Recent Advances in Genitourinary Tumors: Updates From the 5th Edition of the World Health Organization Blue Book Series

Advances in the knowledge of molecular mechanisms of renal tumors are increasingly moving the field toward a coordinated genotype-phenotype classification system; however, this trajectory is not yet complete. Thus, the most significant change in this section, compared to the 4th edition, is the establishment of the category of molecularly defined renal cell carcinomas (RCCs), which have well-defined molecular aberrations but varied histomorphologic phenotypes.²  This includes the MIT family translocation RCC, elongin C (ELOC)-mutated RCC, fumarate hydratase (FH)–deficient and succinate dehydrogenase (SDH)–deficient RCCs, anaplastic lymphoma kinase (ALK)–rearranged RCC, and SMARCB1-deficient renal medullary carcinoma. Some tumors, such as metanephric adenomas and metanephric stromal tumors, despite being defined by BRAF p.V600E mutations, remain classified as morphologically defined neoplasms in this new classification, in part because of the strong phenotype-genotype association.³ 

The MiTF translocation RCC now includes 2 entities: TFE3-rearranged RCC and TFEB-altered RCC. TFE3-rearranged RCCs show papillary architecture with epithelioid clear cells and numerous psammoma bodies (Figure 1, A and B). TFEB-altered RCCs have a biphasic appearance with nests of large epithelioid cells surrounding collections of smaller cells clustered near basement membrane material (Figure 2, A and B). Positivity for the melanocytic markers Melan-A and HMB-45 and cathepsin K are suggestive of these entities.^4–6  However, definitive diagnosis of TFE3-rearranged RCC (Figure 3) requires demonstration of either strong nuclear labeling for TFE3 by immunohistochemistry in a clean background or TFE3 rearrangement by fluorescence in situ hybridization (FISH) or TFE3 gene fusion by RNA sequencing. Definitive diagnosis of TFEB-altered RCC requires the demonstration of TFEB rearrangement or amplification by break-apart FISH or TFEB gene fusion by RNA sequencing.

ELOC (TCEB1)-mutated RCCs often have angioleiomyomatous stroma but are otherwise insufficiently distinctive and often raise the differential diagnosis of clear cell RCC and clear cell papillary renal cell tumor. However, unlike most clear cell RCCs, these tumors are immunopositive for CK7, and unlike clear cell papillary renal cell tumor, ELOC-mutated RCCs show complete membranous positivity for CAIX. However, as neither of these findings is absolute, demonstrating an ELOC mutation is necessary for diagnosis. Absent molecular confirmation, the WHO recommends using the diagnosis of “clear cell RCC with prominent fibromuscular septation and CK7 positivity.”¹ 

FH-deficient RCCs include both sporadic tumors with somatic mutation and those arising in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome from a germline mutation.^7,8  These tumors show an admixture of morphologic patterns, including papillary, solid, tubulocystic, cribriform, and cystic morphologies.⁹  The presence of at least focal eosinophilic macronucleoli is characteristic (Figure 4, A and B). Confirmation of the diagnosis is aided by negativity for FH (high specificity, low sensitivity) and aberrant staining for 2-succinocysteine (2SC; high sensitivity, low specificity). Given the varied morphologic phenotypes of these tumors, the WHO recommends a low threshold for staining for FH and/or 2SC in RCCs that are difficult to classify.¹  It is important to identify these tumors, as they tend to be aggressive, and there may be a role for targeted therapies for these patients.¹⁰ 

SMARCB1-deficient renal medullary carcinomas are high-grade tumors typically seen in association with hemoglobinopathies (mainly sickle cell trait) that show SMARCB1 (INI1) loss by immunohistochemistry (Figure 5, A and B).¹¹  At the molecular level, these tumors are characterized by SMARCB1 translocations or deletions.¹²  Rare tumors with similar morphology in the absence of a hemoglobinopathy have been described.¹³  High-grade RCCs with secondary loss of SMARCB1 are excluded from this category.

ALK-rearranged RCC, which was identified as an emerging entity in the 4th edition, is now considered a unique entity.²  ALK-rearranged tumors are associated with the sickle cell trait in pediatric patients and carry ALK translocations.¹⁴  These RCCs show morphologic heterogeneity depending on the gene fusion partners involved in the translocation. Polygonal neoplastic cells with eosinophilic cytoplasm and vacuolization are seen in tumors with VCL::ALK gene fusions. In contrast, tumors harboring ALK rearrangement with other genes such as TPM3, EML4, STRN, and HOOK1 may show papillary or cribriform architecture with mucinous stroma. Tumors with mucinous tubular and spindle cell morphology or metanephric adenoma-like morphology have also been described. Immunohistochemistry for ALK is recommended as a screening test. Diagnosis requires documentation of ALK rearrangement by break-apart FISH or of ALK gene fusion by sequencing.

The 5th edition also lists “an emerging category” of tumors with molecular associations. These include thyroidlike follicular RCC (associated with EWSR1::PATZ1 fusions), biphasic hyalinizing psammomatous RCC (associated with NF2 mutations), eosinophilic vacuolated tumor (EVT; somatic TSC2-inactivating mutations or MTOR-activating mutation), and papillary renal neoplasm with reverse polarity (associated with recurrent KRAS mutations).^15–18 

The category of morphologically defined renal tumors has a few important changes relative to the 4th edition.²  A major change is the introduction of a category of “other oncocytic tumors of the kidney.” This is a diverse group of oncocytic tumors that are not classifiable as oncocytoma, chromophobe RCC (ChRCC), or other tumors that have eosinophilic features. This group includes the hybrid oncocytic tumors of Birt-Hogg-Dube (BHD) syndrome, which are typically multifocal and bilateral. This group also includes some solitary, sporadic eosinophilic tumors with intermediate features between oncocytoma and ChRCC. Some of these tumors have been associated with mutations in the mTOR pathway genes or in the FLCN locus (hybrid oncocytic tumors in BHD syndrome).⁴  Stringent diagnostic criteria to exclude oncocytoma and ChRCC, as well as other mimics such as SDH-deficient RCC, must be followed before making this diagnosis. This group also has 2 emerging entities: EVT and low-grade oncocytic tumor.^19,20  EVT shows oncocytic cells with frequent large vacuoles and prominent nucleoli with a solid growth pattern. It is positive for cathepsin K, CD117, and CD10, and negative for CK20, CK7, Melan-A, HMB45, and TFE3. A low-grade oncocytic tumor shows oncocytic cells with bland nuclei and sharply delineated loose stromal areas with scattered cells (Figure 6, A and B). It is immunopositive for CK7, while negative for CD117, CK20, and vimentin. Both tumor subtypes are clinically indolent. Also included in the category of other oncocytic tumors is a heterogeneous group of oncocytic tumors with borderline features that are designated as “oncocytic renal neoplasms of low malignant potential, NOS.”

Eosinophilic solid and cystic RCC (ESC-RCC) is a new entity in this edition. This tumor is characterized by solid and cystic architecture and can arise sporadically or in the context of tuberous sclerosis (Figure 7, A and B).^21,22  The cells show voluminous eosinophilic to flocculent cytoplasm with coarse stippling. Biallelic somatic mutations in TSC1 or TSC2 are common. By immunohistochemistry, the tumors show focal to diffuse positivity for CK20 while typically being negative for CK7 and CD117 (Figure 8).

The 5th edition provides explicit delineation for tumors where the WHO/International Society of Urological Pathology (ISUP) nuclear grading system is applicable, given its continued importance as an important prognostic factor for specific tumor subtypes. However, the 5th edition offers more expanded and nuanced guidance on grading. Renal tumors are thus classified into 7 categories depending on the known value, or lack thereof, of nuclear grading in prognosis (Table 1). For tumors where nuclear grading may be misleading or where its significance is unknown, the choice of whether to grade is left to the pathologist’s discretion. If the pathologist chooses to assign a grade to tumors where nuclear grading is of unknown significance, the WHO recommends adding a comment stating that the clinical significance of nuclear grading in these tumors is unknown.¹  Reporting nuclear grade remains mandated by the College of American Pathologists for clear cell and papillary RCCs, with a recommendation that WHO/ISUP grade may be given for other RCC subtypes for descriptive purposes.

Other notable changes include the recommendation to refrain from subclassifying papillary RCCs into type 1 and type 2. Clear cell papillary RCCs are now renamed clear cell papillary renal cell tumor to better reflect the indolent nature of these neoplasms. The 5th edition retains a class of tumors that cannot be readily classified into one of the known RCC subtypes, although the term “RCC not otherwise specified (RCC-NOS)” is preferred to “unclassified RCC.”

The categories of metanephric tumors, mixed epithelial and stromal renal tumors, nephroblastic tumors, and germ cell tumors remain largely unchanged from the previous edition. Like the previous edition, there is a section on renal mesenchymal tumors including chapters on classic angiomyolipoma/perivascular epithelioid cell tumors of the kidney, ossifying renal tumor of infancy, and congenital mesoblastic nephroma. Urothelial carcinoma of the renal pelvis is discussed under tumors of the urinary tract.

The significant updates in the section on urinary tract tumors are summarized in the introductory chapter to the section on urinary tract tumors in the 5th edition and are outlined below.

The nomenclature of papillary urothelial neoplasm with inverted histology has been updated. The term “inverted” is attributed to tumors with predominant (>80%) or nearly exclusive inverted morphology. The WHO guidelines recommend reporting a predominant inverted growth pattern in urothelial carcinomas (UCs) since these lesions appear as smooth nodules rather than papillary lesions on cystoscopy and they may have a lower progression rate.^1,23 

The binary grading system for papillary UC is retained in this edition. Nevertheless, there is acknowledgement of the frequent heterogeneity of grade in papillary UC, which can be observed in up to one-third of papillary tumors.^24–26  This variability of grade has led to greater interobserver variability in the grading of UC and a larger number of UCs being classified as high-grade. Thus, the authors propose an objective cutoff of greater than or equal to 5% for the high-grade component in a predominantly low-grade tumor to designate the tumor as high-grade. However, it is recommended that even lower-volume high-grade components be reported as “low-grade with less than 5% high-grade component” to facilitate data collection to better predict the behaviors of these tumors.

Urothelial carcinoma in situ (UCIS) is the only formally recognized flat neoplastic entity in the 5th edition and shows marked atypia, resembling that seen in high-grade papillary UC. UCIS may have different cytomorphologic patterns, including large cell, small cell, plasmacytoid, pagetoid, and clinging morphologies. These patterns have no significant clinical implications.^27,28  Rare cases of UCIS may demonstrate in-situ glandular differentiation.²⁹  The diagnosis of UCIS can be aided by immunohistochemistry, although routine use is not recommended, as none of the markers have superior sensitivity or specificity. Abnormal full-thickness immunoreactivity for CK20, increased expression of p53, and decreased expression of CD44 are typical for UCIS.³⁰  Other markers, such as CK5/6, AMACR, and Ki-67 may also have utility in the distinction between CIS and reactive urothelial atypia.^28–30 

Several lesions described in the 4th edition have been dropped as distinct neoplastic entities in the 5th edition. While the term “urothelial dysplasia” is retained, it is not recommended as a distinctive diagnostic label. Instead, the recommendation is to use it descriptively and selectively, due to poor diagnostic reproducibility and the lack of objective diagnostic criteria. Furthermore, its clinical significance remains unclear.^31,32  “Urothelial proliferation of uncertain malignant potential” has also been dropped as a unique entity. These lesions show molecular abnormalities that suggest that they represent either early or shoulder extensions of noninvasive low-grade papillary UC.³³ 

There are few changes in the classification of invasive bladder UC in this edition. Invasive bladder UC is subcategorized into those with divergent differentiation, which are tabulated in Table 2.^34,35 

This edition recognizes the importance of urine cytology in the management and follow-up of patients. The Paris system is recommended for reporting, as it optimally identifies clinically actionable cutoffs with improved interobserver variability in diagnosis. It prioritizes the identification of high-grade UC and consolidates low-grade lesions (papilloma, papillary urothelial neoplasm of low malignant potential, and low-grade urothelial carcinoma) under the label of low-grade urothelial neoplasm, as these cannot be reliably discriminated on cytologic evaluation.

This edition endorses the international consensus on the molecular classification of UC. Genomic profiling of muscle-invasive bladder carcinoma reveals 6 distinctive clusters: luminal papillary (24%), luminal nonspecified (8%), luminal unstable (15%), stroma-rich (15%), basal-squamous (35%), and neuroendocrine-like (3%). These findings are based on comprehensive meta-analyses of transcriptomic profiles of 1750 MIBC sourced from 18 published datasets.^36–40 TP53 mutations, frequent in the neuroendocrine-like, basal-squamous, and luminal-unstable subtypes, portend a negative prognosis.^38,40  As with other organ systems, immunohistochemistry to aid the molecular classification of bladder UC is anticipated, but remains to be validated in larger data sets.⁴¹  Luminal (GATA3, CK20, and uroplakin II positive) and basal (CK5/6 and CK14 positive) subsets are most effectively classified by immunophenotyping.⁴² 

Molecular signatures that have clinical applications are highlighted, although most have not yet achieved wide use in clinical practice.⁴³ TERT promoter mutations, the most common alterations in all grades and stages of UC, allow for detection of UC in urine samples and to distinguish between malignant lesions and benign mimics.^44–50 FGFR3  alterations, most common in the luminal-papillary subtype of urothelial carcinoma, help assess the potential for response to anti-FGF agents.^51,52  Tests performed to predict response to immune checkpoint inhibitor therapy include assessments of programmed death ligand-1 expression, tumor mutational burden, and microsatellite instability/mismatch repair protein expressions.

Changes in the classification of prostatic tumors are summarized in this edition in the introduction to the 5th edition, the introduction to the prostate chapter, and a recent review.^53–56  There are “no dramatic changes in classification” relative to the 4th edition.

Prostatic acinar adenocarcinoma subtypes now include signet ring–like adenocarcinoma, sarcomatoid carcinoma, pleomorphic giant cell adenocarcinoma, and prostatic intraepithelial neoplasia (PIN)–like carcinoma.⁵⁷  Patterns previously termed variants, illustrated with excellent figures, and that are important to recognize since they can simulate benign conditions, include atrophic, pseudohyperplastic, microcystic, and foamy gland patterns.^58,59  Also included as a pattern is mucinous adenocarcinoma.

As indicated in the introduction to this review, neuroendocrine, mesenchymal, melanocytic, metastatic, and genetic syndrome–related prostate tumors are now consolidated with similar tumors in other organs in separate chapters. The 2 exceptions are (1) tumor types of specialized prostatic stromal cells—prostatic stromal tumor of uncertain malignant potential and prostatic stromal sarcoma—and (2) treatment-related neuroendocrine carcinoma; these are specific to the prostate. The section on treatment-related neuroendocrine carcinoma briefly mentions non–treatment-related neuroendocrine differentiation, including that detected by immunohistochemistry (for which, as the text appropriately emphasizes, there is insufficient evidence for a prognostic or therapeutic role), Paneth-like cells, small cell neuroendocrine carcinoma, and large cell neuroendocrine carcinoma. These latter 2 entities and mixed neuroendocrine neoplasms are discussed more expansively in the neuroendocrine neoplasms (of the genitourinary tract) chapter.

Cribriform high-grade prostatic intraepithelial neoplasia (HGPIN) is no longer considered a distinct entity, but rather is classified as atypical cribriform proliferation (ACP), atypical intraductal proliferation (AIP), or atypical intraductal proliferation suspicious for intraductal carcinoma (AIPS). In the 4th edition, the term “atypical intraductal cribriform proliferation” was used for lumen-spanning lesions with cytologically atypical cells exceeding the criteria for HGPIN but not meeting those for intraductal carcinoma. The 5th edition discusses the differential diagnosis for ACP/AIP/AIPS under both the HGPIN and intraductal carcinoma sections. Clinically and molecularly, ACP/AIP/AIPS is considered related to intraductal carcinoma but falls short of being classified as such. The 5th edition does not provide recommendations on the clinical management of ACP/AIP/AIPS due to the limited literature currently available; one recommendation is consideration for further clinical work-up to detect unsampled high-risk prostate cancer.⁶⁰ 

The section on intraductal carcinoma of the prostate (IDC-P) is markedly expanded. The 5th edition takes the position that IDC-P may represent 2 distinct entities. There is the rare pure carcinoma in situ type without invasive carcinoma. The second, comprising the vast majority of cases, represents colonization of preexisting ducts by high-grade Gleason pattern 4 or 5 carcinoma. The diagnostic criteria for IDC-P have been revised. The precise size specification of marked nuclear atypia (that is, nuclear size 6 times normal or larger) for loose cribriform patterns has been replaced by the descriptors of enlarged, pleomorphic nuclei.^55,61  “Expansile” replaces “dense” before non-loose cribriform patterns. The essential criteria are thus: “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.” A desirable diagnostic criterion is “immunohistochemistry demonstrating at least partial basal cell retention.”⁶¹ 

The current major controversy in the field of prostate pathology on whether IDC-P should be graded or not is directly and thoroughly addressed, as the recommendations differ between the 2 major genitourinary pathology societies, the Genitourinary Pathology Society (GUPS) and ISUP.^55,57,62,63  ISUP recommends incorporating IDC-P into the Gleason score, while GUPS does not. Both arguments are explored in detail, with the key differences between the ISUP and GUPS recommendations presented in an informative table.^55,57  The 5th edition authors write that more definitive evidence is needed to resolve this dispute and propose that pathologists “specify which version of the Gleason grading recommendations is being used in routine reporting and publications.”⁵⁷ 

Basal cell carcinoma (BCC) has been renamed adenoid cystic (basal cell) carcinoma since the histomorphologic features are similar to adenoid cystic carcinoma of the salivary gland, with 17% to 47% of cases harboring the identical MYB::NFIB fusion.

PIN-like adenocarcinoma is now a subtype of acinar adenocarcinoma and is removed from the section on ductal adenocarcinoma, where it was placed in the 4th edition.^55,57,64  PIN-like adenocarcinoma is characterized as flat or tufted, without the papillary and cribriform growth of ductal adenocarcinoma.^65–67  Cystic change is common. The nuclei may be elongated like ductal adenocarcinoma or rounded like acinar adenocarcinoma (Figure 9, A through C).⁶⁵  The assigned Gleason pattern is 3, rather than the pattern 4 (high-grade) which is typical for ductal adenocarcinoma. A recent molecular study showed distinctive activating mutations in the RAF/RAS pathway in PIN-like adenocarcinoma, which differs from both acinar and ductal adenocarcinoma.⁶⁸ 

As in other sections, there is an expanded discussion of molecular pathology based on knowledge acquired over the past several years. The significance of germline or somatic alterations in DNA repair genes involved in homologous recombination repair (HRR) and mismatch repair (MMR) in prostatic adenocarcinoma is highlighted. Up to 20% of patients with aggressive primary and metastatic prostatic adenocarcinoma harbor genomic alterations in genes involved in the HRR pathway, including, most commonly, BRCA2, BRCA1, and ATM genes; one-half of these are germline.⁶⁹  Pathogenetic mutations in the MMR pathway have been identified in around 10% of castration-resistant prostate cancers compared to less than 3% of primary prostate cancers.⁶⁹  Detection of these alterations can drive treatment considerations, such as the use of poly (ADP-ribose) polymerase (PARP) and immune checkpoint inhibitors. Importantly, HRR mutations are more commonly detected in ductal adenocarcinoma, intraductal carcinoma, and Gleason pattern 5 carcinoma; enrichment of MMR mutations is seen in ductal adenocarcinoma and Gleason pattern 5 carcinoma.⁶⁹  Current guidelines recommend assessment for germline and somatic HRR alterations in patients with castration-resistant prostate cancer before a PARP inhibitor is administered and DNA mismatch repair assessment in patients with advanced castration-resistant prostate cancer under consideration for immunotherapy.⁵⁷ 

A new development pertains to germline testing for DNA repair gene alterations in patients with IDC-P and/or cribriform architecture. The 5th edition section on IDC-P states that “Although germline BRCA2 testing has been formally recommended by the National Comprehensive Cancer Network (NCCN) and the Philadelphia Prostate Cancer Consensus Conference, it remains a controversial topic.”⁶¹  Also, “Compared with primary acinar adenocarcinoma, ductal adenocarcinoma may be relatively enriched for germline or somatic pathogenetic alterations in genes regulating DNA repair….”⁷⁰  The current NCCN prostate cancer guidelines (version 1.2023; September 16, 2022) are that germline testing (for multiple DNA repair genes including BRCA1, BRCA2, ATM, PALB2, CHEK2, MLH1, MSH2, MSH6, and PMS2) may be considered for intermediate-risk prostate cancer patients with IDC-P, invasive cribriform acinar adenocarcinoma, and ductal adenocarcinoma.⁷¹ 

Further notable additions include useful tables such as those summarizing diagnostic immunohistochemical markers of prostatic adenocarcinoma and differential diagnosis. A deletion compared to the 4th edition is that the 5th edition does not provide a Gleason grading diagram. A paragraph provides a view to the future on computer-assisted prostate cancer grading using artificial intelligence. Artificial intelligence is also being used to detect prostate cancer and measure cancer extent in needle-core tissue.^72,73 

The 5th edition presents seminal vesicle tumors as an independent chapter. Earlier editions included these under the section on tumors of the prostate. No new tumor entities are included in this section; however, the tumor classification is now better organized into 3 categories: (1) glandular neoplasms (cystadenoma and adenocarcinoma of the seminal vesicle), (2) squamous neoplasms (squamous cell carcinoma [SCC] of the seminal vesicle), and (3) mixed epithelial and stromal tumors. Mesenchymal tumors and other miscellaneous tumors such as choriocarcinoma, seminoma, or metastatic tumors are described in their respective specific chapters.

Cystadenoma of the seminal vesicle is formalized as a separate entity in the category of glandular neoplasms of the seminal vesicle. In earlier editions, it was bundled with mixed epithelial and stromal tumors. Both lesions show benign glandular proliferation, but hypercellular stroma is present only in mixed epithelial and stromal tumors. In terms of treatment and prognosis, cystadenoma is benign and cured with local resection, whereas a mixed epithelial and stromal tumor has malignant potential depending on the grade of the stromal component.⁷⁴ 

The section on testicular tumors has only minor changes. The chapters on germ cell neoplasia endorse the classification scheme that was implemented in the 4th edition, with some nominal reorganization. Thus, testicular germ cell neoplasia remains broadly divided into a clinically distinctive, larger group of tumors that derive from germ cell neoplasia in situ (GCNIS) and those with no preinvasive lesion.⁷⁵ 

Gonadoblastoma is now categorized under noninvasive germ cell neoplasia, and the essential role of the GBY region of the Y chromosome and the gene encoding testis-specific Y-encoded protein in these tumors is highlighted.⁷⁶  A subset of patients with Turner syndrome, although cytogenetically characterized by a 45X sex chromosome monosomy, harbor cryptic Y chromosome material, detectable only by DNA or FISH analysis.⁷⁷  The presence of either cryptic or overt Y chromosomal material in Turner syndrome patients puts them at risk of developing gonadoblastoma and germ cell tumors, suggesting that screening for Y chromosomal material may be warranted for all patients with Turner syndrome.

The tumors in the GCNIS-derived category remain divided into seminoma and nonseminomatous germ cell tumors. However, seminoma is placed under the broader label of “germinoma family of tumors” to harmonize terminology and highlight commonality with identical tumors at other sites. A minor diagnostic criterion change is in the section on teratoma with somatic malignancy.⁷⁸  Although this edition, like its predecessor, utilizes the 5 mm²/4× field size criterion for the diagnosis of somatic malignancy, it allows for the application of “less stringent criteria” because “the overall amount of tumor may exceed 5 mm in contiguous sections.” Another change in this section is the introduction of the term “embryonic type neuroectoderm or neuroectodermal tumors” for foci or tumors of neuroectodermal differentiation. These were previously variably labeled primitive neuroectoderm or Ewing tumors, as these foci and tumors bear homology to central nervous system embryonal tumors.⁷⁹  However, the label “embryonic” rather than embryonal is recommended to avoid confusion with embryonal carcinoma.

Tumors in the non GCNIS-related group include prepubertal tumors and spermatocytic tumors. The category of prepubertal non-GCNIS includes yolk sac tumor, teratoma, mixed teratoma and yolk sac tumor, and testicular neuroendocrine tumor (NET). The label testicular NET replaces the term “testicular carcinoid,” to harmonize terminology with other organ systems. Although testicular NET is placed in the group of tumors with non-GCNIS related group, it is recognized that a small percentage may occur as “teratoma with somatic-type malignancy.”⁸⁰ 

The section on sex-cord stromal tumors introduces 2 new entities. The signet ring stromal tumor, while likely a variant of Sertoli cell tumor, is considered sufficiently distinctive as to warrant a separate identity.⁸¹  These tumors show periodic acid–Schiff and mucin-negative signet ring cells that are positive for nuclear β-catenin, cyclin D1, S100, CD10, NSE, and synaptophysin and negative for keratins, EMA, inhibin, calretinin, actin, desmin, and Melan-A. They show mutations of the CTNNB1 gene. The critical distinction is from metastatic signet ring carcinoma, which has a poor prognosis. Signet ring stromal tumors of the testis are benign. Myoid gonadal stromal tumor, as the name suggests, is a distinctive, well-circumscribed spindle cell tumor with morphologic and immunochemical overlap between sex-cord and myoid tumors.⁸²  They show positivity for actin, S100, FOXL2, SF1, vimentin, inhibin (focal), and desmin and are benign.

A significant change that crosses the sections between testicular and adnexal neoplasms is on sertoliform cystadenoma, which has been moved to the section on Sertoli cell tumors in the chapter on testicular tumors (it was previously a pattern of “adenoma” under tumors of the collecting duct and rete testis). The tumor involves the rete testis tubules but is histologically and immunohistochemically indistinguishable from Sertoli cell tumors. It is speculated that these tumors perhaps arise from cells at the junction of seminiferous tubules and rete testis, which retain the capability of differentiating towards sex cord stromal cells.⁸³ 

Intratubular large cell hyalinizing Sertoli cell tumor is discussed under the section of Peutz-Jeghers syndrome (PJS) in the chapter on genetic tumor syndromes, because it is only seen in patients with PJS. These tumors harbor a germline mutation in the tumor suppressor gene STK11 (LKB1) located on chromosome 19p13.3 and may resemble intratubular spread from large cell calcifying Sertoli cell tumor. However, large cell calcifying Sertoli cell tumor is associated with either somatic or germline mutations in the PRKAR1A gene, located at 17q24.2.⁸⁴ 

Well-differentiated papillary mesothelial tumor is considered a new entity and identified as a tumor with a favorable prognosis.⁸⁵ 

This section has minor changes. The classification of squamous tumors of the penis and scrotum reiterates the paradigm of the prior edition, harmonizing classification with similar lesions of the female genital tract. Both in situ and invasive lesions are stratified into human papilloma virus (HPV)–associated and HPV-independent subtypes. Of note, unlike the female genital tract where most HPV-associated squamous precursor lesions are low-grade squamous intraepithelial lesions, all penile intraepithelial neoplasia (PeIN) lesions are high-grade. The only benign HPV-associated lesion is a condyloma acuminatum, which is included for the first time as an independent entity. Condyloma acuminatum is an exophytic or warty lesion most often caused by low-risk HPV genotypes 6 and 11. It often resolves spontaneously and does not recur after local treatment.⁸⁶ 

HPV-associated high-grade PeIN is caused by high-risk HPV, most commonly types 16 and 18.⁸⁷  Different morphologic patterns are encountered including basaloid and warty types, and less commonly pagetoid, clear cell, and spindled types. Immunohistochemically, these show a block-positive staining for p16 and wild-type staining for p53. HPV-independent squamous precursors, also known as differentiated PeIN, often arise in a background of inflammatory injury, most prominently lichen sclerosus. The epithelium shows elongated and intercommunicating rete with basal and parabasal atypia with apparent surface maturation. The pathogenesis is not as well understood, but there is a high prevalence of TP53 mutations.^88,89  Of note, despite the high prevalence of TP53 mutation in differentiated PeIN, p53 staining is reported as variable. This apparent discord may relate to the use of variable criteria for p53 “positivity.” The pattern-based classification for mutant p53 staining used in female genital lesions has not been extended to PeIN.⁹⁰ 

HPV-associated SCC shows 4 subtypes, each with different clinical, macroscopic, and histologic features: basaloid squamous cell carcinoma, warty carcinoma, clear cell SCC, and lymphoepithelioma-like carcinoma. HPV-independent SCCs are divided into 5 subtypes: SCC-usual type, verrucous, papillary, pseudoglandular, and sarcomatoid. Carcinoma cuniculatum is now considered a variant of verrucous carcinoma. Adenosquamous carcinoma, mucoepidermoid carcinoma, and extramammary Paget disease are covered under the section on other epithelial tumors.

Scrotal tumors are acknowledged in the WHO classification scheme for the first time. SCCs are most common, followed by extramammary Paget disease, BCC, sarcoma, melanomas, and skin adnexal tumors.^91,92  BCC in the scrotum behaves more aggressively than BCC from other sites and is more likely to metastasize.⁹³ 

The hematolymphoid section is a standalone section in the 5th edition, with individual sections devoted to B cell lymphomas (extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue, diffuse large B-cell lymphoma and plasmacytoma) and histiocytic tumors (juvenile xanthogranuloma).^1,2  This edition recognizes that lymphoma is considered primary to the genitourinary tract only if a genitourinary site is either the only or the predominant site of involvement.⁹⁴  Primary lymphoproliferative disorders of the genitourinary tract are uncommon and only comprise 3.04%, 0.22%, 0.18%, and 0.01% of tumors of the testis, kidney, urinary bladder, and prostate, respectively.⁹⁵  The majority of hematolymphoid neoplasms of the GU tract occur in adults and are usually B-cell non-Hodgkin lymphoma, with Burkitt lymphoma, diffuse large B cell lymphoma, marginal zone lymphoma, and small lymphocytic lymphoma/chronic lymphocytic leukemia being most common.^96–99  Testicular diffuse large B-cell lymphomas show molecular alterations of CIITA, B2M, and HLA foci as well as structural rearrangements of CD274 (PDL1) and PDCD1LG2 (PDL2).^100–102  Genitourinary T-cell lymphoma, plasma cell neoplasms, and myeloid neoplasms are less common. The text recognizes that juvenile xanthogranuloma has shown genetic alterations of PIK3CD, BRAF, and ERK pathway mutations.^103,104 

Although not grouped as such in the 5th edition, we present the genetic syndromes stratified according to multifocality of renal tumors, the concomitant occurrence of systemic manifestations and endocrine manifestations, and bladder or prostate involvement.

Von Hippel-Lindau syndrome (VHL) is an autosomal dominant tumor syndrome due to a mutation in the VHL tumor suppressor gene. Renal lesions associated with VHL include benign cysts with a single layer of low-grade nuclei, atypical cysts, and cystic and solid clear cell carcinomas morphologically identical to sporadic clear cell RCC with low nuclear grade. Features suggesting a syndromic tumor include bilateral, multifocal tumors, microscopic foci of clear cell proliferation, clear cell–lined cysts, and young age.

Birt-Hogg-Dube syndrome (BHD) is a rare autosomal dominant tumor predisposition syndrome due to germline mutations in the folliculin (FLCN) gene involved in the regulation of TFE3 and TFEB transcriptional activity. The classic triad of BHD is skin lesions (acrochordons, fibrofolliculomas, and trichodiscomas), basally located lung cysts, and indolent eosinophilic/oncocytic tumors resembling oncocytoma or chromophobe RCC or hybrid tumors. Key features suggesting BHD syndrome are well-circumscribed, multifocal, and bilateral hybrid tumors and background oncocytosis.

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with broad systemic manifestations due to mutations in either TSC1 encoding the protein hamartin or TSC2 encoding tuberin. Fifty percent to 80% of patients develop angiomyolipomas and 40% develop renal epithelial cysts. Newly described entities included in TSC include ESC-RCC, RCC previously described as renal angiomyoadenomatous tumors, and RCC with smooth muscle stroma.

HLRCC syndrome is an autosomal dominant tumor predisposition syndrome due to pathogenic germline mutations in the FH gene. RCCs in HLRCC can be solitary and unilateral but occur at a younger age than nonsyndromic tumors and are aggressive. The tumor nuclei have prominent eosinophilic nucleoli (cherry red) and show loss of staining for FH with aberrant positive staining for 2SC. Germline testing for mutations in the FH gene is conclusive and recommended in patients with multiple cutaneous leiomyomas.

BRCA-associated protein 1 (BAP1) tumor predisposition syndrome is a rare autosomal dominant syndrome caused by germline pathogenic mutations in the BRCA-associated protein 1 (BAP1) tumor suppressor gene. It is associated with an increased risk for melanocytic tumors, mesotheliomas, RCC, and other malignancies. BAP1-deficient RCCs are aggressive, morphologically resemble clear cell RCC, and can be identified immunohistochemically by loss of nuclear expression of BAP1. Follow-up germline testing is then needed.

SDH-deficient tumor syndrome is an autosomal dominant syndrome with germline mutations in any of the genes encoding the subunits of the SDH complex (SDHA, SDHB, SDHC, SHDD, SHAF2) or SDHC epimutation. Pheochromyocytoma, paraganglioma, RCC, pulmonary chondroma, and pituitary neuroendocrine tumors characterize this syndrome. SDH-deficient RCC is now classified as a distinct entity.

Hereditary papillary renal carcinoma syndrome (HPRC) is an autosomal dominant syndrome due to missense germline mutations in the MET proto-oncogene.

Hereditary pheochromocytoma-paraganglioma syndrome (PPGL) is most commonly due to a mutation of the SDH genes and less commonly due to mutations in the RET (multiple endocrine neoplasia type 2), VHL, and NF1 (neurofibromatosis type 1) genes. Clinical features suggesting a hereditary PPGL syndrome are multifocality, bilaterality, early onset (<45 years old), and recurrence of paragangliomas. Hereditary paragangliomas often occur in the genitourinary system. Histologic features indicative of a hereditary tumor include adrenal medullary hyperplasia, a feature seen with different underlying mutations; hyaline globules in MEN2-related pheochromocytomas; a thick capsule and stromal edema in VHL-related tumors; and pseudorosette formation and nests of epithelioid tumor cells with vacuolated cytoplasm in SDH tumors. All patients with PPGL should undergo germline testing.

Carney complex (CC) is a rare autosomal dominant disease most commonly due to inactivating mutations in the protein kinase c-AMP–dependent type 1 regulatory subunit alpha (PRKAR1A). Neoplasms associated with CC include myxoma, especially cardiac; primary pigmented nodular adrenocortical disease; LCCSCT; follicular adenoma of the thyroid; ductal adenoma of the breast; blue nevi; pituitary adenoma; psammomatous melanotic schwannoma; and osteochondromyxoma. LCCSCT, a hallmark of CC, occurs in about one-third of boys and almost all men with CC.

PJS is an autosomal dominant polyp and cancer predisposition syndrome caused by mutations in the STK11 gene. Mucocutaneous pigmentation and gastrointestinal polyposis are typical. Prepubertal children are at risk for the development of intratubular large cell hyalinizing Sertoli cell neoplasia, a benign, multifocal, and bilateral testicular tumor almost exclusively seen in patients with PJS. These tumors can be associated with estrogen production.

Germline mutations in genes coding for homologous recombination pathways, including BRCA1, BRCA2, CHEK2, and ATM, are associated with increased risk for various cancer types including those of the prostate and urothelium. Prostate carcinomas tend to be higher grade (Gleason score 8 or more). Tumors are particularly responsive to PARP inhibitor and platinum-based chemotherapy.

Lynch syndrome is an autosomal dominant tumor predisposition syndrome caused by pathogenic germline variants of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2 or EPCAM. It is associated with a markedly increased risk for upper urinary tract urothelial carcinoma (pelvicalyceal), which is the third most common tumor in these patients (after colorectal and endometrial carcinoma). Recent data also suggest an increased risk for prostate carcinoma. Immunohistochemistry for mismatch repair proteins is recommended as a screening strategy for patients with upper urinary tract urothelial carcinoma.