Pathology of Prophylactic Thyroidectomies in Patients with Germline Mutations Affecting the Extracellular Cysteine-Rich and the Intracellular Tyrosine Kinase Domains of the RET Protein
Rita Abi-Raad, Renu K Virk, Raffaella A Morotti, Scott A Rivkees, Christopher K Breuer, Robert Udelsman, Julie A Sosa, Manju L Prasad. Yale University School of Medicine, New Haven, CT
Background: Approximately 25% of medullary thyroid carcinomas (MTC) are due to germline mutations in the RET proto-oncogene leading to an abnormally active transmembrane RET tyrosine kinase receptor, and are associated with either multiple endocrine neoplasia-2 (MEN2A and MEN2B) or familial MTC (FMTC). Nearly 98% of the MEN2A patients harbor a point mutation affecting the extracellular cysteine-rich domain, whereas all MEN2B patients, and some MEN2A and FMTC patients harbor mutations affecting the intracellular tyrosine kinase domain of the RET protein. In this study we compare the pathological features in prophylactic thyroidectomies for mutations affecting the extracellular cysteine-rich domain and the intracellular tyrosine kinase domain of the RET protein.
Design: We reviewed 14 prophylactic thyroidectomies with central lymph node dissection performed for known germline mutations in the RET proto-oncogene.
Results: RET proto-oncogene mutations involved codons 618 (n=2) and 634 (n=4) affecting the cysteine-rich domain (group 1), and codons 804 (n=7) and 790 (n=1) affecting the tyrosine kinase domain (group 2). The findings are summarized in the table. Five thyroids harbored a single focus of MTC (micro-MTC, size range 0.1 - 0.8 cm) limited to the thyroid gland. There were no MTC >1 cm and no vascular invasion. Central lymph node dissection, performed in all patients in group 1 (6/6) and in five patients in group 2 (5/8) were negative for metastasis.
|Number of cases||6||8|
|Age range in years (median)||1.5-9 (1.5)||8-52 (14)|
|Sex||4M, 2F||6M, 2F|
|C-cell hyperplasia (nodular and/or diffuse)||5/6||5/8|
|Multifocal C-cell hyperplasia||2/6||2/8|
|Chronic lymphocytic thyroiditis||None||2/8|