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The nested variant of urothelial carcinoma, a frequent mimic of benign lesions on limited specimens, has been associated with high-stage disease including metastases at presentation. While PAX8 immunohistochemistry has been noted to be infrequently present in urothelial carcinoma in general, it has not been studied specifically in a cohort of nested urothelial carcinomas. Furthermore, TERT promoter mutation status is a potentially valuable biomarker for diagnosis of urothelial carcinoma and for noninvasive disease monitoring that has been observed in a majority of urothelial carcinoma and has previously been seen to be prevalent in multiple variant morphologies of urothelial carcinoma, including the nested variant. Twenty-five primary and three metastatic samples of nested urothelial carcinoma, along with 16 benign cases, were identified in a multicenter retrospective record review. PAX8 immunohistochemical stain was performed on all cases. In addition, TERT mutation analysis by allele-specific PCR was performed on 21 of the primary nested urothelial carcinoma cases and all benign cases. Positive PAX8 expression was identified in 52% (13 of 25) primary cases and 67% (2 of 3) metastatic cases of nested urothelial carcinoma; 50% (1 of 2) cases of large nested urothelial carcinoma were positive for PAX8. PAX8 expression was negative in the benign urothelium in all cases. TERT promoter mutation was observed in 83% (15 of 18) nested urothelial carcinoma cases and in 6% (1 of 16) of the benign cases. Recognition of the prevalence of positive PAX8 staining in this clinically relevant variant of urothelial carcinoma is essential to avoiding inaccurate or delayed diagnosis during the diagnostic workup of bladder lesions suspicious for nested variant of urothelial carcinoma. Moreover, the prevalence of TERT promoter mutations in nested urothelial carcinoma is similar to that of conventional urothelial carcinoma, further supporting its use as a biomarker that is stable across morphologic variants of urothelial carcinoma.

Prostatic basal cell carcinoma is a malignant neoplasm composed of basaloid cells forming infiltrative nests and tubules, which may potentially be misdiagnosed as benign basal cell proliferations (i.e., florid basal cell hyperplasia or basal cell adenoma) and also closely resembles adenoid cystic carcinoma of the salivary gland. MYB-NFIB gene rearrangement occurs in 30–86% of salivary gland adenoid cystic carcinomas. We sought to further characterize MYB gene rearrangement in prostatic basal cell carcinoma and correlate MYB-NFIB fusion status with other clinicopathologic characteristics. To this end, FISH analysis for MYB-NFIB gene fusion using fusion probes was performed on formalin-fixed, paraffin-embedded tissue sections from prostatic basal cell carcinoma (n = 30), florid basal cell hyperplasia (n = 18), and basal cell adenoma (n = 4). Fourteen of 30 (47%) cases of basal cell carcinoma were positive for MYB-NFIB gene fusion FISH, and no cases of benign basal cell proliferations were positive (p

Primary mucinous tumors and secondary tumors involving the prostate gland are relatively uncommon, however they have important diagnostic, therapeutic, and prognostic implications. The primary mucinous tumors of the prostate include mucinous (colloid) adenocarcinoma of the prostate, prostatic adenocarcinoma with mucinous features, and mucinous adenocarcinoma of the prostatic urethra (mucin-producing urothelial-type adenocarcinoma of the prostate). Mucinous adenocarcinoma of the prostate is defined as a primary prostatic acinar tumor characterized by the presence of at least 25% of the tumor composed of glands with extraluminal mucin. This diagnosis can only be made in radical prostatectomy specimens. Recent studies have shown that these tumors have a similar or in some cases better prognosis than conventional prostatic adenocarcinoma treated by radical prostatectomy. The preferred terminology for tumors that are composed of

Renal cell carcinomas with MITF aberrations demonstrate a wide morphologic spectrum, highlighting the need to consider these entities within the differential diagnosis of renal tumors encountered in clinical practice. Herein, we describe our experience with application of clinical fluorescence in situ hybridization (FISH) assays for detection of TFE3 and TFEB gene aberrations from 85 consecutive renal cell carcinoma cases submitted to our genitourinary FISH service. Results from 170 FISH assays performed on these tumors were correlated with available clinicopathologic findings. Ninety-eight percent of renal tumors submitted for FISH evaluation were from adult patients. Thirty-one (37%) tumors were confirmed to demonstrate MITF aberrations (21 TFE3 translocation, 4 TFEB translocation, and 6 TFEB amplification cases). Overall, renal cell carcinomas with MITF aberrations demonstrated morphologic features overlapping with clear cell, papillary, or clear cell papillary renal cell carcinomas. Renal cell carcinomas with MITF aberrations were significantly more likely to demonstrate dual (eosinophilic and clear) cytoplasmic tones (P=0.030), biphasic TFEB translocation renal cell carcinoma-like morphology (P=0.002), psammomatous calcifications (P=0.002), and nuclear pseudoinclusions (P=0.001) than renal cell carcinomas without MITF aberrations. Notably, 7/9 (78%) renal cell carcinomas exhibiting subnuclear clearing and linear nuclear array (6 of which showed high World Health Organization/International Society of Urological Pathology nucleolar grade) demonstrated TFE3 translocation, an association that was statistically significant when compared with renal cell carcinomas without MITF aberrations (P=0.009). In this cohort comprising consecutive cases, TFEB-amplified renal cell carcinomas were more commonly identified than renal cell carcinomas with TFEB translocations, and four (67%) of these previously unreported TFEB-amplified renal cell carcinomas demonstrated oncocytic and papillary features with a high World Health Organization/International Society of Urological Pathology nucleolar grade. In summary, TFE3 and TFEB FISH evaluation aids in identification and accurate classification of renal cell carcinomas with MITF aberrations, including TFEB-amplified renal cell carcinoma, which may demonstrate aggressive behavior.

We have described a rare group of prostate adenocarcinomas that show aberrant expression of p63, a protein strongly expressed in prostatic basal cells and absent from usual-type acinar prostate cancers. The partial basal-like immunophenotype of these tumors is intriguing in light of the persistent debate surrounding the cell-of-origin for prostate cancer; however, their molecular phenotype is unknown. We collected 37 of these tumors on radical prostatectomy and biopsy and assessed subsets for a diverse panel of molecular markers. The majority of p63-expressing tumors were positive for the ΔNp63 isoform (6/7) by immunofluorescence and p63 mRNA (7/8) by chromogenic in situ hybridization. Despite p63 positivity, these tumors uniformly expressed luminal-type cytokeratin proteins such as CK18 (13/13), CK8 (8/8), and markers of androgen axis signaling commonly seen in luminal cells, including androgen receptor (10/11), NKX3.1 (8/8), and prostein (12/13). Conversely, basal cytokeratins such as CK14 and CK15 were negative in all cases (0/8) and CK5/6 was weakly and focally positive in 36% (4/11) of cases. Pluripotency markers including β-catenin, Oct4, and c-kit were negative in p63-expressing tumors (0/11). Despite nearly universal expression of androgen receptor and downstream androgen signaling targets, p63-expressing tumors lacked ERG rearrangements by fluorescence in situ hybridization (0/14) and ERG protein expression (0/37). No tumors expressed SPINK1 or showed PTEN protein loss (0/19). Surprisingly, 74% (14/19) of p63-expressing tumors expressed GSTP1 protein at least focally, and 33% (2/6) entirely lacked GSTP1 CpG island hypermethylation by bisulfite sequencing. In contrast to usual prostatic adenocarcinomas, prostate tumors with p63 expression show a mixed luminal/basal immunophenotype, uniformly lack ERG gene rearrangement, and frequently express GSTP1. These data strongly suggest that p63-expressing prostate tumors represent a molecularly distinct subclass and further study of this rare tumor type may yield important insights into the role of p63 in prostatic biology and the prostate cancer cell-of-origin.

Tumors of the urinary bladder may have a variety of histological patterns. Tumors with either glandular or villous features, such as villous adenomas, in situ adenocarcinomas, invasive adenocarcinomas, and variants of urothelial carcinoma such as micropapillary carcinomas have been described. However, urothelial carcinomas with both villous and glandular features have not been well characterized. We identified 14 cases of urothelial carcinoma with villoglandular differentiation. These cases were defined as having villoglandular features if they contained superficial finger-like processes lined by epithelium having true glandular lumina. Mean patient age at presentation was 70 years (range: 46–84 years) with a male predominance (5:1). A total of 3 cases (21%) were non-invasive, five cases (36%) had lamina propria invasion, five cases (36%) had muscularis propria invasion and one case (7%) had extravesicular extension. A concurrent high-grade papillary urothelial carcinoma component was identified in 11 cases (79%), micropapillary component in 5 (36%) cases, in-situ urothelial carcinoma component in 3 cases (21%), plasmacytoid component in 3 cases (21%), invasive adenocarcinoma in 2 cases, sarcomatoid carcinoma component in one case (14%), and small-cell carcinoma component in 1 case (7%). Cystitis cystica et glandularis was present in 3 cases (21%). Angiolymphatic invasion was identified in 3 cases (21%). Histologically, the villoglandular components were composed of finger-like processes lined by glands intimately admixed with high-grade urothelial carcinoma. Many of the glands had cribriform features lined by non-mucin producing cuboidal to columnar cells. Urothelial carcinoma with villoglandular differentiation are high-grade tumors typically seen in elderly males, characterized by superficial filliform processes lined by glands intimately admixed with high-grade urothelial carcinoma (in situ or invasive) and other aggressive variants of urothelial carcinoma. These relatively rare tumors should be recognized as a variant of urothelial carcinoma.

Lymphoid neoplasms of the urinary tract and male genital organs are relatively rare, comprising less than 5% of all primary extranodal lymphomas; only a handful of small case series and isolated case reports have been published describing their predominant sites and subtypes. We identified 40 patients with lymphoid neoplasms of the urinary tract and male genital organs. Hematoxylin and eosin slides and immunohistochemical stains were reviewed, and follow-up data were also obtained. Twenty-six of 40 cases (65%) were primary genitourinary lymphomas. Mean age at diagnosis was 56 years (range 4-86 years). Among renal, bladder, and ureter lymphomas, a male predominance was noted (1.6:1). The subtypes of the lymphoid neoplasms observed were diffuse large B-cell lymphoma (17 cases, 43%); Burkitt lymphoma, extranodal marginal zone lymphoma, SLL/CLL, and follicular lymphoma (4 cases, or 10% each); B-cell ALL (2 cases, 5%); B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, mantle cell lymphoma, plasmacytoma, polymorphic post-transplant lymphoproliferative disorder, and peripheral T-cell lymphoma NOS (1 case, or 2.5% each). In most cases, the genitourinary tract was the site of initial presentation. Genitourinary tract lymphomas most commonly occurred in the kidney. B-cell non-Hodgkin's lymphomas predominated, with diffuse large B-cell lymphoma being the most common subtype in the entire group. Extranodal marginal zone lymphoma was seen only in the kidney, rather than the bladder, where it is typically thought to be more common. Although this study confirms the predominance of diffuse large B-cell lymphoma in extranodal sites, the findings also highlight the variety of lymphomas that may occur in the genitourinary tract. This diversity of subtypes affirms the importance of fully characterizing lymphomas by immunohistochemistry and other modalities, which are indispensable for accurate diagnosis.