Endocrine Abstracts

JOINT1569

Introduction: Multiple Endocrine Neoplasia Type 2 is linked with activated germline mutations of the RET proto-oncogene, one of which, Val804Met (V804M) mutation has been classified as moderate risk to develop medullary thyroid carcinoma (MTC) according to the American Thyroid Association. Our study aims to investigate a cohort of Maltese patients carriers for V804M mutation and compare their clinical, biochemical and histopathological characteristics.

Methods: Genetic screening of relatives of the index case, who was diagnosed with homozygous V804M mutation in the RET gene in 2022, was done in Malta, between November 2022 and December 2024. Detailed clinical, radiological and histopathological data was obtained for each patient who had the mutation.

Results: A total of 57 patients were screened, of which 31 (54.4%) were positive for V804M mutation. Eighteen patients (58.1%) were males and only 1 patient (index’s case brother) was homozygous for this mutation. The median age at diagnosis was 44 years (IQR 26.0-52.5). Five (16.1%) were 1^st degree relatives to the index case, 11 (35.5%) were 2^nd degree, 12 (38.7%) were 3^rd degree and 2 (6.5%) were 4^th degree. The index case had a co-existing somatotropinoma. No patients had phaeochromocytoma, hyperparathyroidism, Hirschsprung disease or cutaneous lichen amyloidosis throughout the study period. The median initial calcitonin was 5pg/ml (IQR 3.7-17.0). The highest initial calcitonin was observed in the index case and her brother, (4300pg/ml and 403pg/ml, respectively). Thirteen (42.0%) patients underwent surgery. Eleven (84.6%) had MTC present on histological analysis, whilst one had only C-cell hyperplasia and another had neither MTC nor C-cell hyperplasia. One of the patients with MTC had an undetectable pre-operative calcitonin level. The median size of the largest focus of MTC was 7mm (IQR 2.5-12.5). Two patients (15.4%) had concurrent papillary thyroid carcinoma. Distant metastasis was only observed in the index case, whilst lymph node metastasis was present in 2 patients (30.8%). Post-operative calcitonin remained elevated in 3 cases at 525pg/ml, 150pg/ml and 10ng/ml, respectively. None received adjuvant radiotherapy or chemotherapy. No patient died during the study period.

Conclusion: This is the first study evaluating carriers of V804M RET mutation in the Maltese Islands. Despite most studies recommend total thyroidectomy based on elevated calcitonin level in carriers, our study suggests that MTC can be present even at undetectable calcitonin levels. However, further screening of the relatives of the index case is still undergoing, which can enhance our understanding of the natural history of this condition.