RAS mutation and associated risk of malignancy in the thyroid gland: An FNA study with cytology‐histology correlation

Abstract

Background Activating point mutations of the RAS gene (NRAS, HRAS, and KRAS) can be seen in benign and malignant thyroid tumors; among these, NRAS mutations are more commonly seen. This study was conducted to evaluate the thyroid risk of malignancy (ROM) associated with RAS mutations in thyroid fine‐needle aspiration (FNA) at the authors' institution. Methods The authors searched their electronic database system between January 2015 and May 2021 for thyroid FNA cases with any type of RAS mutation. Molecular alterations were identified with the ThyroSeq Genomic Classifier, ThyGeNEXT (thyroid oncogene panel)/ThyraMIR (miRNA classifier), or ThyroSure gene panel. Results A total of 127 cases (age, 51 ± 14 years; 100 females and 27 males) were identified, and 72 had histologic follow‐up. The overall ROM associated with RAS mutations (with or without any other molecular alterations) was 29%, whereas the ROM was lower (18%) with RAS mutations only. Isolated NRAS, HRAS, and KRAS mutation–associated ROMs were 15%, 27%, and 14%, respectively. Among these RAS‐mutated cases, the cases with a Bethesda category IV cytologic diagnosis had a higher ROM than the cases with a category III diagnosis (38% vs 17%). Twenty‐one histologically confirmed malignant cases were mostly classified on cytology as category IV lesions (14 of 34; 41%), and the remainder were either category III (6 of 35; 17%) or V lesions (1 of 1; 100%). Conclusions This study demonstrated that the overall RAS mutation–associated ROM in thyroid FNA was intermediate (29%), and isolated HRAS mutations appeared to have a higher ROM (27%) than NRAS and KRAS mutations (15% and 14%, respectively).

Probability of malignancy as determined by ThyroSeq v3 genomic classifier varies according to the subtype of atypia

“…26,27 RAS gene mutations in the AUS category have been associated with a lower ROM (17%) than cases with a cytologic diagnosis of suspicious for a follicular neoplasm, which has a higher ROM (38%). 28 Isolated HRAS mutations appear to have a higher ROM compared with NRAS and KRAS mutations. 28 RAS-like mutations, including BRAF K601E, THADA::IGF2BP3, and PAX8::PPARγ, were mainly found in the FC-A subcategory.…”

“…28 Isolated HRAS mutations appear to have a higher ROM compared with NRAS and KRAS mutations. 28 RAS-like mutations, including BRAF K601E, THADA::IGF2BP3, and PAX8::PPARγ, were mainly found in the FC-A subcategory. BRAF K601E is reported to be the second most common BRAF mutation found in thyroid nodules.…”

Emerging Biomarkers in Thyroid Practice and Research

“…Nodular hyperplasia (NH) morphologically mimics FA, and the two can be difficult to differentiate. However, a growing number of reports have documented RAS mutations in NH [ 11 , 12 , 13 ]. A recent publication implicated additional alterations in the expressions of genes involved in cell cycle, apoptosis, and PI3K pathway, and stromal factors to lead to a stepwise progression of NH to malignancy [ 12 ].…”

Cytomorphologic features of thyroid nodules harboring thyroid adenoma‐associated fusion: A single institutional review of 11 cases

“…14 Gilani et al explored the risk of malignancy of KRAS, HRAS, and NRAS alterations identified on thyroid FNAs and in their representative figures, cases demonstrated either architectural atypia in a microfollicular or crowded pattern with occasionally some nuclear atypia. 17 Similarly, in their cohort of AUS thyroid lesions, Glass et al identified 15 cases with RAS mutations that were varied with cases harboring either architectural atypia, cytologic atypia or Hurthle cell change. 14 Overall, when evaluating thyroid FNAs from RAS-like lesions, it would be difficult to ascribe a particular genetic driver primarily based on cytomorphology, due to significant overlap among RAS-like tumors.…”

“…In the study by Glass et al mentioned previously, their cohort included two cases harboring a PAX8::PPARgamma and four cases with PTEN alterations with all cases showing only architectural atypia 14 . Gilani et al explored the risk of malignancy of KRAS , HRAS , and NRAS alterations identified on thyroid FNAs and in their representative figures, cases demonstrated either architectural atypia in a microfollicular or crowded pattern with occasionally some nuclear atypia 17 . Similarly, in their cohort of AUS thyroid lesions, Glass et al identified 15 cases with RAS mutations that were varied with cases harboring either architectural atypia, cytologic atypia or Hurthle cell change 14 …”