Toward Biological Subtyping of Papillary Renal Cell Carcinoma With Clinical Implications Through Histologic, Immunohistochemical, and Molecular Analysis

Abstract

Papillary renal cell carcinoma (PRCC) has 2 histologic subtypes. Almost half of the cases fail to meet all morphologic criteria for either type, hence are characterized as PRCC not otherwise specified (NOS). There are yet no markers to resolve the PRCC NOS category. Accurate classification can better guide the management of these patients. In our previous PRCC study we identified markers that can distinguish between the subtypes. A PRCC patient cohort of 108 cases was selected for the current study. A panel of potentially distinguishing markers was chosen from our previous genomic analysis, and assessed by immunohistochemistry. The panel exhibited distinct staining patterns between the 2 classic PRCC subtypes; and successfully reclassified the NOS (45%) cases. Moreover, these immunomarkers revealed a third subtype, PRCC3 (35% of the cohort). Molecular testing using miRNA expression and copy number variation analysis confirmed the presence of 3 distinct molecular signatures corresponding to the 3 subtypes. Disease-free survival was significantly enhanced in PRCC1 versus 2 and 3 (P=0.047) on univariate analysis. The subtypes stratification was also significant on multivariate analysis (P=0.025; hazard ratio, 6; 95% confidence interval, 1.25-32.2). We propose a new classification system of PRCC integrating morphologic, immunophenotypical, and molecular analysis. The newly described PRCC3 has overlapping morphology between PRCC1 and PRCC2, hence would be subtyped as NOS in the current classification. Molecularly PRCC3 has a distinct signature and clinically it behaves similar to PRCC2. The new classification stratifies PRCC patients into clinically relevant subgroups and has significant implications on the management of PRCC.

Modulating ATP binding cassette transporters in papillary renal cell carcinoma type 2 enhances its response to targeted molecular therapy

“…Additionally, the tumors demonstrated diffuse strong staining with ABCC2 (Fig. C) as we have previously described in the PRCC2 subtype (Saleeb et al ., ). Taken together, the morphology, immunostaining pattern, and molecular analyses show that CAKI‐2 can serve as a representative model for PRCC2.…”

“…recent review on RCC cell lines describing multiple evidence linking CAKI‐2 to PRCC (Brodaczewska et al ., ). Additionally, CAKI‐2 harbors chromosome 8 aberrations, which has also been described in PRCC2 (Furge et al ., ; Saleeb et al ., ).…”

“…In our previous studies, we have confirmed the distinct molecular profiles of PRCC subtypes 1 and 2. We also uncovered specific molecular pathways and biomarkers that can influence PRCC subtypes response to therapy (Saleeb et al ., , ). PRCC1, as noted from previous literature, had much better prognosis, compared to PRCC2 (Klatte et al ., ; Pignot et al ., ).…”

Reactivity of CK7 across the spectrum of renal cell carcinomas with clear cells

“…P‐RCCs are a highly heterogeneous group of RCCs, traditionally divided into types 1 and 2. However, an increasing number of recent studies showed that P‐RCC is more diverse than previously thought . It seems that these tumours are composed of different subtypes of RCC sharing similar architectural growth pattern, but demonstrating variable immunoprofile and molecular genetic features.…”

Cystic Appearance on Imaging Methods (Bosniak III-IV) in Histologically Confirmed Papillary Renal Cell Carcinoma is Mainly Characteristic of Papillary Renal Cell Carcinoma Type 1 and Might Predict a Relatively Indolent Behavior of Papillary Renal Cell Carcinoma

“…Papillary renal cell carcinoma (pRCC) represents a heterogeneous group of tumors that differ clinically, histologically, genetically, immunohistochemically, and also with regard to prognosis [1][2][3][4][5][6]. In a considerable fraction of pRCC tumors, it remains challenging to histopathologically classify 1 of the 2 official WHO 2016 subtypes (pRCC type 1 and 2).…”