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Aim: Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined., Methods and Results: We reviewed institutional databases for in-house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post- androgen-deprivation therapy (ADT), and 33 post-RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small-cell/high-grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high-grade PCa and small-cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet-like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single-cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with 'Paneth cell-like' change: all primary., Conclusions: In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small-cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high-grade PCa + small-cell/HGNEC and 'Paneth cell-like' change occur in primary disease., (© 2022 John Wiley & Sons Ltd.)

Objective: To determine whether subclassification of positive surgical margins (PSMs) increases predictive ability for biochemical recurrence (BCR) and aids clinical decision-making in patients undergoing radical prostatectomy., Patients and Methods: We studied 2147 patients with pT2 and pT3a prostate cancer with detailed surgical margin parameters and BCR status. We compared a base model, a linear predictor calculated from the Memorial Sloan Kettering Cancer Center postoperative nomogram (prostate-specific antigen, pathological tumour grade and stage), with the addition of surgical margin status to five additional models (base model plus surgical margin subclassifications) to evaluate enhancement in predictive accuracy. Decision curve analysis (DCA) was performed to determine the clinical utility of parameters that enhanced predictive accuracy., Results: Among 2147 men, 205 had PSMs, and 231 developed BCR. Discrimination for the base model with addition of surgical margin status was high (c-index = 0.801) and not meaningfully improved by adding surgical margin subclassification in the full cohort. In analyses considering only men with PSMs (N = 55 with BCR), adding surgical margin subclassification to the base model increased discrimination for total length of all PSMs - alone or with maximum Gleason grade at the margin (c-index improvement = 0.717 to 0.752 and 0.753, respectively). DCA demonstrated a modest benefit to clinical utility with the addition of these parameters., Conclusions: Specific subclassification parameters add predictive accuracy for BCR and may aid clinical utility in decision-making for patients with PSMs. These findings may be useful for patient counselling and future adjuvant therapy trial design., (© 2021 The Authors BJU International © 2021 BJU International.)

Comprehensive understanding of molecular principles in cancer and the diversification of oncological therapy promise individual therapeutic concepts, which have not yet found their way into urogenital cancer therapy. In March 2019 the International Society of Urogenital Pathology (ISUP) therefore held a consensus conference on recommendations for molecular diagnostics of genitourinary tumors, which were published in five separate manuscripts and are summarized in this article.In preparation for the conference, a comprehensive survey of current practices for molecular testing of urogenital tumors was carried out by members of the ISUP. At the conference, the results and the corresponding background information were presented by five working groups and recommendations for action for diagnostics were developed. An agreement between 66% of the conference participants was defined as consensus.

Context.—: In prostate cancer, "tertiary" higher-grade patterns (TPs) have been associated with biochemical recurrence after radical prostatectomy., Objective.—: To determine variation regarding definition and application of TPs., Design.—: Online survey regarding TPs in a range of grading scenarios circulated to 105 experienced urologic pathologists., Results.—: Among 95 respondents, 40 of 95 (42%) defined TPs as "third most common pattern" and 55 (58%) as "minor pattern/less than 5% of tumor." In a tumor with pattern 3 and less than 5% pattern 4, of the 95 respondents, 35 (37%) assigned 3 + 3 = 6 with TP4, while 56 (59%) assigned 3 + 4 = 7. In a tumor with pattern 4 and less than 5% pattern 5, of the 95 respondents, 51 (54%) assigned 4 + 4 = 8 with TP5, while 43 (45%) assigned 4 + 5 = 9. Six scenarios were presented in which the order of most common patterns was 3, 4, and 5 (Group 1) or 4, 3, and 5 (Group 2) with varying percentages. In both groups, when pattern 5 was less than 5%, we found that 98% and 93% of respondents would assign 3 + 4 = 7 or 4 + 3 = 7 with TP5. In scenarios with 15% or 25% pattern 5, most respondents (70% and 80%, respectively) would include pattern 5 as the secondary grade, that is, 3 + 5 = 8 (Group 1) or 4 + 5 = 9 (Group 2). For 85 of 95 (89%), a TP would not impact Grade Group assignment., Conclusions.—: This survey highlights substantial variation in practice patterns regarding definition and application of "tertiary" grading in radical prostatectomy specimens. High consistency was observed in 3 + 4 = 7/4 + 3 = 7 scenarios with truly minor pattern 5. These findings should inform future studies assessing the standardization and predictive value of "tertiary" patterns.

In the eighth edition AJCC staging, all organ-confined disease is assigned pathologic stage T2, without subclassification. We investigated whether total tumor volume (TTV) and/or maximum tumor diameter (MTD) of the index lesion are useful in improving prediction of biochemical recurrence (BCR) in pT2 patients. We identified 1657 patients with digital tumor maps and quantification of TTV/MTD who had pT2 disease on radical prostatectomy (RP). Multivariable Cox regression models were used to assess whether TTV and/or MTD are independent predictors of BCR when adjusting for a base model incorporating age, preoperative prostate-specific antigen, RP grade group, and surgical margin status. If either tumor quantification added significantly, we calculated and reported the c-index. Ninety-five patients experienced BCR after RP; median follow-up for patients without BCR was 5.7 years. The c-index was 0.737 for the base model. Although there was some evidence of an association between TTV and BCR (P=0.088), this did not meet conventional levels of statistical significance and only provided a limited increase in discrimination (0.743; c-index improvement: 0.006). MTD was not associated with BCR (P>0.9). In analyses excluding patients with grade group 1 on biopsy who would be less likely to undergo RP in contemporary practice (622 patients; 59 with BCR), TTV/MTD was not a statistically significant predictor (P=0.4 and 0.8, respectively). Without evidence that tumor quantitation, in the form of either TTV or MTD of the index lesion, is useful for the prediction of BCR in pT2 prostate cancer, we cannot recommend its routine reporting.

Purpose: We evaluated whether the prediction of biochemical recurrence after radical prostatectomy is enhanced by any of 6 parameters, including prostate volume, total tumor volume, high grade total tumor volume, the ratio of high grade total tumor volume to total tumor volume, the ratio of total tumor volume to prostate volume and/or the ratio of high grade total tumor volume to prostate volume., Materials and Methods: A total of 1,261 patients who underwent radical prostatectomy during a 3-year period had tumor maps constructed with the Gleason pattern denoted as low-3 or high-4 or 5 and volumetric data generated using commercially available software. Univariate Cox regression models were used to assess whether each volume related parameter was associated with biochemical recurrence after radical prostatectomy. A multivariable Cox regression base model (age, prostate specific antigen, Gleason score/grade group, pathological stage and margin status) was compared with 6 additional models (base model plus each volume related parameter) to evaluate enhancement in predictive accuracy. Decision curve analysis was performed to determine the clinical utility of parameters that enhanced predictive accuracy., Results: On univariate analysis each parameter was significantly associated with biochemical recurrence except prostate volume. Predictive accuracy of the multivariable base model was high (c-index = 0.861). Adding volume related parameters marginally enhanced discrimination. Decision curve analysis failed to show added benefit even for high grade total tumor volume/total tumor volume, which was the parameter with the highest discriminative improvement., Conclusions: Tumor volume related parameters are significantly associated with radical prostatectomy but do not add important discrimination to standard clinicopathological variables for radical prostatectomy prediction or provide benefit across a range of clinically relevant decision thresholds. Volume related measurement is not warranted in routine pathological evaluation and reporting.

Purpose: To our knowledge the ideal methodology of quantifying secondary Gleason pattern 4 in men with Grade Group 2/Gleason score 3 + 4 = 7 on biopsy remains unknown. We compared various methods of Gleason pattern 4 quantification and evaluated associations with adverse pathology findings at radical prostatectomy., Materials and Methods: A total of 457 men with Grade Group 2 prostate cancer on biopsy subsequently underwent radical prostatectomy at our institution. Only patients with 12 or more reviewed cores were included in analysis. We evaluated 3 methods of quantifying Gleason pattern 4, including the maximum percent of Gleason pattern 4 in any single core, the overall percent of Gleason pattern 4 (Gleason pattern 4 mm/total cancer mm) and the total length of Gleason pattern 4 in mm across all cores. Adverse pathology features at radical prostatectomy were defined as Gleason score 4 + 3 = 7 or greater (Grade Group 3 or greater), and any extraprostatic extension, seminal vesical invasion and/or lymph node metastasis. A training/test set approach and multivariable logistic regression were used to determine whether Gleason pattern 4 quantification methods could aid in predicting adverse pathology., Results: On multivariable analysis all Gleason pattern 4 quantification methods were significantly associated with an increased risk of adverse pathology (p <0.0001) and an increased AUC beyond the base model. The largest AUC increase was 0.044 for the total length of Gleason pattern 4 (AUC 0.728, 95% CI 0.663-0.793). Decision curve analysis demonstrated an increased clinical net benefit with the addition of Gleason pattern 4 quantification to the base model. The total length of Gleason pattern 4 clearly provided the largest net benefit., Conclusions: Our findings support the inclusion of Gleason pattern 4 quantification in the pathology reports and risk prediction models of patients with Grade Group 2/Gleason score 3 + 4 = 7 prostate cancer. The total length of Gleason pattern 4 across all cores provided the strongest benefit to predict adverse pathology features.

From the advent of the Gleason grading system for prostate cancer, cancer displaying intraluminal necrotic cells and/or karyorrhexis within cribriform/solid architecture, a phenomenon termed "comedonecrosis," has been assigned pattern 5. Intraductal carcinoma (IDC-P) shows morphologic overlap with high-grade cribriform/solid adenocarcinoma architecturally and cytologically and may also show central necrosis, yet due to the presence of basal cells at the duct periphery is not currently assigned a grade in clinical practice. On the basis of observations from routine clinical cases, we hypothesized that comedonecrosis was more significantly associated with IDC-P than invasive disease. From a large series of mapped radical prostatectomy specimens (n=933), we identified 125 high-grade (≥Gleason score 4+3=7), high-volume tumors with available slides for review. All slides were examined for the presence of unequivocal comedonecrosis. Standard immunohistochemistry for basal cell markers was performed to detect basal cell labeling in these foci. In total, 19 of 125 (15%) cases showed some ducts with comedonecrosis-9 cases with 1 focus and 10 cases with ≥2 foci; in all, a total of 73 foci of true comedonecrosis were evaluated. Immunohistochemical stains revealed labeling for basal cell markers in a basal cell distribution for at least some comedonecrosis foci in 18 of 19 (95%) cases, 12 with IDC-P exclusively and 6 with a mix of IDC-P and invasive carcinoma comedonecrosis foci. These results suggest that comedonecrosis is strongly associated with IDC-P and hence, the routine assignment of pattern 5 to carcinoma exhibiting comedonecrosis should be reconsidered.

Aim: To study prostate cancer zonal differences in TMPRSS2-ERG gene rearrangement., Methods and Results: We examined 136 well-characterized dominant anterior prostatic tumours, including 61 transition zone (TZ) and 75 anterior peripheral zone (PZ) lesions, defined using strict anatomical considerations. TMPRSS2-ERG FISH and ERG protein immunohistochemistry were performed on tissue microarrays. FISH results, available for 56 TZ and 71 anterior PZ samples, were correlated with ERG staining and TZ-associated 'clear cell' histology. Fewer TZ cancers (four of 56; 7%) were rearranged than anterior PZ cancers (18 of 71; 25%) (P = 0.009); deletion was the sole mechanism of TZ cancer rearrangement. ERG protein overexpression was present in 4% (two of 56; both FISH+) and 30% (21 of 71; 17 FISH+) of TZ and anterior PZ tumours, respectively. 'Clear cell' histology was present in 21 of 56 (38%) TZ and eight of 71 (11%) anterior PZ tumours. Seven per cent of cancers with and 21% without this histology had rearrangement, regardless of zonal origin., Conclusions: TMPRSS2-ERG rearrangement occurs in dominant TZ and anterior PZ prostate cancers, with all rearranged TZ cancers in this cohort showing deletion. ERG immunohistochemistry demonstrated excellent sensitivity (86%) and specificity (96%) for TMPRSS2-ERG rearrangement. TMPRSS2-ERG fusion is rare in TZ tumours and present at a low frequency in tumours displaying 'clear cell' histology., (© 2013 John Wiley & Sons Ltd.)

Mesonephric remnant hyperplasia is a very rare benign mimicker of prostate adenocarcinoma. As most reported cases are from transurethral resection specimens, the anatomic location and histologic spectrum of this entity have not been fully elucidated. Its immunohistochemical profile using current prostatic diagnostic markers has also not been well studied. In this study, we retrospectively characterized 10 cases of mesonephric remnant hyperplasia involving the prostate and periprostatic tissue, including 8 cases seen in radical prostatectomy specimens, with emphasis on the histopathologic and immunohistochemical features. Patients ranged in age from 48 to 70 years (average, 60 y). Seven of them had concurrent prostatic adenocarcinoma and underwent radical prostatectomy; one patient underwent prostatectomy because of the misdiagnosis of mesonephric remnant hyperplasia on transurethral resection as carcinoma; 2 patients had transurethral resection for urinary obstruction. The distribution of prostatic mesonephric hyperplasia was concentrated in 2 areas: one was in the anterior fibromuscular stroma and adjacent anterolateral periprostatic tissue (n=6 of 8); the other was located toward the base posteriorly and posterolaterally either within or exterior to the prostate and around the seminal vesicle (n=4 of 8). Histologic patterns observed included the following: small-to-medium-sized acini or tubules with a lobular distribution (n=10 of 10); cysts either in clusters or scattered containing secretions (n=8 of 10); small or ill-formed glands with an infiltrative growth (n=7 of 10); glands with papillary infoldings or micropapillary tufts (n=4 of 10); and 2 cases exceptionally displayed nodules of ill-formed small glands intermixed with spindle cells, mimicking sclerosing adenosis or Gleason pattern 5 prostate cancer. Most cases (7 of 10) had florid hyperplasia and harbored 3 or more growth patterns. All cases were negative for prostate-specific antigen. Cytokeratin 34βE12 was diffusely positive in 4 of 9 cases, and showed focal immunoreactivity in the remaining 5 cases. Except for focal positivity seen in 4 of 7 cases, p63 was largely negative. Racemase was focally positive in 4 of 7 cases. Small glands with an infiltrative growth pattern, the most difficult to distinguish from cancer, were negative (n=3 of 6) or only focally positive (n=3 of 6) for 34βE12, negative for p63 (n=6 of 6), and focally positive for racemase (n=4 of 6). All cases examined in the study were diffusely positive for PAX8. In conclusion, mesonephric remnant hyperplasia not only involves the bladder neck and base of the prostate as previously described, but may also present as a florid growth in the anterior fibromuscular stroma from the apex to the base, closely mimicking prostate cancer. Although basal cell marker and racemase expression overlaps with prostate cancer, mesonephric hyperplasia's unique morphology along with distinctive immunohistochemical expression of PAX8 and lack of prostate-specific antigen can help in distinguishing this benign entity from prostatic adenocarcinoma.

Primary carcinoid tumors of the urinary bladder are exceedingly rare. Although they have been considered to be potentially malignant neuroendocrine neoplasms, some previously reported cases were associated with a carcinoma component that might have altered the outcome. Only 8 histologically well-documented cases of pure carcinoid tumors of the bladder and 1 of the prostatic urethra have been reported in the literature. In this study, we describe 6 additional primary pure carcinoid tumors arising in the bladder (5 cases) or prostatic urethra (1 case). Patients (4 male, 2 female) ranged in age from 45 to 60 years (average, 55 y) and presented with hematuria (n = 5 of 6), obstruction (n = 1 of 6), or for concurrent genitourinary disease (n = 1 of 6). All 6 cases shared gross and microscopic findings. Cystoscopic examination showed small, smooth surfaced, or polypoid nodules. The 5 cases in the bladder were all located within or near the trigone and bladder neck region. Microscopically, these 6 tumors were subepithelial and confined within the lamina propria, associated with adjacent cystitis cystica et glandularis. The tumors were composed of uniform, cuboidal, or columnar cells with finely stippled chromatin and inconspicuous nucleoli in a prominent pseudoglandular pattern composed of acinar and cribriform structures. The cells had moderate-to-abundant cytoplasm and basally located Paneth cell-like eosinophilic granules. Although occasional atypical cells with prominent nucleoli could be seen, mitotic activity was absent or rare and cases lacked necrosis. Neuroendocrine differentiation was confirmed by immunohistochemistry in all 6 cases. All tumors were completely excised by biopsies. There was no evidence of disease recurrence or progression in all 6 patients, including 3 patients who had clinical follow-up for >4 years. Primary pure carcinoid tumors of the urinary bladder (and prostatic urethra) have distinct pathologic characteristics, with their prominent pseudoglandular features leading to difficulty in diagnosis. They are likely to have a very favorable clinical outcome, and should be distinguished from mixed carcinoid tumors or urothelial carcinomas with neuroendocrine differentiation that show focal carcinoid-like histologic features.

To elucidate the role of ETS gene fusions in castration-resistant prostate cancer (CRPC), we characterized the transcriptome of 54 CRPC tumor samples from men with locally advanced or metastatic disease. Trefoil factor 3 (TFF3) emerged as the most highly differentially regulated gene with respect to ERG rearrangement status and resistance to hormone ablation therapy. Conventional chromatin immunoprecipitation (ChIP)-polymerase chain reaction and ChIP followed by DNA sequencing (ChIP-seq) revealed direct binding of ERG to ETS binding sites in the TFF3 promoter in ERG-rearranged prostate cancer cell lines. These results were confirmed in ERG-rearranged hormone-naive prostate cancer (HNPC) and CRPC tissue samples. Functional studies demonstrated that ERG has an inhibitory effect on TFF3 expression in hormone-naive cancer but not in the castration-resistant state. In addition, we provide evidence suggesting an effect of androgen receptor signaling on ERG-regulated TFF3 expression. Furthermore, TFF3 overexpression enhances ERG-mediated cell invasion in CRPC prostate cancer cells. Taken together, our findings reveal a novel mechanism for enhanced tumor cell aggressiveness resulting from ERG rearrangement in the castration-resistant setting through TFF3 gene expression.

Purpose: Limited data exist on radical prostatectomy findings performed for cancer on repeat biopsy following an initial atypical biopsy (atypical glands suspicious but not diagnostic for carcinoma)., Materials and Methods: We compared 169 such men to 15,810 without an initial diagnosis of atypical glands suspicious for carcinoma who underwent radical prostatectomy from 1993 to 2008., Results: Median time between atypical biopsy and repeat biopsy showing cancer was 6.1 months (range 0.7 to 94.8). An initial diagnosis of atypical glands suspicious but not diagnostic for carcinoma correlated significantly with nonpalpable disease, biopsy Gleason score 6 and lower tumor volume on needle cores. Compared to radical prostatectomy without prior atypical findings, radical prostatectomy cases with an initial atypical biopsy had a significantly lower Gleason score (p <0.0001) and pathological stage (p = 0.001), with 126 (74.5%) Gleason score 6 and 140 (83.0%) organ confined. Only 2 (1.2%) cases showed seminal vesicle involvement and none had lymph node metastases. In addition to known preoperative parameters (clinical stage and biopsy Gleason score), the presence of initial atypical biopsy was an independent predictor of organ confined disease at radical prostatectomy. However, when tumor volume on needle biopsy was included in the multivariate analysis a diagnosis of atypical glands suspicious but not diagnostic for carcinoma lost its independent predictive value., Conclusions: Prostate cancer diagnosed on needle biopsy following a diagnosis of atypical glands suspicious but not diagnostic of carcinoma demonstrates a significantly lower tumor grade and pathological stage at radical prostatectomy than cancer without such a diagnosis. Correlating with lower tumor volume on biopsy, the presence of initial atypical biopsy predicts organ confined disease at radical prostatectomy. However, a few cases with high Gleason score and advanced pathological stage in this group emphasize the importance of re-biopsy within 3 to 6 months following such a diagnosis., (Copyright © 2010 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Although recurrent gene fusions involving erythroblastosis virus E26 transformation-specific (ETS) family transcription factors are common in prostate cancer, their products are considered 'undruggable' by conventional approaches. Recently, rare targetable gene fusions involving the anaplastic lymphoma receptor tyrosine kinase (ALK) gene, have been identified in 1-5% of lung cancers, suggesting that similar rare gene fusions may occur in other common epithelial cancers, including prostate cancer. Here we used paired-end transcriptome sequencing to screen ETS rearrangement-negative prostate cancers for targetable gene fusions and identified the SLC45A3-BRAF (solute carrier family 45, member 3-v-raf murine sarcoma viral oncogene homolog B1) and ESRP1-RAF1 (epithelial splicing regulatory protein-1-v-raf-1 murine leukemia viral oncogene homolog-1) gene fusions. Expression of SLC45A3-BRAF or ESRP1-RAF1 in prostate cells induced a neoplastic phenotype that was sensitive to RAF and mitogen-activated protein kinase kinase (MAP2K1) inhibitors. Screening a large cohort of patients, we found that, although rare, recurrent rearrangements in the RAF pathway tend to occur in advanced prostate cancers, gastric cancers and melanoma. Taken together, our results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.