Conflicting data have been published on the prognostic significance of histologic parameters in papillary renal cell carcinoma (PRCC). We conducted a comprehensive evaluation of clinical and histologic parameters in PRCC in nephrectomies and their impact on prognosis, with an emphasis on World Health Organization (WHO)/International Society of Urological Pathology (ISUP) grade, tumor architecture (solid, micropapillary, and hobnail), and PRCC type. A total of 185 PRCC cases were evaluated, 117 (63.2%) type 1, 45 (24.3%) type 2, and 11 (5.9%) mixed type 1 and type 2. Using WHO/ISUP grading criteria, PRCCs were graded as follows: 6 (3.2%) grade 1; 116 (62.7%) grade 2; 61 (33.0%) grade 3; and 2 (1.1%) grade 4. The solid architecture was present in 3 cases (1.6%) and comprised 10%, 10%, and 30% of the tumor area. Micropapillary architecture was present in 10 cases (5.4%), ranging from 5% to 30% of the tumor (mean=11%; median=10%). Hobnail architecture was seen in 9 cases (4.9%), with mean percentage of 23% (median=15%; range: 5% to 50%) involvement of tumor area. Parameters associated with worse disease-free survival (DFS) and overall survival (OS) in the univariate analysis included WHO/ISUP grade, pathologic stage, tumor size, and solid, micropapillary, or hobnail architecture ( P <0.05). The pathologic stage and WHO/ISUP grade were significantly associated with both DFS and OS in stepwise multivariate Cox regression analysis ( P <0.05). In addition, micropapillary architecture and type 1 histology were linked with an adverse impact on OS ( P <0.05). We found no difference in DFS ( P =0.8237) and OS ( P =0.8222) for type 1 versus type 2 PRCC in our patient cohort. In addition, we performed a meta-analysis with data from studies with reported hazard ratios (HRs) on PRCC type in relation to DFS and OS. We identified 5 studies that reported DFS and found no significant effect for type 2 PRCC ( P =0.30; HR=1.43; 95% confidence interval: 0.73-2.80). We identified 7 studies that reported OS and found no significant association between type 2 PRCC and worse OS ( P =0.41; HR: 1.21; 95% confidence interval: 0.77-1.91). Our findings suggest that high WHO/ISUP grade and unfavorable architecture (solid, micropapillary, or hobnail), rather than typing of PRCC, are associated with worse outcomes.
Aims . Inhibitors of the MET pathway hold promise in the treatment for metastatic kidney cancer. Assessment of predictive biomarkers may be necessary for appropriate patient selection. Understanding MET expression in metastases and the correlation to the primary site is important, as distant tissue is not always available. Methods and Results . MET immunofluorescence was performed using automated quantitative analysis and a tissue microarray containing matched nephrectomy and distant metastatic sites from 34 patients with clear cell renal cell carcinoma. Correlations between MET expressions in matched primary and metastatic sites and the extent of heterogeneity were calculated. The mean expression of MET was not significantly different between primary tumors when compared to metastases (P=0.1). MET expression weakly correlated between primary and matched metastatic sites (R=0.5) and a number of cases exhibited very high levels of discordance between these tumors. Heterogeneity within nephrectomy specimens compared to the paired metastatic tissues was not significantly different (P=0.39). Conclusions . We found that MET expression is not significantly different in primary tumors than metastatic sites and only weakly correlates between matched sites. Moderate concordance of MET expression and significant expression heterogeneity may be a barrier to the development of predictive biomarkers using MET targeting agents.
// Marina K. Baine 1 , Gabriela Turcu 2 , Christopher R. Zito 1, 3 , Adebowale J. Adeniran 4 , Robert L. Camp 4 , Lieping Chen 5 , Harriet M. Kluger 1, * , Lucia B. Jilaveanu 1, * 1 Department of Medicine, Yale University School of Medicine, New Haven, CT, USA 2 Department of Dermatology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 3 Department of Biology, School of Health and Natural Sciences, University of Saint Joseph, West Hartford, CT, USA 4 Department of Pathology, Yale University School of Medicine, New Haven, CT, USA 5 Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA * These authors have contributed equally to this work Correspondence to: Harriet M. Kluger, e-mail: harriet.kluger@yale.edu Keywords: tumor infiltrating lymphocytes (TILs), renal cell carcinoma (RCC), primary, metastatic Received: May 05, 2015 Accepted: June 29, 2015 Published: July 10, 2015 ABSTRACT Renal cell carcinoma (RCC) is one of the most chemo- and radio-resistant malignancies, with poor associated patient survival if the disease metastasizes. With recent advances in immunotherapy, particularly with PD-1/PD-L1 blockade, outcomes are improving, but a substantial subset of patients does not respond to the new agents. Identifying such patients and improving the therapeutic ratio has been a challenge, although much effort has been made to study PD-1/PD-L1 status in pre-treatment tumor. However, tumor infiltrating lymphocyte (TIL) content might also be predictive of response, and our goal was to characterize TIL content and PD-L1 expression in RCC tumors from various anatomic sites. Utilizing a quantitative immunofluorescence technique, TIL subsets were examined in matched primary and metastatic specimens. In metastatic specimens, we found an association between low CD8+ to Foxp3+ T-cell ratios and high levels of PD-L1. High PD-L1-expressing metastases were also found to be associated with tumors that were high in both CD4+ and Foxp3+ T-cell content. Taken together these results provide the basis for combining agents that target the PD-1/PD-L1 pathway with agonist of immune activation, particularly in treating RCC metastases with unfavorable tumor characteristics and microenvironment. In addition, CD8+ TIL density and CD8:Foxp3 T-cell ratio were higher in primary than metastatic specimens, supporting the need to assess distant sites for predictive biomarkers when treating disseminated disease.
509 Background: Sarcomatoid transformation in renal cell carcinoma (ccRCC) is one of the worst prognostic factors and outcome is extremely poor. We evaluate genetic alterations implicated in this process. Methods: Nephrectomy specimens from ccRCC with sarcomatoid transformation had DNA extracted from carcinoma, sarcomatoid, and normal kidney regions. Exome capture/Illumina sequencing was performed in 21 samples. Somatic mutation calling was accomplished by comparing sarcomatoid-normal and carcinoma-normal pairs. Results: Two tumors had evidence of hypermutation and a mutational signature consistent with mismatch repair deficiency. In the remaining tumors, 42.6% of somatic mutations were shared. Sarcomatoid regions had a greater mutation burden (p = 4.0x10 -4 ). A low percentage (57.9%) of tumors had mutations in VHL. Mutations in ccRCC driver genes, including PBRM1, PTEN, SETD2, ARID1A, and BAP1, were common. All mutations in ARID1A and BAP1 were specific to sarcomatoid regions. A high percentage (31.5%) of TP53 mutations were observed, all specific to sarcomatoid regions and occurring with loss of heterozygosity. Lastly, mutations in genes not previously described in ccRCC were observed, most sarcomatoid-specific. These include genes implicated in cell adhesion, polarity, motility, and WNT signaling (FAT1, FAT2, FAT3, PTK7), retinoic acid-regulated cell differentiation (RQCD1, LRIF1), and ubiquitinated protein trafficking and cytokinesis (TSG101). Conclusions: Sarcomatoid transformation in ccRCC results from clonal divergence from a common somatic cell of origin. The sarcomatoid region has significantly greater mutational burden of known cancer driver genes. TP53 mutations occurred at a high frequency and were exclusive to the sarcomatoid region. Hypermutation is a unique characteristic observed in a subset of tumors. Additional cohorts and mechanistic studies are critical to elucidate the role of candidate driver alterations.
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