High-Grade Papillary Thyroid Carcinoma, Diffuse Sclerosing Subtype

High-grade differentiated thyroid carcinoma is a novel classification defined by elevated mitotic count (MC) of ≥5/2 mm 2 and/or tumor necrosis. It may assume a phenotype of papillary thyroid carcinoma, diffuse sclerosing subtype (PTC-DS), and can be termed HGPTC-DS. A detailed clinicopathologic review was conducted on a large series of 18 cases of HGPTC-DS. A control group of 41 PTC-DSs with genomic data was also included. Histologically, HGPTC-DS showed typical features of PTC-DS and HG areas, often exhibiting solid architecture of uniform squamoid cells admixed with tumor necrosis, frequently the comedo type. All HGDTC-DSs had tumor necrosis. The MC was often low (median 1/2 mm 2 ). PTC nuclear features were retained and no nuclear pleomorphism was seen. HGPTC-DS was often subjected to misdiagnosis. Among the 7 external cases, the initial diagnosis was anaplastic carcinoma in 1 and PTC in 5. Compared with PTC-DS, HGPTC-DS was associated with positive resection margin, AJCC eighth edition pT3b and pT4a/4b disease, gross extrathyroidal extension (ETE), a higher number of regional lymph nodes metastasis, a larger size of nodal metastasis, decreased recurrence-free survival (RFS) and regional recurrence-free survival ( P <0.05). Among the 9 HGPTC-DSs sequenced, 5 harbored RET fusions, 2 had STRN::ALK fusion, and 1 had BRAF p.V600E mutation. In conclusion, HGPTC-DS is a rare high-grade carcinoma characterized by uniform squamoid area with comedo-type tumor necrosis, high pT stage, gross ETE, large volume nodal metastasis, poor RFS, and RRFS. Given its rarity, it may be subjected to misdiagnosis as PTC and anaplastic carcinoma.