Synchronous Metastatic Clear-Cell Renal Cell Carcinoma: A Distinct Morphologic, Immunohistochemical, and Molecular Phenotype

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In order to compare synchronous and metachronous metastatic clear cell renal cell carcinoma, we performed a pathologic, immunohistochemical, and molecular study on primary tumors in a retrospective series of 48 consecutive patients with up to 10 years of follow-up. Synchronous metastatic clear cell renal cell carcinoma had a distinct phenotype that may explain their worse prognosis.


Clear cell renal cell carcinomas (ccRCCs) are highly metastatic tumors with metastases detected at diagnosis (synchronous) or during follow-up (metachronous). To date, there have been no reports comparing primary ccRCC of patients with synchronous and metachronous metastases, who are different in terms of prognosis. Determining whether there is a phenotypic difference between these 2 groups could have important clinical implications.

Patients and Methods:

In a retrospective consecutive cohort of 98 patients with ccRCC, 48 patients had metastases, including 28 synchronous and 20 metachronous presentations, with a follow-up of 10 years. For each primary tumor in these metastatic patients, pathologic criteria, expression of vascular endothelial growth factor, partitioning-defective 3, CAIX, and programmed death ligand 1 as detected by immunohistochemistry, and complete VHL status were analyzed. Univariate analysis was performed, and survival was assessed using Kaplan-Meier curves compared by log-rank test.


Compared with primary ccRCC in patients with metachronous metastases, primary ccRCC in patients with synchronous metastases were significantly associated with a poorer Eastern Cooperative Oncology Group performance (P = .045), higher pT status (P = .038), non-inactivated VHL gene (P = .01), sarcomatoid component (P = .007), expression of partitioning-defective 3 (P = .007), and overexpressions of vascular endothelial growth factor (> 50%) (P = .017) and programmed death ligand 1 (P = .019). Patients with synchronous metastases had a worse cancer-specific survival than patients with metachronous metastases even from metastatic diagnosis (median survival, 16 months vs. 46 months, respectively; P = .01).


This long-term study is the first to support the notion that synchronous m-ccRCC has a distinct phenotype. This is probably linked to the occurrence of oncogenic events that could explain the worse prognosis. These particular patients with metastases could benefit from specific therapy.

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