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

Abstract

Background: Clear cell papillary renal cell carcinoma (CCPRCC) is a recently described tumor entity. Several questions remain about its epidemiology, molecular features, and clinical behavior.

Objective: To comprehensively evaluate clinicopathologic and molecular features of CCPRCC, and compare it with more common kidney cancer subtypes.

Design, setting, and participants: We identified 89 CCPRCC patients and compared their clinicopathologic features with 1120 localized clear cell renal cell carcinoma (ccRCC) and 129 type 1 papillary renal cell carcinoma (pRCC) patients.

Outcome measurements and statistical analysis: Nonparametric statistical testing was used to compare relevant features between tumor types. Overall, cancer-specific survival (CSS) and metastasis-free survival estimates were calculated from initial diagnosis using the Kaplan-Meier method. Patients with ipsilateral multifocal disease were explored further. A subset of CCPRCC tumors underwent genomic analysis and were compared with other RCC subtypes.

Results and limitations: A higher proportion of female (45% vs 32%) and African-American (19% vs 3%) patients were observed in the CCPRCC cohort than in the ccRCC and pRCC cohorts. CCPRCC tumors also had increased odds of presenting with additional ipsilateral masses (odds ratio [OR]: 4.41 [confidence interval {CI}: 2.34, 8.15], p < 0.001) and bilateral disease (OR: 4.80 [CI: 2.40, 9.59], p < 0.001) compared with ccRCC tumors. On molecular analysis, CCPRCC tumors showed fewer somatic aberrations and a greater degree of mitochondrial DNA depletion. In multifocal CCPRCC tumors, histologic concordance among the different renal cell carcinoma masses was estimated at 44% (7/16), and none of the individuals presenting exclusively with CCPRCC tumors developed metastatic disease after 5 yr. In contrast, multifocal tumors with CCPRCC and other nonconcordant histologies were more likely to experience adverse outcomes (CSS, log rank p = 0.034).

Conclusions: CCPRCC is characterized by distinct molecular and epidemiologic features that could be used to refine current diagnostic approaches. Although their clinical course is generally indolent, multifocal CCPRCC tumors represent a unique diagnostic challenge. In this context, single-mass biopsies could miss concomitant aggressive disease, with a potential negative impact on patient outcomes. Furthermore, high discordance rates in multifocal CCPRCC tumors have important clinical implications in management.

Patient summary: We explored the molecular and clinical features of clear cell papillary renal cell carcinoma (CCPRCC) relative to other kidney cancer subtypes. While CCPRCC generally conveys a good prognosis, additional caution should be taken when it is diagnosed using biopsy if multiple kidney masses are present.

Keywords: Clear cell papillary; DNA copy number; Genomics; Renal cell carcinoma.

Fig. 1 –

Morphologic and immunohistochemical features of CCPRCC. (A) Low-magnification view showing tubulopapillary and cystic architecture. (B) High-magnification view showing linear arrangement of nuclei oriented away from the basement membrane. (C) “Cup-like” CA-IX positive staining pattern with absence of staining on the luminal side. (D) Diffuse CK7 positive staining. (E) Negative staining for AMACR. (F) Negative staining for CD-10. AMACR = alpha-methylacyl-CoA racemase; CA = carbonic anhydrase; CCPRCC = clear cell papillary renal cell carcinoma; CK = cytokeratin.

Fig. 2 –

Clinical outcomes of pure CCPRCC, ccRCC, and type 1 pRCC tumors. Kaplan-Meier survival curves along with 5-yr estimates are shown for CCPRCC, LG ccRCC, HG ccRCC, and type 1 pRCC groups. (A) HG ccRCC had worse overall survival compared with CCPRCC (log rank, p = 0.02). (B) No disease-specific deaths or (C) cases of distant metastases were observed for CCPRCC. CCPRCC = clear cell papillary renal cell carcinoma; ccRCC = clear cell renal cell carcinoma; CI = confidence interval; CSS = cancer-specific survival; HG = high grade; LG = low grade; MFS = metastasis-free survival; NA = not available; OS = overall survival; pRCC = papillary renal cell carcinoma.

Fig. 3 –

Clinicopathologic features of patients with multifocal CCPRCC tumors. An overview of patients with multiple ipsilateral RCC tumors at any point in their RCC history (n = 16). Patients who had multiple ipsilateral tumors of just CCPRCC histology were grouped as “pure multifocal CCPRCC” patients, and those who had multiple ipsilateral tumors with differing histologies, including CCPRCC, were grouped as “mixed multifocal CCPRCC” patients. Patients with two or more CCPRCC tumors on one side had decreased odds of having a tumor of different histology in the same kidney (OR: 0.00 [CI: 0.00, 0.15], p < 0.001). The top tiles demonstrate this finding, and the pure multifocal CCPRCC group appears to be mutually exclusive from the mixed multifocal CCPRCC group. The middle tiles show the associated clinical characteristics, and the bottom tiles show the histologies of the non-CCPRCC tumors. Tumor size for multifocal tumors of CCPRCC-only histology was larger than multifocal tumors of mixed histology (Wilcoxon rank sum, p = 0.048). CCPAP = clear cell papillary; CCPRCC = clear cell papillary renal cell carcinoma; CI = confidence interval; Nx = nephrectomy; OR = odds ratio; RCC = renal cell carcinoma.

Fig. 4 –

Comparison of genomic features between CCPRCC and other common RCC subtypes. (A) Tumor mutation burden. A scatter plot showing the number of mutations per megabase. Median values are represented by the solid black lines. (B) Fraction of CN alterations (FCNA) in the nuclear genome. Box plots demonstrate the median and IQR of the FCNA values displayed by each tumor subtype; the whiskers represent 1.5× the IQR. (C) Relative mtDNA abundance. Histograms and density plots show the distribution of relative mtDNA content (tumor/normal kidney) across histologies. The dashed lines represent the within-cohort median, and the vertical solid gray line indicates the null value (ie, equal mtDNA content in tumor and kidney). The p values were obtained using Wilcoxon rank-sum tests. Two samples from the KIRC cohort (BP-4760 and BP-4795) were initially diagnosed as ccRCC and then pathologically reconfirmed as CCPRCC. CCPRCC = clear cell papillary RCC cohort; ccRCC = clear cell renal cell carcinoma; CN = copy number; CNA = copy number alteration; IQR = interquartile range; KICH = TCGA chromophobe RCC cohort; KIRC = TCGA clear cell RCC cohort; KIRP = TCGA papillary RCC cohort; mtDNA = mitochondrial DNA; RCC = renal cell carcinoma; TCGA = The Cancer Genome Atlas.