Letter to the Editor: The Somatic RET M918T Variant May Modify the Natural History of Germline RET L790F MEN2-Related Medullary Thyroid Carcinoma

Dear Editor:

Twenty to 25% of medullary thyroid carcinoma (MTC) are due to germline RET activating pathogenic variants as part of multiple endocrine neoplasia type 2 (MEN2). MEN2 is characterized by a strong genotype–phenotype correlation. Patients are stratified into three risk grades for aggressive MTC (moderate, high, and highest risk) based on germline RET variations. For instance, the c.2370G>C, p.Leu790Phe variant (RET-L790F) is considered to be of moderate risk of aggressive MTC, while the germline c.2753T>C, p.Met918Thr RET variant (RET-M918T) presents the highest risk. ¹

A 35-year-old woman presented with a suspicious 13 mm thyroid nodule and right laterocervical nodes. Calcitonin and carcinoembryonic antigen (CEA) levels were 2300 pg/mL (N < 10) and 21 ng/mL (N < 3.5), respectively, in favor of MTC. ¹⁸F-dihydroxyphenyl-alanine positron emission tomography showed high uptake in the thyroid nodule and laterocervical nodes, while millimetric lung nodules did not show any uptake. Total thyroidectomy with neck dissection revealed a pT3N1bMx MTC. Ki-67 was 10%. Germline genetic screening identified a RET-L790F pathogenic variant. During the follow-up, she presented with a locoregional progression with laterocervical nodes. Both calcitonin and CEA increased with a doubling time of 12 and 15 months, respectively.

Imaging identified a suspicious left iliac bone lesion 23 months after the diagnosis, treated by cryoablation. As the patient progressed with distant metastases, somatic analysis was performed on the thyroid specimen, showing a somatic RET-M918T. No variations were founded on cancer-related genes ALK, FGFR1, FGFR2, FGFR3, HRAS, KRAS, JAK1, JAK2, JAK3, and MET. At last follow-up, 6 years after surgery, calcitonin and CEA were 6566 pg/mL and 84.2 ng/mL, respectively (Fig. 1). As imaging showed a stable metastatic disease, the multidisciplinary team recommended a wait-and-watch approach with no systemic treatment. Catecholamines, calcium, and parathormon levels all remained normal. Family screening revealed four RET-L790F carriers aged 12–68 years, with normal calcitonin and neck ultrasound. No thyroidectomy was performed.

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FIG. 1.

Evolution of calcitonin and CEA levels and treatments from the time of diagnosis to last follow-up. CEA, carcinoembryonic antigen.

Most studies reporting the natural history of RET-L790F-related MTC suggested an indolent disease. A French multicentric study involving 77 RET-L790F MEN2A patients reported no distant metastases, and lymph node invasion in only 10/55 (18.2%) operated patients (mean age 32 years). After a follow-up of 89 months, most patients were cured. ² In contrast, several studies reported that somatic RET-M918T is a main driver of tumorigenesis in nonhereditary MTC, leading to a more advanced stage at diagnosis and a worse outcome. ³

Concomitant somatic and germline RET mutations in MEN2-related MTC have been rarely reported. Lombardo et al. described a 12-year-old girl exhibiting an extensive and invasive MTC despite a germline moderate risk 804 RET variant, leading to the identification of a somatic RET-M918T. ⁴ A somatic RET-M918T was also identified in 4 MEN2A MTCs with germline 634, 618, and 620 variants. ⁵ More recently, while no somatic RET mutation had been identified, a somatic variant in FTL3 (a transcription factor involved in growth and differentiation) was reported in a RET-L790F carrier with metastatic progression few years after the diagnosis of a locoregionally advanced MTC. ⁶

To our knowledge, this is the first report highlighting the potential additional role of a somatic RET-M918T in a patient with a germline RET-L790F, who rapidly developed metastases. Further studies should determine whether MEN2 patients with an atypical MTC phenotype should be tested from a somatic viewpoint, and how this could individualize our follow-up strategies in MEN2 patients.