Molecular characterization of tumors meeting diagnostic criteria for the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)

“Follicular variant” papillary thyroid carcinomas (FV-PTC) that do not histologically invade have a miniscule risk of metastasis, and thus been reclassified as a tumor of low malignant potential, the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). There are few molecular studies of this tumor type. We performed gene expression analysis, by RNA sequencing, on a series of FV-PTCs, NIFTPs, and follicular adenomas. A training set comprised tumors from The Cancer Genome Atlas (TCGA) repository (n = 46), digital slides from which were reviewed and classified as invasive or non-invasive FV-PTC. A validation set comprised in-house NIFTPs, invasive FV-PTCs, and follicular adenomas (n = 26). In the training set, unsupervised clustering separated tumors into three distinct expression subtypes, which associated with invasion and characteristic molecular alterations. Specifically, the “BRAF-like” subtype was enriched in invasive FV-PTCs and tumors with BRAF V600E mutations. The “THADA-like” subtype was enriched in non-invasive tumors and those with rearrangements involving THADA. The “RAS-family-like” subtype included many invasive and non-invasive FV-PTCs and was enriched in tumors with mutations in RAS family genes. In the validation set, nearest centroid analysis classified all invasive FV-PTCs as “BRAF-like” and all follicular adenomas as either “RAS-like” or “THADA-like.” NIFTPs were the most molecularly diverse histologic type, with cases classified as “BRAF-like,” “THADA-like,” and “RAS-family-like.” In conclusion, tumors fitting criteria for NIFTP are molecularly diverse, making it difficult to diagnose them with molecular studies, likely including matrial from cytopathology samples.