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Treatment-related neuroendocrine prostate cancer is a distinctive category of prostate cancer that arises after intensive suppression of the androgen receptor by next-generation therapeutic inhibition of androgen receptor signaling. The biological processes that set in motion the series of events resulting in transformation of adenocarcinoma to neuroendocrine carcinoma include genomic (loss of tumor suppressors TP53 and RB1, amplification of oncogenes N-MYC and Aurora Kinase A, dysregulation of transcription factors SOX2, achaete-scute-homolog 1, and others) as well as epigenomic (DNA methylation, EZH2 overexpression, and others). Pathologic diagnosis is key to effective therapy for this disease, and this is aided by localizing metastatic lesions for biopsy using radioligand imaging in the appropriate clinical context. As our understanding of biology evolves, there has been increased morphologic recognition and characterization of tumor phenotypes that are present in this advanced post-treatment setting. New and promising biomarkers (delta-like ligand 3 and others) have been discovered, which opens up novel therapeutic avenues including immunotherapy and antibody-drug conjugates for this lethal disease with currently limited treatment options., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To compare oncologic outcomes and genomic alteration profiles in patients with bladder and urachal adenocarcinoma, urothelial carcinoma (UC) with glandular differentiation, and UC, not otherwise specified (NOS) undergoing surgical resection, with emphasis on response to systemic therapy., Methods: We identified patients with bladder cancer with glandular variants who underwent surgical resection at Memorial Sloan Kettering from 1995 to 2018 (surgical cohort) and/or patients who had tumor sequencing using a targeted next-generation sequencing platform (genomics cohort). Pathologic complete and partial response rates to neoadjuvant chemotherapy (NAC) and recurrence-free and cancer-specific survival were measured. Alteration frequencies between histologic subtypes were compared., Results: Thirty-seven patients with bladder adenocarcinoma, 46 with urachal adenocarcinoma, 84 with UC with glandular differentiation, and 1,049 with UC, NOS comprised the surgical cohort. Despite more advanced disease in patients with bladder and urachal adenocarcinoma, no significant differences in recurrence or cancer-specific survival by histology were observed after adjusting for stage. In patients with UC with glandular differentiation, NAC resulted in partial (≤ pT1N0) and complete (pT0N0) responses in 28% and 17%, respectively. Bladder and urachal adenocarcinoma genomic profiles resembled colorectal adenocarcinoma with frequent TP53 , KRAS , and PIK3CA alterations while the genomic profile of UC with glandular differentiation more closely resembled UC, NOS. Limitations include retrospective nature of analysis and small numbers of nonurothelial histology specimens., Conclusion: The genomic profile of bladder adenocarcinomas resembled colorectal adenocarcinomas, whereas UC with glandular differentiation more closely resembled UC, NOS. Differences in outcomes among patients with glandular bladder cancer variants undergoing surgical resection were largely driven by differences in stage. Cisplatin-based NAC demonstrated activity in UC with glandular differentiation, suggesting NAC should be considered for this histologic variant.

Background: Intraductal carcinoma (IDC) and cribriform architecture (CA) represent unfavorable subpathologies in localized prostate cancer. We recently showed that IDC shares a clonal ancestry with the adjacent glandular adenocarcinoma., Objective: We investigated for the co-occurrence of "aggression" factors, genomic instability and hypoxia, and performed gene expression profiling of these tumors., Design, Setting, and Participants: A total of 1325 men were treated for localized prostate cancer from four academic institutions (University Health Network, CHU de Québec-Université Laval, Memorial Sloan Kettering Cancer Center [MSKCC], and Erasmus Medical Center). Pathological specimens were centrally reviewed. Gene copy number and expression, and intraprostatic oxygenation were assessed., Outcome Measurements and Statistical Analysis: IDC/CA was separately assessed for biochemical relapse risk in the Canadian and MSKCC cohorts. Both cohorts were pooled for analyses on metastasis., Results and Limitation: Presence of IDC/CA independently predicted for increased risks of biochemical relapse (HR Canadian 2.17, p<0.001; HR MSKCC 2.32, p=0.0035) and metastasis (HR pooled 3.31, p<0.001). IDC/CA+ cancers were associated with an increased percentage of genome alteration (PGA [median] 7.2 vs 3.0, p<0.001), and hypoxia (64.0% vs 45.5%, p=0.17). Combinatorial genomic-pathological indices offered the strongest discrimination for metastasis (C-index 0.805 [clinical+IDC/CA+PGA] vs 0.786 [clinical+IDC/CA] vs 0.761 [clinical]). Profiling of mRNA abundance revealed that long noncoding RNA, SChLAP1, was the only gene expressed at >3-fold higher (p<0.0001) in IDC/CA+ than in IDC/CA- tumors, independently corroborated by increased SChLAP1 RNA in situ hybridization signal. Optimal treatment intensification for IDC/CA+ prostate cancer requires prospective testing., Conclusions: The poor outcome associated with IDC and CA subpathologies is associated with a constellation of genomic instability, SChLAP1 expression, and hypoxia. We posit a novel concept in IDC/CA+ prostate cancer, "nimbosus" (gathering of stormy clouds, Latin), which manifests as increased metastatic capacity and lethality., Patient Summary: A constellation of unfavorable molecular characteristics co-occur with intraductal and cribriform subpathologies in prostate cancer. Modern imaging for surveillance and treatment intensification trials should be considered in this adverse subgroup., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Multiple therapeutic options for renal tumors that are now available have put pathologists under increasing pressure to render diagnosis on limited material. Results on biopsies by hematoxylin and eosin (H&E) have historically not been encouraging. Currently, multiple immunohistochemical markers with differential expression in these renal tumors are available. We studied the utility of such markers on needle biopsies that were obtained ex vivo. After nephrectomy, two 18-guage cores were obtained and processed routinely. Expressions of carbonic anhydrase (CA) IX, CD117, α-methylacyl-CoA racemase (AMACR), cytokeratin 7 (CK7), and CD10 were evaluated. Results, with or without immunostaining, were compared with the final nephrectomy diagnosis. We studied 145 tumors, including 119 renal cell carcinomas (83 clear cell, 18 papillary, 14 chromophobe, and 4 type unclassified), 11 oncocytomas, and 15 miscellaneous tumors. Adequate evaluable material was present in 123 (85%) cases. In such biopsies, 81% of cases were correctly classified by H&E alone, with correct diagnosis in 90% of cases in the most common tumor subtypes (clear cell, papillary and chromophobe renal cell carcinoma, and oncocytoma). By adding immunostains, the accuracy was 90% overall and 99% among the 4 most common subtypes. The following extent and patterns of immuneexpression were highly useful in the diagnoses: diffuse, membranous CAIX expression in clear cell renal cell carcinoma, diffuse positivity for AMACR in papillary renal cell carcinoma, distinct peripheral cytoplasmic accentuation for CD117 in chromophobe renal cell carcinoma, widespread and intense positivity for CK7 in chromophobe and papillary renal cell carcinoma, and diffuse membranous reactivity in clear cell and patchy/luminal in papillary renal cell carcinoma for CD10. In conclusion, utilizing immunostains improves classification of renal tumors on needle biopsy, which may be of particular help for pathologists with limited experience. Both extent and patterns must be considered for a definitive diagnosis.

Pelvic lymph node (LN) metastasis is a well-recognized route of prostate cancer spread. However, the relationship between topography and the pathologic features of primary prostatic cancers and patterns of pelvic LN metastasis has not been well studied. We reviewed original slides of radical prostatectomies and pelvic LN dissections from 125 patients with LN metastasis and recorded a total number of LN excised/laterality of positive LN, and localization, staging parameters, lymphovascular invasion, and volume of primary tumors., Ln Quantity and Distribution: 14.6 (mean) and 13 (median) LNs were resected. Seventy-six (61%), 33 (26%), and 16 (13%) cases had 1, 2, and >2 positive LNs; whereas 58, 44, and 20 cases had LN metastasis on the right, left, and bilaterally., Pathologic Features: Eighty-six percent (108 of 125) and 37% (46 of 125) of the cases showed extraprostatic extension and seminal vesicle invasion, whereas 64% cases showed lymphovascular invasion. Mean and median total tumor volumes were 6.39 and 3.92 cm, with ≥50% and ≥90% Gleason patterns 4/5 in 105 (84%) and 73 (58%) cases, respectively., Correlation With Dominant Tumor Location: Dominant lesions on radical prostatectomy were as follows: 50 right lobe, 44 left lobe, and 31 bilateral lobe tumors. Fifteen of 50 (30%) right lobe and 18 of 44 (41%) left lobe dominant tumors had LN metastasis on the contralateral side. Only 4% (5 of 125) of the cases were associated with anterior dominant tumors., Conclusion: Thirty percent to 40% of LN metastases occurred contralateral to the dominant tumor. LN metastasis is overwhelmingly associated with high-grade, high-stage, and large volume disease. LN positivity is rarely associated with anterior dominant tumors.

TMPRSS2-ERG gene rearrangement is seen in about half of clinically localized prostate cancers, yet controversy exists with regard to its prognostic implications. Similarly, the relationship of TMPRSS2-ERG fusion to Gleason score and morphology remains uncertain. We assigned Gleason scores and recorded morphological features for 521 clinically localized prostate cancers sampled in triplicate and arrayed in eight tissue microarray blocks. Fluorescence in situ hybridization was performed to delineate TMPRSS2-ERG aberrations. Using maximum Gleason score, based on three core evaluation, and overall Gleason score, based on prostatectomy sections, Fisher's exact test was performed for tumors with TMPRSS2-ERG translocation/deletion, copy number increase (≥ 3) of the TMPRSS2-ERG region without translocation/deletion, and copy number increase and concomitant translocation/deletion. In all, 217 (42%) translocation/deletion and 30 (5.9%) copy number increase-alone cases were detected. Among 217 translocation/deletion cases, 32 had translocation/deletion with copy number increase. In all, 237, 200, and 75 cancers had maximum core-specific Gleason score of 6, 7, and 8-10, respectively. Tumors with translocation/deletion tended toward lower Gleason scores than those without (P=0.002) with similar results for overall Gleason score (P=0.02); copy number increase cases tended toward higher Gleason scores than those without (P<0.001). Gleason score of 8-10 tumors demonstrated lower odds of translocation/deletion (odds ratio (OR) 0.38; 95% CI 0.21-0.68) and higher odds of copy number increase alone (OR 7.33; 95% CI 2.65-20.31) or copy number increase+translocation/deletion (OR 3.03; 95% CI 1.12-8.15) relative to Gleason score of <7 tumors. No significant difference in TMPRSS2-ERG incidence was observed between patients with and without cribriform glands, glomerulations, signet-ring cells, or intraductal cancer (P=0.821, 0.095, 0.132, 0.375). TMPRSS2-ERG gene fusion is associated with lower core-specific and overall Gleason scores and not with high-grade morphologies. Conversely, TMPRSS2-ERG copy number increase, with or without rearrangement, is associated with higher Gleason score. These findings indicate that translocation/deletion of TMPRSS2-ERG is not associated with histological features of aggressive prostate cancer.

Previous studies have proposed that the morphologic spectrum of prostatic glands of variable size with tall columnar cells displaying basally oriented nuclei and clear to pale pink cytoplasm (TZ-LOOK) is characteristic of the well to moderately differentiated component of transition zone (TZ) tumors. However, the specificity of these findings has not been well studied. In a recent report, we identified dominant peripheral zone (PZ) and TZ tumors situated anterior to the prostatic urethra. Currently, we evaluate the histopathologic features of 215 dominant tumors, including 63 TZ and 73 anterior PZ lesions and an additional cohort of 79 posterior PZ tumors, in radical prostatectomy specimens, to identify the prevalence of this morphology in tumors of different zonal origin. Each dominant tumor was assigned a TZ-LOOK extent score of 0 to 4, with 0 = no such morphology, 1 = 1% to 25%, 2 = 26% to 50%, 3 = 51% to 75%, and 4 = >75%. Overall, 121/215 (56%) tumors showed some degree of this histology, including 56 of 63 (89%) TZ tumors and 65 of 152 (43%) PZ tumors (P<0.0001). Thirty-seven of 215 (17%) lesions had scores of 3 to 4, with 31 (84%) of these being of TZ origin. However, only 31/63 (49%) TZ tumors had >50% TZ-LOOK. Among PZ tumors, 6/152 (4%) had predominant (>50%) TZ-LOOK morphology, yet 23/152 (15%) of all PZ tumors and 23/65 (35%) of PZ tumors displaying any degree of TZ-LOOK had scores of 2 to 3 (>25%; nonfocal). In tumors of both zones with predominant (scores 3 to 4; >50%) TZ-LOOK histology, darker glands of usual acinar adenocarcinoma was often seen at the periphery. Conversely, in tumors with nonpredominant TZ-LOOK (scores 1 to 2; 50% of this histology are very likely of TZ origin, but this scenario occurs in only half of TZ tumors. Importantly, the TZ-LOOK is nonfocal in up to 35% of PZ tumors exhibiting any degree of this morphology. Given this lack of specificity, caution should be exercised in assigning zone of origin based on this histologic appearance, especially in limited samples such as prostate needle biopsy.

Aggressive screening and prostate needle biopsy protocols have been successful in early detection of low-volume posterior tumors. Consequently, we have observed an increased incidence of anterior-predominant prostate cancers. However, the zones of origin, patterns of spread, and patterns of extraprostatic extension of this group of tumors have not been well studied. Of 1312 radical prostatectomies performed at our institution over a span of 4.5 years, 197 had predominant (largest) tumors anterior to the urethra in whole-mounted radical prostatectomy specimens. Detailed histopathologic analysis of this cohort was undertaken emphasizing the variability in anterior prostatic anatomy from apex through base to determine zone of origin and pathologic staging. Using this approach, 97/197 (49.2%) anterior-predominant tumors (ATs) were assigned to the anterior peripheral zone (APZ), 70 (35.5%) to the transition zone (TZ), 16 (8.1%) were of indeterminate zone, and 14 (7.1%) were of both zones. Comparing APZ and TZ tumors, there were no significant differences in Gleason scores, incidence of extraprostatic extension, overall surgical margin positivity rate, or laterality. Involvement of the anterior fibromuscular stroma was significantly more likely in tumors of TZ origin (P< or =0.01), yet was observed in 50.5% of APZ tumors. Conversely, APZ tumors were more commonly localized within the apical one third of the prostate. Most of the prostates (91.4%) also showed additional PZ tumors, which were occasionally stage determining (7/197; 3.9%). In conclusion, ATs of APZ origin are more prevalent than those arising from the TZ. Contrary to previous reports comparing TZ tumors to all PZ tumors, ATs of both zones exhibit similar grading and staging parameters in this series. Given these similarities, long-term clinical outcomes and future molecular analyses will be necessary to assess whether true differences in biology and behavior exist between tumors of TZ and APZ origin.

Chromosomal translocations involving the ERG locus are frequent events in human prostate cancer pathogenesis; however, the biological role of aberrant ERG expression is controversial. Here we show that aberrant expression of ERG is a progression event in prostate tumorigenesis. We find that prostate cancer specimens containing the TMPRSS2-ERG rearrangement are significantly enriched for loss of the tumor suppressor PTEN. In concordance with these findings, transgenic overexpression of ERG in mouse prostate tissue promotes marked acceleration and progression of high-grade prostatic intraepithelial neoplasia (HGPIN) to prostatic adenocarcinoma in a Pten heterozygous background. In vitro overexpression of ERG promotes cell migration, a property necessary for tumorigenesis, without affecting proliferation. ADAMTS1 and CXCR4, two candidate genes strongly associated with cell migration, were upregulated in the presence of ERG overexpression. Thus, ERG has a distinct role in prostate cancer progression and cooperates with PTEN haploinsufficiency to promote progression of HGPIN to invasive adenocarcinoma. [ABSTRACT FROM AUTHOR]