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 5 years. 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: 322 patients were analyzed. Index cases (n=65) had a median age at diagnosis of 57 years (range, 46-66), and relatives (N=257) a median age of 37 years (range, 18-51). Median first calcitonin measurement was 240 ng/l (range, 79-1,344) 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%. 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 4 years 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 6 ng/l, instead of 10ng/l. Long-term surveillance is mandatory, since recurrence remains possible several years after surgery.