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The College of American Pathologists Cancer Protocols have offered guidance to pathologists for standard cancer pathology reporting for more than 35 years. The adoption of computer readable versions of these protocols by electronic health record and laboratory information system (LIS) vendors has provided a mechanism for pathologists to report within their LIS workflow, in addition to enabling standardized structured data capture and reporting to downstream consumers of these data such as the cancer surveillance community. This paper reviews the history of the Cancer Protocols and electronic Cancer Checklists, outlines the current use of these critically important cancer case reporting tools, and examines future directions, including plans to help improve the integration of the Cancer Protocols into clinical, public health, research, and other workflows.

Objectives. To compare the clinicopathologic characteristics of urothelial carcinoma (UC), urothelial carcinoma with squamous differentiation (UCSD), and squamous cell carcinoma (SCC) of the bladder, which have been suggested to differ in terms of risk factors, immunophenotype, and prognosis. Methods. We evaluated the clinicopathologic features of radical cystectomy specimens between 1980 and 2015 with a diagnosis of SCC, UCSD, and UC. PD-L1 immunohistochemistry (clinically available clones 22C3, SP142, and SP263) was performed on SCC and UCSD. Multivariate Cox regression was used to identify prognostic factors. Kaplan–Meier curves were plotted to assess cancer-specific survival (CSS). Results. Of the 1478 cases, there were 1126 UC (76%), 217 UCSD (15%), and 135 SCC (9%). Bladder cancer was more common in men than women (80% vs 20%, P pT2) at the time of cystectomy (UCSD-74%, SCC 71%, UC-44%, P

Outcomes for men with localized prostate cancer vary widely, with some men effectively managed without treatment on active surveillance, while other men rapidly progress to metastatic disease despite curative‐intent therapies. One of the strongest prognostic indicators of outcome is grade groups based on the Gleason grading system. Gleason grade 4 prostate cancer with cribriform morphology is associated with adverse outcomes and can be utilized clinically to improve risk stratification. The underpinnings of disease aggressiveness associated with cribriform architecture are not fully understood. Most studies have focused on genetic and molecular alterations in cribriform tumor cells; however, less is known about the tumor microenvironment in cribriform prostate cancer. Cancer‐associated fibroblasts (CAFs) are a heterogeneous population of fibroblasts in the tumor microenvironment that impact cancer aggressiveness. The overall goal of this study was to determine if cribriform prostate cancers are associated with a unique repertoire of CAFs. Radical prostatectomy whole‐tissue sections were analyzed for the expression of fibroblast markers (ASPN in combination with FAP, THY1, ENG, NT5E, TNC, and PDGFRβ) in stroma adjacent to benign glands and in Gleason grade 3, Gleason grade 4 cribriform, and Gleason grade 4 noncribriform prostate cancer by RNAscope®. Halo® Software was used to quantify percent positive stromal cells and expression per positive cell. The fibroblast subtypes enriched in prostate cancer were highly heterogeneous. Both overlapping and distinct populations of low abundant fibroblast subtypes in benign prostate stroma were enriched in Gleason grade 4 prostate cancer with cribriform morphology compared to Gleason grade 4 prostate cancer with noncribriform morphology and Gleason grade 3 prostate cancer. In addition, gene expression was distinctly altered in CAF subtypes adjacent to cribriform prostate cancer. Overall, these studies suggest that cribriform prostate cancer has a unique tumor microenvironment that may distinguish it from other Gleason grade 4 morphologies and lower Gleason grades.

Objective To evaluate the clinical features, pathologic features, and prevalence of human papilloma virus (HPV) in squamous cell carcinoma (SCC) of the bladder. SCC of the bladder is known to be associated with conditions that cause chronic inflammation/irritation. The literature is inconsistent regarding the association of HPV with pure SCC of the bladder. Methods A multi-institutional study identified cases of SCC of the bladder. Pure squamous histology and the absence of urothelial carcinoma in situ were required for inclusion. Clinical and pathologic features were collected, and tissues were evaluated for high-risk HPV using p16 immunohistochemistry and in situ hybridization. Results We identified 207 cases of SCC of the bladder. Risk factors for bladder cancer included smoking (133/207, 64%) and chronic bladder irritation (83/207, 40%). The majority (155/207, 75%) of patients had > pT2 disease. Mean tumor size was 5.6 ± 3.0 cm and 36/207 (17%) patients had lymph node positive disease. p16 immunohistochemistry was positive in 52/204 (25%) cases but high-risk HPV was identified with in situ hybridization in only 1 (0.5%) case. Tumor size, stage, number of lymph nodes removed, number of positive lymph nodes, lymphovascular invasion, perineural invasion, and positive margins each were associated with cancer-specific mortality when adjusted for demographic factors. A multivariate analysis of variable importance further revealed sex and race as important factors in predicting cancer-specific mortality. Conclusion SCC of the bladder is an aggressive histologic subtype. Although bladder SCC can express p16, it is not typically associated with high-risk HPV, although rare cases can occur.

Our objective was to evaluate the pathologic features and clinical outcomes in cases of invasive penile squamous cell carcinoma (SCC) and the association with p16 immunohistochemistry (IHC) and human papilloma virus (HPV) in situ hybridization (ISH). A retrospective multi-institutional database search was conducted for invasive SCC of the penis diagnosed between 2007 and 2018 that had undergone surgical resection. Pathologic features, p16 IHC, and HPV ISH were investigated with clinical outcomes. A total of 102 patients were included in the study. The average age was 63 ± 13.3 years. Based on histology, 46% of tumors displayed an HPV-related subtype, whereas p16 was positive in 52% of all cases. Tumor histology correlated well with p16 positivity (P .001), and p16 IHC accurately predicted the presence of HPV in 25/26 (96%) cases. On multivariate analysis, perineural invasion was associated with local disease recurrence (P = .02), whereas lymphovascular invasion was associated with progression to metastatic disease (P = .002) and increased overall mortality (P = .02). Urethral involvement was also associated with increased overall mortality (P = .02). In addition, HPV-related tumors based on histologic features correlated with lower rates of metastatic disease (P = .007). HPV is a common cause of penile SCC and can be diagnosed by tumor histology and confirmed by overexpression of p16 on IHC. The presence of lymphovascular invasion, perineural invasion, and urethral involvement are poor prognostic indicators, whereas HPV-related tumors based on histology may have lower risk for metastatic disease.

Cribriform prostate cancer, found in both invasive cribriform carcinoma (ICC) and intraductal carcinoma (IDC), is an aggressive histological subtype that is associated with progression to lethal disease. To delineate the molecular and cellular underpinnings of ICC/IDC aggressiveness, this study examines paired ICC/IDC and benign prostate surgical samples by single-cell RNA-sequencing, TCR sequencing, and histology. ICC/IDC cancer cells express genes associated with metastasis and targets with potential for therapeutic intervention. Pathway analyses and ligand/receptor status model cellular interactions among ICC/IDC and the tumor microenvironment (TME) including JAG1/NOTCH. The ICC/IDC TME is hallmarked by increased angiogenesis and immunosuppressive fibroblasts (CTHRC1+ASPN+FAP+ENG+) along with fewer T cells, elevated T cell dysfunction, and increased C1QB+TREM2+APOE+-M2 macrophages. These findings support that cancer cell intrinsic pathways and a complex immunosuppressive TME contribute to the aggressive phenotype of ICC/IDC. These data highlight potential therapeutic opportunities to restore immune signaling in patients with ICC/IDC that may afford better outcomes.

Mismatch repair (MMR) deficiency is commonly caused by functional inactivation of MLH1, PMS2, MSH2 or MSH6. The morphological and molecular correlates of MMR deficiency have been extensively characterized in certain tumour types such as colorectal and endometrial adenocarcinoma. In contrast, the histological and molecular features of MMR-deficient prostate cancer remain incompletely described. In this study, we evaluated 19 MMR-deficient prostate cancers, including 11 cases without prior systemic treatment.All treatment-naive cases (11 of 11, 100%) were grade group 4-5 and had predominant cribriform and/or solid growth patterns. Solid components (any amount) and tumour infiltrating lymphocytes were 7 cases each (7 of 11, 64%). In 68 MMR-proficient grade group 5 prostate cancers, predominant cribriform or solid growth patterns, solid components (any amount) and tumour infiltrating lymphocytes were seen at significantly lower frequencies (31 of 68, 46%; 9 of 68, 13% and 6 of 62, 9%, respectively; P 0.001 for all comparisons). Molecular evaluation of 19 cases demonstrated that MMR-deficiency was secondary to functional loss of MSH2/MSH6 and MLH1/PMS2 in 15 (79%) and 4 cases (21%), respectively. Definite or probable germline mutations were present in 4 cases (4 of 19, 21%). TMPRSS2::ERG rearrangements were identified in 2 cases (2 of 19, 11%). Recurrent cancer-relevant somatic mutations included (but were not limited to) ATM, TP53, FOXA1, RB1, BRCA2 and PTEN.MMR deficiency was most commonly secondary to inactivation of MSH2/MSH6 in this study. Importantly, MMR-deficient high-grade prostatic adenocarcinomas had morphological features that might be useful to identify selected cases for MMR immunohistochemistry.

Urinary diversion and reconstructive urologic procedures are most often performed by incorporating various intestinal segments into the urinary tract. Although the risk of malignancy, among other complications, is well recognized and occurs most frequently after ureterosigmoidostomies and cystoplasties, data on the histopathologic and immunohistochemical characteristics of these tumors are scant. This study aims to evaluate the clinicopathological features of secondary tumors arising after urologic reconstruction procedures. Eleven cases were identified among five collaborating academic institutions. The average age was 51.7 years, and the M:F ratio was 8:3. Surgical procedures included 7 ileal conduits, 2 gastrocystoplasties, 1 augmentation cystoplasty not otherwise specified (NOS), and 1 Indiana pouch. Median time from reconstruction to malignancy was 36 years. Malignancy included adenocarcinoma in 10 patients (intestinal type in 6, gastric in 2, signet-ring cell in 1, undetermined type after neoadjuvant treatment in 1) and squamous cell carcinoma in 1. By immunohistochemistry, the adenocarcinomas were CK7 (45%), CK20 (89%), CK903 (78%), CDX2 (89%), SATB2 (67%), and beta-catenin (100%) positive. GATA-3 was negative in all cases. Pathologic stage was T1 (30%), T2 (40%), T3 (20%), and T4 (10%). Regional lymph node and distant metastasis were present in 60% and 20%, respectively. Treatment included multimodality therapy in most patients. On follow-up (mean, 27.4 months), 2 patients were dead (1 of disease), 3 were alive with disease, 4 were alive without disease, and 2 were lost to follow-up. Secondary malignancy arising within urologic reconstruction is rare, most frequently has adenocarcinoma morphology, presents late, and behaves aggressively.

Penile intraepithelial neoplasia (PeIN) is classified as human papillomavirus (HPV)- and non-HPV-related. This classification is associated with distinct morphologic subtypes. The natural history and prognosis of PeIN subtypes are not well known. This study aims to evaluate clinicopathological features, HPV status, and outcome of PeIN subtypes. Eighty-two lesions from 64 patients with isolated PeIN were retrospectively reviewed. Mean age was 59 years. Lesions were multicentric in 34% of patients and affected glans (33%), shaft (26%), and foreskin (20%). Histologically, 22% of patients had coexisting lesions, classified as hybrid and mixed. HPV-related PeIN (97%) included basaloid (59%), warty (8%), warty-basaloid (8%), hybrid (19%) and mixed (3%) types. P16 and HPV positivity occurred in 99% and 82% of lesions, respectively. HPV 16 was more common in basaloid PeIN. Multiple genotypes were detected in 35%, more commonly in hybrid PeIN (P = 0.051). Positive margins occurred in 63% of excisions. PeIN recurred in 48% of excisions and 30% of overall repeated procedures, and progression to invasive carcinoma occurred in 2%. At follow-up, 86% of patients had no evidence of disease and 12% were alive with disease. Lichen sclerosus occurred in non-HPV and HPV-related PeIN (100% and 47%).In conclusion, HPV-related and, more specifically basaloid PeIN were the predominant types and preferentially associated with HPV 16. While PeIN had a high recurrence rate, there was a slow and infrequent progression to invasive or metastatic carcinoma with multimodal treatments. Additional studies are needed to understand biology and natural history of PeIN.

We identified an unusual pattern of renal tubular proliferation associated with chronic renal disease, found in 23 patients, diffusely (n=12), or focally (n=11). Incidence was 5% of end-stage renal disease kidneys from one institution (8/177) and 7/23 patients with acquired cystic kidney disease-associated renal cell carcinoma from another. Most (19 patients) had 1 or more neoplasms including papillary (n=9), acquired cystic kidney disease (n=8), clear cell (n=4), or clear cell papillary (n=3) renal cell carcinoma. All (20 men, 3 women) had end-stage renal disease. The predominant pattern (n=18) was the indentation of chronic inflammation into renal tubules forming small polypoid structures; however, 5 had predominantly hyperplastic epithelium with less conspicuous inflammation. In 14 patients both patterns were appreciable, whereas the remainder had only the inflammatory pattern. Immunohistochemistry was positive for cytokeratin 7, high-molecular-weight cytokeratin, PAX8, and GATA3. Staining for alpha-methylacyl-CoA racemase was negative or weak, dramatically less intense than papillary neoplasms or proximal tubules. CD3 and CD20 showed a mixture of B and T lymphocytes in the inflammatory areas. Fluorescence in situ hybridization showed no trisomy 7 or 17 or loss of Y (n=9). We describe a previously uncharacterized form of renal tubular proliferation that differs from papillary adenoma (with weak or negative alpha-methylacyl-CoA racemase, lack of trisomy 7 or 17, and sometimes diffuse distribution). On the basis of consistent staining for high-molecular-weight cytokeratin and GATA3, we propose the name distal tubular hyperplasia for this process. Future studies will be helpful to assess preneoplastic potential and etiology.

Purpose: To survey urologic clinicians regarding interpretation of and practice patterns in relation to emerging aspects of prostate cancer grading, including quantification of high-grade disease, cribriform/intraductal carcinoma, and impact of magnetic resonance imaging-targeted needle biopsy. Materials and methods: The Genitourinary Pathology Society distributed a survey to urology and urologic oncology-focused societies and hospital departments. Eight hundred and thirty four responses were collected and analyzed using descriptive statistics. Results: Eighty percent of survey participants use quantity of Gleason pattern 4 on needle biopsy for clinical decisions, less frequently with higher Grade Groups. Fifty percent interpret "tertiary" grade as a minor/< 5% component. Seventy percent of respondents would prefer per core grading as well as a global/overall score per set of biopsies, but 70% would consider highest Gleason score in any single core as the grade for management. Seventy five percent utilize Grade Group terminology in patient discussions. For 45%, cribriform pattern would affect management, while for 70% the presence of intraductal carcinoma would preclude active surveillance. Conclusion: This survey of practice patterns in relationship to prostate cancer grading highlights similarities and differences between contemporary pathology reporting and its clinical application. As utilization of Gleason pattern 4 quantification, minor tertiary pattern, cribriform/intraductal carcinoma, and the incorporation of magnetic resonance imaging-based strategies evolve, these findings may serve as a basis for more nuanced communication and guide research efforts involving pathologists and clinicians. (C) 2020 Elsevier Inc. All rights reserved.

The severe acute respiratory syndrome Coronavirus-2 (SARS-CoV-2) pandemic has had devastating effects on global health and worldwide economy. Despite an initial reluctance to perform autopsies due to concerns for aerosolization of viral particles, a large number of autopsy studies published since May 2020 have shed light on the pathophysiology of Coronavirus disease 2019 (COVID-19). This review summarizes the histopathologic findings and clinicopathologic correlations from autopsies and biopsies performed in patients with COVID-19. PubMed and Medline (EBSCO and Ovid) were queried from June 4, 2020 to September 30, 2020 and histopathologic data from autopsy and biopsy studies were collected based on 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 58 studies reporting 662 patients were included. Demographic data, comorbidities at presentation, histopathologic findings, and virus detection strategies by organ system were collected. Diffuse alveolar damage, thromboembolism, and nonspecific shock injury in multiple organs were the main findings in this review. The pathologic findings emerging from autopsy and biopsy studies reviewed herein suggest that in addition to a direct viral effect in some organs, a unifying pathogenic mechanism for COVID-19 is ARDS with its known and characteristic inflammatory response, cytokine release, fever, inflammation, and generalized endothelial disturbance. This study supports the notion that autopsy studies are of utmost importance to our understanding of disease features and treatment effect to increase our knowledge of COVID-19 pathophysiology and contribute to more effective treatment strategies.

BackgroundClaudin-2 expression is upregulated in multiple cancers and promotes cancer malignancy. Remarkably, the regulation of claudin-2 expression in kidney cell lines contrasts its reported regulation in other organs. However, claudin-2 role in renal clear cell carcinoma (RCC) remains unknown despite its predominant expression in the proximal tubular epithelium (PTE), the site of RCC origin.MethodsPublicly available and independent patient databases were examined for claudin-2 association with RCC. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by Mass spectroscopy, immunoprecipitation and mutational studies, and functional evaluations.ResultsWe show that the significant decrease in claudin-2 expression characterized PTE cells and Ex-vivo cultured mouse kidney subjected to dedifferentiation. Inhibition of claudin-2 was enough to induce mesenchymal plasticity and invasive mobility in these models. Further, a progressive loss of claudin-2 expression associated with the RCC progression and poor patient survival. Overexpression of claudin-2 in RCC-derived cancer cells inhibited tumorigenic abilities and xenograft tumor growth. These data supported a novel tumor-suppressive role of claudin-2 in RCC. Mechanistic insights further revealed that claudin-2 associates with YAP-protein and modulates its phosphorylation (S127) and nuclear expression. The tumor suppressive effects of claudin-2 expression were lost upon deletion of its PDZ-binding motif emphasizing the critical role of the PDZ-domain in claudin-2 interaction with YAP in regulating RCC malignancy.ConclusionsOur results demonstrate a novel kidney specific tumor suppressive role for claudin-2 protein and further demonstrate that claudin-2 co-operates with the YAP signaling in regulating the RCC malignancy.

Context.— Controversies and uncertainty persist in prostate cancer grading. Objective.— To update grading recommendations. Data Sources.— Critical review of the literature along with pathology and clinician surveys. Conclusions.— Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace “tertiary grade pattern” in radical prostatectomy (RP) with “minor tertiary pattern 5 (TP5),” and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) “atypical intraductal proliferation (AIP)” is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

A 65-year-old male presented with a cystic scrotal mass that fluctuated in size. The cyst was associated with aberrant epididymal tissue and was found to have benign epithelial proliferations, with immunohistochemistry supporting a mesonephric origin (GATA3, CD10, and WT1 positive). Clinical presentation, imaging, and pathologic findings are described.

No well-established staging system exists for bladder leiomyosarcoma (LMS), and the current staging system does not include tumor size, a thoroughly validated prognostic parameter for sarcomas. Uterine and extremity/trunk LMS are more common than those in the bladder and have well-established staging systems incorporating tumor size. We aim to improve the understanding of LMS of the urinary bladder by assessing cancer-specific survival (CSS) and comparing LMS at this unusual anatomic site to those arising at other sites using the Surveillance, Epidemiology, and End Results (SEER) database. The SEER database (1973-2013) was queried for bladder, uterus, and trunk/extremity LMS. Multivariable Cox proportional hazard regression was performed to identify predictors of CSS for each anatomic location and used to compare outcomes at different sites. We identified 165 bladder, 4987 uterus, and 2536 extremity/trunk LMS cases. Five-year CSS was 52% for uterus, 73% for bladder, and 82% for extremity/trunk LMS. For LMS at all sites, uterine location (HR = 2.14, P 0.001) and increasing tumor size (HR = 1.05, P 0.001) were significant predictors of worse CSS on multivariate analysis. For bladder LMS, increasing tumor size (HR = 1.18, P = 0.003) was an independent prognostic factor and the conventional staging cut-off threshold of 5 cm for sarcomas outside the head/neck showed statistical significance in stratifying patient risk of cancer-related death. Bladder LMS appears to have clinical behavior intermediate between those of the extremities/trunk and uterus. We suggest that the conventional sarcoma staging protocols based on tumor size be applied to LMS of the urinary bladder.

The differential diagnosis of glandular lesions of the bladder/urinary tract can be challenging because of significant morphologic and immunohistochemical overlap between primary lesions and metastasis/direct extension from adjacent organs. Special AT-rich sequence-binding protein 2 (SATB2), encoded on chromosome 2q32-33, is a recently described DNA-binding protein involved in osteoblast lineage commitment and expressed in colorectal and appendiceal neoplasms. In this study, we hypothesized that immunohistochemistry for SATB2 may be of value in distinguishing primary adenocarcinoma of the bladder/urinary tract and urothelial carcinoma with glandular differentiation from gastrointestinal and endocervical primaries. Intensity and distribution of SATB2 nuclear labeling were semiquantitatively scored and compared with those of CDX2. The study included 43 primary adenocarcinomas of the bladder/urinary tract, 20 urothelial carcinomas with glandular differentiation, 26 adenocarcinomas of the uterine cervix, and 22 colorectal adenocarcinomas involving the bladder. Positive SATB2 immunostaining was observed in 21 of 43 (49%) primary bladder/urinary tract adenocarcinomas, in 17 of 22 (77%) colorectal adenocarcinomas, and in the glandular component of 4 of 18 (22%) urothelial carcinomas with glandular differentiation. SATB2 was negative in 25 of 26 endocervical adenocarcinomas and showed focal weak immunostaining (1+) in 1 of 26 (4%). The results were not significantly different from those seen with CDX2. We conclude that SATB2 immunohistochemistry is not useful in supporting urothelial versus gastrointestinal or endocervical origin in the differential diagnosis of glandular lesions of the bladder/urinary tract.

OBJECTIVES Primary carcinoid tumor of the renal pelvis is a rare neoplasm with few cases reported in the literature. Here we present the clinical and histopathologic findings of a primary carcinoid tumor arising in the left renal pelvis of a horseshoe kidney in a 61-year-old female patient. MATERIALS AND METHODS Pathologic features were evaluated with standard hematoxylin and eosin sections and immunohistochemical studies. A literature review was performed to place our case in context to previous reports. RESULTS The tumor was associated with intestinal metaplasia with high-grade dysplasia and neuroendocrine hyperplasia. Molecular testing for microsatellite instability and loss of heterozygosity were negative. CONCLUSIONS This report portrays a unique presentation of carcinoid tumor arising from intestinal metaplasia of the pelvic urothelium, and supports its histogenesis from urothelial intestinal metaplasia and neuroendocrine hyperplasia.

BackgroundMost prostate cancers express androgen receptor (AR), and our previous studies have focused on identifying transcription factors that modify AR function. We have shown that nuclear factor I/B (NFIB) regulates AR activity in androgen-dependent prostate cancer cellsin vitro. However, the status of NFIB in prostate cancer was unknown.MethodsWe immunostained a tissue microarray including normal, hyperplastic, prostatic intraepithelial neoplasia, primary prostatic adenocarcinoma, and castration-resistant prostate cancer tissue samples for NFIB, AR, and synaptophysin, a marker of neuroendocrine differentiation. We interrogated publically available data sets in cBioPortal to correlateNFIBexpression and AR and neuroendocrine prostate cancer (NEPCa) activity scores. We analyzed prostate cancer cell lines for NFIB expression via Western blotting and used nuclear and cytoplasmic fractionation to assess where NFIB is localized. We performed coimmunoprecipitation studies to determine if NFIB and AR interact.ResultsNFIB increased in the nucleus and cytoplasm of prostate cancer samples versus matched normal controls, independent of Gleason score. Similarly, cytoplasmic AR and synaptophysin increased in primary prostate cancer. We observed strong NFIB staining in primary small cell prostate cancer. The ratio of cytoplasmic-to-nuclear NFIB staining was predictive of earlier biochemical recurrence in prostate cancer, once adjusted for tumor margin status. Cytoplasmic AR was an independent predictor of biochemical recurrence. There was no statistically significant difference between NFIB and synaptophysin expression in primary and castration-resistant prostate cancer, but cytoplasmic AR expression was increased in castrationresistant samples. In primary prostate cancer, nuclear NFIB expression correlated with cytoplasmic NFIB and nuclear AR, while cytoplasmic NFIB correlated with synaptophysin, and nuclear and cytoplasmic AR. In castration-resistant prostate cancer samples,NFIBexpression correlated positively with an AR activity score, and negatively with the NEPCa score. In prostate cancer cell lines, NFIB exists in several isoforms. We observed NFIB predominantly in the nuclear fraction of prostate cancer cells with increased cytoplasmic expression seen in castration-resistant cell lines. We observed an interaction between AR and NFIB through coimmunoprecipitation experiments.ConclusionWe have described the expression pattern of NFIB in primary and castrationresistant prostate cancer and its positive correlation with AR. We have also demonstrated AR interacts with NFIB.

Aims Neuroendocrine neoplasms (NNs) range from well to poorly differentiated and indolent to highly aggressive. The site of origin in metastatic NNs has therapeutic and prognostic implications. SATB2 is a transcriptional regulator involved in osteoblastic and neuronal differentiation and is a sensitive and specific marker of colorectal epithelium. This study aimed to evaluate the expression of SATB2 in NNs from various primary sites and its utility as a marker in determining the site of origin of these neoplasms. Methods and results SATB2 immunohistochemistry was performed on 266 NNs, including lung small cell carcinomas (n = 39) and carcinoids (n = 30), bladder (n = 21) and prostate (n = 31) small cell carcinomas, and gastrointestinal (GI)/pancreatic NNs of various primary sites (n = 145) consisting of well-differentiated neuroendocrine tumours (WDNET)s (n = 124) and poorly differentiated neuroendocrine carcinomas (PDNEC)s (n = 21). SATB2 was expressed in prostatic (10 of 31, 32%) and bladder (eight of 21, 38%) small cell carcinomas, lung carcinoid tumours (one of 30, 3%), and lung small cell carcinomas (eight of 39, 21%). Among primary GI NNs, SATB2 was expressed in 37 of 124 (30%) WDNETs and four of 21 (19%) PDNECs. Of the former, 15 of 15 (100%) rectal/rectosigmoid and 22 of 22 (100%) appendiceal neoplasms expressed SATB2. Using receiver operator characteristic analysis, SATB2 was a sensitive and specific marker for rectal (100.0%, 80.0%) and appendiceal (100.0%, 84.5%) WDNETs, respectively. Conclusions In summary, SATB2 is a sensitive and specific marker for rectal/rectosigmoid and appendiceal WDNETs, and may represent a useful diagnostic tool when these sites of origin are considered in the differential diagnosis.

Renal cell tumors with mixed morphology resembling multiple renal cell carcinoma (RCC) subtypes are generally regarded as unclassified RCC. However, occasionally, papillary adenoma or RCC appears admixed with a larger, different tumor histology. We retrieved 17 renal tumors containing a papillary adenoma or papillary RCC component admixed with another tumor histology and studied them with immunohistochemistry and fluorescence in situ hybridization (FISH). Larger tumors were oncocytomas (n = 10), chromophobe RCCs (n = 5), borderline oncocytic tumor (n = 1), and clear cell RCC (n = 1). The size of papillary component ranged from 1 to 34 mm. One tumor was an oncocytoma encircled by a cyst (2.0 cm) with papillary hyperplasia of the lining. The papillary lesions were diffusely cytokeratin 7 positive (17/17), in contrast to "host" tumors. Alpha-methylacyl-coA-racemase labeling was usually stronger in the papillary lesions (13/15). KIT was negative in all papillary lesions and the clear cell RCC and positive in 16/16 oncocytic or chromophobe tumors. Eight of 15 (53%) collision tumors had differing FISH results in the two components. A papillary renal cell proliferation within another tumor is an uncommon phenomenon with predilection for oncocytoma and chromophobe RCC, possibly related to their common entrapment of benign tubules. When supported by distinct morphology and immunohistochemistry in these two components, this phenomenon should be diagnosed as a collision of two processes. A diagnosis of unclassified RCC should be avoided, due to potential misrepresentation as an aggressive renal cancer.

Background Renal mass biopsy (RMB) is a safe and accurate method for diagnosis and clinical management of renal masses. However, the non-diagnostic rate is a limiting factor. We tested the hypothesis that imaging characteristics and anatomic complexity of the mass may impact RMB diagnostic outcome using the preoperative aspects and dimensions used for an anatomical (PADUA) classification and radius-exophytic/endophytic-nearness-anterior/posterior-location (RENAL) score. Material and methods Single institution, retrospective study of 490 renal masses from 443 patients collected from 2001 to 2018. Outcome measurements include (1) diagnostic and concordance rates amongst RMB types and RMB with surgical resection specimens; (2) association between diagnostic RMB and anatomical complexity of renal masses. The analysis was conducted in unselected masses and small renal masses (SRMs). Results RMB was performed by fine needle aspiration (FNA), core needle biopsy (CNB), or both (FNA+CNB). Non-diagnostic rate was significantly higher for FNA compared to CNB and FNA+CNB in both unselected and SRMs. Subset analysis in the FNA+CNB group showed similar diagnostic rates for FNA and CNB. In unselected masses, specificity for FNA, CNB, and FNA+CNB was 100%. Sensitivity was higher for CNB (90.1%, P = 0.002) and FNA+CNB (96.3%, P = 0.004) compared to FNA (66.7%). For unselected masses, endophytic growth predicted a non-diagnostic CNB. R.E.N.A.L location entirely between the polar lines (central) and entirely above the upper polar line predicted a diagnostic CNB. Sonography-guidance predicted a diagnostic FNA. For SRMs, non-diagnostic CNB was associated with endophytic growth, while diagnostic CNB was associated with renal sinus invasion and operator experience. More cystic masses were sampled by FNA, but diagnostic results were similar for FNA and CNB. Conclusions Endophytic growth consistently predicted a non-diagnostic CNB in unselected and SRMs, whereas sonography-guidance predicted a diagnostic FNA. Cystic masses could be adequately sampled by FNA.

Mucinous tubular and spindle cell carcinoma (MTSCC) is a relatively rare subtype of renal cell carcinoma (RCC) with distinctive morphologic and cytogenetic features. Here, we carry out whole-exome and transcriptome sequencing of a multi-institutional cohort of MTSCC (n = 22). We demonstrate the presence of either biallelic loss of Hippo pathway tumor suppressor genes (TSG) and/or evidence of alteration of Hippo pathway genes in 85% of samples. PTPN14 (31%) and NF2 (22%) were the most commonly implicated Hippo pathway genes, whereas other genes such as SAV1 and HIPK2 were also involved in a mutually exclusive fashion. Mutations in the context of recurrent chromosomal losses amounted to biallelic alterations in these TSGs. As a readout of Hippo pathway inactivation, a majority of cases (90%) exhibited increased nuclear YAP1 protein expression. Taken together, nearly all cases of MTSCC exhibit some evidence of Hippo pathway dysregulation. Significance: MTSCC is a rare and relatively recently described subtype of RCC. Next-generation sequencing of a multi-institutional MTSCC cohort revealed recurrent chromosomal losses and somatic mutations in the Hippo signaling pathway genes leading to potential YAP1 activation. In virtually all cases of MTSCC, there was evidence of Hippo pathway dysregulation, suggesting a common mechanistic basis for this disease. Cancer Discov; 6(11); 1258–66. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 1197

Objectives: We compared the utility of membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) and α-methylacyl CoA (AMACR) by immunohistochemistry in diagnosing prostatic adenocarcinoma. Methods: Seventy-eight radical prostatectomies were used to construct three tissue microarrays with 512 cores, including benign prostatic tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma. AMACR and MAGI-2 immunohistochemistry were evaluated by visual and image analysis. Results: MAGI-2 and AMACR were significantly higher in adenocarcinoma and HGPIN compared with benign tissue. At H-score cutoffs of 300 and 200, MAGI-2 was more accurate in distinguishing benign from malignant glands than AMACR. Areas under the curve by image and visual analysis were 0.846 and 0.818 for MAGI-2 and 0.937 and 0.924 for AMACR, respectively. The accuracy of MAGI-2 in distinguishing benign from malignant glands on the same core was higher (95% vs 88%). Conclusions: MAGI-2 could represent a useful adjunct for diagnosis of prostatic adenocarcinoma, especially when AMACR is not discriminatory.

Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 2 (MAGI-2) is a scaffolding protein that links cell adhesion molecules, receptors, and signaling molecules to the cytoskeleton and maintains the architecture of cell junctions. MAGI-2 gene rearrangements have recently been described in prostate cancer. We studied the immunohistochemical expression of MAGI-2 protein in prostate tissue. Seventy-eight radical prostatectomies were used to construct 3 tissue microarrays consisting of 512 cores, including benign tissue, benign prostatic hyperplasia, high-grade prostatic intraepithelial neoplasia (HGPIN), and adenocarcinoma, Gleason patterns 3 to 5. Immunohistochemistry for phosphatase and tensin homologue (PTEN) and double-stain MAGI-2/p63 was performed and analyzed by visual and image analysis, the latter as percent of analyzed area (%AREA), and mean optical density multiplied by %AREA (STAIN). By visual and image analysis, MAGI-2 was significantly higher in adenocarcinoma and HGPIN compared with benign (benign versus HGPIN P < .001; benign versus adenocarcinoma, P < .001). HGPIN and adenocarcinoma did not significantly differ by either modality. Using visual intensity to distinguish benign tissue and adenocarcinoma, a receiver operating curve yielded an area under the curve of 0.902. A STAIN threshold of 1470 yielded a sensitivity of 0.66 and specificity of 0.96. There was a significant correlation between PTEN and MAGI-2 staining for normal and benign prostatic hyperplasia, but this was lost in HGPIN and cancer. We conclude that MAGI-2 immunoreactivity is elevated in prostate cancer and HGPIN compared with normal tissue, and suggest that MAGI-2 may contribute to prostate carcinogenesis. This is the first report of MAGI-2 staining by immunohistochemistry in prostate cancer.

Antibody-mediated rejection (ABMR) is implicated in 45% of renal allograft failure and 57% of late allograft dysfunction. Peritubular capillary C4d is a specific but insensitive marker of ABMR. The 2013 Banff Conference ABMR revised criteria included C4d-negative ABMR with evidence of endothelial-antibody interaction. We hypothesized that endothelial activation and lymphangiogenesis are increased with C4d-negative ABMR and correlate with intragraft T-regulatory cells and T-helper 17. Seventy-four renal transplant biopsies were selected to include (a) ABMR with C4d Banff scores ≥2 (n = 35), (b) variable microvascular injury and C4d score 0-1 (n = 24), and (c) variable microvascular injury and C4d score = 0 (n = 15). Controls included normal preimplantation donor kidneys (n = 5). Immunohistochemistry for endothelial activation (P- and E-selectins [SEL]), lymphangiogenesis (D2-40), T-regulatory cells (FOXP3), and T-helper 17 (STAT3) was performed. Microvessel and inflammatory infiltrate density was assessed morphometrically in interstitium and peritubular capillaries. All transplants had significantly higher microvessel and lymph vessel density compared with normal. Increased expression of markers of endothelial activation predicted transplant glomerulopathy (P-SEL, P = .003). Increased P-SEL and D2-40 were associated with longer interval from transplant to biopsy (P = .005). All 3 markers were associated with increased interstitial fibrosis, tubular atrophy, and graft failure (P-SEL, P < .001; E-SEL, P = .0011; D2-40, P = .012). There was no association with the intragraft FOXP3/STAT3 ratio. We conclude that endothelial activation and lymphangiogenesis could represent a late response to injury leading to fibrosis and progression of kidney damage, and are independent of the intragraft FOXP3/STAT3 ratio. Our findings support the therapeutic potential of specifically targeting endothelial activation.

Our recent study revealed recurrent chromosomal losses and somatic mutations of genes in the Hippo pathway in mucinous tubular and spindle cell carcinoma (MTSCC). Here, we performed an integrative analysis of 907 renal cell carcinoma (RCC) samples (combined from The Cancer Genome Atlas and in-house studies) and the Knepper dataset of microdissected rat nephrons. We identified VSTM2A and IRX5 as novel cancer- and lineage-specific biomarkers in MTSCC. We then assessed their expression by RNA in situ hybridization (ISH) in 113 tumors, including 33 MTSCC, 40 type 1 papillary RCC (PRCC), 8 type 2 PRCC, 2 unclassified RCC, 15 clear cell RCC, and 15 chromophobe RCC. Sensitivity and specificity were calculated as the area under the receiver operating characteristics curve (AUC). All MTSCC tumors demonstrated moderate to high expression of VSTM2A (mean ISH score = 255). VSTM2A gene expression assessed by RNA sequencing (RNA-seq) strongly correlated with VSTM2A ISH score (r(2) = 0.81, P = 0.00016). The majority of non-MTSCC tumors demonstrated negative or low expression of VSTM2A. IRX5, nominated as a lineage-specific biomarker, showed moderate to high expression in MTSCC tumors (mean ISH score = 140). IRX5 gene expression assessed by RNA-seq strongly correlated with IRX5 ISH score (r(2) = 0.69, P = 0.00291). VSTM2A (AUC: 99.2%) demonstrated better diagnostic efficacy than IRX5 (AUC: 87.5%), and may thus serve as a potential diagnostic marker to distinguish tumors with overlapping histology. Furthermore, our results suggest MTSCC displays an overlapping phenotypic expression pattern with the loop of Henle region of normal nephrons.

The introduction of Prostate Specific Antigen (PSA) screening has caused a stage shift in diagnosis of prostate cancer and an increasing number of patients receiving early diagnosis. This has led to early detection of limited foci of cancer on prostate biopsy, and clinically insignificant prostate cancer at radical prostatectomy. Therefore, current methods for sampling, diagnosing and managing prostate cancer have significantly evolved in recent years. In light of recent management changes and conservative surveillance protocols prompting new handling, grading and staging guidelines, the evaluation of prostate biopsy in contemporary practice has become pivotal. It is therefore critical to recognize minor foci of cancer or atypical glands, and distinguish these from benign mimics that could lead to a false positive diagnosis.In this chapter, current biopsy modalities and imaging techniques, tissue handling and recent updates in the interpretation of prostate biopsy will be discussed.

Prostatic intraepithelial neoplasia like (PIN-like ductal) carcinoma are rare tumors characterized by crowded, often cystically dilated glands architecturally resembling high-grade prostatic intraepithelial neoplasia, lined by malignant pseudostratified columnar epithelium. The largest prior series studied 9 radical prostatectomies (RPs) and suggested a behavior similar to Gleason score 6. We sought to investigate this rare tumor within a larger series. PIN-like carcinoma cases were identified from in-house and consultation files from 2008 to 2017. A total of 190 total cases were identified (in-house cases n=8, 4.2%, consult cases n=182, 95.8%); the diagnosis of PIN-like carcinoma was made on needle biopsy (n=181), transurethral resection (n=5) and RP (n=4). The average age was 70 years. The average number of cores with involvement by PIN-like carcinoma was 2 (1 to 12). The average maximum percentage by a PIN-like carcinoma component of any core was 43.5% (5% to 90%). In 58/181 (32.0%) biopsy cases, due to selective parts having been submitted for consultation, it was unknown whether there was an association with acinar carcinoma. A total of 72 cases showed exclusively PIN-like carcinoma. Highest grade groups (GGs) on biopsies with known acinar or papillary/cribriform ductal carcinomas were GG1 (n=23, 45.1%), GG2 (n=14, 27.5%), GG3 (n=9, 17.6%), GG4 (n=4, 7.8%), and GG5 (n=1, 2.0%). Of 44 cases where the patient would be considered eligible for active surveillance, 18 (41.0%) underwent RP. RP slides were available in 16 cases; 3 (18.8%) cases diagnosed on biopsy did not show PIN-like carcinoma on review of RP slides. PIN-like carcinoma was present without an associated acinar tumor in 3 (23.1%) RPs; 2 showing tumors with large, cystic dilated glands extending into periprostatic tissue. In 7/13 cases (53.8%), the acinar component was the dominant tumor and the PIN-like carcinoma component was small (1 cm). The overall grade at RP was GG1 (5/13, 38.5%) and GG2 (8/13, 61.5%). In all cases with an acinar component, the acinar tumor was anatomically distinct from the PIN-like carcinoma tumor. The GGs of the separate acinar tumors were GG1 (6/10) and GG2 (4/10) with percent pattern 4 ≤5% in all 4 cases. No cases were associated with metastases to lymph nodes or seminal vesicle invasion. Extraprostatic extension was present in 6/13 (46.1%) cases, from the acinar component in 1 (7.7%) case and the PIN-like carcinoma component in 5 (83.3%) cases. In all 5 cases, there was a peculiar morphology of thin papillary projections into cystic dilated PIN-like carcinoma glands. Immunohistochemical expression of ERG was positive in 1/11 (9.1%) case. 1/11 (9.1%) case showed heterogeneous loss of PTEN. Overall, PIN-like carcinoma tumors are limited in size, not advanced in stage, not associated with high-grade cancer on RP, and show low rates of Gleason pattern 4 and TMPS-ERG rearrangement. Our study supports grading classic PIN-like carcinoma as Gleason pattern 3; at the current time we recommend grading thin papillary projections of PIN-like carcinoma as pattern 4. Longer term studies will be needed to determine the clinical significance of thin papillary projections in PIN-like carcinoma.

We have observed a predominantly mesangial non-immunoglobulin A immune complex mesangial glomerulopathy (MG) in renal transplants with mesangial deposits by immunofluorescence and electron microscopy. Clinicopathological features of 28 patients with MG were analyzed and compared with 28 transplant controls, matched for age, sex, ethnicity, donor type, estimated glomerular filtration rate, and interval from transplant to biopsy. Indications for biopsy in the MG group were allograft dysfunction in 64%, allograft dysfunction/proteinuria in 29%, and proteinuria in 7%. Biopsy indications in controls were allograft dysfunction (61%), allograft dysfunction/proteinuria (18%), proteinuria (14%), and delayed graft function (7%). Most MG cases had mild mesangial hypercellularity with endocapillary proliferation in 2 and crescents in 2 without fibrinoid necrosis. Immunoglobulin M-dominant deposits were present in 83%, and immunoglobulin G was dominant in 17% with mesangial deposits in 93% of cases by electron microscopy. Compared with controls, MG had higher Banff interstitial inflammation score (i) (P = .036) and was associated with concurrent acute T-cell-mediated rejection (P = .023), but not with acute or chronic antibody-mediated rejection. MG patients and controls had similar prevalence of polyomavirus nephropathy and Epstein-Barr virus infection. At follow-up, most MG patients had stable estimated glomerular filtration rate with no or stable proteinuria. Disease-specific graft survival was not different in MG versus controls. We conclude that, in view of the apparent self-limited nature of this lesion, additional treatment may not be required in these patients. Awareness of this lesion may thus spare patients unwarranted further intervention.

There have been conflicting data in studies on the prognostic role of high risk human papillomavirus in penile squamous cell carcinoma. Using P16(ink4a) over expression as a surrogate marker for high risk human papillomavirus, we evaluated high risk human papillomavirus status with respect to various clinical features, including recurrence and overall survival, among others.P16(ink4a) over expression was evaluated by immunohistochemistry for 119 consecutive patients with penile squamous cell carcinoma. Several variables were recorded including age, stage, histological grade, lymph node status, lymphovascular invasion, metastasis and recurrence. Median followup was 30 months.P16(ink4a) over expression was detected in 49.5% (59 of 119) of samples. There was no significant difference between P16(ink4a) negative and P16(ink4a) positive tumors in terms of stage (p = 0.518), histological grade (p = 0.225), lymphovascular invasion (p = 0.388), overall survival (p = 0.156) or lymph node metastasis (p = 0.748). P16(ink4a) negative tumors were more likely to recur overall (p = 0.04), especially if patients had positive lymph nodes at diagnosis (p = 0.002).These data suggest that P16(ink4a)/high risk human papillomavirus status is associated with recurrence, especially in patients with positive lymph nodes at diagnosis. Thus, patients with P16(ink4a) negative penile cancer, particularly those with lymph node metastases, may warrant closer observation after surgery.

Normal physiology relies on the organization of transmembrane proteins by molecular scaffolds, such as tetraspanins. Oncogenesis frequently involves changes in their organization or expression. The tetraspanin CD151 is thought to contribute to cancer progression through direct interaction with the laminin-binding integrins α3β1 and α6β1. However, this interaction cannot explain the ability of CD151 to control migration in the absence of these integrins or on non-laminin substrates. We demonstrate that CD151 can regulate tumor cell migration without direct integrin binding and that integrin-free CD151 (CD151free) correlates clinically with tumor progression and metastasis. Clustering CD151free through its integrin-binding domain promotes accumulation in areas of cell–cell contact, leading to enhanced adhesion and inhibition of tumor cell motility in vitro and in vivo. CD151free clustering is a strong regulator of motility even in the absence of α3 expression but requires PKCα, suggesting that CD151 can control migration independent of its integrin associations. The histologic detection of CD151free in prostate cancer correlates with poor patient outcome. When CD151free is present, patients are more likely to recur after radical prostatectomy and progression to metastatic disease is accelerated. Multivariable analysis identifies CD151free as an independent predictor of survival. Moreover, the detection of CD151free can stratify survival among patients with elevated prostate-specific antigen levels. Cumulatively, these studies demonstrate that a subpopulation of CD151 exists on the surface of tumor cells that can regulate migration independent of its integrin partner. The clinical correlation of CD151free with prostate cancer progression suggests that it may contribute to the disease and predict cancer progression. Cancer Res; 74(1); 173–87. ©2013 AACR.

The classification working group of the International Society of Urological Pathology consensus conference on renal neoplasia was in charge of making recommendations regarding additions and changes to the current World Health Organization Classification of Renal Tumors (2004). Members of the group performed an exhaustive literature review, assessed the results of the preconference survey and participated in the consensus conference discussion and polling activities. On the basis of the above inputs, there was consensus that 5 entities should be recognized as new distinct epithelial tumors within the classification system: tubulocystic renal cell carcinoma (RCC), acquired cystic disease-associated RCC, clear cell (tubulo) papillary RCC, the MiT family translocation RCCs (in particular t(6;11) RCC), and hereditary leiomyomatosis RCC syndrome-associated RCC. In addition, there are 3 rare carcinomas that were considered as emerging or provisional new entities: thyroid-like follicular RCC; succinate dehydrogenase B deficiency-associated RCC; and ALK translocation RCC. Further reports of these entities are required to better understand the nature and behavior of these highly unusual tumors. There were a number of new concepts and suggested modifications to the existing World Health Organization 2004 categories. Within the clear cell RCC group, it was agreed upon that multicystic clear cell RCC is best considered as a neoplasm of low malignant potential. There was agreement that subtyping of papillary RCC is of value and that the oncocytic variant of papillary RCC should not be considered as a distinct entity. The hybrid oncocytic chromophobe tumor, which is an indolent tumor that occurs in 3 settings, namely Birt-Hogg-Dubé Syndrome, renal oncocytosis, and as a sporadic neoplasm, was placed, for the time being, within the chromophobe RCC category. Recent advances related to collecting duct carcinoma, renal medullary carcinoma, and mucinous spindle cell and tubular RCC were elucidated. Outside of the epithelial category, advances in our understanding of angiomyolipoma, including the epithelioid and epithelial cystic variants, were considered. In addition, the apparent relationship between cystic nephroma and mixed epithelial and stromal tumor was discussed, with the consensus that these tumors form a spectrum of neoplasia. Finally, it was thought that the synovial sarcoma should be removed from the mixed epithelial and mesenchymal category and placed within the sarcoma group. The new classification is to be referred to as the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia.

The International Society of Urologic Pathology 2012 Consensus Conference on renal cancer, through working group 3, focused on the issues of staging and specimen handling of renal tumors. The conference was preceded by an online survey of the International Society of Urologic Pathology members, and the results of this were used to inform the focus of conference discussion. On formal voting a Z65% majority was considered a consensus agreement. For specimen handling it was agreed that with radical nephrectomy specimens the initial cut should be made along the long axis and that both radical and partial nephrectomy specimens should be inked. It was recommended that sampling of renal tumors should follow a general guideline of sampling 1 block/cm with a minimum of 3 blocks (subject to modification as needed in individual cases). When measuring a renal tumor, the length of a renal vein/caval thrombus should not be part of the measurement of the main tumor mass. In cases with multiple tumors, sampling should include at a minimum the 5 largest tumors. There was a consensus that perinephric fat invasion should be determined by examining multiple perpendicular sections of the tumor/perinephric fat interface and by sampling areas suspicious for invasion. Perinephric fat invasion was defined as either the tumor touching the fat or extending as irregular tongues into the perinephric tissue, with or without desmoplasia. It was agreed upon that renal sinus invasion is present when the tumor is in direct contact with the sinus fat or the loose connective tissue of the sinus, clearly beyond the renal parenchyma, or if there is involvement of any endothelium-lined spaces within the renal sinus, regardless of the size. When invasion of the renal sinus is uncertain, it was recommended that at least 3 blocks of the tumor-renal sinus interface should be submitted. If invasion is grossly evident, or obviously not present (small peripheral tumor), it was agreed that only 1 block was needed to confirm the gross impression. Other recommendations were that the renal vein margin be considered positive only when there is adherent tumor visible microscopically at the actual margin. When a specimen is submitted separately as "caval thrombus, "the recommended sampling strategy is to take 2 or more sections to look for the adherent caval wall tissue. It was also recommended that uninvolved renal parenchyma be sampled by including normal parenchyma with tumor and normal parenchyma distant from the tumor. There was consensus that radical nephrectomy specimens should be examined for the purpose of identifying lymph nodes by dissection/palpation of the fat in the hilar area only; however, it was acknowledged that lymph nodes are found in

The International Society of Urological Pathology 2012 Consensus Conference made recommendations regarding classification, prognostic factors, staging, and immunohistochemical and molecular assessment of adult renal tumors. Issues relating to prognostic factors were coordinated by a workgroup who identified tumor morphotype, sarcomatoid/rhabdoid differentiation, tumor necrosis, grading, and microvascular invasion as potential prognostic parameters. There was consensus that the main morphotypes of renal cell carcinoma (RCC) were of prognostic significance, that subtyping of papillary RCC (types 1 and 2) provided additional prognostic information, and that clear cell tubulopapillary RCC was associated with a more favorable outcome. For tumors showing sarcomatoid or rhabdoid differentiation, there was consensus that a minimum proportion of tumor was not required for diagnostic purposes. It was also agreed upon that the underlying subtype of carcinoma should be reported. For sarcomatoid carcinoma, it was further agreed upon that if the underlying carcinoma subtype was absent the tumor should be classified as a grade 4 unclassified carcinoma with a sarcomatoid component. Tumor necrosis was considered to have prognostic significance, with assessment based on macroscopic and microscopic examination of the tumor. It was recommended that for clear cell RCC the amount of necrosis should be quantified. There was consensus that nucleolar prominence defined grades 1 to 3 of clear cell and papillary RCCs, whereas extreme nuclear pleomorphism or sarcomatoid and/or rhabdoid differentiation defined grade 4 tumors. It was agreed upon that chromophobe RCC should not be graded. There was consensus that microvascular invasion should not be included as a staging criterion for RCC.

Prostatic adenocarcinoma with aberrant diffuse expression of p63 (p63-PCa) is a recently described variant of prostatic adenocarcinoma. The aim of this study was to investigate the clinical and pathologic features of p63-PCa at radical prostatectomy (RP). We reviewed 21 cases of p63-PCa diagnosed on needle biopsy at subsequent RP. Immunohistochemical analysis for PIN4 and Ki-67 was performed in all RP cases. p63-PCa showed a distinctive morphology consisting of atrophic, poorly formed glands, with multilayered and often spindled nuclei. Gleason grading was 3+3=6 in 28.5%, 3+5=8 in 38%, 3+4=7 in 14.3%, and 4+3=7, 5+3=8, and 5+4=9 in 9.5%. Usual-type acinar carcinoma coexisted in 85.7% with only p63-PCa present in the remaining cases. The usual-type carcinoma was Gleason grade 3+2=5 in 4.7%, 3+3=6 in 57%, 3+4=7 in 19%, and 4+3=7 in 4.3%. Overall, p63-PCa represented 65% of the total cancer volume (median 80%). The tumor was organ-confined in 16 cases (76.2%). In the remaining 5 cases, 2 had p63-PCa extending to the margin in areas of intraprostatic incisions, 2 had usual-type acinar adenocarcinoma extending to the margin and extraprostatic tissue, respectively, and 1 had p63-PCa with an unusual cribriform morphology involving the bladder neck. Ki-67 was low

Fine needle aspiration with and without concurrent core needle biopsy is a minimally invasive method to diagnose and assist in management of renal masses. We assessed the pathological accuracy of fine needle aspiration compared to and associated with core needle biopsy and the impact on management.We performed a single institution, retrospective study of 342 cases from 2001 to 2015 with small and large renal masses (4 or less and greater than 4 cm, respectively). Diagnostic and concordance rates, and the impact on management were analyzed.Adequacy rates for fine needle aspiration only, core needle biopsy only and fine needle aspiration plus core needle biopsy were 21%, 12% and 8% (aspiration vs aspiration plus biopsy p0.026). In the aspiration plus biopsy group adding aspiration to biopsy and biopsy to aspiration reduced the inadequacy rate from 23% to 8% and from 27% to 8% for a total reduction rate of 15% and 19%, respectively, corresponding to 32 cases (9.3%). Rapid on-site examination contributed to a 22.5% improvement in fine needle aspiration adequacy rates. In this cohort 30% of aspiration only, 5% of biopsy only and 12% of aspiration plus biopsy could not be subtyped (aspiration vs biopsy p0.0001, aspiration vs aspiration plus biopsy p0.0127 and biopsy vs aspiration plus biopsy p = 0.06). The diagnostic concordance rate with surgical resection was 99%. Conversion of an inadequate specimen to an adequate one by a concurrent procedure impacted treatment in at least 29 of 32 patients. Limitations include the retrospective design and accuracy measurement based on surgical intervention.Fine needle aspiration plus core needle biopsy vs at least fine needle aspiration alone may improve diagnostic yield when sampling renal masses but it has subtyping potential similar to that of core needle biopsy only.

The diagnosis of minimal prostatic adenocarcinoma can be challenging on prostate needle biopsy, and immunohistochemistry may be used to support the diagnosis of cancer. The International Society of Urologic Pathology currently recommends the use of the basal cell markers high-molecular-weight cytokeraratin and p63, and α-methylacyl-coenzyme-A racemase. However, there are caveats associated with the interpretation of these markers, particularly with benign mimickers. Another issue is that of early detection of presence and progression of disease and prediction of recurrence after clinical intervention. There remains a lack of reliable biomarkers to accurately predict low-risk cancer and avoid over treatment. As such, aggressive forms of prostate cancer may be missed and indolent disease may be subjected to unnecessary radical therapy. New biomarker discovery promises to improve early detection and prognosis and to provide targets for therapeutic interventions. In this review, we present the emerging immunohistochemical biomarkers of prostate cancer PTEN, ERG, FASN, MAGI-2, and SPINK1, and address their diagnostic and prognostic advantages and limitations.

The utility of routine frozen section (FS) analysis for margin evaluation during radical prostatectomy (RP) remains controversial. A retrospective search was conducted to identify RPs evaluated by FS over a 5-year period. The potential of FS to discriminate between benign and malignant tissue and to predict final margins was evaluated. During the study period, 71 (12.3%) of 575 cases underwent FS evaluation of margins, generating 192 individual FSs. There were 8 FSs diagnosed as atypical/indeterminate because of significant freezing, crushing, and/or thermal artifacts; 11 as positive for carcinoma; and 173 as benign. Two FSs classified as benign were diagnosed as positive for carcinoma on subsequent permanent section. Frozen sections' sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for diagnosis of prostatic adenocarcinoma were 85%, 100%, 100%, 99%, and 99%, respectively. Overall RP final margin predictive accuracy was 81%. Positive FS was significantly associated with perineural invasion on biopsy and extraprostatic extension and higher stage disease on RP, but not with the overall final margin status. The high FS accuracy supports its use to guide the extent of surgery. However, FS cannot be used to predict the overall final margin status. Recognition of the histological artifacts inherent to the FS procedure is important to ensure appropriate utilization.

The purpose of the study is to assess whether a protocol for submitting clinically suspected endometrial polyps will improve the detection rate of polyps and evaluation of the background endometrium. A retrospective review from 1999 to 2015 was performed. Cases were divided into (1) polyps and curettings placed in 2 containers (separate, n=61) and (2) polyps and curettings placed in 1 container (combined, n=80). Polyps were identified in 100% of cases in the separate compared with 95% in the combined group (P=.62). The background endometrium was evaluable in 79% of cases in the combined compared to 90% in the separate group (P=.07). The frequency of hyperplasia without atypia, atypical hyperplasia, and carcinoma was 4.4%, 3.6%, and 1.5%, respectively. In conclusion, the enhanced rate of polyp detection and evaluation of the background endometrium in the separate group is minimal. This supports the recommendation of submitting endometrial polyps and curettings combined in 1 container.

Background and objectives: α- and β-dystroglycan (DG), which link the actin cytoskeleton of the podocyte to the glomerular basement membrane, are maintained in FSGS but decreased in minimal change disease (MCD). Fibrosis has been linked to increased fibroblast-specific protein-1 (FSP1) and epithelial–mesenchymal transition. We studied DG, FSP1, and podocyte differentiation in FSGS variants and cases of suspected FSGS. Design, setting, participants, & measurements: We studied renal biopsies with FSGS, not otherwise specified (NOS), tip lesion, or collapsing variants (COLL), versus secondary FSGS or cases without segmental sclerotic lesions where a diagnosis of MCD versus FSGS could not be established (undefined [UNDEF]) and compared the expression of DG, FSP1, and podocyte Wilms9 tumor antigen (WT1). Results: WT1 is markedly decreased in NOS versus normal and correlates with the extent of sclerosis. α- and β-DG are maintained in most primary and secondary FSGS cases. In contrast, α-DG is significantly decreased in UNDEF, supporting a diagnosis of MCD. Furthermore, follow-up shows remission or decreased proteinuria in four of six of these UNDEF cases in response to therapy. Interstitial FSP1 is numerically highest in COLL but is only rarely found in tubules or podocytes in any other forms of FSGS. Conclusions: We conclude that increased FSP1 may be a marker of the aggressive course of collapsing FSGS. Furthermore, DG staining is a useful adjunct to assist in distinction of FSGS versus MCD in biopsies without defining lesions.

Objectives The most common renal neoplasms include clear cell, chromophobe, and papillary renal cell carcinomas (PRCCs) and oncocytomas. While lesions containing hybrid features of different tumor types, such as hybrid oncocytic tumors, have been well documented in the literature, the finding of a collision tumor of two distinct tumor types— PRCC and oncocytoma—is extremely rare. Methods We present a case of PRCC associated with an oncocytoma. Our discussion includes a review of the available literature on this rare type of collision tumor. Results Prosection of a partial nephrectomy performed in a 78-year-old man for painless gross hematuria and nocturia revealed a 6.4 × 5 × 3.6-cm well-delineated orange to yellow-tan mass harboring a white-tan 1 × 0.9 × 0.9-cm mass. Histologic diagnosis of PRCC associated with an oncocytoma was rendered. By immunohistochemistry, focal CK7 expression was present in the oncocytoma, while strong diffuse positive CK7 expression was present in the PRCC component. Fluorescence in situ hybridization (FISH) revealed trisomy 17 in 39.3% of PRCC tumor nuclei but no significant chromosomal aberration in oncocytoma. Conclusions In view of this and previously reported cases, thorough sectioning and examination, especially in large oncocytomas, is recommended to exclude the presence of an associated malignancy. To our knowledge, trisomy 17 by FISH has not been previously reported in these extremely rare tumors.

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.

This report describes the clinicopathologic features of a primary lymphoepithelioma-like carcinoma of the endometrium, representing only the fourth reported case of this tumor at this location. In addition to its classic morphologic features, focal clear cells were also identified within the tumor, thereby expanding the morphologic spectrum of the neoplasm at this location. A comprehensive immunohistochemical characterization of the tumor was performed, as was microsatellite instability testing. The tumor was diagnosed in a 79-year-old woman and was surgically/pathologically staged as IB by the International Federation of Gynecology and Obstetrics (FIGO) criteria. The tumor displayed typical morphologic features (tumor cells with a syncytial appearance in an inflammatory background) with the exception of the aforementioned polygonal cells with well-defined cell membranes and cytoplasmic clarity in1% of the tumor. The epithelial component showed strong and diffuse immunoreactivity for CAM 5.2, p53, p16, E-cadherin, cytokeratin (CK) 7, vimentin, CKAE1/3, and epithelial membrane antigen. The MIB-1 proliferative index in these regions was about 70%. Approximately 10% to 30% of lesional cells showed strong immunoreactivity for CK903, S100, MOC31, CD138, but the pattern of positivity was patchy and discontinuous. The epithelial cells were entirely negative for CK5/6, smooth muscle actin, p504S, CK20, synaptophysin, chromogranin, CD56, CD99, WT-1, thyroid transcription factor-1, p63, CD117 (c-kit), CD34, calretinin, desmin, estrogen receptor, progesterone receptor, FLI-1, ALK-1, D2-40, cytomegalovirus antigen, Epstein-Barr virus-encoded RNA-1, Epstein-Barr virus, monoclonal carcinoembryonic antigen, and HER2/neu. The foci with clear cells were not immunophenotypically distinct from the non-clear cell areas and had an approximately similar proliferative index. The inflammatory component was mixed (lymphocytes, histiocytes, plasma cells, neutrophils) but was composed predominantly of CD45/CD3/CD8 T lymphocytes, with a CD3 to CD20 ratio of approximately 10:1 and CD8 to CD4 T-cell ratio of approximately 3:1. Numerous (100 positive cells per 10 high-power fields) S100-positive tumor-infiltrating Langerhans cells were present. The tumor DNA did not exhibit microsatellite instability at any of the loci analyzed. In summary, the limited data available suggest that lymphoepithelioma-like carcinoma is a distinct histotype of endometrial carcinoma that is typically seen in postmenopausal women, seems to be unrelated to the Epstein-Barr virus, and has an uncertain prognosis. Differential diagnostic and pathogenetic considerations are discussed within the context of the lesional morphologic and immunophenotypic profile as described herein and in previously reported cases.

International audience; The International Society of Urological Pathology convened a consensus conference on renal cancer, preceded by an online survey, to address issues relating to the diagnosis and reporting of renal neoplasia. In this report, the role of biomarkers in the diagnosis and assessment of prognosis of renal tumors is addressed. In particular we focused upon the use of immunohistochemical markers and the approach to specific differential diagnostic scenarios. We enquired whether cytogenetic and molecular tools were applied in practice and asked for views on the perceived prognostic role of biomarkers. Both the survey and conference voting results demonstrated a high degree of consensus in participants' responses regarding prognostic/predictive markers and molecular techniques, whereas it was apparent that biomarkers for these purposes remained outside the diagnostic realm pending clinical validation. Although no individual antibody or panel of antibodies reached consensus for classifying renal tumors, or for confirming renal metastatic disease, it was noted from the online survey that 87% of respondents used immunohistochemistry to subtype renal tumors sometimes or occasionally, and a majority (87%) used immunohistochemical markers (Pax 2 or Pax 8, renal cell carcinoma [RCC] marker, panel of pan-CK, CK7, vimentin, and CD10) in confirming the diagnosis of metastatic RCC. There was consensus that immunohistochemistry should be used for histologic subtyping and applied before reaching a diagnosis of unclassified RCC. At the conference, there was consensus that TFE3 and TFEB analysis ought to be requested when RCC was diagnosed in a young patient or when histologic appearances were suggestive of the translocation subtype; whereas Pax 2 and/or Pax 8 were considered to be the most useful markers in the diagnosis of a renal primary.

Autoantibodies are central to the pathogenesis of several autoimmune diseases including systemic lupus erythematosus. Plasma cells secrete these autoantibodies, but the anatomical sites of these cells are not well defined. Here, we found that although dsDNA-specific plasma cells in NZB/W mice were present in spleen and bone marrow, a large number were in the kidneys and their number correlated with the serum dsDNA-IgG titer. We observed renal plasma cells only in mice with nephritis, where they located mainly to the tubulointerstitium of the cortex and outer medulla. These cells had the phenotypic characteristics of fully differentiated plasma cells and, similar to long-lived bone marrow plasma cells, they were not in cell cycle. In patients with lupus nephritis, plasma cells were often present in the medulla in those with the most severe disease, especially combined proliferative and membranous lupus nephritis. The identification of the kidney as a major site of autoreactive plasma cells has implications for our understanding of the pathogenesis of lupus nephritis and for strategies to deplete autoreactive plasma cells, a long-standing therapeutic aim.

Osteoblastoma, an uncommon primary bone tumor, produces both osteoid and primitive woven bone in a background of fibrovascular connective tissue. Although most osteoblastomas are considered benign, a controversial aggressive variant has been described, which may cause diagnostic confusion with malignant tumors such as osteosarcoma. To date, no specific diagnostic cytogenetic or molecular marker has been identified for osteoblastoma to aid in its distinction. Conventional cytogenetic analysis of an osteoblastoma arising in the femur of a 23-year-old woman revealed a novel three-way translocation involving chromosomes 1, 2 and 14 [t(1;2;14) (q42;q13;q24)]. Rearrangement of 1q42 has been identified in a previously reported case.

Alport posttransplantation anti-glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the alpha3alpha4alpha5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with alpha3alpha4alpha5 NC1 hexamers, targeting their alpha3NC1 and alpha4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the E(A) and E(B) regions of alpha3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate E(A) and E(B) autoepitopes of alpha3NC1 but not the composite alloepitope. Molecular modeling of alpha3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the alpha3 and alpha4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native alpha3alpha4alpha5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, alpha3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the E(A) and E(B) autoepitopes. Thus, the identity of alpha3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of alpha3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.