Abstract

In 2022, after a six-year interval, the International Agency for Research on Cancer (IARC) has published the 5th edition of the WHO Classification of Urinary and Male Genital Tumors, which provides a comprehensive update on tumor classification of the genitourinary system. This review article focuses on prostate carcinoma and underscores changes in the prostate chapter as well as those made across the entire series of the 5th edition of WHO Blue Books. Although no major alterations were made to this chapter, some of the most notable updates include restructure of contents and introduction of a new format; standardization of mitotic counts, genomic nomenclatures, and units of length; refined definition for the terms “variant”, “subtype”, and “histologic pattern”; reclassification of prostatic intraepithelial neoplasia (PIN)-like adenocarcinoma as a subtype of prostatic acinar adenocarcinoma; and recognition of treatment-related neuroendocrine prostatic carcinoma as a distinct tumor type. Evolving and unsettled issues related to grading of intraductal carcinoma of the prostate and reporting of tertiary Gleason pattern, the definition and prognostic significance of cribriform growth pattern, and molecular pathology of prostate cancer will also be covered in this review.

Introduction

The publication of 2022 WHO Classification of Urinary and Male Genital Tumors (5th Edition) marks another major milestone in the field of genitourinary (GU) pathology and is the culmination of scientific advancements in recent years built upon the 4th edition published in 2016. The new edition of this authoritative reference book provides a comprehensive update on tumor classification in the same modular fashion as the previous edition with the addition of several new sections for each disease entity, including cytology, diagnostic molecular pathology, essential and desirable diagnostic criteria, and staging. This review article highlights salient changes made to the prostate chapter as we have gained better understanding of the etiology, pathogenesis, and molecular pathology of prostate cancer. The following topics will be presented in detail: (1) changes in nomenclature and terminology, (2) prostatic ductal adenocarcinoma and prostatic intraepithelial neoplasia (PIN)-like adenocarcinoma, (3) intraductal proliferative lesions and reporting recommendations from the two major urological societies regarding intraductal carcinoma of the prostate, (4) cribriform growth pattern, (5) reporting of tertiary Gleason pattern, (6) treatment-related neuroendocrine prostatic carcinoma, and (7) molecular genetics. In addition to the updates specific to this chapter, the format of the contents had also been restructured across all volumes of the 5th edition series and that pertaining to the prostate chapter will be addressed first to provide an overview of how the new WHO Blue Book is organized.

Restructure of Contents in the 5th Edition Series

In alignment with the new format in the 5th edition series, less common but identical neoplasms from various sites in the GU system, i.e., neuroendocrine neoplasms, mesenchymal tumors, hematolymphoid tumors, melanocytic lesions, metastases, and genetic syndrome-related tumors, are compiled and discussed in separate chapters to consolidate information and minimize repetition. However, stromal tumors of the prostate, thought to originate from prostate stromal cell proper, and treatment-related neuroendocrine prostatic carcinoma, are still included in the prostate chapter due to their uniqueness to the prostate, and distinctive biological and clinical characteristics as well as therapeutic implication for the latter. Likewise, urothelial carcinoma of the prostate and prostatic urethra, is now incorporated into Chapter 3, Tumors of the Urinary Tract, for similar reasons, while maintaining the pT staging criteria for pT2 (transmucosal invasion of the prostatic stroma) and pT4 (transmural or extravesical invasion from the urinary bladder into the prostatic stroma) from the previous edition.

With more than half of the tumors discussed in other chapters, only 11 tumor types remain in the prostate chapter (Tab. I). These tumors are divided into two broad categories: epithelial tumors and mesenchymal tumors unique to the prostate. The epithelial tumor category is further subcategorized into two families: glandular and squamous neoplasms. The glandular family comprises 6 tumor types: cystadenoma, high-grade prostatic intraepithelial neoplasia (HGPIN), intraductal carcinoma of the prostate (IDC-P), prostatic acinar adenocarcinoma (acinar PCa), prostatic ductal adenocarcinoma (ductal PCa), and treatment-related neuroendocrine prostatic carcinoma (t-NEPC). The squamous family comprises 3 tumor types: adenosquamous carcinoma, squamous cell carcinoma, and adenoid cystic (basal cell) carcinoma of the prostate. The mesenchymal tumor category only contains stromal tumor family, which encompasses 2 tumor types: prostatic stromal tumor of uncertain malignant potential and prostatic stromal sarcoma. The order in which these neoplasms are described has been slightly modified so that they progress from benign to malignant ¹ as in most textbooks. The essential and desirable diagnostic criteria, one of the new features of the 5th edition series, are also provided for each tumor.

Other more subtle changes are the standardization of mitotic counts, genomic nomenclatures, and units of length. Mitotic counts have traditionally been quantified per 10 high power fields, but for comparability they are currently expressed as per mm² since different microscopes have eyepiece with different field diameter and hence different area per microscopic field ¹. Fortunately, GU pathologists are exempt from performing mathematical conversion because mitotic count is rarely ever used if at all in our routine practice. In addition, genomic nomenclatures have also been standardized by using Human Genome Variation Society (HGVS) notation ¹. Lastly, the convention used by the International Collaboration on Cancer Reporting and the United Kingdom Royal College of Pathologists has been adopted. As a consequence, tumor size is now given exclusively in millimeters as a substitution for centimeters to eliminate the use of decimal points, which is more prone to error ¹.

Changes in Nomenclature and Terminology

Although the terms “variant”, “subtype”, and “histologic pattern” have been used interchangeably to some extent in the past, the current edition of the WHO Blue Books defines them more stringently. “Variant”, formerly used in a morphological sense, now refers only to genetic alteration ^1,2 or more precisely, a difference between a reference sequence and a sample sequence ³. “Subtypes” are subset of a tumor type that has distinct morphology with implications related to prognosis and/or differential diagnosis ^2,4. In contrast, “histologic patterns” are distinct or unusual morphologies that are not prognostically significant except for their underlying Gleason scores but receive special recognition to help pathologists avoid misdiagnosing cancer as benign mimickers and vice versa ⁴. Although the distinction can be somewhat subjective ⁴, signet-ring cell–like (≥ 25% of the tumor composed of signet-ring cells), sarcomatoid, pleomorphic giant cell, and PIN-like carcinoma are recognized as subtypes of acinar PCa ^4,5, which is the only tumor type in this chapter that has subtypes; while atrophic (including p63-positive), pseudohyperplastic, microcystic, foamy gland, and mucinous (≥ 25% of tumor composed of glands with extracellular mucin) adenocarcinomas are considered histologic patterns ⁵. This terminology scheme is now in effect across all volumes of the 5th edition of WHO Blue Books to harmonize the use of these three terms.

Prostatic ductal adenocarcinoma is defined morphologically as papillary and/or complex and cribriform glands lined by tall pseudostratified columnar cells with elongated nuclei ⁶ (Fig. 1); however, this term is now arbitrarily reserved for prostatic adenocarcinoma (PCa) in radical prostatectomy (RP) specimens showing > 50% ductal morphology⁶. It is also recommended that the percentage of ductal component be reported⁶. When this morphology is encountered in biopsy specimens, the alternative term “prostatic adenocarcinoma with ductal features” should be applied even if pure ductal morphology is present ⁶.

Gleason grading underwent a major modification in 2014 ⁷, and different combinations of Gleason scores were stratified into a prognostic grouping system known by a few names, including Grade Group and ISUP Grade. It is suggested that the nomenclature “WHO Classification of Tumors Grade” or “WHO Grade” be used for simplicity and harmonization, and also to distinguish this system from older grade grouping systems ⁴ used in studies prior to 2013, which was when the system currently in use was proposed ⁸.

Basal cell carcinoma of the prostate, a malignant tumor arising from prostatic basal cells ⁹, is morphologically similar to adenoid cystic carcinoma of the salivary gland and also harbors the same MYB::NFIB fusion in approximately 50% of the cases ¹⁰, a rate remarkably similar to the salivary gland counterpart ¹¹. Interestingly, the same study ¹⁰ also found that most fusion-positive cases (57%) had adenoid cystic-like morphology, whereas almost all fusion-negative cases (93%) did not. To avoid confusion with the much more common cutaneous basal cell carcinoma, this neoplasm has been renamed “adenoid cystic (basal cell) carcinoma of the prostate” ². Nevertheless, the former name is still considered acceptable as are adenoid cystic carcinoma, adenoid basal cell carcinoma, and adenoid cystic carcinoma (solid pattern) ⁹.

Prostatic Ductal Adenocarcinoma and PIN-like Adenocarcinoma

Ductal PCa, also known as ductal carcinoma, was originally believed to originate from Müllerian duct remnants ¹² and was considered to be a completely different tumor from acinar PCa⁶. It is now apparent that ductal PCa and acinar PCa are rather closely related as they share similar immunohistochemical and molecular profiles and frequently coexist ⁶. In fact, ductal PCa comprises 2.6% of all PCa, but the pure form constitutes only 0.2% to 0.4% ⁶. The contemporary view is that both ductal PCa and acinar PCa are derived from prostatic glandular cells, and their coexistence could possibly represent divergent differentiation from a common precursor ⁶. Due to mounting molecular evidence, there have been discussions to reclassify ductal PCa as a subtype of acinar PCa rather than retaining it as a separate tumor type ². Most studies suggested that ductal PCa is clonally related to the admixed acinar PCa component because of shared ERG rearrangements and other molecular aberrations ⁶. However, occasional studies have also found differing genomic profiles in ductal PCa, such as a lower rate of ERG fusion and expression ^13,14; enrichment of germline or somatic alterations of genes related to DNA damage repair, including homologous recombination and mismatch repair genes ^15,16; and a higher frequency of mutations in WNT signaling pathway (activating CTNBB1 and inactivating APC mutations), which are often mutually exclusive with activating mutations in the PI3K signaling pathway ^17,18. While awaiting more evidence, ductal PCa remains a distinct type of PCa due to its more aggressive behavior compared to acinar PCa and the predilection for liver and lung metastases as well as brain, skin, testicular, and penile metastases on rarer occasions ^2,6. Finally, it is worth mentioning that approximately 10% of periurethral ductal PCa initially detected by transurethral biopsy or resection may not have accompanying acinar PCa and could be completely eradicated solely by transurethral resection ¹⁹. In such a situation, patients should undergo follow-up transurethral resection and transrectal prostate biopsy to exclude the presence of concomitant PCa elsewhere in the prostate before definitive and radical treatment such as radical prostatectomy is rendered ¹⁹.

PIN-like adenocarcinoma is characterized by crowded, large, discrete glands with flat or tufted architecture ⁵ as opposed to the papillary or cribriform architecture of ductal PCa. When taken out of context, each individual cancer gland can be very difficult if not impossible to differentiate from HGPIN. The tumor cells can exhibit either ductal PCa morphology or acinar PCa morphology ⁵ (Fig. 2), but regardless of which type of PCa it resembles, this tumor is assigned a Gleason score (GS) of 3 + 3 = 6 and generally has a favorable prognosis comparable to low-grade acinar PCa (GS 3 + 3 = 6) ²⁰. A recent genomic study also found that 60% of PIN-like adenocarcinomas harbor activating mutations in the RAF/RAS pathway, which is distinct from the molecular profile of both ductal PCa and acinar PCa ²¹. Given its unique genetic changes and better outcomes compared to ductal PCa, PIN-like adenocarcinoma had been reclassified as a subtype of acinar PCa in the current edition of the WHO Blue Book ².

Intraductal Proliferative Lesions

HGPIN, atypical intraductal proliferation (AIP), and IDC-P constitute a morphological spectrum of intraductal proliferation with worsening architectural and/or cytological atypia, ranging from mild to severe. Low-grade prostatic intraepithelial neoplasia (LGPIN), also biologically an intraductal lesion, is a proliferation of secretory cells with very mild nuclear atypia, which makes it impossible to be reliably differentiated from benign glandular hyperplasia ². Consequently, this lesion is no longer diagnosed in the 2022 WHO Blue Book and should not be reported for several reasons, including poor reproducibility and no increased risk of cancer detection in subsequent biopsies ²².

HGPIN shows a higher degree of cytological atypia compared to LGPIN and confers a cancer risk of 20% if unifocal and 30-40% if multifocal in subsequent repeat biopsies ²³. Four major histologic patterns of HGPIN were recognized in the 2016 WHO Blue Book: cribriform, tufting, micropapillary, and flat ^24,25; and a variety of less commonly encountered patterns, e.g., vacuolated, foamy, and mucinous, have also been described ^24,25. Of these patterns, cribriform HGPIN is particularly problematic because its morphology overlaps with a similar intraductal proliferative lesion that could represent the lower grade spectrum of IDC-P or AIP. These two lesions have drastically different clinical implicationns; while HGPIN can be conservatively followed, AIP warrants an immediate repeat biopsy ²⁶. For this reason, the diagnosis of cribriform HGPIN on needle biopsy should be avoided as this can lead to inappropriate patient management. Of note, none of the histologic patterns of HGPIN carries any clinical significance, and their designations should be avoided in routine practice ²³. In the new WHO Blue Book, cribriform HGPIN had been revoked of its entity status, leaving only three major patterns; though in the authors’ opinion, cribriform HGPIN does exist but is extremely rare and can only be confidently identified in RP specimens when a few of these glands are present among benign glands (Fig. 3).

AIP, also called atypical cribriform proliferation and atypical intraductal proliferation suspicious for IDC-P, has architectural and/or cytological atypia exceeding HGPIN but fall short of IDC-P ²³ (Fig. 4). Although not yet recognized as a distinct entity, this borderline lesion is associated with a 50% risk of PCa and/or IDC-P on repeat biopsy ²⁷ as well as adverse pathological findings at RP ²⁸. A few studies have also demonstrated that AIP is clinically and molecularly akin to IDC-P, supporting the concept that AIP represents the low-grade spectrum of IDC-P ^29,30. In practice, needle biopsies containing cribriform or lumen spanning intraductal proliferation without the characteristic features of IDC-P should be diagnosed as AIP with a comment that the lesion is suspicious for but not definite for IDC-P ³¹ and an immediate repeat biopsy is warranted to rule out clinically significant PCa ^29,30. The authors suggest to perform immunohistochemical (IHC) stains for PTEN and ERG on selected cases for a more definite diagnosis.

IDC-P is defined as “a neoplastic epithelial proliferation involving preexisting, generally expanded, duct-acinar structures and characterized by architectural and cytological atypia beyond what is acceptable for HGPIN” ³² (Fig. 5). A few sets of similar diagnostic criteria have been published ^33-35, but the one most widely used and endorsed by the WHO Blue Book is based on the study by Guo and Epstein. The presence of at least one of the following architectural and/or cytological atypia is considered diagnostic of IDC-P: solid architecture, dense cribriform architecture (> 50% cellular component relative to lumens), comedonecrosis, or marked atypical nuclei (> 6x size of adjacent benign nuclei) ²⁵. In the 2022 WHO Blue Book, these criteria remain unchanged except for removal of the nuclear size requirement ³² (Tab. II), which should not be applied literally. Rather, it was meant to reflect significantly enlarged and pleomorphic nuclei that are more atypical than HGPIN ³¹.

There is emerging evidence suggesting that IDC-P has two distinct biological pathways ³⁶ despite the two being morphologically indistinguishable. The vast majority of IDC-P are associated with high-grade, high-volume PCa and occur as late events where preexisting PCa retrogradely spreads into and colonizes benign nonneoplastic ducts and acini ³². This pathogenesis is supported by an increasing number of studies demonstrating the overlap of genetic alterations between IDC-P and concomitant PCa ³². A small minority of IDC-P are found without PCa or with low-grade PCa and are thought to be in situ lesions, which progress from HGPIN precursor ³². Nonetheless, it should be noted that IDC-P without concomitant PCa in prostate biopsies typically indicates unsampled high-grade cancer, and IDC-P without PCa is vanishingly rare in RP specimens ³². Unsurprisingly, IDC-P is an independent adverse prognostic factor associated with a multitude of unfavorable pathological parameters and poor outcomes ²⁶, and it is recommended that the presence of IDC-P be reported in both RP and needle biopsy specimens ³². Additionally, the National Comprehensive Cancer Network (NCCN) and the Philadelphia Prostate Cancer Consensus Conference have formally recommended germline BRCA2 testing when IDC-P is present ³⁷. This recommendation is questionable because it is based on a retrospective study that reported the association between intraductal/ductal histology and lymphovascular invasion, and pathogenic germline DNA-repair gene mutations, of which 43% were BRCA2 ³⁸; however, IDC-P have been more recently found to be associated with biallelic loss of BRCA2 but not germline BRCA2 mutations in a case-control study ³⁹.

The most contentious issue of IDC-P diagnosis is related to whether or not to include IDC-P in Gleason grading. The Genitourinary Pathology Society (GUPS) and the International Society of Urological Pathology (ISUP), the two most influential organizations in GU subspecialty, have contradicting opinions regarding this matter (Tab. III). While both societies agree on not grading pure IDC-P and on performing IHC stains on such cases, GUPS recommends not grading IDC-P in any circumstances ³¹, whereas ISUP recommends the exact opposite, i.e., grading IDC-P whenever concurrent invasive PCa is present ⁴⁰. This inevitably led to another discordant views regarding the use of basal cell markers to differentiate IDC-P from invasive PCa. IHC stains for basal cells can be omitted for this purpose according to ISUP ⁴⁰, while GUPS recommends performing basal cell stains when the results may change the highest Grade Group for the case ³¹. The pros and cons of both approaches have been debated ⁴¹ (Tab. IV). The new edition of WHO Blue Book acknowledges these dissimilarities but does not endorse either position because the overall evidence is insufficient, and both positions are mainly based on consensus opinions ³². At this time, either method can be used, but pathologists should specify which of the two is used for clarity and meaningful analyses in the future. While awaiting resolution to this disagreement, the authors use a middle ground approach, which is always reporting the presence of IDC-P, not grading isolated IDC-P, not grading IDC-P with low-grade PCa (GS = 6), and grading IDC-P with any higher grade PCa (GS ≥ 7). The authors would also perform IHC for basal cell stain in the first two scenarios and omit the stain in the last scenario even if the result might affect the Grade Group (Tab. V).

Cribriform Growth Pattern

Various neoplastic and non-neoplastic lesions in the prostate can have cribriform morphology, including central zone glands, clear cell cribriform hyperplasia, basal cell hyperplasia, cribriform HGPIN, AIP, IDC-P, and invasive cribriform carcinoma. Several studies during the past decade have uniformly shown that malignant cribriform morphology, including invasive cribriform cancer and IDC-P, have a significant negative impact on clinical outcomes ^42-47, albeit only a few clearly distinguished invasive and intraductal carcinoma ^48-50. As a result, GUPS and ISUP unanimously recommend reporting the presence of cribriform carcinoma in biopsy and RP specimens ^31,40. Though the distinction of invasive cribriform carcinoma and IDC-P is not always possible without performing basal cell markers, this distinction is not crucial as both lesions negatively influence the outcome. Therefore, the authors use encompassing phrases such as “Cribriform cancer glands present” or “Cribriform growth pattern present” when reporting this finding.

Because of its prognostic value, it is important to accurately recognize and diagnose cribriform pattern. The defining characteristics of cribriform cancer have been published by two parties of investigators, but neither has yet been adopted by the WHO Blue Book. ISUP defines cribriform glands as “a confluent sheet of contiguous malignant epithelial cells with multiple glandular lumina that are easily visible at low power (objective magnification ×10). There should be no intervening stroma or mucin separating individual or fused glandular structures” ⁵¹. Shah et al. found that transluminal bridging, dense cellular proliferation (cell mass ≥ 50% of glandular lumen), a clear luminal space along the periphery of gland occupying < 50% of gland circumference, lack of intraglandular mucin, and lack of contact between the majority of intraglandular cells with stroma were the features diagnostic of cribriform glands; while the opposite morphologies and glomeruloid pattern were features against this diagnosis ⁵² (Tab. VI).

Even though cribriform pattern has a relatively good interobserver reproducibility ^52-55, several authors have explored further to determine the prognostic difference between small and large cribriform glands using various cut-off points, including > 12 lumens ^56-58, glands exceeding the size of average benign glands ⁵⁰, and a diameter of at least twice the size of adjacent pre-existent normal glands ⁴⁸. While others found no association between size and adverse outcomes, the last study found that large but not small cribriform gland is independently predictive of biochemical recurrence-free survival in Grade Group (GG) 2 PCa ⁴⁸. Very recently, two groups of investigators also attempted to address this issue. One of the studies found that cribriform glands, both small and large (at least twice the diameter of adjacent benign glands), were linked to worse metastasis-free survival and disease-specific survival ⁵⁹; whereas the other study found that only large cribriform glands (diameter > 0.25 mm or approximately half of 400x microscopic field) are predictive of biochemical recurrence, metastasis-free survival, and disease specific death ⁶⁰.

Reporting of Tertiary Gleason Pattern

PCa with > 2 Gleason patterns (GPs) are not uncommon in routine practice. While the grading guidelines from GUPS and ISUP are in agreement for biopsy specimens, i.e., Gleason score should include the most common pattern (primary pattern) and highest-grade pattern in prostate biopsies, there is a major divergence in their recommendations regarding minor/tertiary high-grade pattern in RP specimens (Tab. III). Somewhat arbitrary, 5% is considered a cut-off for tertiary high-grade pattern. If ≥ 5% of the tumor volume, the tertiary high-grade pattern becomes the secondary pattern in Gleason scoring. If < 5%, the tertiary high-grade pattern remains as a tertiary pattern. According to GUPS, minor/tertiary high-grade pattern only applies in one setting, that is RP specimens when all three GPs, i.e., GP3, GP4, and GP5, are present with GP5 being < 5% ³¹. Specifically, the Gleason score could only be 3 + 4 = 7 or 4 + 3 = 7 with minor/tertiary pattern 5. This recommendation from GUPS, therefore, is not a modification of the grading rules but rather a clarification of the conventional grading rules currently in use.

In contrast, ISUP also uses this term in an additional setting when there are only two GPs composed of an overwhelming GP of a single lower grade combined with minimal GP of a higher grade. Explicitly stated, there are three possibilities: > 95% GP3 with < 5% GP4 is graded as 3 + 3 = 6 with minor/tertiary pattern 4; > 95% GP3 with < 5% GP5 is graded as 3 + 3 = 6 with minor/tertiary pattern 5; and > 95% GP4 with < 5% GP5 is graded as 4 + 4 = 8 with minor/tertiary pattern 5 ⁴⁰. In these three scenarios, GUPS would grade these tumors as 3 + 4 = 7, 3 + 5 = 8, and 4 + 5 = 9, respectively. These new grading rules by ISUP have not yet been adopted in the 2022 WHO Blue Book due to inconclusive data. Even so, if one opts for ISUP recommendations in these scenarios, it is important to comment on the presence of minor/tertiary pattern in the report.

Treatment-Related Neuroendocrine Prostatic Carcinoma (t-NEPC)

t-NEPC is a prostatic adenocarcinoma that demonstrates partial or complete high-grade neuroendocrine (NE) differentiation following androgen deprivation therapy. It is found in 10-15% of patients with castration-resistant prostate cancer ⁶¹ and usually develops during or after the use of potent androgen blocking drugs, such as enzalutamide or abiraterone. In contrast, de novo high-grade neuroendocrine carcinomas (NECs) in the absence of a history of or treatment for PCa are rare (< 1% of PCa). Studies have suggested that t-NEPC is derived from transdifferentiation of adenocarcinoma as both share clonal origin demonstrated by concordance of ERG rearrangements between the t-NEPC and the matched hormone-naïve carcinoma, or in mixed tumors. Lineage plasticity of PCa plays a critical role in the development of t-NEPC as PCa cells, during treatment with androgen receptor (AR) signaling inhibitors, become AR indifferent and transdifferentiate into high-grade NECs. Such transdifferentiation is thought to be driven by epigenetic changes occurring under specific genomic conditions, including TP53, RB1, and PTEN loss ^62-64. The prognosis is dismal with a median overall survival of 53.5 months after initial PCa diagnosis ⁶⁵ and a median survival of only 7 months after diagnosis of t-NEPC ⁶⁶. If morphology is taken into consideration, pure small cell carcinoma (SmCC) has a worse prognosis compared to tumors with mixed t-NEPC and PCa morphology ⁶⁵. Because of its unique clinical and therapeutic significance, and potential as a model for the study of prostate cancer progression, t-NEPC is classified as a distinct tumor type of prostatic glandular neoplasm similar to acinar PCa in the new WHO Blue Book. Lastly, like IDC-P, germline BRCA2 testing is recommended by the NCCN and the Philadelphia Prostate Cancer Consensus Conference ³⁷.

t-NEPC has a spectrum of histological features ranging from pure NE morphology, most commonly SmCC and rarely large cell neuroendocrine carcinoma (LCNEC), to mixed tumors with a poorly differentiated PCa and high-grade NEC components. The SmCC component in a t-NEPC is morphologically and immunohistochemically identical to its counterpart of other body sites. LCNECs are exceedingly rare and are composed of large polygonal cells exhibiting high-grade nuclei with focal pleomorphism and frequent prominent nucleoli. The tumor cells often have ample eosinophilic cytoplasm and are arranged in a NE architecture with nests, acini, and trabeculae with peripheral palisading. Focal necrosis is also commonly present. Mixed tumors, consisting of admixed typical PCa and high-grade NEC components, account for approximately 50% of prostate SmCC. The transition between both components is usually abrupt, and the concomitant PCa is often high-grade (Fig. 6). The high-grade NE component is not graded, whereas the conventional PCa component in such tumors can be graded and usually has a Gleason score of > 8.

Immunohistochemically, the high-grade NE component shows nuclear p53 staining in the majority of cases, thyroid transcription factor 1 (TTF1) positivity in about half of the cases, and AR positivity in a small subset of tumors. Prostate specific markers including PSA, PAP, P501S, and NKX3.1 are typically negative or at most very focally expressed. Ki-67 index is typically high, > 80%, but < 50% in high-grade PCa. NE markers, including synaptophysin, chromogranin, CD56, and newer markers such as insulinoma-associated protein 1 (INSM1), are positive, although a diagnosis may be made without or with negative NE markers as 10-15% of the SmCC are negative for these markers.

In addition to t-NEPC, other forms of NE differentiation are also found in PCa. In fact, almost all PCas show some degree of NE differentiation if tested for the NE marker expression by IHC ⁶⁷. However, the prognostic and therapeutic association of such IHC expression in a conventional PCa is lacking, and thus performing IHC for NE markers is not recommended for routine PCa cases ⁶⁸.

Not infrequently, prostatic glandular cells show abundant fine or coarse, brightly eosinophilic granules in the cytoplasm (Fig. 7), which are positive for NE markers. This so-called Paneth cell–like NE differentiation can be seen in benign glands, HGPIN, and PCa, and can focally or diffusely involve cancer glands. The involved cancer cells often form single cells, cords, and nests, and would be graded as GP4 or GP5. Despite the concerning GP, these tumors otherwise demonstrate bland histological features with relatively small nuclei and inconspicuous nucleoli. Furthermore, Paneth cell–like NE differentiation has not been shown to negatively impact the prognosis, and Gleason grade assignment does not reflect the clinical behavior in these particular cases ⁶⁹. Accordingly, it is recommended to only grade the conventional PCa component in these tumors. If a tumor comprises pure or predominant Paneth cell–like differentiation, it should not be graded, and a comment should be provided to state that such tumor generally has a favorable prognosis.

Well-differentiated neuroendocrine tumors (NETs) are low-grade epithelial tumors that lack the expression of prostate markers but show NE differentiation (Fig. 8). They were diagnosed in the past as “carcinoid tumor”, with which these tumors share many morphological features ⁷⁰. Vascular invasion, extraprostatic extension, and seminal vesicle invasion may also be observed. Unlike t-NEPC, NETs are not associated with high-grade PCa, or prior hormonal or radiation therapy, although they may be seen with incidentally discovered GG1 PCa.

Molecular Genetics of Prostate Cancer

Molecular genetics of PCa initiation and progression, therapeutically relevant genomic alterations in metastatic PCa, and germline testing are succinctly discussed in several places in the prostate chapter. The molecular events most commonly implicated in PCa initiation include MYC overexpression, inactivation of GSTP1 and other genes by promoter CpG island hypermethylation, and chromosomal structural alterations such as telomere shortening and ETS gene fusions ^71,72. Fusions involving the ETS transcription factor genes constitute the most common oncogenic drivers, reported in up to 50% of PCa cases ⁷². In PCa without ETS gene fusions, somatic mutations involving FLI1, FOXA1, IDH1, and SPOP have been reported and are mutually exclusive of each other. Molecular alterations identified in PCa progression include gain of 8q24 which harbors the MYC gene, loss of PTEN, inactivation of TP53, and additional mutations and hypermethylation events. In addition, genomic instability is also an important contributor in prostate cancer progression ⁷³.

For localized PCa, several prognostic transcript signatures or genomic classifiers have been shown to improve risk stratification additional to clinicopathological features ⁷⁴. These genomic classifiers measure expression of genes that are associated with tumor progression, including proliferation, invasion, and androgen signaling ^75-77. These assays can guide clinical decision making regarding active surveillance or indication of adjuvant therapy following radical prostatectomy. Whether tumor heterogeneity, multifocality, and tissue sampling may affect the validity and clinical utility of these assays remains to be seen.

In metastatic PCa, the main therapeutically actionable alterations are homologous recombination repair deficiency (HRD), microsatellite instability-high (MSI-H), and CDK12-deficiency. Alterations in DNA damage response genes are present in 19% of localized and up to 31% of metastatic PCa. HRD can render PCa susceptible to poly (ADP-ribose) polymerase (PARP) inhibition; therefore, genomic instability assays assessing HRD may predict sensitivity to PARP inhibitors. MSI-H or mismatch repair deficiency (dMMR) has been reported in 1-5 % of PCas ^78,79 and can be identified by IHC, microsatellite PCR, or next generation sequencing (NGS), as well as sequencing of mismatch repair (MMR) genes. dMMR sensitizes PCa to immune checkpoint inhibitors. Finally, CDK12-deficiency, found in 1-5% of PCas, leads to variable degrees of sensitivities to immune checkpoint inhibitors ⁸⁰.

US NCCN guidelines recommend germline testing for patients with a personal history of high or very high-risk localized PCa, regional or metastatic PCa, as well as family history of PCa. It is recommended that the germline panels include Lynch Syndrome-related genes (MLH1, MSH2, MSH6, and PMS2) and HRD-genes (BRCA1, BRCA2, ATM, PALB2, and CHEK2) ⁸¹. Other genes such as HOXB13 should be also considered ^37,81.

Conclusions

The 2022 WHO Classification of Urinary and Male Genital Tumors (5th Edition) has thoroughly updated the GU tumor classification by integrating scientific progress during the last several years. This review article presented important changes in the prostate chapter as well as changes made across all volumes of the 5th edition series as follows: (1) tumors not unique to the prostate are compiled and discussed in separate chapters; (2) mitotic counts are expresses as per mm²; HGVS notation has been adopted for genomic nomenclatures; and tumor size are given in millimeters; (3) “variants” refer to genetic alterations; “subtypes” are distinct morphologies with implications related to prognosis and/or differential diagnosis, whereas “histologic patterns” are distinct morphologies without prognostic significance; (4) ductal PCa is a diagnostic term reserved for PCa in RP specimens with > 50% ductal morphology; (5) basal cell carcinoma of the prostate is renamed adenoid cystic (basal cell) carcinoma of the prostate; (6) PIN-like adenocarcinoma is reclassified as a subtype of acinar PCa; (7) cribriform HGPIN is no longer an entity and should be diagnosed as AIP on biopsy specimens; (8) nuclear size requirement is removed from the diagnostic criteria of IDC-P; (9) IDC-P should be reported, but whether or not IDC-P should be graded is still being debated; (10) cribriform carcinoma should be reported, but the threshold is not yet agreed upon; (11) ISUP recommends grading PCa composed of > 95% GP3 with < 5% GP4 as 3 + 3 = 6 with minor/tertiary pattern 4, > 95% GP3 with < 5% GP5 as 3 + 3 = 6 with minor/tertiary pattern 5, and > 95% GP4 with < 5% GP5 as 4 + 4 = 8 with minor/tertiary pattern 5; while GUPS recommends grading these tumors as 3 + 4 = 7, 3 + 5 = 8 and 4 + 5 = 9, respectively; (12) t-NEPC is newly recognized as a distinct tumor type with very poor prognosis, which occurs following androgen deprivation therapy and shows NE morphology (SmCC or LCNEC), either pure or mixed with PCa; and (13) molecular and genetic testing can help guide management and identify therapeutic options in PCa. Controversial issues related to discordant recommendations from GUPS and ISUP have been acknowledged and will likely be revisited in the next edition when more solid evidences are available.

ACKNOWLEDGEMENTS

The authors wish to acknowledge the support of Genitourinary Pathology Society.

CONFLICTS OF INTEREST

The authors declare no conflict of interest.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

Both authors contributed to the conception, drafting, and approval of the manuscript.

Figures and tables

Figure 1.Prostatic ductal adenocarcinoma (ductal PCa). Ductal PCa showing papillary (A, 200x) and cribriform glands (B, 200x), both of which are lined by the characteristic tall pseudostratified columnar cells with elongated nuclei. Lumens of the cribriform glands in ductal PCa tend to have slit-like shape as opposed to the rounded shape of acinar PCa.

Figure 2.PIN-like adenocarcinoma. PIN-like adenocarcinoma showing acinar (A, 200x) and ductal (C, 200x) morphology with flat or tufted architecture. Each individual gland is morphologically indistinguishable from HGPIN when taken out of context. IHC stain for p63 demonstrates loss of basal cells in the cancer glands (B, 200x) and preserved basal cell layer in benign glands elsewhere in the same core (not shown).

Figure 3.Cribriform HGPIN. A cribriform gland (A, 100x) with many prominent nucleoli (B, 400x) among benign glands in an RP specimen. In the authors’ opinion, this cribriform gland can be diagnosed as cribriform HGPIN, a diagnosis that should, however, be avoided in biopsy specimens.

Figure 4.Atypical intraductal proliferation (AIP). A cribriform lesion (A, 200x) with intact basal cell layer demonstrated by PIN4 stain (B, 200x). The proportion of lumens approaches 50%, which is borderline, and no other features of IDC-P are present. The authors tend to be conservative and would diagnose this lesion as AIP.

Figure 5.Intraductal carcinoma of the prostate (IDC-P). An intraductal proliferative lesion showing the degree of nuclear atypia that the authors think is sufficient for the diagnosis of IDC-P (A, 400x). PIN4 stain also confirms the presence of basal cell layer (B, 400x).

Figure 6.Treatment-related neuroendocrine prostatic carcinoma (t-NEPC). t-NEPC composed of prostatic adenocarcinoma (PCa), Gleason pattern 5, and small cell carcinoma (SmCC) with abrupt transition (A, 200x). The high-grade PCa component (upper half) shows relatively ample cytoplasm and distinct nucleoli, whereas the SmCC component (lower half) shows scant cytoplasm, nuclear molding, and inconspicuous nucleoli (B, 600x). PSA is positive in the former but negative in the latter (C, 200x).

Figure 7.Paneth cell–like differentiation. Prostatic adenocarcinoma (PCa), Gleason score 4 + 3 = 7 (Grade Group 3), with focal Paneth cell–like differentiation (A, 100x), characterized by brightly eosinophilic granules in cytoplasm (B, 600x). Most cancer cells with Paneth cell–like differentiation in this area show cribriform pattern (Gleason pattern 4) and cords of tumor cells (Gleason pattern 5; C, 200x), which were excluded from grading.

Figure 8.Well-differentiated neuroendocrine tumor (NET). Well-differentiated NET composed of cords and trabeculae of monotonous tumor cells (A, 100x) exhibiting the so-called salt-and-pepper chromatin (B, 600x). A focus of unrelated prostatic adenocarcinoma, Gleason score 3 + 3 = 6, is also incidentally discovered elsewhere in the prostate away from the NET (C, 200x).

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