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PRAME (PReferentially expressed Antigen in MElanoma) is a tumor-associated antigen that was recently found to be expressed by malignant melanocytic lesions but not by benign ones, thus resulting useful in this diagnostic field. PRAME could also be expressed by some normal tissues and nonmelanocytic tumors, suggesting as caution should be adopted to use PRAME as a "pan-melanoma" marker for the differential diagnosis with other malignant tumors. Until now, PRAME expression was exclusively investigated through single staining with a monoclonal antibody targeting PRAME and with double staining for Melan A/PRAME found to be useful in specific diagnostic sets. Herein, we studied the expression of PRAME in 40 melanocytic lesions and 23 nonmelanocytic ones using PRAME, Melan A/PRAME, and novel double staining for HMB45/PRAME. Although our results need to be validated, they support the adoption of HMB45/PRAME, alone or in combination with PRAME and Melan A/PRAME, as a helpful marker in the diagnosis of melanocytic neoplasms with a high concordance rate between primary melanoma and corresponding metastases., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Recently cabozantinib, a tyrosine kinase inhibitor with activity against VEGF, MET, AXL, and downregulating cathepsin K in vitro, has been proposed for the treatment of advanced clear and non-clear renal cell carcinomas. Since it is well known that cathepsin K is expressed in the majority of MiT family translocation renal cell carcinomas, we investigated cathepsin K, MET, AXL, and VEGF in a large series of those tumours, looking for possible predictive markers. We collected the clinicopathological features of 34 genetically confirmed MiT family translocation renal cell carcinomas [26 Xp11 and 8 t(6;11) renal cell carcinomas] and studied them using an immunohistochemical panel including PAX8, cathepsin K, HMB45, Melan-A, CD68 (PG-M1), CK7, CA9, MET, AXL and by FISH for VEGFA and MET. Cathepsin K was expressed in 14 of 26, HMB45 in 8 of 25, and Melan-A in 4 of 23 Xp11 renal cell carcinomas, whereas labelling for CK7 and CA9 was minimal. In t(6;11) renal cell carcinoma, cathepsin K and melanogenesis markers were constantly positive, whereas CK7 and CA9 were negative. None of the 34 carcinomas showed CD68 (PG-M1) and AXL expression. One aggressive Xp11 renal cell carcinoma showed increased VEGFA gene copy number (4-5 copies) with concurrent gains of TFE3 and TFEB. None of the 34 carcinomas showed MET gene amplification, whereas staining for MET was found in 7 of 8 t(6;11) and in 16 of 24 Xp11 renal cell carcinomas, and in the latter cases, when the expression was >50%, correlated with aggressiveness (p=0.0049). In Xp11 renal cell carcinomas, the aggressiveness was also correlated with larger tumour size (p=0.0008) and the presence of necrosis (p=0.027) but not nucleolar grading (p=1). Interestingly, in patients with tumours exhibiting two of three parameters (necrosis, larger tumour size and MET immunolabelling >50%) an aggressive clinical behaviour was observed in 88% of cases. In conclusion, cathepsin K, CD68 (PG-M1), CK7, CA9, and PAX8 is a useful panel for the diagnosis. Larger tumour size, the presence of necrosis and MET immunohistochemical expression correlate with aggressive behaviour in Xp11 renal cell carcinomas, especially in combination. VEGF, MET, cathepsin K but not AXL may be potential predictive markers for targeted therapy in MiT family translocation renal cell carcinomas., (Copyright © 2020 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Programmed death ligand 1 (PD-L1) is a protein which, when interacting with its receptor programmed death 1, acts as a negative regulator of the antitumor T-cell-mediated immune response. The prognostic value of PD-L1 expression in renal cell carcinoma (RCC) has been controversial. In this study, the prognostic value of PD-L1 expression in RCC was evaluated by analyzing PD-L1 immunoreactivity in tumor cells and tumor-infiltrating immune cells (TIICs) in 346 RCC patients with long-term follow-up. PD-L1 positivity in tumor cells was associated with higher World Health Organization nucleolar grade (P<0.001), recurrence (P=0.011), and death due to RCC (P=0.031). PD-L1 positivity in TIICs was associated with higher nucleolar grade (P<0.001), higher T-stage (P=0.031), higher N-stage (P=0.01), recurrence (P=0.007), and death due to RCC (P=0.001). A significant positive association of time to cancer-specific death with both PD-L1-positive tumor cells and TIICs were also found. The data indicate that RCC patients with PD-L1-positive tumor cells and TIICs are at significant risk for cancer progression and the expression may be used as a complementary prognostic factor in the management of RCC patients.

Blockade of inhibitory immune checkpoints is currently arising as a potential immunologic option for tumor therapy. Inhibition of programmed cell death protein 1 and/or its specific ligand programmed death-ligand 1 (PD-L1) was effective in clinical trials in advanced melanoma, non-small cell lung cancer (NSCLC) bladder and kidney cancer. The predictive role of the immunohistochemical (IHC) expression of PD-L1 is highly debated. Different reagents, clones, cutoffs of cell expression and subjective interpretation of PD-L1 immunoreactivity in epithelial cells and lymphocytes are the main issue. In this study we selected 58 consecutive NSCLC surgical specimens that underwent pathologic examination from January 2014 to July 2015. Using a tissue microarray approach we evaluated the IHC expression of PD-L1 in tumor-infiltrating lymphocytes and tumor cells (TCs) and compared the ICH staining with tumor histology, grade and the age of the tissue blocks. The main new finding was the fading of PD-L1 IHC expression in TCs in tissues processed in 2014 compared with 2015. PD-L1 expression in tumor-infiltrating lymphocytes in the 2 years was similar. We also found a significant higher immunoreactivity of TCs in high grade NSCLC and in the squamous carcinoma histotype compared with low grade tumors and the adenocarcinoma histology (P=0.013). We demonstrated that the IHC evaluation of PD-L1 in NSCLC archival tissues is feasible and can be implemented in a routine pathology setting, but it should be carefully assessed in tissue blocks older than 1 year.

In very few years, several treatments have significantly improved the prognosis of patients with metastatic renal cell carcinoma (RCC). Despite this, the clinical outcomes of specific subgroups of patients including those with central nervous metastases still remain poor. In this population, a very infrequent and poorly described site of metastases is the pituitary gland. Because of the important endocrinal function and the anatomic site of this specific organ, clinical management of this complication requires several additional precautions compared with other central nervous metastases. Here, we describe a case of a single pituitary metastasis from clear cell RCC in a patient who showed a surprising progression-free survival and overall survival to sunitinib first-line treatment. Because of the uncommon clinical course of the disease of our patient and the atypical site of metastases, we want also to underline the importance of further investigation of molecular pathways associated with a favorable prognosis in patients with metastatic clear cell RCC.

Renal oncocytosis is a rare pathological condition characterised by the presence of multiple oncocytic tumours with a spectrum of histological features ranging from renal oncocytoma, hybrid oncocytic tumour and rarely chromophobe renal cell carcinoma, sometimes overlapping. Here we retrospectively analysed histological, immunohistochemical (IHC), and cytogenetic features of 42 lesions in 11 patients with renal oncocytosis, not associated with Birt-Hogg-Dubé syndrome. The histology of all the lesions was blindly reviewed by three dedicated genitourinary pathologists. IHC for cytokeratin 7 (CK7) and fluorescence in situ hybridisation (FISH) for copy number variation of chromosomes 1, 6, 7 and 17 were performed in all 42 nodules. Among the 42 lesions 36 (85.7%) were histologically renal oncocytomas, two (4.76%) 'hybrid oncocytic tumours' (HOT), one (2.4%) clear cell renal cell carcinoma (ccRCC), one (2.4%) papillary renal cell carcinoma (pRCC), one typical angiomyolipoma (2.4%), and one mixed epithelial/stromal tumour of the kidney (2.4%). FISH analysis confirmed the histological diagnosis of all the lesions. We show that most patients with renal oncocytosis harbour benign or low malignant potential tumours that can be treated conservatively., (Copyright © 2015 The Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

The aim of the present study is to describe the histological and mutational characteristics of a series of both large and small bowel adenocarcinomas in patients with Crohn's disease from a tertiary referral centre of inflammatory bowel disease. Bowel adenocarcinoma was diagnosed in 11 (1.7%) of 660 consecutive patients submitted to surgery for histologically proven Crohn's disease in 5 years. The following data were collected: tumour site, stage and grade, intracellular/extracellular mucin, lymphovascular invasion, immunohistochemistry for keratin 7, keratin 20 and CDX-2, mutation analyses of KRAS, B-RAF, PI3K and microsatellite instability. A strong predominance of male gender was observed (10/11). Four (36.4%) adenocarcinomas arose in the small bowel, five (45.4%) in the anus/rectum, and two (18.2%) in anastomosis. Furthermore, all cases of anorectal adenocarcinoma showed >50% of extracellular mucin, with associated KRAS mutations in three of five. No influence in cancer incidence by infliximab therapy was observed.Our series, one of the largest on the topic with immunomorphological and molecular deepening, showed that bowel adenocarcinomas in Crohn's disease have an aggressive behaviour and a strong predominance of extracellular mucin. In surgical specimens from Crohn's disease patients, mucinous-looking anal fistulas and ileal areas of adhesion/retraction should always be extensively sampled.

Background: The presence of partial necrosis in hepatocellular carcinoma (HCC) nodules is a common histologic finding after liver transplantation, but its correlation with tumor recurrence has never been investigated., Methods: we retrospectively reviewed the outcome of 54 patients with a single histologically proven HCC after liver transplantation. All cases had a survival of more than 6 months, and patients treated preoperatively had a transarterial chemoembolization (TACE) procedure. Since 1996, our center has applied the Milan criteria. Correlations between tumor recurrences and clinicopathologic variables, including the presence of partial necrosis, were performed. Etiologic factors for HCC partial necrosis were also investigated., Results: Sixteen of 54 (29.6%) HCC nodules presented partial necrosis, and 4 (25%) of them developed HCC recurrence compared with 1 of 38 (2.6%) cases without this histologic finding (P<0.05). Partial necrosis was related to TACE procedure (P<0.05), patient age less than 50 years (P<0.05), and tumor diameter greater than 2 cm (P<0.05). Multivariate analysis showed only TACE as an independent variable. The other variables related to the five (9.3%) tumor recurrences were HCC diameter greater than 2 cm (P<0.05), year of liver transplantation before 1996 (P<0.05), and the presence of satellite nodules (P<0.05). The Cox regression analysis showed the presence of partial necrosis as an independent variable related to tumor recurrence. The analysis of the recurrence-free survival confirmed the results of the recurrence rate., Conclusion: Partial necrosis was a risk factor for tumor recurrence after liver transplantation. Patients and procedures should be selected while also bearing in mind the side-effect of incomplete necrosis of the nodules.

Reduction of waiting-list length requires extension of the organ-donor pool to elderly males bearing an higher risk of prostate cancer incidence. Prostate-cancer screening in organ donors is currently based on prostate-specific antigen (PSA) assays (total PSA and free/total PSA). However, the specificity of these assays is restricted, limiting risk-benefit analysis. Since 2001, 33 multiorgan donor candidates presenting within Emilia-Romagna (Italy) with suspect ultrasonography or abnormal PSA values were submitted to a histopathologic screening method of the entire prostate based on extemporary frozen-section analysis (maximum 1 hour) of over 50% of the organ at 0.1 mm cutting levels. Extemporary diagnosis of adenocarcinoma was made in 12 (36%) cases, corresponding to 4.5% of the male candidates aged more than 50 years in the donor pool. In all cases, the final diagnosis confirmed the extemporary analysis. As well as maximizing safety, this novel approach should permit more refined risk-benefit analysis.

Background: We describe the Emilia-Romagna screening protocol for all multiorgan donors within this region of Italy and report on the first 2 years of implementation., Setting: Setting is a 24-hour multidisciplinary call service covering the 16 intensive care units in Emilia-Romagna (3,969,000 inhabitants) and a centralised pathology center, directed by a transplant coordination center. STUDY POPULATION AND PERIOD: All 271 effective donor candidates presenting in Emilia-Romagna in 2001-2002., Protocol: Anamnesis, external examination, and thorough laboratory and instrumental screening is followed by sampling of internal effusions and evaluation of all internal organs. All suspect findings are then investigated by extemporary pathologic evaluation. To fit national legal requirements, candidates are classified as standard risk (no transmissible risk); nonstandard risk (low-risk of transmission, eligibility restricted to certified clinical emergencies pending informed consent); and unacceptable risk (unconditional exclusion because of high-risk pathologies)., Results: The protocol was successfully implemented for all 271 candidates. In addition to 14 independent exclusions, clinical suspicion of cancer was raised for 61 donors presenting with 82 lesions or effusions. Along with one case of lymph-node tuberculosis (unacceptable risk), histocytologic screening revealed eight cases of malignancy (5 prostate, 1 papillary-thyroid, 1 follicular-thyroid, and 1 renal cell, all nonstandard risk); the remainder were benign (standard risk). Protocol implementation led to exclusion of 8 (3.0%) candidates (1 nonstandard risk transplantation was performed)., Conclusions: This stringent protocol-now adopted with some modifications at a national level-provides an initial example of a feasible intervention aimed at maximising donation safety while rationalizing use of marginal donors.