinoma arising from a metastatic teratoma.

Essential and desirable diagnostic criteria Essential: expansile and infiltrative growth of epithelial or mes­ enchymal component measuring > 5 mm. Desirable: specific somatic features and immunohistochemistry are helpful in most cases. Staging Staging follows the 2018 Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM classification. Prognosis and prediction The prognosis is generally not affected if the somatic malig­ nancy is not the predominant component and confined to the testis (1226,2237}. However, in metastasis or recurrence, mor­ tality risk is increased (1226,2237}. The histological type does not seem to be an independent prognostic factor in multivariate analysis {2665}. If the malignancy is localized, surgical resection

Fig. 6.47 Undifferentiated pleomorphic sarcoma. Markedly pleomorphic spindled cells in a collagenous background.

is the treatment of choice {2299}. Patients with somatic-type malignancies respond poorly to the cisplatin-based chemo­ therapy used for conventional germ cell tumour {682,2237}; however, some may respond to specific chemotherapy that is effective for their counterpart in other organs {884}.

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283

Mixed germ cell tumours

KaoCS Colecchia M Looijenga LHJ

Definition A mixed germ cell tumour is any tumour derived from germ cell neoplasia in situ and containing more than one germ cell tumour component. ICD-0 coding 9085/3 Mixed germ cell tumours 9085/3 Polyembryoma 9085/3 Diffuse embryoma ICD-11 coding 2C80.Y & XH2PS1 Other specified malignant neoplasms of tes­ tis & Mixed germ cell tumour

Related terminology None

Subtype(s) Polyembryoma; diffuse embryoma Localization See Tumours of the testis: Introduction (p. 244). Clinical features Patients most commonly present with a testicular mass, some­ times with pain. If there is a substantial choriocarcinoma com­ ponent, the patient is more likely to present with metastasis. The median patient age at presentation is 30 years; the average age of patients with a predominance of embryonal carcinoma is 28 years and that of patients with a predominance of seminoma is 33 years {420,1723}. Serum marker elevations are common and reflect the components of the tumours. Epidemiology See Tumours of the testis: Introduction (p. 244).

Fig. 6.48 Mixed germ cell tumour. Solid white to tan areas with necrosis, haemor­ rhage, and cystic change.

Etiology See Tumours of the testis: Introduction (p. 244).

Pathogenesis See Tumours of the testis: Introduction (p. 244). Macroscopic appearance The tumours are variegated according to the presence of dif­ ferent components. Solid white to tan areas may reflect a semi­ nomatous component, whereas non-seminomatous elements are more often associated with areas of necrosis, haemorrhage, and cystic change. Histopathology The individual components are histologically and immunophenotypically identical to their pure forms. The more common combinations of components include embryonal carcinoma with teratoma, seminoma, or yolk sac tumour (YST), but any combina­ tion (and often more than two components) can be seen. Closely associated components of embryonal carcinoma and YST are particularly common and the YST component is often missed;

Fig. 6.49 Mixed germ cell tumour, postpubertal-type. A Polyembryoma subtype, forming embryoid bodies that consist of embryonal carcinoma and yolk sac tumour, situated in a loose spindle cell stroma. B This example shows an embryonal carcinoma (centre bottom) surrounding a subtle nest of yolk sac tumour (centre top); teratoma is also present (right). C Diffuse embryoma subtype showing a necklace-like arrangement of columnar embryonal carcinoma with a parallel component of flattened yolk sac tumour.

284

Tumours of the testis

Fig. 6.50 Mixed germ cell tumour. A Seminoma (top) and embryonal carcinoma (bottom). B Embryonal carcinoma and yolk sac tumour. C Seminoma, yolk sac tumour, and embryonal carcinoma.

recognition of subtle YST foci may be facilitated by using glypican-3 (GPC3). Distinguishing choriocarcinoma from syncytiotrophoblastic cells in association with seminoma is very important given the difference in treatment and prognosis; OCT3/4 may be helpful in this situation, as well as in cases of syncytiotrophoblastic cells associated with embryonal carcinoma. Two patterns of mixed germ cell tumour are sufficiently distinct to be separately categorized: polyembryoma and diffuse embryoma are two distinctive forms of mixed germ cell tumour that, by definition, have embryonal carcinoma and YST components.

Polyembryoma This distinctive mixed germ cell tumour is composed of embry­ onal carcinoma and YST, resembling the presomitic embryo before day 18 of development {966}. The embryo-like (embry­ oid) bodies consists of a central plate of cuboidal to columnar embryonal carcinoma cells, a dorsal amnion-like cavity typically lined by flattened epithelium, and a ventral yolk sac-like vesicle composed of reticular and myxomatous yolk sac tumour. These bodies are surrounded by a myxoid, embryonic-type mesen­ chyme. Polyembryomas are always part of a mixed germ cell tumour and have not been reported in pure form.

Fig. 6.51 Polyembryoma. Mixed germ cell tumour showing near-perfect recapitula­ tion of the earliest embryonic stages.

Diffuse embryoma This tumour is characterized by an orderly admixture of embryonal carcinoma and YST in roughly equal proportions (523,805). The most characteristic form has been termed a necklace or garland pattern, where ribbons of columnar embryonal carcinoma are par­ alleled by an immediately adjacent layer of flattened YST cells; minor trophoblastic or teratomatous elements may also occur. Cytology Not relevant Diagnostic molecular pathology See Tumours of the testis: Introduction (p. 244). Essential and desirable diagnostic criteria Essential: more than one component of germ cell neoplasia in situ-derived germ cell tumour, in any combination; mor­ phological and immunohistochemical features of the compo­ nents of a mixed germ cell tumour identical to those seen in their pure forms.

Staging The TNM staging system is used. Prognosis and prediction The presence and proportion of embryonal carcinoma, vas­ cular invasion, and rete testis invasion correlate with a higher risk of metastasis in clinical stage I tumours {776,1045,1063, 2882}, whereas the presence of YST and teratoma components is associated with a lower rate of metastasis (1045,3479). Rete testis and hilar soft tissue invasion have also been shown to cor­ relate with clinical stage II or III disease at presentation {3547}. A teratoma component within a primary tumour is also associ­ ated with a higher probability of teratoma in postchemotherapy retroperitoneal lymph nodes in higher-stage tumours {537}. Like in pure tumours, the predominance of choriocarcinoma in a mixed germ cell tumour is associated with high stage at presen­ tation and with aggressive behaviour (116}.

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285

Amin MB Idrees MT Looijenga LHJ Raspollini MR Verrill C

Regressed germ cell tumours

Definition Regressed germ cell tumours represent complete or partial spontaneous regression of a germ cell tumour, resulting in a testicular parenchymal scar. ICD-0 coding 9080/1 Regressed germ cell tumours

ICD-11 coding 2C80.Y & XH4NU1 Other specified malignant neoplasms of tes­ tis & Germ cell tumour, regressed Related terminology Acceptable: burnt-out germ cell tumour.

Subtype(s) None

Localization Testicles Clinical features Fewer than 5% of germ cell tumours have variable degrees of spontaneous regression. The clinical demographic and laterality findings of regressed germ cell tumours are similar to those of testicular germ cell tumours {147,254,1723}. Most cases of spontaneous regression first come to clinical atten­ tion as part of retroperitoneal metastatic disease, with symp­ toms due to mass effect (e.g. back pain). Less commonly, the symptoms are due to primary testicular disease and include testicular enlargement or pain; the testis may be atrophic in as many as 35% of cases. Elevated serum enzyme levels may be encountered during investigation. A diagnosis of malignancy in a young male patient presenting primarily with a retroperitoneal mass, particularly with a carcinoma or unusual histology such as Wilms tumour or primitive neuroectodermal tumour, should raise suspicion for testicular germ cell tumour. Historical cases of primary retroperitoneal germ cell tumours most likely repre­ sent metastasis from the testis in which the primary germ cell tumour had undergone regression. Testicular ultrasound shows some degree of abnormality, which may be nonspecific find­ ings varying from hypoechoic to hyperechoic lesions. Nodular and linear lesions (692,3121} overlapping with findings sugges­ tive of ischaemia are found; as many as 60% of patients may have calcifications.

Epidemiology See Tumours of the testis: Introduction (p. 244). Etiology See Tumours of the testis: Introduction (p. 244).

Pathogenesis Unknown

Fig. 6.52 Regressed germ cell tumour. A An irregular area of discolouration is noted. There is no definite mass lesion. Microscopy showed typical areas of regres­ sion. B There is a well-delineated white fibrotic area with central haemorrhage. Many patients with completely regressed germ cell tumour present with retroperitoneal metastatic disease.

286

Tumours of the testis

Macroscopic appearance In completely regressed tumours, there may be no gross abnor­ mality, and germ cell neoplasia in situ (GCNIS) may be iden­ tified only microscopically. Thorough gross examination may be necessary to identify firmer areas or small fibrotic lesions of completely regressed tumours {777,3327}. Well-delineated nodular, linear, band-like, or stellate grey-white single or multiple lesions may be present. In partially regressed tumours, a com­ ponent of viable germ cell tumour of variable size and appear­ ance may be present. If no scar is visible, the entire testis may be submitted for analysis in difficult cases. Histopathology Seminomas and non-seminomatous tumours may undergo spontaneous regression; spermatocytic tumours rarely

demonstrate features of regression {99,3490,3328}. Although the association of widespread metastatic choriocarcinoma and regressed testicular primary is widely known, seminoma is the most common tumour type associated with regression, in keep­ ing with the prevalence of this germ cell tumour subtype (147, 254}. The hallmark of regression is a vascularized hyaline scar. GCNIS is seen in the background testis in 48% of cases {254}. Before scar formation, a defined area of necrosis containing ghost tumour cells is seen. Immunohistochemistry is usually not required, but it may be performed on the necrotic area for confirmation of germ cell tumour (and possibly subtype). On closer inspection, outlines of sclerotic tubules may be seen within the scarred area, but they may not be visible in a wellestablished collagenous scar. Variable lymphoplasmacytic inflammation, hyalinized tubules, and/or histiocytic aggregates are present in more than half of the cases. Coarse tubular cal­ cifications (regressed intratubular embryonal carcinoma with comedonecrosis) are present in 15% of cases and intratubular microliths (psammomatous calcifications) are present in 30%. Atrophy and sclerosis of adjacent tubules and prominent Ley­ dig cell aggregates may be present in the background testis. The histology of the metastasis and the partially regressed germ cell tumour is not often congruent, and it is not possible to know with certainty which component has regressed {266}. The presence of coarse intratubular calcifications suggests the possibility of a regressed embryonal carcinoma (254, 2172}. The differential diagnosis includes postinflammatory and ischaemic scarring, although extensive sampling and judi­ cious use of immunohistochemistry may be required to confirm GCNIS and the diagnosis of regression. Cytology Not relevant

Diagnostic molecular pathology Not relevant Essential and desirable diagnostic criteria Essential: vascularized scar with GCNIS or metastatic germ cell tumour.

Fig. 6.53 Regressed germ cell tumour. A large, completely regressed germ cell tu­ mour showing an area of necrosis with surrounding fibrous tissue.

Desirable: scar occurring in the setting of an abnormal testis (e.g. atrophy, history of cryptorchidism); elevated serum mark­ ers. Staging TNM staging for germ cell tumours is applicable {3328}.

Prognosis and prediction Completely regressed tumours most often come to clinical attention at a high stage, by their detection through metastatic disease. Orchiectomy is necessary to confirm primary disease and to prevent relapse, with systemic chemotherapy for metas­ tasis. Laterality is determined by the side of metastasis or from clinical and imaging findings. Overall, patients with seminoma have a better prognosis than those with non-seminomatous tumours when identified in metastases.

Fig. 6.54 Regressed germ cell tumour. A Partial regression with a small component of mature teratoma (smooth muscle and enteric-type gland) amid chronic inflamma­ tion. B Vascularized scar with lymphocytic infiltration. A few entrapped seminiferous tubules are present. C Germ cell neoplasia in situ adjacent to a regressed germ cell tumour. Area adjacent to a regressed germ cell tumour with a very focal area of germ cell neoplasia in situ (OC74 immunohistochemistry).

Tumours of the testis

287

Spermatocytic tumour

Definition Spermatocytic tumour is a germ cell tumour derived from postpubertal-type germ cells, in which the tumour cells resemble spermatogonia or early primary spermatocytes. ICD-0 coding 9063/3 Spermatocytic tumour 9063/3 Spermatocytic tumour with sarcomatous differentiation

ICD-11 coding 2C80.Y & XH80D1 Other specified malignant neoplasms of tes­ tis & Spermatocytic seminoma Related terminology Not recommended: spermatocytic seminoma; spermatocytoma.

Subtype(s) Spermatocytic tumour with sarcomatous differentiation Localization Testis exclusively

Clinical features Most patients present with a painless, incidentally found testicu­ lar mass, but a few have pain. Serum markers are not elevated. Bilateral tumours occur more commonly than in other germ cell tumours and can be either metachronous (most commonly) or synchronous (in up to 9% of cases) {3100,1408}. Spermatocytic tumour only rarely metastasizes, with only 5 well-documented cases of non-sarcomatous tumours initially spreading to the retroperitoneum (4 cases) or lung (1 case) (1392,2061,2166,3357). In cases where there is tumour dedifferentiation to sarcoma, a high metastatic rate (approximately 50%) has been reported (3211,1026,2062,1201). Patients with sarcomatous tumours may

Idrees MT Daugaard G KaoCS Looijenga LHJ Menon S Srigley JR

have a history of a longstanding slow-growing testicular mass with a recent sudden increase in size. Tumours with sarcoma­ tous differentiation metastasize haematogenously and most commonly involve the lungs. The metastatic tumour in those patients is exclusively sarcomatous. Epidemiology Spermatocytic tumours represent about 1% of testicular germ cell tumours {3100,533,1115,1408,1114). They occur over a wide patient age range (19-92 years), but incidence peaks in the sixth decade of life, with a mean age of 52-59 years (1115, 3100,533,1408,1300} and median age of 72 years {1114}. The tumours are rare in teenage boys and non-existent in children {3100,533,1408). Spermatocytic tumours lack features asso­ ciated with tumours derived from germ cell neoplasia in situ (GCNIS), including cryptorchidism and racial or ethnic pre­ disposition. There is no ovarian counterpart for spermatocytic tumour; it exclusively occurs in the testis.

Etiology The risk factors that have been attributed to the development of germ cell tumours associated with GCNIS are not present in spermatocytic tumour. The incidence increases with increasing age {1114| and may be attributable to accumulating mutations (see Pathogenesis, below). Pathogenesis Spermatocytic tumour lacks the chromosome 12p amplifica­ tion of the GCNIS-derived tumours. Amplification of the DMRT1 gene (a male-specific transcriptional regulator) on chromo­ some 9p, close to its telomeric end, is a characteristic molecular event {1926,370). Additionally, age-related activating mutations in the FGFR3 and HRAS genes may occur in spermatogonia that promote cell proliferation, probably facilitating tumour for­ mation (1119,1173,1174,1926).

Fig. 6.55 Spermatocytic tumour. A Intratubular growth of tumour cells; the seminiferous tubules are expanded by variably sized tumour cells. B Typical features of spermato­ cytic tumour with variable cytological/nuclear features in the tumour cells. C The predominance of larger intermediate cells with exuberant mitotic activity gives the impression of an aggressive malignant neoplasm. Some authors refer to this type of tumour as anaplastic spermatocytic tumour.

288

Tumours of the testis

Fig. 6.56 Spermatocytic tumour. A Sheet-like arrangement of variably sized tumour cells. Stroma is minimal. Single cells or cell groups with apoptosis create a pseudoglandular appearance. B Intratubular spread.

Macroscopic appearance Spermatocytic tumours are 50-60 mm in diameter on average and range from 14 to 200 mm in larger series (3100,1408,474}. The tumours are solid and lobular to multinodular. The texture may be soft to firm and often friable. The cut surface varies from greyish white to haemorrhagic and from fleshy to myxoid. Occa­ sional cysts and foci of necrosis may be present. Growth into the paratesticular structures may be seen in < 5% of cases, and rare tumours replace the entire testis. Sarcomatous foci may be grossly appreciated as fleshy, sometimes firm, nodular areas with necrosis and haemorrhage.

Histopathology The tumour cells are mostly arranged in diffuse to multinodular patterns, often with stromal oedema. Other (rarer) growth pat­ terns include pseudoglandular, cystic/microcystic, trabecular, nested, or single cells. A pseudoglandular (follicle-like) appear­ ance is usually the result of fluid accumulating centrally in round tumour nests. The most characteristic feature is a polymor­ phous cell population, often described as tripartite, consisting of three distinct cell types with distinguishing features based on cell size and chromatin: the small cells exhibit round, uniformly dense nuclei and scant cytoplasm; intermediate-sized cells have round nuclei with finely granular to filamentous (spireme) chromatin and variably prominent nucleoli; and giant cells have single or multiple nuclei with similar nuclear features to those of the intermediate-sized cells. The intermediate and giant cells usually have dense eosinophilic to amphophilic cytoplasm, but it may be pale in some cases. The cell membranes are often (but not always) poorly defined. Mitotic figures, including atypi­ cal forms, are usually frequent, as are a large number of apoptotic tumour cells. The intermediate cells are the most common cell type, while giant cells are the least in number. The stroma is not prominent and often appears finely fibrous. Unlike in a classic seminoma, prominent lymphocytic infiltrates are not present, and granulomatous inflammation is only rarely seen. Occasionally, tumours containing a more uniform population of intermediate-sized cells with prominent nucleoli are seen and have been designated as anaplastic spermatocytic tumours; however, there is no convincing evidence that these tumours have different biological behaviour {71}; therefore, this nomen­ clature is not favoured. Intratubular growth is common, but GCNIS is absent {2249). Testicular lymphoma may also need to

be excluded, particularly in tumours in which the intermediate cell type predominates. If needed, immunohistochemical mark­ ers easily confirm the distinction.

Spermatocytic tumour with sarcoma The sarcomas may show a pushing interface, or they may inter­ digitate with the usual spermatocytic tumour. In some cases, only a small residual amount of the spermatocytic tumour is present. Rhabdomyosarcomatous differentiation is common, but undif­ ferentiated tumours with spindle cell or pleomorphic forms may be seen. These tumours are distinctively high-grade and usually display necrosis and abundant mitotic figures (627A.3049A).

Immunohistochemistry Spermatocytic tumours are non-reactive to many of the usual embryonic germ cell tumour markers, including OCT3/4, PLAP, AFP, p-hCG, CD30, and AP-2y. The tumour cells express pro­ teins that are usually identified in spermatogonia and early sper­ matocytes such as MAGEA4, KIT, SSX2, SYCP1, XPA, SAGE1, DMRT1, SALL4, and OCT2 (3042,517,1880,1926,2605}. Immu­ noreactivity for several of the cancer/testis antigens has also been described in spermatocytic tumours (225,379,607,1580, 2822,3042}. Tumour cells may express reactivity to CAM5.2 in a punctate fashion {750}.

Fig. 6.57 Spermatocytic tumour. Sarcomatous transformation of spermatocytic tu­ mour. The tumour on the left shows a highly pleomorphic pure spindle cell population. The classic spermatocytic tumour is on the right.

Tumours of the testis

289

is helpful in differentiating spermatocytic tumours from classic seminomas {1930,1899).

Diagnostic molecular pathology On DNA analysis, spermatocytic tumours show diploid, poly­ ploid, or aneuploid DNA content {1725,2249). Frequent gains of chromosome 9 and less frequent gains of chromosomes 1 and 20, with partial loss of chromosome 22, are reported on comparative genomic hybridization {2715}. The gain of chro­ mosome 9 corresponds to the amplification of DMRT1 (1926). Age-related activating mutations of FGFR3 and HRAShave also been seen in a minority of tumours (1119,1174). The epigenetic profile of spermatocytic tumours is completely disorganized, with a mixture of cells displaying various levels of DNA methyla­ tion and both permissive and repressive chromatin modifica­ tions within each tumour {1730}. However, there is a complete loss of biparental genomic imprinting and re-establishment of paternal imprinting only {800,2672,2935).

Fig. 6.58 Spermatocytic tumour. A High-magnification photomicrograph showing three different cell types. The giant cell has a huge nucleus showing finely granular chromatin, and cytoplasm is abundant, showing vacuolation. B Three different types of cells. The giant cell has a large nucleus pushed to the cytoplasmic membrane by a cytoplasmic vacuole. The chromatin is dense and filamentous (spireme).

Cytology Cytology experience is limited. Smears may show high cellularity, and predominantly single cells are dispersed in a clean background {2818). Three distinct cell types (as detailed above) have been described, with intermediate cells predominating. An absence of tigroid background and lymphocytic infiltrate

290

Tumours of the testis

Essential and desirable diagnostic criteria Essentia/: spermatocytic tumours typically occur in an older age group, with most patients in their fifth or sixth decade; tripar­ tite microscopic appearance with three distinct cell types and without lymphocytic infiltrate or prominent fibrous septa; no immunoreactivity for usual embryonic germ cell tumour mark­ ers; no GCNIS. Desirable: absence of 12p overrepresentation; characteristic molecular alterations including gain of chromosome 9. Staging Not relevant

Prognosis and prediction Spermatocytic tumour without sarcomatous differentiation has an excellent prognosis, and orchiectomy is curative. Because spermatocytic tumours metastasize only very rarely, there are no established predictive factors, although vascular space inva­ sion was specifically mentioned in 4 of the 5 documented meta­ static cases (3357,1392,2061,2166,1401). Cases complicated by sarcoma are associated with a high mortality rate.

Teratoma, prepubertal-type

Bode PK Daugaard G KaoCS Looijenga LHJ Srigley JR

Definition Prepubertal-type teratoma is a germ cell tumour usually seen in the prepubertal testis, although it may also occur in postpubertal patients. It is composed of elements resembling somatic tissue derived from one or more of the germ layers.

ICD-0 coding 9084/0 Teratoma, prepubertal-type 9084/0 Dermoid cyst 9084/0 Epidermoid cyst

ICD-11 coding 2C80.4Y & XH52Q4 Other specified malignant teratoma of tes­ tis & Teratoma, prepubertal-type Related terminology Not recommended: type 1 germ cell tumour of the testis; benign postpubertal teratoma. Subtype(s) Dermoid cyst; epidermoid cyst

Localization Testis Clinical features Most prepubertal-type teratomas come to clinical attention as lumps discovered by patients or their parents, or incidentally by examination or imaging. Most are at least partially cystic on ultrasound examination, but they may also be completely solid {944). Epidemiology Prepubertal-type teratomas typically occur before the age of 6 years {3022,1830,2724); the oldest reported patient was 70 years old {3358}. There is no known ethnic or geographical

Fig. 6.59 Epidermoid cyst. Enucleated epidermoid cyst of the testis.

predilection. Because cancer registries do not routinely register benign tumours, reliable data on the incidence of prepubertaltype teratomas are lacking.

Etiology No genetic susceptibility, substance exposures, or other risk factors are known for prepubertal-type teratoma {2924,2565}. Pathogenesis It has been postulated that early primordial germ cells or gonocytes undergo reprogramming due to a lack of maintenance of phenotype and a reversal of germline specification (2385). Prepubertal-type teratoma is diploid and does not harbour any driver mutations {2385,1297}. Chromosome 12p alterations are a common feature of postpubertal type 2 germ cell tumours {1929,3130}, whereas prepubertal-type teratomas lack chromo­ some 12p abnormalities and are not associated with germ cell neoplasia in situ {2879,3597,3358,782}. It is thought that prepubertal-type teratoma in an adult represents a persistent lesion

Fig. 6.60 Teratoma, prepubertal type. A This example shows bone, muscle, and glandular cystic areas. B An example with neuroendocrine tumour (NET). Prepubertal-type teratomas are often associated with small, low-grade NETs. C This example shows the wall of an epidermoid cyst of the testis. No other teratomatous elements are seen.

Tumours of the testis

291

Table 6.04 Features of postpubertal-type and prepubertal-type teratoma

Prepubertal-type teratoma

Feature

Postpubertal-type teratoma

Age

Peak incidence between 25 and 35 years (comparable to non­ seminomas) Complex architecture, proliferative tissue components (especially stroma)

Organoid, structured architecture

Histology

Non-neoplastic testicular tissue

Regressive changes (tubular atrophy and sclerosis, microlithiasis, impaired spermatogenesis, Sertoli cell-only tubules)

Normal with maintained spermatogenesis

Germ cell neoplasia in situ

Usually detectable

Always absent

12p alterations

Always present

Always absent (diploidy)

from a young age {3597,2388,1629,3250}, which might explain tumours detected in patients in their second or third decade of life. However, some studies reported that at least half of the cases were diagnosed after the fourth decade (3597,3358). This finding suggests that some prepubertal-type teratomas may develop by a pathogenetic mechanism comparable to that in the prepubertal period but occurring at a later age (3597, 3358,2388}. Macroscopic appearance The tumours may be solid or have a variably prominent cystic component filled with keratinaceous or mucoid material; they may also show calcification or bone formation. Grossly iden­ tifiable hair may be present in the dermoid subtype, which is a finding never reported in postpubertal-type testicular tera­ tomas.

Histopathology Like all teratomas, prepubertal-type testicular teratoma may show the full spectrum of somatic tissues, although there are some distinct differences from the postpubertal-type ones (see Table 6.04). The various elements are often arranged in an orga­ noid pattern and all lack marked cytological atypia. No germ cell neoplasia in situ (GCNIS) is present, so the background tes­ ticular parenchyma should be closely examined, especially in the postpubertal setting, to exclude the possibility of a GCNISderived tumour. No tubular atrophy, parenchymal scars, tubular microlithiasis, necrosis, or impaired spermatogenesis (dysgenetic features) should be observed. Large lesions may show consequent peritumoural atrophy. Therefore, testicular tissue away from the tumour should be analysed for such changes {3358}.

Dermoid cyst Dermoid cyst is a specialized subtype of prepubertal-type tera­ toma that is morphologically identical to its much more common ovarian counterpart (476,1231,3597(.

292

Tumours of the testis

In children: before 6 years (median: 13-14 months)

In adults: broad range (19-70 years) with majority in the second and third decade of life

Mainly cystic, no tumour necrosis

Mild peritumoural atrophy possible in large tumours

Epidermoid cyst Grossly, an epidermoid cyst is a unilocular cyst that contains keratinaceous material; microscopy shows a stratified squa­ mous epithelium lining without skin appendages or other ele­ ments. This tumour is also cured by complete excision. Cytology Not clinically relevant Diagnostic molecular pathology Prepubertal-type teratomas are diploid and lack the usual genetic abnormalities seen in the postpubertal-type terato­ mas or other GCNIS-associated tumours, including chromo­ some 12p gain. Therefore, molecular investigation for 12p gain is recommended in difficult cases, especially when distant tes­ ticular parenchyma is not represented, such as in testis-sparing surgical excisions. No recurrent somatic mutations have been identified (714,2231,2384}.

Essential and desirable diagnostic criteria Essential: a teratoma with no associated GCNIS and an absence of regressive changes in the non-neoplastic testicular tissue; exclusion of embryonic-type neuroectodermal tumour. Desirable: absence of 12p alterations.

Staging Because prepubertal-type teratoma is benign, a staging system is not applied. Prognosis and prediction There have been no documented cases of prepubertal-type teratomas exhibiting malignant behaviour (2879,3597,3358, 782}. Therefore, patients are sufficiently treated with surgical excision alone, without the need for adjuvant systemic therapy. Testis-sparing surgery might be suitable for small prepubertaltype teratomas {2754,3543,2928}.

Yolk sac tumour, prepubertal-type

Bode PK Daugaard G Kao CS Looijenga LHJ Srigley JR

Definition Prepubertal-type yolk sac tumour (YST) is a germ cell tumour virtually only seen in patients in their first decade of life. It resembles extraembryonic structures (yolk sac, allantois, and extraembryonic mesenchyme) and is associated with increased serum AFP levels. ICD-0 coding 9071/3 Yolk sac tumour, prepubertal-type ICD-11 coding 2C80.Y & XH09W7 Other specified malignant neoplasms of tes­ tis & Yolk sac tumour

Related terminology Not recommended: type 1 germ cell tumour of the testis; endo­ dermal sinus tumour; orchioblastoma; yolk sac carcinoma; infantile embryonal carcinoma; mesoblastoma vitellinum; adenocarcinoma of the infant testis; polyvesicular vitelline tumour; extraembryonic mesoblastoma; malignant endothe­ lioma of perithelioma type.

Subtype(s) None

Localization Testis Clinical features Prepubertal-type YSTs manifest as painless testicular swell­ ings discovered by patients or their parents. As many as 50% are accompanied by a hydrocoele {44). Serum AFP levels are elevated in > 90% of cases, with concentrations > 100 ng/mL (3101). However, in patients under 6 months of age the diagnos­ tic value of AFP is limited because of its physiological elevation in this age group {372,3492). YST does not produce p-hCG. A lower incidence of metastasis at first presentation is reported in children with prepubertal-type YST than in patients with postpubertal germ cell tumours {720}. Interestingly, in some patients there is a predilection for haematogenous metastasis, indicated by the presence of lung metastasis with no involvement of the retroperitoneal lymph nodes {1179(. Bilateral manifestation of prepubertal-type YST is very uncommon (3551). Epidemiology According to testicular tumour registries, prepubertal-type YSTs account for > 50% of prepubertal testicular tumours (2724, 1830}, However, this reported prevalence has been questioned because of the underreporting of benign tumours, especially prepubertal-type teratomas {2549,3051,2143}. Most cases of prepubertal-type YST occur in the first decade of life, with a peak in the first 3 years and a mean age of 16-20 months (2724,1830(.

Etiology The etiology is unknown. No risk factors (including genetic susceptibility, geographical locale, or exposure to certain sub­ stances) have been identified for prepubertal-type YST (2924, 2565,3513}.

Pathogenesis In prepubertal-type YST, it has been postulated that early pri­ mordial germ cells or gonocytes undergo reprogramming due to lack of maintenance of phenotype and reversal of germline specification {2385}. Although prepubertal-type YST is mor­ phologically identical to its postpubertal counterpart, it differs from it not only by the absence of germ cell neoplasia in situ (2016), but also by the lack of 12p overrepresentation {2499, 2501). However, the distal part of 12p (especially 12p13) may be amplified (2222). It is thought that YST progresses from a pure type 1 teratoma that is probably overgrown by the more aggressive YST component {1463,2385). In contrast to diploid prepubertal-type teratoma, YST is mostly aneuploid and shows multiple gains (1q, 3, 3p, 8q24, 20q, 22) and losses (1p, 4, 4q, 6q, 16q, 20p) {2383,2501}.

Macroscopic appearance YSTs appear as solid grey to yellow tumours with occasional small cysts and a myxoid surface on section. Necrosis and haemorrhage are rare. Histopathology Morphologically, paediatric YSTs show a similar broad spec­ trum of growth patterns to YSTs in adults. Most exhibit two or more patterns. Case studies in paediatric patients reported that a reticular/microcystic and glandular architecture is most com­ mon, followed by solid, macrocystic, papillary, and myxomatous

Tumours of the testis

293

(positive in YST, negative in juvenile granulosa cell tumour) and a sex cord stromal tumour marker such as inhibin, calretinin, or SF1 (positive in juvenile granulosa cell tumour, negative in YST) is most appropriate (3253). Although even focal AFP expression is very specific for YST (2333), background staining might be problematic in very young children because of the physiological AFP increase in the first months of life (372,3492,1318}. Other helpful YST markers are glypican-3 (GPC3) (3654,3655,2405} and HNFip (2731,1080}. OCT3/4 is negative in YST.

Cytology There is little information about FNA in the literature on YST, because the diagnosis is reliably established on the basis of AFP elevation in serum. Three-dimensional glomeruloid or pap­ illary structures of loosely arranged immature-appearing cells have been described in aspirates of YST {253,1092}. Fig.6.62 Yolk sac tumour, prepubertal-type. Note the prepubertal seminiferous tu-

Diagnostic molecular pathology

Prepubertal-type YSTs are aneuploid and lack chromosome 12p gain, although the distal part of 12p (especially 12p13) may be amplified {2222}. No recurrent somatic mutations have been identified {714,2231,2384}.

Essential and desirable diagnostic criteria Essential: reticular/microcystic and/or glandular proliferation of tumour cells with limited nuclear atypia; no associated germ cell neoplasia in situ; absence of regressive changes in the non-neoplastic testicular tissue; serum AFP elevation. Desirable: immunohistochemical detection of SALL4 or YST markers can be used in equivocal cases.

Fig. 6.63 Yolk sac tumour, prepubertal-type. This example has adjacent prepubertal testicular tubules.

patterns. Sarcomatoid YST has not been described in children. Intracytoplasmic hyaline globules and Schiller-Duval bodies are highly characteristic. Mitotic activity can be striking (716,3333}. Unlike in adult cases, germ cell neoplasia in situ and regressive changes do not occur in the adjacent testicular tissue.

Immunohistochemistry Although paediatric and adult YST share the same immunophe­ notype (see Yolk sac tumour, postpubertal-type, p, 265), the selection of a potential marker panel should take into account the fact that juvenile granulosa cell tumour is the main differen­ tial diagnosis in infancy. Therefore, the combination of SALL4

294

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Staging Different staging systems for germ cell tumours are in use. In paediatric patients, the staging follows the Children's Oncol­ ogy Group (COG) staging system. A unifying risk-stratification system for children was developed by the Malignant Germ Cell International Consortium (MaGIC) and is applicable for paedi­ atric and adolescent patients with testicular, ovarian, and extragonadal germ cell tumours (1032,2369,1043). Prognosis and prediction Because of the low incidence of advanced-stage disease and excellent response to platinum-based chemotherapy, overall mortality rates are extremely low. The current survival for prepu­ bertal testicular germ cell tumours is close to 100% (67,2701(. Fewer than 20% of patients present with metastasis at the time of diagnosis. In patients with clinical stage I disease who show AFP normalization after surgery, adjuvant chemotherapy is not indicated. Reported recurrence rates in children with stage I disease are between 15% and 20%, which is lower than in adults {1250,2019,2701,2841}.

Testicular neuroendocrine tumour, prepubertal-type

Definition Prepubertal-type testicular neuroendocrine tumour (NET) is usually a well-differentiated NET of the testis, resembling NETs arising in the gastrointestinal tract. ICD-0 coding 8240/3 Well-differentiated neuroendocrine tumour (monodermal teratoma) ICD-11 coding 2F77 & XH8DS0 Neoplasms of uncertain behaviour of male genital organs & Neuroendocrine tumour, NOS

Related terminology Not recommended: neuroendocrine carcinoma; carcinoid; atypical carcinoid.

Colecchia M Boormans JL I drees MT Looijenga LHJ

Macroscopic appearance The tumours are solid, circumscribed, and yellow to tan, and they measure 50-110 mm. Sometimes there are calcifications or cystic changes in associated teratomatous areas. Extratesticular growth is uncommon. Histopathology Primary testicular NETs can be pure (-75% of cases) or asso­ ciated with a testicular teratoma (-25%). Most tumours exhibit an insular or trabecular architecture. Acinar and glandular structures with luminal mucin are present, admixed with other patterns. The stroma is usually fibrous to hyalinized. The mono­ morphic cells contain eosinophilic to pale cytoplasm and uni­ form round nuclei with fine chromatin. Mitotic figures are rare; necrosis and vascular invasion are infrequently seen. In all but two reported cases, germ cell neoplasia in situ has been absent {2134,3}.

Subtype(s) None

Localization Testis Clinical features A testicular mass or swelling is the most common present­ ing symptom. A minority of patients may have carcinoid syn­ drome, with hot flashes, diarrhoea, and palpitations (3392). The tumours mostly occur in adults (age range: 10-83 years) and are more common than other germ cell tumours in older patients (mean age: 46 years). Few cases have been reported in children {3392,3049}. Epidemiology NETs account for < 1% of all testicular tumours {3392). They are about 15 times as common in the ovary as in the testicle (3|. The majority of NETs have been reported in Europe and the USA, with fewer reported in Asia {1964,1613( and in Africa {771).

Fig. 6.64 Testicular neuroendocrine tumour (NET), prepubertal-type. The tumour is well circumscribed and demarcated from the surrounding testicular parenchyma.

Etiology Unknown Pathogenesis These tumours are considered monodermal teratomas. Their histogenesis is a matter of debate, but most are not associated with isochromosome 12p or germ cell neoplasia in situ. Small NETs are seen in association with prepubertal-type teratomas (3358). However, occasional cases probably arise in postpubertal-type teratomas {3}. Although these may arise from a yet unidentified neuroendocrine cell, the most plausible explana­ tion is that they develop from germ cell-derived intestinal-like neuroendocrine cells (2663|.

Fig. 6.65 Testicular neuroendocrine tumour (NET), prepubertal-type. Insular and glandular patterns. Note the punctate chromatin and mucin in the glandular lumen.

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295

neuroendocrine markers {3392}. The characteristic eosinophilic cytoplasm and the salt-and-pepper nuclear pattern are distinc­ tive features of prepubertal-type testicular NETs. a-inhibin, SF1, and p-catenin are positive in Sertoli cell tumours {3392,2810}. Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant Essential and desirable diagnostic criteria Essential: insular or trabecular architecture; salt-and-pepper pattern of nuclear chromatin. Desirable: positivity for neuroendocrine markers. Fig. 6.66 Testicular neuroendocrine tumour (NET), prepubertal-type. Immunostain­ ing for synaptophysin is strongly positive.

Immunohistochemistry The tumour cells express chromogranin A, synaptophysin, serotonin, NSE, CD56, and cytokeratins; less frequently, they express gastrin, substance P, VIP, and neurofilaments. Thyroid transcription factor 1 (TTF1), KIT, CDX2, and OCT3/4 are nega­ tive {3}. Most are well differentiated, but some that metastasize have atypical features including necrosis and increased mitoses {3392}. DNA ploidy studies have revealed a near-diploid profile (3581). Bilateral involvement, multifocality, and extratesticular localization favour metastasis from the gastrointestinal primary (375}. The insular and trabecular patterns of granulosa cell tumour may be confused with NET, but the presence of nuclear grooves and the absence of neuroendocrine markers are use­ ful. Potential pitfalls are Sertoli cell tumours because of their similar growth patterns and often similar immunoreactivity for

296

Tumours of the testis

Staging Not clinically relevant Prognosis and prediction Most primary NETs have a benign clinical course. Atypical NETs are larger tumours with increased mitoses and may be associated with metastases {2663}. The prognosis of primary testicular NETs associated with a testicular teratoma seems to be better than that of pure NEs (139}. The cases associated with carcinoid syndrome have increased metastatic potential (3581, 3392}. Patients with malignant tumours show a prolonged clini­ cal course before death. If metastases occur, the haematogenous spread affects the lungs, liver, bones, soft tissue, skin, and heart (3049(. In patients with metastatic disease, retroperitoneal dissection and receptor-targeted radiotherapy using different isotopes may be used {1847}. Chemotherapy and radiotherapy provide minimal benefits (1056}.

Mixed teratoma and yolk sac tumour, prepubertal-type

Bode PK Daugaard G KaoCS Looijenga LHJ Srigley JR

Definition Mixed teratoma and yolk sac tumour, prepubertal-type, is a tes­ ticular germ cell tumour that combines teratoma and yolk sac tumour (YST) and predominantly occurs in children aged < 6 years. There is no association with germ cell neoplasia in situ. ICD-0 coding 9085/3 Mixed teratoma and yolk sac tumour, prepubertal-type ICD-11 coding 2C80.Y & XH2PS1 Other specified malignant neoplasms of tes­ tis & Mixed germ cell tumour

Related terminology Not recommended: germ cell tumour type 1.

Subtype(s) None

Localization Testis Clinical features See Teratoma, prepubertal-type (p. 291) and Yolk sac tumour, prepubertal-type (p. 293). Epidemiology These tumours occur very rarely in the testis. Therefore, their real incidence is unknown, but case studies suggest that pure prepubertal-type YSTs are at least 10 times as frequent as prepubertal-type mixed tumours {2143,1830,976}. Mixed tumours have also been reported in adults, with 2 well-supported cases,

Fig. 6.67 Mixed teratoma and yolk sac tumour, prepubertal-type. The prepubertal testis is replaced by a solid, pale tumour.

1 in a patient with Down syndrome (2388). See also Teratoma, prepubertal-type (p. 291) and Yolk sac tumour, prepubertaltype^. 293). Etiology See Teratoma, prepubertal-type (p. 291) and Yolk sac tumour, prepubertal-type (p. 293). Pathogenesis The current hypothesis is that YST develops in a teratoma. In sacrococcygeal teratomas, the presence of immature ele­ ments is assumed to be associated with an increased risk of

Fig. 6.68 Mixed teratoma and yolk sac tumour, prepubertal-type. A Mucinous glands representing teratoma in a reticular and microcytic yolk sac tumour background. B A mucinous gland set in a background of yolk sac tumour.

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progression towards YST (793,1322(. Although progression in an early, small, immature teratoma may result in a pure YST by overgrowth, progression in a fully developed teratoma may manifest as a mixed tumour. See also Teratoma, prepubertaltype (p. 291) and Yolk sac tumour, prepubertal-type (p. 293).

Macroscopic appearance Most cases have the same macroscopic appearance as prepubertal-type teratoma, because the YST foci are usually small.

Histopathology YST foci in teratomas are usually small and associated with immature elements, making them easy to overlook on micro­ scopic examination {1322,1318}. Immunohistochemical staining for AFP or SALL4 can help highlight YST components, although weak to moderate expression can also be demonstrated in immature teratomatous elements {2723,2162,3493}. The tumours are not associated with germ cell neoplasia in situ. Cytology Not relevant

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Tumours of the testis

Diagnostic molecular pathology These tumours lack 12p abnormalities. See also Teratoma, pre­ pubertal-type (p. 291) and Yolk sac tumour, prepubertal-type (P- 293).

Essential and desirable diagnostic criteria Essential: a combination of teratoma and YST elements in the absence of germ cell neoplasia in situ. Desirable: immunohistochemical staining for YST (e.g. AFP); absence of 12p abnormalities. Staging See Yolk sac tumour, prepubertal-type (p. 293).

Prognosis and prediction In the absence of metastasis and with adequate AFP normali­ zation after surgery, adjuvant therapy is not required and the patient should continue to be followed up. In the rare case of systemic disease, further management is based on YST therapy.

Leydig cell tumour

Definition Leydig cell tumours of the testis are composed of cells resem­ bling non-neoplastic Leydig cells of the testis, with moderate to abundant eosinophilic cytoplasm.

ICD-0 coding 8650/1 Leydig cell tumour 8650/3 Malignant Leydig cell tumour ICD-11 coding 2F77 & XH51L7 Leydig cell tumour uncertain behaviour of unspecified site, male & Leydig cell tumour of the testis, NOS

Related terminology Not recommended: interstitial cell tumour.

Subtype(s) None Localization Testis; bilaterally in 3% of cases Clinical features Leydig cell tumours are responsible for 10% of all cases of early pseudopuberty in children; patients present with preco­ cious symptoms frequently in the first 5 years of life. Men often present with an incidental (often sonographically detected) and asymptomatic or painful testicular mass, but if the tumour secretes estrogens it can cause feminization, with infertility (in 18% of cases), gynaecomastia (in 7%), erectile dysfunction, and loss of libido, among other presenting symptoms {2749}. Rarely, Leydig cell tumours occur with Cushing syndrome.

Epidemiology Leydig cell tumours represent about 3% of adult testicular tumours and 4-9% of paediatric testicular tumours, showing

Colecchia M Athanazio DA Bremmer F Compdrat EM

two age peaks. The mean age of patients at presentation is 41 years {2749). Rarely, Leydig cell tumours are associated with Klinefelter syndrome {2985}. Etiology Familial occurrence has been described, and this tumour may be seen in association with the hereditary leiomyomatosis and renal cell carcinoma syndrome caused by germline mutations of fumarate hydratase {536}.

Pathogenesis Some Leydig cell tumours in children have activating muta­ tions in a hotspot of the luteinizing hormone/choriogonadotropin receptor gene (LHCGR p.D578H) {536,1902}. The role of G protein-coupled membrane ER in tumorigenesis is still not clear because of conflicting findings relating to its expression in tumour Leydig cells (1175}. Macroscopic appearance Leydig cell tumours are usually small, solid, well-circumscribed masses with a maximum diameter ranging from 5 to 50 mm in most cases. They are yellow, homogeneous, and soft, and they may show gross haemorrhage, necrosis (in about 25% of cases), hyalinization, and calcification. Histopathology The tumour is composed of medium to large polygonal cells that have abundant eosinophilic cytoplasm and a single promi­ nent nucleolus. Occasionally, the cytoplasm may contain small lipid vacuoles. Brownish pigmentation, globular cytoplasmic inclusions, and Reinke crystals are found in one third of cases. A variety of uncommon appearances have been reported, including myxoid degeneration, ossification, ribbon-like pat­ tern, spindle-shaped tumour cells, insular pattern, trabecular pattern, lipid-rich and adrenocortical-like cells, and sarcoma­ toid change {3251}. Rarely, a microcystic appearance has been

Fig. 6.69 Leydig cell tumour. A Nodule with a yellow cut surface. B There is a huge area of necrosis in this malignant neoplasm. C This malignant tumour infiltrates the soft tissue near the epididymis.

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p-catenin are negative. Reinke crystals are positive for calretinin and negative for inhibin {2139). The great majority of Leydig cell tumours are negative for or show weak expression of INSL3 (1783). Testicular tumours of the adrenogenital syndrome, which histologically mimic Leydig cell tumours, are bilateral and typically show bands of fibrosis, more voluminous cytoplasm, prominent lipofuscin, and a greater tendency for adipose meta­ plasia. Generally, testicular adrenal rest tumours lack nuclear reactivity for AR (3397). Psammomatous calcifications are com­ mon features of both Leydig cell tumours and large cell cal­ cifying Sertoli cell tumours; immunohistochemical staining for S100B may help differentiate the two, with large cell calcifying Sertoli cell tumours being positive and most Leydig cell tumours being negative {3260}. Fig. 6.70 Spermatic cord sampling in mixed stromal tumour. The presence of extraparenchymal Leydig cells in perineural spaces is a normal incidental finding and can be observed in the spermatic cord. It should not be misinterpreted as tumour dis­ semination.

reported {358}. Growth of the tumour beyond the testis may rarely occur, but the presence of incidental perineural localiza­ tion of benign nests of Leydig cells must be distinguished to avoid the incorrect prediction of aggressive behaviour {220).

Immunohistochemistry More than 90% of Leydig cell tumours are positive for calretinin, a-inhibin, melan-A, SF1, CD99, FOXL2, and synaptophysin, and 20% are positive for cytokeratin and S100. WT1 and nuclear

Cytology In metastatic sites, FNA cytology of Leydig cell tumours shows cells singly or in clusters. They are large, discohesive, and rounded or polygonal, with indistinct cell borders and abundant finely granular cytoplasm. The nuclei are eccentrically located, imparting a plasmacytoid-like appearance. Some nuclei have grooves {355}.

Diagnostic molecular pathology MDM2 and CDK4 amplifications are reported in one third of malignant Leydig tumours (2298,681). Gain of chromosomes X, 9, and 19p and loss of chromosomes 8 and 16 are the most common genetic changes observed in Leydig cell tumours (3324}.

Fig. 6.71 Leydig cell tumour. A Malignant tumour with plentiful mitoses and some atypia. B Clarified cells but typical nuclei with prominent nucleoli. C Tumour with lipki-rich cells. D Tumour cells with typical nuclei and prominent nucleoli. E Positive immunostaining for MDM2 in malignant Leydig cells in the testis.

300

Tumours of the testis

Essential and desirable diagnostic criteria Essential: medium to large polygonal cells with abundant eosin­ ophilic cytoplasm. Desirable: immunohistochemistry showing inhibin and SF1 posi­ tivity; presence of Reinke crystals. Staging Not applicable Prognosis and prediction Testis-sparing surgery is recommended in children (3647| and an organ-sparing procedure for small, sonographically detected, non-palpable lesions is also recommended in adult patients (2566,2749). The most definitive indicator of malig­ nancy is the presence of metastasis. However, significant dif­ ferences in tumour size, mitotic count, necrosis, angiolymphatic

invasion, infiltrative margins, and nuclear atypia have been reported between tumours with indolent and aggressive clinical behaviour (1654,1317). Mitoses are more frequent in malignant tumours than in benign tumours (633|. The number of proliferat­ ing cells is also greater in malignant cases {633}. Recently, the Leydig cell tumour Scaled Score (LeSS) has been reported to be useful for low- and high-risk classes for metastatic behaviour according to the weight of five parameters (size, mitoses, necro­ sis, infiltrative patterns, vascular invasion), but it needs further prospective validation (681}. Leydig cell tumours occurring with delayed metastasis could potentially benefit from immediate retroperitoneal lymphadenectomy; given the lack of effective alternative treatments, early retroperitoneal lymphadenectomy may be beneficial in those with high-risk features (2938,2322}. In malignant cases, survival times range from 2 months to 17 years {343}.

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Colecchia M Bremmer F Compdrat EM Kao CS Kryvenko ON Srigley JR

Sertoli cell tumour

Definition Sertoli cell tumour is a sex cord neoplasm composed of Sertoli cells arranged in a variety of patterns, most commonly as hollow or solid tubules. ICD-0 coding 8640/1 Sertoli cell tumour 8640/3 Malignant Sertoli cell tumour

Epidemiology Sertoli cell tumours account for < 1% of all testicular tumours and are the second most common sex cord stromal tumour, reportedly constituting approximately 42 cases for every 100 diagnosed Leydig cell tumours {2397}. They can occur at any age (median: 39 years) {2397}, and White people are most frequently affected. Although cases in childhood are rare, Ser­ toli cell tumours represent one of the more common sex cord tumours in patients aged < 12 years {2738}.

ICD-11 coding 2F77 & XH4H24 Neoplasms of uncertain behaviour of male genital organs & Sertoli cell tumour, NOS

Etiology Unknown

Related terminology None

Pathogenesis Unknown

Subtype(s) None

Macroscopic appearance Sertoli cell tumours are usually well-circumscribed, firm, lobulated, tan-white, and usually 5-40 mm in size. They show occa­ sional cystic changes and haemorrhage {3561).

Localization Testis and rete testis Clinical features Sertoli cell tumours typically come to clinical attention inci­ dentally at ultrasound or as a testicular mass. In some cases, gynaecomastia may be the initial manifestation {2738}. Rarely, the first diagnosis of the tumour is at a metastatic site {2397(.

Histopathology The tumour cells mostly form tubular structures, often with inter­ secting bands of fibrous tissue in varying amounts. The tubules can be hollow or solid and range in size from small to large. They are sometimes elongated, cystically dilated, or seen grow­ ing in a retiform pattern. Diffuse sheets of tumour cells with only

Fig. 6.72 Sertoli cell tumour. A Well-circumscribed tumour composed of tubules of variable shape and size. B This tumour shows prominent stromal sclerosis. Many Sertoli cell tumours show variable sclerosing features. C The characteristic solid or hollow tubular architecture is present, at least focally, in most cases. D Tumour with typical trabecular aspects. E Tumour with the typical trabecular pattern. F Sertoli cells lining hollow tubules.

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focal tubular differentiation can cause diagnostic difficulties in some cases. The tumour cells have moderate to occasionally abundant, lightly eosinophilic cytoplasm, which may be pale in some cases that contain lipid vacuoles. Cytoplasmic vacuoliza­ tion may rarely be prominent, with a signet ring-like appear­ ance. Because of the presence of these features, the existence of signet ring stromal tumour as an entity is a matter of debate (see Signet ring stromal tumour, p. 315). Cytological atypia is usually minimal to absent and mitoses are rare. Tumoural stroma may be hyalinized, sclerotic, or myxoid, and it rarely shows ossification. Exuberant sclerotic stroma is a distinctive feature in tumours showing a sclerosing pattern {3652,1585}. These are usually small, with the stroma constituting > 50% of the tumour and the tumoural cells arranged in cords and small clusters. Tumours with this rare morphological pattern appear to have a better prognosis than other Sertoli cell tumours; only one metastatic case has been reported (1585). CTNNB1 gene mutation and nuclear positivity for p-catenin in tumours with the sclerosing pattern are similar to those in other Sertoli cell tumours {680,2505,1585(. Sertoliform cystadenoma of the rete testis, traditionally included under testicular adnexal tumours, is better considered a form of sex cord stromal tumour primarily confined within dilated channels of the rete testis. It has been postulated that cells at the junction between the seminiferous tubules and rete retain the ability to differentiate in the direction of Sertoli cells and may give rise to this neoplasm {1541}. Immunohistochemically, and often morphologically, it resembles a Sertoli cell tumour {2138,2425}. Immunohistochemistry In subsets of the tumour cells, staining is positive for cytokeratins (60-80%), nuclear p-catenin (60-70%) {2505,3598,1586}, and vimentin (90-100%), and less frequently for inhibin (50%), calretinin, SF1, CD99, WT1, SOX9, S100, melan-A, chromogranin, and synaptophysin (2081,1441,1706,697,424,3598}. EMA is more frequently expressed in malignant neoplasms (1326). PAX2/8 and AR are expressed more frequently in sclerosing tumours {2140}. Differential diagnosis Considerations include adenomatoid tumours involving the testicular parenchyma that may simulate Sertoli cell tumours because of the presence of vacuolated cells and gland-like tubules. The primarily paratesticular location as well as the

Hg.6.73 Sertoli cell tumour. Tubules and cords with interanastomosing growth.

positivity for EMA and mesothelial markers and negativity for inhibin are helpful in the distinction. The cord-like pattern in sclerosing tumours has features overlapping with those in neu­ roendocrine tumours, which often have a more prominent insular pattern and may be associated with a teratomatous component. Sertoli cell nuclei lack the coarse nuclear chromatin seen in car­ cinoid tumours. Conspicuous lymphocytic infiltrate associated with a sheet-like arrangement of clear and pale tumour cells can cause diagnostic confusion with seminoma (1326}. In Sertoli cell tumours, the absence of germ cell neoplasia in situ and the negative immunoreactivity for germ cell markers are helpful dif­ ferential features. Sertoli cell nodules are hyperplastic nodules that are well circumscribed and composed of small aggregates of prepubertal-type seminiferous tubules with a prominent base­ ment membrane and a lining of immature Sertoli cells. The pres­ ence of spermatogonia admixed in these microscopic nodules is a distinctive feature. Areas of Sertoli cells with eosinophilic cytoplasm within tubules could resemble Leydig cell tumours, but tubule formation is rarely observed in Leydig cell tumours. Immunohistochemical findings of nuclear p-catenin expression in Sertoli cell tumours is a distinctive difference.

Cytology Not clinically relevant Diagnostic molecular pathology About 40% of tumours show gain of the X chromosome; much less commonly there are entire or partial losses of

Fig. 6.74 Sertoli cell tumour. A,B Diffuse nuclear staining for SF1. C Prominent nuclear immunohistochemical positivity for p-catenin.

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chromosomes 2 and 19 {3323}. CTNNB1 gene mutations are reported variably (60-70%) (2505,3598,424). Rare cases of bilaterality occur in familial adenomatous polyposis (3506). Essential and desirable diagnostic criteria Essential: a testicular mass with conspicuous or at least focal tubular differentiation in varying amounts. Desirable: immunoreactivity for cytokeratins; nuclear positivity for p-catenin.

Staging Not clinically relevant

Prognosis and prediction Most Sertoli cell tumours are benign, but about 5-12% metas­ tasize. Malignant Sertoli cell tumours are often quite large and

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show nuclear pleomorphism, vascular invasion, high-grade cytological atypia, mitotic activity, and necrosis {3561}. High Ki-67 expression (> 20%) has been associated with a poor prognosis. A minimum of two of these criteria are present in the majority of metastatic cases (3561,1326). Clinical stage I tumours in prepubertal patients, adolescents, and young adults appear to behave in a benign manner (2738}. Because radio­ therapy and chemotherapy have not influenced the outcome in metastatic tumours, managing clinical stage I tumours that have malignant features with an early retroperitoneal lymphadenectomy has been suggested but remains controversial (257, 2938}. Sites of metastatic disease include retroperitoneal lymph nodes (76%), lung (36%), bone (16%), liver (10%), inguinal lymph nodes (6%), axillary lymph nodes (4%), brain (2%), and kidney (1%) {1199}. Gynaecomastia seems to be more frequent in malignant cases.

Large cell calcifying Sertoli cell tumour

Definition Large cell calcifying Sertoli cell tumours (LCCSCTs) are com­ posed of Sertoli cells with abundant eosinophilic cytoplasm and coarse calcifications. There is frequent syndromic association with Carney complex. ICD-0 coding 8642/1 Large cell calcifying Sertoli cell tumour

ICD-11 coding 2F77 & XH9E02 Neoplasms of uncertain behaviour of male genital organs & Large cell calcifying Sertoli cell tumour Related terminology None

Subtype(s) None

Localization Testis Clinical features Approximately 60% of LCCSCTs arise in a sporadic setting, with the remainder being syndromic. Patients usually present with a painless testicular mass, but teenagers may present with gynaecomastia and isosexual pseudoprecocity, especially in cases associated with Carney complex (2576}. Ultrasonogra ­ phy shows a hyperechoic, well-vascularized mass with heavy acoustic shadowing (2918}. Uncommon malignant cases occur mostly in older patients, usually on a sporadic basis (1727,3122).

Epidemiology LCCSCTs are rare. They are more commonly seen in patients in their teens to their early twenties. Approximately 40% of cases are linked to Carney complex; occasional cases are associ­ ated with Peutz-Jeghers syndrome. More than three quarters of

Colecchia M Bremmer F Compdrat EM

male patients with Carney complex may have LCCSCT {3329, 719}. Malignant LCCSCTs are uncommon and usually affect older patients; only 1 case has been reported in a prepubertal patient {1861}. Etiology Many cases of LCCSCT have germline mutations in the PRKAR1A gene in patients with Carney complex, but sporadic tumours may also have acquired somatic PRKAR1A gene muta­ tions (3122}. In contrast, Peutz-Jeghers syndrome-associated tumours show germline mutations in the STK11 (LKB1) gene {1177}; they generally develop intratubular large cell hyalinizing Sertoli cell neoplasia, a distinct entity with benign, multifocal, bilateral intratubular proliferations of Sertoli cells with abundant eosinophilic cytoplasm not associated with an invasive compo­ nent. Details on tumours associated with Carney complex and Peutz-Jeghers syndrome are presented in Chapter 14: Genetic tumour syndromes of the urinary and male genital tracts. Pathogenesis Inactivating mutations or large deletions of the PRKAR1A gene, located at 17q24.2, are often found. PRKAR1A acts as a classic tumour suppressor gene leading to increased cAMP-stimulated total kinase activity (3045}.

Macroscopic appearance The tumours are well-circumscribed and firm, with a tan-yellow cut surface and gritty calcifications. In Carney complex-related cases, the tumours are often multifocal and bilateral {2718}. Benign LCCSCTs are smaller than malignant tumours (mean size: 14 mm vs 54 mm, respectively), with rare mitoses; necrosis and haemorrhage may occur in malignant tumours.

Histopathology Nests and cords of cells are embedded in a myxoid to fibrous stroma with neutrophilic infiltrate. Calcification or even ossifica­ tion is present in half of the cases. About 50% of the tumours

Fig. 6.75 Largecell calcifying Sertoli cell tumour. A Tumoural area replaced by collagenous stroma containing large numbers of calcific bodies of various sizes and shapes. B The tumour cells contain abundant eosinophilic cytoplasm; several laminated foci of calcification are present. C The tumour cells with abundant eosinophilic cytoplasm are arranged in cords and nests in a myxoid stroma. D Intratubular tumour shows strong immunohistochemical positivity for inhibin adjacent to the invasive tumour.

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contain an intratubular component {2730). The tumour cells are large, with slightly granular cytoplasm and oval nuclei with prominent nucleoli. Malignant cases are mostly solitary {806}.

Immunohistochemistry LCCSCTs show vimentin, inhibin, calretinin, SF1, S100, NSE, desmin, EMA, and focal cytokeratin reactivity (2509,1727), and they are negative for nuclear p-catenin {3598}. CAM5.2 and melan-A may be expressed. Ultrastructural studies have dem­ onstrated Charcot-Bdttcher crystals {3142). LCCSCTs differs from Leydig cell tumours by the presence of calcifications, larger cell size, a myxoid stromal component with neutrophilic infiltrate, intratubular growth, and the absence of Reinke crystals (2509}. Intratubular growth by LCCSCT may raise the possibility of intratubular large cell hyalinizing Sertoli cell tumour. The latter has exclusive intratubular growth, is invariably associated with Peutz-Jeghers syndrome, and is often multifo­ cal and/or bilateral. It is composed of a neoplastic proliferation of large Sertoli cells with lightly eosinophilic cytoplasm and promi­ nent extracellular basement membrane deposits {1449}. Cytology Not clinically relevant

306

Tumours of the testis

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: nests and cords of large eosinophilic cells (in stroma that may be calcified or even ossified). Desirable: intratubular growth; sex cord marker expression. Staging Not clinically relevant

Prognosis and prediction Necrosis, size > 40 mm, extratesticular growth, severe atypia, vascular invasion, and a mitotic count of > 1 mitosis/mm2 (equat­ ing to >3 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm2 in area) are distinctive criteria of malignancy, and the presence of two or more features is predictive of aggressive behaviour (1727). Retroperitoneal lymph node dissection is performed in metastatic cases, whereas currently chemotherapy or radiation therapy have no standard role.

Adult granulosa cell tumour

KaoCS Bode PK Menon S

Definition Adult granulosa cell tumour is a neoplasm composed of sex cord cells that resemble the granulosa cells of the Graafian fol­ licles of the ovary. These tumours have a histological spectrum similar to that of the much more common granulosa cell tumours of the ovary. ICD-0 coding 8620/1 Adult granulosa cell tumour

ICD-11 coding 2F77 & XH5BN5 Neoplasms of uncertain behaviour of male genital organs & Adult granulosa cell tumour of testis

Related terminology None

Subtype(s) None Localization Testis; almost always unilateral

Fig. 6.76 Adult granulosa cell tumour. Tumour nodules growing diffusely with cystic areas.

Clinical features The patient age range is 12-87 years {1526,902,862,1202}. Patients typically present with a testicular mass, which may

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307

rarely be associated with gynaecomastia (862,1202). The most common site of metastasis is within retroperitoneal lymph nodes; tumours may also (rarely) involve pelvic lymph nodes, liver, lung, and bone {862}.

Epidemiology Adult granulosa cell tumours are rare, accounting for < 0.5% of all sex cord stromal tumours. There are no known epidemiologi­ cal associations.

Etiology Unknown Pathogenesis Acquired FOXL2 mutations have been identified less fre­ quently in these tumours than in their ovarian counterparts {1351,1883(.

Macroscopic appearance Tumour size typically ranges from 30 to 50 mm {862,1202}. The tumours are well circumscribed and solid, although cysts may be seen, and the cut surface is lobulated and tan-white to yellowish-tan. Histopathology The tumours often have a nodular growth pattern, with the neoplastic cells within the tumour nodules growing diffusely. Microfollicles (Call-Exner bodies), trabeculae, nests, cords, gyriform structures, or spindled morphology can be seen. The associated stroma is typically inconspicuous but when present may be fibrous or oedematous. The cells have scant cytoplasm and elongated nuclei, often with nuclear grooves; luteinization of the cells and a few mitotic figures may be seen.

308

Tumours of the testis

The tumour cells may be positive for SF1, vimentin, inhibin, calretinin, SMA, S100, ER, PR, CD56, and cytokeratins (weak or dot-like); EMA, desmin, and HMB45 are negative {1526,902, 1361,717}. FOXL2 shows consistent staining in the few cases in which this immunostain has been performed {1351|. Cytology Not relevant Diagnostic molecular pathology Demonstration of FOXL2 mutations may be helpful (1351,1883). Essential and desirable diagnostic criteria Essential: composed of small ovoid cells with elongated, often grooved nuclei and scant cytoplasm; various architectural patterns exist. Desirable: immunohistochemistry for SF1, inhibin, or calretinin may be helpful in selected cases; reticulin may be helpful; FOXL2 immunoreactivity is frequent, but testicular cases do not consistently show somatic F0XL2 gene mutation; may show Call-Exner bodies.

Staging Not relevant

Prognosis and prediction Given the overall rarity of these tumours and the fact that a small number have demonstrated malignant behaviour, it is difficult to assess features that consistently predict which tumours will metastasize. However, larger tumour size (> 50 mm) and vas­ cular invasion are the most consistent features across several studies that show significant correlation with malignant behav­ iour (862,1202,630,1272,1290}.

Juvenile granulosa cell tumour

Bode PK Kao CS Menon S

Definition Juvenile granulosa cell tumour (JGCT) is a sex cord tumour composed of primitive-appearing granulosa cells growing in solid and follicular patterns. ICD-0 coding 8622/0 Juvenile granulosa cell tumour

ICD-11 coding 2F34 & XH2U25 Benign neoplasm of male genital organs & Granulosa cell tumour of the testis, juvenile Related terminology None

Subtype ⑥ None Localization Testis

Clinical features The usual presentation is a testicular mass; very rarely, there is gynaecomastia or premature puberty {1202}. JGCTs are occa­ sionally associated with karyotypic abnormalities {2327,3260) or cryptorchidism {1202}. Epidemiology JGCTs predominantly occur in the first 6 months of life, and very rarely beyond the first year {1202} or in adults (1185,1885). They account for 6-7% of all prepubertal tumours of the testis and

Fig. 6.78 Juvenile granulosa cell tumour. Cut surface showing cystic and solid areas.

< 0.5% of all sex cord stromal tumours of the testis (1813,1296, 3649,556,1202}. Etiology Unknown Pathogenesis Unknown

Fig. 6.79 Juvenile granulosa cell tumour. A Overview showing follicle-like structures. B Solid area composed of primitive-appearing granulosa cells without nuclear atypia.

Tumours of the testis

309

Macroscopic appearance The median tumour size is 20 mm (range: 5-50 mm). The cut surface is often partly cystic, containing watery or mucoid fluid, with tan-white/yellow solid areas (1202,1581,1813).

unlike YSTs, JGCTs are negative for SALL4, AFP, and glypican-3 (GPC3) {1581}. The differentiation from other sex cord stromal tumours may be difficult, but the presence of follicles and a younger age favour a diagnosis of JGCT.

Histopathology A lobulated growth pattern with macrocystic and microcystic areas is characteristic. The cysts are filled with eosinophilic or basophilic fluid. A solid component is also usual; papillary, basaloid, and spindle cell patterns rarely occur. The tumour cells are polygonal with vacuolated or eosinophilic cytoplasm; they have ovoid nuclei without grooves and with small nucleoli. Fibrous or fibromyxoid stroma is frequent. Mitotic activity (> 5 mitoses/mm2) and apopto­ sis may be prominent. Regressive changes (hyalinization) may be seen. Rete testis involvement, entrapment of seminiferous tubules, and lymphovascular invasion can occur {1581,1813}. JGCTs commonly express SF1, calretinin, inhibin, SOX9, WT1, and FOXL2, as well as (focally) low-molecular-weight cytokeratins (1581,1570). Differential diagnoses include yolk sac tumour (YST) and other sex cord stromal tumours. The nuclear features distin­ guish the JGCT from the adult granulosa cell tumour. Unlike JGCTs, only one fifth of prepubertal YSTs arise in patients aged < 1 year {716). Microscopically, follicular elements are not a fea­ ture of YST. Immunohistochemistry is usually straightforward;

Cytology There are no reports in the literature.

310

Tumours of the testis

Diagnostic molecular pathology FOXL2 mutations have not yet been systematically investigated; one investigated case was F0XL2-wildtype (1883,2897).

Essential and desirable diagnostic criteria Essential: a partially macrocystic or microcystic tumour com­ posed of primitive granulosa cells; diffuse or lobular growth; follicles of variable size and shape. Desirable: manifestation in neonates and infants in the first year of life; typical sex cord stromal tumour immunophenotype. Staging Not relevant Prognosis and prediction JGCTs show benign behaviour, even after testis-sparing sur­ gery (1202|.

Tumours in the fibroma thecoma group

Definition Tumours of the fibroma thecoma group are composed of fibro­ blastic cells and of cells resembling theca cells.

ICD-0 coding 8600/0 Thecoma 8810/0 Fibroma ICD-11 coding 2F34 & XH34A0 Benign neoplasm of male genital organs & Thecoma, NOS

Related terminology Acceptable: fibrothecoma; thecofibroma. Not recommended: fibroma of gonadal stromal origin; sex cord stromal tumour of the testis with a predominance of spindle cells; fibroma; thecoma; theca cell tumour. Subtype(s) None

Bremmer F Hartmann A

Localization Testis or paratesticular Clinical features Patients present with a testicular mass, or the tumour is identi­ fied incidentally on ultrasound. Epidemiology Tumours of the fibroma thecoma group are rare. Patients are aged between 16 and 69 years {3602,849,89}. Etiology Unknown

Pathogenesis Unknown Macroscopic appearance Tumour size ranges from 5 to 76 mm. Tumours appear as well-circumscribed tan-white or red lesions. Rare cases with

Tumours of the testis

311

haemorrhage and cystic changes have been reported (3602, 849}.

Cytology Not clinically relevant

Histopathology Tumours are relatively well circumscribed and can surround seminiferous tubules, particularly those in the periphery of the tumour. Various growth patterns (storiform, short fascicles, or both) have been described. The cellular content is also variable. Some reported cases were hypercellular, but cases with epithe­ lioid areas or a looser background have also been described. The nuclei can be plump ovoid, or spindled. Mitotic activity is generally low {3602}. Reticulin staining is seen around each of the tumour cells. Immunohistochemistry is not helpful in distinguishing fibrothecoma from other sex cord stromal tumours. Most fibrothecomas are positive for inhibin; some may show positivity for calretinin, melan-A, actin, or keratin {3602,849}.

Diagnostic molecular pathology Not clinically relevant

312

Tumours of the testis

Essential and desirable diagnostic criteria Essential: a morphology resembling that of the more frequent ovarian counterparts of these tumours; Sertoli cell tumour and sex cord stromal tumour NOS must be excluded. Desirable: inhibin positivity. Staging Not clinically relevant Prognosis and prediction Tumours in the fibroma thecoma group are benign neoplasms (3602}.

Mixed sex cord stromal tumour

Colecchia M Athanazio DA Bremmer F Compdrat EM Roth LM

Definition Mixed sex cord stromal tumours consist of various combina­ tions of sex cord elements with differentiation towards Leydig, Sertoli, or granulosa cells admixed with stromal spindle cells.

ICD-0 coding 8592/1 Mixed sex cord-stromal tumour I CD-11 coding 2F77 & XH19F9 Neoplasms of uncertain behaviour of male gen­ ital organs & Sex cord-gonadal stromal tumour, mixed forms

Related terminology None Subtype(s) None

Localization Testis

Clinical features Painless testicular enlargement is the most common present­ ing symptom. Gynaecomastia has been reported in 10% of the cases. Epidemiology The tumours can occur in patients of any age, but they typically arise in middle-aged or elderly men. One third of cases occur in children {1176). Etiology Unknown

Pathogenesis Unknown

Fig. 6.82 Mixed sex cord stromal tumour. Well-circumscribed grey-white to yellow tumour.

Macroscopic appearance Many mixed sex cord stromal tumours are white to yellow and replace most or all of the testis, often growing in proximity to the rete 拍 stis. Histopathology Mixed sex cord stromal tumour contains (in varying combinations) Leydig, Sertoli, and granulosa cells intermixed with a stromal component with spindled morphology. The sex cord elements are arranged in sheets, small nests, tubules, or trabeculae. Small cysts are present with Call-Exner-like bodies. The stromal com­ ponent generally consists of spindle-shaped cells in a collagen­ ous background intimately admixed with the sex cord element {3252,3067). Cellular pleomorphism and mitotic figures are varia­ ble. Rarely there are admixed germ cells; typically, these are most conspicuous peripherally {3252}. This phenomenon may raise the consideration of a mixed germ cell sex cord stromal tumour where the germ cells have malignant features {2730}. Reticulin stain can

Fig. 6.83 Mixed sex cord stromal tumour. A Well-circumscribed tumour with sex cord cells and a stromal component with spindled morphology. B Sex cord cells intermixed with a stromal component with spindled morphology. C Sex cord cells and spindled stromal cells are intimately admixed.

Tumours of the testis

313

Fig. 6.84 Mixed sex cord stromal tumour. A Inhibin immunohistochemistry. B Focal positivity for SF1 can be seen.

be helpful in the diagnosis because the sex cord elements have inconspicuous reticulin fibres, whereas stromal cells are individu­ ally surrounded by reticulin fibres (2730). Tumour cells, single or in aggregates, can show reactivity for inhibin (2658} and WT1, and they are positive for SMA and S100. Focally they show positivity for SF1, calretinin, CD34, and occasionally EMA. Focal nuclear expression of DMRT1 and/or positivity for SALL4 may raise the possibility of an intermixed germ cell component (observed in mixed germ cell-sex cord stromal tumour of the testis) (2153). Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: combinations of sex cord elements admixed with spindle stromal cells. Desirable: positive immunohistochemistry for SMA and S100 in selected cases.

314

Tumours of the testis

Staging Not applicable

Prognosis and prediction Approximately 25-30% of the tumours are malignant with metastases to retroperitoneal lymph nodes and to abdominal organs. Features that are commonly associated with malig­ nant outcome are invasive growth pattern, vascular invasion, nuclear atypia, mitotic activity, increased cellularity, and necro­ sis (1449}. The subgroup terms "mixed forms" and 'Incom­ pletely differentiated" listed under sex cord / gonadal stromal tumours in the 2004 WHO classification have been replaced by "mixed sex cord stromal tumour" and "sex cord stromal tumour NOSM, respectively, in the new WHO classification. The former is defined as showing two or more distinct forms of sex cord stromal elements, whereas in the latter, the tumour cells show indeterminate differentiation. These tumours may, on occasion, behave in a malignant fashion, with the morphological criteria employed for the assessment of malignancy in Sertoli and Ley­ dig cell tumours being useful for judging malignant risk (3561}.

Signet ring stromal tumour

Colecchia M Bremmer F Cheng L Comp6rat EM

Definition Signet ring stromal tumours of the testis are solid tumours con­ taining signet-ring cells and showing morphological similari­ ties to their ovarian counterparts and to solid pseudopapillary neoplasia of the pancreas. Some authors consider this tumour to be a morphological pattern of Sertoli cell tumour.

ICD-0 coding 8590/0 Signet ring stromal tumour ICD-11 coding 2F77 & XH69N5 Neoplasms of uncertain behaviour of male genital organs & Signet-ring stromal tumour

Related terminology None

Subtype(s) None Localization Testis Clinical features These tumours are asymptomatic intratesticular masses.

Epidemiology Patients are 29-69 years of age {1005,2154,1752}.

Etiology Unknown Pathogenesis The tumours show mutations of the CTNNB1 gene (2154,2155).

Macroscopic appearance The cut surface of the testis shows a small, well-circumscribed, solid, white to grey lesion, 10-28 mm in diameter (1005).

Histopathology These tumours are surrounded by a thick fibrous capsule and lobulated by thin fibrous septa. Tumour cells are arranged in solid nests and trabeculae in a background of loose oedematous stroma. Most parts of the tumour consist of PAS- and mucin-negative signet ring-like cells with eccentric nuclei and large cytoplasmic vacuoles and may contain eosinophilic cells or sclerotic areas {2154}. The possibility that signet ring stromal tumour is a specific morphological pattern of Sertoli cell tumour with unique histopathological features was first suggested by Kuo et al. {1752(, and this opinion has been recently supported by others {3257,1586}. These authors compared the morpho­ logical and immunohistochemical features of pancreatic solid

Fig. 6.85 Signet ring stromal tumour. A The tumour cells are arranged in solid nests of cells with a signet-ring cell appearance. B The tumour shows signet ring-like cells with eccentric nuclei and large cytoplasmic vacuoles, and it may contain eosinophilic cells or sclerotic areas. C Most parts of the tumour consist of PAS- and mucin-nega­ tive signet ring-like cells with eccentric nuclei and large cytoplasmic vacuoles.

pseudopapillary neoplasms and testicular Sertoli cell tumours and found significant differences between them, demonstrat­ ing the value of the continued separate classification of testis tumours and pseudopapillary pancreatic neoplasms {1586}.

Tumours of the testis

315

Immunohistochemistry The tumours are positive for vimentin, nuclear p-catenin, cyclin D1, S100, CD10, NSE, and synaptophysin. They are negative for inhibin, cal retinin, actin, desmin, and melan-A {2154}.

Differential diagnosis The most important differential diagnosis is with metastatic signet-ring cell carcinoma because of its distinct prognosis and treatment. Signet ring stromal tumours do not secrete mucin, and immunoreactivity for vimentin and negativity for cytokeratin and EMAs help rule out metastases.

Cytology Not clinically relevant

316

Tumours of the testis

Diagnostic molecular pathology Mutations of the CTNNB1 gene have been identified (2154, 2155}.

Essential and desirable diagnostic criteria Essential: a solid neoplasm with signet-ring cells. Desirable: positive immunostaining for vimentin and negativity for cytokeratins; positivity for p-catenin in selected cases.

Staging Not applicable Prognosis and prediction So far, all reported cases have behaved in a benign fashion {1752,1005}.

Myoid gonadal stromal tumour

Colecchia M Bremmer F Cheng L Compdrat EM

Definition Myoid gonadal stromal tumour of the testis is a spindle cell tumour showing myoid differentiation towards intertubular primi­ tive mesenchymal cells. ICD-0 coding 8590/0 Myoid gonadal stromal tumour

ICD-11 coding 2F77 & XH9G57 Neoplasms of uncertain behaviour of male genital organs & Sex cord-gonadal stromal tumour, NOS

Related terminology Not recommended: testicular stromal tumour with myofilaments. Subtype(s) None

Localization Testis

Clinical features The tumours arise as intratesticular masses. Epidemiology This neoplasm is mainly found in adults (mean age: ~40 years), but 1 case has been reported in a 4-year-old boy {965}.

Etiology Unknown Pathogenesis Unknown Macroscopic appearance Myoid gonadal stromal tumours are unencapsulated and well circumscribed, with a yellow/tan appearance. The tumours measure 10-35 mm {1587,898}.

Histopathology The tumours consist of short fascicles of spindled tumour cells that may surround residual seminiferous tubules, particularly in the periphery of the tumour {1449(. The tumour cells are fusi­ form with scant to moderate and lightly eosinophilic cytoplasm. Tumour nuclei show no or only mild atypia; lymphovascular invasion and necrosis are absent. The mitotic count is variable (1587,898). All reported tumours are positive for actin, S100, FOXL2, SF1, vimentin, inhibin (focal), and desmin {1587}. At the ultrastructural level the tumour nuclei show occa­ sional grooves, and the cells show scant cytoplasm rich in mitochondria, with small cytoskeletal myofilaments {2655}.

Fig. 6.86 Myoid gonadal stromal tumour. A Well-circumscribed intratesticular unen­ capsulated lesion with entrapped atrophic tubules. B Fascicles of fusiform to elon­ gated spindled cells with relatively scant to eosinophilic cytoplasm. C Tumour cells are positive for S100.

Myoid gonadal stromal tumours lack the broad fascicles, cigar­ shaped nuclei, and perinuclear vacuoles seen in leiomyoma. Tumours of the testis

317

The tumours are distinguished from fibroma by negativity for SOX9 and the absence of collagen bundles forming hyaline plaques. Cytology Not clinically relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: a pure spindle cell tumour lacking sex cord differen­ tiation; positivity for both actin and S100. Staging Not clinically relevant

Fig. 6.87 Myoid gonadal stromal tumour.日ectron micrograph showing thin myofila­ ments (arrow) in the cytoplasm of a cell with a nuclear groove (57 000* magnification).

318

Tumours of the testis

Prognosis and prediction Myoid gonadal stromal tumours of the testis are small indolent tumours adequately managed by orchiectomy. All the reported cases are benign.

Sex cord stromal tumour NOS

Definition Sex cord stromal tumours NOS are tumours with incomplete or undifferentiated sex cord or stromal elements.

ICD-0 coding 8590/1 Sex cord-stromal tumour, NOS

ICD-11 coding 2F77 & XH9G57 Neoplasms of uncertain behaviour of male genital organs & Sex cord-gonadal stromal tumour, NOS Related terminology Acceptable: sex cord stromal tumour not elsewhere classified. Subtype(s) None

Colecchia M Bremmer F Cheng L Comperat EM

Histopathology Sex cord stromal tumours NOS consist of tumour cells without a specific line of differentiation and do not lend themselves to classification as Sertoli or granulosa cell tumours. They may have epithelioid cells with variable amounts of pale cytoplasm or ovoid to elongated tumour cells. In addition, the tumours show undifferentiated stromal elements that may be dominant, con­ sisting of a pure spindle cell component. The tumour cells may form fascicles or show compact growths. Cellular pleomorphism is uncommon; in clinically benign tumours mitoses are rare (423). Reticulin fibres surround aggregates of cells rather than individual cells. Invasive margins, pleomorphism, angioinvasion, nuclear atypia, frequent mitosis, necrosis, and large tumour size are features that are more commonly associated with malignant behaviour of these tumours (3252,3008,3117,2658).

Immunohistochemistry Localization Testis Clinical features Patients can present with a painless intratesticular mass. Epidemiology About 50% of sex cord stromal tumours NOS occur in children; the remainder occur in men of any age.

Etiology Unknown

Pathogenesis Unknown

Macroscopic appearance The tumours are well-circumscribed lesions with a solid, white to yellow cut surface.

Positive immunostaining for SF1, desmin, vimentin, actin, S100, CD99, FOXL2, inhibin (focal), and calretinin has been reported. Epithelial markers (cytokeratins) are not expressed by neoplas­ tic cells, but focal immunoreactivity is rarely observed (2658, 3117,1994}. Immunohistochemistry is not helpful in distinguish­ ing sex cord stromal tumour NOS from other sex cord stromal tumours. Most cases of sex cord stromal tumour NOS are posi­ tive for inhibin; some may show positivity for calretinin, melan-A, actin, or keratin (3602,849}.

Differential diagnosis Some tumours, particularly those with hypercellular histology, can raise the possibility of fibrothecoma. Reticulin staining is useful in separating such rare cases, being positive around some individual tumour cells in fibrothecoma.

Cytology Not clinically relevant

Fig- 6.88 Sex cord stromal tumour NOS. A Small, well-circumscribed tumour with low-grade spindle cell component. B The tumour shows undifferentiated stromal elements consisting of a spindle cell component. C Prominent spindle cell growth.

Tumours of the testis

319

Diagnostic molecular pathology Not clinically relevant

Staging Not applicable

Essential and desirable diagnostic criteria Essential: a tumour with incomplete or undifferentiated sex cord stromal elements; specific sex cord stromal tumours should be excluded. Desirable: immunoreactivity for the markers described above, in selected cases.

Prognosis and prediction In children these tumours are almost always benign. In adults, malignant cases have been reported.

320

Tumours of the testis

Tumours of the testicular adnexa Edited by: Berney DM, Raspollini MR, Tickoo SK

Ovarian-type tumours of the collecting ducts and rete testis Serous cystadenoma Serous tumour of borderline malignancy Serous cystadenocarcinoma Mucinous cystadenoma Mucinous borderline tumour Mucinous cystadenocarcinoma ..EndometriQidlumours _____ Clear cell adenocarcinoma Brenner tumour Tumours of the colFecting ducts and rete testis Adenoma Adenocarcinoma “ Paratesticular mesothelial tumours Adenomatoid tumour Well-differentiated papillary mesothelial tumour Mesothelioma Tumours of the epididymis Cystadenoma Papillary cystadenoma Adenocarcinoma Squamous cell carcinoma Melanotic neuroectodermal tumour

Tumours of the testicular adnexa: Introduction

The testicular adnexa and anatomically associated parts include the embryologically diverse rete testis, epididymis, spermatic cord, testicular appendages, surrounding soft tissue, and mesothelium. Primary paratesticular soft tissue tumours are rare entities. However, for genitourinary sarcomas, the paratesticular region is the site most commonly involved, and spermatic cord adipocytic tumours are the most frequent tumours at this anatomical site. They usually occur in the adult population, with the excep­ tion of lipoblastoma, which occurs in children. An important change in the fifth edition of the WHO classification of urinary and male genital tumours is that the soft tissue tumours of the paratesticular region and spermatic cord are now handled in

Tickoo SK Compdrat EM LaxSF Raspollini MR

Chapter 10: Mesenchymal tumours. Table 7.01 summarizes the soft tissue tumour types that can uncommonly be identified in this region. For the fifth edition, this chapter on testicular adnexa tumours is organized systematically and describes rare and different entities whose place of origin is the common denominator. Table 7.02 (p. 323) and Fig. 7.01 (p. 325) summarize the tumour entities described in this chapter. Other than soft tissue tumours, the majority of the tumours in the testicular adnexa are derived from mesothelium (tunica vaginalis) {1642,105}, with adenomatoid tumour being by far the commonest among these {105,123}. Some others are believed to originate from multiple appendages/inclusions of Mullerian or

Table 7.01 Uncommon soft tissue tumour types that can be identified in the testicular adnexa

Tumours or pseudotumours

Uncommonly involved sites of testicular adnexa

Fibroblastic and myofibroblastic tumours Inflammatory myofibroblastic tumour

Spermatic cord

Myxofibrosarcoma

Spermatic cord

Spermatic cord myofibroblastoma

Spermatic cord

Vascular tumours Angiosarcoma

Epididymis

Spermatic cord deep angiomyxoma

Spermatic cord

Pericytic (perivascular) tumours

Cellular angiofibroma

Spermatic cord

Smooth muscle tumours Leiomyoma

Spermatic cord, epididymis, tunica albuginea

Leiomyosarcoma

Spermatic cord

Skeletal muscle tumours Rhabdomyoma

Epididymis, spermatic cord, paratesticular region

Rhabdomyosarcoma

Paratesticular region

Chondro-osseous tumours

Osteosarcoma

Spermatic cord

Peripheral nerve sheath tumours Schwannoma

Spermatic cord

Neurofibroma

Paratesticular region

Malignant peripheral nerve cell tumour

Paratesticular region

Tumour of adipocytic differentiation

Adipocytic tumours

Spermatic cord

Tumours of uncertain differentiation

Desmoplastic small round cell tumour

Spermatic cord

Synovial sarcoma

Spermatic cord

Undifferentiated pleomorphic sarcoma

Spermatic cord

Paratesticular fibrous pseudotumour

Tunica vaginalis, tunica albuginea, epididymis, spermatic cord

Proliferative funiculitis

Spermatic cord

322

Tumours of the testicular adnexa

kblo7.02 Clinicopathological characteristics of testicular adnexa tumours (continued on the next page)

Tumour

Localization

Patient age

Histological features

Immunohistochemical and molecular analysis

Behaviour and outcome

Mimics

Benign

Reactive mesothelial hyperplasia

Serous cystadenoma

Intratesticularor paratesticular

Fourth to eighth decade

Cystic tumour lined by a cuboidal or columnar ciliated epithelium with bland nuclei

Positive: ER, PRWT1, PAX8

Serous tumour of borderline malignancy

Intratesticularor paratesticular

Second to seventh decade

Papillary tumour with hierarchical branching and stratified ciliated columnar cells with moderate cytological atypia

Positive: ER, PR,M1, PAX8, BRAF

Serous cystadeno­ carcinoma

Intratesticularor paratesticular

First to seventh decade

Infiltrating serous-type tumour within a desmoplastic stroma with psammoma bodies

Mucinous cystadenoma

Intratesticularor paratesticular

Second to eighth decade

Cystic tumour lined by a muci­ nous epithelium without cellular atypia

Mucinous borderline tumour

Intratesticular or paratesticular

Fourth to sixth decade

Cystic tumour with papillae lined by mucinous epithelium, with moderate atypia

Mucinous cyst­ adenocarcinoma

Intratesticularor paratesticular

Fourth to eighth decade

Invasive mucinous tumour with cribriform glands and papillary structures

Endometrioid tumours

Intratesticularor paratesticular

Fifth to eighth decade

Tumours with endometrioid epithelial differentiation and tumours with endometrial stromal differentiation

Polygonal, columnar, or hobnail-shaped clear cells with solid, tubulocystic, or papillary architecture

Clear cell adenocarcinoma

Intratesticular or paratesticular

Fourth to seventh decade

Brenner tumour

Intratesticular or paratesticular

Mainly adults

Adenoma of the collecting ducts and rete testis

Rete testis

Second to seventh decade

Cystic spaces lined by cuboidal ciliated cells without atypia

Mainly adults

Papillary, solid, glandular, cribriform, and glomeruloid architecture with eosinophilic to clear cells; transition from normal to neoplastic rete epithelium is a useful diagnostic clue

Adenocarcinoma of the collecting ducts and rete testis

Rete testis

Benign: nests of bland urothelialtype cells within fibromatous stroma

Malignant: invasive tumour with urothelial morphology associated with benign or borderline tumour

Negative: calretinin

Reactive mesothelial hyperplasia Good prognosis

Negative: calretinin

Well-differentiated papillary mesothelial tumour

Epithelioid mesothelioma The majority of the reported tumours are low-grade, but serous cystadenocar­ cinomas can metastasize

Positive: PAX8

Negative: calretinin

Positive: CK20.CDX2

Benign

Variable: CK7

Mesothelioma Adenocarcinoma of the rete testis Adenocarcinoma of the 叩 ididymis

Teratomatous elements with mucinous differentiation Metastasis

Positive: CK20

Good prognosis

Variable: CK7, CDX2

Teratomatous elements with mucinous differentia­ tion Metastatic adenocarcinoma

Positive: CK20, CDX2, MUC2

Tumour with metastatic potential

Variable: CK7

Positive: CK7, ER, PAX8 (for epithelial tumours); CD10, IFITM1 (for low-grade endometrial stromal sarcoma)

No metastasis reported for the endometrioid carcinomas

Mesothelioma

Somatic malignancy in a germ cell tumour Other types of ovarian epithelial-type tumours

Rete testis adenocarcinoma Metastatic carcinoma Endometrioid-type yolk sac tumour

Mesothelioma

Positive: CK7, EMA, PAX8.AR

Serous carcinoma

Negative: calretinin, WT1, PR, ER, RCCm Positive: CK7.GATA3, p63, uroplakin

Negative: CK20, PAX8, WT1.ER, PR (in ovarian counterparts)

Not required

Malignant

Metastatic renal cell carcinoma with clear cell morphology

Malignant Brenner tumour has metastatic potential

Metastatic carcinoma

Benign

None Mesothelioma

Positive: CK7, AE1/AE3, EMA, vimentin, BerEP4 (no specific lineageassociated markers)

Ovarian-type tumours

Malignant

Metastatic adenocarcinoma

Epididymal carcinoma

Malignant Sertoli cell tumour

CKs, cytokeratins; DSRCT, desmoplastic small round cell tumour; NET, neuroendocrine tumour; PNET, primitive neuroectodermal tumour; SCC, squamous cell carcinoma.

Tumours of the testicular adnexa

323

Tabl,7.02 Clinicopathological characteristics of testicular adnexa tumours (continued) Tumour

Localization

Patient age

Histological features

Immunohistochemical and molecular analysis

Adenomatoid tumour

Epididymis (spermatic cord, testis, tunica albuginea, and tunica vaginalis)

Mainly fourth decade

Bland cytomorphological features, with gland-like or vascular-like spaces

Positive: mesothelial markers, L1CAM, pancytokeratin, podoplanin (D2-40);BAP1 retained

Well 5 mm in linear extent. Goblet cells can be identified. Pools of mucin containing atypi­ cal epithelial cells can be present. Carcinoma can be mixed with background borderline and benign areas (3135,1474}. Unlike ovarian mucinous carcinomas, testicular and paratesticular mucinous cystadenocarcinomas are typically positive for CK20, CDX2, and MUC2, and they show various degrees of CK7 positivity, in keeping with an intestinal phenotype (3135, 1474,3115}. Primary mucinous cystadenocarcinoma of the testicular adnexa should be distinguished from metastatic adenocarci­ noma, mesothelioma, and somatic malignancy in a germ cell tumour. Metastatic adenocarcinoma to the testis from a gastro­ intestinal primary tumour shows a similar immunophenotype to that of a primary testicular tumour {3255). Consequently, appro­ priate radiological and/or endoscopic investigations may be necessary to differentiate a primary tumour from a metastasis. Mesothelioma arising from the tunica vaginalis can also show mucinous differentiation and can be distinguished from primary mucinous cystadenocarcinoma by its expression of mesothelial markers such as CK5/6, calretinin, and WT1 {1006). Mucinous

Fig. 7.11 Mucinous cystadenocarcinoma. A Paratesticular tumour mixed with background benign component. B The neoplastic cells show severe cytological atypia and form cribriform glandular structures. The tumour infiltrates into and between seminiferous tubules. C Pools of mucin containing severely atypical columnar to cuboidal epithelial cells.

Tumours of the testicular adnexa

335

cystadenocarcinoma can also arise from somatic elements of a germ cell tumour {2835). Differentiating these tumours from primary mucinous cystadenocarcinoma of the testicular adnexa requires exclusion of germ cell neoplasia in situ or exclusion of 12p gain (typically seen in postpubertal teratoma) by molecular testing. Negative serum germ cell tumour markers and the fact that testicular germ cell tumours tend to occur at a younger age may also help to distinguish these tumours. Cytology Not clinically relevant Diagnostic molecular pathology Not relevant

336

Tumours of the testicular adnexa

Essential and desirable diagnostic criteria Essential: an invasive mucinous carcinoma with atypia and architectural complexity; invasion measuring 2 5 mm in linear extent; no invasive or intratubular germ cell neoplasia identi­ fied in the background testis. Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for these tumours. Prognosis and prediction Mucinous cystadenocarcinomas can show distant metastatic potential, with metastatic disease having a poor prognosis {233, 3256).

Endometrioid tumours

Definition Endometrioid tumours are tumours with endometrioid epithelial differentiation showing a spectrum from benign (adenoma) to malignant (adenocarcinoma), including atypical epithelial prolif­ eration (borderline tumour), and tumours with endometrial stro­ mal differentiation. ICD-0 coding 8380/1 Endometrioid tumour, borderline 8380/3 Endometrioid adenocarcinoma ICD-11 coding 2F77 & XH5DQ2 Neoplasms of uncertain behaviour of male genital organs & Endometrioid adenoma, borderline malig­ nancy 2F77 & XH0SD2 Neoplasms of uncertain behaviour of male genital organs & Endometrioid adenocarcinoma, NOS Related terminology None

Subtype(s) None Localization Intratesticular or paratesticular (there is 1 reported case from the appendix testis) {1635) Clinical features The mean patient age is 68 years (range: 59-82 years). Patients present with scrotal swelling (1886). Endometriosis may occur as a tumour-like lesion {3562} or as an incidental finding (3578).

Lax SF

Pathogenesis The pathogenesis of epithelial tumours has not been studied. For the case of low-grade endometrial stromal sarcoma, a JAZF1::SUZ12 gene fusion was reported. Macroscopic appearance The epithelial tumours reported were mostly solid and/or cystic and have measured 30-90 mm {1886}. The single endometrial stromal sarcoma reported was a firm and multinodular lesion measuring 20 mm (34}. Histopathology The histological pattern varies according to the biological cat­ egory. Tumour-like endometriosis exhibits well-formed endo­ metrioid glands and stroma surrounded by bundles of smooth muscle {3562}. The borderline endometrioid tumour is cystic with a papillary architecture (2346). The adenocarcinomas show a glandular, papillary, cribriform, or solid growth pattern consistent with a stratified columnar epithelium with variable degrees of atypia {1635,2342,3562}. Squamous differentiation with focal keratinization has also been reported (3562). By immunohistochemistry, endometrioid tumours are posi­ tive for CK7, PAX8, ER, and PR {1886,3174} and negative for CK20, CDX2, and glypican-3 (GPC3) (939). The differential diagnosis includes other types of testicular ovarian epithelialtype tumours (1886}, adenocarcinoma of the rete testis )109), metastatic carcinomas from the upper gastrointestinal tract and colon (3255,1310}, and endometrioid-type yolk sac tumour (positive for CDX2 and GPC3) {566}.

Epidemiology These are very rare tumours, with only 4 endometrioid epithelial tumours reported to date: 1 borderline tumour (2346} and 3 car­ cinomas {1635,2342,3562). Tumour-like endometriosis (3562, 1058} and 1 low-grade endometrial stromal sarcoma of the paratestis (34} have also been reported. In addition, 1 seromucinous borderline tumour was reported, similar to that encoun­ tered within the morphological pattern of endometrioid tumours (2850). It is possible that in the past, endometrioid tumours were not designated as such (105).

Etiology An association with estrogen therapy for prostate carcinoma was observed {3562,1058). An association with endometriosis and teratoma has also been hypothesized (1886). Fig. 7.12 Endometrioid adenocarcinoma. A paratesticular endometrioid adenocarci­ noma of the ovarian surface epithelial type showing confluent glands and cribriform pattern (right) and hyalinized and atrophic seminiferous tubules (left).

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337

Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: a tumour with endometrioid-type morphology; bor­ derline tumours exhibit atypical epithelial proliferation; adeno­ carcinomas show a confluent (maze-like) or complex papil­ lary growth pattern similar to that of corresponding tumours of the female reproductive organs; endometrial stromal sarco­ mas show tumour cells resembling endometrial stroma cells with an infiltrative growth pattern; exclusion of metastasis or spread from adjacent organs. Desirable: CK7, ER, and PAX8 positivity for epithelial tumours; CD10 and IFITM1 positivity for low-grade endometrial stromal sarcomas. Fig. 7.13 Endometrioid adenocarcinoma. A paratesticular endometrioid adenocarci­ noma of the ovarian surface epithelial type showing malignant endometrioid glands with squamous/squamoid morules.

Low-grade endometrial stromal sarcoma resembles its uter­ ine counterpart, consisting of proliferative phase-type endome­ trial stromal cells and exhibiting a multinodular infiltrative growth pattern {34}. It is immunoreactive for CD10, IFITM1, vimentin, ER, and PR {2572,1887}.

338

Tumours of the testicular adnexa

Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for these tumours.

Prognosis and prediction For the few endometrioid tumours described, including carci­ nomas, no metastatic events were reported {1635,2342,3562}.

Clear cell adenocarcinoma

Definition Clear cell adenocarcinoma is a malignant epithelial tumour consisting of Mullerian-type epithelium with clear cell morphol­

Macroscopic appearance These are solid or cystic tumours with a haemorrhagic cut surface.

ogy.

Histopathology The tumours consist of polygonal, columnar, or hobnail cells with clear cytoplasm and show a solid, tubulocystic, or papillary architecture. Nuclear atypia is mild to moderate; the mitotic count may be low. By immunohistochemistry, the tumours are positive for CK7, EMA, PAX8, and AR, and negative for WT1, CA19-9, CK20, calretinin, D2-40, ER, and PR {1886}. Despite a low mitotic count, the Ki-67 index is high {1886}. The differential diagnosis includes mesothelioma (positive for calretinin and D2-40) {2177); serous carcinoma (more pronounced cellular budding and more frequent psammoma bodies) (825}; and metastatic renal cell car­ cinoma, particularly with clear cell morphology (775,3372,939}.

ICD-0 coding 8310/3 Clear cell adenocarcinoma ICD-11 coding 2C9Y & XH6L02 Other specified malignant neoplasms of uri­ nary tract & Clear cell adenocarcinoma, NOS

Related terminology None Subtype ⑥ None

Localization Intratesticular or paratesticular

Clinical features The patient age range is 43-71 years (mean: 52 years). Patients present with an intratesticular or paratesticular mass, with or without local or abdominal pain.

Epidemiology Clear cell adenocarcinoma is a very rare tumour, with only 3 cases reported (3223,1886}. Etiology Unknown

Pathogenesis Unknown

Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: a tumour with clear and hobnail cells in a solid, tubulocystic, confluent, or complex papillary pattern; exclusion of metastasis. Desirable: immunoreactivity for CK7 and PAX8; negativity for mesothelial markers and RCCm. Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for these tumours. Prognosis and prediction Both an aggressive and an indolent course have been reported, as well as response to radiotherapy (1886}.

Fig. 7.14 Clear cell adenocarcinoma. A This ovarian 叩ithelial-type tumour is characterized by clear and eosinophilic cells. B Tumour abuts the paratesticular tissue. It consists of clear and eosinophilic cells. C Ovarian epithelial-type tumour showing polygonal cells with clear cytoplasm and papillary architecture.

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339

Lax SF

Brenner tumour

Definition Brenner tumours are composed of urothelial-type cells within a dense fibromatous stroma. They show a range of features, from benign to borderline to malignant.

Related terminology None

Histopathology Brenner tumours in the testis or paratestis resemble their coun­ terparts in the ovary. Benign tumours are typically composed of nests of bland urothelial-type cells with elongated grooved nuclei within a fibromatous stroma. Borderline tumours usu­ ally exhibit papillary projections of atypical urothelial-type epi­ thelium in cystic spaces without infiltrative growth. Malignant tumours consist of nests of highly atypical urothelial-type epi­ thelium showing invasive growth. Mitoses are frequent. Malig­ nant Brenner tumours are usually associated with a benign or borderline Brenner tumour component. Immunohistochemical studies performed on ovarian Brenner tumours reveal positivity for CK7, GATA3, p63, and uroplakin, and negativity for CK20, PAX8, WT1.ER, and PR {2705,1707}.

Subtype ⑥ None

Cytology Not relevant

Localization Intratesticular or paratesticular

Diagnostic molecular pathology Not relevant

Clinical features The mean patient age is 53 years. Patients present with scrotal swelling, sometimes with tenderness.

Essential and desirable diagnostic criteria Essential: for benign Brenner tumour: nests of bland urothelialtype cells within fibromatous stroma; for borderline Brenner tumour: a papillary growth resembling low-grade papillary urothelial neoplasms of the urothelial tract or crowded nests of urothelial-type epithelium, without stromal invasion; for malignant Brenner tumour: an invasive tumour with urothelial morphology and a benign or borderline Brenner tumour com­ ponent in the background.

ICD-0 coding 9000/0 Brenner tumour ICD-11 coding 2F77 & XH5DX3 Neoplasms of uncertain behaviour of male genital organs & Brenner tumour, NOS

Epidemiology These tumours are very rare, with only 7 benign cases and 1 malignant case reported {1435,2592,485,3562}.

Etiology There is some evidence that Brenner tumours may originate from Walthard nests, which are common in the tunica vaginalis of the testis, or from mesothelium, because an association with adenomatoid tumour has been observed {2332}. Pathogenesis Unknown

Macroscopic appearance Brenner tumours are solid and fib的matous, measuring 27-73 mm. A cystic tumour has also been described {2592}.

340

Tumours of the testicular adnexa

Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for these tumours. Prognosis and prediction All reported benign tumours showed a favourable course. The malignant tumour revealed lymph node metastasis but the patient survived for more than 2 years (485).

Adenoma of the collecting ducts and rete testis

Srigley JR Kryvenko ON

Definition Adenoma of the collecting ducts and rete testis is a benign, often cystic neoplasm of the rete epithelium characterized by tubular, papillary, and/or fibrous elements. ICD-0 coding 8140/0 Adenoma ICD-11 coding 2F34 & XH3DV3 Benign neoplasm of male genital organs & Adenoma, NOS

Related terminology Acceptable: cystadenoma; papillary cystadenoma; adenofibroma. Subtype(s) None

Localization Rete testis Clinical features Patients generally present with a unilateral painless mass, or the tumour is found incidentally in an orchiectomy specimen.

Fig. 7.15 Adenoma of the rete testis. Cystadenoma of the rete testis characterized by dilated cystic spaces with papillae lined by a single layer of cytologically bland columnar cells.

Etiology Unknown

cystic spaces (1236,114,240). There may be prominent fibrous stroma; such cases are often referred to as cystadenofibromas (105}. Occasionally, solid lesions composed of elongated tubules embedded in a fibrous stroma may be seen {2255}. No atypia or infiltration of adjacent testis is present and mitoses are rare. The tumour formerly known as sertoliform cystadenoma of the rete testis is now considered a Sertoli cell tumour arising in the rete testis (see Sertoli cell tumour, p. 302).

Pathogenesis Unknown

Cytology Not relevant

Macroscopic appearance The tumours are circumscribed cystic, mixed cystic/solid, or solid lesions in the mediastinal (hilar) aspect of the testis {1541, 123,105). They range from 10 to 55 mm in diameter.

Diagnostic molecular pathology Not relevant

Epidemiology Rete testis adenomas are rare, with < 15 well-described cases (1541,123,105}. They affect a wide age range (12-79 years).

Histopathology Most of the tumours are cystadenomas composed of variably sized dilated cystic spaces lined by cuboidal to low columnar cells, sometimes ciliated, with bland nuclear features {1541,123, 105}. Transition from normal rete testis epithelium is helpful for diagnosis. The cystic spaces may merge imperceptibly with back­ ground rete glands. The epithelium may be stratified with areas of tufting or budding. Papillary structures can be present within

Essential and desirable diagnostic criteria Essential: rete epicen伽；multicystic and/or solid lesion with dilated glands, papillae, and/or tubules; fibrous stroma; bland nuclei. Staging Not applicable Prognosis and prediction All reported cases have behaved in a benign fashion.

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341

Adenocarcinoma of the collecting ducts and rete testis

Kryvenko ON Srigley JR

Definition Adenocarcinoma of the collecting ducts and rete testis is a malignant gland-forming tumour originating in the rete epithe­ lium.

ICD-0 coding 8140/3 Adenocarcinoma

ICD-11 coding 2C84 & XH74S1 Malignant neoplasms of other specified male genital organs & Adenocarcinoma, NOS Related terminology None Subtype ⑥ None Fig.7.16 Adenocarcinoma of the rete testis. Neoplastic rete epithelium.

Localization The tumour is centred in the rete testis.

Epidemiology The tumour is exceedingly rare. It occurs in a wide age range, although most reported cases are in adults.

anatomy and this transition is not documentable. Immunohisto­ chemistry is positive for CK7, AE1/AE3, EMA, vimentin, PAX8, and BerEP4; there are no specific lineage-associated (rete epithelium) markers (109}. The differential diagnosis includes mesothelioma, ovarian-type tumours, metastatic adenocarci­ noma, epididymal carcinoma, and malignant Sertoli cell tumour. Supportive immunohistochemistry ruling out other lineage dif­ ferentiation tumours such as metastatic adenocarcinoma, germ cell tumours, Sertoli cell tumour, or mesothelioma can help in the accurate diagnosis of rete testis carcinoma (109).

Etiology Unknown

Cytology No published reports

Pathogenesis Unknown

Diagnostic molecular pathology Not relevant

Macroscopic appearance The tumours are centred in the testicular hilum and have solid and cystic cut surfaces (109). They are typically large, with reported diameters of 20-90 mm (105); extension to spermatic cord and overlying skin with satellite nodules is common.

Essential and desirable diagnostic criteria Essential: a tumour centred in the testicular hilum; exclusion of other testicular or paratesticular tumours; exclusion of metas­ tases. Desirable: evidence of transition from normal to neoplastic rete epithelium.

Clinical features Most patients present with a mass and/or pain. The tumour can be associated with hydrocoele {2986}. Local spread and metas­ tasis to para-aortic and iliac lymph nodes are common.

Histopathology Histologically, the tumours^shp.w intrarete and invasive growth, with a range of patterns, ouch as papillary, solid, glandular, cribriform, and giomerutoid (109}. Tumour cells are cuboidal to columnar with nuclear pseudostratification and noticeable cyto­ logical atypia. The cytoplasm varies from eosinophilic to clear. Desmoplasia and necrosis are common. Evidence of a transition from normal to neoplastic rete epithelium is a useful diagnostic clue if present; even so, large masses can obliterate the normal

342

Tumours of the testicular adnexa

Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for these tumours. Prognosis and prediction These tumours have a poor prognosis, with a 5-year survival rate of approximately 15% {109,735,3539}. Tumour diameter > 50 mm at presentation is a poor prognostic factor (2801}.

Adenomatoid tumour

Idrees MT Comp6rat EM Galateau-Salle F

Definition Adenomatoid tumour is a benign mesothelial neoplasm display­ ing a spectrum of nested, tubular, or cord-like patterns.

ICD-0 coding 9054/0 Adenomatoid tumour ICD-11 coding 2E8Y & XH6BY3 Benign neoplasm of mesothelial tissue, other specified organs & Adenomatoid tumour, NOS

Related terminology None Subtype(s) None Localization The majority of adenomatoid tumours arise from the epididymis tail, but they may occur anywhere in the epididymis. The sper­ matic cord, tunica albuginea, tunica vaginalis, and testis are involved less commonly (1154,1644,2169,2415,79}.

Clinical features The most common presentation is a mass discovered by the patient (2811} or occasionally an incidental finding on routine examination or imaging. Pain due to torsion may lead to4he identification of the tumour {2963}. Ultrasound imaging shows a well-circumscribed mass {2457}. The typical ultrasonographic appearance is an isoechoic and homogeneous mass, which is sometimes cystic. Identifying the characteristic appearance of the tumour by imaging in the epididymis often avoids the need for orchiectomy, and intraoperative frozen sections are helpful

Fig. 7.17 Adenomatoid tumour. Paratesticular adenomatoid tumour arising from the epididymis and pushing into the testicular parenchyma. The cut surface is homoge­ neous and greyish to whitish tan.

in surgical decision-making. Tumours arising from the tunica often involve the testicular parenchyma {1644,2169}, mimicking germ cell tumours; these are difficult to distinguish by imaging. T2-weighted MRI shows a low-intensity signal compared with that of the testicular parenchyma (2457} and slow or decreased enhancement with contrast.

Fig. 7.18 Adenomatoid tumour. A Low magnification of a paratesticular adenomatoid tumour adjacent to the tunica vaginalis of the testis. B The tumour shows tubules and cys­ tic spaces lined by flattened to plump mesothelial cells. Thin, thread-like cytoplasmic bridges are present. Basophilic material may be seen within the tubular or cystic structures. The stroma is fibrous to collagenous. C Intratesticular adenomatoid tumour extending between the seminiferous tubules.

Tumours of the testicular adnexa

343

Fig. 7.19 Adenomatoid tumour. A Tubules lined by plump mesothelial cells with cribriform architecture. The mesothelial cells are rounded and show prominent nuclei. The stroma is collagenous to fibrous. B A cellular adenomatoid tumour with tubules and cord-like structures. The cells are plump and round to oval with prominent nuclei. C Promi­ nent lymphocytic sprinkling and aggregates are present in many tumours. D Necrosis in an adenomatoid tumour may be confusing and lead to its erroneous interpretation as a malignant neoplasm. E The cells are plump with abundant eosinophilic cytoplasm and rounded nuclei with conspicuous nucleoli. Prominent nuclear inclusions are present.

Epidemiology Adenomatoid tumours account for one third of all adnexal tumours and represent 60% of all benign adnexal tumours {105}. The tumour occurs predominantly in the fourth decade of life, but it has been described in all age groups. It is uncommon in children (368,2233). Etiology An association between adenomatoid tumours and immunosup­ pression in patients undergoing treatment for autoimmune dis­ ease or after allograft organ transplantation has been reported, which is hypothesized to be due to immune dysregulation within mesothelial cells {1164). Pathogenesis Adenomatoid tumours carry a somatic missense mutation in the TRAF7 gene, which encodes an E3 ubiquitin ligase. Mutant TRAF7 leads to the phosphorylation of NF-kB with an increase in L1CAM expression |1164). Macroscopic appearance The tumours are well-circumscribed round to oval masses, v 20 mm in diameter, with a homogeneous white to grey or tan bulging surface. Uncommonly, cases as large as 50 mm may occur. Adenomatoid tumours are always solitary and unilateral. When present in the tunica, they are plaque-like and appear infiltrative into the testicular parenchyma.

344

Tumours of the testicular adnexa

Histopathology Adenomatoid tumours appear as rounded nodules and typically show slowly proliferating gland-like or vascular-like spaces lined by an attenuated to columnar layer of neoplastic cells. Thin, thread-like, bridging strands spanning the lumen are identified in most tumours {1349,2811,3354). The tubules vary in size and may be rounded, oval to elliptical, or slit-like. The dilated tubules may produce a microcystic pattern. Prominent epithelioid neo­ plastic cells are occasionally seen in chains or solid clusters and may contain abundant pale to dense granular eosinophilic cyto­ plasm. Intracytoplasmic vacuolization may be seen. Mitotic fig­ ures are rare. The background stroma is fibrous, fibromuscular, or collagenous. Scattered lymphoid aggregates are commonly present. Infarcted adenomatoid tumours may show worrisome regenerative features, with mitotic figures, and may be at risk of misdiagnosis as malignant neoplasms (2963|. Immunohisto­ chemistry is helpful for the differential diagnosis of adenomatoid tumour with respect to other entities such as lymphangioma, the adenomatoid-like pattern of mesothelioma, and metastatic signet-ring cell carcinoma (956,2201,1299,3528,1704,3635).

Immunohistochemistry The cells express pancytokeratin, CAM5.2, CK7, calretinin, WT1, HBME1, BAP1, L1CAM, and podoplanin (1164,956}; immunoreactivity for CK5/6 and h-caldesmon is variable (820, 2811}. CD15, p53, inhibin, BerEP4, CEA, B72.3, and endothelial markers (factor VIII, CD31, CD34, and ERG) stains are negative {820,2811,3354(.

Cytology The neoplastic cells are bland and uniform; they are present in cords, tubules, loose clusters, and in monolayered sheets {2635,1572,2201,2003}. The nuclei are rounded to oval, with slightly eccentric placement in pale eosinophilic cytoplasm. The nuclear chromatin is finely granular, and nuclei may show small nucleoli, The background shows pink amorphous material, bare nuclei, and few lymphocytes (2003}. Diagnostic molecular pathology TRAF7 mutation is highlighted by L1 CAM-positive immunohis­ tochemical expression {1164}. There is no homozygous deletion of CDKN2A(P16).

Essential and desirable diagnostic criteria Essential: paratesticular location, most often in the epididymis; bland cytomorphological features, with gland-like or vascularlike spaces; immunoprofile consistent with a mesothelial phe­ notype; BAP1 always retained. Desirable: L1CAM positivity; absence of homozygous deletion of CDKN2A (P16). Staging Not applicable Prognosis and prediction Adenomatoid tumours are benign, and surgical resection is curative {1349,105,2811}.

、ick

Tumours of the testicular adnexa

345

Idrees MT Compdrat EM Galateau-Salle F

Well-differentiated papillary mesothelial tumour

Definition Well-differentiated papillary mesothelial tumour (WDPMT) is a neoplasm arising from the tunica vaginalis, exhibiting a papillary architecture in which the papillae are lined by a single layer of bland cuboidal cells without invasion.

Epidemiology WDPMT of the testicular adnexa is a very rare tumour, less fre­ quent than its counterpart in the pleura and in the peritoneum. The patient age range is 18-70 years. Some cases have been related to asbestos exposure (481,3110).

ICD-0 coding 9052/0 Well-differentiated papillary mesothelial tumour

Etiology Unknown

\CD-11 coding 2E8Y & XH67N8 Benign neoplasm of mesothelial tissue, other specified organs & Well-differentiated papillary mesothelioma

Pathogenesis Because of its rarity, the pathogenesis of WDPMT has not yet been established.

Related terminology Not recommended: well-differentiated papillary mesothelioma; benign papillary mesothelioma.

Macroscopic appearance Most tumours arise within the hydrocoele sac as solitary papil­ lary nodular lesions with a bulging cut surface. Multifocality is rarely reported. They range from 3 to 30 mm in size (431,1083}.

Subtype(s) None Localization WDPMT arises from the tunica vaginalis, which is the double layer of mesothelium that lines the testis (the outer surface of the tunica albuginea or epiorchium, and the inner layer of the scrotum or periorchium). Clinical features Most cases are associated with a hydrocoele; tumours rarely occur as a scrotal mass (1083).

Histopathology WDPMTs display papillary structures with a stromal formation, lined by a single row of cuboidal cells that have bland nuclear features and exceptional to absent mitosis {431). Nuclear pseudoinclusions are usually present. Absent or minimal stro­ mal invasion is the key to diagnosis {658). Other, more com­ plex, patterns have been described, but whether they can be characterized as WDPMT is debatable {431,3203}. There is a consensus that WDPMT is a benign lesion and should be exclusively composed of papillary structures lined by bland mesothelial cells {3203,1083). Tumours with a complex archi­ tecture and increased mitotic activity would be better catego­ rized as mesothelioma of uncertain malignant potential (431}.

Fig. 7.21 Well-differentiated p叩illary mesothelial tumour. A Papillary structures with stromal formation, lined by a single row of cuboidal cells with bland nuclear features and exceptional to absent mitosis. B Higher-power view.

346

Tumours of the testicular adnexa

WDPMT is positive for mesothelial markers including calretinin, WT1, HBME1, and D2-40. Pancytokeratin, AE1/AE3, CK7, and CAM5.2 are uniformly positive. BerEP4 shows focal (< 20%) expression and MOC31 shows variable expression. B72.3, CEA, and CD15 are negative {1083,3203,484(. Unlike mesothelioma, WDPMT retains BAP1 expression, and there is no homozygous deletion of CDKN2A {3033,1823}. Differential diagnoses include all mesothelial proliferations mimicking WDPMT (reactive meso­ thelial hyperplasia, epithelioid mesothelioma) and ovarian-type serous tumours of the testis. Cytology The diagnosis cannot be established from cytology samples. Diagnostic molecular pathology Molecular alterations that are observed in mesothelioma are not observed in WDPMT: the tumour is characterized by an absence of homozygous deletion of CDKN2A (P16)t and BAP1

is retained. There is also an absence of BRAF p.V600E muta­ tions {1823(.

Essential and desirable diagnostic criteria Essential: solitary papillary neoplasms with bland cytomorphological features; positive mesothelial markers; retained BAP1 expression; absence of homozygous deletion of CDKN2A (P16), Staging Not applicable

Prognosis and prediction Because of the limited numbers of cases and the lack of long-term follow-up in many cases, there is a hesitancy to categorize these tumours as benign despite them all showing indolent behaviour to date. Local excision is curative. Orchiectomy is required for larger tumours. Close follow-up is recommended (3110(.

Tumours of the testicular adnexa

347

Mesothelioma

Definition Mesothelioma is a malignant tumour arising from the mesothe­ lium lining the outer surface of the tunica albuginea and the inner layer of the scrotum. ICD-0 coding 9050/3 Mesothelioma 9052/3 Epithelioid mesothelioma 9051/3 Sarcomatoid mesothelioma 9053/3 Biphasic mesothelioma ICD-11 coding 2C51.2 & XHOXVO Mesotheliomas of peritoneum & Mesotheli­ oma, malignant Related terminology Acceptable: epithelioid mesothelioma; sarcomatoid mesotheli­ oma; biphasic mesothelioma. Not recommended: mixed mesothelioma; mixed epithelioid and sarcomatoid mesothelioma; mixed epithelial and sarcomatoid mesothelioma; sarcomatous mesothelioma.

Subtype(s) Epithelioid mesothelioma; sarcomatoid mesothelioma; biphasic mesothelioma Localization Mesothelioma arises from the tunica vaginalis; it can infiltrate the testis and the paratesticular soft tissue.

Idrees MT Compdrat EM Galateau-Salle F

Clinical features Many patients present with a hydrocoele; the diagnosis is possi­ ble only after surgical resection {480,1207,1607}. Some patients have a palpable mass, whereas in others the tumour is discov­ ered incidentally during hernia repair {480}. Epidemiology Mesothelioma of the tunica vaginalis is rare and represents < 1% of pleural and peritoneal mesotheliomas {223,480,362}. It occurs in patients in their sixth to seventh decade of life {2495); occasional cases have also been reported in children (2518, 1638). Etiology Mesotheliomas are associated with asbestos exposure; how­ ever, this association is not well documented with mesothelioma of the tunica vaginalis (480,1024,1501). A history of asbestos exposure is found in only 30-40% of reported cases {362}, although in the few case series where detailed histories were available, 67-80% of the patients had asbestos exposure {480, 2131). Asbestos is the only known likely risk factor for meso­ thelioma of the tunica vaginalis, but because of the rarity of the tumour the etiological role of environmental risk factors remains elusive {2028,2147}. Other (non-asbestos) causes, such as recurrent epididymitis and trauma, have been described {265, 222}.

Pathogenesis The pathogenesis of mesothelioma is complex and follows the mechanisms described in other locations, such as the pleura, pericardium, and peritoneum (3448A}. The mechanisms

Fig. 7.22 Mesothelioma. A Low-magnification photomicrograph showing a nodular invasive tumour with tubulopapillary and solid architecture and a surrounding desmoplastic reaction. Prominent necrosis is present in high-grade mesothelioma. B Invasive tubular and tubulopapillary mesothelioma with a prominent desmoplastic reaction. The cells are moderately pleomorphic.

348

Tumours of the testicular adnexa

Fig. 7.23 Mesothelioma. A Invasive mesothelioma in continuity with the normal mesothelium lining of the tunica vaginalis. B High magnification of a solid epithelioid mesotheli­ oma with variably pleomorphic tumour cells that have prominent nucleoli, prominent mitoses, single-cell apoptosis, and multinucleation, in a collagenous background.

cribriform foci invaginating into the underlying stroma. Stro­ mal desmoplasia is apparent. Slit-like glandular structures or rounded tubules may show papillary projections. Tumour cells show moderate to marked pleomorphism and mitoses. Necrosis is common in high-grade mesothelioma. Mesothelioma in situ areas may coexist and line the tunica vaginalis. Psammoma bodies are rare. About 35% of tumours show a mixed epithe­ lioid and sarcomatoid pattern, but predominant or exclusive sarcomatoid morphology is rarely seen {598,1544,2131,2916}. Rarely, squamous differentiation {2215} and heterologous dif­ ferentiation of the spindled component to bone and cartilage {2827} have been reported.

Immunohistochemistry

Fig. 7.24 Mesothelioma. There is a mixture of plump epithelioid cells, with some spin­ dle cell components (right), consistent with a biphasic mesothelioma.

include genotoxic and non-genotoxic effects of asbestos, chronic inflammation, and deregulation of cell death, as well as genomic copy-number losses and some gains. BAP1 mutations are the most common germline mutations in mesothelioma of the tunica vaginalis (2445,1142).

Mesothelioma cells are positive for calretinin, podoplanin, HBME1, WT1, thrombomodulin, pancytokeratin, and CK7. Tumour cells may show a weak focal stain with BerEP4 and a patchy stain with CK5/6 (480,3477}. Immunostains for CK20 and CEA are negative (480,3477,1544,1059,111}. The mesothelioma cell ultrastructure shows elongated microvilli {36,342}.

Differential diagnoses

Macroscopic appearance The gross appearance is unique. Thickening of the tunica vagi­ nalis forms white, tan, or haemorrhagic solid nodules studding the surface and surrounding the testicular parenchyma. The fluid-filled hydrocoele sac may show multiple nodular areas. Mesotheliomas usually display invasion into the testicular paren­ chyma, appendages, and soft tissue. Rarely, the mesothelioma is entirely localized within the testicular parenchyma {2544}.

Differential diagnoses include both of the other mesothelial lesions (benign atypical mesothelial hyperplasia and welldifferentiated papillary mesothelial tumour) and epithelial tumours such as ovarian epitheliaktype tumours, tumours of the collecting duct and rete testis, epithelial tumours of the epididymis, and metastases. Loss of immunohistochemical expression of BAP1 and homozygous deletion of CDKN2A with FISH, and/or loss "of immunohistochemical expression of MTAP to identify CDKN2A deletion, is helpful in distinguish­ ing mesothelioma from benign/borderline proliferations. Posi­ tive staining for mesothelial markers is useful in the differential diagnosis with testicular adnexa epithelial tumours and metas­ tases.

Histopathology Tumours are predominantly epithelioid, with papillary, tubular, and/or tubulopapillary architecture in various combinations. A solid component may also be present. Some areas may show

Cytology Cytology specimens show small papillary clusters, cell groups, and single cells. The cells are polygonal with moderately pleo­ morphic nuclei, prominent nucleoli, and abundant cytoplasm Tumours of the testicular adnexa

349

Fig. 7.25 Mesothelioma. A Testicular parenchyma and mesothelioma of the tunica vaginalis. B Infiltration of the epididymis.

with vacuoles. Multinucleated cells with elongated cytoplasmic processes are present. Occasional mitotic figures are seen. The cell clusters show intercellular windows {256}.

Diagnostic molecular pathology Mesothelioma is characterized by the presence of CDKN2A homozygous deletion (evaluable with MTAP immunohistochem­ istry and with FISH) and BAP1 loss {2445,1142}. Essential and desirable diagnostic criteria Essential: tunica vaginalis localization with extension into the testis and appendages; predominant papillary and tubular architecture or (less commonly) a biphasic pattern with stro­ mal invasion; positive staining for mesothelial markers includ­ ing calretinin, podoplanin, and WT1. Desirable: BAP1 loss and CDKN2A homozygous deletion.

350

Tumours of the testicular adnexa

Staging There is no American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) staging system for mesothelioma of the tunica vaginalis. Prognosis and prediction Recurrences typically occur within the first 2 years of follow­ up. Recurrence is local or in the surgical scar. Aggressive local treatment is suggested (1200}. Metastases may be to the retro­ peritoneal or inguinal nodes, but also to distant sites such as the brain, lung, and bone (2059,2444}. In metastatic disease, sur­ vival and response to any treatment are limited. Retroperitoneal lymph node dissection {2974}, chemotherapy, and radiotherapy are used for treatment, generally with disappointing results {1257,2544). The prognosis is better in patients aged < 60 years and with tumours showing epithelioid morphology (2631,2544}.

Cystadenoma of the epididymis

Bharti JN Idrees MT Mondal K

Definition Cystadenoma of the epididymis is a benign epithelial tumour that arises from epididymal ducts. ICD-0 coding 8440/0 Cystadenoma of the epididymis

ICD-11 coding 2F34 & XH5RJ2 Benign neoplasm of male genital organs & Cystadenoma, NOS Related terminology None

Subtype(s) None

Localization Epididymal cystadenoma is usually located in the caput epididymis (1140(. Clinical features The symptoms include scrotal mass and infertility, and 10% of patients present with pain. Bilaterality has been reported {733}. Epidemiology Insufficient data

Etiology Unknown Pathogenesis Epididymal cystadenoma is derived from a proliferation of the epithelium of the efferent ductular system located in the caput epididymis (1140(. Epididymal cystadenoma may also represent a hamartomatous lesion of ectatic efferent ducts {2677}.

these may also be papillary, they lack the cuboidal, clear cell morphology of the papillary cystadenoma. No mitosis, necrosis, or pleomorphism is observed (1140}. The differential diagnosis includes metastases from prostatic carcinoma in the paratesticular region. The cystadenoma may show microcystic, cribriform, and microglandular areas; how­ ever, the cells lack nuclear atypia and prominent nucleoli. The cells are negative for PSA and PAP (2326,1534}. Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: presence of tubules, papillae, and a cyst arising from the epididymis, lined by bland tall columnar epithelium; eosin­ ophilic cytoplasm; absence of mitotic figures and features of malignancy. Desirable: absence of cuboidal, clear cell morphology.

Macroscopic appearance The cyst surface is smooth. On the cut section, the cyst may be unilocular or multilocular and is often filled with clear fluid (2326(.

Staging Not relevant

Histopathology The tubular and cystic structures are lined by a single row of bland tall columnar cells with eosinophilic cytoplasm. Although

Prognosis and prediction Cystadenoma is a benign tumour, and surgical excision is cura­ tive {733}.

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351

Papillary cystadenoma of the epididymis

Definition Papillary cystadenoma of the epididymis is a benign epithelial tumour with a papillary configuration and bland clear cells aris­ ing from the efferent epididymal ductules. ICD-0 coding 8450/0 Papillary cystadenoma ICD-11 coding 2F34 & XH0FM6 Benign neoplasm of male genital organs & Papillary cystadenoma, NOS Related terminology None

Subtype⑥ None Localization Head of the epididymis (3527)

Bharti JN Idrees MT Mondal K

Clinical features Most patients present in their third decade of life (age range: 12-81 years) {2351,3002,441} with a painless, slowly grow­ ing scrotal swelling. Few cases cause pain. Uncommonly, the tumour is found during the workup of von Hippel-Lindau syn­ drome (VHL) or infertility (2351}.

Epidemiology Papillary cystadenoma can occur sporadically or as a manifes­ tation of VHL Papillary cystadenomas are unilateral in 60% of cases and bilateral in 40% of cases. Of the unilateral cases, 20.3% are associated with VHL. Of the bilateral cases, one third are associated with VHL {2351,3183}. Only 1 unilateral papillary cystadenoma was reported as an initial manifestation of VHL {2176). See also Von Hippel-Lindau syndrome (p. 464). Etiology The etiology of sporadic cases is unknown. Familial cases are often a manifestation of VHL.

Fig.7.27 Papillary cystadenoma. A Tubules and papillae projecting into the lumen. B The cyst contains an eosinophilic, colloid-like secretion. C Tubules and papillae with slender fibrovascular cores. The cells have bland apical nuclei and clear basal cytoplasm. D Tumour cells with bland nuclei and clear cytoplasm.

352

Tumours of the testicular adnexa

Pathogenesis Papillary cystadenoma arises from VHLassociated maldeveloped mesonephric ductules (precursor lesions) coupled with a loss of the VHL allele (2117(. Overexpression of angiogenic proteins like VEGF and HIF1 in the epithelial cells promotes vascular permeability, fluid accumulation, and cyst formation (1854,2351). Macroscopic appearance The tumours are circumscribed, firm, and tan or grey-white, with glistening cut surfaces. The size ranges from 5 to 80 mm.

Histopathology Papillary processes and cysts are lined by cuboidal to colum­ nar epithelial cells with small round nuclei and clear or vacu­ olated cytoplasm. Prominent cell borders and occasional cilia may be seen. Spaces between papillae and cysts contain deeply eosinophilic, homogeneous, colloid-like material. Cel­ lular atypia, mitosis, and necrosis are absent, and the stroma is often fibrous with focal hyalinization (23511. Rare features include psammoma bodies, solid/nested growth, and focal reverse nuclear polarity with subnuclear vacuoles {1743, 3527). The cells are immunoreactive for cytokeratin, AE1/AE3, CK7, PAX8, and CAIX with cup-like basolateral positivity; they are negative for CD10, calretinin, and WT1. Papillary cystade­ noma has an immunoprofile similar to that of clear cell papil­ lary renal cell tumour; positive CK7 and lectin histochemistry with negative CD10, AMACR, and RCCm argue against the

latter (727,2118,1724,3183). PAS stain may highlight cytoplas­ mic glycogen. Cytology A monotonous population of polygonal epithelial cells in sheets and multilayered groups is seen in papillary cystadenoma. Tumour cells contain eccentrically placed round or ovoid bland nuclei with ample pale or clear cytoplasm and without nucleoli or mitoses {2203,2305}. Diagnostic molecular pathology In patients with VHL, loss of heterozygosity at 3p25-26 and VHL gene mutations at nucleotides 712, 713, and 694 have been demonstrated (1123}.

Essential and desirable diagnostic criteria Essential: epididymal location; papillary fronds with a fibrovascular core; bland morphology with clear cytoplasm; absence of features of malignancy. Desirable: VHL association in bilateral cases. Staging Not relevant

Prognosis and prediction Papillary cystadenoma is a benign tumour, and surgical exci­ sion is curative. One recurrence and two malignant transforma­ tions to cystadenocarcinoma have been reported {2351,3527(.

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353

Adenocarcinoma of the epididymis

Bharti JN Harik L Idrees MT Mondal K

Definition Adenocarcinoma of the epididymis is a primary malignant epi­ thelial neoplasm with glandular differentiation. ICD-0 coding 8140/3 Adenocarcinoma of the epididymis

ICD-11 coding 2C84 & XH74S1 Malignant neoplasms of other specified male genital organs & Adenocarcinoma, NOS Related terminology None

Subtype(s) None Localization The tumours arise within the epididymis and may involve the paratesticular tissues.

Clinical features The symptoms include a scrotal mass, hydrocoele, and pain {635,1756,105}. The duration of reported symptoms ranged from 1 month to 5 years (2780,1086}. No bilaterality or side pre­ dilection has been reported.

Epidemiology Epididymal adenocarcinoma represents only 2% of all testicular appendage tumours (105(. The patient age range is 24-82 years (mean: 55 years).

Etiology Unknown

Pathogenesis Unknown Macroscopic appearance The tumours are grey-white and firm with necrosis and haemor­ rhage. Cystic areas may be present. The size ranges from 20 to 140 mm (1543,3565}. Large tumours can involve the surround­ ing structures. Histopathology The morphological patterns are tubular, papillary, tubulopapillary, papillary cystic, and undifferentiated sheet-like growth. The tubules and papillae are lined by cuboidal to columnar cells with clear to amphophilic cytoplasm (1543). A single case of mucinous differentiation has been reported (1244}. A clear cell pattern may be present {2339}. Stromal invasion, necrosis, and psammoma bodies have been observed (1543}.

354

Tumours of the testicular adnexa

Fig. 7.28 Adenocarcinoma of the epididymis. A Malignant glands and tu­ bules. B Area of necrosis along with malignant glands and tubules. C Tubules are lined by tall cuboidal to columnar cells with hyperchromatic nuclei and clear to eosino­ philic cytoplasm.

Immunohistochemistry is positive for EMA, CEA, PAX8, PAX2, and villin. Tumours with mucinous and clear cell differentiation express CK20 and CK7 {1244,2339). Immunohistochemistry is negative for WT1, CDX2, AMACR, PSA, and RCCm. The dif­ ferential diagnosis includes mesothelioma, ovarian-type serous or mucinous cystadenocarcinoma, adenocarcinoma of the rete testis, and metastatic adenocarcinomas.

Cytology Not relevant Diagnostic molecular pathology Not relevant Essential and desirable diagnostic criteria Essential: epididymal location; malignant cytomorphological features; glandular differentiation; infiltrative growth; exclusion of rete testis carcinoma, ovarian-type tumours, mesothelioma, and metastatic adenocarcinomas.

Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for this tumour.

Prognosis and prediction Due to the scarcity of reported cases, the prognostic factors remain uncertain. Radical orchiectomy with retroperitoneal lymphadenectomy, irrespective of lymph node status, is suggested to achieve relapse-free survival {3023}. Cases in which retroper­ itoneal lymph node metastasis is found at the time of diagnosis

Fig. 7.29 Adenocarcinoma of the epididymis. Tumour cells are immunoreactive for EMA.

may have a better prognosis than those in which metastasis develops after retroperitoneal lymph node dissection (3646). Distant metastases (paraurethral tissue {3565}, acetabulum, spleen, and liver (192() are associated with a poor prognosis.

Tumours of the testicular adnexa

355

Squamous cell carcinoma of the epididymis

Bharti JN Idrees MT Mondal K

Definition Squamous cell carcinoma (SCC) of the epididymis is a primary malignant epithelial neoplasm exhibiting squamous differentia­ tion.

Localization Paratesticular SCC has been reported to arise from the epididymis and the tunica vaginalis lining chronic hydrocoele (456,2697}.

ICD-0 coding 8070/3 Squamous cell carcinoma

Clinical features Patients present with a hard scrotal mass with or without hydro­ coele {2739,208}.

ICD-11 coding 2C84 & XH0945 Malignant neoplasms of other specified male genital organs & Squamous cell carcinoma, NOS

Related terminology None

Subtype(s) None

Epidemiology To date, 4 cases have been reported: 2 in the epididymis and 2 in the tunica vaginalis. The patient age range is 27-85 years. Etiology SCC is related to chronic inflammatory processes and subse­ quent squamous metaplasia. However, this relationship has not been evaluated because of the extremely low incidence of SCC {1606,1660}.

Fig-7.30 Squamous cell carcinoma arising from the tunica vaginalis. A Low-power view showing cords and nests of cells with eosinophilic to clear cytoplasm and necro­ sis. B Low-power view of the carcinoma and benign testis. C,D Foci of nests of cells with eosinophilic cytoplasm.

356

Tumours of the testicular adnexa

Pathogenesis Unknown

Diagnostic molecular pathology Not relevant

Macroscopic appearance Tumour size ranges from 45 to 110 mm {2739,208,456,2697}. In 2 cases, the tumours were centred at the epididymis (1 of these involved the tunica vaginalis and testis). The remaining 2 cases originated from the tunica vaginalis lining the hydro­ coele wall. The tumour appears grey-white and infiltrative, with areas of necrosis and haemorrhage {2739,208}.

Essential and desirable diagnostic criteria Essential: malignant cytological features (nuclear atypia, enlargement, pleomorphism, hyperchromasia, loss of polar­ ity, and overlapping) and architectural features (abnormal epithelial maturation) with squamous differentiation; exclusion of metastases and direct involvement from other sites.

Histopathology The tumours display variably pleomorphic squamous cells, indi­ vidual cells, keratinization, nuclear hyperchromasia, eosinophilic to amphophilic to clear cytoplasm, well-demarcated cell borders, and an absence of intercellular bridges. Mitotic figures, necrosis, and lymphovascular invasion may be identified (456,2697). The differential diagnosis includes a direct extension of a scrotal or skin adnexal primary SCO, teratoma with somatictype malignancy, and SCC metastasis from extratesticular sites {2697}.

Cytology Not relevant

Staging There is no American Joint Committee on Cancer (AJCC) stag­ ing system for this tumour.

Prognosis and prediction In a well-documented case, a 46-year-old man with SCC of the epididymis developed ascites and died after 7 weeks (2739). The patient with epididymal squamous carcinoma with tunica vaginalis and testicular involvement developed lymph node and lung metastases and was treated with chemotherapy (2739, 208). One of the two patients with SCC arising in the tunica vaginalis received adjuvant radiation and chemotherapy but developed inguinal lymph node metastasis 2 months after the initial diagnosis {2697}.

Tumours of the testicular adnexa

357

Melanotic neuroectodermal tumour of the epididymis

Definition Melanotic neuroectodermal tumour (MNT) is a neoplasm char­ acterized by variable proportions of melanin-containing epithe­ lioid cells and neuroblast-like cells in a cellular fibrous stroma.

ICD-0 coding 9363/0 Melanotic neuroectodermal tumour

ICD-11 coding 2C84 & XH6C72 Malignant neoplasms of other specified male genital organs & Melanotic neuroectodermal tumour Related terminology Not recommended: congenital melanocarcinoma; melanotic hamartoma; melanotic progonoma. Subtype(s) None

Bharti JN Compdrat EM Idrees MT Mondal K

Localization Epididymis and paratesticular tissues

Clinical features Patients present with a firm, painless, rapidly growing, wellcircumscribed scrotal mass, often accompanied by hydrocoele {2256,859,2446}. Testicular involvement has been reported in 3 cases {2669,839,969} and rete testis and spermatic cord involvement in 1 case (795,1116). Patients may show high levels of serum catecholamine metabolites and high levels of urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA); these markers are helpful in monitoring the disease (394|. Epidemiology MNT is an uncommon tumour of childhood, and only occasional cases occur in the genitourinary tract. The tumour mainly arises in the first few months of life, but it may occur up to the age of 8 years {2515).

Fig-7.31 Melanotic neuroectodermal tumour of the epididymis. A Epididymis involved by melanotic neuroectodermal tumour. B Biphasic tumour cells are interspersed among epididymal tubules. C Biphasic tumour cells are present between the muscle layers. D Dual populations of tumour cells comprising small neuroblast-like cells and large pigment­ laden cells arranged in a tubular pattern.

358

Tumours of the testicular adnexa

mitochondria, and other organelles. Elliptical membrane-bound bodies containing dense fibrillar material in the cytoplasm of large cells correspond to stage III melanosomes. The small tumour cells are deficient in cytoplasmic organelles and show microfilaments, microtubules, cytoplasmic processes, and desmosomes {3169). The differential diagnosis needs to exclude small round cell tumours including melanoma, neuroblastoma, alveolar rhab­ domyosarcoma, lymphoma, desmoplastic small round cell tumour, and Ewing sarcoma / primitive neuroectodermal tumour (1596,2947}.

Fig. 7.32 Melanotic neuroectodermal tumour of the epididymis. Small tumour cells immunoreactive for synaptophysin.

Etiology MNT is a tumour of neural crest origin with retinal-like epithe­ lial and neuroblastic differentiation. It probably represents a dysembryogenetic neoplasm that recapitulates the retina at 5 weeks of gestation {2515} and it may originate from primitive neuroectodermal rests {100}. Pathogenesis Evidence from tissue culture, immunohistochemical, and ultrastructural studies indicates that the tumour originates from primitive neuroectodermal rests {100}. A recent study revealed the role of M2 macrophages in its pathogenesis and modelling (3047|.

Macroscopic appearance MNTs are well-circumscribed, grey-white, firm tumours measur­ ing 10-50 mm {2515|. The cross-section typically displays dark­ brown to black pigmentation or may appear cream coloured or greyish tan (3260}.

Histopathology MNT is a biphasic tumour characterized by nests, cords, gland­ like structures, or pseudo-alveolar spaces in a fibrocollagenous stroma. Large epithelioid cells and small neuroblast-like cells distinguish the tumour. The epithelioid cells, which are characterized by abundant eosinophilic cytoplasm, vesicular nuclei, prominent nucleoli, and variable melanin pigment, are at the periphery of the nests/cords. The primitive neurogenic cells, which have scant cytoplasm (without pigment) and round hyperchromatic nuclei, are located in the centre {100}. Small cells may show an alveolar arrangement with silver impregna­ tion stain {3169}. The smaller cells are immunoreactive for CD57, NSE, NB84, and synaptophysin; in addition, they show weak expression of PAX5, S100, CD99, and calretinin. The epithelioid cells are posi­ tive for pancytokeratins, vimentin, NSE, HMB45, DBH, and EMA {478,100]. On electron microscopy, the large polygonal cells show poorly developed desmosomes. The abundant cytoplasm of these cells is rich in endoplasmic reticulum, ribosomes,

Cytology Smears are dominated by loose aggregates and occasional rosettes formed by neuroblast-like, small, monotonous cells that have hyperchromatic nuclei, mild pleomorphism, occasional nucleoli, and scant cytoplasm (2947}. Also, there are a few acini from groups of larger cells with regular round nuclei, conspicu­ ous nucleoli, a moderate amount of eosinophilic cytoplasm, and a focal presence of coarse brown to black cytoplasmic pigment granules (2948,2446). The fibrillary background shows nuclear crush artefacts, stripped nuclei, and extracellular pigment gran­ ules {2446}. Atypical mitoses and necrosis are absent. In cases where the melanin-containing cells are sparse, the cytologi­ cal features seen in aspirates may mimic those of a malignant tumour. The cytospin of hydrocoele fluid may show tight clusters of large cells with smooth borders, along with smaller dyscohesive cells. Identification of a large cell population can avoid misdi­ agnosis as a small malignant round cell tumour, which needs aggressive management {2446}. The preoperative diagnosis can be made on scrotal fluid aspiration cytology (3169}. Diagnostic molecular pathology There are no molecular pathology data in the literature on MNTs of the genitourinary organs.

Essential and desirable diagnostic criteria Essential: a tumour in a paediatric patient, characterized by two cell types (large melanin-containing cells and small hyper­ chromatic cells) within a fibrous stroma; absence of atypical mitoses and necrosis. Desirable: high serum levels of catecholamine metabolites; increased urinary levels of VMA/HVA. Staging Not relevant

Prognosis and prediction The tumour is considered borderline, because it shows a low percentage of malignant behaviour (14%) with metastasis to adjacent lymph nodes. To date, 3 patients have been described with lymph node metastasis; these patients were alive after 28-48 months of follow-up {105}. Malignant behaviour can be related to the predominance of neuroblast-like components, a high mitotic count and a high Ki-67 index, CD99 positivity, and onset before the first month of life {2554,283}. MNT recurrence has been reported in an infant after an epididymectomy and the subsequent treatment was simple orchiectomy {845}.

Tumours of the testicular adnexa

359

Tumours of the penis and scrotum Edited by: Amin MB, Menon S, Moch H

Benign and precursor squamous lesions Condyloma acuminatum Squamous cell carcinoma precursors, HPV-associated Penile intraepithelial neoplasia, HPV-associated Squamous cell carcinoma precursors, HPV-independent Differentiated penile intraepithelial neoplasia, HPV-independent Invasive epithelial tumours of the penis and scrotum Invasive squamous epithelial tumours HPV-associated squamous cell carcinoma HPV-independent squamous cell carcinoma Squamous cell carcinoma NOS Other epithelial tumours Penile adenosquamous and mucoepidermoid carcinomas Extramammary Paget disease Other scrotal tumours Basal cell carcinoma of the scrotum

Tumours of the penis and scrotum: Introduction

Squamous cell carcinoma (SCC) is by far the most common malignant tumour of the penis. In this edition of the WHO classi­ fication of urinary and male genital tumours, the system for clas­ sifying tumours of the penis fundamentally follows the paradigm adopted in the previous edition, in which tumours are broadly classified into those that are associated with HPV and those that are HPV-independent. This is consistent with the approach used for tumours of the female genital system, such as those of the cervix and vulva (3447}. Currently there are no established prognostic or treatment differences between HPV-associated and HPV-independent penile tumours. Although penile tumours are relatively rare, particularly in high-income countries, experience with the range of morphology of the tumours within the two categories has increased, and the histological features are fairly reproducible as surrogate markers for the infection in more than two thirds of the tumours, although the reproducibility depends on the expe­ rience of the pathologist {513). A gamut of immunohistochemi­ cal and molecular markers are available and may be deployed according to the clinical and histological presentation, although we recommend block-type p16 immunohistochemistry as the most practical and reliable method where morphological asso­ ciation is not straightforward and/or molecular methods are una­ vailable. We also recommend reporting tumours as HPV-associated or HPV-independent in pathology reports, in addition to reporting the histological subtype. It is perfectly acceptable for a morphological diagnosis of SCC to be made without differ­ entiating between the two categories where facilities to make the distinction are not available, with the designation SCC-NOS. Consistent with the approach used throughout the fifth edi­ tion, we advocate the use of the term "subtype" instead of "variantM in this chapter. In contrast to the approach taken in the pre­ vious edition and in the literature, we have outlined a simplified histological classification of the subtypes of HPV-associated and HPV-independent penile SCCs (see Box 8.01). Previously reported subtypes are grouped, and coalesced as largely descriptive patterns, into an overarching SCC histology (e.g. usual-type SCC includes pseudohyperplastic and acantholytic/ pseudoglandular carcinoma, and carcinoma cuniculatum is included as a pattern of verrucous carcinoma) or mixed histo­ logical patterns. If there is an additional component of the usual type of invasive SCC (formerly hybrid histology), the tumour would be a mixed carcinoma (e.g. carcinoma cuniculatum or verrucous carcinoma with usual invasive SCC); in such cases, we advocate the specification of subtypes and the provision of percentages. Although we encourage reporting of the relative percentages in mixed tumours, we concede that the prognostic significance of (and justification for) this recommendation is not established. We believe that the consistent use of nomenclature and reporting of percentages will inform the refinement of future reporting classification schemes and guidelines/recommendations by the appropriate national and international committees. 362

Tumours of the penis and scrotum

Amin MB Moch H

Box 8.01 Classification of carcinoma of the penis and precursor lesions

Precursor lesions (lesions are not graded; all are considered high-grade) Penile intraepithelial neoplasia, HPV-associated Common patterns: basaloid (undifferentiated) and warty (condylomatous, bowenoid) Other (less frequent) patterns: pagetoid and clear cell

Diffe陷ntiated penile intraepithelial neoplasia, HPV-independent Invasive carcinoma HPV-associated squamous cell carcinoma Subtypes: Basaloid Warty

Clear cell Lymphoepithelioma-like

Mixed

HPV-independent squamous cell carcinoma

Subtypes: Squamous cell carcinoma, usual type (includes pseudohyperplastic and pseudoglandular) Verrucous carcinoma (includes carcinoma cuniculatum)

Papillary Sarcomatoid Mixed

Squamous cell carcinoma NOS (invasive keratinizing carcinoma without special features, for which evaluation ofp16 is not available) Adenosquamous carcinoma

Mucoepidermoid carcinoma

We have used a similar approach for precursor lesions, wherein entities described as "variants" in the fourth edition are referred to as "patterns" in this edition. Therefore, pathological prognostic factors of penile SCC, irre­ spective of their HPV association, include histological subtypes (discussed above), histological grade, depth of invasion / tumour thickness, perineural invasion, lymphovascular invasion, resec­ tion margin status, and pathological stage - this last factor being of paramount importance. The WHO Classification of Tumours / International Society of Urological Pathology (WHO/ISUP) three­ tiered grading scheme (grades 1, 2, and 3) may be used based on the degree of differentiation, pleomorphism, and keratin pro­ duction for reporting histological grade. Tumours of the scrotum Scrotal malignancies have not been the subject of prior WHO classification schemes, nor have they been acknowledged in WHO editions 1 through 4. Scrotal tumours, albeit extraordinarily rare, are historically noteworthy in the field of medicine because

of their association with cancers occurring in chimney sweeps in the eighteenth century (circa 1740-1775). Over the next two and a half centuries, this pioneering observation first made in scrotal cancer has stimulated research linking numerous indus­ trial and occupational carcinogens to different cancers through­ out the human body. In more contemporary large studies (one being a survey of 766 patients with scrotal cancer), SCO was the most frequent type of tumour, followed by extramammary Paget disease, sarcomas, basal cell carcinomas, melanomas, and adnexal skin tumours {1539}. Another large study of pri­ mary scrotal cancers revealed that the most common histologi­ cal types were SCC followed by extramammary Paget disease,

basal cell carcinoma, and sarcomas {3487}. Interestingly, the spectrum of intraepithelial lesions and invasive scrotal cancers follows the same paradigm as that described above for penile cancer, based on their association (or lack thereof) with HPV disease. Therefore, the use of a similar nomenclatural approach is recommended for these rare cancers, using the specific ter­ minology outlined above for penile cancers. As recommended in the other major chapters (anatomical sites) in this volume, the reader is referred to the general chapters on haematolymphoid, mesenchymal, melanocytic, and metastatic tumours, which are presented separately and include tumours occurring in other male genital and urological sites.

Tumours of the penis and scrotum

363

Condyloma acuminatum

Tamboli P Alvarado-Cabrero I Velazquez EF

Definition Condylomata acuminata are non-neoplastic tumour-like lesions caused by HPV. ICD-0 coding None

ICD-11 coding 1A95.1 Genital warts Related terminology Acceptable: condylomata acuminata; genital wart; anogenital wart.

Subtype(s) None Localization Condylomata acuminata occur on the penis, scrotum, peri­ neum, and anus. Lesions involving the penis most often arise on the glans penis, followed by the foreskin and the skin of the penile shaft. Giant condyloma acuminatum (Buschke-Ldwenstein tumour) occurs in the urethra, coronal sulcus, frenulum, or shaft (941,2364).

Clinical features Patients usually present with a nodular wart, which is most often multifocal. Unifocal and flat lesions may also be present. The giant condyloma acuminatum (Buschke-Ldwenstein tumour) appears as an exophytic warty growth that can be as large as 150 mm in diameter (2887). The large confluence of the condy­ loma replaces normal tissue, imparting a cancerous appear­ ance. Malignant transformation can be associated with these condylomas, but such transformation is due to genetic muta­ tions and/or coinfection with high-risk HPV types {2888}.

Epidemiology Condylomata acuminata are most common in young men in their twenties and thirties (1454,665}. Etiology HPV genotypes 6 and 11 are the most common etiological agents (148}.

Pathogenesis Condyloma acuminatum is an HPV-induced proliferation of squamous epithelial cells, whose pathogenesis is similar to that of other HPV-associated lesions. Low-risk HPV genotypes, such as HPV6 and HPV11, are also associated with giant con­ dyloma acuminatum. These genotypes are not thought to be actively involved in carcinogenesis, because it has been shown that their oncoproteins do not cause significant dysregulation of

364

Tumours of the penis and scrotum

Fig. 8.01 Condyloma acuminatum. Prominent koilocytic atypia (viral cytopathic change) in the upper levels of the epithelium close to the surface. The koilocytes have enlarged, wrinkled nuclei surrounded by a perinuclear halo.

the RB1, p53, and p16 (p16INK4a) tumour suppressor pathways {2887,2046}.

Macroscopic appearance Grossly, the lesions appear pink or tan to brown, exophytic, soft, and warty (cauliflower-like). Sometimes they appear as filiform growths or flat patches or plaques. In size, they vary from very small lesions measuring a few millimetres to large lesions meas­ uring several centimetres. They can affect the glans, coronal sulcus, foreskin, and shaft, often affecting multiple locations, and they may extend into the meatus. Penile condylomata acuminata may reach a large size (> 80 mm) and may, after years of neglect, become locally destructive (giant condyloma) (381(.

Histopathology Condylomata acuminata show papillomatosis, acanthosis, and a well-demarcated bulbous base. The papillae frequently show an arborescent pattern with prominent central fibrovascular cores. The surface of the lesion shows hyperkeratosis and parakeratosis. The hallmark of the lesion is the presence of koilocytic atypia (viral cytopathic change). Koilocytes have enlarged, wrinkled nuclei surrounded by a perinuclear halo. Binucleated and multinucleated forms and dyskeratotic cells may be seen. Koilocytic changes tend to be more prominent on the upper levels of the epithelium, in contrast to the atypi­ cal koilocytosis observed in warty carcinoma, which tends to affect deeper portions of the lesion. Although koilocyto­ sis is the most classic and best-recognized feature, it is not always prominent. Occasionally, condylomata acuminata have features similar to those of seborrhoeic keratosis, including horn pseudocysts and minimal to no koilocytosis. Such fea­ tures appear to correspond to older lesions. Some studies

have shown that in genital locations, lesions with features of fibroepithelial polyps and seborrhoeic keratosis without clear­ cut koilocytosis are often associated with HPV {1863}. Ses­ sile (flat) and inverted patterns have been described but are rare. Condyloma acuminatum is a benign lesion, hence true dysplasia is not seen in these lesions. However, condylomata acuminata previously treated with topicals (e.g. podophyllum resin, also known as podophyllin) may show prominent degen­ erative changes such as vacuolization (pallor of the epithe­ lium), nuclear enlargement, numerous necrotic keratinocytes in the lower half of the epidermis, and an increased number of mitotic figures (metaphase arrest) (3355(. It is important to keep this in mind so as not to confuse such reactive changes with true dysplasia (2263). Cytology Not relevant

Diagnostic molecular pathology Condyloma acuminatum is most often associated with the lowrisk HPVs (HPV6 and HPV11). Association with other types of low-risk HPV as well as with high-risk HPVs such as HPV16 and HPV18 has been described in as many as 15% of cases. Patho­ logical methods of virus identification are immunohistochemis­ try, in situ hybridization, and PCR (998,997). Essential and desirable diagnostic criteria Essential: acanthosis and papillomatosis with formation of papil­ lary structures and thickened rete ridges; parakeratosis and hyperkeratosis; variable degrees of koilocytic atypia.

Staging Not applicable

Prognosis and prediction Condyloma acuminatum is a benign lesion. The majority of cases resolve spontaneously or do not recur after removal.

Tumours of the penis and scrotum

365

Penile intraepithelial neoplasia, HPV-associated

Harper DM Alvarado-Cabrero I Tamboli P

Definition HPV-associated penile intraepithelial neoplasia (PelN) is an HPV-driven precursor/premalignant lesion of penile squamous cell carcinoma, which is characterized by dysplastic squamous epithelium with an intact basement membrane.

Subtype(s) None

Clinical features HPV-associated PelN accounts for 80% of all PelN lesions (2364). The signs and symptoms of HPV-associated PelN (pre­ viously known clinically as erythroplasia of Queyrat and Bowen disease) include one or more abnormal growths or sores (ulcers) on the penis. PelN may have sharply defined plaques with a velvety erythematous appearance on the glans; these are often painless, but with erosions, and occur mostly in uncircumcised men with phimotic foreskins. On the shaft of the penis, PelN lesions are usually raised or flat with irregular borders, white or red in colour, and crusty or scaly; they may bleed or itch. Simi­ lar changes have also been found in suprapubic and inguinal regions (1735,2364}. Bowenoid papulosis (HPV16/18-associated) may appear as warty, raised areas that vary in size and are reddish or of regular skin pigmentation. These occur mostly on the shaft of the penis or the nearby perineal skin and mons. They are usually multiple, red, velvety, maculopapular areas, which can coalesce to form larger plaques that may be pigmented. They are often pruritic but very rarely malignant {2364}.

Localization HPV-associated PelN caused by HPV16/18 can occur on the glans or foreskin (previously, such cases were sometimes referred to clinically as erythroplasia of Queyrat) or on the shaft of the penis (where it was called either Bowen disease, which was usually a unifocal and flat white lesion, or bowenoid papu­ losis when multifocal and papillomatous) {562}.

Epidemiology PelN is rarely diagnosed, with an incidence of 0.47 cases per 100 000 person-years in men in Europe; the incidence is slowly increasing {1374,250}, attributed to a high prevalence of HPV and a low rate of circumcision {250). Only 30% of cases of PelN progress to penile cancer {941,1374}, and HPV-associated PelN constitutes only 25% of these cases (941), a similar rate to

ICD-0 coding 8077/2 High-grade squamous intraepithelial lesion

ICD-11 coding 2E67.41 & XN8JY Squamous cell carcinoma in situ of mucocu­ taneous epithelium of penis & Human papillomavirus Related terminology Acceptable: squamous intraepithelial lesions. Not recommended: penile carcinoma in situ; Bowen disease; erythroplasia of Queyrat.

Fig. 8.02 Penile intraepithelial neoplasia, HPV-associated. A Warty (condylomatous) penile intraepithelial neoplasia. B At higher power, there is mixed (warty/basaloid) penile intraepithelial neoplasia showing basaloid features (small immature cells) at the base and more differentiated cells with warty features (koilocytic atypia) towards the surface.

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that reported for cervical intraepithelial neoplasia {2839}. Pat­ tern distributions vary according to geographical areas. The basaloid pattern is more common than the warty pattern. Both patterns are predominantly caused by HPV16/18. The basaloid pattern is significantly more prevalent in Europe than in South America (3003). The other HPV-associated pattern is the clear cell pattern, which is rarer {941}.

Etiology HPV-associated PelN starts with an infection of the squamous cell layer of the epithelium with a high-risk HPV type, which then transforms over time to an invasive cancer. HPV types 16, 18, 31, 33, 45, 51, 52, 53, and 58 are the high-risk types most commonly associated with PelN {455). Oncogenic transforma­ tion occurs in about 25% of cases of HPV-associated PelN {941}. Pathogenesis High-risk HPV transformation occurs through the inactivation of the retinoblastoma protein (RB1) by the E7 protein, which results in uncontrolled cell-cycle progression and leads to the overex­ pression of p16 (p16INK4a). In addition, the E6 protein binds to the p53 tumour suppressor protein, preventing DNA repair and leading to apoptosis and growth arrest. E6 also mediates the activation of telomerase, leading to cellular immortalization. Both p16 (p16INK4a) and TERT (hTERT) have been used as surrogate molecular diagnostic markers for a transformed HPV infection. Although PelN is rare, and the rate of progression to cancer is low, HPV-associated PelN is reported to account for 70-89% of all cases of PelN {2364}. HPV16/18-dominant PelN has a malignant potential of 30% on the glans, whereas on the shaft it has a malignant potential 5% (941}. HPV16/18associated lesions on the mons pubis and shaft (bowenoid papulosis) are highly contagious and eminently treatable using local therapies; female partners must be notified and screened for cervical cancer.

Macroscopic appearance Lesions may be flat to slightly elevated macules, papules, or plaques, which appear velvety, moist, erythematous, and pig­ mented. The surface may be smooth, warty, granular, or vil­ lous. The contours vary from being well delineated to subtle in appearance with irregular outlines. Although solitary lesions are more common, multifocality is not rare. Distinguishing between patterns of PelN is not always straightforward on gross exami­ nation. Histopathology Histologically, HPV-associated PelN shows multiple patterns including basaloid (undifferentiated) and warty (condyloma­ tous, bowenoid). Less frequent patterns include pagetoid and clear cell. Basaloid PelN demonstrates a monotonous replace­ ment of usually the full-thickness epithelium by small immature cells with high N:C ratios, numerous mitoses, and prominent apoptosis. Warty (bowenoid) PelN has a spiky surface in which the epithelium is replaced by pleomorphic cells with koilocytic atypia and numerous mitoses. Mixed PelN (warty/basaloid) shows combined features of PelN with basaloid features (small immature cells) at the base and more differentiated cells with warty features (koilocytic atypia) towards the surface. These HPV-associated patterns of PelN are frequently seen adjacent to HPV-associated invasive carcinomas. Immunohistochemistry shows block p16 positivity, supporting the presence of highrisk HPV. Ki-67 shows suprabasal extension, and p53 is usually negative to variable {1374,2029}.

Cytology Not relevant Diagnostic molecular pathology In situ hybridization is positive for high-risk HPV and negative for low-risk HPV. PCR analyses show HPV16 in most cases, although other subtypes (HPVs 18, 30, 33, 39, 56, 66, 73, 11,

Fig. 8.03 Undifferentiated penile intraepithelial neoplasia. A,B Monotonous replacement of the entire epithelium by small immature cells with a high N:C ratio. Numerous mitoses and prominent apoptosis are also seen (B).

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84, and 87) may be positive. Warty PelN is usually associated with multiple HPV genotypes {513}. Essential and desirable diagnostic criteria Essential: loss of maturation; nuclear hyperchromasia; high N:C ratio; cytological and architectural atypia; increased mitotic activity, with mitoses in the upper layers of the epi­ dermis. Desirable: block-type p16 immunohistochemistry.

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Staging HPV-associated PelN is staged as pTis using the TNM clas­ sification for pure PelN.

Prognosis and prediction The prognosis for precursor lesions is unknown because of a lack of sufficient data. Most studies are retrospective and use differing terminology. Recurrence and association with invasive carcinoma is high {941}.

Differentiated penile intraepithelial neoplasia, HPV-independent

Definition Differentiated penile intraepithelial neoplasia (PelN) is an HPVindependent precursor/premalignant lesion of penile squamous cell carcinoma (SCO) and characterized by dysplastic squa­ mous epithelium primarily of basal and parabasal cells within an otherwise well-differentiated epithelium with an intact basement membrane.

ICD-0 coding 8071/2 Differentiated penile intraepithelial neoplasia ICD-11 coding 2E67.41 & XH6824 Squamous cell carcinoma in situ of mucocu­ taneous epithelium of penis & Differentiated PelN Related terminology Not recommended: squamous intraepithelial lesion; squamous cell carcinoma in situ; low- and high-grade dysplasia; PelN3; simplex type of penile intraepithelial neoplasia.

Menon S Alvarado-Cabrero I Tamboli P

dermatoses such as eczema, psoriasis, lichen planus, and Zoon balanitis may be difficult. In general, these benign conditions respond to treatment with a combination of topical steroids and emollients {211}. A high index of clinical suspicion, close follow­ up, and planned early biopsy of unresponsive lesions is essen­ tial to diagnose premalignant penile disease.

Epidemiology PelN predominates over invasive lesions in countries with a low incidence of penile cancer, whereas in countries with a high incidence of penile cancer, PelN is usually diagnosed in asso­ ciation with invasive cancer {2352,3003}. Differentiated PelN is more common in countries with a high incidence of penile can­ cer. The mean patient age at diagnosis of differentiated PelN is 64 years {589}.

Localization Differentiated PelN preferentially involves the foreskin, in par­ ticular the inner surface.

Etiology Differentiated PelN is commonly associated with lichen sclerosus, which is considered a risk factor for the development of penile cancer (993,514). Recently, a pattern designated as lym­ phocytic depleted lichen sclerosus has been found to be asso­ ciated with penile neoplasia and differentiated PelN {2538,514}. Chronic inflammation and conditions causing chronic irritation/ injury (such as phimosis, balanoposthitis, and lichen sclerosus) are known risk factors for penile SCC and differentiated PelN (1623,941}. Penile trauma and smoking are other risk factors associated with differentiated PelN (652}.

Clinical features Differentiated PelN tends to develop in slightly older men than HPV-associated PelN (589). Patients are usually uncircumcised and have a history of longstanding lichen sclerosus. Differenti­ ated PelN preferentially affects the inner foreskin {993}. Lesions may be solitary or multiple and appear white or pink and plaque­ like. The borders of the lesion may be either well demarcated and smooth, or irregular and poorly defined (582,3319(. Clinically, distinguishing premalignant penile lesions from benign genital

Pathogenesis The pathogenesis of differentiated PelN and associated penile SCC is less well understood than that of HPV-associated precur­ sors and carcinogenesis. COX-2, a prime mediator in chronic inflammatory conditions like lichen sclerosus and balanoposthitis, has been shown to be strongly expressed in early-stage PelN, invasive penile SCC, and lymph node metastasis, but not in nor­ mal tissue (803}. There is a high prevalence of TP53 mutations (including several gain-of-function mutations) in differentiated

Subtype(s) Differentiated PelN is not graded. All differentiated PelNs are considered high-grade.

Fig. 8.04 Differentiated penile intraepithelial neoplasia, HPV-independent. A The hyperplastic squamous epithelium shows the presence of some enlarged keratinocytes with eosinophilic cytoplasm. The basal layer shows nuclear abnormalities. B The basal layers show abnormal nuclear changes that are more pronounced in some of the elongated rete. The eosinophilic cytoplasm of scattered keratinocytes may be a prominent feature.

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PelN and associated penile SCC (1608). Differentiated PelN lacks p16 overexpression but commonly shows nuclear p53 expression in the tumour cells (585(. Macroscopic appearance Macroscopically, differentiated PelN appears as a solitary white plaque in a circumcised specimen, with the atrophic-appearing skin of lichen sclerosus. Rarely it can be seen as multiple slightly raised white or pink lesions. The borders of the lesion may be well defined or irregular {515,993}.

Fig. 8.05 Differentiated penile intraepithelial neoplasia, HPV-independent. A Hyperplastic squamous epithelium of the foreskin showing parakeratosis and hyperkeratosis. B Characteristic 叩ithelial hyperplasia with surface maturation and hypergranulosis with hyperchromatic, atypical cells confined to the basal and parabasal layers.

Fig. 8.06 Differentiated penile intraepithelial neoplasia, HPV-independent. The basal and parabasal nuclei of the squamous epithelium are atypical, with many showing prominent nucleoli. Cells with abundant eosinophilic cytoplasm are seen, along with prominent intercellular bridges.

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Histopathology Differentiated PelN is characterized by epithelial hyperplasia, hyperkeratosis, and parakeratosis. Elongated and intercom­ municating rete ridges may be seen, creating a reticulated epithelial architecture. Dyskeratosis, keratin pearls, and prominent intercellular bridges with spongiosis are commonly seen. At low magnification, there is an impression of surface maturation and hypergranulosis, with hyperchromatic, atypical cells confined to the basal and parabasal layers {3319,589(. However, higher magnification reveals a scattered, full-thickness presence of subtle atypical keratinocytes with abundant eosinophilic cytoplasm, vesicular nuclei, and occasional prominent nucleoli. Frank atypia to pleomorphism may be present in a third to half of cases. The histological spectrum includes patterns such as hyperplasia-like, classic, and pleomorphic differentiated PelN {515). Lichen sclerosus may be present within the background. Koilocytic atypia is absent (514). A subtle but helpful feature is the comparative transition from normal benign squamous epithelium to hyperplastic areas with scattered non-reactive nuclear abnormalities. Differentiated PelN may be difficult to distinguish from reactive conditions such as squamous hyperplasia, pseudoepitheliomatous hyperplasia, lichen simplex chronicus, and lichen sclerosus with hyperplastic epithelium (515). Adjacent invasive carcinoma (HPV-independent type) may be present. Differentiated PelN is not graded; by default, all cases of differentiated PelN are considered high-grade. Most lesions of differentiated PelN can be recognized on morphology, but in some challenging cases a panel comprising p16, p53, and Ki-67 immunohistochemistry appropriately used in strict correlation with morphology may aid the classification of penile intraepithelial lesions {585}. Caution is urged when relying on immunohistochemistry because the data are limited. Squamous hyperplasia is usually negative for p16 and p53 (restricted to basal cells only), with variable and scattered Ki-67 positivity. Differentiated PelN, on the other hand, is negative for p16 (non­ block staining) and positive for Ki-67 iri basal and sometimes suprabasal cells, with variable p53 positivity (negative, basal to suprabasal positivity) (585). In p16-negative cases and minimal atypia, the diagnosis becomes more challenging when separating benign lesions (squamous hyperplasia) from precancerous lesions (differentiated PelN). Some forms of differentiated PelN mimicking squamous hyperplasia can be extremely challenging to diagnose; Ki-67 may aid in this distinction. Positive nuclei above the basal layer favour the diagnosis of differentiated PelN. Differentiated PelN shows at least a basal or parabasal continuous Ki-67 staining pattern, whereas in squamous hyperplasia, only scattered basal cells stain or staining is negative. Differentiated PelN with pleomorphism may morphologically mimic high-grade HPV-associated PelN, but p16 is negative (515}.

Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: hyperplastic squamous epithelium with parakeratosis and hyperkeratosis; atypical squamous cells (enlarged nuclei with hyperchromasia) prominent in the basal layers, with retained squamous maturation in the upper layers; dyskeratotic individual squamous cells with dense eosinophilic cyto­ plasm and prominent intercellular bridges. Desirable: elongated, irregular, and anastomosing rete ridges; acanthosis; hypergranulosis.

Staging Differentiated PelN is staged as pTis using the TNM classifica­ tion for pure PelN. Associated invasive carcinoma is staged in the same way as penile carcinoma. Prognosis and prediction The exact rate of progression of differentiated PelN to invasive cancer is not known {1374}. Differentiated PelN is associated with low-grade keratinizing non-HPV-driven invasive SCC (usual, verrucous, and papillary squamous subtypes). Differen­ tiated PelN associated with lichen sclerosus may progress to invasive penile cancer in 2-8% of cases, with a latency period of 12-17 years (842,211,270,1728(.

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HPV-associated squamous cell carcinoma

Definition HPV-associated squamous cell carcinoma (SCC) is an invasive keratinizing carcinoma arising from penile mucosal or cutaneous compartments that is associated with HPV infection.

ICD-0 coding 8085/3 Squamous cell carcinoma, HPV-associated 8083/3 Basaloid squamous cell carcinoma 8054/3 Warty carcinoma 8084/3 Clear cell squamous cell carcinoma 8082/3 Lymphoepithelial carcinoma ICD-11 coding 2C81.0 & XN8JY Squamous cell carcinoma of penis & Human papillomavirus

Related terminology Acceptable: basaloid squamous cell carcinoma; basaloid carcinoma; warty carcinoma. Not recommended: condylomatous carcinoma. Subtype ⑥ Basaloid squamous cell carcinoma; warty carcinoma; clear cell squamous cell carcinoma; lymphoepithelioma-like carcinoma

Localization Basaloid SCC is typically localized in the glans and foreskin, variably involving the coronal sulcus (it rarely occurs exclusively at this last site) (742,740}. Warty carcinoma may involve single or multiple anatomical sites such as the glans, coronal sulcus, and foreskin {744,588}. Clear cell SCC occurs as a large tumour mass and affects the foreskin, coronal sulcus, or glans (1877|. Lymphoepithelioma-like carcinoma is mainly located in the glans, although all compartments are involved. Clinical features

Basaloid SCC The average patient age at presentation is about 53 years (range: 33-84 years). More than half of the patients show enlarged inguinal nodes as a result of metastasis at the time of diagnosis (743}. Basaloid SCC with papillary features accounts for 1-2% of all SCCs of the penis. Patient age ranges from 35 to 90 years (median: 79 years). Inguinal lymph nodes are clinically palpable in most cases {740}.

Warty carcinoma Warty carcinomas represent 7-10% of penile carcinomas. The median patient age is about 48-55 years (~10 years younger than that for the usual subtype of SCC). HPV DNA has been detected in 22-100% of these tumours. The typical appearance is a cauliflower-like exophytic tumour {2800}.

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Alvarado-Cabrero I Chaux A Muneer A Tamboli P

Clear cell SCC The tumours are large, exophytic, and partly ulcerated. Most of the patients have extensive partly cystic inguinal lymph node metastasis at diagnosis or within several months of diagnosis (1877(.

Lymphoepithelioma-like carcinoma Patients are uncircumcised and their age is variable (5070 years). They present with large tumours in the glans, with extension to the foreskin {2133). Epidemiology Penile cancer is an exceedingly rare malignancy in high-income countries. For example, it accounts for < 1% of all malignancies in men in the USA, with about 2100 new cases and about 400 deaths annually (2933(. The incidence of penile cancer in Europe varies geographically, ranging from 0.5 to 1.6 cases per 100 000 person-years {285}. However, the incidence of this malignancy is much higher in the low- and middle-income countries of Africa, Asia, and South America (73). Brazil has a high incidence, and the state of Maranhao, located in the north-eastern region of the country, has the highest incidence of penile cancer in the world (age-standardized incidence rate: 6.1 cases per 100 000 inhabitants per year) (3331}.

Etiology High-risk HPVs are associated with about 33% of all penile cancer cases, with HPV16 being the most prevalent subtype. HPVs 16, 18, 31, 33, 45, 51, 52, 53, and 58 are the most commonly associated high-risk types found in HPV-associated SCC {923}. Pathogenesis HPV-induced penile cancers develop through the non-invasive precursor lesion penile intraepithelial neoplasia (PelN) after the inactivation of host cell-cycle regulatory proteins by the binding of E7 oncoproteins of high-risk HPV genotypes to hypophosphorylated retinoblastoma protein and the binding of E6 oncoproteins of high-risk HPV genotypes to p53. The ensuing autonomous cell proliferation (without G1 cell-cycle stops) allows nuclear accumulation of the cyclin-dependent kinase inhibitor p16 (p16INK4a) (2364).

Macroscopic appearance

Basaloid SCC Patients usually present with a large, ulcerated, non-exophytic tumoural mass. The cut surface is variable, ranging from an exclusively villiform superficial lesion in non-invasive tumours to a solid tan, firm lesion in invasive carcinomas involving the glans, corpus spongiosum, or preputial dartos {742}. Basaloid tumours may be extensively papillary.

Fig. 8.07 HPV-associated squamous cell carcinoma. A Basaloid squamous cell carcinoma showing surface ulceration and deep invasion of the stroma by islands of basaloid cells. B Basaloid squamous cell carcinoma, characterized by solid nests of small uniform basaloid cells, inconspicuous nucleoli, and numerous mitotic figures.

Warty carcinoma Grossly, these are cauliflower-like, exophytic, white to grey tumours. The cut surface shows a papillomatous growth, usually penetrating into the corpora cavernosa or corpus spongiosum {583,2013}. These carcinomas are large, ranging from 15 to 80 mm (average: 48 mm) in largest diameter. There is an exophytic papillomatous surface in some cases, and other tumours are irregular {590}.

carcinomas are noted. Frequently, a papillomatous tumour is observed at the surface, with an underlying basaloid SCC invading the corpus spongiosum or cavernosum {588}. Differential diagnosis from verrucous carcinoma and giant condyloma is straightforward, owing to the malignant cytology and infiltrative architecture of warty carcinoma.

Clear cell SCC Clear cell SCCs are large white-grey tumours measuring 25-55 mm and sometimes replacing the distal penis (2799(.

Lymphoepithelioma-like carcinoma These are exophytic, well- to poorly circumscribed white-grey tumour masses.

Histopathology

Basaloid SCC Basaloid SCC is characterized by solid nests of small, uniform basaloid cells, usually with central necrosis (comedonecrosis) or central abrupt keratinization. Perinuclear haloes are rare. Nucleoli are inconspicuous and numerous mitotic figures may be seen. Vascular and perineural invasion are frequent findings {742}. Strong block positivity for p16 (a surrogate marker for HPV) is commonly seen in these tumours. The differential diagnosis includes urothelial carcinoma of the distal urethra, small (neuroendocrine) carcinoma, and metastatic carcinoma {3046}. The tumour may have a papillary architecture in which the papillae are straight, foliaceous, or rounded, and composed of a central fibrovascular core; the papillae resemble those in condylomatous or urothelial tumours. The entire thickness of the papillae is composed of small, uniform, poorly differentiated basophilic cells. Associated changes can include basaloid PelN {740}.

Warty carcinoma Warty carcinoma is a morphologically distinct HPV-associated verruciform neoplasm that shares histological features with a giant condyloma but has definitive cytological atypia and a malignant infiltrative architecture. Tumours have a combined exophytic/endophytic growth pattern and a parakeratotic papillomatous surface with conspicuous frankly atypical koilocytosis throughout the tumour (not only at the surface). Microscopically, mixed features of warty and basaloid

Fig. 8.08 HPV-associated squamous cell carcinoma: warty squamous cell carcinoma. A Definitive cytological atypia and malignant infiltrative architecture. Tumours have a combined exophytic/endophytic growth pattern and a parakeratotic papillomatous surface with conspicuous frankly atypical koilocytosis throughout the tumour. B Endophytic growth with a malignant infiltrative pattern.

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Fig. 8.09 HPV-associated squamous cell carcinoma: warty squamous cell carcinoma. A,B Immunohistochemistry positive for p16.

Clear cell SCC Tumours are composed of large clear cells with intracytoplasmic PAS-positive, diastase-resistant material and extensive lymphatic and vascular invasion. They exhibit a typically nested growth pattern with confluent nests in some areas and prominent geographical as well as comedo-type necrosis. The differential diagnosis includes warty carcinoma, cutaneous adnexal sweat gland tumours, and metastatic neoplasm with a clear cell morphology (1877).

papillary architecture and a deeper infiltrative component composed of frankly atypical cells with koilocytic atypia; for clear cell SCC: invasive carcinoma with prominent cytoplasmic clear cell features; for lymphoepithelioma-like carcinoma: poorly differentiated to undifferentiated SCC with tumour cells arranged in syncytia and with prominent inflammatory (lymphoplasmacytic) infiltrate surrounding or obscuring neoplastic cells. Desirable: surface HPV-associated PelN lesions; mixed patterns of HPV-associated carcinomas may be present.

Lymphoepithelioma-like carcinoma Lymphoepithelioma-like carcinoma is a rare HPV-associated and poorly differentiated subtype of SCC with a rich accompanying inflammatory infiltrate, and which derives its name from lymphoepithelioma or undifferentiated nasopharyngeal carcinoma. EBV testing is negative (2133}. The tumour has a syncytial growth pattern, with irregular geographical sheets, nests, trabeculae, or cords of tumoural cells intermixed with a dense lymphoplasmacytic and eosinophilic infiltrate, which obscures carcinoma boundaries and occasional isolated tumour cells. The differential diagnosis is with lymphomas and poorly differentiated usual SCCs. Positivity for p63 and p16 would favour the diagnosis of a lymphoepithelioma-like carcinoma {2133,2800).

Staging Staging is performed according to the eighth edition of the Union for International Cancer Control (UICC) TNM classification.

Cytology Not clinically relevant

Warty carcinomas have an intermediate prognosis between that of other types of low-grade verruciform tumours (verrucous and papillary) and that of SCC of the usual type. They may be associated with inguinal lymph node metastasis (583,2013,588, 582}.

Prognosis and prediction

Basaloid SCC Basaloid carcinoma is an aggressive neoplasm. Deeply invasive tumours are associated with regional lymph node metastasis, indicating a potential for tumour-related death {742,743}. The mortality rate associated with basaloid SCC with papillary features is high, but it is lower than that associated with classic basaloid SCC (740).

Warty carcinoma

Diagnostic molecular pathology In situ hybridization is positive for high-risk HPV and negative for low-risk HPV {559). PCR analyses show HPV16 in most cases, although other subtypes (HPVs 18, 30, 33, 39, 56, 66, 73, 11, 84, 87) may be positive. Warty carcinoma is usually associated with multiple HPV genotypes (2364).

These are highly aggressive tumours with the potential for inguinal lymph node metastasis {1877,2799}.

Essential and desirable diagnostic criteria Essential: p16 block positivity or evidence of HPV on molecular testing； for basaloid SCC: invasive carcinoma with sheets and nests, solid tumour with scant cytoplasm, comedonecrosis, and brisk mitoses; for warty carcinoma: tumour with surface

The most important factors in determining the prognosis are the anatomical level of infiltration (pathological stage); vascular, lymphatic, and perineural invasion; and inguinal lymph node metastasis {1218,581).

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Clear cell SCC

Lymphoepithelioma-like carcinoma

HPV-independent squamous cell carcinoma

Alvarado-Cabrero I Canete Portillo S Chaux A Muneer A Tamboli P

Definition HPV-independent squamous cell carcinoma (SCO) is an invasive keratinizing carcinoma arising from penile mucosal or cutaneous compartments that is not associated with HPV infection.

ICD-0 coding 8086/3 Squamous cell carcinoma, HPV-independent 8086/3 Squamous cell carcinoma, usual type 8051/3 Verrucous carcinoma (including carcinoma cuniculatum) 8052/3 Papillary squamous cell carcinoma 8074/3 Sarcomatoid squamous cell carcinoma ICD-11 coding 2C81.0 Squamous cell carcinoma of penis 2C81.Y & XH6D80 Other specified malignant neoplasm of penis & Squamous cell carcinoma, spindle cell Related terminology Acceptable: spindle cell carcinoma (for sarcomatoid type).

Subtype ⑥ Squamous cell carcinoma, usual type; verrucous carcinoma (including carcinoma cuniculatum); papillary squamous cell carcinoma; sarcomatoid squamous cell carcinoma Localization

SCC, usual type The majority (48%) of lesions are found on the glans {2507). The pseudohyperplastic pattern is typically confined to the foreskin and associated with lichen sclerosus {745}. The pseudoglandular pattern usually involves the glans, coronal sulcus, and foreskin (753).

Verrucous carcinoma (including carcinoma cuniculatum) The glans is the most common site affected, alone or in combination with other anatomical sites (2798,282). Most cases affect the glans and extend to the coronal sulcus and foreskin.

Papillary SCC The tumour is usually located in the glans, although other compartments may also be involved {587}.

Sarcomatoid SCC The glans is preferentially affected, either exclusively or in combination with the coronal sulcus and foreskin (3320}.

Fig. 8.10 Squamous cell carcinoma, usual type. Cut surface of a penectomy specimen showing a predominantly superficially spreading carcinoma.

45-65% of penile SCCs are of this subtype (1217). Patients with the pseudoglandular pattern are younger (aged ~50 years) and typically present with a high-grade carcinoma with deep invasion of erectile tissues, especially the corpora cavernosa. Metastasis to regional lymph nodes is common and may be identified at presentation {753)

Verrucous carcinoma Verrucous carcinoma is a rare penile tumour affecting older men. It accounts for 3-7% of all penile SCCs and 12-38% of all verruciform tumours (2189}. The average age of patients with the carcinoma cuniculatum pattern is 77 years. Longstanding tumours of several years of evolution usually begin as small warts in the glans or foreskin and then slowly progress to a larger exophytic tumour {282}.

Papillary SCC Papillary SCC accounts for 5-15% of penile carcinomas and 27-53% of all verruciform tumours. The average patient age is 63 years (range: 43-85 years) {587,2798}.

Sarcomatoid SCC Clinical features

SCC, usual type SCC of the usual type arises most frequently in the sixth and seventh decades of life (average patient age: 58 years). About

The average patient age is 59 years (range: 28-81 years). A history of a slow-growing tumoural mass with a recent antecedent of rapid enlargement and ulceration is frequent (3320,1922}.

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Pathogenesis Several tumour suppressor pathways, including the p16 (p16INK4a) / cyclin D1 / RB1 and p14ARF/MDM2/p53 pathways, have been implicated in HPV-independent penile carcinogenesis (2548,941,2692). About half of HPV-negative penile cancers are driven by oncogenic activation of TP53t and another quarter are induced by loss of 7P53 tumour suppressor function, possibly in cooperation with additional oncogenic mutations in PIK3CA, KRAS, and HRAS{999}. Macroscopic appearance

SCC, usual type Fig. 8.11 HPV-independent squamous cell carcinoma. Invasive keratinizing carcinoma arising from penile mucosal or cutaneous compartments.

The spectrum of clinical presentations varies from subtle areas of induration, erythema, or exophytic growths to more advanced nodular and ulcerated lesions (586}. Grossly, tumours with the pseudoglandular pattern are large, irregular masses involving multiple penile anatomical compartments and deeply invading into the corpora (590).

Verrucous carcinoma Verrucous carcinomas are exophytic lesions with papillomatous growth, and the interface between tumour and stroma is sharply delineated. They exhibit a cobblestone to filiform and spiky surface (16,2189). Carcinoma cuniculatum is white to grey, exophytic/endophytic, and papillomatous, with a cobblestone or spiky appearance {1805}.

Papillary SCC

Fig. 8.12 HPV-independent squamous cell carcinoma. Invasive keratinizing carcinoma arising from penile mucosal or cutaneous compartments.

Papillary SCCs are large, cauliflower-like, firm, white-grey granular tumours with a characteristic verruciform pattern of growth (587,2189).

Sarcomatoid SCC Epidemiology Penile cancer is a rare malignancy in high-income countries. For example, it accounts for < 1% of all malignancies in men in the USA, with about 2100 new cases and about 400 deaths annually. The incidence of penile cancer in Europe varies geographically, ranging from 0.5 to 1.6 cases per 100 000 person-years (285}. Brazil has a high incidence, and the state of Maranhao, located in the north-eastern region of the country, has the highest incidence of penile cancer in the world (age-standardized incidence rate: 6.1 cases per 100 000 inhabitants per year) (3331}. Sarcomatoid SCC represents 1-4% of all penile carcinomas; all are HPV-independent {1217,741}.

Etiology Risk factors for HPV-independent SCC include phimosis, poor hygiene, and lichen sclerosus. These conditions lead to chronic inflammation of the glans and prepuce and are hypothesized to promote the development of differentiated PelN and non-HPVassociated penile cancer (1388). A strong association has been found between the presence of a foreskin and the development of differentiated PelN or penile SCC {211}. The risk is 3.2 times greater in men who were never circumcised, and 3 times greater in men who were circumcised after the neonatal period, than in men who were circumcised as neonates (1982). Early circumcision protects against phimosis, poor penile hygiene, and retention of smegma (868(.

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Tumours of the penis and scrotum

Sarcomatoid carcinomas are large, irregular, white-grey or reddish, and fungating or polypoid masses, with frequent surface ulceration and haemorrhage, measuring 30-50 mm (range: 25-70 mm) (2900). Histopathology

SCC, usual type This is an invasive keratinizing carcinoma arising from penile mucosal or cutaneous compartments. There is a variable spectrum of carcinomas, ranging from well- to poorly differentiated SCC. Penile SCCs are graded using the three­ tiered WHO Classification of Tumours / International Society of Urological Pathology (WHO/ISUP) system (2189). Welldifferentiated carcinomas are not common; the nests must show extreme differentiation to qualify as grade 1. Poorly differentiated SCC consist of small nests, cords, trabeculae, or isolated anaplastic cells. Keratinization is rare, focal, or poorly developed. Patterns of growth include pseudohyperplastic, pseudoglandular, superficial spreading, vertical, verruciform, and multicentric. Pseudoglandular growth is an unusual pattern characterized by prominent acantholysis and the formation of pseudoglandular spaces. The tumours have a honeycomb or glandular appearance and central acantholysis, mimicking an adenoid cystic carcinoma {753,2798}. Usual SCC should be distinguished from pseudoepitheliomatous hyperplasia, distal urethral carcinomas, and

carcinomas metastatic to the penis with squamous features {1217,2800(.

Verrucous carcinoma Microscopically, verrucous carcinoma is a very well differenti­ ated SCC without koilocytic atypia but with exophytic or endo­ phytic papillary growth {16}. Central fibrovascular cores are not prominent. Characteristically, the tumour shows a broad-based pushing pattern of infiltration. The cross-section of the tip of a papilla shows a central keratin plug, with neoplastic cells at the periphery. Foci of early invasive usual SCC in the lamina propria may be seen, referred to as Hmicroinvasive verrucous carcinoman; if there is extensive usual SCC, the tumour should be labelled a mixed carcinoma (with a comment noting the relative proportions of each component) (2189}. Carcinoma cuniculatum is a pattern of verrucous carcinoma with a bulbous front of invasion. The hallmark of the lesion is noted on the cut surface, where deep tumoural invaginations form irregular narrow and elongated neoplastic sinus tracts connecting the surface of the neoplasm to deep anatomical structures~(282}.

Fig. 8.13 Sarcomatoid squamous cell carcinoma. There is a heterogeneous spectrum of features simulating various sarcomas along with confluent squamous cell carcinoma of the usual type.

short or elongated; for sarcomatoid carcinoma: fascicles of atypical spindle cells in which pleomorphic giant cells may be seen and PelN may be present on the surface.

Papillary SCC Papillary SCCs are exophytic invasive SCCs with complex, irregular papillae that usually have a jagged interface with the underlying stroma. The papillae may be short or elongated, and spiky or blunt, with or without a central fibrovascular core reach­ ing the top. Irregular wide areas of keratinization (keratin lakes) are present between adjacent papillae, sometimes reaching their tips {587).

Staging Staging is performed according to the eighth edition of the TNM classification. Prognosis and prediction Grade and stage are the most reliable prognostic factors for penile carcinoma, although stage is dominant.

Sarcomatoid SCC

SCC, usual type

Sarcomatoid SCCs show a heterogeneous spectrum of features simulating various sarcomas. Spindle cells predominate; in such cases, the tumour resembles fibrosarcoma or leiomyosar­ coma. There are fibrous histiocytoma-like patterns, with spin­ dle and giant cells in a fascicular or storiform pattern. Strap or rhabdoid cells simulating rhabdomyosarcoma, melanoma, or rhabdoid tumours may be noted. The differential diagnosis is with a variety of sarcomas, and immunohistochemistry for soft tissue tumours and melanomas is of value in cases where obvi­ ous carcinoma in situ or invasive carcinoma is not identified. The immunohistochemical markers 340E12 and p63 are useful for demonstrating epithelial histogenesis (3320,1217}.

The most important factors in determining the prognosis are histological grade; anatomical level of infiltration (pathological stage); vascular, lymphatic, and perineural invasion; and ingui­ nal lymph node metastasis (1218,581}. Tumours with the pseudoglandular growth pattern invade deeper anatomical struc­ tures and are associated with a higher incidence of regional metastasis and mortality (753,590}.

Cytology Not clinically relevant Diagnostic molecular pathology Infection with high-risk HPV types should be excluded.

Verrucous carcinoma It is very important not to apply the diagnosis of verrucous carcinoma to all tumours with any verruciform appearance, because pure verrucous carcinoma is thought to harbour no metastatic potential {590). Carcinoma cuniculatum has the same good prognosis as verrucous carcinoma. Despite deep penetration, none of the reported cases have shown groin metastasis or systemic dissemination and all patients are alive (282,1805}.

Papillary SCC Essential and desirable diagnostic criteria Essential: for SCC, usual type: a well-, moderately, or poorly dif­ ferentiated carcinoma with squamous differentiation; for ver­ rucous carcinoma (including carcinoma cuniculatum): a very well differentiated carcinoma with hyperkeratotic and acantholytic papillae with keratin cysts (central fibrovascular cores are uncommon); for papillary SCC: a papillomatous pattern of growth - papillae are architecturally complex and may be

There is a good prognosis for patients with papillary carcinoma (587,2798}.

Sarcomatoid SCC Inguinal lymph node metastasis is seen in 75-89% of cases. Mortality is high (40-75%). Local and systemic recurrences develop in as many as two thirds of patients, and most die within 1 year of diagnosis (741,1922}.

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377

Squamous cell carcinoma NOS

Alvarado-Cabrero I Canete Portillo S Chaux A Muneer A

Definition Squamous cell carcinoma NOS (SCC-NOS) is an invasive keratinizing carcinoma without any special histological features, for which p16 immunohistochemistry and HPV testing are not available.

ICD-0 coding 8070/3 Squamous cell carcinoma, NOS ICD-11 coding 2C81.0 Squamous cell carcinoma of penis 2C83.0 Squamous cell carcinoma of scrotum Related terminology Not recommended: epidermoid carcinoma NOS.

Subtype(s) None Localization The majority of these tumours arise on the mucosal squamous epithelium of the distal portion of the organ (glans, coronal sul­ cus); primary or exclusive involvement of the foreskin is rare {1460}.

Clinical features The clinical features of SCC-NOS are similar to those described for the usual SCC type {2800}. Epidemiology See Tumours of the penis and scrotum: Introduction (p. 362). Etiology SCC-NOS is an acceptable alternative diagnosis where p16 immunohistochemistry and HPV testing are not available.

Fig. 8.15 Squamous cell carcinoma NOS. Nests of invasive squamous cells.

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Tumours of the penis and scrotum

Fig. 8.14 Squamous cell carcinoma NOS. Nests of invasive keratinizing squamous cells.

Pathogenesis Smoking, chronic inflammation, phimosis, and poor hygiene are contributory in most cases; approximately 10-25% of cases may be HPV-associated but lack histological, immunohistochemical, and molecular evidence to support the association {652}.

Macroscopic appearance Gross features are non-distinctive and like those of SCC of the usual type, with nodular, ulcerative to cauliflower-like masses {923}. Histopathology The histological features are like those of a variably keratiniz­ ing SCC seen elsewhere. The differential diagnoses include pseudoepitheliomatous hyperplasia, in which a gross mass and

microscopic stromal reaction to deeply penetrating squamous mucosa is absent. Urothelial carcinoma of the distal urethra is also in the differential because it may have variable keratinization. An antecedent history of urothelial carcinoma and/or car­ cinoma in situ of the urethra is important to confirm urothelial carcinoma of the distal urethra. Urothelial carcinoma is also positive for CK20, GATA3, and uroplakin-2. Metastatic SCC to the penis is also a consideration. In such cases, there is usually an absence of surface intraepithelial carcinoma, an anteced­ ent history of carcinoma elsewhere, and the presence of tumour primarily in lymphovascular spaces {1568}.

Cytology Not clinically relevant Diagnostic molecular pathology See Tumours of the penis and scrotum: Introduction (p. 362).

Essential and desirable diagnostic criteria Essential: an invasive carcinoma; evidence of keratinization in most cases; no information on (and no testing available for) HPV status. Staging Staging is performed according to the eighth edition of the Union for International Cancer Control (UICC) TNM classifica­ tion (2443). Prognosis and prediction The most important prognostic factors are similar to those of SCC of the usual type. Although series specifically looking at SCC-NOS are not available, the prognostic factors probably include histological grade; anatomical level of infiltration (patho­ logical stage); vascular, lymphatic, and perineural invasion; and inguinal lymph node metastasis (252).

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Tamboli P Alvarado-Cabrero I Canete Portillo S Zynger DL

Penile adenosquamous and mucoepidermoid carcinomas

Definition Penile adenosquamous carcinomas (ASCs) and mucoepidermoid carcinomas (MECs) are invasive squamous cell carcinomas (SCCs) with glandular and/or mucinous features.

ICD-0 coding 8560/3 Adenosquamous carcinoma 8430/3 Mucoepidermoid carcinoma

ICD-11 coding 2C81Y & XH7873 Other specified malignant neoplasm of penis & Adenosquamous carcinoma Related terminology None

Subtype(s) None

Fig. 8.17 Penile adenosquamous carcinoma. A tumour with both glandular and squamous features.

Localization These rarely reported tumours are said to affect the glans penis, usually around the urethral meatus. Tumours may also extend to the coronal sulcus and foreskin. They are less common on ventral penile shaft skin {739,2753}.

intraepithelial neoplasia may be present. The glandular component is often in the perimeatal region, with columnar or cuboidal cells, intracellular mucin, and sometimes intraluminal mucin. The glandular component stains for CEA and highmolecular-weight cytokeratin (340E12) {2708). The term "MEC” is more appropriate for tumours with only mucin-producing cells, without glandular structures {3554}. Mucin stains, CK7, EMA (MUC1), MUC5AC, and MUC6 are positive in the mucinous component. CK5, CK14, p40, p16, and p63 are negative in the mucinous cells.

Clinical features Patients are usually in their sixth decade of life and present with a penile mass. Epidemiology To date, < 15 cases have been reported as ASC or MEC {3554}.

Etiology Unknown Pathogenesis It is hypothesized that the glandular/mucin-producing tumour cells are from mucinous glands around the meatus. Rarely, metaplastic goblet cells may be present in the foreskin.

Cytology Not applicable Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: SCO with gland formation and/or mucin-producing cells positive for CK7, CEA, and mucin stains and negative for p16.

Macroscopic appearance These tumours are large, firm, erythematous masses involving the glans penis, sometimes with ulceration. They are white-grey and deeply infiltrative, most often replacing the glans penis and sometimes extending to the coronal sulcus and foreskin.

Staging Staging follows the same Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC) system as staging of SCO of the penis.

Histopathology ASCs are considered to be gland-forming SCCs, whereas MECs are solid tumours without overt gland formation. At present, both entities are placed under the rubric of ASC. The SCO component is predominant, with morphological features of usual-type grade 1-2 SCC. Adjacent penile

Prognosis and prediction Lymph node involvement has been reported in about 50% of patients at the time of diagnosis {721}. The mortality rate is reported to be low, but this is based on data from limited follow-up periods. Aggressive behaviour has been reported in some cases of MEC (721(.

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Tumours of the penis and scrotum

Extramammary Paget disease

Definition Paget disease of the penis and scrotum is a rare intraepidermal adenocarcinoma arising either as a primary tumour or by secondary involvement.

ICD-0 coding 8542/3 Paget disease, extramammary ICD-11 coding 2C81.Y & XH70F8 Other specified malignant neoplasm of penis & Paget disease, extramammary

Related terminology Acceptable: Pagefs disease; extramammary Paget disease; extramammary Pagefs disease. Subtype ⑥ None

Localization The tumour occurs in the epithelium and occasionally in the dermis of the penoscrotal region. Scrotal involvement is more common, with approximately half of the cases involving the scrotum only, one third involving both the scrotum and penis, and the remainder involving the penis alone {1407,1822,2923,3396}.

Clinical features Paget disease occurs in older men (age range: 42-91 years; reported median ages: 65-73 years) {1407,1822,3384,2923, 3396,762}. Patients often have pruritus, erythema, pain, rash, erosion, and exudation {1407,2923). Most patients are initially misdiagnosed with a non-neoplastic disease. A median delay of 3-4 years has been reported from initial symptoms to the correct diagnosis {1407,3384,2923,3605,3396,762}.

Epidemiology Population frequencies have not been reported; however, there are recent large series from China and the USA {1407,1822,3384}. In the 2004-2014 SEER registry, which covers approximately 28% of the population of the USA, 421 penoscrotal cases were reported (1822). Of these, 61% were in White people and 36% in people of Asian descent or Native Americans.

Tamboli P Alvarado-Cabrero I Canete Portillo S Zynger DL

found in other regions, have not been identified in the penis or scrotum {3018). The cells giving rise to primary Paget disease may originate from apocrine glands, eccrine glands, or epidermal basal cells (3018). In secondary Paget disease, the cells arise from direct extension of an underlying tumour or from epidermotropic spread, usually urogenital, colorectal, or cutaneous in origin. Typically, metastatic lesions are metachronous rather than synchronous, presenting at a median interval of 4 years {1822}.

Macroscopic appearance Lesions are erythematous and scaly, with possible ulceration and exudation. They generally cover a large area (median: 20.5 cm2) (1407). Histopathology Paget cells occur singly or in small clusters in the epidermis (in situ), whereas 10-20% have invasive tumour cells within the dermis (1407,3384}. Infiltration of the dartos muscle of the scrotum may be seen (2923}. Tumour cells are round with abundant pale eosinophilic cytoplasm, large nuclei, and prominent nucleoli. Not infrequently, Paget cells involve sweat glands and hair follicles. An in situ tumour can form glandular structures (2923}. An invasive tumour can form nodules, glands, or sheets (2923). Hyperkeratosis and parakeratosis are frequently present, and the upper dermis can have dense inflammation. Lymphovascular invasion is not infrequent. Perineural invasion is uncommon {2923}. Cells in primary Paget disease are reported to express CK7 and CEA, with variable expression of ERBB2 and GCDFP-15. HMB45, S100, CK20, vimentin, CDX2, and HPV are usually negative or focally positive (1407,2923,110). Immunohistochemistry in secondary disease is similar to that of the underlying carcinoma type.

Cytology Not clinically relevant

Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: single and/or clusters of atypical intraepithelial cells positive for CK7 and negative for CK20 and melanocytic markers. Desirable: correlation with clinical history; evaluation of expression of possible secondary malignancies.

Etiology There are no known risk factors. Primary lesions are not HPV-associated (110). Approximately 10% are secondary to a genitourinary malignancy, most frequently prostatic adenocarcinoma, followed by urothelial carcinoma (1822}.

Staging Not relevant

Pathogenesis In primary Paget disease, a currently unidentified precursor cell gives rise to the tumour. Toker cells, potential precursor cells

Prognosis and prediction Lesions are treated with wide local excision or Mohs micrographic surgery. Resection is associated with improved survival {1407,

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381

Fig. 8.18 Paget disease of the scrotum associated with invasive carcinoma. A Nests and single tumour cells involve the epidermis. Single cells and cords of tumour cells are present within the dermis. A hair follicle (right) is also involved. B CK7 immunohistochemical stain highlights tumour cells in the epithelium, dermis, and hair follicle.

3018,1664,1822,3540}. Potential risk factors for progression include younger age, shorter symptom duration, delay in diagnosis, exudation, elevated serum CEA, adnexal involvement, depth of invasion, wide horizontal invasion, nodule formation, marked inflammation, lymphovascular invasion, and ERBB2 and p53 expression (1407,3384,2923,3638}. Recurrence is reported

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in 10-40% of cases {3384,2923,3396}. The most frequent metastatic sites are regional inguinal lymph nodes. Non-regional lymph nodes and bone are the most common distant metastatic sites {3638,3605,762}. Lymph node metastasis is seen in 5-34% of patients (3384,2923,3605}. Overall 3- to 5-year survival is approximately 70% {1822,2923,3384,762}.

Basal cell carcinoma of the scrotum

Alvarado-Cabrero I Canete Portillo S

Definition Basal cell carcinoma of the scrotum (BCC-S) is a carcinoma derived from basal cells of the interfollicular epidermis and/or hair follicle, histologically similar to carcinomas found in sunexposed areas.

ICD-0 coding 8090/3 Basal cell carcinoma ICD-11 coding 2C81.Y & XH2615 Other specified malignant neoplasm of penis & Basal cell carcinoma, NOS Related terminology None

Subtype(s) Potentially all subtypes of basal cell carcinoma (BCC) of sunexposed skin can be found, although the majority of cases reported are of the nodular and superficial types.

Localization Scrotum

Clinical features Isolated case reports constitute the basis of knowledge about BCC-S, with patients ranging in age from 42 to 82 years (961, 3325}. BCC-S typically appears as red papules, plaques, or nodules, and local invasion is the rule (763|. There are no specific symptoms, and in most cases diagnosis is delayed for several years {763}.

Epidemiology BCCs involving the genital epithelium are rare, with an incidence of v 0.1 cases per 100 000 person-years (3325,1278). They account for 5-19% of all scrotal tumours {3487(. Etiology The etiology is unknown. An association with lichen simplex chronicus and other inflammatory conditions has been suggested (1190}. Studies have failed to demonstrate an association with HPV (1678). Pathogenesis Although mutations in TP53 and PTCH1 are associated with sunexposed sporadic BCC, there have been no molecular studies of BCC-S. Both mutations are associated with ultraviolet (UV) exposure and are not known to be associated with BCC-S {867}. Macroscopic appearance Tumour size varies from 10 to 50 mm (763), with no specific gross appearances.

Fig. 8.19 Basal cell carcinoma of the scrotum. The proliferating nests and cords of basaloid cells show characteristic peripheral palisading with occasional central squamous differentiation, microcyst formation, and retraction spaces.

Histopathology Histologically, the lesions are similar to BCCs of other sites. The proliferating nests and cords of basaloid cells show the charac­ teristic peripheral palisading with occasional central squamous differentiation, microcyst formation, and retraction spaces. BCC should be distinguished from basaloid carcinoma, an aggressive subtype of squamous cell carcinoma. Basaloid carcinoma is characterized by a typical downward proliferation of nests composed of small anaplastic cells with numerous mitoses and often with central necrosis (413). Cytology Not relevant

Diagnostic molecular pathology •Not relevant

Essential and desirable diagnostic criteria Essential: basaloid epithelium typically forms a palisade with a cleft forming from the adjacent tumour stroma; crowded nuclei with scattered mitotic figures; mucinous stroma. Staging The staging system for scrotal cancer was proposed by Lowe and is not included in the current American Joint Committee on Cancer (AJCC) staging classification {1958,2443|.

Prognosis and prediction The treatment of choice is surgery. Because of the difficulty of defining the edges of the tumour, Mohs microscopic surgery has been suggested as the best option (1278}. BCC-S has been reported to be more aggressive and more likely to metastasize than BCC arising at other sites (763}. Therefore, patients with BCC-S should be kept under surveillance for metastasis for 2-5 years after excision of the tumour {2989}. Tumours of the penis and scrotum

383

Neuroendocrine neoplasms Edited by: Menon S, Moch H

Neuroendocrine tumours Welkdifferentiated neuroendocrine tumour Neuroendocrine carcinomas Small cell neuroendocrine carcinoma Large cell neuroendocrine carcinoma Mixed neuroendocrine neoplasms Paragangliomas 喜色 gangljoniQ

Neuroendocrine neoplasms: Introduction

In this fifth-edition volume, the neuroendocrine neoplasms (NENs) affecting the urinary system and the male genital organs will be discussed in this chapter, rather than being covered indi­ vidually in the anatomically arranged chapters as was done in the previous edition of the WHO classification of urinary and male genital tumours. This avoids repetition because many characteristics of NENs, especially their basic morphology and immunohistochemistry, are similar across anatomical sites. This approach also follows the organization used in other volumes in the fifth edition. The exception here is the neuroendocrine car­ cinoma (NEC) arising in the posttreatment (androgen ablation) setting of prostatic adenocarcinoma, which is discussed in a separate section in the prostate chapter (see Treatment-related neuroendocrine prostatic carcinoma, p. 223). These tumours are unique in their biology and are thought to represent a trans­ differentiation phenomenon (2571}. The NENs associated with various epithelia are covered in this chapter, along with the family of paragangliomas that arise from paraganglia in and around the genitourinary structures. The classification system developed at the 2017 International Agency for Research on Cancer (IARC) consensus meeting on neuroendocrine neoplasia is used in this chapter (2674). The major categories are neuroendocrine tumours (NETs), refer­ ring to well-differentiated NENs (historically called carcinoid tumours), and NECs, which are considered high-grade. The latter are further categorized into small cell neuroendocrine car­ cinomas (SCNECs) and large cell neuroendocrine carcinomas (LCNECs). In the urological system, SCNECs are considerably more common than LCNECs, and NETs are the rarest (2904). NENs are distinguished by their characteristic architecture, cytological features, and immunophenotypic patterns. The main neuroendocrine markers used in routine diagnostics are chromogranin, synaptophysin, and CD56. INSM1 immunohisto­ chemistry is being increasingly used as a sensitive and specific marker for neuroendocrine differentiation {3508}. The potential cells of origin of NENs are protean and vary to some extent by anatomical site {2904}, In the kidney, NENs may arise from stem cells within a tubular compartment, or from native neuroendocrine cells or stem cells associated with the urothelium of the renal calyces. Interestingly, chromophobe renal cell carcinoma and mucinous, tubular, and spindle cell carcinoma with neuroendocrine differentiation have been described {2478,1561). Well-differentiated NETs have been

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Srigley JR Rubin MA

described in horseshoe kidneys and may also be a component of prepubertal-type teratomas {3066,3553(. It is quite conceiv­ able that some NETs represent monodermal subtypes of pre­ pubertal teratoma. In the urinary bladder, pure NETs and NECs may arise from native neuroendocrine cells or (more plausibly) from stem cells {2904). Mixed carcinomas with components of NEC are relatively common in the bladder, and they are thought to arise from stem cells through a process of divergent differ­ entiation. In the prostate gland, native neuroendocrine cells are com­ monly found and may be the source of some NENs, especially the rare well-differentiated NETs (formerly known as carcinoids). Neuroendocrine cells are also commonly found in acinar adeno­ carcinomas, and NECs are generally thought to arise through the transdifferentiation of adenocarcinoma {2571}. This is especially the case in NECs arising in patients who have been treated with antiandrogenic hormones (see Treatment-related neuroendo­ crine prostatic carcinoma, p. 223). Some NECs arising in hor­ mone-naive patients may also arise through a transdifferentiation phenomenon. However, an origin from native neuroendocrine cells, luminal cells, or basal stem cells is also possible (2571). In the testis, well-differentiated NETs are thought to arise from teratoma or (rarely) from other germ cell tumours {2904}. The NET may be a component of a teratoma, but most cases probably represent a monodermal teratoma related to the pre­ pubertal teratoma family (see Testicular neuroendocrine tumour, prepubertal-type, p. 295). Rare cases have been associated with germ cell neoplasia in situ or with isochromosome 12p and 12p amplification, suggesting that some cases may arise via the postpubertal teratoma pathogenetic pathway {3}. In the urinary tract and male genital organs, NECs may be pure or a component of mixed neuroendocrine/non-neuroendocrine carcinoma. Historically, there has been limited guidance on the terminology to be used with mixed tumours, which has resulted in a plethora of names. Genitourinary pathologists prefer to mention the type and percentage of NEC component (SCNEC or LCNEC) admixed with the non-neuroendocrine component, which both conveys prognostic information and has management ramifications {1258}. Mixed NECs most com­ monly occur in the urinary bladder and the prostate. The pres­ ence of a NEC component in a mixed tumour should alert the clinician to consider the potential role of neoadjuvant/adjuvant chemotherapy (1258}.

Well-differentiated neuroendocrine tumour

de Krijger RR Hansel DE Perez-Montiel D RoJY Rubin MA

Definition Well-differentiated neuroendocrine tumour (NET) is a low-grade tumour showing neuroendocrine differentiation.

ICD-0 coding 8240/3 Neuroendocrine tumour, NOS 8240/3 Neuroendocrine tumour, grade 1 8249/3 Neuroendocrine tumour, grade 2 ICD-11 coding 2C90.Y & XH9LV8 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Neuroendocrine tumour, grade 1 2C90.Y & XH51K1 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Neuroendocrine tumour, grade 2 2C9Y & XH9LV8 Other specified malignant neoplasms of uri­ nary tract & Neuroendocrine tumour, grade 1 2C9Y & XH51K1 Other specified malignant neoplasms of uri­ nary tract & Neuroendocrine tumour, grade 2 Related terminology Not recommended: carcinoid tumour.

Subtype(s) None

Localization NET is a rare tumour in the genitourinary tract, but it may occur in the kidney, bladder, prostate, testicle, or urethra. Clinical features Patients with renal NET most frequently present with abdominal (flank or back) pain and haematuria, which are also the most fre­ quent symptom of bladder NET. A minority of these tumours are detected incidentally. Carcinoid syndrome has been reported in a few patients {2254}.

Epidemiology Renal and bladder NETs occur over a wide age range in adults (median: ~53 years) and without sex predilection {3132). NETs of the kidney, bladder, and prostate are extremely rare, with < 100 reported cases of renal NET, approximately 20 cases of bladder NET, and even fewer cases of primary urethral NET {603,3400). It is difficult to report on the frequency of prostate NET because of the longstanding discussion of whether pure NET really exists as an entity. As many as 15% of renal NETs have been reported in horseshoe kidney, but there is no familial clus­ tering or other association (2709,1790,1287,2374,3592). Etiology Unknown Pathogenesis The pathogenesis is largely unknown owing to the rare incidence of this tumour. Loss of heterozygosity on chromosome 3p21 has

Fig. 9.02 Well-differentiated renal neuroendocrine tumour (NET). A Islands, trabeculae, and cords of well-differentiated neuroendocrine cells separated by thick and thin fibrovascular septa. B Higher-power view of trabeculae and small groups of NET cells. C Immunohistochemistry. Tumour cells within this NET strongly express chromogranin.

Neuroendocrine neoplasms

387

Fig. 9.03 Well-differentiated neuroendocrine tumour (NET). A NET of the urinary bladder showing the bland monotonous tumour cells in nests separated by thin capillaries as a network within the lamina propria beneath the native urothelium. B NET of the prostate showing well-differentiated neuroendocrine cells in a trabecular pattern. Note the monomorphic appearance of the cells.

been demonstrated in a subset of renal NETs, and the mutated genes were CDH1 and TET2 {2542}. Macroscopic appearance Renal NETs have an average size of about 50 mm, although some as large as 300 mm have been described. They are wellcircumscribed and lobular, and yellow to tan. Areas of haem­ orrhage and calcification may be found, but necrosis is rare {1790(. In contrast, bladder and urethral NETs are much smaller (3-12 mm) and frequently polypoid because of their location {603).

Histopathology NETs at all sites of the genitourinary tract have a similar micro­ scopic appearance, which resembles that of NETs elsewhere. The tumours are composed of bland, monotonous cells with mild nuclear pleomorphism and typical speckled chromatin, which are arranged in acini, cords, nests, and trabeculae {1287}. Mitoses are scarce and the Ki-67 labelling index is usually low (1652}. Immunohistochemically, the tumour cells are reactive for chromogranin A, synaptophysin, and CD56. Reactivity for PSA and thyroid transcription factor 1 (TTF1) has been reported to be negative. PAP is usually negative but may be positive in some cases {2254,3132}. Renal NETs may closely abut or involve the pelvicalyceal system and as many as one third of patients may have a nodal metastasis (1484). In the urinary bladder, NETs are usually confined within the lamina propria and may have an associated cystitis cystica et glandularis. The tumour cells are uniform, cuboidal, or columnar, with fine chromatin and inconspicuous nucleoli in a prominent pseudoglandular pattern composed of acinar and cribriform structures. The pseudoglandular pattern may pose a diagnostic difficulty, and a differential diagnosis of a urothelial carcinoma with neuroendocrine differentiation and carcinoid-like areas may also need to be entertained. Occa­ sional atypical cells with prominent nucleoli may occur among

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these monotonous cells; however, mitotic activity and necrosis are absent (603}. There is no established grading system for NET in the geni­ tourinary tract. However, we recommend the gastrointestinal and pancreatic NET grading systems for future use and multiinstitutional collaborative studies. Cytology The bland cytomorphology of NETs is characterized by rela­ tively uniform cells with smooth round nuclei, finely stippled chromatin, and delicate cytoplasm. Spindle cells may be seen, but not necrosis or mitoses.

Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: typical histology combined with positive immuno­ staining for synaptophysin and chromogranin A.

Staging Stage as carcinoma at site of origin.

Prognosis and prediction Because of the relative rarity of these tumours, most have been described in case reports or small series, precluding the sys­ tematic analysis of prognostic factors. Stage (including the extent of local and distant spread) has been shown to be the strongest predictor of survival in renal NET, although with wide variation in duration. More recently, an attempt has been made to use the Ki-67 index as a prognosticator, with 3% as a cut-off value for favourable versus unfavourable behaviour {227,1652}. Bladder NETs usually have a favourable prognosis because of their small size and superficial location, but no specific prog­ nostic or predictive factors have been described. There is no established grading system for NET in the genitourinary tract.

Small cell neuroendocrine carcinoma

de Krijger RR Fine SW Lotan TL Ro JY Rubin MA WeiQ

Definition Small cell neuroendocrine carcinoma (SCNEC) is a high-grade tumour composed of relatively small cells with characteristic nuclear features, scant cytoplasm, and neuroendocrine differ­ entiation. ICD-0 coding 8041/3 Small cell neuroendocrine carcinoma ICD-11 coding 2C82.Y & XH9SY0 Other specified malignant neoplasms of prostate & Small cell neuroendocrine carcinoma 2C94.Y & XH9SY0 Other specified malignant neoplasms of bladder & Small cell neuroendocrine carcinoma

Related terminology None

Subtype(s) None Localization SCNEC of the genitourinary tract most commonly occurs in the prostate and urinary bladder and rarely in the kidney, ureter, or urethra (2904).

Clinical features Patients with renal tumours most frequently present with flank or back pain and/or haematuria. Bladder tumours usually have haematuria as the presenting symptom, whereas patients with tumours in other locations, including those in the prostate, present with urinary obstruction. Patients with SCNEC may present with paraneoplastic syndromes, due to the overproduc ­ tion of PTHrP leading to hypercalcaemia, the production of ACTH leading to Cushing syndrome, or as a syndrome of inappropriate antidiuretic hormone production. Other rare paraneoplastic syn­ dromes associated with SCNEC include peripheral neuropathy, Lambert-Eaton syndrome, and limbic encephalitis (2904}. In the prostate, SCNEC and conventional prostatic adenocarcino­ mas have overlapping clinical features, although a diagnosis of SCNEC is favoured by the presence of visceral and lymph node metastases, osteolytic rather than osteoblastic bone metastases, a low PSA level in combination with widely metastatic disease, the presence of raised serum levels of chromogranin A, rapidly progressive urinary symptoms, and resistance to androgen-dep­ rivation therapy (947,158,1008,701}. SCNECs form a predominant proportion of the increasingly recognized and clinically defined aggressive prostate cancer spectrum (2209).

Epidemiology SCNECs are relatively rare, although they are more frequent than large cell neuroendocrine carcinomas (LCNECs) and

Fig. 9.04 Small cell neuroendocrine carcinoma (SCNEC) of the urinary bladder. A Note the malignant SCNEC cells (with a high N:C ratio, nuclear moulding, and crush arte­ fact) in the lamina propria. Urothelial carcinoma in situ is evident in the surface epithe­ lium. B The malignant SCNEC cells show prominent apoptosis and nuclear moulding.

well-differentiated neuroendocrine tumours (NETs). SCNECs of the kidney are extremely rare, with < 50 cases reported; they have an equal sex distribution and occur at an average age of just under 60 years. Bladder SCNECs occur between the fifth and eighth decades of life, have a male predilection, and

Neuroendocrine neoplasms

389

Fig. 9.05 Small cell neuroendocrine carcinoma (SCNEC). A SCNEC showing high-grade nuclei without nucleoli and with scant cytoplasm. Apoptosis is prominent. B Cells are strongly positive for synaptophysin. C CD56 positivity, although not specific for SCNEC, is the most sensitive marker for neuroendocrine differentiation.

represent < 1% of bladder tumours (958,1717). De novo small cell carcinoma arising in the prostate is an extremely rare entity (0.03% of prostatic adenocarcinomas) (3575}. However, it may also develop in the later stages of prostate cancer progres­ sion in as many as 15-20% of patients treated with hormone therapies (see Treatment-related neuroendocrine prostatic car­ cinoma, p. 223) {1008,3336,701). Etiology Smoking has been implicated in the etiology of bladder SCNECs. The etiology of de novo SCNECs in other genitouri­ nary tract organs remains unknown (3505(.

Pathogenesis Urinary bladder SCNECs are hypothesized to arise from malig­ nant transformation of Kulchitsky-type neuroendocrine cells in the bladder mucosa, from transdifferentiation of conventional urothelial carcinoma, or from a common multipotential cancer stem cell {3370). More than 90% of bladder SCNECs lack RB1 expression on immunohistochemical analysis, indicating that inactivation of the RB1 gene may be a critical molecular event in the development of SCNECs (3370). The pathogenesis of prostatic SCNEC has not been entirely elucidated. However, molecular data suggest that many cases may arise from the transdifferentiation (clonal evolution) of conventional adenocar­ cinoma, even in patients who are treatment-naive. ERG gene rearrangements are commonly concordant between the SCNEC and adenocarcinoma components (1951), and genomic stud­ ies suggest a common precursor cell (316|. Like for SCNECs of other sites, losses of the RB1 and TP53 tumour suppressor genes are key genomic drivers of this disease; they occur in the majority of patients {3235,3107) and contribute to the lin­ eage plasticity that is characteristic of SCNEC (2244,1742}. The pathogenesis of renal and urethral SCNEC is unknown. Macroscopic appearance Usually, SCNECs are large tumours with extensive infiltration into the surrounding structures. Renal SCNECs range from 100 to 230 mm in size and frequently spread into the renal pelvis and perirenal fat and show gross vascular invasion {2562}. Bladder SCNECs are also large tumours with infiltration of the muscle wall or perivesical adipose tissue. They may occur in any wall of the bladder and manifest with mucosal ulceration,

390

Neuroendocrine neoplasms

and they may have a nodular or polypoid appearance. Grossly identifiable necrosis is common.

Histopathology In general, these tumours have typical microscopic features of SCNECs elsewhere, with relatively small cells (< 3 lymphocyte diameters), a high N:C ratio, and scant cytoplasm. Nuclei may be speckled (salt-and-pepper chromatin pattern), with small or absent nucleoli. In addition, nuclear moulding is frequently present. Tumours show neuroendocrine features with large sheets, trabeculae, or an acinar growth pattern. Individual cell necrosis or large areas of geographical necrosis are always present. These tumours are mitotically active, and apoptosis is almost always conspicuous.

Immunohistochemistry Neuroendocrine differentiation is demonstrated by positive staining for synaptophysin, chromogranin A, cytokeratins, and CD56, although this last marker is less specific. SCNEC may completely lack synaptophysin and chromogranin A labelling but still be diagnosed on the basis of characteristic nuclear mor­ phology alone. Thyroid transcription factor 1 (TTF1) immunohis­ tochemistry cannot be used for the distinction from metastatic pulmonary SCNEC because about 50% of urogenital cases demonstrate TTF1 staining (2488,1008,947). Urinary bladder SCNECs are pure only in about one third of the cases, and the rest are admixed either with a urothelial carcinoma component or with other histology of urothelial car­ cinoma, such as adenocarcinoma, micropapillary, squamous, or sarcomatous histology (3370). Pure prostatic SCNEC should not be graded using the Gleason system (2209}. Immunostain­ ing for PSA, PAP, NKX3-1, or HOXB13 may identify an adeno­ carcinoma component in seemingly pure SCNECs; depending on the extent of labelling, such cases should be classified as mixed tumours (see Mixed neuroendocrine neoplasms, p. 394) (2904,1951,947}. The novel neuroendocrine marker INSM1 shows superior or similar sensitivity to chromogranin, synapto­ physin, and CD56 (3508,597). SCNECs of the urinary bladder and those of the prostate look morphologically similar. In difficult situations, demonstration of the TMPRSS2::ERG fusion in prostatic SCNEC and TERT pro­ moter mutation in bladder SCNEC may aid in the differential diagnosis to ascertain the primary site {1223,3615,2573).

Cytology Cytology may be helpful for the diagnosis of metastatic foci. Diagnostic molecular pathology Not clinically relevant Essential and desirable diagnostic criteria Essential: characteristic high-grade histology, including nuclear and architectural features as described above. Desirable: positive immunostaining for synaptophysin, chromogranin A, and/or additional neuroendocrine markers.

Staging The Union for International Cancer Control (UICC) eighth-edi­ tion staging system is used.

Prognosis and prediction SCNECs of all the sites in the genitourinary tract are poor-prog­ nosis tumours. This is because of the advanced stage at pre­ sentation, the inherent aggressiveness, and the rapid progres­ sion to palliation. Bladder SCNECs are reported to have a better prognosis than similar prostatic tumours. However, they have a poorer outcome than their urothelial counterparts {2488). No prognostic or predictive factors are currently available to iden­ tify with certainty those patients who may fare better or worse.

Neuroendocrine neoplasms

391

Large cell neuroendocrine carcinoma

Definition Large cell neuroendocrine carcinoma (LCNEC) is a high-grade carcinoma consisting of large cells with prominent nucleoli, exhibiting neuroendocrine differentiation.

ICD-0 coding 8013/3 Large cell neuroendocrine carcinoma ICD-11 coding 2C94.Y & XH0NL5 Other specified malignant neoplasms of bladder & Large cell neuroendocrine carcinoma 2C90.Y & XH0NL5 Other specified malignant neoplasms of kidney, except renal pelvis & Large cell neuroendocrine car­ cinoma 2C94.Y & XH0NL5 Other specified malignant neoplasms of bladder & Large cell neuroendocrine carcinoma 2C9Y & XH0NL5 Other specified malignant neoplasms of uri­ nary tract & Large cell neuroendocrine carcinoma

Related terminology None

Subtype ⑥ None Localization LCNEC occurs in the kidney, bladder, prostate, and ureter; rarely, it can occur in the penis {1788}.

Clinical features Patients with renal tumours most frequently present with flank or back pain and/or haematuria. Tumours from the ureter may occur with hydronephrosis, and bladder tumours usually have haematuria as a presenting symptom {2812}.

de Krijger RR Compdrat EM Evans AJ Fine SW

Lotan TL Rubin MA WeiQ

Epidemiology LCNECs are rare in all sites in the urinary tract, with < 10 pri­ mary renal LCNECs and < 40 primary bladder LCNECs having been reported. Prostate LCNEC has been seen almost exclusively in the context of prior androgen-deprivation therapy; its incidence is difficult to assess because of its rarity and confusion with other entities under the rubric of prostate adenocarcinomas with neu­ roendocrine differentiation {2812,2904,3503,947}.

Etiology Unknown

Pathogenesis LCNEC in the prostate develops as a transdifferentiation of a castration-resistant prostate cancer upon androgen-depriva­ tion therapy (especially with the newer AR signalling inhibitors) (2904,1008}.

Macroscopic appearance Renal LCNECs are large (frequently > 100 mm in diameter), in contrast to those in other locations that are between 10 and 90 mm. In the bladder, tumours may be polypoid or nodular {2904,3503,2226}. Histopathology LCNECs of all locations in the urogenital tract have a similar microscopic appearance. Pure LCNECs are composed of cells with high-grade nuclei that show focal pleomorphism and frequent prominent nucleoli. These are arranged in a neuroen­ docrine architecture with nests, acini, and trabeculae. Many tumours may have an admixture with urothelial carcinoma or prostatic adenocarcinoma in their respective primary sites and should be labelled as mixed tumours.

Fig. 9.06 Large cell neuroendocrine carcinoma (LCNEC) of the prostate. A LCNEC with an admixture of necrotic and viable tumour areas. B High-power view highlighting nuclear pleomorphism with prominent nucleoli and ample eosinophilic cytoplasm.

392

Neuroendocrine neoplasms

Fig. 9.07 Large cell neuroendocrine carcinoma (LCNEC) of the prostate. A There is diffuse cytoplasmic labelling for chromogranin A. B Synaptophysin immunoreactiv­ ity. C Immunostaining shows a high Ki-67 labelling index, which may be as high as 90%. D These tumours are typically negative for AR.

Immunohistochemically, tumour cells are reactive for chro­ mogranin A, synaptophysin, and CD56 {2456}. Mitoses are fre­ quent, and the Ki-67 labelling index may be as high as 90%. AR is usually negative in prostatic LCNEC. PSA and PAP should be negative or weak in tumours originating from the prostate {2904). Thyroid transcription factor 1 (TTF1) and cytokeratins may be expressed in LCNEC {3622).

Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: typical histology combined with positive immuno­ staining for synaptophysin and chromogranin A. Staging The Union for International Cancer Control (IIICC) eighth-edi­ tion staging system is used. Prognosis and prediction Regardless of location, these tumours have a dismal prognosis. The median survival time of bladder LCNEC is < 1 year, and 3-year survival is just over 20% (3503}.

Neuroendocrine neoplasms

393

Mixed neuroendocrine neoplasms

Definition Mixed neuroendocrine neoplasms (NENs) are tumours com­ posed of an admixture of a neuroendocrine component and a non-neuroendocrine component (urothelial carcinoma, squa­ mous cell carcinoma, adenocarcinoma).

ICD-0 coding 8154/3 Mixed neuroendocrine-non-neuroendocrine neoplasm 8045/3 Combined small cell neuroendocrine carcinoma 8013/3 Combined large cell neuroendocrine carcinoma ICD-11 coding 2C94.Y & XH8E54 Other specified malignant neoplasms of bladder & Mixed neuroendocrine non-neuroendocrine neo­ plasm (MiNEN) 2C90.Y & XH8E54 Other specified malignant neoplasms of kidney, except renal pelvis & Mixed neuroendocrine nonneuroendocrine neoplasm (MiNEN) 2C94.Y & XH8E54 Other specified malignant neoplasms of bladder & Mixed neuroendocrine non-neuroendocrine neo­ plasm (MiNEN) 2C9Y & XH8E54 Other specified malignant neoplasms of uri­ nary tract & Mixed neuroendocrine non-neuroendocrine neo­ plasm (MiNEN) Related terminology None

Subtype(s) None Localization Kidney; bladder; prostate

de Krijger RR Fine SW Lotan TL Raspollini MR Rubin MA WeiQ

Clinical features These tumours have clinical features similar or identical to those described for small cell neuroendocrine carcinomas (SCNECs) and large cell neuroendocrine carcinomas (LCNECs) in these locations - see Small cell neuroendocrine carcinoma (p. 389) and Large cell neuroendocrine carcinoma (p. 392).

Epidemiology Mixed neuroendocrine renal tumours have been described in chromophobe renal cell carcinoma {2478}. Neuroendocrine tumours (NETs) in the bladder are admixed with non-neuroen­ docrine components in as many as 50% of cases, although some studies indicate that pure SCNEC may represent only 12% of all high-grade bladder neuroendocrine carcinomas (NECs) {2562,14}. Most high-Gleason-score prostatic adeno­ carcinomas show at least focal neuroendocrine differentiation by immunohistochemistry {947}. Treatment-related neuroendo­ crine prostate cancer (t-NEPC) represents 15-20% of prostate adenocarcinomas (66,157} and is dealt with separately (see Treatment-related neuroendocrine prostatic carcinoma, p. 223). Etiology Unknown

Pathogenesis There is mounting evidence supporting the role of epigenetic events as a mechanism for transdifferentiation (clonal evolu­ tion) of prostate cancer to an AR-indifferent state under spe­ cific genomic conditions, including (but not limited to) losses of TP53, RB1, and PTEN {2455(. Emerging evidence from geneti­ cally engineered prostate cancer mouse models with combined Trp53 and Pten loss demonstrate that NET cells can arise directly from pre-existing luminal adenocarcinoma cells and do

Fig. 9.08 Mixed neuroendocrine neoplasm (NEN). A Prostatic acinar adenocarcinoma component (Gleason score: 5 + 4; grade group: 5) in a mixed NEN. B Small cell neuroen­ docrine carcinoma (SCNEC) component in a mixed NEN of the prostate.

394

Neuroendocrine neoplasms

not emerge from a second, independent population of neuroen­ docrine or intermediate cells {3645}. These and other data sug­ gest that lineage plasticity is driven by epigenetic changes that arise in a specific genomic context {2244,3588). In patient cohorts, small cell carcinomas or neuroendocrine prostatic carcinomas are characterized by an overexpression of several epigenetic regulators (e.g. EZH2) and a specific DNA methylation profile {316,785,2581}. Insights into what additional epigenetic factors could provoke multipotent prostate cancer cells to transdifferentiate into neuroendocrine prostatic car­ cinoma are still emerging, Recent studies have deduced that AURKA and MYCN amplifications occur early in hormone-naive tumours from patients who ultimately progress and develop t-NEPC after androgen-deprivation therapy (2226). These may have therapeutic implications when management with AR sig­ nalling inhibitors is being considered in the setting of a meta­ static prostate cancer.

Macroscopic appearance The gross appearance of mixed NETs or those with treatmentrelated changes is not specific and not different from that of

other high-grade NETs, including LCNEC and SCNEC (see Large cell neuroendocrine carcinoma, p. 392, and Small cell neuroendocrine carcinoma, p. 389). Histopathology Tumours of the kidney parenchyma are mostly pure NETs, including LCNEC and SCNEC, however chromophobe renal cell carcinoma may have mixed neuroendocrine components {2478}. The neuroendocrine neoplasms arising from the renal pelvis are frequently admixed with urothelial or squamous cell carcinoma. These can be highlighted by immunohistochem­ istry for CK20 in urothelial carcinoma, p40 in squamous cell carcinoma, and synaptophysin and chromogranin A in the neu­ roendocrine component. In the bladder, mixed tumours are fre­ quently seen, showing the same combination of tumour types as in the renal pelvis. In the prostate, almost all prostatic adenocarcinomas show some degree of neuroendocrine differentiation if tested for by neuroendocrine markers {2904}. Because there is insuf­ ficient support for a prognostically or therapeutically rel­ evant role of quantifying a neuroendocrine component,

Fig. 9.09 Mixed neuroendocrine neoplasm (NEN). A A tumour composed of large cell neuroendocrine carcinoma (LCNEC) (right) and prostatic acinar carcinoma (Gleason score: 5 + 4) (left). B Positive chromogranin A stain in the neuroendocrine carcinoma component (right) and negative chromogranin A stain in the prostatic acinar carcinoma component (Gleason score: 5 + 4) (left).

Fig. 9.10 Mixed neuroendocrine neoplasm (NEN). A High Ki-67 proliferation index in the small cell carcinoma component (left) and low Ki-67 proliferation index in the urothelial carci­ noma component (right). B Small cell carcinoma component at high magnification showing nuclei with salt-and-pepper chromatin, as well as a high mitotic count and tumour necrosis.

Neuroendocrine neoplasms

395

immunohistochemistry for chromogranin A or synaptophysin is not recommended in routine pathology (3139,2571,2815,41). A subgroup of prostatic adenocarcinomas has been described with Paneth cell-like neuroendocrine differentiation. The single­ cell infiltrative pattern of these Paneth cell-like components should not upgrade the Gleason score {2984,2571}. Paneth-like cells have relatively small nuclei lacking prominent nucleoli, but they have typical eosinophilic cytoplasmic granularity. They show neuroendocrine differentiation by immunohistochemis­ try. Recently, a clinically aggressive subtype of prostate can­ cer showing dual exocrine and neuroendocrine differentiation on immunohistochemistry, proposed as prostate cancer with amphicrine features, has been identified (2570}. Also in the prostate, SCNEC and LCNEC are frequently admixed with areas of typical prostatic adenocarcinoma. The transition between the components is usually abrupt. The SCNEC component is not taken into account for Gleason grading, but overall such tumours have a Gleason score > 8 (3391}. The SCNEC compo­ nent shows nuclear p53 staining in the majority of cases, thyroid transcription factor 1 (TTF1) in about half of the cases, and AR in a subset; PSA and PAP are typically negative in SCNEC, but they are expressed in the adenocarcinoma component (41}. It is increasingly recognized that t-NEPC, in all probability, is best regarded as a separate clinical entity that has a spec­ trum of histological features including pure neuroendocrine

396

Neuroendocrine neoplasms

morphology (most commonly small cell carcinoma) and mixed tumours with a poorly differentiated adenocarcinoma compo­ nent {2226} (see Treatment-related neuroendocrine prostatic carcinoma, p. 223).

Cytology Not relevant Diagnostic molecular pathology There are no diagnostically relevant molecular tests.

Essential and desirable diagnostic criteria Essential: a neuroendocrine component, characterized by syn­ aptophysin and chromogranin A immunostaining, in combi­ nation with a substantial non-neuroendocrine component; for t-NEPC: a high-grade prostatic carcinoma with neuroendo­ crine differentiation and a clinical history of androgen-depri­ vation therapy. Staging The Union for International Cancer Control (UICC) eighth-edi­ tion staging system is used.

Prognosis and prediction All mixed tumours have a poor prognosis {2455,2904}.

Paraganglioma

de Krijger RR Cheng L Gill AJ Merino MJ Mete 0 Varma M

Definition Paragangliomas (PGLs) are neuroendocrine neoplasms (NENs) that develop from the neural crest-derived progenitors in para­ ganglia associated with the prevertebral and paravertebral sympathetic chains, sympathetic nerve plexuses, and sympa­ thetic nerve fibres.

ICD-0 coding 8693/3 Extra-adrenal paraganglioma ICD-11 coding 2C9Y & XH1UN6 Other specified malignant neoplasms of uri­ nary tract & Extra-adrenal paraganglioma 2C9Y & XH0EW6 Other specified malignant neoplasms of uri­ nary tract & Paraganglioma, NOS 2C9Y & XH4G21 Other specified malignant neoplasms of uri­ nary tract & Sympathetic paraganglioma

Fig. 9.11 Paraganglioma. Maximum-intensity projection of 68Ga-DOTATOC PET-CT in a patient with extra-adrenal sympathetic paraganglioma.

Related terminology Acceptable: extra-adrenal paraganglioma; sympathetic para­ ganglioma. Not recommended: extra-adrenal phaeochromocytoma; phaeochromocytoma.

Subtype(s) None Localization PGLs occur in the lower abdomen, retroperitoneum, pelvis, or bladder wall and are related to the presence of paraganglia. Rare sites of occurrence of PGLs in the genitourinary tract include the urethra, prostate, seminal vesicles, kidneys, and paratestis (2106,1235).

Fig. 9.12 Paraganglioma. Intense SSTR uptake is observed in soft tissue located centrally in the pelvis, cranial to the bladder; coronal (A) and axial (B) fused PET-CT reconstruction.

Clinical features Most PGLs are sympathetic and functional, so clinical mani­ festations may be due to catecholamine excess and/or mass effects. Symptoms of adrenaline/noradrenaline excess include sweating, palpitation, and anxiety; signs include paroxysmal hypertension and tachycardia. Some PGLs of the bladder wall have been described with micturition-associated symptomatol­ ogy (1956). The tumours with SDH mutations tend to be non­ sec retory or produce dopamine only.

Epidemiology In the Netherlands and the Republic of Korea, which have national registries, the respective incidence rates of PGL are approximately 0.5 and 0.18 cases per 100 000 person-years (323,1658). Patients typically present in their fifth or sixth decade of life (age range: 0-88 years) {323}. There is a slight female predominance or (in some series) an equal sex distribu­ tion (323,1658}, Only 10-20% of PGLs occur in children. PGL of the bladder wall accounts for 0.05% of all bladder tumours (312).

Imaging The use of imaging modalities for the detection of PGL depends on their genetic background (see Pathogenesis, below). Those that have pseudohypoxic pathogenesis express SSTR and are well visualized with 68Ga-DOTATATE PET-CT or the less sensi­ tive indium-labelled somatostatin scans. Tumours with kinase pathway abnormalities can be imaged with 18F-DOPA PET-CT or iobenguane (metaiodobenzylguanidine; 1231-MIBG) (2769,1137).

Etiology Overall, 30-40% of PGLs in adults, and an even higher per­ centage in children, arise in the context of hereditary disease, and genetic testing for > 20 susceptibility genes facilitates risk reduction strategies across entire kindreds (380,2052). Younger age at presentation, multiple tumours, and the pres­ ence of extra-adrenal tumours are significantly associated with the presence of a germline mutation (2312}.

Neuroendocrine neoplasms

397

Fig. 9.13 Paraganglioma. A Malignant pelvic extra-adrenal paraganglioma in a 9-year-old girl with a germline SDHB mutation. She presented with two lesions that were shown to be clonally related, for which reason the smaller lesion was considered a metastasis. H&E image of the primary tumour showing typical nested tumour cells (Zellballen). B Im­ munostaining for chromogranin A showing strong diffuse cytoplasmic labelling. C Immunostaining forSSTR2A showing diffuse membranous and cytoplasmic labelling. D Immu­ nostaining for GATA3 showing diffuse nuclear labelling, which may be seen in paragangliomas and cannot be used for discrimination from urothelial carcinoma.

Fig. 9.14 Paraganglioma. A Immunostaining for SDHB showing absent cytoplasmic labelling but retained granular cytoplasmic labelling in normal endothelial cells (internal positive control). This pattern strongly suggests the presence of a mutation in any of the SDH subunit genes (with the exception of SDHA, because the pattern was normal). Upon further genetic counselling and testing, a germline SDHB mutation was found. B Immunostaining for SDHA showing strong diffuse granular cytoplasmic labelling, which is the normal pattern in all cells and indicates that an SDHA mutation is unlikely to be present.

Pathogenesis Susceptibility genes have been clustered according to patho­ genetic processes into a pseudohypoxia-associated cluster, including all hypoxia-related genes (SDH genes, VHL, EGLN2 [PHD1], EGLN1 [PHD2], EPAS1 [HIF2A\), the Krebs cycle genes (FH, MDH2, IDH1, and IDH2), a kinase-signalling cluster (including RET, TMEM127, HRAS, and NF1)t and a WNT-altered cluster (including CSDE1 and MAML3). A possible fourth clus­ ter, initially designated as the (adrenal) cortex admixture sub­ type, harbouring both MAX mutations might have a separate biological background (1017}. Macroscopic appearance PGLs have no specific gross appearance. When they are in the vicinity of the adrenal gland, care should be exercised to

398

Neuroendocrine neoplasms

assure tumours are indeed extra-adrenal. Bladder PGL may occur anywhere in the wall, and it may be exophytic with intact mucosa or lead to ulcerations. PGLs may be as large as 90 mm {312}.

Histopathology PGLs have a characteristic nested growth pattern with a Zell­ ballen appearance. These are separated by a delicate fibrovascular network and supported by sustentacular cells. Nuclei in PGLs are round to oval and sometimes pleomorphic or hyperchromatic, while the cytoplasm usually is eosinophilic (in contrast to phaeochromocytomas, which have amphophilic to basophilic cytoplasm). Some PGLs have cells with clear cyto­ plasm, which can cause them to be mistaken for urinary bladder (3626J, prostate (3375), or renal {1325} carcinomas. Muscularis

propria invasion is common in urinary bladder PGLs, leading to misdiagnosis as urothelial carcinoma (2130). Immunohistochemical staining for neuroendocrine markers including synaptophysin and chromogranin A yields diffuse strong staining. S100 and SOX10 staining highlights the sus­ tentacular cells. Additionally on immunohistochemistry, PGL may express cytoplasmic tyrosine hydroxylase, SSTR2A, and nuclear GATA3 (212,2982,1669}. Most PGLs (with the excep­ tion of spinal PGL) are immunonegative for cytokeratins (843|. A loss of SDHB immunoreactivity in tumour cells with granular cytoplasmic staining of stromal cells (positive internal control) supports the diagnosis of SDH-related disease )1126,3293}; in tumours that lack SDHB immunoreactivity, the addition of SDHA staining can identify loss in patients with SDHA muta­ tions {1711).

Cytology Not relevant Diagnostic molecular pathology No specific molecular analyses are necessary in the context of the diagnosis.

Essential and desirable diagnostic criteria Essential: typical PGL morphology. Desirable: genetic studies to identify specific genetic mutations; positive immunohistochemistry for synaptophysin and chro­ mogranin A; biochemical demonstration of catecholamine excess for functional tumours; imaging studies.

Staging The eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system is used; there is no Union for Interna­ tional Cancer Control (UICC) staging system for paraganglioma. A multidisciplinary international pathology reporting template was introduced in 2014 {2145}. Recently, a pathology-standardized reporting guideline for PGL was introduced by the International Collaboration on Cancer Reporting (ICCR) {3150}.

Prognosis and prediction There is no single histological finding or biomarker that reliably predicts metastatic spread in patients with PGLs {212,2145). PGLs tend to have a lifelong risk of metastases. The 2017 edi­ tion of the WHO classification of endocrine tumours did not endorse a formal prognostic/predictive grading or scoring sys­ tem for these tumours. There are currently three scoring systems for extra-adrenal PGLs: the grading system for adrenal phaeochromocytoma and paraganglioma (GAPP) (1670); the modified GAPP (1700}; the age, size, extra-adrenal location, and secretory type (ASES) score {639}; and the recently proposed composite phaeochromocytoma/paraganglioma prognostic score (COPPS) (2526). Application of these systems has demonstrated variable prognostic/predictive performance and utility {3029,3030). From a molecular perspective, with the exception of germline SDHB mutations (1533,1673), somatic alterations that correlate with aggressive biology include somatic SETD2 or ATRX mutations, MAML3 fusions, and the WNT-altered pathway (1017} and TERT activation (1532). Large tumour size, molecular clusters (espe­ cially pseudohypoxia and SDHB mutations), biochemical pheno­ type, and resectability status are often considered components of the dynamic risk factors in patients with PGL (3030,3519(.

Neuroendocrine neoplasms

399

Mesenchymal tumours Edited by: Gill AJ, Hartmann A, Lazar AJ

Fibroblastic and myofibroblastic tumours The angiofibroma family of tumours Solitary fibrous tumour Inflammatory myofibroblastic tumour Vascular tumours Haemangioma Angiosarcoma Pericytic (perivascular) tumours __ Glomus lumour Myointimoma Myopericytoma Extrarenal PEComa Smooth muscle tumours Leiomyoma Leiomyosarcoma Skeletal muscle tumours Rhabdomyosarcoma Tumours of uncertain differentiation Synovial sarcoma Extrarenal rhabdoid tumour Desmoplastic small round cell tumour

Mesenchymal tumours: Introduction

It is acknowledged that most mesenchymal neoplasms arise throughout the body; however, in this chapter the discussion is limited to the lesions that are most relevant to the urinary tract because they are more common here than elsewhere, they can pose specific problems in the differential diagnosis, or they dis­ play distinctive clinical features. For example, Ewing sarcoma of the urinary tract is well reported, particularly in the kidney {1523}; however, it is assessed and treated using the same principles applied to Ewing sarcomas elsewhere and is there­ fore more appropriately discussed in the Soft tissue and bone tumours volume of this series {3448). Inflammatory myofibroblastic tumours and other myofibroblastic tumours are common diagnoses in the urinary bladder, and they are sometimes difficult to distinguish from sarcomatoid urothelial carcinoma. Because of the clinical implications, these differential diagnoses (including possible molecular tests) are discussed in detail. The angiofibroma family of tumours, also known as the 13q/ RB1 family, comprises angiofibroma, myofibroblastoma, and spindle cell / pleomorphic lipoma. Although these are distinct entities, they are all discussed together (see The angiofibroma family of tumours, p. 403) so that their similarities rather than their differences are emphasized. Not only do these tumours demon­ strate some similar morphological features and natural history, they are also all characterized by a loss of genetic material from the 13q14 region (monoallelic deletion of RB1 and often FOXO1) {1403,33,1027).

402

Mesenchymal tumours

Gill AJ Lazar AJ

First described in 2000 (1003} and increasingly reported since then, myointimoma is now newly recognized with its own entity section (see Myointimoma, p. 416). This distinctive myofibroblastic proliferation of the glans penis almost always arises in the corpus spongiosum, but it has also been reported in the corona sulcus or close to the urethral meatus {1003, 2097). Although also discussed in the renal tumour section, extrarenal perivascular epithelioid cell tumour (PEComa), which is now considered an umbrella term for lesions including angiomyolipoma, is discussed separately (see Extrarenal PEComa, p. 419). It is acknowledged that the PEComa category includes tumours associated with the inactivation of the TSC1 or TSC2 gene (2426,1630} as well as a subgroup characterized by TFE3 gene rearrangements (2008). Selected soft tissue tumours that are more fully described in the Soft tissue and bone tumours volume, including glomus tumour, myopericytoma, leiomyoma, rhabdomyosarcoma, syn­ ovial sarcoma, extrarenal rhabdoid tumour, and desmoplastic small round cell tumour, are discussed in this chapter only when they are relatively common in the urinary tract or cause par­ ticular diagnostic difficulties. Although most of these tumours are discussed more fully elsewhere, the opportunity has been taken to update diagnostic approaches, for example the util­ ity of SS78::SSX fusion-specific immunohistochemistry for the diagnosis of synovial sarcoma (267,3573).

The angiofibroma family of tumours

Definition Cellular angiofibroma is a benign fibroblastic neoplasm com­ posed of bland spindle cells, collagenous stroma, and promi­ nent vasculature. Other members of the angiofibroma family of tumours are myofibroblastoma and spindle cell / pleomorphic lipoma, with similar morphology, immunohistochemical profiles, and molecular genetic backgrounds. ICD-0 coding. 9160/0 Cellular angiofibroma 8825/0 Myofibroblastoma 8857/0 Spindle cell / pleomorphic lipoma

ICD-11 coding EE6Y & XH4E06 Other specified fibromatous disorders of skin and soft tissue & Cellular angiofibroma EE6Y & XH1JJ2 Other specified fibromatous disorders of skin and soft tissue & Angiofibroma, NOS EE6Y & XH73S9 Other specified fibromatous disorders of skin and soft tissue & Giant cell angiofibroma

Related terminology Not recommended: male angiofibroblastoma-like tumour.

Subtype ⑥ None

Localization Angiofibroma is usually located in the superficial soft tissues of the inguinoscrotal or paratesticular area. Very rarely, angiofi­ broma can occur in the kidney, testis, spermatic cord, or pros­ tate {1477,3501,1027,595}.

Hes 0 Calid A Iwasa Y Martignoni G Raspollini MR

Clinical features The clinical features are mostly nonspecific; patients usually present with a slow-growing, painless mass. It may occasion­ ally be associated with a hernia {1477,1800}. Epidemiology Angiofibroma occurs over a wide age range in both sexes (peak incidence is in the fifth decade of life for women and the seventh decade for men), with a slight female predominance {1477,3501, 1027,595,1800}.

Etiology Unknown Pathogenesis Cellular angiofibroma shares morphological and immunohisto­ chemical features with mammary and soft tissue myofibroblas­ toma and spindle cell / pleomorphic lipoma. Moreover, all these tumours are characterized by a loss of genetic material from the 13q14 region (monoallelic deletion of RB1 and FOXO1). There­ fore, a unifying conceptual name, “13q/RB7 family", has been proposed for all these tumours (1403,33,1027}. Macroscopic appearance The size ranges from 6 to 250 mm (median: 28 mm in women, 70 mm in men). Tumours usually present as well-circumscribed, oval or lobulated masses with a soft to rubbery consistency. The colour on cross-section ranges from white to grey-pink or yellow-brown {1477,3501,1027,595}.

Histopathology Angiofibroma is composed of a moderately to highly cellular proliferation of uniform short spindle cells, which are haphaz­ ardly arranged or form vague fascicular or palisading patterns. Stroma is prominent and composed of bundles of wispy col­ lagen and small to medium-sized thick-walled vessels. A fatty

Fig. 10.01 Cellular angiofibroma. A The tumour is composed of short spindle cells in a rich fibrovascular stroma. B The cellularity is variable and the tumour is highly vascular.

Mesenchymal tumours

403

In the differential diagnosis, solitary fibrous tumour has to be considered.

Cytology Not clinically relevant

Diagnostic molecular pathology Analysis of the RBI gene, located on chromosome band 13q14, can be used to support the diagnosis (1990,1027}.

Fig. 10.02 Cellular angiofibroma. Numerous small to medium-sized vessels are present, with thick hyalinized walls.

component is present in about half of the cases. Hyalinization, oedema, or myxoid change is common within the stroma. Mitoses are rare. Areas with sarcomatoid transformation have been observed in rare cases {1027}. Neoplastic cells frequently show loss of RB1 protein expression and are variably positive for CD34 and SMA. Desmin is positive in a minority of cases.

404

Mesenchymal tumours

Essential and desirable diagnostic criteria Essential: bland spindle cells growing within a stroma composed of short bundles of wispy collagen punctuated by numerous small to medium-sized thick-walled vessels. Desirable: a fatty component may be present; loss of RB1 pro­ tein expression may support the diagnosis.

Staging Not clinically relevant Prognosis and prediction Local recurrences are rare and have mostly occurred after an incomplete excision. No metastases have been recorded.

Solitary fibrous tumour

Definition Solitary fibrous tumour (SFT) is a fibroblastic tumour charac­ terized by a prominent, thin-walled, staghorn vasculature and NAB2::S7AT6 gene rearrangement.

ICD-0 coding 8815/0 Solitary fibrous tumour, benign 8815/1 Solitary fibrous tumour, NOS 8815/1 Lipomatous solitary fibrous tumour 8815/1 Dedifferentiated (anaplastic) solitary fibrous tumour 8815/3 Solitary fibrous tumour, malignant ICD-11 coding 2F7C & XH7E62 Neoplasms of uncertain behaviour of connec­ tive or other soft tissue & Solitary fibrous tumour, NOS 2B5Y & XH1HP3 Other specified malignant mesenchymal neo­ plasms & Solitary fibrous tumour, malignant Related terminology Not recommended: haemangiopericytoma.

Nesi G ChevilleJ Fritchie KJ McKenney JK

Subtype(s) Lipomatous solitary fibrous tumour; dedifferentiated (anaplas­ tic) solitary fibrous tumour Localization Although infrequent in the genitourinary tract, SFT may occur at any anatomical location, with reported cases in the kidney, uri­ nary bladder, prostate, seminal vesicles, and penis (1718,1765, 3068,1338,249,3614,545}.

Clinical features SFTs are often discovered incidentally or may be associated with mass effect symptoms. They can sometimes cause para­ neoplastic syndromes such as Doege-Potter syndrome, char­ acterized by severe hypoglycaemia due to tumour production of IGF2 {1718,1276,801}. Epidemiology SFTs are generally seen in adults aged 20-70 years, with peak incidence in the fifth decade of life. There is no significant sex predilection {1718,3068,1338,1307}.

Fig. 10.03 Solitary fibrous tumour. A Typical solitary fibrous tumour consisting of haphazardly arranged uniform spindle cells with scant cytoplasm. B Some tumours may have a predominantly collagenous appearance with low cellularity. C Dedifferentiated solitary fibrous tumour exhibiting increased cellularity with marked nuclear pleomor­ phism. D Strong and diffuse nuclear expression of STAT6 is characteristic.

Mesenchymal tumours

405

Etiology Unknown

Cytology Not clinically relevant

Pathogenesis The NAB2::STAT6 fusion converts NAB2, a transcriptional repressor of EGR target genes, into a transcriptional activator, ultimately resulting in increased cell proliferation and survival {2195,2691,637).

Diagnostic molecular pathology NAB2::STAT6ger>e fusions are the molecular hallmark of SFT but their detection by conventional cytogenetics and PCR-based assays may be difficult because of the diversity of breakpoints; nuclear expression of STAT6 by immunohistochemistry is a sen­ sitive and highly specific surrogate for all fusions (1221,2764).

Macroscopic appearance SFTs are well-circumscribed solid masses measuring 20-150 mm in greatest diameter {1718,249,3441(. The cut sur­ face is tan-grey to reddish-brown in colour and occasionally displays haemorrhage or myxoid change. Histopathology SFTs consist of bland ovoid to spindled cells arranged hap­ hazardly in a disorganized architecture (a so-called pattern­ less pattern), admixed with variable stromal collagenization and prominent, staghorn-shaped (haemangiopericytomatous) blood vessels. The morphology varies from hypocellular lesions with abundant stromal hyalinization to highly cellular tumours with little or no intervening stroma {1718,1338,801}. Lipomatous SFTs contain admixed mature adipose tissue. Dedifferentiated SFTs show abrupt transition from conven­ tional SFT to a high-grade sarcoma {249(. Immunohistochemically, the vast majority of SFTs stain positively for CD34 and STAT6 {1307,894,1221}. Expression of PAX8 by a subset of SFTs can lead to diagnostic confusion with sarcomatoid renal cell carcinoma (3262).

406

Mesenchymal tumours

Essential and desirable diagnostic criteria Essential: uniform ovoid to spindled cells arranged in short or haphazard fascicles; variable stromal hyalinization; prominent branching (staghorn) vasculature; nuclear STAT6 expression by immunohistochemistry. Desirable: demonstration of NAB2::STAT6fusion (in challenging cases).

Staging Risk stratification models are favoured over anatomical staging.

Prognosis and prediction The clinical course of SFT is largely indolent; however, approxi­ mately 10% of these tumours behave in an aggressive manner, with local relapse or metastasis. Features generally associated with malignant SFTs include patient age (> 55 years), large size (> 150 mm), increased mitotic activity, and necrosis {2462, 834,2774). For additional details, see the Soft tissue and bone tumours volume of this series (3448(.

Inflammatory myofibroblastic tumour

Williamson SR Bertz S Lopez-Beltran A

Definition Inflammatory myofibroblastic tumour is a mesenchymal neo­ plasm with the capacity for local recurrence and rare metas­ tasis, demonstrating a myofibroblastic cell phenotype accom­ panied by a stromal inflammatory infiltrate of lymphocytes and plasma cells.

ICD-0 coding 8825/1 Inflammatory myofibroblastic tumour

ICD-11 coding 2B53.Y & XH66Z0 Other specified fibroblastic or myofibroblas­ tic tumour, primary site & Myofibroblastic tumour, NOS Related terminology Not recommended: plasma cell granuloma; inflammatory pseu­ dotumour; inflammatory myofibrohistiocytic proliferation; omental-mesenteric myxoid hamartoma; inflammatory fibro­ sarcoma.

Fig. 10.04 Inflammatory myofibroblastic tumour. Cytologically bland spindle-shaped cells are interspersed with rare lymphocytes.

Subtype(s) None

Epidemiology Tumours primarily occur in middle-aged adults {3137,3220}; how­ ever, development in children also occurs and is estimated to make up about 25% of reported cases {1873,686}. ALK-positive tumours have been noted to have a slight female predilection and occur at a younger age than ALK-negative tumours {3136,3220}.

Localization Inflammatory myofibroblastic tumour can occur at various sites in the genitourinary system, but the urinary bladder is over­ whelmingly the most common site among the genitourinary organs {3137,72,2208}.

Etiology The precise etiology of this tumour is unknown, although a substantial fraction of patients have a history of a previous pro­ cedure, raising the question of whether trauma plays a role in development {2208).

Clinical features The clinical presentation often includes haematuria, dysuria, or abdominal pain {3137,686(. A subset of lesions occur after a previous procedure.

Pathogenesis A subset of tumours are genetically associated with ALK gene rearrangement, among which most urinary tract tumours have recently been shown to harbour an FNT..ALK fusion (17};

Fig. 10.05 Inflammatory myofibroblastic tumour. A Immunohistochemistry for ALK protein shows positive labelling. This tumour was molecularly confirmed to have FN1::ALK fusion. B Immunohistochemistry for SMA shows diffuse labelling, supporting a myofibroblastic phenotype.

Mesenchymal tumours

407

usually shows a wildtype pattern {347}. Rare examples with overtly sarcomatous morphology have been reported, in which behaviour has been aggressive {2208). The absence of a coexisting carcinoma (particularly urothelial carcinoma) argues against sarcomatoid carcinoma; however, some myofibroblastic proliferations may occur either concur­ rently with or after carcinoma.

Cytology Cytopathology may demonstrate atypical spindle-shaped cells, raising a differential diagnosis of sarcoma or other mesenchy­ mal neoplasms {2998}.

Fig. 10.06 Pseudosarcomatous myofibroblastic proliferation. This urinary bladder myofibroblastic proliferation resembles inflammatory myofibroblastic tumour but dem­ onstrated no detectable gene fusions by next-generation sequencing, and immunohis­ tochemistry for ALK was negative.

however, other rare partners of ALK have been described in urinary tract tumours, such as HNRNPA1 {1453} and >4770 (810). (There are also morphologically similar tumours that are nega­ tive for ALK rearrangements, in which no definite gene fusion is currently known, often termed "pseudosarcomatous myofibro­ blastic proliferations*'.) Despite the overlap in the morphology of inflammatory myofibroblastic tumour and nodular fasciitis, urinary tract tumours appear to lack the USP6 gene rearrange­ ments of nodular fasciitis. Alternative fusions described in inflammatory myofibroblastic tumour, such as those of ETV6 or ROS1, also appear to be lacking in the ALK-negative tumours (1503). Recently, an ALK-negative bladder inflammatory myofi­ broblastic tumour with a novel FN1::FIET gene fusion detected by RNA-based fusion analysis has been reported (347|.

Macroscopic appearance The gross appearance often resembles a mesenchymal neo­ plasm with a white or tan fibrous cut surface. Many urinary tract tumours are diagnosed first via transurethral resection, in which the gross appearance is generally nonspecific. Histopathology Inflammatory myofibroblastic tumour is composed of spindleshaped cells with a myofibroblastic appearance (thin, fusiform cells with elongated cytoplasmic processes and usually cytologically bland nuclei). An admixture of inflammatory cells, par­ ticularly lymphocytes, is common. Many tumours intermingle with the bladder muscularis propria, which is not necessarily evidence of malignancy {2208}. Using immunohistochemistry, tumours are almost inherently positive for SMA, supporting the myofibroblastic phenotype, and variably positive for cytokeratin, desmin, and h-caldesmon {2208). Tumours are negative for S100, CD34, KIT, CD21, and CD23 {2208}. A variable propor­ tion (35-89%) show positive immunohistochemistry for ALK protein (3137,686,640,3136,3054,3220,2208,1046}, which usually correlates with genetically confirmed rearrangement of ALK, although not always (640,3109,3054,1046,1359}. Although cytokeratin immunohistochemistry is often positive, urothe­ lial markers such as p63, GATA3, and high-molecular-weight cytokeratin are usually negative (3440}. p53 immunostaining

408

Mesenchymal tumours

Diagnostic molecular pathology Molecular studies such as FISH or sequencing may be used to confirm the presence of an ALK gene rearrangement; how­ ever, a subset of tumours with similar features are negative for currently known gene fusions {1503,640,3054}. Both fusion­ positive and fusion-negative tumours typically have favourable behaviour, so although a positive result is supportive of this diagnosis, a negative result does not exclude a myofibroblas ­ tic proliferation. TERT promoter mutation, which is common in urothelial carcinoma, is absent from myofibroblastic prolifera­ tions and may be helpful if the differential diagnosis includes sarcomatoid carcinoma (347(. Essential and desirable diagnostic criteria Essential: a mass-forming proliferation of spindle-shaped cells with a myofibroblastic appearance of thin, fusiform cells with cytologically bland nuclei and admixed scattered inflamma­ tory cells; diffuse immunohistochemical labelling for SMA. Desirable: absence of coexisting carcinoma; ALK positivity is supportive but a negative result does not exclude the diag­ nosis.

Staging No staging system is currently available, because the tumours usually have favourable behaviour regardless of their size or muscularis propria involvement {2208,686}. Prognosis and prediction In general, inflammatory myofibroblastic tumour is considered a neoplasm of intermediate malignant potential with the capabil­ ity for rare metastasis; however, in the urinary tract it appears even more favourable, with almost no examples of metastasis (3136,17}. Rare possible metastasis from a tumour with typical features originating in the urinary bladder has been reported recently {1875), although some historical reports of malignant behaviour may represent histologically deceptive examples of sarcomatoid urothelial carcinomas. Local recurrence has been described in a small fraction of cases, predominantly in adults (3136}, and is typically thought to be associated with incom­ plete resection. Complete surgical resection is generally con­ sidered the preferred treatment. Response to ALK inhibitors has been recently reported in unresectable tumours, facilitating subsequent resection via partial cystectomy (2638,2275}. Treat­ ment with anti-inflammatory agents has also been used in some circumstances {3217}.

Haemangioma

Williamson SR Drakos E Thway K Zhou M

Definition Haemangiomas are benign vascular neoplasms or malforma­ tions. ICD-0 coding 9120/0 Haemangioma, NOS 9121/0 Cavernous haemangioma 9131/0 Capillary haemangioma 9120/0 Anastomosing haemangioma 9125/0 Epithelioid haemangioma

ICD-11 coding 2F35 & XH5AW4 Benign neoplasm of urinary organs & Haem­ angioma, NOS 2F35 & XH3U29 Benign neoplasm of urinary organs & Capillary haemangioma 2F35 & XH1GU2 Benign neoplasm of urinary organs & Cavern­ ous haemangioma 2F35 & XH10T4 Benign neoplasm of urinary organs & Epithe­ lioid haemangioma Related terminology Acceptable: arteriovenous malformation; venous malformation. Not recommended: angioma.

Subtype(s) Cavernous haemangioma; capillary haemangioma; anastomo­ sing haemangioma; epithelioid haemangioma

Localization Haemangiomas involving essentially all of the genitourinary organs, especially the kidney, testis, spermatic cord, and urinary bladder, have been reported. These include various

Fig. 10.07 Anastomosing haemangioma. Macroscopic examination shows an unen­ capsulated red-brown lesion in the renal hilum.

subtypes, but the more recently recognized anastomosing subtype features prominently {1738,1528,1739}. Anastomosing haemangioma has been most frequently reported in the kidney, especially the medulla (2207,444,2489}. The cortex, renal sinus, and perirenal tissues may be involved. Haemangiomas of the urinary bladder appear to be most often of the cavernous type (619,3125}. Haemangiomas of the testis may include the epithe­ lioid, anastomosing, cavernous, and capillary types (1738,262). Haemangioma of the prostate is extremely rare. Clinical features Involvement of the genitourinary system may occur in the set­ ting of systemic angiomatosis, such as in Sturge-Weber and

Fig. 10.08 Anastomosing haemangioma. A This haemangioma intermingles with renal sinus fat. B Interconnecting vascular channels are present, and there is focal extramed­ ullary haematopoiesis manifesting as megakaryocytes and erythrocyte precursors.

Mesenchymal tumours

409

Fig. 10.09 Haemangioma. A This urinary bladder haemangioma shows denuded surface epithelium with complex capillary proliferation in the lamina propria. B This cavern­ ous-type haemangioma of the urinary bladder demonstrates large vascular channels containing focal fibrin.

Etiology Unknown

Pathogenesis Activating point mutations of GNAQ, GNA11, or GNA14, result­ ing in the upregulation of the MAPK signalling pathway, have been reported in the majority of anastomosing haemangiomas {299,298,1874}.

Fig. 10.10 Epithelioid haemangioma. This epithelioid haemangioma of the testis sur­ rounds a benign seminiferous tubule and is composed of plump endothelial cells with eosinophilic cytoplasm.

Klippel-Trdnaunay syndromes. Patients with urinary bladder haemangiomas may present with macroscopic haematuria or irritative urinary symptoms (619,3125}. Most anastomosing haemangiomas are asymptomatic {2207}. About two thirds of renal cases are incidental imaging findings, associated with compromised renal function including end-stage renal disease {1797,482,1740). However, haematuria and back pain have also been reported for renal tumours (1739}. Testicular haemangi­ omas may manifest as self-detected palpable masses or with pain {1738). Epidemiology Haemangiomas affect people of all ages, predominantly adults (mean age: ~50 years for renal cases) {2489}. A male predomi­ nance has been reported for renal cases (2489,2372(.

410

Mesenchymal tumours

Macroscopic appearance The mean size of renal lesions is about 20 mm. Tumours as large as 75 mm, as well as bilateral and multifocal renal lesions, have been reported {2489}. Testicular haemangiomas range from approximately 5 to 30 mm (mean: 17 mm) {1738). Urinary bladder haemangiomas are usually < 10 mm (619}. Capillary haemangiomas may appear solid, whereas cavernous and anastomosing haemangiomas appear more spongy with a redbrown and mahogany-like colour.

Histopathology Cavernous and capillary haemangiomas with typical histologi­ cal features have been reported in the kidney, urinary bladder, and testis. Many genitourinary haemangiomas are now recog­ nized to be of the anastomosing subtype, which appears diffuse or vaguely lobulated and well circumscribed, but usually not encapsulated at low magnification. Infiltration into the surround­ ing renal parenchyma, with entrapment of renal tubules, as well as intravascular and perirenal fat tissue extension, may be observed. These lesions form irregular, anastomosing, sinusoi­ dal, capillary-sized spaces lined by a single layer of endothelial cells with frequent hobnail morphology. There is minimal or no nuclear atypia, and mitoses are rare {2207(. Moderate lympho­ cytic inflammation, vascular thrombi, fibrotic and myxoid areas, foci of extramedullary haematopoiesis, and PAS-positive hyaline globules are common {1739). Cavernous-like vascular spaces associated with larger vessels at the border of the lesion may be observed. Renal lesions associated with end-stage renal

disease frequently exhibit features of acquired cystic disease in the surrounding parenchyma. Immunohistochemistry high­ lights the vascular channels with CD31, CD34, and ERG (but not D2-40) in the endothelial cells and with SMA in the regular pericytic layer. The Ki-67 index is low. Cytology Not clinically relevant Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: a single layer of benign-appearing endothelial cells with minimal nuclear atypia lining cavernous, capillary, or anastomosing channels. Desirable: extramedullary haematopoiesis and hyaline globules in the anastomosing subtype.

Staging Not clinically relevant Prognosis and prediction Haemangiomas behave in a benign fashion, even when an infil­ trative or multicentric growth pattern is present.

Mesenchymal tumours

411

Angiosarcoma

Omiyale AO Thway K

Definition Angiosarcoma is a malignant vascular neoplasm showing endothelial differentiation.

associated with previous radiation therapy, most frequently for prostate and endometrioid carcinoma {3125,2064,508,565, 1746}.

ICD-0 coding 9120/3 Angiosarcoma 9120/3 Epithelioid angiosarcoma

Pathogenesis Angiogenesis genes and vascular-specific receptor tyrosine kinase genes (TIE1, FLT4, KDR, and TEK) are frequently upregulated (153,1472|. MYC gene amplifications occur in almost all postirradiation and chronic lymphoedema-associated angio­ sarcomas {1229,2021,1694,996).

ICD-11 coding 2B56.Y & XH6264 Angiosarcoma, other specified primary site & Haemangiosarcoma

Related terminology Not recommended: haemangiosarcoma. Subtype(s) Epithelioid angiosarcoma

Localization Within the male urogenital tract, angiosarcoma most frequently arises in the kidney (2373,444} and bladder (3125,2064}, with extremely rare cases occurring in the prostate {508,565}, semi­ nal vesicle {571), and penis (1150). Clinical features Presenting symptoms are site-dependent and may include haematuria and flank pain. The most frequent sites of metastases are the lungs and liver {2373,2064}.

Epidemiology Angiosarcoma is extremely rare in these sites. Most tumours occur in the sixth or seventh decade of life {2373,2064}, although a wide age range (24-95 years) is reported (2373). There is a male predominance (2373,444,2064). Etiology Although the etiology of most urogenital angiosarcomas is unknown, those of the bladder and prostate have been

Macroscopic appearance Angiosarcomas are usually large, haemorrhagic, diffuse or mul­ tinodular masses, often with necrosis.

Histopathology These tumours are morphologically identical to their coun­ terparts elsewhere. Appearances range from well-formed, anastomosing vascular channels to solid sheets of high-grade epithelioid or spindled cells with minimal vasoformation. Vaso­ formative areas are composed of anastomosing channels lined by atypical spindled or epithelioid cells, with variable endothe­ lial multilayering, hobnailing, or papillary tufting. Epithelioid angiosarcomas typically have a solid growth pattern and comprise sheets of large atypical polygonal cells with ovoid nuclei, prominent nucleoli, and abundant cytoplasm {2064,1023}. Angiosarcomas show CD31 and ERG positivity with variable expression of CD34, von Willebrand factor (factor VIIl-related antigen)⑵ 60,2163,1029}, and FLI1 {1029}. Keratin and EMA expression may be seen, particularly in epithelioid subtypes, and this may lead to an erroneous diagnosis of carcinoma (58,1023}. Cytology Not clinically relevant Diagnostic molecular pathology Not clinically relevant

Fig. 10.11 Angiosarcoma of the bladder. A Transurethral resection of bladder tumour (TURBT) specimen. B Pleomorphic hyperchromatic nuclei. C,D Strong nuclear positivity for FLI1 (C) and ERG (D).

412

Mesenchymal tumours

Fig. 10.12 Angiosarcoma. A This lesion shows well-formed (although frequently angulated and irregular) vascular spaces lined by moderately atypical endothelial cells with areas of stratification and hobnailing. The surrounding stroma shows chronic inflammation with haemosiderin-laden macrophages. B Although the neoplastic endothelial cells here show relatively minimal atypia, vasoformation is rudimentary, with small, poorly defined vascular channels containing erythrocytes.

Fig. 10.13 Epithelioid angiosarcoma. A Poorly defined vascular channels are lined by large, moderately pleomorphic cells with ovoid nuclei, with areas of stratification. There is prominent surrounding blood, with mixed inflammation and haemosiderin deposition. B This neoplasm has a predominantly solid architecture, with sparse vasoformation. The cells are large with moderately atypical vesicular nuclei and prominent nucleoli. Foci of rudimentary vasoformation with intracytoplasmic lumina are present.

Essential and desirable diagnostic criteria Essential: malignant endothelial histology; positive immunohis­ tochemistry for vascular markers. Staging Staging of angiosarcoma is not recommended because its typi­ cally aggressive natural history is not consistent with soft tissue staging systems.

Prognosis and prediction Angiosarcomas are associated with a dismal outcome due to their highly aggressive clinical course, widespread metastases, and limited response to surgical treatment, chemotherapy, and radiotherapy.

Mesenchymal tumours

413

Glomus tumour

Definition Glomus tumour is a mesenchymal tumour composed of cells resembling the modified perivascular smooth muscle cells of the glomus body.

ICD-0 coding 8711/0 Glomus tumour, NOS 8712/0 Glomangioma 8713/0 Glomangiomyoma 8711/1 Glomangiomatosis 8711/1 Glomus tumour of uncertain malignant potential 8711/3 Malignant glomus tumour ICD-11 coding 2F35 & XH47J2 Benign neoplasm of urinary organs & Glomus tumour, NOS 2C9Y & XH21E6 Other specified malignant neoplasms of uri­ nary tract & Glomus tumour, malignant

Related terminology None Subtype(s) Glomangioma; glomangiomyoma; glomangiomatosis; glomus tumour of uncertain malignant potential; malignant glomus tumour

Localization In the genitourinary tract, glomus tumours primarily occur in the kidney and are extremely rare in the bladder and testis. Clinical features Most renal glomus tumours are discovered incidentally. Other presentations include flank pain, haematuria, or a mass lesion (2950).

Sirohi D Amin MB

Epidemiology Renal glomus tumours are rare, arising at any age (mean: 50 years) with no sex predilection (3612).

Etiology Autosomal dominant inheritance has been reported in the set­ ting of multiple familial glomus tumours due to inactivating muta­ tions or uniparental disomy of the GLMN gene {493,376,390}. Biallelic inactivation of NF1 in neurofibromatosis type 1 has been reported (1302}. Besides GLMN and NF1 gene mutations, N0TCH2 gene rearrangements are seen in as many as 52% of glomus tumours (38(. Malignant glomus tumours are more likely to have BRAF P.V600E mutations, a potential therapeutic target (1600). Pathogenesis Because of the absence of glomus bodies in visceral organs, the pathogenesis of visceral glomus tumours remains unknown.

Macroscopic appearance The tumours are small, well-circumscribed lesions with a solid, cystic, haemorrhagic, or spongy cut surface {2950}. Histopathology Glomus tumours are composed of monotonous small round cells with central round nuclei and well-defined cell borders, lacking marked atypia and mitotic activity, arranged around small vessels. Stromal hyalinization, as well as myxoid, cys­ tic, and symplastic changes, may be present (97}. Cavernous haemangioma-like malformations characterize glomangioma, whereas areas of smooth muscle differentiation are seen in glo­ mangiomyoma. Immunohistochemistry shows SMA, MSA, h-caldesmon, pericellular collagen IV, and calponin positivity; keratins and melanoma-associated markers are negative. Ultrastructurally,

Fig. 10.14 Glomus tumour. A Solid glomus tumour with bland, small, round to oval monomorphic cells arranged around small-calibre blood vessels. B Glomangiomyoma. Glo­ mus cells are arranged around blood vessels with areas of smooth muscle differentiation. C Glomangioma. A cavernous haemangioma-like architecture with vascular spaces lined by glomus cells is present. D Glomus tumour with symplastic change. This tumour demonstrates cytological atypia in the absence of mitotic activity.

414

Mesenchymal tumours

Fig. 10.15 Glomus tumour. A Diffuse immunoreactivity for SMA is present in glomus tumours. B Ultrastructural studies demonstrate cytoplasmic filaments consistent with the myoid origin of glomus tumours.

the neoplastic cells contain cytoplasmic filaments compatible with myoid differentiation. Because of the monotonous epithelioid morphology, a lowgrade clear cell renal cell carcinoma may be mimicked, particu­ larly in core needle specimens. The main differential diagnosis is juxtaglomerular cell tumour with associated hypertension; rhomboid-shaped renin crystals on ultrastructural analysis are diagnostic.

Cytology Not relevant Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: round monomorphic cells with well-defined cell bor­ ders and diffuse positivity for muscle markers. Desirable: epithelial, vascular, and melanoma markers are negative.

Staging Not relevant

Prognosis and prediction The majority of glomus tumours are benign. Malignant behav­ iour is rare and does not correlate with the histological predic­ tors of aggressive behaviour established for soft tissue tumours. Metastasis is the only reliable criterion of malignancy.

Mesenchymal tumours

415

Myointimoma

Definition Myointimoma is a distinctive intravascular myoepithelial prolif­ eration occurring within the corpus spongiosum of the glans penis.

ICD-0 coding 9137/0 Myointimoma

ICD-11 coding 2F34 & XH37N4 Benign neoplasm of male genital organs & Myointimoma

HesO Calid A Martignoni G Raspollini MR

Related terminology Not recommended: penile myointimoma; penile intravascular leiomyoma; intravascular leiomyomatosis; leiomyoma of the glans penis; intravascular fasciitis solitary cutaneous myofi­ broma; benign perivascular myoid cell tumour; myofibroma of the glans penis. Subtype(s) None

Localization Myointimoma occurs within the corpus spongiosum of the glans penis {1003,2097}. Occasionally it may be detected in the corona sulcus or in close proximity to the urethral meatus (1003}.

Clinical features Patients with myointimoma usually present with a painless and otherwise asymptomatic nodule within the glans penis {1003, 2097}. Epidemiology Myointimoma has been documented mainly in boys and less frequently in men {1003,2097,2684,3312}. Etiology The etiology of myointimoma is unknown. All cases have been sporadic, and no familial predisposition has been confirmed.

Fig. 10.16 Myointimoma. The tumour grows within the pre-existing vascular spaces of the corpus spongiosum of the glans penis.

Pathogenesis Unknown Macroscopic appearance The size of myointimomas ranges from 4 to 18 mm. The usual appearance is a firm mass with a beige or white colour (1003, 2097,2684,3312}.

Fig. 10.17 Myointimoma. The cytoplasm of the neoplastic cells is mostly eosinophilic. Nuclei are small and lack any mitotic activity.

416

Mesenchymal tumours

Histopathology Myointimoma is arranged in a plexiform pattern, which is due to its extension within the pre-existing vascular spaces of the spongiosum of the glans penis {1003,2097}. Neoplastic cells are spindled or stellate with long cytoplasmic processes, and they are surrounded by abundant fibromyxoid matrix. The cyto­ plasm is eosinophilic and may rarely contain intracytoplasmic vacuoles. The nuclei are small and lack any mitotic activity. Neoplastic cells are positive for SMA and calponin; desmin is positive only focally {1003,2097}. The differential diagnosis includes myofibroma, leiomyoma, myopericytoma, late-fibrous-stage intravascular fasciitis, plexi­ form fibrohistiocytic tumour, epithelioid haemangioendotheli­ oma, nerve sheath myxoma, and plexiform schwannoma.

Cytology Not clinically relevant

Staging Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

Prognosis and prediction Myointimomas are benign lesions, and complete surgical resection is curative. They do not recur or metastasize {1003, 2097}.

Essential and desirable diagnostic criteria Essential: homogeneous plexiform myofibroblastic proliferation within the vascular spaces of the corpus spongiosum. Desirable: SMA positivity.

Mesenchymal tumours

417

Myopericytoma

Hartmann A

Definition Myopericytoma is a perivascular myoid neoplasm, which rarely affects the genitourinary tract. ICD-0 coding 8824/0 Myopericytoma ICD-11 coding 2F34 & XH2HE9 Benign neoplasm of male genital organs & Myopericytoma Related terminology Not recommended: myofibroma of the glans penis.

Subtype(s) None Localization Myopericytomas typically occur within the dermis or subcutis of distal extremities; visceral involvement is rare. They rarely affect the genitourinary tract, but they have been reported in the kid­ ney and bladder )1864,3610). Clinical features Renal myopericytomas are usually asymptomatic and dis­ closed incidentally during examination for other reasons {1864(. Patients with bladder tumours presented with gross haematuria or dysuria and urinary frequency (3610,2266}. Epidemiology Renal myopericytomas are observed exclusively in adults, with a male predominance.

Etiology Myopericytomas may occur on a familial basis, but no such association has been noted in genitourinary cases (3610,1864}.

Fig. 10.18 Myopericytoma. Myopericytoma is characterized by a perivascular con­ centric proliferation of bland, oval to spindle-sh叩ed cells with round to spindled nuclei.

Histopathology Myopericytoma is characterized by a perivascular concentric proliferation of bland, oval to spindle-shaped cells. Nuclei are usually round to spindled, and they may rarely show degenera­ tive features. Numerous thin-walled vessels are always present. Stroma is oedematous and can exhibit hyalinization or myxoid change. Necrosis may be present {3610). Some cases show more pronounced whorled or fascicular architecture, similar to that seen in myofibromas {895}. By immunohistochemistry, myopericytomas express SMA and h-caldesmon, whereas only focal positivity is observed with desmin and/or CD34 {3610,1864}. Cytology Unknown Diagnostic molecular pathology Not clinically relevant

Essential and desirable diagnostic criteria Essential: bland, myoid-like cells growing in a concentric perivascular pattern. Desirable: SMA positivity, PDGFFIB alterations.

Pathogenesis Abnormalities/mutations of the PDGFRB gene are common in myopericytomas but are not specific to these entities (31, 1426}.

Staging Not clinically relevant

Macroscopic appearance Renal myopericytoma is usually a well-circumscribed, solid, rubbery tumour with a variable colour (grey-tan to red-brown). The size of renal and other genitourinary cases ranges from 18 to 73 mm (2266,3610,1864}.

Prognosis and prediction Myopericytomas are benign lesions and complete surgical resection is curative. They do not recur or metastasize. Exceed­ ingly rare malignant myopericytomas have been described out­ side the genitourinary tract, which had a poor outcome {2102}.

418

Mesenchymal tumours

Extrarenal PEComa

Definition A perivascular epithelioid cell tumour (PEComa) is a mesenchy­ mal tumour with melanocytic and smooth muscle differentiation.

ICD-0 coding 8714/0 PEComa, benign 8860/0 Sclerosing PEComa/angiomyolipoma 8714/3 Malignant PEComa ICD-11 coding 2F3Y & XH4CC6 Benign non-mesenchymal neoplasms of other specified site & Perivascular epithelioid tumour, benign 2F7C & XH4CC6 Neoplasms of uncertain behaviour of con­ nective or other soft tissue & Perivascular epithelioid tumour, benign 2B5F.2 & XH9WD1 Sarcoma, not elsewhere classified of other specified sites & Perivascular epithelioid tumour, malignant Related terminology Acceptable: perivascular epithelioid cell tumour.

Subtype ⑥ Sclerosing PEComa/angiomyolipoma Localization In the genitourinary organs, PEComas mostly occur in the kid­ ney, but uncommon cases have been reported in the bladder, urachus, urethra, and prostate (732,796,3427,2430(. Occa­ sional angiomyolipoma cases have been observed in the testis (1792,2770}.

Clinical features The tumour mass causes an enlargement of the involved organs; small tumours may be incidental findings.

HesO Calid A Martignoni G Raspollini MR

Epidemiology Patient ages range from 15 to 67 years (796,3311(, and there is no sex predilection. Pure epithelioid PEComas of the kidney have been reported in patients aged up to 80 years. Etiology With the exception of those involving the kidney, genitourinary tract PEComas are sporadic; none of the patients described to date had tuberous sclerosis. A possible correlation of bladder PEComas with previous chemotherapeutic treatment has been hypothesized {3311}.

Pathogenesis Syndromic and sporadic PEComas have demonstrated inacti­ vation of the TSC1 or 73C2genes {2426}, with subsequent acti­ vation of the mTOR pathway (1630) and loss of expression of the protein tuberin, which is encoded by the 7SC2gene {1335}. Alongside this pathogenetic pathway, there is a different patho­ genetic mechanism in 7FE3-rearranged PEComas that does not involve TSC2, suggesting that 7FE3-rearranged PEComas represent an entity that morphologically overlaps with conven­ tional PEComas (2008}. PEComas have shown TFE3 rearrangements associated with balanced Xp11 translocation in the few genitourinary cases evaluated {2755,3455,2358,601,3394,3374,3311}.

Macroscopic appearance PEComas are single, solid, well-circumscribed masses. Infiltra­ tive margins and necrosis may be present. The size ranges from 5 to 90 mm. Histopathology PEComas are composed of epithelioid cells with a clear and granular cytoplasm, associated with spindle cells in a variable ratio. Cells containing intracytoplasmic melanin are present.

Fig. 10.19 Extrarenal PEComa. A This tumour is composed of epithelioid cells with clear and/or granular cytoplasm combined with eosinophilic spindle cells. B PEComas are positive for melanocytic markers, such as HMB45 in this tumour.

Mesenchymal tumours

419

Fig. 10.20 Extrarenal PEComa. A Low-power view of a PEComa arranged in a nested and alveolar architecture in the bladder wall, with normal overlying urothelium. B The neoplasm is characterized by epithelioid cells that have a large amount of eosinophilic to clear, slightly granular cytoplasm and round nuclei with inconspicuous nucleoli. Occa­ sional cells show readily visible melanin. C There is nuclear positivity for TFE3 in the neoplastic cells. D There is weak staining for tyrosinase in this example.

The neoplastic cells have an alveolar architecture arranged in a radial way around the walls of the hyalinized blood ves­ sels. Tumour cells are mostly characterized by nuclei with slight atypia and inconsistent nucleoli; however, tumour cells with moderate/severe atypia, mitoses, necrosis, and lymphovascular invasion may be observed. Tumours may show expansive or infiltrative patterns. Sclerosing PEComa is composed of cords and trabeculae of bland epithelioid cells embedded in abundant sclerotic stroma. Other than in the kidney, these tumours have been described in the retroperitoneum, pararenal region, pelvis, uterus, and abdominal wall {1396}. Uncommon cases with overt sarcomatous features mimicking other malignancies have been reported and may therefore escape recognition {3427). PEComas show positive staining for both melanocytic (HMB45 and/or melan-A) and muscle (actin and/or desmin) markers, which are helpful for confirming the diagnosis. Usually the epithelioid cells show stronger expression of melanocytic markers, and the spindle cells express muscle markers {1031(. In addition, tumour cells show positive staining for TFE3, MITF, and cathepsin K, as well as patchy, focally positive immuno­ staining for tyrosinase. Cytokeratins are negative. The differential diagnosis includes carcinoma (which stains for epithelial markers) and paraganglioma (which stains for S100), as well as leiomyosarcoma and myofibroblastic tumour in cases of PEComas that may escape recognition because of the presence of overt sarcomatous features mimicking the aforementioned malignancies. Cytology Not clinically relevant

Diagnostic molecular pathology Not clinically relevant

420

Mesenchymal tumours

Essential and desirable diagnostic criteria Essential: presence of epithelioid tumour cells with melanocytic and muscle differentiation. Desirable: presence of cells containing intracytoplasmic mela­ nin. Staging There is no Union for International Cancer Control (UICC) / American Joint Committee on Cancer (AJCC) staging system for extrarenal PEComa.

Prognosis and prediction Because there have been few reported cases, limited data are available for defining the criteria for benign outcome, uncer­ tain malignant potential, and malignant outcome for patients with PEComa. However, different authors have proposed certain histological features as general criteria for stratify­ ing tumour behaviour in cases with tumour size > 50 mm, infiltrative growth patterns, high nuclear grade and cellularity, mitotic count, necrosis, and vascular invasion {1031); or for size > 80 mm, mitotic count, and necrosis (1395}. Large tumours should be extensively sampled to exclude areas with worrisome histological features. The biological behaviour of PEComas does not seem related to the presence of TFE3 rearrangement. Notably, the presence of TFE3 translocation has been documented in all cases of PEComa of the genitouri­ nary tract where it has been investigated, regardless of benign or malignant behaviour (2755,3455,2358,601,3394,3374, 3311}. Proposed target treatment with mTORCI inhibitors in malignant PEComas (3356| should be indicated in cases with TSC2 inactivation, whereas patients with TFE3-rearranged PEComa without TSC2 gene involvement may not respond to mTORCI inhibitors.

Magi-Galluzzi C Billings SD McKenney JK

Leiomyoma

Definition Leiomyoma is a benign tumour of smooth muscle.

ICD-0 coding 8890/0 Leiomyoma, NOS 8897/1 Smooth muscle tumour of uncertain malignant potential ICD-11 coding 2E86.1 Leiomyoma of other or unspecified sites Related terminology None Subtype ⑥ None Localization Leiomyomas can be found in all organs of the urinary tract, most frequently in the urinary bladder. Clinical features Most bladder and urethral tumours are detected incidentally during cystoscopy or imaging, but some may present with obstruction, irritative voiding symptoms, and/or haemorrhage. Kidney leiomyomas are more commonly an incidental finding. Penile and scrotal leiomyomas manifest as palpable masses.

Epidemiology Leiomyomas most commonly occur in the urinary bladder and urethra (718,2049), with a wide age range but predominantly in middle-aged adults, and with a female predominance. The scrotum is another common site {2063,2316}. Renal leiomyo­ mas are rare, and many reported cases represent angiomyo­ lipoma {2467}. When carefully diagnosed, renal leiomyomas have a striking female predominance and are usually located in the renal hilum associated with blood vessels. Leiomyoma is

Fig. 10.21 Bladder leiomyoma. There are eosin叩hilic spindle cells showing uniform nuclei and fascicular growth.

the second most common mesenchymal neoplasm of the parat­ estis, after lipoma, with a predilection for the epididymis {2706, 2572}. Rare penile leiomyomas have been described {287), but some reported cases represent penile myointimoma. Although prostatic leiomyomas have been described, their distinction from prostatic stromal hyperplasia and neoplasia is subjective (1399), Rare tumours in immunocompromised patients have been associated with EBV (873).

Etiology Unknown

Pathogenesis See the Soft tissue and bone tumours volume of this series {3448) for details of somatic leiomyoma, and the Female genital tumours volume (3447) for details of uterine leiomyoma.

Fig. 10,22 Renal leiomyoma. A A renal tumour with eosinophilic spindle cells arranged in intersecting fascicles. B The cells have uniform blunt-ended, cigar-shaped nu­ clei C The tumour cells are positive for SMA.

Mesenchymal tumours

421

Macroscopic appearance Most leiomyomas are small (mean size: 20 mm), but tumours as large as 250 mm have been reported (1157J. Tumours are well cir­ cumscribed and tan to white with a bulging, whorled cut surface. Histopathology Neoplastic cells closely resemble normal smooth muscle cells with eosinophilic cytoplasm and uniform blunt-ended, cigar­ shaped nuclei. They are arranged in orderly intersecting fas­ cicles. They have little or no nuclear atypia, and they have at most an extremely low level of mitotic activity. Rare examples of leiomyoma with bizarre nuclei have been described in the scrotum, paratestis, and urinary bladder, but long-term follow­ up data are limited {398,2063,1834}. Tumour cells are positive for SMA, desmin, and h-caldesmon, at least focally, but negative for S100. In the kidney, negative staining for cathepsin K is useful to distinguish leiomyoma from angiomyolipoma {2467}. ER and PR expression is common in renal and urethral leiomyomas {1614,2467).

422

Mesenchymal tumours

Cytology Unknown Diagnostic molecular pathology Not clinically relevant Essential and desirable diagnostic criteria Essential: intersecting fascicles of bland spindle cells with eosinophilic cytoplasm.

Staging Not relevant

Prognosis and prediction Leiomyomas are treated by biopsy and surveillance, transure­ thral enucleation/resection, or segmental resection (for large tumours). Resection is curative; recurrence is probably due to incomplete excision (1834).

Leiomyosarcoma

Definition Leiomyosarcoma is a malignant mesenchymal neoplasm with smooth muscle differentiation. ICD-0 coding 8890/3 Leiomyosarcoma, NOS 8890/3 Superficial leiomyosarcoma 8890/3 Deep leiomyosarcoma

ICD-11 coding 2B58.Y Leiomyosarcoma, other specified primary site

Related terminology None

Subtype(s) Superficial leiomyosarcoma; deep leiomyosarcoma

Magi-Galluzzi C Billings SD McKenney JK

Localization Genitourinary tract sarcomas are rare, accounting for 1-2% of all genitourinary malignancies {2296,3265}, and leiomyosar­ coma is the most common histological type {3265}. About half to three quarters of all soft tissue leiomyosarcomas arise in the retroperitoneum, with a smaller number occurring in the peritoneal cavity and pelvis (247,1855}. Primary genitourinary sites include the bladder {3640,2694,1834), prostate {3124,2092,3322,3307}, and kidney; in this last site, tumours may arise from the renal capsule, renal parenchyma, smooth muscle cells of the intrarenal blood vessels, main renal vein, or renal pelvis {2337,3574,1075). Primary sarcomas of the paratesticular tissue (891,1018,3352} are very uncommon and may arise from the epididymis (3571}, scrotum {2110}, or spermatic cord {1082,2241}. Small series and individual cases of penile leiomyosarcomas have been reported {1616,3198,660,1004}, most of which are of vascular origin and classified as either superficial or deep-seated.

Fig. 10.24 Bladder leiomyosarcoma. A A leiomyosarcoma of the bladder with necrosis and nuclear atypia. B A leiomyosarcoma of the bladder with nuclear atypia and high mitotic activity.

Mesenchymal tumours

423

Clinical features Patients with leiomyosarcoma typically present with a mass discovered at imaging for abdominal fullness or pain {247). Tumours are usually clinically silent or cause mild symptoms until they involve vital organs {1855}. Back pain, abdominal distention, and changes in bladder or bowel habits are due to mass effect or organ involvement. Patients with urinary blad­ der leiomyosarcoma commonly present with gross haematuria, urinary frequency, and dysuria (2726). Penile leiomyosarcomas may cause dysuria and difficulty voiding (1004}.

Epidemiology Leiomyosarcoma is one of the most common soft tissue sar­ comas {891}, accounting for 5-10% of cases. They commonly affect middle-aged and older adults (peak incidence occurs in the seventh decade), with a female predominance (M:F ratio: 2:3) {247}. Leiomyosarcoma is the most common sarcoma of the adult kidney and accounts for 50-60% of all renal sarco­ mas. Primary leiomyosarcomas of the paratesticular tissue {891, 1018) are very uncommon. Etiology Unknown

Pathogenesis Please see the Soft tissue and bone tumours volume of this series {3448) for details. Macroscopic appearance Leiomyosarcomas are large, well-circumscribed, white to grey, soft to firm, fleshy, encapsulated masses; their cut surface may have a whorled appearance. Large tumours frequently exhibit haemorrhage, necrosis, or cystic changes (247).

Histopathology Leiomyosarcomas are typically composed of elongated spindle cells with blunt-ended nuclei arranged in intersecting fascicles. Well-differentiated tumours contain spindle cells with abundant eosinophilic cytoplasm and mild cytological atypia; epithelioid cells may be seen admixed with spindle cells. Poorly differenti­ ated neoplasms demonstrate nuclear pleomorphism, increased mitotic activity, or necrosis {247}. Adult genitourinary sarcomas have been subdivided into low-grade and high-grade {891, 3393,2296). In the urinary bladder, the distinction has been

424

Mesenchymal tumours

based on mitotic activity (> 1 mitosis/mm2), nuclear atypia (mild to moderate), and tumour necrosis (< 25%) (2049). High­ grade leiomyosarcomas of the bladder appear to behave more aggressively than low-grade tumours (2049}. Most leiomyosar­ comas arising in the genitourinary tract are high-grade (2572, 3393}, with the exception of paratesticular tumours. Leiomyosarcoma cells are typically positive for a-SMA, desmin, h-caldesmon, and calponin, at least focally; they are negative for S100. In the differential diagnosis, rare cases of gastrointestinal stromal tumours have to be considered, espe­ cially in the prostate.

Cytology Not clinically relevant Diagnostic molecular pathology Not clinically relevant Essential and desirable diagnostic criteria Essential: nuclear atypia, pleomorphism, > 1 mitosis/mm2, and/ or necrosis; immunoreactivity for SMA and desmin.

Staging The American Joint Committee on Cancer (AJCC) staging system for soft tissue sarcoma is the most widely used system for staging leiomyosarcoma. It combines primary tumour size, lymph node involvement, presence of metastasis, sarcoma type and grade, and tumour depth (1855).

Prognosis and prediction Tumour size, extent of local invasion (depth), surgical margin/ resectability, histological grade, and presence of metastatic disease are the most important prognostic factors (891}. Sur­ gical resection with negative margins remains the only poten­ tial curative treatment {3038,247,3265}. Primary renal sarco­ mas are highly aggressive neoplasms with a poor prognosis {1610]. Patients with sarcomas of the bladder, prostate, and kidney have worse survival than those with paratesticular and scrotal sarcomas {2296,2202}. The most common sites of metastases are the liver and lung. Superficial leiomyosarco­ mas of the penis are usually low-grade, with limited capacity for distant metastasis. However, deep-seated tumours often show aggressive behaviour and are associated with a poor prognosis {663,155,1004}.

Rhabdomyosarcoma

Definition Rhabdomyosarcoma is a family of malignant mesenchymal tumours with skeletal muscle differentiation and includes four major subtypes: embryonal (ERMS), including the botryoid pat­ tern; alveolar (ARMS); pleomorphic (PRMS); and spindle cell / sclerosing (SCSRMS). Ectomesenchymoma contains rhabdo­ myosarcoma intermixed with neuronal/neuroblastic compo­ nents. ICD-0 coding 8910/3 Embryonal rhabdomyosarcoma, NOS 8920/3 Alveolar rhabdomyosarcoma 8912/3 Spindle cell / sclerosing rhabdomyosarcoma

ICD-11 coding 2B55.2 & XH0GA1 Rhabdomyosarcoma of male genital organs & Rhabdomyosarcoma, NOS 2B55.2 & XH83G1 Rhabdomyosarcoma of male genital organs & Embryonal rhabdomyosarcoma, NOS 2B55.2 & XH7099 Rhabdomyosarcoma of male genital organs & Alveolar rhabdomyosarcoma 2B55.2 & XH7NM2 Rhabdomyosarcoma of male genital organs & Spindle cell rhabdomyosarcoma 2B55.2 & XH5SX9 Rhabdomyosarcoma of male genital organs & Pleomorphic rhabdomyosarcoma, NOS Related terminology None

Subtype(s) None Localization ERMS, often the botryoid subtype, is the most common sar­ coma of the urinary tract in children, frequently involving the urethra, urinary bladder, and/or prostate. ERMS is the most common mesenchymal tumour of the paratestis in children, but

McKenney JK Bode PK

SCSRMS and ARMS may also occur (534,1839,1000}. Rhabdo­ myosarcoma of the testicular parenchyma generally represents somatic transformation from teratoma. Rare cases of ERMS have been reported in the kidney {2614}, but most renal neo­ plasms with rhabdomyosarcoma in children represent heterolo­ gous differentiation of Wilms tumour. Rhabdomyosarcomas in the urinary bladder of older adults often represent sarcomatoid differentiation of urothelial carcinoma. Ectomesenchymoma has been reported in the external genitalia, prostate, bladder, and paratestis (409,1413}. PRMS is not typically primary to the geni­ tourinary tract. Clinical features Patients with rhabdomyosarcoma of the genitourinary tract may present with a scrotal mass, haematuria, or urinary retention.

Epidemiology ERMS of the urinary bladder or prostate is the most common sarcoma in children {736}. Paratesticular rhabdomyosarcomas arise predominantly in children and adolescents, with only rare cases in adults (2735,1617}. The exceedingly rare non-Wilms tumour-associated rhabdomyosarcoma of the kidney also occurs predominantly in children {2614). Etiology Patients with germline TP53 alterations (Li-Fraumeni syn­ drome) have an increased risk of rhabdomyosarcoma, often with diffuse anaplasia {2552}. Patients with inherited RASopathy syndromes, such as neurofibromatosis type 1, Noonan syndrome, and Costello syndrome, have an increased risk of ERMS, especially of the urinary bladder and urachus (3071, 1726,1196,2802). Beckwith-Wiedemann syndrome is asso­ ciated with rhabdomyosarcomas of variable type (in ~5% of tumours), some occurring in the urinary bladder {434}. Mosaic variegated aneuploidy syndrome type 1 has an association with ERMS of the urinary bladder, often with the botryoid pat­ tern {1069,1567).

Fig. 10.25 Embryonal rhabdomyosarcoma. A The botryoid type of embryonal rhabdomyosarcoma, such as this tumour in the urinary bladder, is characterized by a cellular condensation of neoplastic cells abutting the epithelium-lined surface. B There is usually strong staining for desmin. C Nuclear staining for myogenin.

Mesenchymal tumours

425

ERMS admixed with neuroblastic components, ranging from scattered ganglion cells to mature ganglioneuroma, intermedi­ ate ganglioneuroblastoma, and neuroblastoma. By definition, all rhabdomyosarcoma subtypes show evi­ dence of skeletal muscle differentiation by immunohistochem­ istry. Desmin is almost always positive, and nuclear myogenin (MYF4) and MYOD1 expression is typically present, albeit highly variable in extent {2219}. Myogenin expression tends to be more diffuse in ARMS. A subset of SCSRMSs with MYOD1 mutations may be negative for myogenin, but nuclear MYOD1 is typically strong and diffuse.

Fig. 10.26 Spindle cell rhabdomyosarcoma of the paratestis. The monomorphic spin­ dle cell morphology and fascicular architecture are characteristic.

Pathogenesis Sporadic ERMS is often aneuploid, with frequent polysomy 8; extra copies of chromosomes 2, 11, 12, 13, and/or 20; mono­ somy 10 and 15; and frequent somatic driver mutations in the RAS pathway (428,2912,3034}. SCSRMS encompasses a group with distinct molecular subtypes, including VGLL2::NCOA2, VGLL2::CITED2, and TFCP2..NCOA2 rearrangements, or MYOD1 mutation {37,59,3446,3212}; however, rhabdomyosar­ coma of the paratestis typically lacks these alterations. Either a PAX3::FOXQ1 fusion or a PAX7::FOXO1 fusion is detected in most ARMSs (1353,2178,2959). PRMSs have complex karyo­ types but no known recurring alterations {1862}. Ectomesenchy­ moma has molecular overlap with ERMS {1413). Macroscopic appearance Regardless of subtype, rhabdomyosarcoma has a bulging, tan, fleshy appearance on cut section.

Histopathology ERMS is morphologically heterogeneous with spindled to fusi­ form cells set in a variably loose myxoid stroma with variable cellularity. Scattered differentiating rhabdomyoblasts are often present. Focal cellular areas in ERMS may resemble ARMS. The botryoid subtype of ERMS contains linear aggregates of condensed tumour cells (cambium layer) that abut an epithe­ lial surface, along with hypocellular polypoid nodules that may appear deceptively bland. Heterologous cartilaginous differen­ tiation is occasionally present in ERMS. ARMS is composed of a monomorphic population of primitive round cells organized into sheets or a nested/alveolar pattern separated by fibrous septa. PRMS is composed of polygonal, round, and spindle cells with variable eosinophilic cytoplasm and marked nuclear pleomorphism. SCSRMS has a monomorphic fascicular spin­ dle cell architecture with an intersecting/herringbone pattern and/or prominent sclerosis with tumour cells set in a densely hyalinized matrix and arranged in cords, nests, microalveoli, or trabeculae. Anaplasia in rhabdomyosarcoma, whether focal or diffuse, is defined by the presence of markedly enlarged (at least three times the size of adjacent nuclei), atypical cells with hyperchromatic nuclei that often have bizarre multipolar mitotic figures {2591). Ectomesenchymoma typically has a pattern of

426

Mesenchymal tumours

Cytology FNA specimens of rhabdomyosarcoma are usually cellular, but ARMS shows higher cellularity than ERMS. ARMS exhibits a round cell pattern with scant cytoplasm and occasionally scat­ tered rhabdomyoblasts and multinucleated giant cells. ERMS is characterized by a primitive spindle cell component (216,1649, 2946,1650,881,1686). Diagnostic molecular pathology Rhabdomyosarcomas with a round cell pattern are potential ARMSs. In approximately 85% of ARMSs, a PAX3::FOXO1 or PAX7::FOXO1 fusion can be detected (2747,899|. Because fusion status is a prognostic factor, molecular testing is strongly recommended. AP-2p, P-cadherin, NOS1, and HMGA2 have been described as useful immunohistochemical surrogate markers for an underlying fusion {1183,2748,3353). Rhabdo­ myosarcoma with spindle cell pattern may represent SCS­ RMS with VGLL2::NCOA2 or VGLL2::CITED2 rearrangements, whereas SCSRMS in the paratesticular region usually lacks these fusions (2228,59). ERMS lacks the PAX3::FOXO1 and PAX7::FOXO1 gene fusions (781}.

Essential and desirable diagnostic criteria Essential: a malignant mesenchymal neoplasm with expression of skeletal muscle markers. Desirable: molecular subclassification.

Staging Rhabdomyosarcoma may be staged using the American Joint Committee on Cancer (AJCC) / Union for International Cancer Control (UICC) system for soft tissue sarcomas; however, stag­ ing for paediatric rhabdomyosarcoma is based on the Inter­ group Rhabdomyosarcoma Study Group (IRSG) system (2005), which is heavily weighted towards the site of origin. Prognosis and prediction Risk stratification for rhabdomyosarcoma is based on staging and fusion-based classification (the IRSG grouping system) {2005). Age and tumour stage are the most important risk fac­ tors in ERMS (1353). The prognosis for fusion-positive ARMS is worse than that for fusion-negative rhabdomyosarcoma and ERMS (1353,2178,2959), and the prognosis of PAX3::FOXO1 ARMS is worse than that for E4X7::FOXO1 ARMS {2959, 3453,2178,899,2875). For SCSRMS, MYOD1 mutation is associated with aggressive disease (2644,37,3212}, whereas VGLL2::NCOA2 and VGLL2::CITED2 rearrangements predict a favourable outcome {59,3446}.

Synovial sarcoma

Definition Synovial sarcoma (SS) is a malignant mesenchymal neoplasm with variable epithelial differentiation and a specific SS姑::SSX

Chen S Suurmeijer AJH

Localization Urogenital SS mainly affects the kidney and prostate {170,1433, 2851,2368,2712}.

fusion gene.

ICD-0 coding 9040/3 Synovial sarcoma, NOS 9041/3 Synovial sarcoma, monophasic 9043/3 Synovial sarcoma, biphasic 9040/3 Synovial sarcoma, poorly differentiated ICD-11 coding 2B5A.Y & XH9B22 Synovial sarcoma, other specified primary site & Synovial sarcoma, NOS

Related terminology None

Subtype(s) Synovial sarcoma, monophasic; synovial sarcoma, biphasic; synovial sarcoma, poorly differentiated

Clinical features Renal SS is associated with abdominal pain followed by haematuria (170,1433}. Intraprostatic SS is associated with dysuria, increased urinary frequency, and nocturia (2368}.

Epidemiology SS of the genitourinary tract is very rare. Patients have a wide age range (15-78 years), and peak incidence is in the third and fourth decades of life {170,1433,2851,2712,2368).

Etiology SS harbours a unique and oncogenic SS78::SSX fusion gene {267}. Pathogenesis The SS18::SSX oncoprotein exerts oncogenic activity by hijack­ ing the targeting and function of the BAF complex as well as disrupting epigenetic control (261,2078}

Mesenchymal tumours

427

Macroscopic appearance Renal SS usually appears as a large, tan, rubbery mass. Cys­ tic change, haemorrhage, and necrosis may be present. The tumour may extend into the inferior renal cava, renal hilum, and perirenal adipose tissue (170,2851,2712}. Intraprostatic SS has similar gross features to those of renal SS {2368}.

Cytology Not relevant

Histopathology Monophasic SS consists of fascicles of monomorphic blue spin­ dle cells with a high N:C ratio, oval to elongated nuclei, and inconspicuous nucleoli. Biphasic SS has epithelial and spindle cell components in varying proportions. Haemangiopericytomalike vessels, wiry collagen, and dystrophic calcification are rela­ tively common. Poorly differentiated SS with spindle or round cell morphology shows greater cellularity and nuclear atypia than other SS, along with high mitotic activity {2851,2712(.

Essential and desirable diagnostic criteria Essential: monomorphic spindle cells showing variable epi­ thelial differentiation, or solid sheets of closely packed small round to short-spindled cells. Desirable: demonstration of SS78::SSX fusion by immunohisto­ chemistry or molecular methods.

Diagnostic molecular pathology Molecular testing is strongly recommended when histology and immunohistochemistry are insufficient to establish a diagnosis.

Staging The American Joint Committee on Cancer (AJCC) or Union for International Cancer Control (UICC) TNM system may be used.

Immunohistochemistry Application of a novel SS78::SSX fusion-specific antibody (267} allows a sensitive and specific diagnosis of SS. In addition, TLE1 shows diffuse nuclear staining in most cases of SS, but it is also expressed in histological mimics such as malignant peripheral nerve sheath tumour and solitary fibrous tumour {3138,1713}.

428

Mesenchymal tumours

Prognosis and prediction Patients with renal or intraprostatic SS have a poor outcome, with metastases to the lung and/or other sites (2851,2368,2712(. In general, prognostic factors include age, size, poorly differenti­ ated histology, and stage {3275,325,1216,3061,3134,1729,3157}.

Extrarenal rhabdoid tumour

de Krijger RR Amin MB

Definition Rhabdoid tumour is a highly malignant tumour, typically com­ posed of sheets of cells that have eccentric pleomorphic nuclei with prominent nucleoli and characteristic intracytoplasmic inclusions, and complemented by a loss of SMARCB1 (INI1) immunostaining and frequent SMARCB1 genetic abnormalities.

ICD-0 coding 8963/3 Extrarenal rhabdoid tumour

ICD-11 coding 2B5F.2 & XH3RF3 Sarcoma, not elsewhere classified of other specified sites & Malignant rhabdoid tumour Related terminology Acceptable: malignant rhabdoid tumour; atypical teratoid/rhabdoid tumour; rhabdoid tumour predisposition syndrome. Subtype ⑥ None

Localization Rhabdoid tumours occur in the soft tissues and viscera of the urinary tract and pelvis, with the exception of the kidney.

Clinical features There are no specific clinical features, but most patients present with the consequences of an abdominal mass. Epidemiology Rhabdoid tumours are rare tumours that occur in infants and young children (mean/median patient age: 1 year), with 80% of patients diagnosed before the age of 2 years. Although con­ genital cases have been described, it is rare to find them in children aged > 3 years {3420}.

Etiology Biallelic inactivation of the SMARCB1 gene, located on chro­ mosome 22q11.23, is the almost universal hallmark of rhabdoid tumour. Inactivation may occur through mutation, segmental chromosomal deletion, or whole-chromosome loss. SMARCB1 mutations may occur in the germline in as many as one third of patients; these patients are affected by familial rhabdoid tumour predisposition syndrome type 1. A small proportion (《5%) of patients with rhabdoid tumour have biallelic inactiva­ tion of SMARCA4, another component of the SWI/SNF complex {2474}. Pathogenesis Because rhabdoid tumours are genetically silent tumours, char­ acterized by SMARCB1 or SMARCA4 inactivation, deregulation of the SWI/SNF chromatin remodelling complex is thought to

Fig. 10.28 Rhabdoid tumour. A Microscopic image of a tumour composed of sheets of cells without differentiation. B Higher magnification of tumour cells with prominent nuclear pleomorphism and occasional prominent nucleoli. The typical feature of rhab­ doid cells with eosinophilic cytoplasmic inclusions was lacking in most of the tumour cells. Compare with Fig. 2.99C (p. 114) in Rhabdoid tumour of the kidney. C SMARCB1 (INI1) immunostaining showing a complete loss of staining in the tumour cells, with the retained labelling of endothelial cells lining small vessels serving as an internal posi­ tive control.

lead to carcinogenesis by its epigenetic effect on the promoter and enhancer regions of other genes.

Macroscopic appearance These are large, highly infiltrative tumours with a haemorrhagic and necrotic appearance. Mesenchymal tumours

429

Histopathology Rhabdoid tumours are composed of sheets of large, non­ cohesive cells with large, vesicular nuclei and one or more prominent eosinophilic nucleoli, growing in a diffuse infiltrative pattern. Many rhabdoid tumours have foci with cells contain­ ing characteristic eosinophilic intracytoplasmic inclusions. Mitoses and necrosis are frequent. Not all tumours are entirely composed of these typical cells and careful analysis for typi­ cal areas is important. Rhabdoid tumours may have different architectural growth patterns, including solid, sclerosing, cys­ tic, cord-like, myxoid, or myxohyaline. In addition, the cellular composition may vary, showing clear cells, spindle cells, or epithelioid cells. Apart from their typical morphology, rhabdoid tumours are characterized by the loss of nuclear SMARCB1 (INI1) staining, which is otherwise universally present in all cells. Thus, normal cells represent an internal positive control for this staining {1558). A limited spectrum of other tumours may also show a loss of SMARCB1 (INI1) staining, including epithelioid sarcoma, synovial sarcoma, chordoma, epithelioid malignant peripheral nerve sheath tumour, and myoepithelial carcinoma, all of which may arise in the same location but in a diverse age group. For rhabdoid tumour with SMARCA4 inactivation, SMARCA4 (BRG1) immunohistochemistry may be used, showing a loss of nuclear staining in tumour cells and normal expression in all other cells {2474}. Such tumours should be distinguished from the rare hypercalcaemic-type small cell carcinoma of the

430

Mesenchymal tumours

ovary, which may occur in a similar location but in women and adolescent girls. Cytology Not relevant Diagnostic molecular pathology Mutation analysis by next-generation sequencing techniques will show SMARCB1 or SMARCA4 mutations. This should be complemented with other techniques to demonstrate the loss of the other allele. Patients with mutations should be referred to clinical genetics for germline analysis and counselling.

Essential and desirable diagnostic criteria Essential: recognition of typical rhabdoid morphology, supported by absent SMARCB1 (INI1) immunostaining; alternative diag­ noses should be excluded (see Histopathology, above). Desirable: demonstration of biallelic SMARCB1 or SMAFICA4 loss. Staging No specific staging system exists for rhabdoid tumours. Most patients present with advanced-stage tumours. Prognosis and prediction Rhabdoid tumours are highly aggressive tumours, with 5-year overall survival rates ranging from 15% to 36% (2474).

Desmoplastic small round cell tumour

McKenney JK Bahrami A

Definition Desmoplastic small round cell tumour (DSRCT) is a malignant mesenchymal neoplasm composed of small round tumour cells associated with prominent stromal desmoplasia, polyphenotypic differentiation, and EWSR1::WT1 gene fusion.

ICD-0 coding 8806/3 Desmoplastic small round cell tumour ICD-11 coding 2B5F.2 & XH5SN6 Sarcoma, not elsewhere classified of other specified sites & Desmoplastic small round cell tumour

Related terminology Acceptable: polyphenotypic small round cell tumour. Subtype(s) None Localization The most common genitourinary site for DSRCT is the paratestis (751}. Rarely, it occurs in the kidney {1079}.

Clinical features Patients with paratesticular tumours present with a palpable mass. Patients with kidney tumours present with haematuria or flank pain. Spread to the intra-abdominal cavity is common. Epidemiology DSRCT primarily affects children and young adults (751,1111), with a striking male predominance. Peak incidence is in the third decade of life.

Etiology Unknown Pathogenesis DSRCTs harbour a t(11;22)(p13;q12) translocation, resulting in EWSR1::WT1 fusion {1777,2828(.

Macroscopic appearance DSRCTs typically have a multilobulated appearance with a white to grey fleshy cut surface. Cystic change and necrosis may be present.

Histopathology DSRCT is characterized by sharply outlined nests of uniform small cells with scant cytoplasm embedded in a prominent des­ moplastic stroma. The nests vary considerably in size, ranging from minute clusters to large, irregular, confluent sheets. Other histological patterns include epithelioid, rhabdoid, corded,

Fig. 10.29 Desmoplastic small round cell tumour. A Sharply outlined nests of neo­ plastic cells set in a desmoplastic stroma. B The individual neoplastic cells are com­ monly uniform small cells with scant cytoplasm.

pseudopapillary, and spindled morphology. Rare cases may show epithelial features (glands or a rosette pattern) or cel­ lular pleomorphism. Mitoses are frequent and individual cell necrosis is common. The desmoplastic stroma is composed of fibroblasts or myofibroblasts embedded in a loose extracellular matrix or collagen. Immunohistochemically, DSRCT has an unusual multiphenotypic expression pattern with reactivity for markers of epithelial, muscle, and neural differentiation. Most cases are immunoreac­ tive for cytokeratins, EMA, and desmin (1110). Distinctive dot­ like cytoplasmic immunoreactivity is seen for desmin and some­ times for keratin. Rare cases may not coexpress cytokeratin and desmin. Myogenin and MYOD1 are consistently negative. Nuclear expression of WT1 (using antibodies to the C-terminus but not the N-terminus) is typical {278,1357}.

Mesenchymal tumours

431

Cytology Not clinically relevant

Staging Soft tissue sarcoma staging is applicable.

Diagnostic molecular pathology The presence of EWSR1 and WT1 gene rearrangements or the EWSR1::WT1 chimeric transcript is characteristic {1112,792,2828).

Prognosis and prediction Spread to the intra-abdominal cavity is common, and the prog­ nosis is poor {3260}.

Essential and desirable diagnostic criteria Essential: sharply defined nests of small round tumour cells (epithelioid or rhabdoid cells in some cases) associated with prominent stromal desmoplasia and coexpression of cytokeratin and desmin. Desirable: EWSR1 and WT1 gene rearrangement.

432

Mesenchymal tumours

Haematolymphoid tumours Edited by: Khoury JD, Menon S

Mature B-cell lymphomas Extranodal marginal zone lymphoma of MALT Diffuse large B-cell lymphoma Plasmacytoma Histiocytic tumours Juvenile xanthogranuloma

Haematolymphoid tumours: Introduction

This chapter discusses haematolymphoid tumours involving the urinary tract and testes (genitourinary tract). Because haemato­ lymphoid neoplasms are often systemic, a particular case can be considered to arise in the genitourinary tract if it is the only or the predominant site of involvement. Otherwise, genitourinary tract involvement would be regarded as secondary. Determin­ ing such cases usually requires radiographic imaging {2703} and could have prognostic implications {929}. Primary haematolymphoid tumours of the genitourinary tract are uncommon. An analysis of SEER data (1998-2015) showed that primary extranodal lymphomas of the testis, kidney, urinary bladder, and prostate accounted for 3.04%, 0.22%, 0.18%, and

Moch H Amin MB

0.01%, respectively, of all localized tumours in those organs {2424}. Most patients are adults. The presenting symptoms depend on the specific organ involved and include testicular swelling, haematuria, pain, and constitutional symptoms {591, 2849,294). Nearly all primary genitourinary tract lymphomas are B-lineage non-Hodgkin lymphomas. The most common are diffuse large B-cell lymphoma, Burkitt lymphoma, extranodal marginal zone lymphoma, and chronic lymphocytic leukaemia / small lympho­ cytic lymphoma (2849,294,599}. Other B-cell lymphomas, T-cell lymphomas, plasma cell neoplasms, and myeloid neoplasms may also involve genitourinary organs (see Table 11.01).

Table 11.01 Haematolymphoid neoplasms that may occur in the male genitourinary system (continued on the next page)

Type of lymphoma

Frequency and common GU anatomical subsite

Usual cellular composition

Usual immunophenotype

Molecular features

Differential diagnosis

Centroblasts, immunoblasts, anaplastic large B cells

Positive for one or more B-cell antigens (CD19, CD20,CD79a,PAX5) along with frequent positivity for CD45,BCL2,CD10,BCL6, and/or IRF4(MUM1)

Clonal IGH

Poorly differentiated carcinoma including metastasis; in testis, spermatocytic tumour and germ cell tumours

Marginal zone B cells admixed with small lymphocytes and plasma cells; reactive lymphoid follicles and lymphoepithelial lesions are rare

Positive for one or more B-cell antigens (CD19, CD20,CD79a,PAX5); negative for CD5, CD10, BCL6, LEF1,cyclinD1,and SOX11

t(11;18) (urinary bladder); t(14;18) (kidney); trisomy 3 (urinary bladder)

Chronic inflammatory infiltrate

Sheets of mature or atypical plasma cells

Positive for CD38, CD138, IRF4(MUM1),and monotypic kappa or lambda light chain

Clonal IGH rearrangement

Plasmacytoid urothelial carcinoma; MALT lymphoma; lymphoplasmacytic lymphoma; lgG4 disease; neuroendocrine tumour (NET)

Mixture of centrocytes, centroblasts, and follicular dendritic cells

Positive for CD20,CD10, BCL6; negative for CD5, cyclin D1, CD43; positive or negative for BCL2

Clonal IGH

Chronic inflammatory process

Medium-sized atypical lymphoid cells with round nuclei, coarse chromatin, numerous mitoses, and tingiblebody macrophages

Positive for CD20.CD10, BCL6.MYC; negative for BCL2; Ki-67 index is typically-99-100%

Clonal IGH; t(8:14),t(2,8), ort(8;22)(MyC); endemic cases EBV+, minority EBV-

Other high-grade lymphomas

Small to medium­ sized blasts with high NC ratio and scant cytoplasm

Positive for CD19, TdT; negative for CD10, CD3, and myeloperoxidase

Clonal IGH; other changes variable

Small round cell tumours

B-cell lymphomas

Diffuse large B-cell lymphoma (2942,1923,2496}

MALT lymphoma (1091,3510)

Plasmacytoma (1002,1637}

Follicular lymphoma (1255,596}

Most common type of high-grade lymphoma of the GU tract Kidney is the most com­ mon subsite

Most common low-grade lymphoma of the GU tract Urinary bladder is the most common subsite

Rare Testis, epididymis, and urinary bladder

Rare in GU tract

Burkitt lymphoma

Rare in GU tract

(2849,3318}

Kidney and testis

B-lymphoblastic leukaemia/lymphoma

Testis and kidney

(3318,1090,3600}

GU, genitourinary; MALT lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; RS, Reed-Sternberg.

434

Haematolymphoid tumours

Table 11.01 Haematolymphoid neoplasms that may occur in the male genitourinary system (continued)

Type of lymphoma

Frequency and common GU anatomical subsite

Usual cellular composition

Usual immunophenotype

Molecular features

Differential diagnosis

Small, medium-sized, and/or large atypical lymphoid cells; necrosis; vascular damage may be prominent

Positive for cytoplasmic CD3,CD2,CD56, granzyme B, perforin; negative for CD5

NK-lineage cases: germline TR, EBV+

High-grade lymphomas; inflammatory process may be confused with NK/T-cell lymphomas with extensive necrosis

Variable; small, medium-sized, and/or large cells

Variable expression of pan-T-cell antigens; positive for CD4 and CD8

Clonal TR

For low-grade cases, chronic inflammatory process; for high-grade cases, other poorly differentiated neoplasms

Small to medium-sized blasts with round, irregular, or convoluted nuclei; finely dispersed to dark chromatin; variably prominent nucleoli; scant cytoplasm; frequent mitoses

Positive for CD3.CD7, TdT,CD1a,CD10; often double-positive for CD4 andCD8

Clonal TR; clonal IGH in a minority

Other high-grade lymphomas; small round cell tumours

RS cells and subtypes in a reactive lymphoid background

Positive for CD15, CD30, CD20 (variable), PAX5; negative for CD3

EBV+in subset of cases

If RS cells are a minor component it may be confused with reactive conditions; if RS cells are abundant it may mimic any other high-grade malignancy

Variably sized (usually medium-sized) blasts with prominent nucleoli; admixed maturing myeloid elements maybe seen; single-file pattern may be seen

Positive for lysozyme, CD33.CD43, CD68 (variable), myeloperoxidase, CD34, KIT (CD117); negative for CD20andCD3

Varied

All large cell lymphomas; metastatic poorly differentiated carcinomas

T-cell and NK/Pcell lymphomas

Extranodal NK/T-cell lymphoma, nasal-type (3214,1416)

Peripheral Pcell lymphoma {6}

^lymphoblastic leukaemia/lymphoma

{231}

Very rare Testis

Very rare

Testis

Very rare Testis

Hodgkin lymphoma

Classic Hodgkin lymphoma

{2876,1096)

Extremely rare as a primary GU tract tumour

Myeloid neoplasms

Acute myeloid leukaemia, myeloid sarcoma

{1984,2768}

Rare in GU tract Testis is the most com­ mon subsite

GU, genitourinary; MALT lymphoma, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue; RS, Reed-Stemberg.

Haematolymphoid tumours

435

Extranodal marginal zone lymphoma of MALT

Definition Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MAU lymphoma) is an extranodal lymphoma composed of marginal zone B cells (centrocyte-like cells), cells resembling monocytoid cells, small lymphocytes, large lymphoid cells resembling centroblasts or immunoblasts, and plasmacytic cells. ICD-0 coding 9699/3 Extranodal marginal zone lymphoma of mucosa-associ­ ated lymphoid tissue

ICD-11 coding 2A85.3 & XH3FE9 Extranodal marginal zone B-cell lymphoma, primary site excluding stomach or skin & Mature B-cell lym­ phomas

Naresh KN Nakamura S Osunkoya AO

Related terminology None

Subtype(s) None Localization MALT lymphoma may occur at any location in the genitourinary tract; the urinary bladder is the most common site (1628,2849, 3510(.

Clinical features The presenting symptoms are location-dependent and may include haematuria, frequency, urinary obstruction, dysuria, and lower abdominal pain (1628,2849}. Some patients are asymptomatic.

Fig. 11.01 MALT lymphoma. A Urinary bladder biopsy shows a urothelium-covered lymphoid lesion with a poorly defined large-nodular pattern. B The centre of the nodule shows clusters of larger cells representing remnants of a reactive germinal centre. C Most of the infiltrate is monomorphic small lymphoid cells with cleaved nuclei and a moder­ ate amount of pale/clear cytoplasm (characteristic centrocyte-like cells). These cells do not have a prominent nucleolus. These cells expressed CD20 and BCL2, and they were negative for CD5, CD10, BCL6, cyclin D1, and S0X11. Ki-67 expression was < 10%. D In parts of the lesion, lymphoid cells show plasmacytic differentiation.

Fig. 11.02 MALT lymphoma of the urinary bladder. A The lamina propria is expanded by sheets of small monomorphic lymphocytes beneath the native urothelium. B Transure­ thral resection of bladder tumour (TURBT) specimen showing aggregates of small lymphoid cells with interspersed hyalinized blood vessels.

436

Haematolymphoid tumours

Table 11.02 Aspects related to the etiopathogenesis of MALT lymphoma of the genitourinary tract Additional information

Agent/aspect

Association

Infective agents, e.g. E. coli

Cystitis or prostatitis

Tumour regresses after treatment of infection with antibiotics

Autoimmune

Autoimmune/interstitial cystitis

-

Structural and numeric chromosomal changes in common with other MALT lymphomas, investigated using FISH studies on paraffin sections

t(11;18)(q21 ;q21) {BIRC3 [API2\::MAU1) - urinary bladder

It may also be useful to investigate fort(3;14)(p14.1 ;q32) (FQYP7::IGH) and t(1 ;14)(p22;q32)(BCLlO::IGH), as well as for trisomy 18, because these abnormalities are seen in MALT lymphomas at other sites

t(14;18)(q32;q21) (IGH::AMm)- kidney

Trisomy 3-urinary bladder

Table 11.03 Key differential diagnoses of MALT lymphoma in the genitourinary tract Key additional features

Entity

Morphology

Small lymphocyte-rich and plasma cell-rich reactive infiltrates

Lymphoid follicles with germinal centres; mature plasma cells

Polytypic light chain expression; polyclonal IG gene rearrangement; also investigate for excess lgG4+ plasma cells

Other small B-cell lymphomas

Some overlap with MALT lymphoma in morphological features

MALT lymphomas typically lack expression of CD5, CD10, BCL6, cyclin D1, SOX11, and LEF1: lymphoplasmacytic lymphoma and Waldenstrom macroglobulinaemia are positive for MYD88 mutation

Extramedullary plasmacytoma

Plasma cell infiltrate that is not accompanied by small B cells; plasma cells may show variable atypia

Cells showing plasmacytoid differentiation in MALT lymphomas do not show expression of CD56, KIT (CD117), or cyclin D1, and these may be expressed by plasma cells of extramedullary plasmacytoma

Diffuse large B-cell lymphoma

Sheets of large nucleolated cells variably admixed with other inflammatory cells including reactive small lymphocytes; cases with variability in the size of the neoplastic cells have > 20% large nucleolated cells

Ki-67 expression is seen in > 50% (often > 80%) of cells

acquired as a result of a chronic inflammatory process or an immunological disorder (see Table 11.02) (3510,2398,2217,2496}.

Epidemiology MALT lymphoma is the most common primary low-grade lymphoma involving the genitourinary tract {1628,2849,1923}. MALT lymphoma of the genitourinary tract accounts for < 5% of extranodal lymphomas and < 1% of all genitourinary tumours. There is a slight female predominance (1923).

Pathogenesis Chromosomal translocations associated with MALT lymphomas have been rarely reported (see Table 11.02) (1970,1091,1736}.

Etiology Because there is no native lymphoid tissue in the mucosa of the genitourinary tract, the lymphoma arises from lymphoid tissue

Macroscopic appearance MALT lymphomas may appear as single or multiple masses that are pale pink or tan in colour and firm, solid, or fleshy, with

Fig. 11,03 MALT lymphoma. A Lymphoid cells express CD20. These were negative for CD5, CD10, and cyclin D1. B CD21 immunostaining identifies collapsed follicular dendritic cell meshworks in the lymphoid infiltrate.

Haematolymphoid tumours

437

overlying distended vessels, erythema, and focal necrosis {294, 2589,1615,3510,1563}.

Table11.04 Immunohistochemistry of MALT lymphoma

Aspect

Markers

n wExpression of one or more B-cell antigens (CD19, CD20, Defining feature CD79&PAX5)

Histopathology The histology is characterized by a diffuse infiltrate of centro­ cyte-like cells with moderate amounts of pale-staining cyto­ plasm accompanied by scattered larger nucleolated cells and cells showing plasmacytic features. Lymphoepithelial lesions are not frequent. Residual reactive follicles with or without fol­ licular colonization by lymphoma cells may be seen. Rare cases show amyloid deposition. Ki-67 expression is usually low (see Table 11.03 and Table 11.04) (1513,3416,1091(. Rare cases may show transformation to diffuse large B-cell lymphoma {2942). Ki-67 immunostaining can be a good aid for this assessment {1091(.

Essential and desirable diagnostic criteria Essential: see Table 11.04. Desirable: see Table 11.04; in addition: demonstration of light chain restriction; demonstration of follicular dendritic cell meshworks using CD21 and/or CD23 immunohistochemistry; low Ki-67 proliferation index.

Cytology On urine cytology, MALT lymphoma is characterized by dis­ persed, single, atypical, small to medium-sized lymphoid cells with a high N:C ratio and hyperchromatic nuclei without nucleoli, and it can mimic urothelial carcinoma {3097}.

Staging The Lugano classification is used for staging extranodal mar­ ginal zone lymphoma. The Ann Arbor staging system has often been used for non-gastric extranodal marginal zone lymphoma {3647A,2598A|. “

Diagnostic molecular pathology Molecular pathology is not essential for the diagnosis (see Table 11.02, p. 437).

Prognosis and prediction It is important to assess for large nucleolated cells in sheets or in a high proportion (> 20%) to exclude progression to diffuse large B-cell lymphoma.

438

Haematolymphoid tumours

Frequently positive

CD45, IgM, BCL2, MNDA, andIRF4 (MUM1)

Negative

CD5, CD10, BCL6, LEF1, cyclin D1,and S0X11

Naresh KN Javaugue V Osunkoya AO

Diffuse large B-cell lymphoma

Related terminology None

Definition Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of medium or large B-lymphoid cells whose nuclei are the same size as, or larger than, those of normal macrophages, or more than twice the size of those of normal lymphocytes, with a dif­ fuse growth pattern.

Subtype(s) None

Localization DLBCL may occur at any location in the genitourinary system; the kidney is the most common site {2849,1923).

ICD-0 coding 9680/3 Diffuse large B-cell lymphoma, NOS

ICD-11 coding 2A81.Z Diffuse large B-cell lymphoma, NOS

Clinical features Signs and symptoms are location-dependent and include haematuria, urinary obstruction, dysuria, back pain, abdominal

GCB-like

First effort based on gene expression analysis (Allzadeh et al., 2000) ABC-like

Genomic classifier (Schmitz et al.. 2018)

MCD Co-occurrence of MYD88 and CD79B mutations

BN2 BCL6 fusions and NOTCH2 mutations

NOTCH1 mutations

EZB EZH2 mutations and BCL2 translocations

Other GCB-like

Other ABC-like

Other unclassified

Genomic classifier (Chapuy et al., 2018)

Cluster 1 BCL6 structural variants and mutations of NOTCH2 signalling pathway components

Cluster 2 TP53 mutations with 17p copy loss; copy Iossof9p21.13 / CDKN2A and 13q14.2/ copy gains 0f1q23.3/MC£7； 13q31.31/miR-17-92 copy gain and 1q42.12copyloss

Cluster 3 BCL2 mutations; SCL2-IGH translocation; mutations in chromatin modifiers, KMT2D, CREBBP, and EZH2; PTEN inactivation

Cluster 4 Mutations in CD83, CD58, CD70, RHOA, GNA13,SGK1,CARD11, NFKBIE, NFKBIA, BRAF, and STAT3

Cluster 5 18q gain; mutations in CD79B and MYD88; gains of 3q,19q13.42, and 18p, and inactivation of PRDM7

Fig. 11.04 Diffuse large B-cell lymphoma. Key stages in the development of genomic classifiers/algorithms in terms of concepts and clinical applications. A Alizadeh et al., 2000 (87}. B Hans et al., 2004 {1285}. C Schmitz et al., 2018 (2847}, D Chapuy etal., 2018 (575). ABC, activated B cell; GCB, germinal-centre B cell.

Haematolymphoid tumours

439

Epidemiology DLBCL is the most common lymphoma of the genitourinary sys­ tem, accounting for < 5% of extranodal lymphomas and < 1% of all genitourinary tumours (1923}. High-grade primary blad­ der lymphomas (most of which are DLBCL) represent roughly 20% of the primary lymphomas of the urinary bladder, which themselves account for just 0.2% of all extranodal non-Hodgkin lymphomas {2942}. There is a slight male predominance in the occurrence of primary genitourinary lymphomas {2849,1923).

Etiology The etiology is mostly unknown {546,673,2132,846).

Fig. 11.05 Diffuse large B-cell lymphoma. Macroscopic image of a testicular tu­ mour. Note the pale/tan and fleshy appearance of the neoplasm. It extends to involve epididymis and base of the cord.

pain, and scrotal swelling (2849,3405). Some patients are asymptomatic.

Pathogenesis DLBCL is usually a de novo malignancy. Less often, it arises as a transformation from an indolent B-cell lymphoma. Primary genetic abnormalities that drive the malignant clone include rearrangements in BCL2 (most frequently), BCL6, and MYC. The precise subclassification of DLBCL based on genomics is an ongoing effort. Immune escape is a major pathway in the pathogenesis of primary testicular DLBCL, with tumours show­ ing genomic alterations in CII7At B2M, and HLA loci (all relevant to antigen presentation). They also show structural rearrange ­ ments of CD274 (PDL1) and PDCD1LG2(PDL2) (87,3233,2847, 575,2632,3083}.

Fig. 11.06 Diffuse large B-cell lymphoma. A Sheets of large neoplastic lymphoid cells replace most of the renal parenchyma. An engulfed glomerulus is appreciated among the malignant lymphoid cells. B Neoplastic cells from the same specimen are large and have scant cytoplasm, irregular nuclear contours, and prominent nucleoli. A few small reactive lymphocytes are also seen accompanying the neoplastic infiltrate. C The neoplastic B cells diffusely and strongly express CD20. D Malignant lymphoid cells from the same specimen show strong IRF4 (MUM1) expression.

440

Haematolymphoid tumours

Table 11 .05 Key differential diagnoses of diffuse large B-cell lymphoma (DLBCL)

Entity

Morphology

Key additional features

EBV+DLBCL

Monomorphic and polymorphic types identified; usually has large areas of necrosis; cells resembling Hodgkin/ Reed-Stemberg cells can be seen

EBV+ (as demonstrated by EBER in situ hybridization) is seen in most lymphoma cells {546}

Monomorphic posttransplant lymphoproliferative disorder of DLBCL type

Similar to DLBCL

Can be EBV+; transplanted kidney can be a site for the development of DLBCL {673}

High-grade B-cell lymphoma with MYC, BCL2, and/or BCL6 rearrangement (2132)

Can be similar to DLBCL, with some features overlapping with those of Burkitt lymphoma

FISH analysis for MYC, BCL6, and BCL2 rearrangements is essential for the confirmation of this diagnosis

Intravascular large B 80% {3517,1405}. For differential diagnosis, see Table 11.05; for immunohistochemistry, see Table 11.06. Cytology In urine, lymphoma cells are large, with an increased N:C ratio in a necrotic/apoptotic background. They are round to oval and have centrally located nuclei with prominent nucleoli {2594}. Urine flow cytometry may be used as an ancillary technique for diagnosis {1525}.

Diagnostic molecular pathology Molecular pathology is not essential for the diagnosis.

Essential and desirable diagnostic criteria Essential: appropriate morphology; expression of CD20 and/or other B-cell antigens. Desirable: absence of CD3, cyclin D1, and TdT expression; CD10, BCL2, BCL6, MYC, and Ki-67 for subtyping and prog­ nosticating, according to Table 11.06. Staging The Lugano system is used to stage lymphomas and has been adopted by the Union for International Cancer Control (IIICC) TNM classification {628A}.

Prognosis and prediction See Table 11.07 {1285,707,3639,118,1538}. Table 11.06 Immunohistochemistry of diffuse large B-cell lymphoma Aspect

Markers

Defining feature

Expression of one or more B-cell antigens (CD19, CD20, CD79a, PAX5)

Frequently positive

CD45, BCL2, CD10, BCL6, IRF4 (MUM1)

CD5 expression in a subset of cases {3517) Rarely positive

Focal expression of cyclin D1 (in the absence of SOX11 expression) (1405}

Always negative

T-cell antigens, TdT, and EBER

EBER, EBV-encoded small RNA.

Table 11.07 Key prognostic predictors (biomarkers) in diffuse large B-cell lymphoma (DLBCL)

Biomarker

Significance

Hans classifier

Subtyping into germinal-centre B-cell and norngerminal-centre categories based on the expression of CD10, BCL6, and IRF4 (MUM1)(1285); the non-germinal-centre type has a poor prognosis

MYC-\G rearrangement

DLBCL with MYC-\G rearrangement is associated with a poor prognosis (707}

MYC expression

MYC expression in > 70% of lymphoma cells is a strong indicator of a poor prognosis (3639,118)

MYC and BCL2 dual expression

Dual expressers are associated with a poor prognosis {1538}

Haematolymphoid tumours

441

Plasmacytoma

Gujral S Ferry JA

Definition Solitary plasmacytoma is a localized plasma cell neoplasm.

ICD-0 coding 9734/3 Plasmacytoma, extramedullary ICD-11 coding 2A83.2 & XH4BL1 Solitary plasmacytoma & Plasmacytoma, NOS 2A83.2 & XH0N40 Solitary plasmacytoma & Plasmacytoma, extramedullary Related terminology None Subtype(s) Solitary plasmacytoma of bone; extramedullary plasmacytoma

Localization Extramedullary plasmacytoma may rarely involve the genitouri­ nary tract including the testis (3419,2280,2529,1002), epididymis

442

Haematolymphoid tumours

Fig. 11.07 Testicular plasmacytoma. A fleshy tan tumour bulges from the cut surface of the testis. The patient had a history of plasma cell myeloma.

(1002), bladder (713,1637}, kidney (2119,80,2204}, and ureter (1685}. Genitourinary plasmacytoma can occur in isolation (soli­ tary) as the first presentation of plasma cell myeloma (PCM), in patients with known PCM {1002,975,2717,3098,1685,713), or as a relapse of treated PCM {2280,2529,146,2341}.

Table 11.08 Genitourinary plasmacytoma: differential diagnosis

Diagnostic entity

Histology

Usual immunophenotype

Associations

Plasmacytoma

Sheets of mature or atypical, immature plasma cells; few admixed cells of other types

CD38+, CD138+, CD20-, CD56+/-, monotypic lg+ (IgG, IgA, or light chain only in most cases), EBER-

Subset of patients have plasma cell myeloma

Chronic inflammation

Lymphocytes, mature plasma cells; fibrosis may be present

Mix of CD3+ T cells, CD20+ B cells, and polytypic plasma cells

Variable

lgG4-reiated disease

Lymphoplasmacytic infiltrate with reactive lymphoid follicles, eosinophils, storiform fibrosis, and obliterative phlebitis

Mix of CD3+ T cells, CD20+ B cells, and polytypic plasma cells; increased proportion of lgG4+ plasma cells

lgG4-related disease in other extranodal sites; lymphadenopathy and/or elevated serum lgG4

Neuroendocrine tumour (NET)

Nests and sheets of epithelial cells, sometimes with peripheral palisading, with slight to prominent atypia, sometimes with eccentric cytoplasm imparting a plasmacytoid appearance

Cytokeratin+, synaptophysin+, chromogranin+

May be associated with metastasis, but marrow involvement is rare

Plasmacytoid urothelial carcinoma

Diffuse growth of discrete cells, often with high­ grade nuclear atypia and eccentric cytoplasm, with little intervening stroma

Cytokeratin+, CD138+, E-cadherin loss is characteristic

Metastatic disease may be present at unusual sites like peritoneum or small intestine serosa

Spermatocytic tumour

Tripartite population of neoplastic cells with small, intermediate, and multinucleated giant cells; fine spireme chromatin; sparse to absent lymphocytes; stroma generally shows oedema

Subset of cells OCT2+; PLAP-

Extratesticular disease is rare; may be bilateral; other types of germ cell tumours are absent

Extramedullary myeloid tumour

Sheets of primitive cells with variable amounts of pink cytoplasm

CD34+, KIT (CD117)+, myeloperoxidase+/-, CD138- CD20-, CD3-

Acute myeloid leukaemia in many cases

Plasmablastic lymphoma

Sheets of plasmablasts with large nuclei, prominent nucleoli, and moderate cytoplasm; frequent mitoses

CD20-, CD79a+/-, CD138+/-, IRF4 (MUM1)+, monotypic lg+/-, HHV8-, high proliferation; EBER+ in most cases

HIV infection; iatrogenic or other immunosuppression

Lymphoplasmacytic lymphoma

Diffuse infiltrate of small lymphocytes, plasmacytoid lymphocytes, and plasma cells

Lymphocytes: CD20+, monotypic lgM+; plasma cells: CD138+, monotypic lgM+

Marrow involvement is common; manifestations of Waldenstrom macroglobulinaemia may be present

MALT lymphoma

Diffuse and vaguely nodular infiltrate of small lymphoid cells with pale cytoplasm, with few to many plasma cells, and reactive lymphoid follicles

Lymphoid cells: CD20+, CD5-, CD10monotypic lg+ (usually IgM); plasma cells (if present) can be monotypic or polytypic

MALT lymphoma is often isolated, but there may be other sites of disease, usually extranodal

EBER, EBV-encoded small RNA; Ig, immunoglobulin.

Clinical features Patients with genitourinary plasmacytoma may present with a mass lesion (1002,975,2717,874} or haematuria {3098,1685}, or they may present without symptoms (713). Rare allograft recipients have developed plasmacytoma-like posttransplant lymphoproliferative disorders involving the kidney or urinary bladder (1754,3098}. Epidemiology Plasmacytoma accounts for 2-5% of all plasma cell neoplasms {1693,869,889}. Solitary plasmacytoma of bone is more com­ mon than extramedullary plasmacytoma {1876(. The median patient age at diagnosis is 62 years, and the M:F ratio is 2.64:1 {889}. Approximately 0.9% of all plasmacytomas are not associ­ ated with PCM {1178), and 3.7% of all isolated extramedullary plasmacytomas arise in the urinary tract or male genital tract {80}. Testicular plasmacytoma is more common than other geni­ tourinary plasmacytomas; however, it is usually associated with PCM (146,1002), occasionally associated with other extramed­ ullary plasmacytomas {1002,1574,2341}, and rarely solitary {80, 2341).

Etiology The etiology is largely unknown. Plasmacytoma is rarely related to immunosuppression (1754,3098).

Pathogenesis Unknown Macroscopic appearance Testicular plasmacytomas are hard and well demarcated from the normal parenchyma (1002). Histopathology Biopsy shows sheets of mature or atypical plasma cells (1002, 975,2717(. Neoplastic cells typically express CD38, CD138, 旧F4 (MUM1), and monotypic kappa or lambda light chain, with a low proliferation index. Some cases express CD56, cyclin D1, KIT (CD117), and CD19, with variable expression of CD45 and CD20 {1040,577,486(. The differential diagnosis for genitouri­ nary tract plasmacytoma is broad (see Table 11.08) (1945,2849, 40,2623}.

Haematolymphoid tumours

443

Cytology FNA at extramedullary sites usually yields cellular smears com­ posed of numerous plasma cells with binucleated and multi­ nucleated forms {1281). Flow cytometry on an aspirate from an extramedullary plasmacytoma may aid in the confirmation of the diagnosis {2519}.

Diagnostic molecular pathology There is a clonal IGH gene rearrangement in solitary plasma­ cytoma; other data are limited for genitourinary plasmacytoma. Essential and desirable diagnostic criteria Essential: a mass lesion composed of clonal plasma cells; absence of clonal B cells; exclusion of multiple myeloma and MALT lymphoma.

444

Haematolymphoid tumours

Staging There is no staging system for plasmacytoma; however, patients should be evaluated for PCM with complete blood count, serum creatinine and calcium, serum and urine protein electrophore­ sis, serum free light chains, radiological evaluation (2602,486), and bone marrow aspiration/biopsy with flow cytometry and/or immunohistochemistry. Prognosis and prediction The prognosis for isolated genitourinary plasmacytoma appears to be favourable (2204,2341}. Patients with PCM have a poor prognosis {1002,146(. Radiation therapy is the standard treat­ ment for solitary plasmacytoma of bone and extramedullary plasmacytoma (486,869,889,1876,1040}. Genitourinary plas­ macytomas are sometimes treated with resection in addition to other therapies {1002,2341}.

Juvenile xanthogranuloma

Alaggio R Cheville J UlbrightTM

Definition Juvenile xanthogranuloma (JXG) is a proliferation of non­ Langerhans cell histiocytes with a favourable outcome except in uncommon cases with systemic dissemination. ICD-0 coding 9749/1 Juvenile xanthogranuloma

ICD-11 coding 2B31.0 Juvenile xanthogranuloma Related terminology Not recommended: xanthogranuloma; solitary xanthogranu­ loma. Subtype(s) None

Localization Solitary JXG in the genitourinary tract is extremely rare, with only a few cases reported in the testis (3078,3430), one in associa­ tion with cutaneous involvement {3184(. Renal JXG is found in the context of disseminated disease (1703). Rarely, the penis is the primary site {2002}. Clinical features Testicular JXG mostly arises as a mass in infants aged 2.513 months. It may be associated with pain. One patient pre­ sented with obstructive uropathy due to ureteric compression by retroperitoneal JXG in an undescended testis {3078}. Dis­ seminated JXG shows multivisceral involvement (1703,880}. A single case in the penile shaft, in a young adult, has been described recently {2002}. Epidemiology No distinct epidemiological findings for testicular cases are known, owing to their rarity. At other sites, JXG has been asso­ ciated with neurofibromatosis type 1 (505}, leukaemia {2493}, Langerhans cell histiocytosis (314}, and Wiskott-Aldrich syn­ drome {3200}. Occurrence in monozygotic twins suggests a genetic predisposition {3108). Etiology Unknown

Pathogenesis There are no molecular studies on JXG of the genitourinary tract. Somatic mutations have been reported in cutaneous JXG, including PIK3CD mutations in 3 cases (91A}, as well as BRAF mutations in CNS lesions (2521} and after Langerhans cell his­ tiocytosis (314}, suggesting a pathogenetic role of MAPK/ERK

Fig. 11.10 Juvenile xanthogranuloma of testis. There are sheets of foamy histiocytes with interspersed capillaries and a sprinkling of eosinophils. A primitive/immature seminiferous tubule can be 叩predated (upper left).

pathway activation. JXG family neoplasms may have ERK path­ way mutations (940}.

Macroscopic appearance JXGs appear as pale-yellow to tan-white masses with occa­ sional fibrous bands {3078}. In the penis they may be solid or cystic and may grossly resemble an epidermal inclusion cyst (2002}. Histopathology JXG is an unencapsulated, well-demarcated, histiocytic pro­ liferation intermixed with variable numbers of lymphocytes, eosinophils, plasma cells, neutrophils, and mast cells. The lesion involves the testicular interstitium, with partial effacement of seminiferous tubules, and it may extend to the epididymis (3078}. The features vary in relation to the temporal evolution. Early lesions show a predominance of small oval to spindleshaped histiocytes with eosinophilic cytoplasm and a minor degree of lipidization. Large xanthomatous histiocytes and multinucleated Touton giant cells with foamy cytoplasm and a ring-like arrangement of nuclei are more frequent in older JXGs {812,3430}. Fibrosis may be present (812,3430}. JXGs are positive for CD68, CD163, factor Xllla, CD4, and fascin, and they are negative for CD1a, CD207 (langerin), and S100. JXG with predominant spindle cells and rare Touton giant cells can mimic a sex cord stromal tumour {3430}. Appropri­ ate immunohistochemical markers can help in differentiating these entities; CD4, CD163, and factor Xllla are positive in JXG, whereas inhibin, SF1, and calretinin are positive in sex cord stro­ mal tumour {2805}.

Haematolymphoid tumours

445

Cytology Not clinically relevant

Staging There is no staging system for JXG.

Diagnostic molecular pathology Not relevant

Prognosis and prediction The prognosis for solitary testicular JXG is excellent. Dissemi­ nated JXG has an overall mortality rate of 5-10% (812.1298A}. BRAFp.V600E-mutated JXGs have been demonstrated to have a more aggressive course in a primary CNS location, but simi­ lar studies have not been done in genitourinary system JXGs (2521}.

Essential and desirable diagnostic criteria Essential: an interstitial histiocytic lesion with variably prominent mixed inflammatory infiltrate; positivity for CD4, CD68, and CD163; negativity for CD1a and CD207 (langerin). Desirable: presence of Touton giant cells.

446

Haematolymphoid tumours

Melanocytic lesions Edited by: Cree IA, Rubin MA

Mucosal melanoma

Scolyer RA

Definition Mucosal melanoma of the male genital tract and urinary system is a malignant melanocytic neoplasm arising in a non-cutaneous urogenital site.

ICD-0 coding 8720/3 Mucosal melanoma 8746/3 Mucosal lentiginous melanoma 8721/3 Nodular melanoma ICD-11 coding 2C9Y & XH5QP3 Other specified malignant neoplasms of uri­ nary tract & Mucosal lentiginous melanoma Related terminology Acceptable: mucosal melanoma; mucosal lentiginous mela­ noma; penile melanoma; urethral melanoma.

Subtype(s) None Localization In the male genital system and urinary tract, these rare tumours typically arise on the glans penis or distal urethra in the fossa navicularis (264,1289,156,2363}. Rarely reported locations include the urinary bladder and proximal urethra (1263,580}. Melanomas involving the kidney or ureter most commonly rep­ resent metastases rather than primary tumours {555}. Melano­ mas of the shaft of the penis usually represent cutaneous mela­ nomas. Clinical features The median patient age at diagnosis is approximately 65 years - about a decade older than for cutaneous melanoma {2449}. Symptoms and signs depend on the anatomical loca­ tion. Patients with penile melanomas usually present with a pigmented or non-pigmented macule or nodule, with or without surface ulceration {269,1872,2716}. Patients with melanomas of the urethra or the proximal urinary system may present with haematuria, dysuria, frequency, or symptoms related to urinary obstruction {2431,442(. Urethral melanomas show no sex pre­ dilection. Epidemiology Primary melanomas involving the male genital system and uri­ nary tract are rare, accounting for < 1% of malignancies at these sites (1972} and < 0.1% of all melanomas (1485).

Etiology The etiology of mucosal melanomas is unknown. Unlike cutane­ ous melanomas, they show no association with ultraviolet (UV) radiation exposure (1314}. 448

Melanocytic lesions

Fig. 12.01 Mucosal melanoma. Clinical photograph of mucosal melanoma involving the glans penis around the external urethral meatus.

Pathogenesis In contrast to cutaneous melanomas, mucosal melanomas show a low mutation burden, without a UV signature. Instead, they are characterized by numerous chromosomal structural variants and abundant copy-number changes, including mul­ tiple high-level amplifications (2315,1314,1066(. The most com­ mon somatic mutations involve SF3B1, KIT, ATRX, TP53, ARID2, SETD2, and BRAF (occurring at a lower frequency than in cutaneous melanomas) (1314,244). Molecular data on mucosal melanoma of the male genital tract and urinary system are lim­ ited. No BRAF or KIT mutations were identified in a series of 12 penile melanomas {2410(. Macroscopic appearance Mucosal melanomas of the penis usually appear as pigmented macules or plaques, but amelanotic ulcerated nodules are also common {3522). Urethral melanomas and melanomas involv­ ing the urinary bladder are usually ulcerated, nodular masses (580). An associated naevus is rarely present (3269}.

Histopathology The tumour is usually formed by sheets or expansive nodules of large pleomorphic epithelioid or (less commonly) spindleshaped malignant melanocytic cells. Necrosis is uncommon. The nuclei often have vesicular chromatin and prominent nucleoli. Occasionally, small or naevoid cells may predominate. Melanin production is variable but usually focally present both within melanoma cells and within macrophages. The junctional component is typically characterized by a lentiginous growth of

single atypical melanocytes in the basal epithelial layer, some­ times with nests or confluent growth (1273). A subepithelial lym­ phocytic infiltrate is common. Immunohistochemically, there is usually reactivity of the tumour cells for S100, SOX10, HMB45, and melan-A (MARTI).

Cytology Urethral or bladder melanoma may be detected by urinary cytology. FNA specimens are usually obtained from metasta­ ses. The typical cytological appearance includes a dissociated population of large epithelioid (or sometimes spindle-shaped) cells (2253}. Isolated giant cells and intranuclear pseudoinclu­ sions are often present. Cytoplasmic pigment is usually present in a minority of cells. Pigmented macrophages may be seen in the background. Diagnostic molecular pathology The characteristic mutations include several with clinical signifi­ cance for treatment. Mucosal melanomas should be tested for BRAF and KIT mutations, in particular when systemic treatment with targeted therapy is being considered {1314,244,2637}. PDL1 testing, tumour mutation burden analysis, and expression of an interferon-y gene signature may provide useful information when systemic treatment with immunotherapy is being consid­ ered.

Essential and desirable diagnostic criteria Essential: a demonstrated malignancy with melanocytic differ­ entiation; relation to the mucosa of the urinary or male genital system; no evidence of previous or synchronous melanoma (exclusion of metastasis); exclusion of differential diagnostic considerations using immunohistochemistry. Desirable: BRAF and KIT mutation screening.

Staging There are no Union for International Cancer Control (UICC) staging criteria for mucosal melanomas of the urinary or male genital system. Prognosis and prediction Unlike cutaneous melanoma, primary melanomas of the male genital tract and urinary system are associated with a relatively poor overall survival (median survival time: 28 months; 5-year survival: 28%) {2449} despite the use of multiple treatment modalities, including surgery, radiotherapy, and systemic thera­ pies {2965,301,365,2973,3288}. This is partly attributable to delayed detection (3197). Treatment of penile melanomas with topical imiquimod has been reported {2286,2829). Outcome after systemic immunotherapy for metastatic mucosal mela­ noma appears to be poorer than that for cutaneous melanoma, but the data are limited {2922}.

Fig. 12.02 Mucosal melanoma involving the glans penis around the external urethral meatus. A The invasive tumour cells are large, pleomorphic, and ovoid to spindled in shape; many include fine intracytoplasmic pigmentation. There are scattered pigment-laden macrophages and lymphocytes in the background. A few scattered single atypical melanocytes are present in the basal portion of the overlying squamous 叩ithelium. B SOX10 immunostain highlighting both the invasive pigmented melanoma and the overlying in situ melanoma. C In s血 mucosal melanoma involving the fossa navicularis of the distal urethra. Numerous moderately atypical melanocytes are present involving the basal half of the squamous epithelium. D SOX10 immunostain highlights the in situ mucosal melanoma involving the fossa navicularis.

Melanocytic lesions

449

Metastases in the genitourinary system Edited by:

Raspollini MR, Srigley JR

Metastasis to the testis and paratestis

Metastases in the genitourinary system: Introduction

In this chapter, the term “metastatic" is used synonymously with "secondary" and therefore includes tumours that involve a given anatomical site either by direct spread from adjacent structures or through haematogenous seeding. In a series of 27 000 necropsies at the Royal London Hospital in the UK, there were 623 secondary neoplasms in the genitourinary tract (kid­ ney: 425; bladder: 155; prostate: 24; testis: 14; penis: 5) (292). In surgical pathology practice, secondary tumours account for 1.6-3% of genitourinary neoplasms {293}.

Fig. 13.01 Carcinoma stomach metastasis to prostate. Metastatic tumour cells from the stomach lying singly in the prostate.

452

Metastases in the genitourinary system

Srigley JR Raspollini MR

In the tight confines of the pelvis there are adjacent urologi­ cal, gynaecological, and gastrointestinal structures that often give rise to cancer. It is therefore not surprising that prostatic and colorectal adenocarcinomas and cervical squamous cell carcinomas are the most common secondary tumours of the urinary bladder. Similarly, urothelial carcinoma of the bladder and colorectal adenocarcinoma are the most common second­ ary tumours affecting the prostate gland. In contrast, secondary tumours of the kidney and testis usually represent haematog­ enous spread from more distant sources (2214(. The possibility of a metastatic tumour at a given anatomical site should be kept in mind especially when the morphological pattern does not conform to the usual tumour morphology seen at that site. The presence of multiple tumours and lymphovascular involvement should also raise suspicion for metastasis. The correct diagnosis can usually be reached by careful morpholog­ ical assessment coupled with knowledge of the clinical picture (especially a history of prior cancer) and immunohistochemistry. Like for all surgical pathology, secondary tumours must always be kept in mind in the context of unusual tumours at a particular site, especially because an antecedent history of malignancy may be lacking or unavailable. Accurate recognition is key for the purposes of classification, prognosis, and treatment. In this chapter, there are dedicated sections on metastatic tumours involving the urinary bladder, kidney, and testis (includ­ ing the paratestis). Secondary tumours of the prostate gland and penis will be briefly covered in the following paragraphs. Secondary tumours in the prostate gland accounted for 2.1% of neoplasms in one large surgical series, with 85% being bladder carcinomas directly invading the prostate gland (291(. These cases are typically easy to diagnose when a history of bladder cancer is present and a typical morphological pattern is seen; however, sometimes poorly differentiated carcinomas involve the prostate and bladder neck, and the histogenesis is unclear. In addition to direct invasion of the prostate, urothelial carcinoma may manifest as an in situ process within the pros­ tate gland. Urothelial carcinoma in situ can spread from the bladder or prostatic urethra to involve the ductal/acinar system and in rare cases may extend into the ejaculatory ducts and seminal vesicles. Some cases of urothelial carcinoma in situ are thought to arise directly from the proximal periurethral prostatic ducts, which normally are lined by urothelium (see Urothelial carcinoma in situ, p. 147), and they are deemed to be primary urothelial carcinomas of the prostatic urethra; most often, though, they occur concurrently or subsequently as a manifes­ tation of multifocality. Markers for urothelial carcinoma (GATA3, p63, high-molecular-weight cytokeratin) and prostatic adeno­ carcinoma (PSA, NKX3-1, PSMA, P501S) are often helpful in establishing histogenesis (137,952}. Similarly, primary urethral adenocarcinomas of the prostatic urethra, such as those with a clear cell, endometrioid, or mucinous histology, may secondar­ ily involve the prostate.

A less common source of local spread is colorectal carcinoma {2404,2401}. These tumours are usually adenocarcinomas, and they often have a mucinous component. The diagnosis is gener­ ally straightforward when there is relevant clinical history and when the typical morphology of colorectal adenocarcinoma is seen. However, there may be specific differential challenges with the mucinous and signet ring-like patterns of prostatic ade­ nocarcinoma and some forms of ductal carcinomas, especially the rare primary mucinous adenocarcinoma of the prostate, which can have a distinctly intestinal morphology (755,2402}. Useful histological features in diagnosing secondary colorectal carcinoma are the presence of tall columnar cells with mucin production, dirty necrosis, villous architecture, mucin-positive signet-ring cells, and fibroinflammatory stroma. Immunohisto­ chemistry for colonic markers (nuclear p-catenin) and prostatic markers (NKX3-1) can be helpful. The prostate gland may be secondarily involved by haematolymphoid neoplasms, and these are covered in Chapter 11: Haematolymphoid tumours. Metastatic solid tumours from distant sites are rare and generally occur in the context of

Fig. 13.03 Ureteric metastasis. Ureteric metastasis from adenocarcinoma of the cervix,

widespread disease; however, exceptionally, a prostatic tumour may be the first manifestation of disease (3591,291,2214}.

Fig. 13.04 Penile metastasis from urothelial carcinoma of the bladder. A There is substantial lymphovascular invasion beneath the normal epithelium of the penile ure­ thra. B Higher-power view of urothelial metastasis to the penis.

Fig. 13.05 Metastatic urothelial carcinoma. A Urothelial carcinoma infiltrating the prostate. B Tumour cells are positive for CK7.

Metastases in the genitourinary system

453

Fig. 13.06 Pagetoid spread from urothelial carcinoma. Pagetoid invasion of the epi­ thelium of the glans penis from urothelial carcinoma of the bladder.

In general, the morphological patterns of metastasis are distinct from the commonplace patterns of prostatic adeno­ carcinoma. Careful microscopy coupled with immunohisto­ chemistry can usually be used to establish a diagnosis. Once again, knowledge of the oncological history is critically impor­ tant. The most common remote sources of metastases to the prostate include lung carcinoma, gastric and pancreatic car­ cinoma, melanoma, renal carcinoma, and (exceptionally) germ cell tumours. Diagnosing small cell neuroendocrine carcinoma (SCNEC) of the lung metastatic to the prostate can be a par­ ticular challenge because SCNEC also occurs de novo in the prostate gland. Clinical history and the presence of a usual prostatic adenocarcinoma component are important in estab­ lishing the correct diagnosis. Immunohistochemistry can also be helpful; however, thyroid transcription factor 1 (TTF1), which is characteristic of pulmonary SCNEC, is also positive in most

454

Metastases in the genitourinary system

cases of prostatic SCNEC. The TMPRSS2::ERG rearrangement in prostatic SCNEC detected by FISH is more useful than ERG immunohistochemistry for the differential diagnosis (2836). The penis is a rare site of metastasis, either through local spread or through a vascular route (318,907,1362). Clinical presentations include priapism, penile pain, enlargement, and ulceration. Roughly 75% of penile metastases represent spread from genitourinary organs, with the bladder and prostate being the most common sites of origin (1362|. Urothelial carcinoma of the bladder or penile urethra and locally advanced prostatic adenocarcinoma can infiltrate penile structures including the corpora spongiosa and cavernosa, skin, and mucosa of the glans. Direct extension into the corpora cavernosa can result in malignant priapism, and histological plugging of the corpus cavernosa vasculature is common. Appreciation of a urothe­ lial carcinoma in situ process in the penile urethra is useful for determining that a tumour is a urethral primary and for distin­ guishing it from mucosally originating primary penile poorly differentiated squamous carcinomas. Renal carcinoma and testicular germ cell tumours may also spread to the penis. The pathological diagnosis of penile metastasis depends on careful morphological assessment (including tumour distribution in the penis) coupled with knowledge of the clinical circumstances. In exceedingly rare circumstances, urothelial carcinoma may manifest as a pagetoid process involving penile squamous mucosa or skin (2972}. This pattern must be distinguished from extramammary Paget disease. Metastases from distal sites account for approximately 25% of secondary penile tumours, with colorectal sites and lung being the more frequent sources {1362}. They are usually part of widespread disease but may occasionally represent a soli­ tary site of metastasis. In exceedingly rare cases, carcinomas of the stomach, pancreas, liver, tonsil, and nasopharynx, as well as haematolymphoid tumours, melanoma, and sarcoma, may spread to the penis.

Metastasis to the urinary tract

Definition Metastases to the urinary tract are neoplasms of non-urothelial origin, from a primary site other than the urinary tract, that have spread to the urinary tract by direct extension or haematogenously. ICD-0 coding None

ICD-11 coding 2E01 Malignant neoplasm metastasis in bladder 2E02 Malignant neoplasm metastasis in other or unspecified urinary system organs

Related terminology Acceptable: secondary tumours of the urinary tract.

Subtype ⑥ None Localization These may occur anywhere in the urinary tract, most commonly in the bladder neck and trigone.

Clinical features Patients often present with haematuria and obstructive uropathy. Incontinence and irritative voiding symptoms may occur because of detrusor involvement. The time interval between the initial primary diagnosis and the development of bladder metas­ tasis ranges from a few months to 30 years (1605,2758}. Epidemiology Secondary tumours constitute 2-3% of all malignancies of the urinary tract, with autopsy studies reporting a higher incidence (as high as 20%) {2214,1273,290}. Most patients are in their fifth

Kaushal S Guo CC Lopez-Beltran A Montironi R

to seventh decade of life, and there is a slight female predomi­ nance (1273,988). Etiology The most common mode of involvement is by direct spread from tumours originating in adjacent organs, including the coIo­ rectum, prostate, and female genital tract. The other mode is by bloodborne metastasis from distant organs, such as the breast, stomach, skin, kidney, and lung. Rare cases of non-primary haematopoietic malignancies and sarcomas involving the uri­ nary tract have been reported (290,988}.

Pathogenesis Tumour spread occurs either by direct spread or via the lymphatic/haematogenous route.

Macroscopic appearance On cystoscopy, a submucosal tumour with normal overlying mucosa is highly suggestive of metastasis {2214,3552}. Histopathology Most secondary tumours involving the urinary tract are adeno­ carcinomas (1273}. Colorectal adenocarcinomas pose a diag­ nostic challenge because their morphology and immunohisto­ chemistry overlap with those of primary bladder and urachal adenocarcinomas. Nuclear expression of p-catenin favours a colorectal primary and contrasts with the membranous expres­ sion seen in primary bladder adenocarcinoma. Presence of an in situ urothelial lesion favours urothelial carcinoma with glandu­ lar differentiation {988,2620,2626}. Metastatic adenocarcinomas of the gynaecological tract usually express PAX8 but not p63 or GATA3. NKX3-1 and PSA expression is helpful in poorly differentiated prostatic adenocar­ cinoma {1590).

Fig. 13.07 Metastasis to bladder from ovarian carcinoma. A This tumour resembles an endometrioid carcinoma. B The nuclei of the ovarian carcinoma stain positively for ER, which helps to confirm the origin of the metastasis.

Metastases in the genitourinary system

455

Fig. 13.08 Metastasis to bladder from lobular breast carcinoma. A Note the single cells with eccentric nuclei in the submucosa. B The nuclei stain positively for ER.

Fig. 13.09 Metastasis to bladder from prostatic adenocarcinoma. A The lesion has produced a polypoid mass. B The tumour cells stain for NKX3-1. C The urothelium stains for CK7 whereas the metastatic tumour cells are negative.

Squamous cell carcinomas of the cervix are morphologi­ cally indistinguishable from bladder urothelial carcinomas with squamous differentiation or pure squamous cell carcinoma. Detection of HPV DNA by in situ hybridization favours a cervical primary. Lobular breast carcinoma mimics the plasmacytoid sub­ type of urothelial carcinoma. Expression of mammaglobin and GCDFP-15 in breast carcinoma can be helpful {988(. Metastasis from other primary carcinomas, melanoma, sar­ comas, and lymphomas can be differentiated by morphology and appropriate immunohistochemistry in conjunction with the clinical history.

Cytology Not relevant

456

Metastases in the genitourinary system

Diagnostic molecular pathology Molecular testing is not currently used because diagnosis is based on clinical history, morphology, and immunohistochemistry.

Essential and desirable diagnostic criteria Essential: a malignant neoplasm of non-urothelial origin, with mor­ phology and phenotype conforming to another primary tumour. Staging Metastases to the urothelial tract are staged by the Union for International Cancer Control (UICC) system according to the primary tumour. Prognosis and prediction Regardless of the origin, metastasis to the urinary tract has a poor prognosis, with a median survival of 20-23 months {1273}.

Metastasis to the kidney

Definition Metastatic tumours of the kidney are epithelial or mesenchymal malignancies that have arisen from another site and spread to the kidney. ICD-0 coding None

ICD-11 coding 2E00 Malignant neoplasm metastasis in kidney or renal pelvis

Related terminology None Subtype(s) None

Cheville J Lopez-Beltran A Montironi R Tamboli P

Localization Metastatic tumours can affect any part of the kidney. Clinical features Metastatic tumours manifesting as renal masses are rare. Metastases that are biopsied or resected frequently occur as an isolated renal mass mimicking a primary renal tumour. A new renal tumour in a patient with a history of a non-renal malig­ nancy that has not progressed is nearly always a new primary renal tumour; in contrast, in a patient with a progressive nonrenal malignancy, it may be a metastasis {2803}.

Epidemiology All types of malignancies have been reported to metastasize to the kidney, affecting both male and female patients with a wide age range {3491). As many as 10% of renal masses evalu­ ated in one centre were metastatic tumours {1097); however, the

Fig. 13.10 Kidney metastasis from colonic adenocarcinoma. A There is a desmoplastic and inflammatory response around the metastatic glands, and the kidney parenchyma is atrophic. B The surrounding renal parenchyma is compressed and atrophic. C CDX2 stain is positive.

Fig. 13.11 Kidney metastasis from lung adenocarcinoma. A Malignant glands extend between the renal glomeruli. B Tumour cells are positive for thyroid transcription factor 1 (TTF1).

Metastases in the genitourinary system

457

overall frequency of non-renal metastases manifesting as renal masses is probably < 1% {3491}. Rarely, a non-renal metastasis may metastasize to a primary renal tumour such as an angiomyolipoma, oncocytoma, or renal cell carcinoma (1391,121,115(. In nearly 90% of cases, the primary tumour is known before a diagnosis of metastatic tumour to the kidney is made, and rarely is the diagnosis of the primary tumour made by evaluation of the renal mass (3491). Most metastatic tumours (> 80%) are carci­ nomas, and lung is the most frequent primary, but non-epithelial tumours have been reported as well as multiple primary tumour types {3491(.

Etiology Unknown Pathogenesis Most metastases to the kidney are believed to occur through haematogenous spread. Secondary involvement by direct exten­ sion, such as from a retroperitoneal sarcoma, may also occur. Macroscopic appearance Tumours typically manifest as a solid mass with a variable appearance, but occasionally metastases can be cystic (3491}.

Histopathology The histopathological features reflect the primary origin of the tumour. There is usually locoregional spread of the tumour, with involvement of the renal sinus fat or perinephric fat. Thyroid car­ cinomas of all types can metastasize to the kidney and must be distinguished from thyroid-like follicular carcinoma of the kidney

458

Metastases in the genitourinary system

(129}. Thyroid-like follicular carcinoma is non-reactive for thyroid transcription factor 1 (TTF1) and thyroglobulin, whereas meta­ static thyroid carcinoma should be positive for these proteins. PAX8 can be positive in both. Tumour-to-tumour metastases may occasionally involve primary benign and malignant renal tumours (115,661|. Cytology Cytological examination of a renal mass may be useful in iden­ tifying a metastatic tumour, particularly in patients with another known primary tumour, and may avoid unnecessary surgery (1097,3619}.

Diagnostic molecular pathology Not relevant

Essential and desirable diagnostic criteria Essential: a renal mass with morphological features of a nonrenal site of origin. Desirable： a known history of the primary malignancy; confirma­ tory immunohistochemistry. Staging Metastases to the kidney are staged using the Union for Interna­ tional Cancer Control (UICC) system according to the primary tumour. Prognosis and prediction The prognosis is dependent on the type and extent of the pri­ mary malignancy.

Metastasis to the testis and paratestis

Montironi R Lopez-Beltran A MochH

Definition Metastases to the testis and paratestis are tumours that involve the testis or paratestis via a haematogenous or lymphatic path­ way but that do not originate from these structures. ICD-0 coding None ICD-11 coding 2E06 Malignant neoplasm metastasis in male genital organs Related terminology None

Subtype(s) None

Fig. 13.12 Colon adenocarcinoma metastatic to the paratestis. This colonic adeno­ carcinoma (colloid/mucinous type) has produced a mass adjacent to the testis.

Localization Testis and/or paratestis {775)

Etiology Unknown

Clinical features Metastases to the testis and paratestis usually occur in patients with a history of cancer {3255}. In 10% of cases, the first mani­ festation is testicular enlargement, a palpable testicular mass, or hydrocoele (2214}. Metastases occur mainly in adulthood, but uncommon cases may arise in children {123}.

Pathogenesis Metastasis may take several routes: retrograde lymphatic exten­ sion from para-aortic lymph nodes, spermatic vein extension, or arterial embolism (1280).

Epidemiology Metastasis accounts for 2.4-3.6% of testicular tumours, and 8.1% of malignant tumours of the paratestis are metastatic. Most metastases are from the prostate (33%) or lung (20%), with other sources being skin melanoma (8%), appendix and colo­ rectal malignancy (8%), kidney (6%), stomach, and pancreas {468,462,2569,2737}. Haematopoietic tumours may involve the testis {1002}. In children, sources include neuroblastoma, Wilms tumour, and rhabdomyosarcoma {907}.

Macroscopic appearance Metastatic tumours are most commonly a solitary nodule (62% of cases, with equal distribution between the left and right testes), or they are multiple nodules (17% of cases). In 21% of cases there is diffuse involvement of the organ (2214|. Histopathology A multitude of secondary tumour types can be seen. The most common growth patterns are interstitial (40% of cases), destructive (26%), and nodular (21%). Intratubular growth can be observed in lymphomas and in carcinomas from the

Fig. 13.13 Prostate cancer metastatic to the testis. A The metastasis has produced a solitary nodule, as seen in a whole mount. B An interstitial growth pattern is present in this field. C The neoplasm is intensely positive for PSMA.

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Table 13.01 Secondary neoplasms of the testis and paratestis that pose diagnostic challenges, and the primary tumours they mimic Secondary neoplasm

Primary tumour mimicked

Testis

Metastatic adenocarcinoma Merkel cell carcinoma Carcinoma of the prostate

Renal cell carcinoma

Melanoma

Sertoli cell tumour Lymphoma

Well-differentiated NET Leydig cell tumour Sertoli cell tumour

Seminoma Lymphoma Leydig cell tumour

that pose diagnostic challenges and the primary tumours they mimic. Appropriate immunohistochemical studies are usually nec­ essary for the identification of the origin of metastatic tumours {123}. Lineage-directed markers (e.g. PSA) are helpful but must be used with caution because some patterns overlap with those of primary tumours {2214).

Cytology FNA cytology has a limited role in the diagnosis of metastases. Metastases can appear cytologically indistinguishable from pri­ mary tumours of the testis (1356). Diagnostic molecular pathology Not clinically relevant

Paratestis

Mesothelioma Metastases from the gastrointestinal tract, lung, pancreas, etc.

Epididymal carcinoma Rete testis carcinoma

Ovarian-type tumours Carcinoma with signet-ring cell features

Adenomatoid tumour

Renal cell carcinoma NET, neuroendocrine tumour.

prostate, kidney, and bladder. Infiltration of the rete testis can mimic a primary rete testis carcinoma. Table 13.01 summa­ rizes the secondary neoplasms of the testis and paratestis

460

Metastases in the genitourinary system

Essential and desirable diagnostic criteria Essential: a testicular or paratesticular mass with morphological features of another site of origin. Desirable: known history of the primary malignancy; confirma­ tory immunohistochemistry. Staging Metastases to the testis and paratestis are staged using the Union for International Cancer Control (UICC) system accord­ ing to the primary tumour.

Prognosis and prediction Metastasis indicates advanced disease and a poor prognosis. The diagnosis helps determine the appropriate therapy (12}.

Genetic tumour syndromes of the urinary and male genital tracts Edited by: Gill AJ, Lax SF, Lazar AJ, Rubin MA

― _

Von Hippel-Lindau syndrome Birt-Hogg-Dube syndrome Hereditary papillary renal carcinoma Hereditary leiomyomatosis and renal cell carcinoma syndrome Succinate dehydrogenase-deficient tumour syndromes gAp[ tumour predisposition syndrome Hereditary phaeochromocytoma-paraganglioma syndromes Tuberous sclerosis Genitourinary system and Lynch syndrome Hereditary tumour syndromes associated with homologous recombination pathway mutations Carney complex Peutz-Jeghers syndrome

留螃 FjnnSP

Genetic tumour syndromes of the urinary and male genital tracts: Introduction

In the genitourinary system, neoplasia arises because of patho­ genic variants in DNA (mutations) and other genomic altera­ tions {1279). These mutations may be somatic, i.e. acquired postzygotically and present only in the affected tumour cells (or sometimes in a region of the body or cellular lineage, as seen in somatic mosaicism), or they may be constitutional, meaning they are present in all cells within the body. Constitutional muta­ tions are most often inherited in the germline contribution from an affected individuaPs parents (rather than acquired by spon­ taneous mutation in early embryonic life). Tumours may be characterized as sporadic (i.e. not associ­ ated with genetic predisposition) or genetic (e.g. hereditary or familial). Hereditary or familial tumours, arising through germline mutations present throughout all cells in an individual, are often associated with syndromic phenotypic features that co-occur because of context-dependent manifestations of mutations in different organ systems. Many, but not all, of the genetic tumour syndromes described within this chapter have multiorgan mani­ festations of varying neoplastic, malignant, or other pathophysi­ ological consequences. Importantly, individual tumour types defined within the WHO Classification of Tumours may arise with varying incidence rates and either sporadically or within certain tumour syndromes. For example, the vast majority of papillary renal cell carcinomas

(RCCs) are sporadic, rather than being part of the hereditary papillary RCC syndrome driven by germline MET mutation. In contrast, the overwhelming majority of succinate dehydroge­ nase-deficient RCCs and the majority of fumarate hydratase­ deficient RCCs arise in the setting of germline mutation {526}. Determining whether a tumour has arisen in the context of a genetic tumour syndrome requires correlation of clinicopathological and genetic features with other features. Therefore, this fifth-edition WHO classification of urinary and male genital tumours has assigned new names to certain tumour types (e.g. fumarate hydratase-deficient RCC) to avoid the conflation of diagnosis of histological type and syndrome using prior diag­ nostic terminology. Next-generation sequencing has become increasingly inex­ pensive and widely available, but it poses important conceptual challenges in the determination of whether a given mutation observed from profiling a tumour represents a constitutional (usually implicitly germline) mutation or an acquired somatic mutation within the tumour itself {1034}. This particular scenario is important, because observing mutations of a gene causative of a genetic tumour syndrome in somatic sequencing studies of a tumour sample does not necessarily imply that it is germ­ line. Only by comparison with paired sequencing of uninvolved tissues (usually peripheral blood), generally in the context of

Table 14.01 Genes associated with genetic tumour syndromes in the genitourinary tract (continued on the next page) Genes*

Syndromeb

BAP1

BAP1 tumour predisposition syndrome

RCC, renal cysts

614327

AD

BRCA1, BRCA2, ATM, CHEK2, LB2, BRIP1, NBN(NBS1), RAD51C,and RAD51D

Multiple, related to homologous recombination pathway

PCa, UC

Multiple

CDC73

Hyperparathyroidism­ jaw tumour syndrome

Renal cysts, renal mixed epithelial and stromal tumours

FH

Hereditary leiomyomatosis and renal cell carcinoma syndrome

FLCN GSTM1

闵

Protein

Protein function

3p21.1

BAP1

Deubiquitinase enzyme interacting with BRCA1 and regulating multiple cancerassociated pathways

AD, other

Multiple

Multiple

145001

AD

1q31.2

Parafibromin

Component of complex associating with RNA polymerase II

RCC

150800

AD

1q43

Fumarate hydratase

Citric add cycle enzyme

Birt-HoggrOube syndrome

RCC

135150

AD

17p11.2

Folliculin

GTPase-activating protein regulating mTORCI signalling

No syndrome

UC

N/A

P

1p13.3

GSTM1

Enzymatic detoxification of numerous drugs and toxins

GU tumoursc

MIMbd

Inheritance*

Locus

Repair of double-stranded DNA

AD, autosomal dominant; GU, genitourinary; ILHSCN, intratubular large cell hyalinizing Sertoli cell neoplasia; LCCSCT, large cell calcifying Sertoli cell tumour; P, predisposition syndrome with less penetrance; PCa, prostatic adenocarcinoma; RCC, renal cell carcinoma; UC, urothelial carcinoma. aHuman Genome Organisation (HUGO) gene names. Prevalent syndrome name. Associated tumour types in the genitourinary tract. dPhenotype MIM number. Characteristic inheritance pattern.

462

Genetic tumour syndromes of the urinary and male genital tracts

Table 14.01 Genes associated with genetic tumour syndromes in the genitourinary tract (continued)

Genes3

Syndromeb

GU tumours6

Minr

Inheritance6

Locus

Protein

Protein function

HOXB13

Hereditary prostate cancer

PCa

610997

P

17q21.32

HOXB13

Transcription factor

MET

Growth factor receptor

Hereditary papillary renal carcinoma

Papillary RCC

605074

AD

7q31

c-Met

MLH1,MSH2, MSH6, PMS2, EPCAM

Lynch syndrome

UC, PCa

Multiple

AD

Multiple

Multiple

DNA mismatch repair

NAT2

N/A; slow and fast acetylation phenotypes

uc

243400

p

8d22

NAT2

Enzymatic detoxification of arylamine and hydrazine drugs

Numerous

Multiple hereditary phaeochromocytomaparaganglioma syndromes

Paragangliomas (and various other tumours)

Multiple

AD, multiple

Multiple

Multiple

Various

PRKAR1A

Kinase complex regulatory subunit

PRKAR1A

Carney complex

LCCSCT (testis)

160980

AD

17q24.2

PTEN

Cowden syndrome

PCa, RCC

158350

AD

10q23.31

PTEN

Protein and lipid phosphatase

SDHA, SDHB, SDHC,SDHD, SDHAF2

Succinate dehydrogenase ­ deficient tumour syndromes

RCC, paragangliomas

AD

Multiple

Succinate dehydrogenase

Citric add cycle enzyme subunit; mitochondrial complex II

STK11

Peutz-Jeghers syndrome

ILHSCN (testis)

175200

AD

19p13.3

STK11

Kinase

TSC1, TSC2

Tuberous sclerosis

Angiomyolipomas, RCC, renal cysts

191100; 613254

AD

9q34; 16p13.3

Hamartin, tuberin

mTOR signalling regulation

VHL

Von HippekLindau syndrome

Renal cysts, RCC,叩ididymal cystadenoma

193300

AD

3p25.3

VHL

Regulation ofHIF degradation

Multiple

AD, autosomal dominant; GU, genitourinary; ILHSCN, intratubular large cell hyalinizing Sertoli cell neoplasia; LCCSCT, large cell calcifying Sertoli cell tumour; P, predisposition syndrome with less penetrance; PCa, prostatic adenocarcinoma; RCC, renal cell carcinoma; UC, urothelial carcinoma. aHuman Genome Organisation (HUGO) gene names. Prevalent syndrome name. Associated tumour types in the genitourinary tract.叩henotype MIM number. ^Characteristic inheritance pattern.

genetic counselling and germline testing, can a genetic diagno­ sis be definitively established (1865}. Contemporary practice increasingly emphasizes a growing role of the pathologist and of histopathological correlation in the recognition of hereditary tumour syndromes (35). Not only has the emergence of next-generation sequencing strategies facilitated the detection of mutations (whether from tumour or germline profiling), in many cases increasing the suspicion for genetic syndromic disease, but also immunohistochemical markers have been increasingly deployed to facilitate the rec­ ognition of tumour types suggestive of syndromic disease {145}. Although in many cases the relative prevalence of sporadic

versus genetic syndrome-associated examples of each histo­ logical tumour type is not fully understood, the increasing use of immunohistochemical markers that can prompt the consid­ eration of genetic disease renders this an area of increasing salience in diagnostic practice. The sections in this chapter on genetic tumour syndromes describe key syndromes and genetic tumour predispositions involving the genitourinary tract that, at present, are best char­ acterized and clinically actionable. Table 14.01 summarizes the genes involved in these conditions, as well as noting selected additional genes for which a growing body of data supports their relevance to genitourinary tumours.

Genetic tumour syndromes of the urinary and male genital tracts

463

Von HippekLindau syndrome

Rao P Gill AJ

Definition Von Hippel-Lindau syndrome (VHL) is an autosomal dominant disorder caused by pathogenic germline variants of the VHL tumour suppressor gene, located on chromosome 3p25.3 and characterized by the development of haemangioblastoma of the CNS and retina, clear cell renal cell carcinoma (CCRCC), phaeochromocytoma, pancreatic neuroendocrine tumours (NETs), and endolymphatic sac tumours.

MIM numbering 193300 Von Hippel-Lindau syndrome; VHLS

ICD-11 coding 5A75 Adrenomedullary hyperfunction Related terminology Acceptable: von Hippel-Lindau disease.

Subtype ⑥ VHL types 1,2A, 2B, and 2C Localization Kidney; testis; adrenal gland; pancreas; CNS

Clinical features Tumours associated with VHL in the urinary tract include renal cysts, renal cell carcinoma (RCC), and epididymal cystade­ noma {1967,1087}. Multiple bilateral renal cysts are a frequent manifestation and can be seen in as many as 70% of patients with VHL About 30% of patients develop RCCs over their life­ time; these are usually of the clear cell type and may manifest as bilateral renal masses that arise at a younger age than do

Fig. 14.01 Von Hippel-Lindau syndrome. Gross image of a kidney from a patient with known von Hippel-Lindau syndrome. There are multiple cystic lesions as well as solid areas of clear cell renal cell carcinoma.

sporadic CCRCCs )2313,1631}. Epididymal cystadenomas are reported in as many as 60% of men with VHL; when bilateral, they are considered virtually pathognomonic of VHL (1141). VHL can be divided into two broad clinical subtypes based on the genotypic-phenotypic correlation. Type 1 VHL is associ­ ated with retinal and CNS haemangioblastoma and RCC, but not phaeochromocytoma. Type 2 VHL includes phaeochromocytoma. Type 2 VHL is further categorized into type 2a (low risk of RCC); type 2b (high risk of RCC); and type 2c, which only occurs with phaeochromocytoma (644,3317). In addition to developing tumours of the genitourinary tract, patients also have a high propensity to develop retinal and CNS haeman­ gioblastomas, pancreatic islet cell tumours, and endolymphatic sinus tumours {1995(.

Fig. 14.02 Von Hippel-Lindau syndrome. A A cystic lesion in the kidney in a patient with von Hippel-Lindau syndrome. Although this bears a superficial resemblance to clear cell papillary renal cell tumour, this is best considered a precursor lesion to clear cell renal cell carcinoma. B Clear cell renal cell carcinoma arising in von Hippel-Lindau syn­ drome. This tumour is morphologically indistinguishable from sporadic clear cell renal cell carcinoma.

464

Genetic tumour syndromes of the urinary and male genital tracts

Epidemiology The estimated incidence of VHL is 2.8 cases per 100 000 live births. It is inherited as an autosomal dominant trait with a pen­ etrance of > 90% (1141).

Etiology The VHL gene is a tumour suppressor gene located on the short arm of chromosome 3. It encodes VHL protein, a tumour sup­ pressor protein involved in cellular signalling pathways. Most patients with VHL inherit a germline mutation of the VHL gene from affected parents and a wildtype gene from the unaffected parent {1802,1141,1995,203}. Pathogenesis Although the majority of cases of VHL are familial, as many as 20% are due to a new sporadic mutation. The development of VHL-associated disorders is explained by the classic theory of the Knudson two-hit hypothesis, which postulated that both VHL alleles are inactivated by the mutation and deletion of the VHL gene, resulting in the functional loss of the tumour suppres­ sor gene (1143,2926). VHL protein plays a key part in cellular oxygen sensing by targeting HIFs for ubiquitination and proteasomal degradation. Biallelic inactivation of VHL, resulting in the loss of function of VHL protein and subsequent accumulation of HIF with downstream effects on cellular metabolism and dif­ ferentiation, is thought to be the basis of tumorigenesis in VHL {605,1141,2927}.

Macroscopic appearance Renal cysts may be simple or complex and are frequently bilat­ eral. RCC arising in the setting of VHL may appear as a solid or cystic mass and is grossly indistinguishable from sporadic CCRCC (636). Epididymal cystadenoma appears as a wellcircumscribed brown or yellow tumour nodule with a cystic or haemorrhagic cut surface with visible papillary fronds.

Histopathology Renal cysts occurring in the setting of VHL are lined by clear cells with low-grade nuclei that may show a single layer or mul­ tiple layers of epithelium and may be classified as benign or atypical. Benign cysts typically show a single layer of epithelial lining the cyst walls. Atypical cysts show a cyst wall lining that is two or three cell layers thick with focal papillary tufting. RCC arising in the VHL setting is typically of the clear cell subtype. Tumours may be unifocal or multifocal and bilateral, and they are usually of low nuclear grade (2990,605). Some RCCs aris­ ing in the setting of VHL have a morphological resemblance to clear cell papillary renal cell tumour, including a tubulopapillary growth pattern, small papillary tufts, and branched tubules with apically arranged nuclei. However, the molecular and immuno­ histochemical profile of these tumours (negative or focal CK7 reactivity, diffuse expression of CD10, and diffuse staining for CAIX (3469)) is more in keeping with CCRCC. Because these tumours show the classic 3p deletions that are observed in VHL-associated RCCs, they are best classified as CCRCC, despite the unusual morphology. Epididymal cystadenomas and phaeochromocytomas occurring in the setting of VHL are histologically identical to those that occur in sporadic settings.

Fig. 14.03 Von Hippel-Lindau syndrome. Clear cell renal cell carcinoma in von Hippel-Lindau syndrome showing areas that resemble clear cell papillary renal cell tu­ mour. These areas may show a tubullopapillary growth pattern, papillary tufting, and apically located nuclei.

Cytology The cytology of VHLassociated tumours is similar to that of their sporadic counterparts. Diagnostic molecular pathology The VHL gene consists of three exons and encodes two iso­ forms of VHL protein, each containing 213 amino acid residues (1897,1007). Inactivating gene deletions, frameshifts, and mis­ sense mutations of the gene have been implicated in VHL The sensitivity of molecular genetic analysis of VHL through sequencing and deletion/duplication studies approaches 100%. Type 1 VHL is predominantly associated with large dele­ tion or truncation mutations and type 2 VHL is associated with missense mutations {70,3039,644,3317}. The loss of the p arm of chromosome 3 in CCRCC serves as a potential diagnostic marker and may be detected by FISH or other copy-number assessment techniques {3460,1985}.

Essential and desirable diagnostic criteria Essential: identification of a single VHL tumour (e.g. retinal or CNS haemangioblastoma, CCRCC, phaeochromocytoma, pancreatic endocrine tumour, or endolymphatic sac tumour) in an at-risk relative; or, in a patient without a positive family history, the presence of two tumours. Desirable: identification of a heterozygous germline VHL patho­ genic variant on molecular genetic testing establishes the diagnosis if clinical features are inconclusive (3310}. Staging The renal carcinomas are staged according to the eighth-edi­ tion Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) classification.

Prognosis and prediction Metastatic CCRCC is responsible for 35-45% of deaths of patients with VHL (and is historically the leading cause of death in VHL), although deaths due to metastatic CCRCC have decreased in recent years because of improved surveillance. Ultimately, the prognosis depends on the tumour type and stage at the time of presentation.

Genetic tumour syndromes of the urinary and male genital tracts

465

Birt-Hogg-Dube syndrome

Merino MJ Cunha IW Margulis V

Definition Birt-Hogg-Dub6 syndrome (BHD) is an autosomal dominant tumour predisposition syndrome associated with pathogenic germline variants in the FLCN gene. It is characterized by skin lesions (fibrofolliculomas, trichodiscomas, and acrochordons), lung cysts that predispose to pneumothorax, and renal tumours. MIM numbering 135150 Birt-Hogg-Dube syndrome; BHD

ICD-11 coding LD27.5 Genetic hamartoneoplastic syndromes affecting the skin Related terminology None

Subtype(s) None

Localization The skin lesions show a predisposition for the face, neck, and upper torso {1475,3207,2844(. In the lung, in contrast to the api­ cal location seen in most cases of sporadic pneumothorax, the cysts associated with BHD are predominantly basal {1071,1232, 3168). Clinical features BHD was first described in 1977 as a hereditary condition in a large Canadian family affected with small papules predomi­ nantly in the face and neck {361). Recently the syndrome has been redefined, and it is now known that BHD is an autoso­ mal dominant genodermatosis that predisposes patients to the development of skin fibrofolliculomas, trichodiscomas, and acrochordons, as well as to spontaneous pneumothorax, lung cysts, and renal tumours {2579,2844). It has been reported that patients with BHD have a 15-30% increased risk of developing renal tumours (3179). BHD can be suspected when the characteristic triad of facial skin papules, renal tumours, and lung cysts is diagnosed in the patient. The clinical manifestations frequently appear in patients aged > 20 years, and the hallmark of BHD is the presence of multiple skin papules, predominantly on the face, neck, and scalp {2844}. The number of lesions varies between patients, even among members of the same family, but usually the pres­ ence of > 10 lesions is considered highly suspicious for the syndrome. The papules are 2-3 mm in size, painless, and his­ tologically consistent with fibrofolliculomas. The skin phenotype appears to be less severe in female patients, as well as in male patients that develop the lesions late in life.

466

Fig. 14.04 Birt-Hogg-Dub6 syndrome. The renal tumours are usually well circum­ scribed, with a pale to tan colour.

Some patients give a history of chest pain and spontaneous pneumothorax not related to trauma. CT of the lungs may reveal multiple cysts in both lungs, more frequently in the lower lobes. These cysts have been identified even in very young children. They can be asymptomatic and an incidental finding during the evaluation of the patient. Cysts are, however, a very common finding in patients with BHD. On rare occasions, patients may present with cysts and renal tumours in the absence of skin lesions {2321). Some authors have reported the presence of colonic polyps in these patients, but whether they are a coincidence or part of the syndrome has not been established yet. Other tumours seen in some patients include parotid gland tumours (oncocy­ tomas) and lipomas. Approximately 15-30% of patients will develop multiple and bilateral renal tumours at an average age of 45 years, with an M:F ratio of 2.5:1. Overall, it is estimated that 35% of BHDaffected families with germline FLCN (BHD) mutations contain individuals who are affected with renal tumours (2472,3586}. The number of renal tumours present in affected individuals var­ ies from 1 to > 40, with an average of 5.3 tumours per patient. Epidemiology BHD is a rare syndrome. It is estimated that 400-500 families have been identified and studied. Etiology The BHD disease locus maps to chromosome 17p11.2, and germline mutations have been identified in the FLCN gene, which encodes folliculin {2846.2844J. Uniparental disomy (also known as copy-neutral loss of heterozygosity) and some

Genetic tumour syndromes of the urinary and male genital tracts

copy-number variations have been reported in BHD-related renal cell carcinomas (RCCs) with variable histology {1462|. Pathogenesis Folliculin plays a role in the regulation of TFE3 and TFEB tran­ scriptional activity, amino acid-dependent mTOR activation, TGF-p signalling, PGC1a-driven mitochondrial biogenesis, and autophagy {2844,2610,2843,2269}.

Macroscopic appearance All the tumours have a solid appearance with a brown mahog­ any to yellowish colour, and they can range in size from 4 to 110 mm (mean: ~25 mm). Occasionally a central white scar can be present. The tumours are scattered throughout the renal parenchyma and surrounded by areas of normal-appearing renal tissue. Histopathology BHD-related renal tumours demonstrate a range of morpholo­ gies but all share a predominantly eosinophilic/oncocytic differ­ entiation {2473,1070}. These include tumours with morphologies resembling oncocytoma and chromophobe RCC (ChRCC), but also hybrid tumours with mixed oncocytoma-chromophobe features that may not precisely fit into any type, as well as clear cell renal cell carcinoma (2473,3207,3209}. Among the 130 tumours from 30 patients reported by Pavlovich et al. (2473}, the most common type were hybrid tumours (50%) followed by chromophobe tumours (45%) and

oncocytomas. Clear cell renal cell carcinoma has also been reported in some patients with BHD. Hybrid tumours were originally described by Tickoo et al. {3161} and are characterized by the presence of oncocytoma and chromophobe cells that are found coexisting within the same tumoural nests. The population of chromophobe cells identified in hybrid tumours may vary, even within the same tumour, from cells with clear pale cytoplasm and crisp borders usually exhibiting round, dark nuclei to cells with granular eosin­ ophilic cytoplasm that in some cases form irregular groups or nests. Eosinophilic cells with perinuclear clearing (haloes) are also present. Typically, hybrid tumours form nodules with an admixture of all these cell types of chromophobe and oncocytoma-like cells. These tumours are well circumscribed and not encapsulated. Sometimes, a central myxohyaline scar (as seen in oncocytomas) is present. The average size for hybrid tumours is 19 mm. The architectural growth pattern seen in hybrid tumours can be very variable, ranging from solid and sheet-like (seen in most cases) to ribbon-like, broad alveolar, or nested growths. ChRCC is the second most frequently seen subset of neo­ plasms in patients with BHD. The mean size is 25 mm. The diagnosis of classic ChRCC is made when most of the cells exhibit a finely eosinophilic or clear cytoplasm. Of the ChRCC pathological phenotypes, the classic type is the most com­ mon and the eosinophilic type is the least frequently seen. The growth patterns seen in these tumours are predominantly broad alveolar, nested, or solid. The percentage of chromophobe cells

Fig. 14.06 Birt-Hogg-Dube syndrome. A Cells resembling chromophobes may be positive for MOC31. B Immunohistochemistry for CK7 highlights the clear cells but is com­ monly negative in the oncocytic cells. C BerEP4 immunohistochemistry.

Genetic tumour syndromes of the urinary and male genital tracts

467

in a hybrid tumour, and occasionally, the larger masses are pre­ dominantly composed of chromophobe cells. The percentage of different cells in the hybrid tumours has no clinical impact. The tumours are low-grade and do not follow an aggressive course, although new tumours develop frequently. Oncocytosis or microscopic foci of clear cells can be found in the non-tumoural renal parenchyma. These nests range in size from very small lesions (sometimes just a few cells) to nodules measuring 4 mm in diameter, and in most cases the cells have pale/clear cytoplasm. Lesions measuring > 4 mm are generally considered oncocytic neoplasms. The oncocytomas occurring in BHD are identical to sporadic oncocytomas. Occasionally patients can also have clear cell cancers that are morphologically identical to sporadic tumours and that can have associated mutations in the VHL gene.

Immunophenotype All tumours stain positively for PAX8. Immunohistochemis­ try staining for KIT (CD117) reveals a patchy pattern in hybrid tumours (in contrast to the diffuse pattern seen in oncocyto­ mas), with positivity predominantly seen in the eosinophilic cells. Staining for CK7, on the other hand, is positive in the clear cells and negative in the oncocytic cells. Some clear cells can be positive for CD10. The Ki-67 (M旧 1) proliferation index is low (< 5%), and p53 is positive in a few scattered nuclei.

Cytology Not relevant Diagnostic molecular pathology FLCN (BHD) is a 14-exon gene localized on the short arm of chromosome 17, at 17p11.2. Affected family members may inherit an insertion or deletion of a cytosine in a C8 tract in exon 11. Among patients with a mutation in the exon 11 hotspot,

468

significantly fewer renal tumours were observed in those with the C-deletion mutation than in those with the C-insertion muta­ tion. The known insertions, deletions, and nonsense mutations are all predicted to result in the formation of a truncated folliculin protein. Genetic testing is necessary to confirm the diagnosis and to provide genetic counselling to the family. Uniparental disomy (also known as copy-neutral loss of heterozygosity) is a common finding in BHD {1462). Interestingly, bilateral multifocal renal oncocytomas in patients without BHD have been found to have disruptive mitochondrial DNA mutations, whereas renal tumours from patients with BHD do not (1796,3207}.

Essential and desirable diagnostic criteria Essential: one or more of the following: skin papules in the face and neck consistent with trichodiscomas; lung cysts; hybrid renal tumours; mutation of the FLCN gene. Staging Not relevant

Prognosis and prediction The prognosis of patients with BHD depends on the associated lesions, such as pneumothorax and pulmonary cysts. The char­ acteristic renal cancers are now considered to be of low malig­ nant potential because metastatic spread is very rare (1796). In general, the favourable oncological outcome of tumours that occur in the context of BHD, and their propensity to develop multifocal and bilateral disease, supports the management of these cases in a conservative way, i.e. periodic imaging to detect and/or monitor the evolution of renal neoplasms. If sur­ gical treatment is needed, nephron-sparing surgery is recom­ mended whenever possible (2472}. However, patients may rarely also develop Clear cell renal cell carcinoma, and in this case they will have a worse prognosis {2473}.

Genetic tumour syndromes of the urinary and male genital tracts

Hereditary papillary renal carcinoma

MochH Cunha IW Margulis V

Definition Hereditary papillary renal carcinoma (HPRC) is a specific form of inherited kidney cancer. MIM numbering 605074 Renal cell carcinoma, papillary ICD-11 coding 2C90.Y & XH1D07 Other specified malignant neoplasms of kid­ ney, except renal pelvis & Papillary renal cell carcinoma

Related terminology Acceptable: familial papillary renal cell carcinoma syndrome.

Subtype(s) None Localization The tumours occur in the renal cortex and are multifocal.

Fig. 14.07 Hereditary papillary renal carcinoma. Shows features of typical low-grade papillary carcinoma (formerly known as type 1 papillary carcinoma).

Clinical features Multiple and bilateral renal tumours are seen on CT, ultrasound, or MRI. There is always a family history of renal cancer, although some family members may be asymptomatic. No other types of cancer or non-cancerous health problems are known to be related to HPRC. Epidemiology HPRC is considered to be rare. The number of people and fami­ lies who have HPRC is unknown.

Etiology HPRC is caused by missense germline mutations in the MET proto-oncogene on chromosome 7q31, which leads to constitu­ tive activation of the c-Met protein (2842,3536).

Pathogenesis MET is a gene that encodes a receptor tyrosine kinase that binds to HGF, an important growth factor. Macroscopic appearance HPRC manifests as bilateral and multiple solid renal tumours, ranging from nodules of a few millimetres to larger masses. The tumours may be encapsulated or unencapsulated (3014, 3207}.

Histopathology Almost all HPRCs are typical papillary carcinomas (formerly known as type 1 papillary carcinomas). Papillary renal cell car­ cinomas of this type have papillae covered by cells with nuclei arranged in a single layer on the papillary cores, mostly with scant pale cytoplasm. Psammoma bodies and haemosiderin

Fig. 14.08 Hereditary papillary renal carcinoma. This type of papillary renal cell car­ cinoma has papillae covered by cells with nuclei arranged in a single layer on the papillary cores.

deposition are frequent. In addition to low-grade papillary renal cell carcinomas, tubulopapillary adenomas are also seen (3014, 3207}.

Cytology Not clinically relevant Diagnostic molecular pathology HPRC is caused by germline mutations of the MET proto-onco­ gene.

Genetic tumour syndromes of the urinary and male genital tracts

469

Fig. 14.09 Hereditary papillary renal carcinoma. This type of papillary renal cell carcinoma has papillae covered by cells with nuclei arranged in a single layer on the papillary cores. Most of the cells covering the papillae have scant pale cytoplasm, and there is frequent haemosiderin deposition (A); many foamy macrophages are seen (B).

Essential and desirable diagnostic criteria Essential: HPRC is suspected when multiple family members have low-grade papillary renal cell carcinoma or an individual has bilateral, multifocal, low-grade papillary renal cell carcinoma.

Prognosis and prediction The specific risk for low-grade papillary renal cell carcinoma in families with HPRC is extremely high, with some estimates showing the lifetime risk is nearly 100%.

Staging Staging follows the eighth-edition Union for International Can­ cer Control (UICC) and American Joint Committee on Cancer (AJCC) TNM classification.

470

Genetic tumour syndromes of the urinary and male genital tracts

Hereditary leiomyomatosis and renal cell carcinoma syndrome

Gill AJ ChenN Margulis V Merino MJ OheC Trpkov K

Definition Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome is an autosomal dominant tumour predisposition syndrome associated with pathogenic germline FH variants. It is characterized by fumarate hydratase (FH)-deficient cutane­ ous and uterine leiomyomas, FH-deficient renal cell carcinoma (RCC), and (occasionally) phaeochromocytoma-paraganglioma. MIM numbering 150800 Hereditary leiomyomatosis and renal cell cancer; HLRCC ICD-11 coding XH5085 Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome-associated renal cell carcinoma

Related terminology Not recommended: hereditary multiple cutaneous leiomyomas; multiple cutaneous and uterine leiomyomas; Reed syndrome (1682).

Subtype(s) None Localization Common: skin; uterus; kidney. Rare: adrenal gland; paraganglia. Very rare: testes; ovary.

Clinical features Cutaneous leiomyomas, which may be sensitive to cold or light touch, are found in at least 75% of individuals with HLRCC syn­ drome, with a mean age of onset of 30 years and increasing in size and number with age {2970}. As many as 80% of women with HLRCC syndrome develop symptomatic uterine leiomyo­ mas, with many undergoing surgery at a young age (< 35 years) (3180,2970,2050,2250,1303}. About 15% of patients with HLRCC syndrome develop renal carcinomas with a median age of onset of 44 years {2539,2128,3180}. Epidemiology HLRCC syndrome is rare, with no data on exact prevalence. The estimated population incidence of pathogenic germline FH variants is 0.0308-0.0390% (2559}. Tumours associated with germline FH variants occur at a younger age than do their spo­ radic counterparts. The leiomyomas are more penetrant and on average arise 10-15 years before the renal carcinoma (3180(. The majority of patients with even a single FH-deficient RCC at any age will be shown to have germline mutation (3205,1803), as do close to 90% of patients with multiple cutaneous leiomyo­ mas (64). In contrast, it is thought that only 2.7-13.9% of patients

Fig. 14.10 Multiple cutaneous leiomyomas arising in hereditary leiomyomatosis and renal cell carcinoma syndrome. A,B The cutaneous leiomyomas arising in this syn­ drome are more common on the trunk and may be clustered in a segmental distribu­ tion.

with a single FH-deficient uterine leiomyoma carry pathogenic germline mutation (2559}. Although the great majority of patients undergoing surgery for FH-deficient uterine leiomyomas at a younger age have syndromic disease (2050}, the majority of patients aged > 50 years who present with a single FH-deficient uterine leiomyoma do not {1303,2559}. Approximately 1% of patients with phaeochromocytoma-paraganglioma have germline FH mutation (3228,2250). There have been isolated case reports of patients with testicular and ovarian Leydig cell tumours {536,1376,3043}. Etiology HLRCC syndrome is caused by germline pathogenic variants in the FHgene (chromosome 1q43) (65,1094,2817}. More than 100 different FH mutations and large-scale deletions have been reported {3425,1094,2880). There are no known genotype­ phenotype correlations (3425,2880(.

Genetic tumour syndromes of the urinary and male genital tracts

471

Fig. 14.11 Fumarate hydratase-deficient cutaneous leiomyoma. A,B These leiomyomas are morphologically indistinguishable from sporadic leiomyomas.

Fig. 14.12 Fumarate hydratase (FH)-deficient cutaneous leiomyoma. A Negative staining for FH in an FH-deficient cutaneous leiomyoma. Positive staining in non-neoplastic cells, which acts as an internal positive control, is noted. B Aberrant positive staining for 2-succinocysteine (2SC). C FH-deficient cutaneous leiomyoma demonstrating a loss of expression of FH. FH immunohistochemistry may be difficult to interpret in cutaneous tumours because of admixed neural and other non-neoplastic elements.

Pathogenesis Biallelic inactivation of FH, the gene encoding a Krebs cycle enzyme that converts fumarate to L-maleate, occurs in the syn­ dromic setting due to germline mutation with the addition of a somatic second hit. The subsequent accumulation of fumarate and other oncometabolites leads to neoplasia through epige­ netic modification and suppression of DNA repair (3060,1094, 2861(.

2817,1552}. However some FH-deficient uterine leiomyomas and the majority of FH-deficient cutaneous leiomyomas can­ not be distinguished morphologically from usual leiomyomas {1303,535,464}. To date, no morphological clues to FH defi­ ciency have been described in the smaH number of HLRCC syndrome-associated phaeochromocytoma-paragangliomas (1979,3237} or Leydig cell tumours {1376,536).

Macroscopic appearance The renal carcinomas and uterine leiomyomas associated with HLRCC syndrome grossly resemble their sporadic counter­ parts. The cutaneous leiomyomas are more common on the trunk, and they may be single, clustered, or in a linear, segmen­ tal, or dermatome-like distribution {64}.

Negative immunohistochemical staining for FH in the presence of a positive control (i.e. retained expression) in non-neoplas­ tic cells is highly specific for all FH-deficient neoplasms, but imperfectly sensitive. In contrast, aberrant positive staining for 2-succinocysteine (2SC) is highly sensitive for all FH-deficient neoplasms, but it is less specific, particularly for renal carci­ noma (602,3205,1803,2980,2251,320}. Because the morpho­ logical clues described above may be subtle or absent, a low threshold for immunohistochemistry screening for FH and/or 2SC is helpful in any difficult-to-classify renal carcinoma (2979, 1869,2980,3205,1803} and in a solitary cutaneous leiomyoma {535,464}. Genetic testing is recommended in any patient with multiple cutaneous leiomyomas regardless of the immunohis­ tochemical pattern. In view of the relative frequency of uterine leiomyoma resection specimens, and the much lower inci­ dence of germline FH mutation in older patients with a single

Immunohistochemistry

Histopathology The renal carcinomas associated with HLRCC syndrome are now classified as a distinct entity termed FH-deficient RCC (see Fumarate hydratase-deficient renal cell carcinoma, p. 78) {2817, 1303}. Most FH-deficient uterine leiomyomas show distinctive morphological features at least focally, including symplastictype nuclear atypia, multinucleation, prominent eosinophilic nucleoli, a staghorn vasculature, stromal oedema, and occa­ sionally eosinophilic cytoplasmic inclusions (2159,1303,2664,

472

Genetic tumour syndromes of the urinary and male genital tracts

Fig. 14.13 Hereditary leiomyomatosis and renal cell carcinoma syndrome. A Fumarate hydratase-deficient phaeochromocytoma arising in the setting of hereditary leiomy­ omatosis and renal cell carcinoma syndrome is morphologically indistinguishable from sporadic cases. B This fumarate hydratase-deficient uterine leiomyoma shows marked stromal oedema (alveolar oedema).

Fig. 14.14 Fumarate hydratase-deficient uterine leiomyoma. A Symplastic-type nuclear atypia, multinucleation, and eosinophilic cytoplasmic inclusions. B Nuclear atypia, multinucleation, and prominent staghorn vasculature. C Symplastic-type nuclear atypia with some multinucleation.

FH-deficient uterine leiomyoma, it is recommended that mor­ phology and clinical features are used to triage immunohisto­ chemistry for FH and 2SC in uterine leiomyomas {1095,1303, 1552,2597}. Although phaeochromocytoma-paraganglioma and Leydig cell tumour are recognized associations of HLRCC syndrome, they are such infrequent associations that immuno­ histochemistry screening is rarely performed {1979,3237,1376, 536}. Cytology In cytological specimens, the presence of prominent inclusion­ like nucleoli, sometimes with a perinucleolar halo, is a clue to the associated renal carcinoma {2929}. Diagnostic molecular pathology Although FH and 2SC immunohistochemistry identify FH-defi­ cient neoplasms, they do not replace genetic testing, because biallelic FH mutation/inactivation can occur as a purely somatic phenomenon (rarely in renal carcinoma, but commonly in uter­ ine leiomyoma, particularly at an older age). Immunohistochem­ istry may also be useful to assess the pathogenicity of genetic variants of uncertain significance.

Essential and desirable diagnostic criteria Essential: demonstration of a germline pathological variant in FH; or the presence of multiple histologically confirmed FHdeficient leiomyomas or FH-deficient RCCs; or the presence of two or more of the following: FH-deficient leiomyoma, FHdeficient RCC, a first-degree relative with FH-deficient neo­ plasms (2970}. Staging The renal carcinomas are staged according to the eighth-edi­ tion Union for International Cancer Control (UICC) or American Joint Committee on Cancer (AJCC) classification.

Prognosis and prediction FH-deficient RCCs arising in HLRCC syndrome are aggres­ sive (2135,3180,3205). Although the presence of symplastic cytological atypia and multifocality may lead to misclassifica­ tion of the cutaneous and uterine smooth muscle tumours as leiomyosarcoma, no clinical evidence exists that such leiomy­ omas behave in a biologically malignant manner (1303,2159, 3550,2250}.

Genetic tumour syndromes of the urinary and male genital tracts

473

Succinate dehydrogenase-deficient tumour syndromes

Definition Succinate dehydrogenase (SDH)-deficient tumour syndromes are a group of syndromes characterized by SDH-deficient neo­ plasia, usually associated with germline mutations in the SDH genes (SDHA, SDHB, SDHC, SDHD, SDHAF2) or with SDHC epimutation.

Gill AJ Agaimy A de Krijger RR Erickson LA Mete 0 Turajlic S

Not recommended: Carney-Stratakis dyad; Carney-Stratakis syndrome. Subtype(s) See Table 14.02. Localization SDH mutations are more commonly associated with paragan­ gliomas than with phaeochromocytomas. Therefore, in the geni­ tourinary tract, paragangliomas of the urinary bladder or those arising in the periaortic sympathetic chain are more commonly SDH-deficient than are adrenal phaeochromocytomas. There is an inconsistent phenotype-genotype correlation between the individual SDH subunit that is mutated/epimutated and the most common location of the syndromic paragangliomas (see Table 14.02 and Table 14.03). For example, SDHB mutations are more common in intra-abdominal extra-adrenal paragan­ gliomas, and SDHD mutations are more common in head and neck paragangliomas {1125}. With one exception, all SDH-deficient gastrointestinal stromal tumours (GISTs) reported to date have arisen in the stomach (1127,2164,937}.

MIM numbering 168000 Paragangliomas 1; PGL1 601650 Paragangliomas 2; PGL2 605373 Paragangliomas 3; PGL3 115310 Paragangliomas 4; PGL4 614165 Paragangliomas 5; PGL5

ICD-11 coding None Related terminology Acceptable: hereditary phaeochromocytoma-paraganglioma syndromes 1-5; Carney triad (restricted to syndromic but non-hereditary disease).

Table 14.02 Clinical manifestations of different succinate dehydrogenase (SDH)-related tumour syndromes: paraganglioma (PGL) syndrome types 1-5 (PGL1-5) and Carney triad Characteristic

PGL1

PGL2

PGL3

PGL4

PGL5

Carney triad

Gene

SDHD

SDHAF2

SDHC

SDHB

SDHA

SDHC promoter hypermethylation

Locus

11q23.1

11q12.2

1q23.3

1p36.13

5p15.33

1q23.3

Inheritance

AD;PT

AD;PT

AD

AD

AD

Not hereditary

Frequency8

~5%

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