The International Society of Urological Pathology (ISUP) 2014 consensus meeting recommended a novel grade grouping for prostate cancer that included dividing Gleason score (GS) 7 into grade groups 2 (GS 3+4) and 3 (GS 4+3). This division of GS 7, essentially determined by the percent of Gleason pattern (GP) 4 (< or >50%), raises the question of whether a more exact quantification of the percent GP 4 within GS 7 will yield additional prognostic information. Modifications were also made by ISUP regarding the definition of GP 4, now including 4 main architectural types: cribriform, glomeruloid, poorly formed, and fused glands. This study was conducted to analyze the prognostic significance of the percent GP 4 and main architectural types of GP 4 according to the 2014 ISUP grading criteria in radical prostatectomies (RPs). The cohort included 585 RP cases of GS 6 (40.2%), 3+4 (49.0%), and 4+3 (10.8%) prostate cancers. Significantly different 5-year biochemical recurrence (BCR)-free survival rates were observed among GS 6 (99%, 95% confidence interval [CI]: 97%-100%), 3+4 (81%, 95% CI: 76%-86%), and 4+3 (60%, 95% CI: 45%-71%) cancers (P70% (P<0.001). Among the GP 4 architectures, cribriform was the most prevalent (43.7%), and combination of architectures with cribriform present was more frequently observed in GS 4+3 (60.3%). Glomeruloid was mostly (67.1%) seen combined with other GP 4 architectures. Unlike the other GP 4 architectures, glomeruloid as the sole GP 4 was observed only as a secondary pattern (ie, 3+4). Among patients with GS 7 cancer, the presence of cribriform architecture was associated with decreased 5-year BCR-free survival when compared with GS 7 cancers without this architecture (68% vs. 85%, P<0.01), whereas the presence of glomeruloid architecture was associated with improved 5-year BCR-free survival when compared with GS 7 cancers without this architecture (87% vs. 75%, P=0.01). However, GS 7 disease having only the glomeruloid architecture had significantly lower 5-year BCR-free survival than GS 6 cancers (86% vs. 99%, P<0.01). Multivariable Cox proportional hazards regression model for factors associated with BCR among GS 7 cancers identified age (hazard ratio [HR] 0.95, P<0.01), preoperative prostate-specific antigen (HR 1.07, P<0.01), positive surgical margin (HR 2.70, P70% [HR 6.57], all P<0.01), presence of cribriform glands (HR 1.78, P=0.02), and presence of glomeruloid glands (HR 0.43, P=0.03) as independent predictors. In conclusion, our study shows that increments in percent of GP 4 correlate with increased risk for BCR supporting the ISUP recommendation of recording the percent of GP 4 in GS 7 prostate cancers at RP. However, additional larger studies are needed to establish the optimal interval for reporting percent GP 4 in GS 7 cancers. Among the GP 4 architectures, cribriform independently predicts BCR, whereas glomeruloid reduces the risk of BCR. Distinction should be made between cribriform and glomeruloid architectures, despite glomeruloid being considered as an early stage of cribriform, as cribriform confers a higher risk for poorer outcome.

Although well recognized in the literature, the contemporary clinicopathologic data regarding choriocarcinoma (CC) as a pure or the predominant component of a testicular germ cell tumor (GCT) are limited. Herein, we present a series of pure CC and predominant CC in mixed GCT of the testis obtained from a single oncology institution. A comprehensive histologic review of 1010 orchiectomies from 1999 to 2011 yielded 6 (0.6%) pure CC and 9 (0.9%) mixed GCT cases with a predominant CC component. Patients’ ages ranged from 20 to 39 years (median 29 y). All patients had markedly elevated serum β-hCG levels (median 199,000 IU/mL) at presentation. All tumors were unilateral and involved the right (9/15) and left (6/15) testis. The mean tumor size was 6.5 cm (range, 1.5 to 8 cm). Histology was similar for pure CCs and the CC component of mixed GCTs. CC commonly showed expansile hemorrhagic nodular cysts surrounded by variable layers of neoplastic trophoblastic cells (mononucleated trophoblasts and syncytiotrophoblasts). The syncytiotrophoblasts usually covered columns of mononucleated trophoblasts and occasionally formed plexiform aggregates and pseudovillous protrusions. Immunohistochemical stains suggested a mixture of cytotrophoblasts (p63⁺, HPL⁻) and intermediate trophoblasts (p63⁻, HPL weak +/−) in the columns of mononucleated cells. In the 9 mixed GCTs, CC comprised 50% to 95% (7/9 were ≥80% CC) of the tumor; 7 were combined with 1, and 2 were combined with 2 other GCT components. The non-CC components included teratoma (5/9), seminoma (2/9), yolk sac tumor (2/9), and embryonal carcinoma (2/9). Lymphovascular invasion, spermatic cord invasion, and tunica vaginalis invasion were present in 15/15, 5/15, and 1/12 cases, respectively. In mixed GCTs, these locally aggressive features were attributed to the CC component, except in 1 tumor in which it was also exhibited by the embryonal carcinoma component. Lymphovascular invasion was multifocal to widespread in 73% of tumors. The stages of the 15 tumors were: pT2 (10), pT3 (5); NX (1), N1 (4), N2 (5), N3 (5); and M1a (2) and M1b (13). Distant organ metastasis mostly involved the lungs (11) and liver (10). Follow-up information was available in 14 patients, all of whom received cisplatin-based chemotherapy. All 6 pure CC patients were dead of disease (range, 6 to 14 mo, median 9.5 mo). Follow-up of 8 patients with predominant CC (range, 10 to 72 mo, median 27 mo) showed that 5 died of the disease, and 1 was alive with disease and 2 were alive with no evidence of disease at 60 and 72 months of follow-up, respectively; these latter 2 patients were the only ones with M1a disease on presentation. This series confirms the proclivity for high-stage presentation including presence of distant metastasis, hematogenous spread, and poor outcome of testicular CC. Mixed GCT with a predominant CC component has similar tendency for high-stage presentation, marked elevation of serum β-hCG levels, and aggressive behavior compared with pure CC. This study also showed that distant metastasis by CC when only involving the lungs (M1a) may not be uniformly fatal with chemotherapy. The mononucleated trophoblastic columns in testicular CC appear to be a mixture of cytotrophoblasts and intermediate trophoblasts, similar to that described in gestational CC.

Bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. There is debate and uncertainty in the literature regarding the clinicopathologic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. Use of the World Health Organization 2004/International Society of Urological Pathology 1998 grading nomenclature and recent molecular studies highlight certain unique features of bladder urothelial neoplasms in young patients, particularly in patients below 20 years of age. In this meta-analysis and review, the clinical, pathologic, and molecular features and risk factors of bladder urothelial neoplasms in patients 40 years or less are presented and analyzed according to decades of presentation. Similar to older patients, bladder urothelial neoplasms in patients 40 years or younger occur more common in male patients, present mainly with gross painless hematuria, and are more commonly located at bladder trigone/ureteral orifices, but in contrast have a greater chance for unifocality. Delay in diagnosis of bladder urothelial neoplasms seems not to be uncommon in younger patients probably because of its relative rarity and the predominance of benign causes of hematuria in this age group causing hesitancy for an aggressive work-up. Most tumors in patients younger than 40 years were low grade. The incidence of low-grade tumors was the lowest in the first 2 decades of life, with incremental increase of the percentage of high-grade tumors with increasing age decades. Classification according to the World Health Organization 2004/International Society of Urological Pathology grading system identified papillary urothelial neoplasms of low malignant potential to be relatively frequent among bladder tumors of young patients particularly in the teenage years. Similar to grade, there was marked predominance of low stage tumors in the first 2 decades of life with gradual inclusion of few higher stage and metastatic tumors in the 2 older decades. Bladder urothelial neoplasms occurring in patients <20 years of age lack or have a much lower incidence of aberrations in chromosome 9, FGFR3, p53, and microsatellite instability and have fewer epigenetic alterations. Tumor recurrence and deaths were infrequent in the first 2 decades and increased gradually in each successive decade, likely influenced by the increased proportion of higher grade and higher stage tumors. Our review of the literature shows that urothelial neoplasms of the bladder occurring in young patients exhibit unique pathologic and molecular features that translate to its more indolent behavior; this distinction is most pronounced in patients <20 years. Our overall inferences have potential implications for choosing appropriate noninvasive diagnostic and surveillance modalities, whenever feasible, and for selecting suitable treatment strategies that factor in quality of life issues vital to younger patients.

The vast majority of urachal epithelial neoplasms are adenocarcinomas with several described morphologic subtypes that include both enteric and nonenteric histologies. Adenocarcinoma from several other primaries may mimic any of these urachal adenocarcinoma subtypes in the bladder or at distant sites. However, data regarding the immunohistochemical profile of urachal carcinoma are limited, let alone its correlation with the different histologic subtypes that may have implications in the differential diagnostic workup with their morphologic mimics. Herein, we performed an immunohistochemical analysis in a broad spectrum of 39 urachal epithelial neoplasms (34 adenocarcinomas, 1 urothelial carcinoma, and 4 noninvasive mucinous cystic tumors), 13 urachal remnants, and 6 secondary colonic adenocarcinomas of the bladder, using an antibody panel that included novel and traditional gastrointestinal tract-associated markers. Expression levels of p63, CK7, CK20, CDX2, nuclear β-catenin, claudin-18, and Reg IV in urachal adenocarcinoma were as follows: 3%, 50%, 100%, 85%, 6%, 53%, and 85%. In urachal adenocarcinoma subtypes, expression levels of CDX2, nuclear β-catenin, claudin-18, and Reg IV were as follows: mucinous (8/8, 0/8, 6/8, 8/8), enteric (10/11, 1/11, 3/11, 8/11), not otherwise specified (5/7, 0/7, 3/7, 5/7), and signet ring cell (4/6, 0/6, 4/6, 6/6) type. All urachal adenocarcinomas had membrano-cytoplasmic β-catenin staining and only 2 tumors had nuclear localization that were focal to moderate, in contrast to secondary colonic adenocarcinoma of the bladder, which mostly had both membrano-cytoplasmic and nuclear positivity. Claudin-18 positivity was observed only in frankly malignant tumors and not in noninvasive urachal tumors and urachal remnants. Reg IV expression seemed to be related to mucin production, which was often diffuse in mucinous and signet ring cell subtypes and focal in enteric subtype, with goblet cell-like reactivity similar to secondary colonic adenocarcinoma. p63 expression was present in urothelial urachal remnants (3/3) and contrasted with CDX2 expression seen in glandular (5/6) and mixed urothelial/glandular remnants (2/4). Thus, this study showed that CDX2 is expressed by urachal remnants of glandular type, noninvasive urachal mucinous cystic tumors and urachal adenocarcinomas, and can be diffuse in urachal adenocarcinomas, even without the classic enteric morphology. Nuclear localization of β-catenin can rarely occur in urachal adenocarcinoma; however, diffuse nuclear reactivity argues against its diagnosis. The novel gastrointestinal tract markers claudin-18 and Reg IV are both expressed in urachal adenocarcinoma, including in signet ring cell carcinoma, and thus refutes the suggested specificity for gastrointestinal tract signet ring cell carcinomas. An immunohistochemical panel that includes β-catenin and CK7 may have value in differentiating urachal adenocarcinoma of enteric morphology from colonic adenocarcinoma. Overall, this study suggests that the different morphologic presentations of urachal adenocarcinomas have a relatively similar or overlapping immunophenotype. Knowledge of the similarity in immunostaining to its different morphologic mimics may help avoid misdiagnosis in urachal adenocarcinoma.

The vast majority of malignant urachal epithelial tumors have a glandular morphology (ie, adenocarcinoma), to which our principal understanding of urachal carcinoma and its prevailing set of diagnostic criteria are largely ascribed. The 2004 World Health Organization classification of genitourinary tumors recognizes other rarer histologic types of urachal carcinomas such as urothelial, squamous cell, and other carcinomas. However, the clinicopathologic data for these nonglandular groups of urachal carcinomas are very limited, being detailed only in sporadic case reports. Some of the criteria recommended for pathologic confirmation of urachal carcinomas were formulated almost exclusively for urachal adenocarcinoma and may not be relevant or applicable for nonglandular tumors. Here, we present 7 examples of pure (5) and mixed predominant (2) nonglandular urachal carcinomas. Patients were 45 to 85 years of age (mean, 64.1) with a male predominance (male-to-female ratio=6:1). Six tumors were related to the bladder [dome (3) or dome/supravesical (3)] and 1 was entirely supravesical. Histologically, 5 were urothelial carcinomas, of pure or mixed histology, all were high grade and invasive, and 2 were small cell carcinomas. Two urothelial carcinomas had focal (<5%) glandular differentiation and signet ring cell change, and 1 had admixed focal malignant squamous cells and high-grade dedifferentiated components. Four of 5 urachal urothelial carcinomas exhibited solid and partly cavitary or luminal growth with papillary structures and a variable amount of necrosis within the cavity. The 2 small cell carcinomas were pure, had classic undifferentiated neuroendocrine histology, were situated at the bladder dome, and were partly cavitary filled with necrotic debris. Urachal remnant was identified in 6 tumors mainly with dysplastic transitional cells in the urachal canal or rudimentary nests and tubules. All 6 bladder-related urachal tumors exhibited reverse invasive front from the surface, including 2 tumors that ulcerated the bladder mucosa. One tumor had concomitant in situ and noninvasive high-grade papillary urothelial carcinomas in the main bladder lumen. Sheldon stages at presentation were IIIA (2), IVA (3), and IVB (2). Follow-up in all 7 cases (<1 to 60 mo; median, 12.5 mo) showed that 6 patients had died of disease, including the 2 patients with small cell carcinoma. In conclusion, nonglandular urachal carcinoma may occur with pure histology or admixed with high-grade dedifferentiated morphologies and a minor adenocarcinoma component. These tumors may arise as deep-seated bladder-related or completely supravesical tumors along the urachal tract and may exhibit reverse invasive spread toward the bladder surface. Cavitary or luminal growth may occur that could be attributed to the intraurachal neoplastic proliferation. Urachal urothelial carcinomas in particular may contain papillary structures within the tumor and urachal cavity. Concomitant primary urothelial carcinoma outside of the urachus and tumor extension to bladder mucosa may occur, which should not negate diagnosis of an urachal primary. Behavior appears poor, as most tumors present with higher stage.