Hobnail Variant of Papillary Thyroid Carcinoma: Clinicopathologic and Molecular Evidence of Progression to Undifferentiated Carcinoma in 2 Cases.

The hobnail variant (HV) of papillary thyroid carcinoma (PTC) is an unusual entity recently proposed as an aggressive variant of PTC. We describe the pathologic and molecular features of 2 cases of HV of PTC. Both tumors presented in stage III (pT3 pN1a M0). The first case was diagnosed in a 62-year-old man, whereas the second was in a 53-year-old woman. Both patients were treated with total thyroidectomy and radioactive iodine. The primary tumors showed a hobnail/micropapillary pattern in ≥50% of the neoplasm, and positivity for TTF-1, TTF-2, thyroglobulin (TG), cyclin D1, and p53. The Ki-67 index was 4.6% and 5%, respectively. In case 1, the tumor disclosed BRAFV600E and TERT C228T (124:G>A) promoter gene mutation, negativity for NRAS, HRAS, and KRAS mutations, and negativity for RET/PTC1, RET/PTC3, and PAX8/PPARγ rearrangements. After 11 years the patient died with cervical lymph node, bone, and liver metastases. In the liver metastasis, the tumor displayed columnar cell PTC areas (positive for TTF-1, TG, and BRAFV600E) merging with undifferentiated carcinoma (UC) areas (positive for TTF-1 and BRAFV600E; negative for TG). In case 2, the patient died 6 years after treatment with local recurrence and disseminated metastases to the lung, pleura, bone, and liver. The tumor recurrence showed a UC component (positive for cyclin D1 and p53; negative for TTF-1 and TG) with a residual HV of PTC (positive for cyclin D1, p53, TTF-1, and TG). No BRAF, TERT, NRAS, HRAS, nor KRAS mutations were detected in the primary tumor or recurrence in case 2. Our findings suggest that p53-positive HV is a very aggressive form of PTC prone to progression to UC.