Chromophobe thyroid carcinoma: a distinct entity associated with TSC gene alterations

Chromophobe thyroid carcinoma (CTC) is a rare thyroid carcinoma with distinct morphology, often occurring in patients with tuberous sclerosis complex (TSC). The molecular drivers remain poorly understood. We report two additional CTC cases and review the literature including genetic query. Patient 1, an 11-year-old boy, had a 10.3-cm bilateral thyroid mass with tumoral capsular and vascular invasion. Microscopically, the tumor showed trabecular and nested growth, prominent cell membranes, raisinoid nuclei, eosinophilic granular cytoplasm, and perinuclear halos resembling chromophobe renal cell carcinoma. The tumor expressed thyroid markers (TTF-1, PAX-8, thyroglobulin) and renal cell markers (colloidal iron, parvalbumin, CD117) with peripheral mitochondrial accentuation by anti-mitochondrial staining. A somatic TSC2 p.Y1650Cfs*4 frameshift mutation was identified. Patient 2, a 24-year-old woman, had a 3.8-cm infiltrative, angioinvasive right lobe tumor with similar morphology and marker expression and positive lymph nodes. Molecular analysis showed somatic TSC2 c.2071dupC p.R691Pfs*12 and TSC2 c.2353C > T p.Q785* mutations. A cBioPortal query (2285 cases) found TSC1 alterations in 2% and TSC2 in 1%, mostly deletions, enriched in poorly differentiated and anaplastic thyroid carcinomas. Literature review identified seven CTC cases; 42.8% had TSC association and 42.8% showed locoregional recurrence. Median follow-up of 36 months showed all patients alive. Common morphologic and immunophenotypic features were consistent; 85.7% exhibited vascular invasion. None harbored common mutations like BRAF p.V600E and RAS. CTC is a distinct, rare thyroid carcinoma often linked to TSC or TSC mutations, characterized by unique morphology and immunophenotype.