A recently published study in Pathology – Research and Practice has revealed that in the presence of Val804Met RET, several types of thyroid premalignancy and malignancy should be screened in addition to medullary thyroid carcinoma (MTC). The study suggested that the possibility of multiple tumors should be considered in the setting of RET gene mutation.
Additionally, clinical surveillance for the RET Val804Met mutation should not be limited to calcitonin testing alone, as isolated papillary thyroid carcinoma may occur in relatives of the affected individual, the researchers noted.
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Moreover, a low threshold for surgery is recommended when a genetic syndrome is identified in a patient with thyroid cancer. In such complex scenarios, multidisciplinary counseling involving a head and neck surgeon, endocrinologist, and geneticist is considered the best approach, they added.
Differentiated thyroid cancer (DTC), including both follicular and papillary types, is the most common endocrine neoplasm. On the other hand, MTC originates from the ectodermal parafollicular C cells and accounts for less than 5% of all thyroid cancers. MTC is associated with hereditary syndromes such as multiple endocrine neoplasia, MEN2A or MEN2B, or familial MTC in 25% of cases.
MEN2A is a known autosomal dominant genetic syndrome described by MTC and/or its precursor, pheochromocytoma C-cell hyperplasia, and parathyroid hyperplasia/adenoma. It is associated with various mutations in the RET gene, located on chromosome 10q11.2.1, which encodes a tyrosine kinase bound to the plasma membrane.
Prophylactic total thyroidectomy, introduced for RET mutation carriers in recent years, has decreased mortality rates and can be performed as early as the first year of life, depending on the specific alteration. A recent study has indicated that the lifetime penetrance for MTC in RET p.Val804Met is estimated to be only 4%. As a result, the authors have raised concerns about the necessity of prophylactic TT for this mutation, particularly in the absence of a family history of thyroid cancer.
The study involved a clinical, genetic, and pathological analysis of a family cluster of thyroid neoplasms associated with Val804Met RET mutation. The proband, a 28-year-old female, was initially diagnosed with chronic lymphocytic thyroiditis, but further investigations revealed a suspicious right nodule and MTC. She underwent TT and bilateral central compartment dissection, with a final diagnosis of pT1bN0M0 MTC.
Her brother, a 29-year-old male, had both MTC and PTC simultaneously, while her father had a follicular adenoma and a pT1aPTC, and her uncle showed C-cell hyperplasia. All kindreds received TT +/- VI level dissection.
“Although it is difficult to demonstrate, the presentation of our cases seems to favor the common proto-oncogene theory, without excluding the simple chance,” the authors highlighted.
Miani C, Locatello LG, Rugiu MG et al. The protean role of Val804Met RET mutation in thyroid neoplasms: an example of a “MEN2C” syndrome? Pathology – Research and Practice 2023. Published online February 24, 2023.