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. 2021 Jan 4;4(1):e2021869.
doi: 10.1001/jamanetworkopen.2020.21869.

Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival

Shaan Dudani  1 , Guillermo de Velasco  2 , J Connor Wells  1 , Chun Loo Gan  1 , Frede Donskov  3 , Camillo Porta  4   5 , Anna Fraccon  6 , Felice Pasini  7 , Jae Lyun Lee  8 , Aaron Hansen  9 , Georg A Bjarnason  10 , Benoit Beuselinck  11 , Sumanta K Pal  12 , Takeshi Yuasa  13 , Nils Kroeger  14 , Ravindran Kanesvaran  15 , M Neil Reaume  16 , Christina Canil  16 , Toni K Choueiri  17 , Daniel Y C Heng  1
Affiliations

Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival

Shaan Dudani et al. JAMA Netw Open. .

Abstract

Importance: There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse.

Objective: To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC).

Design, setting, and participants: In this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020.

Exposures: Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected.

Main outcomes and measures: The primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases.

Results: A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site.

Conclusions and relevance: Sites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect differences in underlying disease biology. Further work to investigate differences in immune, molecular, and genetic profiles between metastatic sites and histologic subtypes is encouraged.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr de Velasco reported receiving grants and personal fees from Pfizer, Roche, and Ipsen; and personal fees from Bristol-Myers Squibb, Astellas, Janssen, Bayer, Merck, and MSD outside the submitted work. Dr Wells reported receiving personal fees from Pfizer outside the submitted work. Dr Donskov receiving reported grants from Pfizer, Ipsen, and MSD outside the submitted work. Dr Porta reported receiving personal fees from Bristol-Myers Squibb, MSD, Astra Zeneca, Pfizer, Novartis, Ipsen, EUSA, Eisai, General Electric, and Roche outside the submitted work. Dr Hansen reported receiving grant/research support from Novartis, Bristol-Myers Squibb, Genetech, AstraZeneca/Medimmune, Merck, Karyopharm, GSK, Boerhinger-Ingelheim, Pfizer, and Roche; and receiving consultant/advisory arrangements from Merck (compensated), GSK (compensated), Bristol-Myers Squibb (uncompensated), and Eisai (compensated) outside the submitted work. Dr Beuselinck reported receiving consultancy fees from Bristol-Myers Squibb, Pfizer, Merck, and AstraZeneca; speaker fees from Bristol-Myers Squibb, Merck; and research grants from Bristol-Myers Squibb, all outside the submitted work. Dr Pal reported receiving personal fees from Genentech, Aveo, Eisai, Roche, Pfizer, Novartis, Exelixis, BMS, Ipsen, and Astellas outside the submitted work. Dr Kanesvaran reported receiving grants and personal fees from MSD, Bristol-Myers Squibb, Eisai, Ipsen, and Pfizer outside the submitted work. Dr Reaume reported receiving personal fees from Bayer, Pfizer, Bristol-Myers Squibb, Astra Zeneca, Novartis, Eisai, Ipsen, Merck, and Roche during the conduct of the study. Dr Canil reported receiving personal fees from Bayer, Janssen, Pfizer, Ipsen, Bristol-Myers Squibb, Roche, Eisai, and AstraZeneca; and education travel grants from Sanofi Genzyme, Janssen, Pfizer, and Amgen. Dr Choueiri reported receiving grants and personal fees from AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Roche, Pfizer, and Novartis during the conduct of the study; grants, personal fees, and nonfinancial support from Pfizer, grants from Exelixis, Bristol-Myers Squibb, Merck, Roche/Genentech, and grants, personal fees from Novartis outside the submitted work. Dr Heng reported receiving grants from Pfizer, Novartis, Bristol-Myers Squibb, Ipsen, Merck, and Eisai outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Sites of Renal Cell Carcinoma (RCC) Metastasis by Histologic Subtype
The percentage of patients with involved site of metastasis at the time of first systemic therapy initiation for metastatic disease are presented. The 5 most frequent sites of metastasis across all histologic profiles are highlighted in bold type.
Figure 2.
Figure 2.. Survival by Site of Metastatic Involvement in Clear Cell Renal Cell Carcinoma (RCC)
Survival time is presented in descending order (error bars indicate 95% CIs) for: pancreas (353 patients), thyroid (48 patients), bowel (46 patients), adrenal (678 patients), lung (6189 patients), peritoneum (117 patients), lymph nodes (3874 patients), spleen (55 patients), bone (2847 patients), liver (1560 patients), brain (705 patients), and pleura (295 patients). Overall survival was calculated from time of first systemic therapy initiation for metastatic disease to death from any cause or censored at the time of last follow-up. aComparing involved vs noninvolved site of metastasis, adjusted by number of International mRCC Database Consortium criteria, number of sites of metastasis, sarcomatoid features, and year started systemic therapy. Hazard ratio greater than 1 denotes worse overall survival.
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