High-Grade, Nonsarcomatoid Chromophobe Renal Cell Carcinoma: A Series of 22 Cases With Novel Molecular Features on a Subset.

Chromophobe renal cell carcinoma (ChRCC) is the third most common subtype of renal cell carcinoma and typically exhibits indolent behavior, though a rare subset can exhibit high-grade morphologic features and is associated with a poor prognosis. Although there are limited data on the molecular characteristics of metastatic and sarcomatoid ChRCC, the molecular features of high-grade, nonsarcomatoid ChRCC remain unexplored. Herein, we characterize 22 cases of ChRCC with high-grade, nonsarcomatoid components. High-grade ChRCC frequently demonstrated advanced stage at diagnosis (64% ≥pT3a or N1), with regions of extrarenal extension, nodal metastases, and vascular invasion consisting solely of high-grade ChRCC morphologically. We performed spatially guided panel-based DNA sequencing on 11 cases comparing high-grade and low-grade regions (n = 22 samples). We identified recurring somatic alterations emblematic of ChRCC, including deletions of chromosomes 1, 2, 6, 10, 13, 17, and 21 in 91% (10/11) of cases and recurring mutations in TP53 (81.8%, n = 9/11) and PTEN (36.4%, n = 4/11). Notably, although PTEN and TP53 alterations were found in both high-grade and low-grade regions, private mutations were identified in 3 cases, indicating convergent evolution. Finally, we identified recurring RB1 mutations in 27% (n = 3) of high-grade regions leading to selective protein loss by immunohistochemistry not observed in adjacent low-grade regions. This finding was confirmed in The Cancer Genome Atlas cohort where 2 of 66 cases contained RB1 mutations and demonstrated unequivocal high-grade, nonsarcomatoid morphology. We also detected multiple chromosomal gains confined to the high-grade regions, consistent with imbalanced chromosome duplication. These findings broaden our understanding of the molecular pathogenesis of ChRCC and suggest that subclonal RB1 mutations can drive the evolution to high-grade, nonsarcomatoid ChRCC.

Radical prostatectomy cancer grade and percentage of Gleason pattern 4 estimated by global vs individual tumor grading correlate differently with the risk of biochemical recurrence in Grade Group 2 and 3 cancers.

OBJECTIVES: There are 2 grading approaches to radical prostatectomy (RP) in multifocal cancer: Grade Group (GG) and percentage of Gleason pattern 4 (GP4%). We investigated whether RP GG and GP4% generated by global vs individual tumor grading correlate differently with biochemical recurrence. METHODS: We reviewed 531 RP specimens with GG2 or GG3 cancer. Each tumor was scored separately with assessment of tumor volume and GP4%. Global grade and GP4% were assigned by combining Gleason pattern 3 and 4 volumes for all tumors. Correlation of GG and GP4% generated by 2 methods with biochemical recurrence was assessed by Cox proportional hazard regression and receiver operating characteristic curves, with optimism adjustment using a bootstrap analysis. RESULTS: Median age was 63 (range, 42-79) years. Median prostate-specific antigen was 6.3 (range, 0.3-62.9) ng/mL. In total, the highest-grade tumor in 371 (36.9%) men was GG2 and in 160 (30.1%) men was GG3. Global grading was downgraded from GG3 to GG2 in 37 of 121 (30.6%) specimens with multifocal disease, and 145 of 404 (35.9%) specimens had GP4% decreased by at least 10%. Ninety-eight men experienced biochemical recurrence within a median of 13 (range, 3-119) months. Men without biochemical recurrence were followed up for a median of 47 (range, 12-205) months. Grade Group, GP4%, and margin status correlated with the risk of biochemical recurrence using highest-grade tumor and global grading, but the degrees of these correlations varied and were statistically significantly different between the 2 grading approaches. CONCLUSIONS: Grade Group, GP4%, and margin status derived by global vs individual tumor grading predict postoperative biochemical recurrence statistically significantly differently. This difference has important implications if results derived from cohorts graded using different methods are compared.

Mesothelioma of Uncertain Malignant Potential (MUMP) of the Tunica Vaginalis: Proposal for Reclassification as "Complex Mesothelial Tumor of the Tunica Vaginalis".

A well-differentiated papillary mesothelial tumor (WDPMT) and malignant mesothelioma are 2 well-recognized entities arising from the testis tunica vaginalis. Another mesothelial lesion exclusively seen at this site is mesothelioma of uncertain malignant potential (MUMP)-a lesion reminiscent of WDPMT yet demonstrating variable proportions of more complex architectural patterns that could be confused with invasion. MUMP was first described in 2010 with a total of 11 cases reported to date. Herein, we describe 19 additional patients who underwent hydrocelectomy, excision, and/or orchiectomy. Novel morphologic patterns found in addition to the 2010 series include spindle cells, keloidal-type collagen, and multicystic architecture lined by bland mesothelial cells. Clinical follow-up in 9 patients for more than 1 year (1.5 to 22.5 y, median 4.5 y) revealed no evidence of disease recurrence or metastases. Despite greater architectural complexity, MUMP has (1) bland cytology; (2) merging in with WDPMT areas; (3) low mitotic rate and Ki-67 nuclear labeling index; (4) retention of MTAP and BAP1 expression; and (5) benign clinical follow-up. If these cases were malignant mesotheliomas, one would have expected at least some of the patients to demonstrate disease recurrence/progression without adjuvant therapy within the available follow-up time, particularly with limited resection in most patients. Thus, we propose that "mesothelioma of uncertain malignant potential" be renamed as "complex mesothelial tumor of the tunica vaginalis." Using the term "complex" draws a contrast with the simple cuboidal lining and simple papillary architecture seen in WDPMT. Also, labeling the lesion as "tumor" removes the stigmata of "uncertain malignant potential" and "mesothelioma" that are alarming to patients and clinicians, and potentially could unduly lead to more extensive surgery in an attempt at "complete" resection. At the same time, not definitively labeling the lesion as benign allows recommendations for follow-up.

Metastatic Pleomorphic Lobular Carcinoma of the Breast to the Urinary Bladder: A Report of 10 Cases and Assessment of TRPS1 in the Differential Diagnosis With Plasmacytoid Urothelial Carcinoma.

CONTEXT.­: Metastatic pleomorphic lobular carcinoma (MPLC) to the bladder is rare and has considerable histologic and immunohistochemical overlap with plasmacytoid urothelial carcinoma (PUC). OBJECTIVE.­: To distinguish MPLC from PUC morphologically and immunohistochemically, including a newer marker, TRPS1. DESIGN.­: Ten MPLCs to the bladder were reassessed and stained with estrogen, progesterone, and androgen receptors; GATA3; keratin 5/6; HMWK; GCDFP-15; and TRPS1. Sixteen PUCs constituted controls. RESULTS.­: We studied 4 transurethral resections of bladder tumors and 6 biopsies from 10 women (median age, 69 years) who had breast cancer on average 15 years prior. Microscopic patterns included single cells and cords of cells (n = 4), nests/sheets of dyscohesive cells (n = 2), or both (n = 4). All tumors had cells with voluminous eosinophilic cytoplasm and eccentric nuclei mimicking PUC, and 7 of 10 tumors had signet ring cells. MPLCs were positive for estrogen (8 of 10), progesterone (3 of 7), and androgen receptors (4 of 10); GCDFP-15 (7 of 10); GATA3 (9 of 10); HMWK (7 of 8); and TRPS1 (7 of 10). No MPLCs stained for keratin 5/6 (n = 9). Of 16 PUCs, 2 showed faint and 2 demonstrated strong TRSP1 staining; 7 of 16 were negative for p63. CONCLUSIONS.­: MPLC to bladder often presents in patients with a remote history of breast cancer, exhibiting significant histologic and immunohistochemical overlap with PUC. Based on prior works and the current study, estrogen receptor (particularly SP-1), mammaglobin, and p63 help differentiate MPLC from PUC. Keratin 5/6 may aid in distinguishing a less frequent basal type PUC because it is typically negative in MPLC. Some PUCs express TRPS1. Caution should be exercised because immunophenotypes of these tumors greatly overlap, and ramifications of misclassification are major.

Clinicopathologic Classification of Renal Cell Carcinoma in Patients ≤40 Years Old From Peru.

INTRODUCTION: There are scant data on renal cell carcinoma (RCC) from relatively younger patients in South America using contemporary classification. METHODS: Fifty-nine consecutively treated patients with RCC (≤40 years old) were assessed from the National Institute of Neoplastic Diseases in Peru from 2008 to 2020 (34 males; 25 females), age range of 13 to 40 years. RESULTS: Most common presenting symptoms were flank pain (n = 40), hematuria (n = 19), and weight loss (n = 12). Associated conditions included 4 patients with proven or presumed tuberous sclerosis and 1 patient with von Hippel Lindau syndrome, all with clear cell RCC. Tumor histopathology was clear cell RCC in 32 of 59 (54%), chromophobe RCC in 6 of 59 (10%), and 5 of 59 (8%) each of papillary RCC and MiT family translocation-associated RCC. Four of 59 (7%) were FH-deficient RCC and 2 of 59 (3%) remained unclassified. The remaining tumors were isolated examples of clear cell papillary renal cell tumor, eosinophilic solid and cystic RCC (ESC RCC), RCC with fibromyomatous stroma, sarcomatoid RCC, and sarcomatoid clear cell RCC. Of the 4 FH-deficient RCCs, none had the classic morphology. The 5 MiT family translocation RCCs had variable morphology. There were 41 tumors without recurrence or metastases, 3 tumors with local recurrence only, 8 tumors with metastases only, and 7 tumors with both local recurrence and metastases. CONCLUSIONS: The current study demonstrates the importance of special studies in accurately classifying RCC in younger individuals. The distribution of RCC subtypes in younger individuals is similar between 2 representative large institutions of the United States and Peru.

Risk of Biochemical Recurrence in Patients With Grade Group 1 Prostate Cancer With Extraprostatic Extension Treated With Radical Prostatectomy.

PURPOSE: We sought to examine the association of extraprostatic extension (EPE) with biochemical recurrence (BCR) separately in men with Grade Group (GG) 1 and GG2 prostate cancer (PCa) treated with radical prostatectomy. MATERIALS AND METHODS: We reviewed our institutional database of patients who underwent radical prostatectomy for PCa between 2005 and 2022 and identified patients with GG1 and GG2 disease on final pathology. Fine-Gray competing risk models with an interaction between EPE (yes vs no) and GG (GG1 vs GG2) were used to examine the relationship between disease group and BCR-free survival. RESULTS: The cohort consisted of 6309 men, of whom 169/2740 (6.2%) with GG1 disease had EPE while 1013/3569 (28.4%) with GG2 disease had EPE. Median follow-up was 4 years. BCR occurred in 400/6309 (6.3%) patients. For men with GG1, there was no statistically significant difference in BCR-free survival for men with vs without EPE (subdistribution HR = 0.88; 95% CI: 0.37-2.09). However, for GG2 patients BCR-free survival was significantly worse for those with vs without EPE (subdistribution HR = 1.97, 95% CI: 1.54-2.52). CONCLUSIONS: Although there is a subset of GG1 PCas capable of invading through the prostatic capsule, patients with GG1 PCa and EPE at prostatectomy experience similar biochemical recurrence and survival outcomes compared to GG1 patients without EPE. However, among men with GG2, EPE connotes a worse prognosis.

Characterization of HOXB13 expression patterns in localized and metastatic castration-resistant prostate cancer.

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.

Adenocarcinomas of the Gynecologic Tract Involving the Urinary Bladder: A Series of 16 Cases Potentially Mimicking Urothelial Malignancy.

CONTEXT.­: There is limited literature describing gynecologic adenocarcinomas involving the urinary bladder, and potential diagnostic pitfalls. OBJECTIVE.­: To describe key features distinguishing metastatic (or extension of) gynecologic adenocarcinomas from urothelial carcinomas with glandular differentiation. DESIGN.­: Retrospective review of surgical pathology cases of gynecologic adenocarcinomas involving the bladder, from 2 different institutions, retrieved from surgical pathology archives, was performed. Morphologic features were recorded, along with immunohistochemistry results when available. Electronic medical records were reviewed for clinical and radiographic information. RESULTS.­: Sixteen cases of gynecologic adenocarcinomas (9 endometrial endometrioid adenocarcinomas, 4 endometrial serous carcinomas, 2 high-grade tubo-ovarian serous carcinomas, and 1 cervical adenosquamous carcinoma) involving the bladder were identified. All included cases had mucosal involvement potentially mimicking primary bladder neoplasms, including 4 cases originally diagnosed as urinary carcinomas. Tumors expressed keratin 7 (12 of 13; 92%), PAX8 (11 of 12; 92%), estrogen receptor (11 of 15; 73%), p16 (8 of 11; 73%), progesterone receptor (8 of 14; 57%), GATA3 (5 of 12; 42%), and p63 (3 of 11; 27%); all tumors were negative for keratin 20 (0 of 12). Features supportive of Müllerian origin included prior history of gynecologic malignancy, lack of morphologic heterogeneity in nonendometrioid tumors, and immunophenotypic coexpression of PAX8 and estrogen receptor with absent GATA3. Potential pitfalls seen in a subset of cases included misleading radiologic and cystoscopic findings, replacement of the overlying urothelial mucosa by tumor mimicking precursor lesions, focal GATA3 and/or p63 positivity, and areas of squamous differentiation in tumors of endometrioid histology. CONCLUSIONS.­: A combination of clinical history, certain morphologic features, and proper selection of immunohistochemical stains is key for the correct diagnosis of secondary gynecologic adenocarcinomas involving the urinary bladder.

Baseline prostate health index risk category and risk category changes during active surveillance predict grade reclassification.

BACKGROUND: It is not known whether baseline prostate health index (PHI) at the initiation of active surveillance (AS) or repeated PHI testing during AS is of clinical value after confirmatory biopsy in AS men followed with multiparametric magnetic resonance imaging (mpMRI). METHODS: We identified 382 AS patients with no greater than Grade Group 1 (GG1) prostate cancer on diagnostic and confirmatory biopsy, at least one mpMRI and PHI test, of which 241 had at least 2 PHI tests. Grade reclassification (GR) was defined as ≥GG2 on surveillance biopsy. PHI risk categories 1 to 4 were as defined by the manufacturer. Associations between baseline PHI risk category or baseline PSA density (PSAD), change in PHI risk categories over time or PSAD changes over time and GR were evaluated with multivariable Cox proportional hazard regression models adjusted for age, Prostate Imaging-Reporting and Data System score and number of positive cores. RESULTS: Men with baseline PHI scores in the highest risk categories had lower rates of GR-free survival (log-rank P < 0.001), as did those who increased in PHI risk category or remained in a high PHI risk category during surveillance (log-rank P = 0.032). On multivariable regression, baseline PHI risk category was a predictor of GR (risk category 4 [vs. 1] hazard ratio [HR] 2.74, 95% confidence interval [CI] 1.32-5.66, P = 0.002, model C-index 0.764, Akaike Information Criterion [AIC] 797), as were PHI risk category changes over time (risk category 4 [vs. 1] HR 4.20, 95% CI 1.76-10.05, P = 0.002, C-index 0.759, AIC 489). Separate models with baseline PSAD and PSAD changes over time yielded C-indices of 0.709 (AIC 809) and 0.733 (AIC 495) respectively. CONCLUSIONS: Baseline PHI risk category and PHI changes over time were both independent predictors of GR after confirmatory biopsy, but the added benefit over PSAD seemed modest. However, baseline PHI and PHI risk category changes provided clinically useful risk stratification for time to GR, so further evaluation of PHI's ability to help reduce the frequency of mpMRI and/or surveillance biopsies with more PHI data points over time may be warranted.

Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) Magnetic Resonance Imaging Scoring to Predict Clinical Outcomes in Active Surveillance for Grade Group 1 Prostate Cancer.

OBJECTIVE: To determine whether radiological change on serial multiparametric magnetic resonance imaging scored using the Prostate Cancer Radiological Estimation of Change in Sequential Evaluation (PRECISE) Scoring system predicts grade reclassification (GR) at surveillance biopsy in men on active surveillance (AS) with Grade Group 1 (GG1) prostate cancer (PCa). METHODS: We retrospectively reviewed records of 255 men with low-risk PCa on AS with magnetic resonance imaging (MRI)-informed diagnostic and confirmatory biopsies and studied the subset who had surveillance biopsies (n = 163) within 6months of an interval MRI. RESULTS: We studied 309 PRECISE scores in 255 men. 14% demonstrated radiological progression (PRECISE 4-5) on interval MRI performed within 24months, compared to 34% of those whose interval MRI was performed at a >3-year interval (P = .002). 28% (46/163) of men undergoing surveillance biopsy experienced GR to ≥ GG2 PCa. There was no significant increase in the rate of GR with increasing PRECISE score (PRECISE 1-2: 24%, PRECISE 3: 23%, PRECISE 4-5: 38%; P = .11). There was a significant increase in the rate of GR with increasing PI-RADS score (P < .05). On multivariable analysis, a PI-RADS score of 4-5 was significantly associated with GR compared to men who had a highest PI-RADS ≤3 (OR=1.98 [95% CI: 1.45-3.09, P = .01]). CONCLUSION: In a low-risk AS cohort with limited follow-up, a patient's highest PI-RADS rather than their PRECISE score on interval MRI was predictive of GR on surveillance biopsy.

Lipoblastoma-Like Tumor and Fibrosarcoma-Like Lipomatous Neoplasm Represent the Same Entity: A Clinicopathologic and Molecular Genetic Study of 23 Cases Occurring in Both Men and Women at Diverse Locations.

Lipoblastoma-like tumor (LLT) is a benign soft tissue tumor demonstrating mixed morphologic features of lipoblastoma, myxoid liposarcoma, and spindle cell lipoma but lacking genetic alterations associated with those tumors. LLT was originally thought to be specific to the vulva but has since been reported in the paratesticular region. The morphologic features of LLT overlap with those of "fibrosarcoma-like lipomatous neoplasm" (FLLN), a rare, indolent adipocytic neoplasm considered by some to form part of the spectrum of atypical spindle cell and pleomorphic lipomatous tumor. We compared the morphologic, immunohistochemical, and genetic features of 23 tumors previously classified as LLT (n = 17) and FLLN (n = 6). The 23 tumors occurred in 13 women and 10 men (mean age, 42 years; range, 17 to 80 years). Eighteen (78%) cases arose in the inguinogenital region, whereas 5 tumors (22%) involved noninguinogenital soft tissue, including the flank (n = 1), shoulder (n = 1), foot (n = 1), forearm (n = 1), and chest wall (n = 1). Microscopically, the tumors were lobulated and septated, with variably collagenized fibromyxoid stroma, prominent thin-walled vessels, scattered univacuolated or bivacuolated lipoblasts, and a minor component of mature adipose tissue. Using immunohistochemistry, 5 tumors (42%) showed complete RB1 loss, with partial loss in 7 cases (58%). RNA sequencing, chromosomal microarray, and DNA next-generation sequencing study results were negative for significant alterations. There were no clinical, morphologic, immunohistochemical, or molecular genetic differences between cases previously classified as LLT or FLLN. Clinical follow-up (11 patients [48%]; range, 2-276 months; mean, 48.2 months) showed all patients were alive without disease, and only one patient had experienced a single local recurrence. We conclude that LLT and FLLN represent the same entity, for which "LLT" seems most appropriate. LLT may occur in either sex and any superficial soft tissue location. Careful morphologic study and appropriate ancillary testing should allow for the distinction of LLT from its potential mimics.

Patterns of Immunoreactivity with TTF-1 Antibodies 8G7G3/1 and SPT24 Suggest Distinct Immunoprofiles Between Most Pulmonary and Nonpulmonary Small Cell Carcinomas.

Introduction. Small cell carcinoma can arise from various sites. Herein, we analyze the ability of 2 thyroid transcription factor-1 (TTF-1) antibodies (SPT24 and 8G7G3/1) to separate pulmonary from nonpulmonary small cell carcinoma. Materials and Methods. We analyzed 26 pulmonary and 83 nonpulmonary small cell carcinomas, and 14 Merkel cell carcinomas. Each tumor was stained with SPT24 and 8G7G3/1. Extent of nuclear staining was scored as diffuse (>50%), focal (11%-50%), rare (1%-10%), or negative (<1%). Results. All pulmonary small cell carcinomas were positive for SPT24 and 8G7G3/1. Four Merkel cell carcinomas (29%) were positive for SPT24 (ranging from rare-to-diffuse), while 2 (14%) showed rare expression with 8G7G3/1. For nonpulmonary small cell carcinomas, 69 (83%) were positive for SPT24 and 40 (48%) were positive for 8G7G3/1. For SPT24 positive tumors, the extent of 8G7G3/1 expression was equal in 17 (25%) and less in 52 tumors (75%), including 29 (42%) that were negative for 8G7G3/1. No nonpulmonary small cell carcinoma had more staining with 8G7G3/1 compared to SPT24. The differences in staining between 8G7G3/1 and SPT24 in the nonpulmonary cohort were statistically significant (P < 0.0001) with no significant difference between primary and metastatic lesions for 8G7G3/1 (P = 0.66) or SPT24 (P = 0.77). Conclusion. Most pulmonary small cell carcinomas are diffusely positive for both SPT24 and 8G7G3/1, whereas most nonpulmonary small cell carcinomas exhibit focal-to-no staining with 8G7G3/1 and significantly less staining with 8G7G3/1 compared to SPT24. However, these trends are not absolute and should be interpreted in conjunction with clinical and radiological findings.

Identifying Men Who Can Remain on Active Surveillance Despite Biopsy Reclassification to Grade Group 2 Prostate Cancer.

PURPOSE: Men on active surveillance with Grade Group 1 prostate cancer who reclassify to Grade Group 2 on surveillance biopsy often leave active surveillance. We aimed to identify subgroups of men who can safely remain on active surveillance despite preoperative reclassification to Grade Group 2. MATERIALS AND METHODS: We studied 249 active surveillance patients with surveillance biopsies classified as Grade Group 1 or Grade Group 2 who underwent radical prostatectomy. Perineural invasion, cancer volume, linear length and maximum percentage of Gleason pattern 4, and prostate-specific antigen density were evaluated. Radical prostatectomy adverse pathology was defined by any of: pN1; ≥pT3; ≥Grade Group 2 with ≥20% Gleason pattern 4; intraductal carcinoma; large cribriform glands. RESULTS: A multivariable logistic regression model incorporating prostate-specific antigen density and perineural invasion stratified radical prostatectomy adverse pathology risk among Grade Group 1 and Grade Group 2 active surveillance patients. 57% (39/68) of Grade Group 1 men reclassified to Grade Group 2 while on active surveillance had favorable radical prostatectomy pathology. Those without biopsy perineural invasion and with low prostate-specific antigen density were more likely to have favorable radical prostatectomy pathology. CONCLUSIONS: Most Grade Group 1 men who enter active surveillance and subsequently reclassify to Grade Group 2 have favorable findings at radical prostatectomy and can remain on active surveillance. Among patients reclassified to Grade Group 2, those with low prostate-specific antigen density and without perineural invasion had the lowest risk of radical prostatectomy adverse pathology, comparable to (or below) that of Grade Group 1 patients who were not reclassified to Grade Group 2 preoperatively. Prostate-specific antigen density and perineural invasion stratify risk in active surveillance patients reclassified to Grade Group 2 and, if concordant with other clinicopathological and radiographic findings, can enable more patients to remain on active surveillance. Reclassification to Grade Group 2 alone should not disqualify men from remaining on active surveillance.

NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023.

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

Nested Subtype of Urothelial Carcinoma in the Upper Urinary Tract: A Series of 15 Cases.

Nested subtype of urothelial carcinoma (NVUC) of the upper urinary tract is rare. While this subtype has an aggressive behavior in the urinary bladder, little is known about this subtype in the renal pelvis and ureter. In addition, due to NVUC's bland morphology and resemblance to von Brunn nests proliferation, which can be florid in the renal pelvis and ureter, establishing a diagnosis of NVUC in these sites can be difficult, especially on small biopsies. Nineteen cases of NVUC of the renal pelvis and the ureter were identified. One was in-house and 18 cases were sent to the genitourinary pathology consult service. Four cases were excluded due to difficulty in obtaining the slides from other institutions. In all, 8/15 (53.33%) cases showed large nested morphology, 4/15 (26.66%) cases showed mixed large and small nested morphology, and only 3/15 (20%) cases showed predominantly small nested morphology. In all cases, the invasive component was pure nested subtype, and tumors were all unifocal. In 8/15 cases, there was the presence of an overlying low-grade papillary urothelial carcinoma. An associated desmoplastic stromal reaction was none/minimal in 12/15 (80%) cases, with a prominent reaction in the remaining 3/15 (20%) cases. Pathologic stages for the resections were pT1 (n=1), pT2 (n=3), pT3 (n=8), and pT4 (n=1). There was only 1 case with a lymph node metastasis at the time of resection who had pT4 disease. Follow-up was available in 10/15 cases, 7/10 cases showed no recurrences or metastases, and the remaining 3/10 cases later developed urothelial carcinoma of the bladder. In 5/15 cases, follow-up could not be obtained. Similar to NVUC in the urinary bladder, NVUC in the upper tract typically lacks an associated desmoplastic reaction and has by definition bland cytology. In contrast to NVUC of the urinary bladder, NVUC in the upper urothelial tract is: (1) more frequently associated with an overlying papillary urothelial carcinoma; (2) more commonly has a large nested pattern; and (3) appears to behave less aggressively.

Mesonephric Adenocarcinoma and Mesonephric-like Adenocarcinoma of the Urinary Tract.

Given the association of mesonephric adenocarcinoma (MA) of the uterine cervix with florid mesonephric hyperplasia, one would expect MAs to rarely arise in other anatomical locations that harbor mesonephric remnants. In contrast, mesonephric-like adenocarcinoma (MLA) is thought to arise from Müllerian origin without an association with mesonephric remnants. The current case series characterizes 4 cases of MA arising in the urinary bladder (1 woman and 3 men), 1 case of MA in the perirenal region (woman), and 1 case of MLA in the ureter (woman). All cases displayed morphologic features similar to MA of the uterine cervix and MLA of the ovary and endometrium, characterized by predominant tubular and focal glandular/ductal architecture. Mesonephric remnants in the bladder wall were closely associated with adjacent MA in cases 1 and 4. MLA in case 6 was associated with mesonephric-like proliferations and endometriosis. All cases (6/6) were diffusely positive for Pax8, and all displayed a luminal pattern of CD10 staining, except case 4 for which CD10 immunostain was not available for review. Gata3 was either focally positive (cases 1, 2, and 6), negative (case 3), or diffusely positive (case 5). TTF-1 was diffusely expressed in cases 1 and 3 and negative in cases 2, 5, and 6. Although a KRAS G12C somatic mutation was detected in case 6, hotspot mutations in KRAS, NRAS, and PIK3CA were not present in other tested cases. Our study demonstrates that MAs and MLAs of the urinary tract share similar histopathogenesis, morphology, and immunophenotype to their counterparts in the female genital tract. We propose that, in the urinary tract, MA might be classified as a distinctive tumor that arises from mesonephric remnants or presumed Wolffian origin if they are not related to Müllerian-type precursors. The tumor displaying similar morphology and immunoprofile to MA but associated with Müllerian-type precursors should be classified as MLA.

MED15::TFE3 Renal Cell Carcinomas: Report of Two New Cases and Review of the Literature Confirming Nearly Universal Multilocular Cystic Morphology.

We report two novel cases of Xp11 translocation renal cell carcinomas with the MED15::TFE3 gene fusion in adult females aged 40 and 74 years. Both cases were extensively cystic and contained only minimal clear cells lining cysts and within septal walls, raising the differential diagnosis of multilocular cystic renal neoplasm of low malignant potential. By immunohistochemistry, both neoplasms labeled for PAX8, TFE3, cathepsin K and Melan A but not for HMB45. On review of the published literature and the two cases reported herein, over 90% of MED15::TFE3 renal cell carcinomas (RCCs) have been described as cystic. The correlation of the MED15::TFE3 fusion with extensively cystic morphology represents the strongest association of TFE3 fusion partner with clinicopathological features among TFE3-rearranged RCC reported to date.

Genomic Classifiers in Personalized Prostate Cancer Radiation Therapy Approaches: A Systematic Review and Future Perspectives Based on International Consensus.

Current risk-stratification systems for prostate cancer (PCa) do not sufficiently reflect the disease heterogeneity. Genomic classifiers (GC) enable improved risk stratification after surgery, but less data exist for patients treated with definitive radiation therapy (RT) or RT in oligo-/metastatic disease stages. To guide future perspectives of GCs for RT, we conducted (1) a systematic review on the evidence of GCs for patients treated with RT and (2) a survey of experts using the Delphi method, addressing the role of GCs in personalized treatments to identify relevant fields of future clinical and translational research. We performed a systematic review and screened ongoing clinical trials on ClinicalTrials.gov. Based on these results, a multidisciplinary international team of experts received an adapted Delphi method survey. Thirty-one and 30 experts answered round 1 and round 2, respectively. Questions with ≥75% agreement were considered relevant and included in the qualitative synthesis. Evidence for GCs as predictive biomarkers is mainly available to the postoperative RT setting. Validation of GCs as prognostic markers in the definitive RT setting is emerging. Experts used GCs in patients with PCa with extensive metastases (30%), in postoperative settings (27%), and in newly diagnosed PCa (23%). Forty-seven percent of experts do not currently use GCs in clinical practice. Expert consensus demonstrates that GCs are promising tools to improve risk-stratification in primary and oligo-/metastatic patients in addition to existing classifications. Experts were convinced that GCs might guide treatment decisions in terms of RT-field definition and intensification/deintensification in various disease stages. This work confirms the value of GCs and the promising evidence of GC utility in the setting of RT. Additional studies of GCs as prognostic biomarkers are anticipated and form the basis for future studies addressing predictive capabilities of GCs to optimize RT and systemic therapy. The expert consensus points out future directions for GC research in the management of PCa.

Genomic Characterization of Prostatic Basal Cell Carcinoma.

Basal cell carcinoma (BCC) of the prostate is a rare tumor. Compared with the more common acinar adenocarcinoma (AAC) of the prostate, BCCs show features of basal cell differentiation and are thought to be biologically distinct from AAC. The spectrum of molecular alterations of BCC has not been comprehensively described, and genomic studies are lacking. Herein, whole genome sequencing was performed on archival formalin-fixed, paraffin-embedded specimens of two cases with BCC. Prostatic BCCs were characterized by an overall low copy number and mutational burden. Recurrent copy number loss of chromosome 16 was observed. In addition, putative driver gene alterations in KIT, DENND3, PTPRU, MGA, and CYLD were identified. Mechanistically, depletion of the CYLD protein resulted in increased proliferation of prostatic basal cells in vitro. Collectively, these studies show that prostatic BCC displays distinct genomic alterations from AAC and highlight a potential role for loss of chromosome 16 in the pathogenesis of this rare tumor type.