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Aims: Papillary renal cell carcinoma (PRCC) histologic subtyping is no longer recommended in the 2022 WHO classification. Currently, WHO/ISUP nucleolar grade is the only accepted prognostic histologic parameter for PRCC. ABCC2, a renal drug transporter, has been shown to significantly predict outcomes in PRCC. In this study we evaluated the prognostic significance of ABCC2 IHC staining patterns in a large, multi‐institutional PRCC cohort and assessed the association of these patterns with ABCC2 mRNA expression. Methods and results: We assessed 254 PRCCs for ABCC2 IHC reactivity patterns that were stratified into negative, cytoplasmic, brush‐border <50%, and brush‐border ≥50%. RNA in situ hybridization (ISH) was used to determine the transcript level of each group. Survival analysis was performed with SPSS and GraphPad software. RNA‐ISH showed that the ABCC2 group with any brush‐border staining was associated with a significant increase in the transcript level, when compared to the negative/cytoplasmic group (P = 0.034). Both ABCC2 groups with brush‐border <50% (P = 0.024) and brush‐border ≥50% (P < 0.001) were also associated with worse disease‐free survival (DFS) in univariate analysis. Multivariate analysis showed that only ABCC2 IHC brush‐border (<50% and ≥50%) reactivity groups (P = 0.037 and P = 0.003, respectively), and high‐stage disease (P < 0.001) had a DFS of prognostic significance. In addition, ABCC2 brush‐border showed significantly worse DFS in pT1a (P = 0.014), pT1 (P = 0.013), ≤4 cm tumour (P = 0.041) and high stage (P = 0.014) groups, while a similar analysis with high WHO/ISUP grade in these groups was not significant. Conclusion: ABCC2 IHC brush‐border expression in PRCC correlates with significantly higher gene expression and also independently predicts survival outcomes. [ABSTRACT FROM AUTHOR]

Objective: Papillary renal cell carcinoma (PRCC) is common in end stage kidney disease (ESKD). They are known to have multiple distinct subtypes. Papillary adenomas (PAs) are small benign papillary lesions that are thought to be PRCC precursors and are also very prevalent in ESKD. The evolution of PAs to PRCCs and their relationship to ESKD are poorly understood. Methods: A total of 135 cases of PAs, normal kidneys, ESKD and PRCCs were collected. Molecular analysis of the different groups was performed using miRNA expression, Copy number variations (CNV), and whole exome sequencing (WES). Stem cell markers BCL2, CK7, LGR5 were assessed using immunohistochemical image analysis. Data and Results: Molecular analysis showed similarities between ESKD and PA. Renal tubular progenitor cell markers were significantly increased in ESKD (p <0.0001) and PAs (p= 0.02) in comparison to the normal kidney. Embryonic developmental pathways were enriched in PA and all the PRCC subtypes. Lysine methyltransferase2C (KMT2C) was found to have a common frameshift insertion among all papillary lesions. Pathway analysis showed an evolutionary interconnected model from ESKD as a first stage to the different PRCC tumour subtypes as final stage. Conclusion: Normal kidney progenitor cells are likely cells of origin of PRCCs that in ESKD, and hence the frequency of PRCCs in ESKD. There are connected molecular events that underlie the transformation of ESKD to PAs to the different PRCC subtypes. The results shed light on novel biological aspects of PRCC development and can aid in clinical management and early prevention of these tumours. [ABSTRACT FROM AUTHOR]

Objective: Papillary Renal Cell Carcinoma (PRCC) is recognized to have two histologic subtypes. Previous studies have shown the subtypes have different characteristic genetic alterations, and clinical behavior. We aimed to elucidate the molecular differences between the subtypes on the genetic, and epigenetic level and to gain insight into the molecular pathways that drive tumour behavior. Methods: Patient cohort PRCC, 291, of the Cancer Atlas Genome (TCGA) was divided on histologic criteria into type 1, type 2 or not-otherwise specified (NOS). Gene expression (RNA seq) data for the cohort was examined using unsupervised clustering, and supervised clustering bioinformatics analysis. A total of 35 primary PRCC specimens were also collected, for miRNA analysis, after similar histologic subclassification. Gene set enrichment analysis (GSEA) was performed on both cohorts. Data and Results: Analysis of gene expression and miRNA expression between the subtypes using unsupervised clustering revealed two distinct genetic tumour signatures. Supervised clustering produced statistically significant identifying markers for each subtype. GSEA revealed considerably different pathways implicated in each type including VEGF, mTOR, and Wnt signaling pathways. Conclusions: Investigating the subtypes of PRCC at the molecular level, revealed that each have distinct genetic signatures and implied molecular pathways. Our findings highlight the need to segregate between the types in clinical assessment and management; given that the subtypes may have differing responses to current targeted molecular therapies. There is also a need to identify robust markers for pathologists to aid in the distinction between the subtypes, and to accurately classify tumours within the PRCC NOS category. [ABSTRACT FROM AUTHOR]

Objective: Papillary renal cell carcinoma (PRCC) is comprised of two histological subtypes. PRCC2 is more aggressive and molecularly distinct from PRCC1. Despite this PRCCs are clinically treated as one entity, with lack of any evidence-based management recommendations. We have previously detected ABCC2 (ABC transporter) and mTOR pathway to be enriched in PRCC2. In this study we assess the therapeutic potential of targeting these pathways in PRCC2. Methods: Bioinformatics analysis was performed on twenty RCC cell lines and compared to the PRCC2 signature derived from cancer genome atlas cohort (290 cases). Selected cell lines were grown in vitro and in vivo. Cells were treated with five different conditions, untreated, anti-VEGF (Sunitinib), ABCC2 blocker (MK571), mTOR inhibitor (Everolimus) and Sunitinib + MK571. Tumour Sunitinib uptake and apoptosis were measured by flow cytometry. Mice tumours were examined histologically and Ki67 was quantified with digital analysis. Data and Results: The Sunitinb+ABCC2 blocker group showed significant response to therapy both in vitro (p = <0.0001) and in vivo (p = 0.0132). ABCC2 blockage resulted in almost double the uptake of Sunitinib, (p= 0.0016). The Everolimus treated group demonstrated second best response in vivo. The dual treatment group showed the highest apoptotic, and lowest ki67 proliferation rate. Conclusion: There is need for individualized therapies of RCC subtypes that take into account their specific biology. Our study demonstrates that targeting ABC transporter ABCC2 in PRCC2 has therapeutic potential. The results are also significant for similar ABCC2 high tumours. Clinical trials are needed to confirm these effects in patients. [ABSTRACT FROM AUTHOR]

MiT family translocation tumors are a group of neoplasms characterized by translocations involving MiT family transcription factors. The translocation renal cell carcinomas, TFE3 (Xp11.2) and TFEB (t6;11) are known members of this family. Melanotic Xp11 translocation renal cancer is a more recently described entity. To date only 14 cases have been described. It is characterized by a distinct set of features including a nested epithelioid morphology, melanin pigmentation, labeling for markers of melanocytic differentiation, lack of labeling for markers of renal tubular differentiation, predominance in a younger age population and association with aggressive clinical behavior. There are noted similarities between that entity and TFE3 associated PEComas. There are no cases reported of equivalent melanotic TFEB translocation renal cancer. We report 2 rare cases of melanotic translocation renal neoplasms. The first is a melanotic TFE3 translocation renal cancer with an indolent clinical course, occurring in a patient more than 3-decades older than the usual average age in which such tumors have been described. The other case is, to our knowledge, the first reported melanotic TFEB translocation cancer of the kidney. Both cases exhibit the same H&E morphology as previously reported in melanotic translocation renal cancers and label accordingly with HMB45 and Melan-A. While the TFE3 melanotic tumor lacked any evidence of renal tubular differentiation, the TFEB melanotic cancer exhibited some staining for renal tubular markers. Based on the unique features noted above, these two cases expand the clinical and molecular spectrum of the melanotic translocation renal cancers., (Copyright © 2017 Elsevier GmbH. All rights reserved.)