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Aims: Histological grading of prostate cancer is a powerful prognostic tool, but current criteria for grade assignment are not fully optimised. Our goal was to develop and test a simplified histological grading model, based heavily on large cribriform/intraductal carcinoma, with optimised sensitivity for predicting metastatic potential. Methods and results: Two separate non‐overlapping cohorts were identified: a 419‐patient post‐radical prostatectomy cohort with long term clinical follow‐up and a 209‐patient post‐radical prostatectomy cohort in which all patients had pathologically confirmed metastatic disease. All prostatectomies were re‐reviewed for high‐risk histological patterns of carcinoma termed 'unfavourable histology'. Unfavourable histology is defined by any classic Gleason pattern 5 component, any large cribriform morphology (> 0.25 mm) or intraductal carcinoma, complex intraluminal papillary architecture, grade 3 stromogenic carcinoma and complex anastomosing cord‐like growth. For the outcome cohort, Kaplan–Meier analysis compared biochemical recurrence, metastasis and death between subjects with favourable and unfavourable histology, stratified by pathological stage and grade group. Multivariable Cox proportional hazards models evaluated adding unfavourable histology to the Memorial Sloan Kettering Cancer Center (MSKCC) post‐prostatectomy nomogram and stratification by percentage of unfavourable histology. At 15 years unfavourable histology predicted biochemical recurrence, with sensitivity of 93% and specificity of 88%, metastatic disease at 100 and 48% and death at 100 and 46%. Grade group 2 prostate cancers with unfavourable histology were associated with metastasis independent of pathological stage, while those without had no risk. Histological models for prediction of metastasis based on only large cribriform/intraductal carcinoma or increasing diameter of cribriform size improved specificity, but with lower sensitivity. Multivariable Cox proportional hazards models demonstrated that unfavourable histology significantly improved discriminatory power of the MSKCC post‐prostatectomy nomogram for biochemical failure (likelihood ratio test P < 0.001). In the retrospective review of a separate RP cohort in which all patients had confirmed metastatic disease, none had unequivocal favourable histology. Conclusions: Unfavourable histology at radical prostatectomy is associated with metastatic risk, predicted adverse outcomes better than current grading and staging systems and improved the MSKCC post‐prostatectomy nomogram. Most importantly, unfavourable histology stratified grade group 2 prostate cancers into those with and without metastatic potential, independent of stage. While unfavourable histology is driven predominantly by large cribriform/intraductal carcinoma, the recognition and inclusion of other specific architectural patterns add to the sensitivity for predicting metastatic disease. Moreover, a simplified dichotomous model improves communication and could increase implementation. [ABSTRACT FROM AUTHOR]

HOXB13 is a key lineage homeobox transcription factor that plays a critical role in the differentiation of the prostate gland. Several studies have suggested that HOXB13 alterations may be involved in prostate cancer development and progression. Despite its potential biological relevance, little is known about the expression of HOXB13 across the disease spectrum of prostate cancer. To this end, we validated a HOXB13 antibody using genetic controls and investigated HOXB13 protein expression in murine and human developing prostates, localized prostate cancers, and metastatic castration‐resistant prostate cancers. We observed that HOXB13 expression increases during later stages of murine prostate development. All localized prostate cancers showed HOXB13 protein expression. Interestingly, lower HOXB13 expression levels were observed in higher‐grade tumors, although no significant association between HOXB13 expression and recurrence or disease‐specific survival was found. In advanced metastatic prostate cancers, HOXB13 expression was retained in the majority of tumors. While we observed lower levels of HOXB13 protein and mRNA levels in tumors with evidence of lineage plasticity, 84% of androgen receptor‐negative castration‐resistant prostate cancers and neuroendocrine prostate cancers (NEPCs) retained detectable levels of HOXB13. Notably, the reduced expression observed in NEPCs was associated with a gain of HOXB13 gene body CpG methylation. In comparison to the commonly used prostate lineage marker NKX3.1, HOXB13 showed greater sensitivity in detecting advanced metastatic prostate cancers. Additionally, in a cohort of 837 patients, 383 with prostatic and 454 with non‐prostatic tumors, we found that HOXB13 immunohistochemistry had a 97% sensitivity and 99% specificity for prostatic origin. Taken together, our studies provide valuable insight into the expression pattern of HOXB13 during prostate development and cancer progression. Furthermore, our findings support the utility of HOXB13 as a diagnostic biomarker for prostate cancer, particularly to confirm the prostatic origin of advanced metastatic castration‐resistant tumors. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Penile cancer is an under‐studied disease that occurs more commonly in developing countries and 30–50% of cases show high‐risk human papillomavirus (HPV) infection. Therapeutic advances are slow, largely due to the absence of animal models for translational research. Here, we report the first mouse model for HPV‐related penile cancer. Ten‐week‐old mice expressing all the HPV16 early genes under control of the cytokeratin 14 (Krt14) gene promoter and matched wild‐type controls were exposed topically to dimethylbenz(a)anthracene (DMBA) or vehicle for 16 weeks. At 30 weeks of age, mice were sacrificed for histological analysis. Expression of Ki67, cytokeratin 14, and of the HPV16 oncogenes E6 and E7 was confirmed using immunohistochemistry and quantitative PCR, respectively. HPV16‐transgenic mice developed intraepithelial lesions including condylomas and penile intraepithelial neoplasia (PeIN). Lesions expressed cytokeratin 14 and the HPV16 oncogenes E6 and E7 and showed deregulated cell proliferation, demonstrated by Ki67‐positive supra‐basal cells. HPV16‐transgenic mice exposed to DMBA showed increased PeIN incidence and squamous cell carcinoma. Malignant lesions showed varied histological features closely resembling those of HPV‐associated human penile cancers. Wild‐type mice showed no malignant or pre‐malignant lesions even when exposed to DMBA. These observations provide the first experimental evidence to support the etiological role of HPV16 in penile carcinogenesis. Importantly, this is the first mouse model to recapitulate key steps of HPV‐related penile carcinogenesis and to reproduce morphological and molecular features of human penile cancer, providing a unique in vivo tool for studying its biology and advancing basic and translational research. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Background: The current study was conducted to determine the clinical characteristics and prognostic features associated with prostatic small cell carcinoma (SCC).Methods: Between January 1985 and May 2005, 83 patients with SCC of the prostate were identified. Univariate and multivariate Cox proportional hazards modeling were used to assess the prognostic significance of the clinical parameters associated with disease-specific outcomes.Results: Twenty-one patients had no evidence of distant metastasis at the time of the diagnosis of SCC, with the remaining patients demonstrating radiologic or biopsy-proven evidence of metastatic disease. Compared with patients with metastases, patients without metastases at the time of diagnosis were older (P = .001) and had a lower serum lactate dehydrogenase (LDH) level at the time of diagnosis (P = .002). On multivariate analysis, an elevated serum LDH level and low serum albumin at the time of SCC diagnosis was found to be predictive of inferior progression-free survival (P = .02 and P = .008, respectively) and inferior disease-specific survival (DSS) (P = .02 and P = .01, respectively). At the time of last follow-up, 72 patients (87%) had died of disease, with a median DSS duration of 13.1 months (range, 10.7-17.1 months). There was a statistically significant difference noted with regard to the median DSS of patients with nonmetastatic versus those with metastatic SCC (17.7 months [95% confidence interval (95% CI), 12.1-39.2 months] vs 12.5 months [95% CI, 8.1-16.1 months], respectively; P = .03).Conclusions: SCC of the prostate is a highly aggressive tumor, with serum LDH and albumin levels at the time of diagnosis believed to be predictive of disease-related outcomes. Although palliative, current systemic therapy does not result in cure and does not provide long-term survival for patients with metastases. For patients with nonmetastatic disease, a strategy utilizing systemic and local therapies should be evaluated further. [ABSTRACT FROM AUTHOR]

OBJECTIVES To examine changes in prostate biopsies at different intervals after salvage cryotherapy and the effect of biopsy type (transrectal ultrasonography-guided vs transurethral resection, TUR), as the sequence and extent of histological changes occurring in the prostate after salvage cryotherapy for local failure of prostate cancer treatment are unknown. PATIENTS AND METHODS In all, 158 prostate biopsies from 150 patients were examined histologically after salvage cryotherapy for prostate cancer after radiotherapy had failed. Specimens were grouped by time from cryotherapy and biopsy technique. RESULTS Biopsies showed hyalinization, necrosis, inflammation and residual cancer. Hyalinization became predominant over time, most notably in biopsies with no residual cancer. Core biopsies showed more hyalinization and regenerating glands, while TUR biopsies showed more necrosis and inflammation. CONCLUSIONS Tissue cryo-injury and reactive changes last for >1 year; more extensive cryo-injury suggests more effective cancer ablation. A long-term follow-up is necessary, as prostate cancer might remain indolent for >1 year. [ABSTRACT FROM AUTHOR]