Unique Thyroid Carcinoma With Somatic Inactivating TSC2 Mutations, Follicular and Melanocytic Differentiation and...

Thyroid carcinomas with mutations in the TSC2 gene have been described rarely. Here, we report a unique thyroid carcinoma that has somatic mutations in TSC2, follicular and melanocytic differentiation and distinct morphologic features, supported by a comprehensive molecular-genetic analyses. No other known pathogenic driver mutations were identified. The TSC2 mutations are predicted to be truncating and result in constitutive activation of mammalian target of rapamycin (mTOR) signaling that was confirmed by transcriptome expression profiling. This is the first demonstration of a thyroid follicular tumor with melanocytic differentiation and corresponding Melan-A expression may be a biomarker for this thyroid cancer. Its diffuse papillary architecture, macronuclei, multinuclear aggregates and intratumoral T lymphocytes are morphologic features not yet described in other TSC2-mutated thyroid carcinomas. Morphologic overlap with classic thyroid papillary carcinoma and known technical difficulties in sequencing the large TSC2 gene make it likely that TSC2-mutated thyroid carcinomas have been underdiagnosed so far. We suggest that TSC2-mutated thyroid carcinoma should be considered in the differential diagnosis of any thyroid tumor that has unusual morphologic and immunohistochemical features or lacks known driver mutations in thyroid cancer.