Preoperative detection of RAS mutation may guide extent of thyroidectomy

Abstract

Background Preoperative detection of RAS mutations can contribute to cancer risk assessment in indeterminate thyroid nodules, although RAS is not always associated with malignancy. Methods Fine-needle aspiration samples classified in 1 of 3 indeterminate cytology categories were prospectively tested for N-, H-, and K-RAS mutations using next-generation sequencing assay. Results In the study, 93 patients with 94 nodules had preoperative RAS detected, of whom 86 patients had an operation (69% total thyroidectomy, 29% lobectomy). In total, 76% of RAS-positive nodules were malignant and follicular variant papillary thyroid cancer was the most common cancer type (83%). HRAS mutations had the greatest risk of cancer (92%) followed by NRAS (74%) and KRAS (64%; P = .05). No preoperative variables were associated with malignancy including age (P = .07), sex (P = .49), RAS isoform (P = .05), mutational allelic frequency (P = .49), nodule size (P = .14), cytology category (P = .63), or ultrasound bilaterality (P = .24), multifocality (P = .23), or presence of ≥1 suspicious feature (P = .86). Only 60% of patients with a unifocal nodule on ultrasound had single focus low-risk encapsulated follicular variant papillary thyroid cancer or benign disease. Conclusion Preoperative RAS mutation detection in thyroid nodules carries a substantial risk of cancer with a greater risk associated with HRAS and NRAS. Most RAS malignancies are follicular variant papillary thyroid cancer, which may inform the extent of operation.

Hürthle cell lesions on thyroid fine needle aspiration cytology: Molecular and histologic correlation

“…Prior studies have shown that RAS mutations have a significant risk of malignancy. One study found that 76% of RAS‐positive indeterminate thyroid nodules were malignant; however, 56% of the RAS‐positive malignant cases were encapsulated FVPTC . RAS mutations are now indicative of a clonal tumor with 80% probability of low risk carcinoma or NIFTP, which are managed by lobectomy .…”

“…ThyroSeq® v3 was also validated to identify Hürthle cell neoplasms including Hürthle cell adenomas and carcinomas. Clonal CNA is a nonspecific molecular alteration that is specifically associated with Hürthle cell neoplasms . Analysis of global CNA in one study showed significantly different patterns of chromosomal aberrations in HCC compared with PTC or FTC; however, there was no difference in chromosomal aberrations between HA and HCC.…”

Impact of oncogene panel results on surgical management of cytologically indeterminate thyroid nodules

“…This suggests that the well‐recognized low interobserver agreement for the classification of noninvasive encapsulated lesions with follicular pattern that have, if at all, very‐low malignant potential, is behind the differences in the prevalence of malignancy of RAS and perhaps other mutations . A recent publication on 94 RAS ‐mutant tumors has also suggested that a lobectomy seems appropriate for these tumors . However, the authors of that study concluded that finding a RAS mutation preoperatively could be used to guide the extent of thyroidectomy .…”

“…In our experience, this panel seemed reliable as rule‐out test in follicular neoplasms but not in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) . Besides the need to bring the performance of oncogene panels into sharper focus, their role in planning the extent of surgery is controversial and needs to be defined . The 2015 American Thyroid Association (ATA) recommends thyroid lobectomy for solitary, cytologically indeterminate thyroid nodules (ITNs) but suggest that total thyroidectomy may be preferred if a mutation specific for carcinoma is identified, given the higher risk for cancer (recommendation #20) .…”

The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives

“…1a). 1 Follicular variant PTC comprises mostly low grade tumors and RAS-like tumors [86][87][88][89][90][91][92][93][94][95][96][97] (Table 2). It can be classified into either borderline (WDT-UMP or NIFTP) or malignant (invasive encapsulated PTC or infiltrative PTC) according to the absence of, incomplete or definite capsular/lympho-vascular invasion.…”