Natural history of medullary thyroid carcinoma in MEN 2 patients carrying a variant at codon 804 in the RET proto-oncogene: A study by the French Neuroendocrine Tumor Group (GTE)

Abstract

Background: RET variants affecting codon 804 are part of the low-to-moderate risk group in the ATA classification, with indications for prophylactic thyroidectomy beyond age of 5years. However, aggressiveness seems to be variable. The objective of this study was to report a large cohort of French carriers of a pathogenic variant at codon 804 in the RET proto-oncogene.

Methods: Patients from 12 university hospitals with a RET 804 variant were recruited in this retrospective non-interventional French national study, from the French GTE-ENDOCAN-RENATEN database. Incidence and severity (TNM stage and calcitonin levels) of medullary thyroid carcinoma (MTC), phenotype-genotype correlation and clinical outcome were assessed.

Results: A total of 322 patients were analyzed. Index cases (n=65) had a median age at diagnosis of 57years (range: 46-66), and relatives (n=257) a median age of 37years (range: 18-51). Median first calcitonin measurement was 240ng/L (range: 79-1344) in index cases, and 6.7ng/L (range: 0-22) in relatives. In index cases, the pathogenic variant c.2410G>A (p.Val804Met) in RET was more frequent (80% of cases) than c.2410G>C or c.2410G>T (p.Val804Leu). MTC was multifocal, node-positive and metastatic in 64%, 51% and 20% of cases respectively. TNM stage, preoperative calcitonin level and male gender were predictive of persistent disease (defined by postoperative calcitonin>5ng/L) (P<0.001). Ten-year disease-free survival (DFS) was 61%. In total, 113 relatives were operated on: 62% with MTC and 34% with isolated C-cell hyperplasia (CCH); the youngest patients were aged 20 for MTC and 4years for CCH. Ten-year DFS was 90%.

Conclusion: The RET pathogenic variants affecting the codon 804 mainly led to low aggressiveness disease, with late presentation and prolonged DFS. We suggest surgery in relatives if calcitonin values are above 6ng/L, instead of 10ng/L. Long-term surveillance is mandatory, since recurrence remains possible several years after surgery.

Keywords: MEN2a; Medullary thyroid carcinoma; Natural history; Prophylactic thyroidectomy; RET 804 variant; p.Val804Leu; p.Val804Met.