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Objective: To review the presentation and long-term oncologic outcomes of patients with regressed ("burnt out") primary testicular germ cell tumors (GCT). Certain testicular GCT can present with complete regression of the primary tumor. It is not well established if this is associated with more aggressive disease or worse oncologic outcomes., Methods: We queried our prospectively maintained testicular cancer clinical database at a tertiary cancer center and identified patients without prior chemotherapy who had regressed primary GCT at radical orchiectomy from 1990 to 2023. All specimens were reviewed by a genitourinary pathologist at diagnosis. Long-term clinical outcomes were reported by Kaplan-Meier method., Results: Fifty-six patients met inclusion criteria; at diagnosis, 17 had no evidence of extra-testicular disease and 39 had advanced (clinical stage [CS] II+) GCT. All CSx (no viable disease or germ cell neoplasia in situ at orchiectomy, and no evidence of advanced disease) and CS0 patients were managed with surveillance and had 5-year recurrence-free survival (RFS) of 88% (95% CI: 39%, 98%). All patients with CS II+ disease underwent primary treatment with surgery (n = 5) or first-line chemotherapy (n = 34). Two- and 5-year RFS for patients with CSII+ disease was 94% (95% CI: 78%, 98%) and 90% (95% CI: 72%, 97%), respectively., Conclusion: Patients with regressed primary testicular GCT often present with advanced disease, possibly due to lack of early clinical signs from the primary tumor. Our analysis shows excellent long-term oncologic outcomes similar to those reported in the literature for patients with viable primary testicular GCT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The 2022 World Health Organization (WHO) classification of the urinary and male genital tumors was recently published by the International Agency for Research on Cancer. This fifth edition of the WHO "Blue Book" offers a comprehensive update on the terminology, epidemiology, pathogenesis, histopathology, diagnostic molecular pathology, and prognostic and predictive progress in genitourinary tumors. In this review, the editors of the fifth series volume on urologic and male genital neoplasms present a summary of the salient changes introduced to the classification of tumors of the prostate and the urinary tract., (Copyright © 2022. Published by Elsevier B.V.)

The fifth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "Blue Book"), published in 2022, contains significant revisions. This review summarises the most relevant changes for renal, penile, and testicular tumours. In keeping with other volumes in the fifth edition series, the WHO classification of urogenital tumours follows a hierarchical classification and lists tumours by site, category, family, and type. The section "essential and desirable diagnostic criteria" included in the WHO fifth edition represents morphologic diagnostic criteria, combined with immunohistochemistry and relevant molecular tests. The global introduction of massive parallel sequencing will result in a diagnostic shift from morphology to molecular analyses. Therefore, a molecular-driven renal tumour classification has been introduced, taking recent discoveries in renal tumour genomics into account. Such novel molecularly defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carcinoma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC. Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The diverse morphologic patterns of penile squamous cell carcinomas are grouped as human papillomavirus (HPV) associated and HPV independent, and there is an attempt to simplify the morphologic classification. A new chapter with tumours of the scrotum has been introduced. The main nomenclature of testicular tumours is retained, including the use of the term "germ cell neoplasia in situ" (GCNIS) for the preneoplastic lesion of most germ cell tumours and division from those not derived from GCNIS. Nomenclature changes include replacement of the term "primitive neuroectodermal tumour" by "embryonic neuroectodermal tumour" to separate these tumours clearly from Ewing sarcoma. The term "carcinoid" has been changed to "neuroendocrine tumour", with most examples in the testis now classified as "prepubertal type testicular neuroendocrine tumour"., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior., Objective: To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes., Design, Setting, and Participants: We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients., Outcome Measurements and Statistical Analysis: Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes., Results and Limitations: A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034)., Conclusions: CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management., Patient Summary: We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present., (Copyright © 2020. Published by Elsevier B.V.)

Objective: To report the mutational profile and clinical outcomes of a cohort of patients with KIT-mutant seminomas and nonseminomatous germ-cell tumors (SGCT/NSGCTs)., Patients and Methods: Retrospective cohort study of all patients with KIT-mutant GCTs sequenced at Memorial Sloan Kettering between March 2014 and March 2020. Tumors were assessed with MSK-IMPACT, a DNA next-generation sequencing assay for targeted sequencing of up to 468 key cancer genes., Results: Among 568 patients with GCTs, 8.1% had somatic KIT mutations, including 28 seminomas and 18 mixed/NSGCTs. Exons 17 (67.3%), 11 (22.4%), and 13 (6.1%) were most commonly affected. KIT-mutant cases were enriched for oncogenic RAS/MAPK pathway alterations compared to KIT-wildtype cases (34.8% vs 19.2%, P = .02). Among KIT-mutant cases, concurrent mutations were noted in KRAS (21.7%), RRAS2 (11.8%), CBL (6.5%), NRAS (4.3%), MAP2K1 (2.2%), and RAC1 (2.2%). Mutations in KRAS, RRAS2, and NRAS were mutually exclusive. In all, 73.9% of patients developed metastases and 95.7% received chemotherapy. No patients received KIT-directed tyrosine kinase inhibitors (TKIs). Classification as a NSGCT rather than a SGCT was associated with an increased risk of death (hazard ratio 9.1, 95% confidence interval 1.1-78.4, P = .04) while the presence of a concurrent RAS/MAPK pathway alteration was not (hazard ratio 0.8, 95% confidence interval 0.1-4.3, P = .76)., Conclusion: Mitogenic driver alterations can co-occur with activating KIT mutations, which may explain the lack of efficacy of KIT-directed TKIs in prior trials. Novel KIT-directed TKIs that target exon 17 mutations may benefit chemotherapy-refractory patients with KIT-mutant GCTs without RAS/MAPK alterations. Dual MEK/KIT inhibitor therapy in KIT-mutant GCTs with concurrent RAS/MAPK alterations could also be a plausible therapeutic strategy., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To assess which patients respond best following cytoreductive nephrectomy for renal cell carcinoma (RCC) with sarcomatoid dedifferentiation (sRCC) and whether outcomes are improving over time., Methods: We identified 562 patients with metastatic RCC treated between 1989 and 2018 with cytoreductive nephrectomy. We reviewed baseline clinical and pathologic characteristics, including the presence of sRCC, and metastatic sites at time of nephrectomy. The primary study endpoint was overall survival (OS). Univariate and multivariate Cox-regression analyses were used to identify significant predictors of OS., Results: The study cohort had 192 sRCC patients, with a median age of 59 years. Frequently involved metastatic locations were lung (n = 115), retroperitoneal nodes (n = 63), and axial skeleton (n = 43). Lung metastasis were more prevalent in clear cell histology (P = .0017) whereas nodal involvement was associated with nonclear cell subtypes (P = .0064). Median follow-up was 14 months. Estimated 2- and 5-year OS were 34.1% and 14.8%, respectively. On multivariate analysis, metastases to the liver (HR = 1.64; 95% CI 1.02-2.63; P = .04), lung (HR = 1.50; 95% CI 1.05-2.14; P = .03), retroperitoneal nodes (HR = 1.52; 95% CI 1.03-2.25; P = 0.04) and nonclear cell histology (HR = 1.61; 95% CI 1.10-2.35; P = .01) were associated with worse OS in the sRCC cohort., Conclusion: OS after cytoreductive nephrectomy for sRCC and non-sRCC is improving over time. In patients with sRCC, presentations with unifocal metastasis not involving the liver or lung, clear cell histology and node negative disease have better outcomes following cytoreductive nephrectomy and may yield greater benefit from the procedure., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To evaluate, in detail, the histopathologic features of metastatic testicular germ cell tumors to retroperitoneal lymph nodes treated with primary retroperitoneal lymph node dissection (RPLND) and correlate the findings with patients' outcomes., Materials and Methods: We studied 183 patients with documented pathologic stage II disease with or without elevated serum tumor markers, selected from 453 patients who underwent primary RPLND at our institution from 1989 to 2002. Tumor type(s), size and extent of disease, and amount of tumor necrosis were assessed and correlated with outcome., Results: Embryonal carcinoma was the most common tumor type, present as the only component in 99 cases (54%) and the predominant tumor type (>50%) in 142 (78%). The number of positive lymph nodes ranged from 1 to 40 from a total of 2-80 lymph nodes examined (median, 28). Extranodal extension (ENE) was identified in 120 cases (66%). Among 73 patients followed up expectantly and with normal serum tumor markers, 19 experienced relapse, the probability of which was higher in patients with more positive nodes, larger metastases, and presence of ENE. However, none of these differences was statistically significant (all P >.2). The predominance of embryonal carcinoma and the presence of tumor necrosis were not significantly associated with outcome., Conclusion: In this cohort, most patients treated with primary RPLND and with positive lymph nodes also had ENE. We did not identify any variables to be significantly associated with relapse after RPLND in patients managed expectantly. Additional studies with more patients are needed to validate our findings., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Historically, VHL was the only frequently mutated gene in clear cell renal cell carcinoma (ccRCC), with conflicting clinical relevance. Recent sequencing efforts have identified several novel frequent mutations of histone modifying and chromatin remodeling genes in ccRCC including PBRM1, SETD2, BAP1, and KDM5C. PBRM1, SETD2, and BAP1 are located in close proximity to VHL within a commonly lost (approximately 90%) 3p locus. To date, the clinical and pathologic significance of mutations in these novel candidate tumor suppressors is unknown., Objective: To determine the frequency of and render the first clinical and pathologic outcome associated with mutations of these novel candidate tumor suppressors in ccRCC., Design, Setting, and Participants: Targeted sequencing was performed in 185 ccRCCs and matched normal tissues from a single institution. Pathologic features, baseline patient characteristics, and follow-up data were recorded., Outcome Measurements and Statistical Analysis: The linkage between mutations and clinical and pathologic outcomes was interrogated with the Fisher exact test (for stage and Fuhrman nuclear grade) and the permutation log-rank test (for cancer-specific survival [CSS])., Results and Limitations: PBRM1, BAP1, SETD2, and KDM5C are mutated at 29%, 6%, 8%, and 8%, respectively. Tumors with mutations in PBRM1 or any of BAP1, SETD2, or KDM5C (19%) are more likely to present with stage III disease or higher (p = 0.01 and p = 0.001, respectively). Small tumors (<4 cm) with PBRM1 mutations are more likely to exhibit stage III pathologic features (odds ratio: 6.4; p = 0.001). BAP1 mutations tend to occur in Fuhrman grade III-IV tumors (p = 0.052) and are associated with worse CSS (p = 0.01). Clinical outcome data are limited by the number of events., Conclusions: Most mutations of chromatin modulators discovered in ccRCC are loss of function, associated with advanced stage, grade, and possibly worse CSS. Further studies validating the clinical impact of these novel mutations and future development of therapeutics remedying these tumor suppressors are warranted., (Copyright © 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

We report a case of renal cell carcinoma (RCC) with extensive oncocytoid features developing in a 12-year-old African-American boy after chemotherapy for cardiac leiomyosarcoma at 3 months of age. The tumor showed histopathologic features similar to those previously reported in RCC after chemotherapy for neuroblastoma and now considered a specific entity in the World Health Organization classification of renal tumors as "RCC associated with neuroblastoma." Our report expands the spectrum of tumors (beyond neuroblastoma) in which RCCs with such an appearance can arise in the pediatric age group after chemotherapy.

Objectives: To evaluate 5-alpha-reductase (5alphaR) expression in benign and malignant urothelium and to assess the relationship between 5alphaR expression and tumor stage, tumor grade, and clinical outcome in patients with urothelial carcinoma/transitional cell carcinoma., Methods: We performed immunohistochemistry for 5alphaR on 53 urothelial specimens from 36 patients with transitional cell carcinoma treated at our institution between June 2002 and July 2003. For each tumor and the adjacent nontumor urothelium, a semiquantitative staining score was calculated. We used t tests and analysis of variance to compare the staining score across groups. Kaplan-Meier and logistic regression analyses were performed to assess the relationship between 5alphaR expression and clinical outcome., Results: 5alphaR was expressed throughout the non-neoplastic urothelium. Nontumor urothelium had greater mean staining scores than did tumor specimens (160.1 versus 105.5, P <0.01). Low staining scores were associated with high grade (P <0.05), Stage pT3, pT4, and pTis (P <0.05), and disease progression (P <0.05). A staining score less than the median was a risk factor for progression (odds ratio 6.2, P <0.01) on univariate regression analysis. Patients with a staining score less than the median had a greater likelihood of disease progression (log-rank P <0.05) and cause-specific mortality (log-rank P <0.05)., Conclusions: We demonstrated 5alphaR expression in human urothelium and found that expression is decreased in transitional cell carcinoma in relation to tumor grade and stage. Decreased 5alphaR expression was associated with disease progression and cause-specific mortality.

Objectives: To evaluate the expression of the androgen receptor (AR) in transitional cell carcinoma (TCC) of the bladder, and to assess whether its expression correlated with pathologic tumor stage. TCC of the bladder is three times more common in males than in females. The origin of this sex difference in incidence is unknown., Methods: We evaluated tumor specimens from 49 consecutive patients treated for TCC of the bladder at our institution between July 2002 and June 2003. Immunohistochemistry was performed using a monoclonal mouse anti-AR antibody on paraffin-embedded tissue sections of tumors obtained from transurethral resection, radical cystectomy, or resection of metastases. Specimens were assessed for AR expression, and, in tumors that demonstrated AR staining, the percentage of nuclei that stained positive was recorded., Results: Of the 49 tumors, 26 (53.1%) expressed the AR. The percentage of tumors that expressed the AR decreased with increasing pathologic stage, from 88.9% of pTa lesions to 0% of pT3 tumors. Overall, 75% of superficial tumors (pTa + pT1 + carcinoma in situ) expressed the AR compared with 21.4% of invasive tumors (pT2 + pT3; P = 0.002). In addition, among AR-expressing tumors, the mean percentage of nuclei that stained positive for the AR was significantly greater in pTa tumors (62.5%) than in pT1 (31%) or pT2 (20%) tumors (P = 0.005)., Conclusions: We found a decrease in AR protein expression in tumors with increased pathologic stage. Our data suggest that the loss of AR expression is associated with invasive bladder cancer.