Molecular alterations in Hürthle cell nodules and preoperative cancer risk

Abstract

Hürthle cell carcinoma (HCC) is a distinct type of thyroid cancer genetically characterized by DNA copy number alterations (CNA), typically of genome haploidization type (GH-type). However, whether CNA also occur in benign Hürthle cell adenomas (HCA) or Hürthle cell hyperplastic nodules (HCHN), and have diagnostic impact in fine needle aspiration (FNA) samples, remains unknown. To address these questions, we (i) analyzed 26 HCC, 24 HCA, and 8 HCHN tissues for CNA and other mutations using ThyroSeq v3 (TSv3) next-generation sequencing panel, and (ii) determined cancer rate in 111 FNA samples with CNA and known surgical outcome. We identified CNA, more often of the GH-type, in 81% of HCC and in 38% HCA, but not in HCHN. Among 4 HCC with distant metastasis, all had CNA and 3 TERT mutations. Overall, positive TSv3 results were obtained in 24 (92%) HCC, including all with ATA high risk of recurrence or metastasis. Among 111 FNA cases with CNA, 38 (34%) were malignant, and 73 (66%) benign. A significant correlation between cancer rate and nodule size was observed, particularly among cases with GH-type CNA, where every additional centimeter of nodule size increased the malignancy odds by 1.9 (95% CI 1.3-2.7; P=0.001). In summary, the results of this study demonstrate that CNA characteristic of HCC also occur in HCA, although with lower frequency, and probability of cancer in nodules with CNA increases with nodule size. Detection of CNA, in conjunction with other mutations and nodule size, is helpful in predicting malignancy in thyroid nodules.

Impact of molecular testing on detecting mimics of oncocytic neoplasms in thyroid fine‐needle aspirates diagnosed as follicular neoplasm of Hürthle cell (oncocytic) type

“…With this limitation with every additional centimeter of nodule size, malignancy odds were reported to be increased by 1.9 (95% CI, 1.3-2.7; P = .001). 10,11 Consistent with our prior report, among FNHCT nodules with GH-CNA only, resected nodules were on average approximately 1 cm larger than the clinically observed ones. Furthermore, among resected nodules, GH-CNA-positive thyroid cancers were approximately 2.3 cm larger than GH-CNA-positive FOAs.…”

“…Our results in this large series of FNHCT confirm that GH-CNA represents a molecular signature of follicular oncocytic neoplasms, including both benign FOA and malignant FOCa or EOFVPTC, but is absent in oncocytic metaplasia. 10 The reported preoperative risk of cancer for nodules with GH-CNA varies depending on nodule size. Clinically observed nonresected nodules tend to be smaller.…”

“…[4][5][6][7][8][9] It is now accepted that the near total GH-type DNA copy-number alterations (referred to here as GH-CNA) are a feature of oncocytic follicular neoplasms, including FOA and follicular oncocytic carcinoma (FOCa). 10,11 GH-CNAs are early genetic events separating some oncocytic neoplasms from such reactive changes as oncocytic metaplasia.…”

Genetics, Diagnosis, and Management of Hürthle Cell Thyroid Neoplasms

“…Several studies examined whether known thyroid oncogenes and tumor suppressor genes were recurrently mutated in HCC. Two studies reported recurrent RET-PTC translocations in HCCs using FISH and PCR methods (18,19). However, in larger cohorts using DNA-sequencing based methods, RET-PTC (CCDC6-RET and NCOA4-RET) translocations were not detected, nor were RET-PTC translocations recurrently identified in molecular testing of FNA specimens with Hürthle cell cytology (20-26).…”

“…HCCs harbor mutations in known thyroid cancer oncogenes including RAS , TSHR , EIF1AX , TP53 , PTEN , BRAF , PAX8-PPARγ , and MEN1 ( 20 , 22 – 31 ). However, mutations in these genes occur in a small fraction of HCC.…”