Hyalinizing trabecular tumors with areas resembling noninvasive follicular thyroid neoplasm with papillary-like nuclear features: an immunohistochemical and molecular analysis

Background: The coexistence of hyalinizing trabecular tumor (HTT) and areas with a morphology of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) within a single thyroid nodule has not been previously reported. We aimed to determine whether such tumors represent two independent neoplasms or a single tumor exhibiting divergent morphology. Methods: Ten tumors containing both HTT and NIFTP-like areas were examined. The term “NIFTP-like” was used strictly as a descriptive morphological designation for areas that fulfill the histologic criteria of NIFTP. Immunohistochemical analyses of Ki-67 (MIB-1) and type IV collagen and targeted molecular testing were performed. Ten NIFTPs, 10 follicular adenomas, and three HTTs were used as controls. Results: HTT components consistently showed characteristic membranous Ki-67 staining and intra-trabecular type IV collagen deposition, whereas NIFTP-like areas lacked these features, except for focal apical Ki-67 staining. Intranuclear cytoplasmic inclusions in HTT were positive for type IV collagen. NIFTPs showed neither membranous Ki-67 nor intra-trabecular type IV collagen. Molecular analysis demonstrated identical profiles between HTT components and NIFTP-like areas: three tumors harbored PAX8::GLIS3 fusions, and none showed RAS mutations. Pure HTT controls exhibited the same pattern. Conclusions: Our findings indicate that these follicular-patterned areas represent a morphological variant within the spectrum of HTT rather than a true NIFTP-related component or two separate neoplasms. These findings expand the recognized histologic diversity of HTT and highlight a potential diagnostic pitfall in follicular-patterned thyroid tumors. Focal apical Ki-67 staining may serve as a useful clue for distinguishing HTT from NIFTP.