Clinicopathological and Molecular Features of Penile Melanoma With a Proposed Staging System.

Penile melanomas (PM) are an exceedingly rare subtype of mucosal melanoma (MM), and we reviewed the clinicopathologic features and molecular profile in 8 PMs. The patient ages ranged from 46 to 78 (mean: 62.8) years with involvement on the glans (n=5; 62.5%), penile urethra (n=2; 25%), and foreskin (n=1, 12.5%). Tumor depth ranged from 1.6 to 10.0 (mean: 5.25) mm. Most of the patients underwent partial penectomy (n=6; 75%) and sentinel lymph node (LN) biopsy N=7; 87.5%). Seven patients had metastatic disease at diagnosis, 6 involving LNs and 1 the adrenal gland, and 4 died of disease with a mean follow-up period of 40.5 (2 to 95) months. Five of 7 (71%) cases identified 15 molecular alterations within KIT , CDKN2A , NF1 , PTEN , and APC (n=2 each), and NRAS , MAP3K1 , CDH1 , MSH6 , and TERT (n=1 each). Two cases were not found to harbor genetic aberrations, and 1 case failed testing. In addition, we reviewed the English literature and included 93 cases with a reported depth of invasion and follow-up. A total of 101 PMs were analyzed for prognostic parameters, and the overall survival was significantly worse in patients with LN metastasis (P=0.0008), distant metastasis (P=0.0016), and greater depth of invasion (P=0.0222) based upon T-stage. While T4 conferred substantially worse survival, the delineation of the survival curves between T2 and T3 was less clear, and combining T2+T3 disease had a strong prognostic impact ( P =0.0024). Prognostic parameters used in the staging of cutaneous melanomas may also be used in PMs. An alternative staging system expanding the inclusion criteria for T2 might provide a more accurate prognostic stratification.

To stage or not to stage: determining the true clinical significance of the biopsy tract through perinephric fat in assessing renal cell carcinoma.

AIMS: Perinephric fat invasion (PFI) is a key component of renal cell carcinoma (RCC) staging, but there are limited data pertaining to biopsy tract seeding (BTS) resulting in perirenal tissue involvement [BTS with perinephric fat invasion (BTS-P)].The aim is to correlate clinical outcomes with pathologic stage to determine whether the presence of BTS-P should be considered a criterion to stage RCC as part of the pT3a category in the absence of any other upstaging variables. MATERIALS AND RESULTS: We identified 304 renal biopsies from patients with subsequent nephrectomies for RCC; 33 of the tumours contained PFI. Each case was reviewed to determine the presence of BTS-P and other forms of invasion [e.g. non-BTS-P PFI, sinus fat invasion (SFI), and/or renal vein invasion (RVI)], and these findings were compared with survival outcomes. Ten (30%) of 33 tumours with PFI showed BTS-P as the only finding, and were otherwise pT1 tumours; six (60%) patients were alive without disease (AWOD) (mean, 77.5 months), three were lost to follow-up (LTF), and one died of other disease (DOOD). Two patients showed true PFI plus BTS-P; one was LTF and one is AWOD at 107 months. Ten (43%) of 23 patients with tumours with true invasion (PFI ± SFI and/or RVI) are AWOD (mean, 97.7 months), eight (35%) died of disease (DOD), four were LTF, and one DOOD. Kaplan-Meier survival curves showed that the cancer-specific survival was significantly worse in patients with true invasion (P = 0.044) than in those with BTS-P as the sole finding. CONCLUSION: Patients with tumours showing BTS-P only appear to have better outcomes than those with other non-PFI invasion, suggesting that this finding should not be upstaged to pT3a. Additional studies are needed to corroborate the significance of our observations.

Update on Renal Neoplasms: Clinicopathologic-Radiologic Correlation With Case-Based Examples.

OBJECTIVE. This article provides a brief overview of the clinicopathologic and radiologic correlation of 12 renal neoplasms, encompassing the conventional subtypes of renal cell carcinoma and a few of the newly recognized subtypes from the 2016 World Health Organization classification of renal tumors. In addition, we touch upon infrequent neoplasms that may enter the differential diagnosis of a renal mass, with corresponding radiologic and gross images and histologic findings of case-based examples. CONCLUSION. Familiarity with the radiologic and pathologic characteristics of renal cell carcinoma and other renal neoplasms is important to correctly identify and treat these masses.

Updates in Histologic Grading of Urologic Neoplasms.

CONTEXT.­: Tumor histology offers a composite view of the genetic, epigenetic, proteomic, and microenvironmental determinants of tumor biology. As a marker of tumor histology, histologic grading has persisted as a highly relevant factor in risk stratification and management of urologic neoplasms (ie, renal cell carcinoma, prostatic adenocarcinoma, and urothelial carcinoma). Ongoing research and consensus meetings have attempted to improve the accuracy, consistency, and biologic relevance of histologic grading, as well as provide guidance for many challenging scenarios. OBJECTIVE.­: To review the most recent updates to the grading system of urologic neoplasms, including those in the 2016 4th edition of the World Health Organization (WHO) Bluebook, with emphasis on issues encountered in routine practice. DATA SOURCES.­: Peer-reviewed publications and the 4th edition of the WHO Bluebook on the pathology and genetics of the urinary system and male genital organs. CONCLUSIONS.­: This article summarizes the recently updated grading schemes for renal cell carcinoma, prostate adenocarcinomas, and bladder neoplasms of the genitourinary tract.

PNL2: A Useful Adjunct Biomarker to HMB45 in the Diagnosis of Uterine Perivascular Epithelioid Cell Tumor (PEComa).

Perivascular epithelioid cell tumors (PEComa) are rare neoplasms characterized by co-expression of melanocytic and muscle markers. HMB45 and Melan-A are used to confirm a PEComa diagnosis; however, both are often focally expressed and sensitivity for Melan-A is low. PNL2 is a reliable biomarker for epithelioid melanoma and renal angiomyolipoma/PEComa. The objective of this study was to determine PNL2 utility in diagnosing uterine PEComas as well as distinguishing PEComas from uterine smooth muscle tumors (SMTs). Twenty-one uterine PEComas and 45 SMTs were analyzed for PNL2; a subset was also stained for HMB45, Melan-A, Cathepsin-K, Desmin, and h-Caldesmon. Cases were scored as negative (0), focal (<10% of tumor cells), or patchy to diffusely positive (>10% of tumor cells). PEComas were positive for PNL2, HMB45, and Melan-A in 86%, 100%, and 57% of cases, respectively. In PEComas, PNL2 was patchy to diffusely positive more frequently (10/18, 56%) than Melan-A (4/12, 33%). In contrast, 2 of 45 (4%) SMTs were focally PNL2 positive; HMB45 was focally positive in 4 SMTs (11%) and all were negative for Melan-A. Desmin and h-Caldesmon were positive in 90% and 57% of PEComas, and 91% and 82% of SMTs. Cathepsin-K was positive in 100% of PEComas and 93% of SMTs. PNL2 is a useful biomarker for the diagnosis of uterine PEComa, with comparable sensitivity and specificity to HMB45. In contrast, PNL2 stains more PEComas when compared with Melan-A. Cathepsin-K, Desmin, and h-Caldesmon are of little utility for distinguishing PEComas and SMTs; however, lack of Cathepsin-K argues against PEComa. These results suggest that PNL2 should be used in conjunction with HMB45 in the diagnosis of PEComa of the uterine corpus.

Utility of Immunohistochemistry in Distinguishing Primary Adnexal Carcinoma From Metastatic Breast Carcinoma to Skin and Squamous Cell Carcinoma.

The distinction between primary adnexal carcinoma (PAC) from metastatic breast carcinoma (BrCa) to skin and squamous cell carcinoma (SCC), particularly those with ductal differentiation (SCCDD), can be quite challenging, despite adequate history. The aim of the study was to determine the utility of an immunohistochemistry (IHC) panel to differentiate these entities and apply them to ambiguous tumors. Twenty-seven PAC, 7 metastatic BrCa, 28 SCC, and 16 ambiguous cases (SCCDD vs. PAC, n = 13 and metastatic BrCa vs. PAC, n = 3) were analyzed using CD23, PAX5, D2-40, P63, and CD117 immunohistochemistry. A total of 9 (33%) PAC were CD117 positive, whereas all metastatic BrCa and SCC were negative (P = 0.0002). D2-40 was expressed in 16 (59%) PAC and 16 (57%) SCC cases, but none of the metastatic BrCa cases (P = 0.0041). Of the 13 ambiguous tumors with a differential diagnosis of SCCDD versus PAC, all were positive for P63, 10 were positive for D2-40, and 1 was positive for CD117. Of the 3 ambiguous tumors with a differential diagnosis of PAC versus metastatic BrCA, 2 were positive for CD117, whereas none showed reactivity for D2-40 or P63. All cases were negative for CD23 and PAX5. Our study indicates that CD117 reactivity favors a PAC with a sensitivity and specificity of 33% and 100%, respectively. D2-40 and P63 expression highlighted both PAC and SCC and seems to be useful in excluding metastatic BrCa with a sensitivity and specificity of 58% and 100%, and 98% and 100%, respectively. Despite previous reports, CD23 and PAX5 do not seem to be useful.

The Value of Direct Immunofluorescence on Proteinase-Digested Formalin-Fixed Paraffin-Embedded Skin Biopsies.

Direct immunofluorescence (DIF) on frozen tissue (DIF-F) is the method of choice for the identification of immune deposits present in skin and other tissues. DIF can also be performed on formalin-fixed paraffin-embedded tissue (DIF-P) after antigen retrieval with proteases and has proven to be of value in renal pathology. However, its utility in skin biopsies has not been fully examined. In this study, we performed DIF-P on 60 skin biopsies that comprised of bullous pemphigoid (n = 18), pemphigoid gestationis (n = 1), pemphigus (n = 7), linear IgA disease (n = 7), vasculitis (n = 20), lupus erythematosus (n = 3), and dermatitis herpetiformis (n = 4) cases. We compared the results of DIF-P with those of DIF-F from the same patients. The diagnostic features were found in 15 of 19 (79%) pemphigoid (bullous pemphigoid and pemphigoid gestationis), 3 of 7 (43%) pemphigus, 3 of 7 (43%) linear IgA disease, 14 of 20 (70%) vasculitis, 1 of 3 (33%) lupus erythematosus, and none (0%) of the dermatitis herpetiformis cases tested. Overall, DIF-P is less sensitive than DIF-F but seems to be a valuable technique that could aid in the diagnosis of vasculitides, immunobullous, and connective tissue disorders when fresh tissue is unavailable.

Transcription factor TFEB cell-autonomously modulates susceptibility to intestinal epithelial cell injury in vivo.

Understanding the transcription factors that modulate epithelial resistance to injury is necessary for understanding intestinal homeostasis and injury repair processes. Recently, transcription factor EB (TFEB) was implicated in expression of autophagy and host defense genes in nematodes and mammalian cells. However, the in vivo roles of TFEB in the mammalian intestinal epithelium were not known. Here, we used mice with a conditional deletion of Tfeb in the intestinal epithelium (Tfeb ΔIEC) to examine its importance in defense against injury. Unperturbed Tfeb ΔIEC mice exhibited grossly normal intestinal epithelia, except for a defect in Paneth cell granules. Tfeb ΔIEC mice exhibited lower levels of lipoprotein ApoA1 expression, which is downregulated in Crohn's disease patients and causally linked to colitis susceptibility. Upon environmental epithelial injury using dextran sodium sulfate (DSS), Tfeb ΔIEC mice exhibited exaggerated colitis. Thus, our study reveals that TFEB is critical for resistance to intestinal epithelial cell injury, potentially mediated by APOA1.