Chromophobe Renal Cell Carcinoma With Extensive Retraction Artifact: A Potential Diagnostic Pitfall From Micropapillary Urothelial Carcinoma.

In addition to "classic" and eosinophilic subtype, chromophobe renal cell carcinoma (RCC) is well-known to demonstrate various morphological patterns including adenomatoid, microcystic, pigmented, multicystic, papillary, neuroendocrine-like, and small cell-like, all of which are important to appreciate for accurate diagnosis. Herein, we expand on a unique chromophobe RCC morphology not previously described consisting of tumor cells with extensive stromal retraction, mimicking upper urothelial tract micropapillary carcinoma (MPC). Twelve MPC-like chromophobe RCC nephrectomies were reviewed with clinicopathological features recorded; molecular testing was performed on 7 of 12 tumors. Patients were mostly men (n=10) with a mean age of 65 years. Mean tumor size was 6.4 cm with pathological stage distribution as follows: 4 (33%) T1a, 2 (17%) T1b, 1 (8%) T2b, and 3 (25%) T3a. The extent of MPC-like chromophobe RCC foci ranged from 10% to 40% (mean=26%; there was no correlation between the extent of MPC-like chromophobe RCC foci and tumor stage). Other chromophobe RCC morphological patterns were not identified. When performed, all (100%) tumors depicted prototypic chromophobe RCC staining pattern of KIT positivity/KRT7 positivity. Molecular showed 6 of 7 (86%) with multiple chromosomal losses. Clinically significant mutations were identified in NF1, TP53, FLCN (likely somatic), CHEK2, and ZFHX3 genes. Follow up available in 9 patients showed no evidence of disease (mean=23 months). Although the etiology behind the extensive stromal retraction in our tumors is unknown, this may likely be artifactual in nature. Nonetheless, it is important to include MPC-like chromophobe RCC in the spectrum of "variant" morphologies to avoid diagnostic pitfalls from micropapillary carcinoma.

GATA3 Expression in Prostatic Adenosquamous Carcinoma: A Potential Diagnostic Pitfall.

Urothelial carcinoma and prostatic adenocarcinoma can have overlapping histologic features and in some instances pose challenges to pathologists. GATA binding protein 3 (GATA3) immunohistochemistry (IHC) is a well-established tool to aid in this specific diagnostic dilemma as it has been shown to be a sensitive marker for urothelial carcinoma and a putatively specific marker in excluding prostatic adenocarcinoma. However, in encountering an index tumor of prostatic adenosquamous carcinoma positive for GATA3, herein we sought to investigate this potential diagnostic pitfall in a larger series of tumors. In this study, we retrospectively reviewed prostatic adenosquamous carcinomas diagnosed in 17 patients across the authors' institutions and personal consult collections in the past 10 years. GATA3 IHC was either reviewed or performed on tumors not previously tested. We also recorded other immunostains that were performed at initial diagnosis. Positivity for GATA3 was found in 9 of 17 (53%) tumors, all within squamous regions (2 tumors also showed concomitant moderate GATA3 positivity within glandular elements). The GATA3 positive tumors were all positive for p63 in the 7 tumors where p63 was also performed. Of all tumors tested, NKX3.1 was positive in 100% (13/13) of the glandular elements (3 tumors also showed NKX3.1 concomitant positivity within squamous regions). In summary, when encountering a carcinoma with mixed glandular/squamous features in which prostatic origin is being considered, awareness of GATA3 immunoreactivity in a subset of prostatic adenosquamous carcinoma is critical to avoid diagnostic pitfalls.

Molecular Characterization of Juxtaglomerular Cell Tumors: Evidence of Alterations in MAPK-RAS Pathway.

Juxtaglomerular cell tumor (JGCT) is a rare neoplasm, part of the family of mesenchymal tumors of the kidney. Although the pathophysiological and clinical correlates of JGCT are well known, as these tumors are an important cause of early-onset arterial hypertension refractory to medical treatment, their molecular background is unknown, with only few small studies investigating their karyotype. Herein we describe a multi-institutional cohort of JGCTs diagnosed by experienced genitourinary pathologists, evaluating clinical presentation and outcome, morphologic diversity, and, importantly, the molecular features. Ten JGCTs were collected from 9 institutions, studied by immunohistochemistry, and submitted to whole exome sequencing. Our findings highlight the morphologic heterogeneity of JGCT, which can mimic several kidney tumor entities. Three cases showed concerning histologic features, but the patient course was unremarkable, which suggests that morphologic evaluation alone cannot reliably predict the clinical behavior. Gain-of-function variants in RAS GTPases were detected in JGCTs, with no evidence of additional recurrent genomic alterations. In conclusion, we present the largest series of JGCT characterized by whole exome sequencing, highlighting the putative role of the MAPK-RAS pathway.

Patterns of B-cell lymphocyte expression changes in pre- and post-malignant prostate tissue are associated with prostate cancer progression.

BACKROUND: Inflammation characterized by the presence of T and B cells is often observed in prostate cancer, but it is unclear how T- and B-cell levels change during carcinogenesis and whether such changes influence disease progression. METHODS: The study used a retrospective sample of 73 prostate cancer cases (45 whites and 28 African Americans) that underwent surgery as their primary treatment and had a benign prostate biopsy at least 1 year before diagnosis. CD3+, CD4+, and CD20+ lymphocytes were quantified by immunohistochemistry in paired pre- and post-diagnostic benign prostate biopsy and tumor surgical specimens, respectively. Clusters of similar trends of expression across two different timepoints and three distinct prostate regions-benign biopsy glands (BBG), tumor-adjacent benign glands (TAG), and malignant tumor glandular (MTG) regions-were identified using Time-series Anytime Density Peaks Clustering (TADPole). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of time to biochemical recurrence associated with region-specific lymphocyte counts and regional trends. RESULTS: The risk of biochemical recurrence was significantly reduced in men with an elevated CD20+ count in TAG (HR = 0.81, p = 0.01) after adjusting for covariates. Four distinct patterns of expression change across the BBG-TAG-MTG regions were identified for each marker. For CD20+, men with low expression in BBG and higher expression in TAG compared to MTG had an adjusted HR of 3.06 (p = 0.03) compared to the reference group that had nominal differences in CD20+ expression across all three regions. The two CD3+ expression patterns that featured lower CD3+ expression in the BBG compared to the TAG and MTG regions had elevated HRs ranging from 3.03 to 4.82 but did not reach statistical significance. CONCLUSIONS: Longitudinal and spatial expression patterns of both CD3+ and CD20+ suggest that increased expression in benign glands during prostate carcinogenesis is associated with an aggressive disease course.

Topline/Final Diagnostic Inclusion of Relevant Histologic Findings in Surgical Pathology Reporting of Carcinoma in Prostate Biopsies.

INTRODUCTION: As the list of histologic parameters to include in surgical pathology reports of prostate cancer biopsies grows, some pathologists include this information in the microscopic description or summary sections of the report, whereas others include it in the "topline" or final diagnosis section. This prompted us to develop a multi-institutional survey to assess reporting trends among genitourinary (GU) pathologists. METHODS: A survey instrument was shared among 110 GU pathologists via surveymonkey.com. Anonymized respondent data was analyzed. RESULTS: Eighty-four (76%) participants completed the survey across four continents. Most participants report tumor volume quantitation (88%), number of cores involved (89%), and both Gleason grade and Grade group (93%) in their topline; 71% include percent of pattern 4, with another 16% including it depending on cancer grade; 58% include the presence of cribriform growth pattern 4, with another 11% including it depending on cancer grade. When present, most include extraprostatic extension (90%), prostatic intraductal carcinoma (77%), and perineural invasion (77%). Inclusion of atypical intraductal proliferation (AIP) in the topline diagnosis was cancer grade-dependent, with 74% including AIP in Grade group 1, 61% in Grade group 2, 45% in Grade group 3, 30% in Grade group 4, and 26% in Grade group 5 cancers. CONCLUSION: Certain histologic features such as Gleason grade and tumor volume/cores involved are frequently included in the topline diagnosis, whereas the incorporation of other findings are more variably included. Prostate biopsy reporting remains a dynamic process with stylistic similarities and differences existing among GU pathologists.

Vascular, adipose tissue, and/or calyceal invasion in clear cell tubulopapillary renal cell tumour: potentially problematic diagnostic scenarios.

AIMS: The 2022 WHO classification for kidney tumours recently downgraded clear cell tubulopapillary (also known as clear cell papillary) renal cell carcinoma (RCC) to a benign neoplasm (i.e. clear cell tubulopapillary renal cell tumour) based on the overwhelmingly banal nature of this neoplasm. However, it has been recognized that some clear cell tubulopapillary renal cell tumours demonstrate vascular, adipose or pelvicalyceal invasion, raising the possibility of more aggressive behaviour. The goal of this study was to determine if these 'high stage' features have an effect on tumour prognosis, warranting a carcinoma designation. METHODS AND RESULTS: After excluding cases with tissue artefact (i.e. prior core biopsy track changes) and other RCC subtypes with next-generation sequencing, nine clear cell tubulopapillary renal cell tumours with these so-called 'high stage' features, and otherwise classic morphologic and immunophenotypic findings, including low-grade cytology and 'cup-like' CA9 expression, were evaluated. Median tumour size was 2.2 cm with a range of 0.8 to 6.7 cm. Eight cases (89%) demonstrated perinephric or hilar adipose tissue invasion, although most of these cases showed a bulging (in contrast to an infiltrative) growth pattern. One case demonstrated renal vascular invasion in addition to hilar adipose tissue invasion, and one case demonstrated extension into the pelvicalyceal system. There were no recurrences or evidence of metastatic disease. CONCLUSION: These overall findings continue to support the benign designation for clear cell tubulopapillary renal cell tumours, despite morphologic features that might raise the possibility of a 'higher stage' neoplasm.

Are Renal Tumor Diagnostics Becoming Too Advanced for Many Pathology Laboratories?

The recent influx of novel renal neoplasms, particularly molecularly-defined renal carcinomas, has introduced new challenges in the daily practice of most pathology laboratories. These tumors are uncommon, they do not always have well-established morphologic features, and the expression profile of most common biomarkers is not well understood. Moreover, the diagnosis of molecularly-defined renal carcinomas requires the documentation of the disease-defining molecular alteration, with molecular studies or surrogate immunohistochemical markers. Unfortunately, most pathology laboratories lack molecular laboratories, or it is not cost-effective to maintain assays of the specific biomarkers in these unusual tumors. Pathologists should have updated knowledge about the recent changes in renal neoplasms and be aware of these limitations.

Mechanistic Target of Rapamycin Kinase is a Common Convergent Pathway to Renal Neoplasia: A Contemporary Review.

Mechanistic target of rapamycin kinase (mTOR) is a member of the phosphatidylinositol-3-hydroxide kinase (PI3 K)-related protein kinase family that functions as a central regulator of cell growth, metabolism, proliferation, and survival. The role of the TSC-mTOR signaling pathway in kidney tumors has been implicated in some hamartoma syndromes; however, with the advent and wide utilization of molecular studies, a growing number of kidney tumors have been linked to somatic or germline mutations involving genes that encode for this pathway, including eosinophilic solid and cystic renal cell carcinoma, low-grade oncocytic tumor, eosinophilic vacuolated tumor, renal cell carcinoma with fibromyomatous stroma and angiomyolipoma, among others. Herein, we review the contemporary developments of mTOR pathway-related renal neoplasia, focusing on the clinicopathologic features of the tumor entities.

Current gross examination and reporting patterns of post-neoadjuvant chemotherapy cystectomy specimens: Is it time for a standardized approach?

OBJECTIVES: Neoadjuvant chemotherapy (NACT) is recommended for muscle-invasive bladder cancer, and robust treatment response may result in lack of grossly identifiable tumor in the cystectomy specimen. Current gross examination and reporting protocols, however, do not include specific guidance on the approach to these specimens. METHODS: A Qualtrics survey was disseminated by email and X (formerly Twitter). Responses from pathologists and pathologists' assistants (PAs) were included. The survey interrogated demographics, practice settings, prevalence of NACT use, approach to gross examination, and reporting practices in the setting of both grossly visible tumor or ulcer bed and the complete absence of a gross lesion. RESULTS: Based on 55 respondents' experience, identifying gross tumor occurred less frequently than tumor or ulcer bed (40% vs 71%). Lack of identification of any gross lesions was estimated to occur in 29% of cases. Gross examination practices were relatively consistent in cases with residual gross tumor or gross tumor bed, with agreement that gross tumor should be submitted as 1 block per centimeter (66%), and tumor or ulcer bed should be submitted in its entirety (97%). Gross examination practices appeared more varied when no gross lesions were identified. Overall, most responders stated they "definitely" or "maybe" support a standardized gross examination (89%) and reporting (96%) protocol. CONCLUSIONS: With the increased use of NACT, lack of any gross lesion leads to inconsistent gross examination techniques. This study provides insight into the current approach to examination of post-NACT cystectomies and suggests that a desire exists among pathologists and pathologists' assistants for more standardized practice.

International Society of Urological Pathology (ISUP) Consensus Conference on Current Issues in Bladder Cancer: Working Group 3: Subcategorization of T1 Bladder Cancer.

Emerging data on T1 bladder cancer subcategorization (aka substaging) suggests a correlation with oncological outcomes. The International Society of Urological Pathology (ISUP) organized the 2022 consensus conference in Basel, Switzerland to focus on current issues in bladder cancer and tasked working group 3 to make recommendations for T1 subcategorization in transurethral bladder resections. For this purpose, the ISUP developed and circulated a survey to their membership querying approaches to T1 bladder cancer subcategorization. In particular, clinical relevance, pathological reporting, and endorsement of T1 subcategorization in the daily practice of pathology were surveyed. Of the respondents of the premeeting survey, about 40% do not routinely report T1 subcategory. We reviewed literature on bladder T1 subcategorization, and screened selected articles for clinical performance and practicality of T1 subcategorization methods. Published literature offered evidence of the clinical rationale for T1 subcategorization and at the conference consensus (83% of conference attendants) was obtained to report routinely T1 subcategorization of transurethral resections. Semiquantitative T1 subcategorization was favored (37%) over histoanatomic methods (4%). This is in line with literature findings on practicality and prognostic impact, that is, a shift of publications from histoanatomic to semiquantitative methods or by reports incorporating both methodologies is apparent over the last decade. However, 59% of participants had no preference for either methodology. They would add a comment in the report briefly stating applied method, interpretation criteria (including cutoff), and potential limitations. When queried on the terminology of T1 subcategorization, 34% and 20% of participants were in favor of T1 (microinvasive) versus T1 (extensive) or T1 (focal) versus T1 (nonfocal), respectively.

Adenoid cystic carcinoma metastatic to the kidney: a series of 10 patients emphasizing unilateral presentation and long time interval from primary diagnosis.

Adenoid cystic carcinoma (AdCC) metastasis to kidney is rare. We identified 10 patients with metastatic AdCC in multi-institutional collaboration. Core needle biopsy was the most common specimen (n = 6). Patients were predominately female (n = 7) with a median age of 48 years (35-62 years). The most common primary location of the AdCC was head and neck (n = 6, among them parotid gland = 4), followed by lung (n = 2), breast (n = 1), and vulva (n = 1). Median lapse between primary AdCC and renal metastasis was almost 13 years (154 months, range 1-336 months). Moreover, all but one patient had unilateral kidney metastasis. The majority of metastatic AdCC within the kidney demonstrated mixed growth patterns, frequently cribriform, and tubular morphology. Follow-up available for 8 patients showed 6 alive with disease and 2 died of disease (the longest survival was 4 years past the diagnosis of renal metastasis). A systematic literature review including 29 patients revealed that kidney metastasis by AdCC is usually a late event, is typically unilateral, and is usually composed of one to three foci, and thus has clinical features which mimic a primary renal tumor.

Nested and Large Nested Subtypes of Urothelial Carcinoma of the Upper Urinary Tract: A Multi-institutional Study.

Nested urothelial carcinoma (NUC) and large nested urothelial carcinoma (LNUC) of the upper urinary tract are exceedingly rare. This has contributed to the paucity of information regarding their clinicopathological and molecular characteristics. To address this knowledge gap, we explored the largest cohort to date of these rare tumors, comprising resection specimens of 10 LNUC and 7 NUC, from 7 participating institutions. Clinicopathological data were retrieved and documented. Whole exome sequencing and RNA sequencing were performed on the Illumina NovaSeq 6000 sequencer. The data generated were analyzed using the genome analysis toolkit pipeline. Somatic mutations were annotated using funcotator tool to identify pathogenic/likely pathogenic variants. Tumor mutational burden was calculated using python-based "pyTMB" tool. Microsatellite instability analysis was done using MSIsensor2 and the Idylla platform. Differential expression analysis of genes in LNUC and NUC along with mRNA expression-based molecular subtyping was performed by analyzing expression pattern of markers used in The Cancer Genome Atlas subclassification of bladder carcinoma. Both tumor types were more common in older males, were unifocal, and occurred more commonly mixed with minor components of predominantly conventional urothelial carcinoma. Overlying low-grade papillary urothelial carcinoma was significantly more common in LNUC (P = .034). On follow-up (LNUC: median, 10 months; range, 3-84 months; NUC: median, 9 months; range, 2-48 months), LNUC had better clinical outcomes (P = .031). Pathogenic mutations in FGFR3 and PIK3CA were significantly more common in LNUC (P = .049 and P = .044, respectively), with the latter present exclusively in LNUC. Seventy-five percent of the cases showed tumor mutational burden of <10, and all cases were microsatellite-stable. FGFR3 mutations were also more common in low-stage tumors. This study expands on the clinicopathological spectrum of NUC and LNUC of the upper urinary tract and is the first to comprehensively analyze the molecular profile of these tumors, highlighting pathogenic genetic alterations of potential therapeutic and prognostic value.

International Opinions on Grading of Urothelial Carcinoma: A Survey Among European Association of Urology and International Society of Urological Pathology Members.

Background: Grade of non-muscle-invasive bladder cancer (NMIBC) is an important prognostic factor for progression. Currently, two World Health Organization (WHO) classification systems (WHO1973, categories: grade 1-3, and WHO2004 categories: papillary urothelial neoplasm of low malignant potential [PUNLMP], low-grade [LG], high-grade [HG] carcinoma) are used. Objective: To ask the European Association of Urology (EAU) and International Society of Urological Pathology (ISUP) members regarding their current practice and preferences of grading systems. Design setting and participants: A web-based, anonymous questionnaire with ten questions on grading of NMIBC was created. The members of EAU and ISUP were invited to complete an online survey by the end of 2021. Thirteen experts had previously answered the same questions. Outcome measurements and statistical analysis: The submitted answers from 214 ISUP members, 191 EAU members, and 13 experts were analyzed. Results and limitations: Currently, 53% use only the WHO2004 system and 40% use both systems. According to most respondents, PUNLMP is a rare diagnosis with management similar to Ta-LG carcinoma. The majority (72%) would consider reverting back to WHO1973 if grading criteria were more detailed. Separate reporting of WHO1973-G3 within WHO2004-HG would influence clinical decisions for Ta and/or T1 tumors according the majority (55%). Most respondents preferred a two-tier (41%) or a three-tier (41%) grading system. The current WHO2004 grading system is supported by a minority (20%), whereas nearly half (48%) supported a hybrid three- or four-tier grading system composed of both WHO1973 and WHO2004. The survey results of the experts were comparable with ISUP and EAU respondents. Conclusions: Both the WHO1973 and the WHO2004 grading system are still widely used. Even though opinions on the future of bladder cancer grading were strongly divided, there was limited support for WHO1973 and WHO2004 in their current formats, while the hybrid (three-tier) grading system with LG, HG-G2, and HG-G3 as categories could be considered the most promising alternative. Patient summary: Grading of non-muscle-invasive bladder cancer (NMIBC) is a matter of ongoing debate and lacks international consensus. We surveyed urologists and pathologists of European Association of Urology and International Society of Urological Pathology on their preferences regarding NMIBC grading to generate a multidisciplinary dialogue. Both the "old" World Health Organization (WHO) 1973 and the "new" WHO2004 grading schemes are still used widely. However, continuation of both the WHO1973 and the WHO2004 system showed limited support, while a hybrid grading system composed of both the WHO1973 and the WHO2004 classification system may be considered a promising alternative.

Metastatic solid tumors to the testis: a clinicopathologic evaluation of 157 cases from an international collaboration.

To elucidate the spectrum of metastatic solid tumors to the testis and their clinicopathologic features. The databases and files of 26 pathology departments from 9 countries on 3 continents were surveyed to identify metastatic solid tumors to the testis and to characterize their clinicopathologic features in detail. We compiled a series of 157 cases of metastatic solid tumors that secondarily involved the testis. The mean patient age at diagnosis was 64 years (range, 12-93 years). Most patients (127/144; 88%) had clinical manifestation of the disease, with testicular mass/nodule (89/127; 70%) being the most common finding. The main mechanism of testicular involvement was metastasis in 154/157 (98%) cases. Bilateral testicular involvement was present in 12/157 (8%) patients. Concurrent or prior extratesticular metastases were present in 78/101 (77%) patients. The diagnosis was made mainly in orchiectomy specimens (150/157; 95%). Different types of carcinomas (138/157; 87%), most commonly adenocarcinoma (72/157; 46%), were the most common malignancies. The most common primary carcinomas included prostatic (51/149; 34%), renal (29/149; 20%), and colorectal (13/149; 9%). Intratubular growth was identified in 13/124 (11%) cases and paratesticular involvement was found in 73/152 (48%) cases. In patients with available follow-up (110/157; 70%), more than half (58/110; 53%) died of disease. In this largest series compiled to date, we found that most secondary tumors of the testis represent metastases from the genitourinary and gastrointestinal tract carcinomas and typically occur in the setting of disseminated disease.

Renal Neoplasia Occurring in Patients With PTEN Hamartoma Tumor Syndrome : Clinicopathologic Study of 12 Renal Cell Carcinomas From 9 Patients and Association With Intrarenal "Lipomas".

The aim of this study was to assess the histopathologic spectrum of renal tumors in patients with PTEN hamartoma tumor syndrome (PHTS), with a specific focus on potential features predictive of the underlying syndrome. A multi-institutional study was conducted to obtain clinical and pathologic data on renal tumors arising in patients with PHTS, either diagnosed by germline mutational analysis or clinical criteria for Cowden syndrome. Histologic sections of the renal tumors were re-reviewed for classification. Twelve renal epithelial tumors from 9 patients were identified (4 males and 5 females, with a mean age of 41.8 y), 7 of whom carried germline PTEN mutations. All 12 renal epithelial tumors were renal cell carcinomas (RCCs): 5 were chromophobe RCCs, 4 papillary RCCs, and 3 RCC not otherwise specified. Pathologic stage distribution was: 7 (59%) pT1a, 2 (17%) pT1b, 1 (8%) pT2a, 1 (8%) pT2b, and 1 (8%) pT3a. World Health Organization/International Society of Urological Pathology (WHO/ISUP) histologic grade was applicable in 7 (54%) nonchromophobe tumors: 4 (57%) G2, 2 (29%) G3, and 1 (14%) G4. An unexpected histologic finding was the presence of 2 patients with incidental microscopic collections of intrarenal adipocytes that had no features of angiomyolipoma (and were negative with 2 sensitive PEComa markers: cathepsin-K and GPNMB); both were classified as lipoma/"lipomatous hamartomas." The average follow-up interval was 67.8 months (13 to 172 mo): 5 patients had no evidence of disease, 2 were lost to follow-up, 1 died of other (non-PHTS) causes (ie, prostate cancer), and 1 was alive with metastatic RCC to the lung (RCC not otherwise specified with rhabdoid differentiation). All tumors showed loss of nuclear PTEN staining by immunohistochemistry. Fumarate hydratase was retained and 2SC was negative in all papillary RCCs. CK7 was moderate-strong/diffuse positive in 4 of 5 chromophobe RCCs and in 3 of 4 papillary RCCs. Renal epithelial tumors associated with PHTS represent a heterogeneous group of RCCs, but classic chromophobe and papillary RCC are most common. The majority have a favorable clinical behavior as would be predicted by subtype. In contrast to other hereditary renal neoplasia syndromes, morphologic features of the RCCs do not allow identification of PHTS-associated neoplasia with any degree of specificity in the absence of clinical setting and/or prior history, but the presence of microscopic "lipomas" within the kidney may provide a clue in rare cases. Therefore, clinical suspicion and genetic counseling with germline testing remain necessary for identifying PHTS-associated RCC.

Metastatic solid tumours to the penis: a clinicopathologic evaluation of 109 cases from an international collaboration.

AIMS: To elucidate the spectrum of metastatic tumours to the penis and their clinicopathologic features. METHODS: The databases and files of 22 pathology departments from eight countries on three continents were queried to identify metastatic solid tumours of the penis and to characterize their clinical and pathologic features. RESULTS: We compiled a series of 109 cases of metastatic solid tumours that secondarily involved the penis. The mean patient age at diagnosis was 71 years (range, 7-94 years). Clinical presentation commonly included a penile nodule/mass (48/95; 51%) and localised pain (14/95; 15%). A prior history of malignancy was known in 92/104 (89%) patients. Diagnosis was made mainly on biopsy (82/109; 75%), or penectomy (21/109; 19%) specimens. The most common penile locations were the glans (45/98; 46%) and corpus cavernosum (39/98; 39%). The most frequent histologic type was adenocarcinoma (56%). Most primary carcinomas originated in the genitourinary (76/108; 70%) and gastrointestinal (20/108; 18%) tracts, including prostate (38/108; 35%), urinary bladder (27/108; 25%), and colon/rectum (18/108; 17%). Concurrent or prior extrapenile metastases were identified in 50/78 (64%) patients. Clinical follow-up (mean 22 months, range 0-171 months) was available for 87/109 (80%) patients, of whom 46 (53%) died of disease. CONCLUSION: This is the largest study to date of metastatic solid tumours secondarily involving the penis. The most frequent primaries originated from the genitourinary and gastrointestinal tracts. Metastatic penile tumours usually presented with penile nodules/masses and pain, and they often occurred in the setting of advanced metastatic disease, portending poor clinical outcomes.

Convolutional Neural Network Quantification of Gleason Pattern 4 and Association With Biochemical Recurrence in Intermediate-Grade Prostate Tumors.

Differential classification of prostate cancer grade group (GG) 2 and 3 tumors remains challenging, likely because of the subjective quantification of the percentage of Gleason pattern 4 (%GP4). Artificial intelligence assessment of %GP4 may improve its accuracy and reproducibility and provide information for prognosis prediction. To investigate this potential, a convolutional neural network (CNN) model was trained to objectively identify and quantify Gleason pattern (GP) 3 and 4 areas, estimate %GP4, and assess whether CNN-predicted %GP4 is associated with biochemical recurrence (BCR) risk in intermediate-risk GG 2 and 3 tumors. The study was conducted in a radical prostatectomy cohort (1999-2012) of African American men from the Henry Ford Health System (Detroit, Michigan). A CNN model that could discriminate 4 tissue types (stroma, benign glands, GP3 glands, and GP4 glands) was developed using histopathologic images containing GG 1 (n = 45) and 4 (n = 20) tumor foci. The CNN model was applied to GG 2 (n = 153) and 3 (n = 62) tumors for %GP4 estimation, and Cox proportional hazard modeling was used to assess the association of %GP4 and BCR, accounting for other clinicopathologic features including GG. The CNN model achieved an overall accuracy of 86% in distinguishing the 4 tissue types. Furthermore, CNN-predicted %GP4 was significantly higher in GG 3 than in GG 2 tumors (P = 7.2 × 10-11). %GP4 was associated with an increased risk of BCR (adjusted hazard ratio, 1.09 per 10% increase in %GP4; P = .010) in GG 2 and 3 tumors. Within GG 2 tumors specifically, %GP4 was more strongly associated with BCR (adjusted hazard ratio, 1.12; P = .006). Our findings demonstrate the feasibility of CNN-predicted %GP4 estimation, which is associated with BCR risk. This objective approach could be added to the standard pathologic assessment for patients with GG 2 and 3 tumors and act as a surrogate for specialist genitourinary pathologist evaluation when such consultation is not available.

Clear cell renal cell carcinoma with focal psammomatous calcifications: a rare occurrence mimicking translocation carcinoma.

AIMS: Renal cell carcinoma (RCC) with clear cells and psammoma-like calcifications would often raise suspicion for MITF family translocation RCC. However, we have rarely encountered tumours consistent with clear cell RCC that contain focal psammomatous calcifications. METHODS AND RESULTS: We identified clear cell RCCs with psammomatous calcifications from multiple institutions and performed immunohistochemistry and fluorescence and RNA in-situ hybridisation (FISH and RNA ISH). Twenty-one tumours were identified: 12 men, nine women, aged 45-83 years. Tumour size was 2.3-14.0 cm (median = 6.75 cm). Nucleolar grade was 3 (n = 14), 2 (n = 4) or 4 (n = 3). In addition to clear cell pattern, morphology included eosinophilic (n = 12), syncytial giant cell (n = 4), rhabdoid (n = 2), branched glandular (n = 1), early spindle cell (n = 1) and poorly differentiated components (n = 1). Labelling for CA9 was usually 80-100% of the tumour cells (n = 17 of 21), but was sometimes decreased in areas of eosinophilic cells (n = 4). All (19 of 19) were positive for CD10. Most (19 of 20) were positive for AMACR (variable staining = 20-100%). Staining was negative for keratin 7, although four showed rare positive cells (four of 20). Results were negative for cathepsin K (none of 19), melan A (none of 17), HMB45 (none of 17), TFE3 (none of 5), TRIM63 RNA ISH (none of 13), and TFE3 (none of 19) and TFEB rearrangements (none of 12). Seven of 19 (37%) showed chromosome 3p deletion. One (one of 19) showed trisomy 7 and 17 without papillary features. CONCLUSIONS: Psammomatous calcifications in RCC with a clear cell pattern suggests a diagnosis of MITF family translocation RCC; however, psammomatous calcifications can rarely be found in true clear cell RCC.