Sporadic medullary thyroid cancer in children linked to RET alterations

medwireNews: The majority of sporadic medullary thyroid cancer (sMTC) cases in children may be positive for RET mutations that are potentially amenable to treatment with a targeted agent, suggests research published in the Journal of Clinical Endocrinology & Metabolism.

“Our study’s finding of 92% of sMTCs with a druggable gene alteration underscores the importance of comprehensive somatic molecular testing in children and young adults with advanced sMTC who would benefit from systemic therapy”, say Steven Waguespack, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

The study compared the presentation and outcomes of 144 patients with sMTC or hereditary (h)MTC, aged up to 21 years at time of diagnosis, at the institution between 1961 and 2019.

Initial analysis indicated that the 20 patients with sMTC were significantly older at time of diagnosis than their 120 counterparts with hMTC (median age 19 vs 13 years) and their primary tumours were both significantly larger (median 2.5 vs 0.8 cm) and significantly more likely to be unifocal (53 vs 17%) and at stage IV (79 vs 38%). Although lateral neck lymph node metastases also occurred at a significantly higher frequency in sMTC than hMTC (79 vs 35%), the rates of distant metastases were statistically comparable (25 vs 7%).

Waguespack et al report that the hMTC cohort had multiple endocrine neoplasia type 2 (MEN2) disease associated with RET alterations, with 64% having MEN2A and 36% having MEN2B. The clinical presentations of the latter group aligned “more closely with sMTC” with a “predominant clinical presentation, including the non-endocrine manifestations of MEN2B”, such as diarrhoea, they observe.

The median duration of follow-up was comparable in the sMTC and hMTC cohorts (median 8.9 vs 10.5 years) and at the time of last follow-up, patients with sMTC were significantly more likely than those with hMTC to have persistent disease (95 vs 64%) and distant metastases (79 vs 37%), and significantly less likely to be free from disease (5 vs 36%).

Of 138 evaluable patients, MTC deaths were reported for three patients with sMTC including one patient with a somatic RET deletion, three patients with MEN2A and the pC634R variant, and six patients with MEN2B, three of whom had the pM918T variant.

Estimated median overall survival (OS) was 34.3 years for patients with sMTC and 39.3 years for patients with MEN2B, while median OS was not reached for the overall hMTC cohort or those with MEN2A.

Although the 10-year rate of OS was significantly lower for patients with sMTC or MEN2B than for those with MEN2A (93 and 90 vs 100%, respectively), when only patients who presented clinically, rather than by family history or genetic screening were considered there was no significant difference in the “excellent” OS achieved by the three groups, the researchers say.

Waguespack and co-authors found that sMTC patients diagnosed before and after the availability of commercial testing for the RET alteration in 1995 did not significantly differ in terms of OS.

Nevertheless, the researchers found that 10 of the 12 children with sMTC who underwent genetic testing had a RET alteration and one patient had an ALK fusion, seven of whom received systemic therapy.

The investigators conclude that “once MTC develops, the clinical course and outcomes are similar whether sporadic or hereditary and regardless of RET variant in hMTC, in which the major difference is the age of onset of hMTC determined by the underlying RET variant.”

They say: “This highlights the importance of early detection and surgery in hMTC before it becomes clinically apparent or metastatic.”

By Lynda Williams

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2024 Springer Healthcare Ltd, part of the Springer Nature Group

J Clin Endocrinol Metabol 2023; doi:10.1210/clinem/dgae133
Martin Savage
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