The Clinicopathologic and Molecular Landscape of Clear Cell Papillary Renal Cell Carcinoma: Implications in Diagnosis and Management - Beyond the Abstract

Clear cell papillary renal cell carcinoma (CCPRCC) accounts for 2-4% of renal cortical tumors and was recently recognized by the World Health Organization in 2016 as a new tumor entity. Initially described in patients with end-stage renal disease (ESRD) by Tickoo et al,1 later studies found that CCPRCC also arises sporadically in patients with normal renal function.

In this study, we sought to characterize both the clinical and pathologic features of CCPRCC, as well as compare these features to clear cell and papillary type 1 tumors. In a cohort of 89 patients, we found a balanced gender distribution (45% female vs. 55% male), a higher rate in African-American patients (CCPRCC: 19% vs. clear cell: 3%, p=<0.001; vs. papillary: 9%, p=0.02), and a high rate of multifocality (25%), which was often discordant (56%) in pathology. We also saw no enrichment for ESRD.

Regarding clinical outcomes of patients with only CCPRCC tumors, our results showed that their prognosis was highly favorable with five-year overall survival at 92.1% (95% confidence interval [CI]: 90.7, 94.5). No patients died of the disease nor were there any documented metastases. However, the median follow-up time for the CCPRCC cohort was only 38 months (Interquartile Range [IQR]: 20,73).

This work also expands upon previous efforts with Reznik et al.2 characterizing the odd metabolic changes in this tumor type, which is known to activate the hypoxia-inducible factor (HIF) pathway despite having an intact VHL gene. From a genomic standpoint, CCPRCC tumors are remarkably “boring” with no recurrent copy number events or mutations. Additionally, we demonstrated that these tumors have a significantly lower mitochondrial DNA content compared to other RCC subtypes.

Is CCPRCC a benign entity given the lack of metastases and relatively bland genome? We think time will tell as we characterize larger data sets with longer follow-up periods. However, the biggest challenge comes on the pathology side.

Morphologically, CCPRCC exhibits overlapping features with other RCC entities such as clear cell, papillary, TCEB1-deficient, and TSC-associated variants. Clear cell tumors may also contain focal regions that appear to be “clear cell papillary-like”, making CCPRCC a challenging diagnosis to make. Furthermore, these tumor histologies are associated with potentially aggressive disease. This complicates a solely, biopsy-based diagnosis, and therefore in the context of limited tumor sampling, a combination of both morphologic and immunohistochemical criteria should always be used for diagnosis. Pathologists should make sure that sufficient sample material is available for review and exclude the presence of CCPRCC-like features in a clear cell RCC context, which can greatly impact patient prognosis.

The high rate of multifocality and histologic discordance in CCPRCC tumors add additional complexity to the management of this disease. A diagnosis based on biopsy of only a single tumor site does not preclude additional tumor foci in the same kidney from harboring more aggressive RCC subtypes and therefore, multifocal CCPRCC diagnoses based on single-mass biopsy should warrant further caution from surgeons. CCPRCC patients need to be followed and new tumors should not be assumed to be of the same histology. Tissue sampling of at least two distinct masses may also help drive clinical management decisions.   

Written by: Stanley Weng and A. Ari Hakimi, Urology Department, Memorial Sloan Kettering Cancer Center


  1. Tickoo, Satish K., Mariza N. dePeralta-Venturina, Lara R. Harik, Heath D. Worcester, Mohamed E. Salama, Andrew N. Young, Holger Moch, and Mahul B. Amin. "Spectrum of epithelial neoplasms in end-stage renal disease: an experience from 66 tumor-bearing kidneys with emphasis on histologic patterns distinct from those in sporadic adult renal neoplasia." The American journal of surgical pathology 30, no. 2 (2006): 141-153.
  2. Xu, Jianing, Ed Reznik, Ho-Joon Lee, Gunes Gundem, Philip Jonsson, Judy Sarungbam, Anna Bialik et al. "Abnormal oxidative metabolism in a quiet genomic background underlies clear cell papillary renal cell carcinoma." Elife 8 (2019): e38986.
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