Case series describes four clear cell variant papillary thyroid carcinoma cases with NCOA4-RET fusions

The clear cell variant of papillary thyroid carcinoma (CLCVPTC) is an exceedingly rare and diagnostically challenging subtype of papillary thyroid carcinoma (PTC), defined by distinctive histomorphologic features. Here, we aimed to delineate the clinicopathologic, immunohistochemical, and molecular genetic characteristics of CLCVPTC by retrospectively analyzing four pathologically confirmed cases diagnosed at our institution between 2018 and 2025, together with a comprehensive review of the published literature. The male to female ratio of the four CLCVPTC cases is 1: 3, with a median age of 60 years (range 45-68) and presented clinically with thyroid nodules. Histopathological evaluation demonstrated infiltrative tumor growth patterns with solid, trabecular, and focal papillary architectures. Tumor cells displayed abundant clear cytoplasm (more than 90% of all tumor cells in our cases, meeting the diagnostic threshold of >50%) and classic nuclear features of PTC, including ground-glass nuclei, nuclear grooves, and intranuclear inclusions. Lymph node metastases were observed in three cases. Immunohistochemical profiling revealed consistent positivity for TTF-1, Pax8, CK7, thyroglobulin (TG) and Galectin-3, and absence of expression for TPO, BRAF V600E mutation, and various neuroendocrine markers. Polymerase chain reaction (PCR) identified an NCOA4-RET gene fusion in 50% (2/4) of the cases. All patients underwent thyroidectomy and central lymph node dissection, among which three of them also underwent contralateral thyroidectomy, with no evidence of disease recurrence during follow-up periods ranging from 2 to 54 months. However, due to the short follow-up for some cases and the loss to follow-up, long-term outcomes for CLCVPTC remain undefined. In conclusion, CLCVPTC is a rare variant of PTC characterized by distinctive clear-cell change with canonical PTC nuclear features. The detection of an NCOA4-RET fusion in half of our cases suggests a recurrent genetic alteration that may contribute to its pathogenesis, though this finding requires validation in larger cohorts.