Molecular characterization of tumors meeting diagnostic criteria for the non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)
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“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.
KeywordsThyroid cancer Follicular variant papillary thyroid carcinoma Non-invasive follicular thyroid neoplasm with papillary-like nuclear features BRAF-like RAS-like
The authors would like to thank the Penn State Department of Pathology for the intradepartmental grant that funded this project.
Christopher Pool, MD—data curation, methodology, writing of the original manuscript
Vonn Walter, PhD—data analysis, visualization, writing of the original manuscript
Darrin Bann, MD PhD—conceptualization, data curation, critical review of the final manuscript
David Goldenberg, MD—supervision, critical review of the final manuscript
James Broach, PhD—supervision, critical review of the final manuscript
Max Hennessy—data curation
Elizabeth Cottrill, MD—data curation, critical review of the final manuscript
Erik Washburn, MD—data curation
Nicole Williams, MD—critical review of the final manuscript
Henry Crist, MD—data curation, critical review of the final manuscript
Yuka Imamura, PhD—methodology, supervision, formal analysis, critical review of the final manuscript
Joshua I. Warrick, MD—conceptualization, data curation, formal analysis, writing original manuscript, critical review of the final manuscript
This study received financial support (intradepartmental research grant) from the Penn State Department of Pathology.
Compliance with ethical standards
This study was performed with approval from the Penn State College of Medicine Human Subjects Protection Office (Institutional Review Board). The study complies with all ethical standards as stated in the Ethical Responsibilities of Authors on the Virchows Archiv webpage (https://www.springer.com/medicine/pathology/journal/428). This study was entirely funded by departmental funds from the Department of Pathology at Penn State University College of Medicine.
Conflict of interest
The authors declare that they have no conflicts of interest.
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