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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.”

Background: Thyroid adenoma-associated (THADA)-IGF2BP3 fusions have been identified as an oncogenic event in thyroid neoplasms. However, the prevalence of this gene fusion and associated phenotypic...

While the association of the BRAF(V600E) mutation with aggressive histopathological tumor features and clinical behavior has been extensively studied in papillary thyroid carcinoma (PTC), the BRAF(K601E) mutation has not been well characterized. This study reports what is currently the largest series of BRAF(K601E) mutated thyroid nodules.Histopathologic, cytologic, and molecular reports over a period of seven years (June 2007 to June 2014) were reviewed to identify thyroid cases with various types of BRAF mutations. All cases positive for the BRAF(K601E) mutation were reviewed to confirm histopathologic diagnosis and establish tumor variant, and clinical charts were reviewed to obtain clinical characteristics and follow-up information.The BRAF(K601E) mutation was identified in 39 patients and comprised 5.3% of all BRAF mutations noted in thyroidectomy specimens. Twenty-seven out of 29 nodules (93%) with BRAF(K601E) mutated tumors with surgical pathology results available for review were PTC, one (3.4%) was a follicular thyroid carcinoma, and one (3.4%) was a follicular adenoma. The majority of K601E-mutant PTCs (20 cases) were follicular variant PTC. Encapsulation was present in all but one case, and one case showed capsular invasion. Coexisting mutations overall were not identified in BRAF(K601E) mutated thyroid nodules except in a case that exhibited a complex K601E + T599I mutation and had a classic PTC phenotype. The majority of K601E mutant nodules were T1 lesions (69%) and T2 lesions (28%) by TNM staging. With a median follow-up of 19.6 months, no structural or biochemical recurrence or metastases were found in patients with an isolated BRAF(K601E) mutation.The BRAF(K601E) mutation is the second most common BRAF mutation found in thyroid nodules. Unlike BRAF(V600E), the most common mutation, K601E is strongly associated with follicular-patterned cancer, particularly with the encapsulated follicular variant of PTC, and may also be found in follicular thyroid carcinomas. Overall, BRAF(K601E) mutant tumors show better clinical outcomes than BRAF(V600E) positive tumors, and preoperative BRAF(K601E) analysis may provide important prognostic information for use in clinical management.