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Accurate recognition of Gleason pattern 5 (GP5) prostate adenocarcinoma (PCa) on core biopsy (NBX) is critical because it is associated with disease progression and the worst clinical outcome. We evaluated 1557 consecutive and prospectively collected NBXs to determine the frequency of diagnosis, morphologic subpatterns, and their relation to the amount and pattern distribution of GP5 PCa based on the 2005 modified Gleason grading system. Tertiary GP5 was upgraded to a secondary pattern to derive the final Gleason score. GP5 accounted for 6% of all NBXs and 14% of PCa cases. GP5 PCas were associated with high-risk preoperative clinical and biopsy characteristics, regardless of the amount of GP5. Most patients (85%) with % GP5 greater than 5% of PCa had the final Gleason score of 9 to 10, compared with % GP5 of 5% or less of PCa (P < .0001). The morphologic subpatterns of GP5 PCas were as follows: infiltrating cords (96%), single cells (76%), solid sheets (29%), and comedocarcinoma (2%). Infiltrating cords and single-cell patterns frequently coexisted (76%). The GP5 was distributed in a tertiary (66%), followed by secondary (32%) and primary (2%) components of PCa. Infiltrating cords and single cells were the 2 most frequently encountered patterns, specifically when GP5 involved 5% or less of PCa and represented secondary or tertiary component of PCa. GP5 PCa is a relatively frequent presentation in the contemporary NBX practice. Because of its important prognostic and therapeutic implications, pathologists must be aware of its varied morphologic presentations and to the fact that most cases with GP5 represent a tertiary component of PCa.

Immunohistochemical (IHC) staining for ERG is used as a surrogate for TMPRSS2-ERG gene fusion, a specific molecular event seen in ~50% of prostate carcinomas (PCas) and ~20% of high-grade prostatic intraepithelial neoplasia (HGPIN) intermingled with adjacent PCa demonstrating identical gene fusions. We studied 84 "atypical glands suspicious for cancer (ATYP)" cases using multiplex ERG/α-methylacyl-CoA-racemase (AMACR)/high-molecular-weight cytokeratin/p63 IHC to determine how often ERG contributes to resolving an ATYP diagnosis beyond that provided by AMACR and basal markers. Final diagnoses of benign, ATYP, and cancer were rendered after review of morphology and all markers in 3, 30, and 51 cases, respectively. Of 51 cancer diagnoses, 45% and 94% were positive for ERG and AMACR, respectively. Of 30 atypical diagnoses, 10% and 67% were positive for ERG and AMACR, respectively. Of 3 benign diagnoses, none and 83% were positive for ERG and AMACR, respectively. Three ERG-positive atypical cases were classified as "HGPIN with adjacent ATYP." ERG was expressed in adjacent noncancer glands of 20% of PCas, whereas AMACR was expressed in noncancer glands in all diagnostic categories in 40% of cases. Positive ERG staining helped establish the initial ATYP diagnosis to PCa in 28% cases whose diagnoses would otherwise remain ATYP based on AMACR and basal markers. ERG positivity in small atypical glands where HGPIN diagnosis is excluded helps establish a definitive cancer diagnosis in a small proportion of additional ATYP cases. We recommend judicious use of ERG, preferably as a component of multiplex IHC, in evaluation of difficult prostate biopsies.

To better represent the Gleason score of radical prostatectomy, the International Society of Urologic Pathologists Consensus Committee recommends assigning individual Gleason scores to prostate cancer cores submitted in separate containers and/or multiple cores in the same container with site identifiers. However, scenarios where multiple cores are submitted in the same container without site identifiers or labeled "left/right" are common. To assess this scenario, we analyzed 110 extended biopsies containing different Gleason scores with corresponding radical prostatectomy for clinically significant grade differences. Because cores are individually labeled and submitted at our institution, we simulated a scenario of multiple intact cores with different Gleason scores in the same container(s) by analyzing as if submitted in containers labeled "left/right." For each biopsy, a Global (all positive cores averaged as 1 long positive core), Worst, and Largest tumor volume Gleason score was determined and compared with grade of radical prostatectomy using kappa statistics. Biopsies containing core(s) with 3+4 and other core(s) 3+3 were excluded because in this situation, both Global and Worst Gleason score will be always 3+4. The following scenarios were considered clinically significant upgrading: biopsy Gleason score 6 / 3+4 to radical prostatectomy 4+3; biopsy 7 to radical prostatectomy 8-10; biopsy 7 to radical prostatectomy 7 with tertiary Gleason pattern 5. Overall, 51 cases met inclusion criteria. Biopsy Worst Gleason score had the best correlation with radical prostatectomy (kappa agreement of 0.37). Clinically significant upgrading at radical prostatectomy was least with Worst (4%) and highest with Global Gleason score (37%). Upgrading and downgrading were noted in 14% and 8%, respectively, of 59 cases containing core(s) with a Gleason score of 3+4 and other core(s) 3+3, suggesting that any amount of higher Gleason pattern should be recorded. When multiple intact cores are submitted in the same container without specific identifiers, individual cores with cancer should be graded and/or the Worst Gleason score should be recorded.

Papillary renal cell carcinoma (PRCC), a morphologically and genetically distinct subtype of RCC, is morphologically separated into 2 subtypes, type 1 and 2, for prognostic purposes. Type 1 PRCC (single layer of small cells, scant pale cytoplasm) is more common and has a favorable prognosis compared with type 2 (pseudostratified high-grade nuclei, abundant eosinophilic/oncocytic cytoplasm). We report the clinicopathologic, immunohistochemical, and molecular data of 7 adult papillary tumors with morphological features distinct from type 1 or 2 PRCC. All tumors demonstrated predominant papillary architecture, lined by cells with oncocytic cytoplasm, and nonoverlapping low Fuhrman grade nuclei (1 or 2). Foamy macrophages were noted in 2 of 7 tumors. No case demonstrated necrosis or psammoma bodies. Most tumors (6/7) were small (mean size, 2.0 cm; range, 0.8-5.7 cm) and limited to the kidney. No tumor recurrence or metastasis was identified (median follow-up, 22 months). All tumors demonstrated trisomy for 7 and 17 by fluorescence in situ hybridization analysis and uniform CK 7, CD10, and alpha-methylacyl-coenzyme A racemase expression, characteristic of PRCC. These results suggest that these tumors are distinct from type 1 (owing to oncocytic cells) and type 2 (owing to low-grade nonstratified nuclei, low stage, and good outcome). Awareness of this favorable spectrum of PRCC is important to avoid its potential misinterpretation as an aggressive type 2 PRCC (owing to oncocytic cells) or rarely as an oncocytoma (owing to oncocytic cells and low-grade nuclei). Morphologic spectrum of these PRCCs emphasizes that the future prognostic model of PRCC may need to be based primarily on the nuclear characteristics, irrespective of the cytoplasmic features.

ERG and PTEN biomarkers are increasingly being analyzed on prostate core biopsies (NBXs); ERG as a marker of clonality and number of separately arising tumor foci and PTEN for prognostic information. Yet, in patients with multiple biopsy cores positive for cancer (PCa), there is no standardized approach for interrogation of these biomarkers in terms of the number of positive cores to evaluate. A total of 194 NBX cases containing more than one positive core with cancer were evaluated for ERG overexpression and PTEN loss by immunostaining (immunohistochemistry) of all positive cores. ERG overexpression or PTEN loss in at least one cancer core was present in 111 (57%) and 69 (36%) cases respectively. ERG overexpression was significantly associated with PTEN loss (P < .0001), and PTEN loss was associated with a high Gleason score (P < .0001). Inter- and intra-tumor core staining heterogeneity for ERG overexpression occurred in 42% and 5% cases and for PTEN loss both intra- and inter-tumor core heterogeneity was 68%. PTEN staining was highly discordant between PCa sites regardless of laterality. When the Gleason score was non-uniform across PCa sites, the combination of cores showing the highest Gleason score and largest tumor volume provided the best representation of ERG overexpression (92%) and PTEN loss (98%). When grades were uniform across cancer sites, the highest tumor volume core was generally representative of ERG overexpression (90%) but was less representative for PTEN loss (76%). Our results suggest that knowledge of this heterogeneity is critical for developing optimal yet cost-effective strategies to identify these underlying molecular abnormalities.

Nested urothelial carcinoma (UC) is a rare histologic variant of UC, characterized by deceptively bland histologic features resembling von Brunn's nests but usually with a poor outcome. In our experience, this variant is frequently misclassified or underrecognized as its clinicopathologic spectrum is not well defined. In addition, its relationship to usual UC and response to traditional bladder cancer management are largely unknown. Herein we report the largest series to date of 30 UC cases with pure or predominant nested morphology to identify its associated histopathologic findings, clinical outcome, and immunophenotype. Patient age ranged from 41 to 83 years (average, 63 years) with a male-female ratio of 2.3:1. The architectural pattern of the nested component ranged from a predominantly disorderly proliferation of discrete, small, variably sized nests (90%) to focal areas demonstrating confluent nests (40%), cordlike growth (37%), and cystitis cystica-like areas (33%) to tubular growth pattern (13%). The deep tumor-stroma interface was invariably (100%) jagged and infiltrative. Despite overall banal cytology, tumor nests demonstrated focal random cytologic atypia (90%) and focal high-grade cytologic atypia centered within the base of the tumor (40%). The tumor stroma ranged from having minimal stromal response to focally desmoplastic and myxoid. A component of usual UC was present in 63% of cases. The nested component demonstrated an immunophenotype identical to usual UC, with CK7, CK20, p63, and CK903 expression in 93%, 68%, 92%, and 92% of cases, respectively. At resection, all but 1 case demonstrated invasive carcinoma-9% into lamina propria, 4% into muscularis propria, 65% into perivesical fat, and 17% into adjacent organ(s). When compared with pure high-grade UC, nested UC was associated with muscle invasion at transurethral resection (31% versus 70%; P < .0001), extravesical disease at cystectomy (33% versus 83%; P < 0.0001), and metastatic disease (19% versus 67%; P < .0001). Follow-up was available on 29 patients (97%) with a median of 12 months (range, 1-31 months) of follow-up; 3 (10%) died of disease, 16 (55%) are alive with persistent or recurrent disease, and 10 (34%) are alive without disease. Response to neoadjuvant chemotherapy was observed in 2 (13%) of 15 patients. Nested UC seen either in pure form or with a component of usual UC had similarly unfavorable outcomes (P = .78). Increased awareness and familiarity with the clinicopathologic spectrum is critical for confident recognition and adequate management of this very aggressive variant of UC.

Distinguishing aggressive prostate cancer from indolent disease represents an important clinical challenge, because current therapy may lead to overtreatment of men with limited disease. The prostate-specific membrane antigen (PSMA) is a membrane-bound glycoprotein that is highly restricted to the prostate. Previously, studies analyzing the expression of PSMA have found an up-regulation in correlation with prostate cancer, particularly in advanced cancer. This association is ideal for an application as a prognostic marker. In the current study, we characterized PSMA expression in a high-risk cohort and evaluated its potential use as predictive marker of prostate-specific antigen (PSA) recurrence. PSMA expression was analyzed by immunohistochemistry using tissue microarrays composed of tumor samples from 450 patients. Protein intensity was recorded using a semiautomated quantitative microscope system (ACIS II; Clarient Chromavision Medical Systems, San Juan Capistrano, CA). PSMA expression levels differed significantly (P.001) between benign prostatic tissue, localized prostate cancer, and lymph node metastases. Dividing the cohort into high- and low-PSMA expressing cancers based on the median area of positive staining, we found that high PSMA levels were associated with significant increase of PSA recurrence (P = .004). This was independent of clinical parameters such as lymph node tumor burden (lymph node density,20%; P.001), extraprostatic extension (P = .017), seminal vesicle invasion (P.001), and high Gleason score (8-10, P = .006). In a multivariate model, PSMA expression and metastases to pelvic lymph nodes were significantly associated with time to PSA recurrence (HR, 1.4; 95% confidence interval, 1.1-2.8, P = .017; and hazard ratio, 5; 95% confidence interval, 2.6-9.7, P.001, respectively). In summary, PSMA is independently associated with PSA recurrence in a high-risk cohort and thus might provide insight into the additional use of adjuvant therapy. Validation on other cohorts is required.

With increasing sophistication of imaging modalities, many small indeterminate renal masses are detected, posing therapeutic dilemmas. Minimally invasive techniques such as radio frequency ablation (RFA) and cryotherapy are increasingly used in such settings, making it essential to classify renal mass in biopsies. We evaluated indications, adequacy, spectrum, and limitations of pathological diagnoses in 52 (79%) of 66 adequate biopsies that impacted management by having conservative therapy (less than total nephrectomy). Indication for biopsies in this group was exclusively for indeterminate mass. Biopsies were categorized as 52% clear cell renal cell carcinoma (RCC); 11% papillary RCC; 23% oncocytic neoplasms, subdivided as oncocytoma (10), chromophobe RCC (1), and cannot rule out RCC (1); 8% spindle cell neoplasms; 2% round blue cell tumors; and 4% inflammatory. After biopsy, 29% underwent nephron-sparing surgery, 36% underwent RFA, and 35% were followed up with observation only. One (2%) unresolved oncocytic neoplasm proved to be a chromophobe RCC in the total nephrectomy. Of the 19 patients, 15 who underwent RFA after diagnostic biopsy subsequently underwent post-RFA biopsy to assess therapy response. Complete ablation at first attempt was achieved in 12 of 15 patients. In contemporary urological practice, biopsies are increasingly performed for incidentally detected renal mass to influence the clinical management. Most biopsies can be classified into clinically relevant categories; however, caution is advised while interpreting oncocytic neoplasms because sampling and tumor heterogeneity may adversely affect interpretation.