Case Report: Membranous/cytoplasmic Ki-67 staining and PAX8-GLIS3 fusion: defining the clinicopathological spectrum of hyalinizing trabecular tumor to optimize patient management

Hyalinizing trabecular tumor (HTT) is a rare thyroid neoplasm with an excellent prognosis, yet its morphological resemblance to malignancies such as papillary thyroid carcinoma (PTC) often complicates its diagnosis. To characterize the clinicopathological, immunohistochemical, and molecular profiles of HTT, this study analyzed 21 HTT cases and 10 PTC cases, and the findings were supplemented by a literature review. The HTT cohort included 18 female and 3 male patients, with a mean age of 51 years. Cytologically, HTT can be distinguished from PTC by its distinctive membranous/cytoplasmic Ki-67 staining pattern and the presence of the <i>PAX8-GLIS3</i> gene fusion and occasional polyploid cells. Histologically, the tumors were well-demarcated and exhibited trabecular or organoid growth, eosinophilic to granular cytoplasm, paranuclear yellow inclusions, and hyalinized stroma. Immunohistochemically, HTT consistently expressed TG, TTF1, and CD56, while Ki-67 showed a unique membranous/cytoplasmic distribution. Molecular profiling identified no <i>KRAS</i>, <i>NRAS</i>, <i>BRAF</i>, or <i>PIK3CA</i> mutations. However, <i>PAX8-GLIS3</i> fusion was detected in all HTT cases, a finding absent from PTC. The use of Ki-67 immunohistochemistry or <i>PAX8-GLIS3</i> testing on cytological specimens can aid in definitive diagnosis and prevent unnecessary surgery. Thus, an integrated approach combining cytological, histological, immunohistochemical, and molecular data is essential for the accurate diagnosis and optimal clinical management of HTT.