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

Abstract

BACKGROUND: Some thyroid nodules cytologically presenting as follicular neoplasm, Hürthle cell (Oncocytic) type (FNHCT), are not oncocytic tumors and represent autonomously functioning thyroid nodules (AFTNs) with TSHR, GNAS, and EZH1 mutations or oncocytic metaplasia. A to be defined subset of FNHCT harbors genome haploidisationtype DNA copy number alterations (GH-CNA). Molecular profiling of FNHCT may distinguish oncocytic neoplasms from its mimics. METHODS: Consecutive fine-needle aspirates of 180 thyroid nodules over 37 months diagnosed as FNHCT and tested by ThyroSeq v3 were identified. Histologic follow-up was available for 79 of 180 nodules (44%). RESULTS:No molecular alterations were found in 76 of 180 nodules (42%), of which 15 were resected (oncocytic metaplasia, n = 7; follicular oncocytic adenoma, n = 8). Of nodules followed without surgery, 17 of 101 (17%) showed TSHR, EZH1, and GNAS mutations of AFTNs. Papillary thyroid carcinoma was identified by BRAF V600E (n = 2) and hyalinizing trabecular adenoma by PAX8-GLIS3 (n = 1). GH-CNA alone was detected in 42 of 180 FNHCT nodules (23%), of which 29 were resected and histologically diagnosed as follicular oncocytic neoplasms. All remaining resected nodules were histologically proven oncocytic neoplasms: 1) RAS-like alterations without GH-CNA (n = 25) and 2) TERT and/or TP53 mutations co-occurring with GH-CNA (n = 6), including anaplastic thyroid carcinoma arising from follicular oncocytic carcinoma with TP53, TERT mutations with GH-CNA (n = 2). CONCLUSIONS: A proportion of FNHCT nodules are AFTNs and oncocytic metaplasias, which can be suspected based on characteristic mutations or lack of alterations on molecular testing. Among resected FNHCTs, GH-CNAs characterize approximately half of histologically confirmed follicular oncocytic neoplasms.

Probability of malignancy and molecular alterations as determined by ThyroSeq v3 genomic classifier in Bethesda Category IV

“…In addition, two aspirates with focal oncocytic change classified as FN showed OA in surgical follow‐up (composed of >75% of oncocytic cells). These aspirates lacked any genetic alterations associated with thyroid cancer, which may suggest that these tumors are driven by other molecular changes not detected by ThyroSeq v3 GC 20 …”

Molecular testing in fine‐needle aspiration of thyroid nodules

“…Reactive Hürthle cells are more likely to have TSHR, EZH1, or GNAS mutations and less likely to contain other molecular alterations. 146 In a study of 188 nodules classified as indeterminate with Hürthle cells on cytology, 5 were HCC containing alterations in HRAS, TERT, PIK3CA, and TP53. HCA were found to have alterations in NRAS, KRAS, EIF1AX, MET, and TSHR.…”

“…Molecularly, Hürthle cell lesions have been difficult to distinguish reliably. Reactive Hürthle cells are more likely to have TSHR , EZH1 , or GNAS mutations and less likely to contain other molecular alterations 146 . In a study of 188 nodules classified as indeterminate with Hürthle cells on cytology, 5 were HCC containing alterations in HRAS , TERT , PIK3CA , and TP53 .…”

“…HCA were found to have alterations in NRAS , KRAS , EIF1AX , MET , and TSHR 147 . Copy number alterations are associated with Hürthle cell morphology and are identified in approximately 80% of HCCs and 40% of HCAs 122,146,148 . Although most HCCs contain at least one molecular alteration, there is no distinguishing alteration compared to HCAs 149 …”

“Copy number alteration” as the sole molecular finding of a Thyroseq test is more commonly seen in Hurthle cell neoplasms

“…13 CNAs have been identified in thyroid tumors and may even suggest a role in driving thyroid cancer. 14 Furthermore, the presence of CNAs is more likely predictive of a neoplastic rather than hyperplastic process in Hurthle cell lesions, [15][16][17] although the exact significance of these genetic alterations remains uncertain.…”