The Diagnosis of Hyalinizing Trabecular Tumor: A Difficult and Controversial Thyroid Entity

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Abstract

Hyalinizing trabecular tumor (HTT) is a benign, follicular-derived neoplasm composed of thick trabeculae with round or elongated cells having irregular and clear nuclei, and containing intra-trabecular hyaline material. The cytological features of HTT resemble those of papillary carcinoma, which helps explain why these lesions are usually classified as indeterminate/suspicious according to the Bethesda system for reporting thyroid cytology. A review of the literature indicates that reaching the correct preoperative cytologic diagnosis of HTT remains elusive, as the correct interpretation was achieved in only 8% of cases. In contrast, the correct diagnosis posed a less significant diagnostic challenge in the majority of histological series, despite the reported controversy on the relationship of this tumor with papillary and medullary thyroid carcinomas. The aim of this review is to highlight the cytological and histological clues in the diagnosis of HTT, as well as its molecular profile.

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Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay.

Yuri E. Nikiforov, Sally E. Carty, Simon Chiosea … (2014)

Fine-needle aspiration (FNA) cytology is a common approach to evaluating thyroid nodules, although 20% to 30% of FNAs have indeterminate cytology, which hampers the appropriate management of these patients. Follicular (or oncocytic) neoplasm/suspicious for a follicular (or oncocytic) neoplasm (FN/SFN) is a common indeterminate diagnosis with a cancer risk of approximately 15% to 30%. In this study, the authors tested whether the most complete next-generation sequencing (NGS) panel of genetic markers could significantly improve cancer diagnosis in these nodules.

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Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in The Bethesda System for Reporting Thyroid Cytopathology.

William Faquin, Lawrence Wong, Amir Afrogheh … (2016)

Recent discussions have focused on redefining noninvasive follicular variant of papillary thyroid carcinoma (NI-FVPTC) as a neoplasm rather than a carcinoma. This study assesses the potential impact of such a reclassification on the implied risk of malignancy (ROM) for the diagnostic categories of The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC).

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GLIS Rearrangement is a Genomic Hallmark of Hyalinizing Trabecular Tumor of the Thyroid Gland

Marina Nikiforova, Alyaksandr V Nikitski, Federica Panebianco … (2019)

Background: Hyalinizing trabecular tumor (HTT) is a rare thyroid neoplasm with a characteristic trabecular growth pattern and hyalinization. This lesion has been the subject of long-term controversy surrounding its genetic mechanisms, relationship to papillary thyroid carcinoma (PTC), and malignant potential. Due to the presence of nuclear features shared with PTC, HTT frequently contributes to a false-positive cytology, which hampers patient management. The goal of this study was to apply genome-wide sequencing analyses to elucidate the genetic mechanisms of HTT and its relationship to PTC. Methods: Whole-exome, RNA-Seq, and targeted next-generation sequencing analyses were performed to discover and characterize driver mutations in HTT. RNA-Seq results were used for pathway analysis. Tissue expression of GLIS3 and other proteins was detected by immunohistochemistry. The prevalence of GLIS fusions was studied in 17 tumors initially diagnosed as HTT, 220 PTC, and 10,165 thyroid fine-needle aspiration samples. Results: Using whole-exome and RNA-Seq analyses of the initial three HTT, no known thyroid tumor mutations were identified, while in-frame gene fusion between PAX8 exon 2 and GLIS3 exon 3 was detected in all tumors. Further analysis identified PAX8 – GLIS3 in 13/14 (93%) and PAX8 – GLIS1 in 1/14 (7%) of HTT confirmed after blind pathology review. The fusions were validated by Sanger sequencing and FISH. The fusions resulted in overexpression of the 3′-portion of GLIS3 and GLIS1 mRNA containing intact DNA-binding domains of these transcription factors and upregulation of extracellular matrix genes including collagen IV. Immunohistochemistry confirmed upregulation and deposition of collagen IV and pan-collagen in HTT. The analysis of 220 PTC revealed no PAX8 – GLIS3 and one PAX8 – GLIS1 fusion. PAX8 – GLIS3 was prospectively identified in 8/10,165 (0.1%) indeterminate cytology fine-needle aspiration samples; 5/5 resected fusion-positive nodules were HTT on surgical pathology. Conclusions: This study demonstrates that GLIS rearrangements, particularly PAX8–GLIS3 , are highly prevalent in HTT but not in PTC. The fusions lead to overexpression of GLIS, upregulation of extracellular matrix genes, and deposition of collagens, which is a characteristic histopathologic feature of HTT. Due to unique genetic mechanisms and an indolent behavior, it is proposed to rename this tumor as “ GLIS -rearranged hyalinizing trabecular adenoma.”