Rethinking Malignancy Risk in Indeterminate Thyroid Nodules with Positive Molecular Studies: Southern California Permanente Experience

Abstract

Objectives To recognize that thyroid nodules with atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS; Bethesda III) have different risks of malignancy based on genetic mutation and to consider molecular testing of nodules with AUS/FLUS to help avoid unnecessary morbidity or cost. Study Design Retrospective cohort study. Setting Multiple locations within Southern California Permanente Medical Group. Subjects and Methods Patients included those with indeterminate thyroid nodules and AUS/FLUS on 2 separate fine-needle aspirations with positive ThyGenX testing from 2014 to 2017 who underwent thyroid surgery. Patients were classified as having benign or malignant disease. Noninvasive follicular thyroid neoplasm with papillary-like nuclear features was considered benign. Results A total of 231 patients had repeat AUS/FLUS with positive molecular testing and surgery. The most frequent type of malignancy was papillary carcinoma, followed by follicular carcinoma. The overall prevalence of malignancy in nodules with mutations was 74.0%, although there was considerable variation: BRAF = 100%, RET = 100%, PAX8-PPARγ = 84.6%, HRAS = 70.7%, NRAS = 63.4%, and KRAS = 33%—a statistically significant finding ( P < .001). Conclusions Not all molecular mutations in thyroid nodules with AUS/FLUS have a high risk of malignancy. Of note, patients with BRAF and RET mutations in our population had a 100% risk of malignancy. Patients with PAX, HRAS, or NRAS mutations had a high risk of malignancy, while patients with KRAS mutations had a lower risk of malignancy. Further studies are needed to determine if the presence of certain molecular mutations can help personalize care and aid in the decision for thyroid surgery.

Risk Stratification Study of Indeterminate Thyroid Nodules with a next-generation Sequencing Assay with Residual ThinPrep® Material

“…As in previous reports, RAS was the most frequent mutation identified in the indeterminate nodules in this study, and was not specifically associated with malignant or potentially malignant outcomes 20 - 22 . Another false positive molecular result in our study was the mutation of PTEN .…”

Incremental utility of expanded mutation panel when used in combination with microRNA classification in indeterminate thyroid nodules

“…However, the individual detection of drivers that are more weakly associated with malignancy presents a challenge to guiding patient management. 25 8,25 Our results support that subsequent microRNA testing can help to overcome this uncertainty. Approximately half of nodules with weak drivers had positive microRNA results consistent with a higher risk of malignancy.…”

“…25 to either mechanism, the lack of detectable oncogenic change cannot provide complete assurance that a nodule is benign and as such those nodules have a residual cancer risk of 5% to 25%. However, the individual detection of drivers that are more weakly associated with malignancy presents a challenge to guiding patient management.…”

“…8,[22][23][24][25] Other mutations and fusions can occur at a much lower frequency, making their PPV difficult to study and consequently not well understood. RAS mutations are the most common to indeterminate nodules and have been found in both benign and malignant nodules, presenting an uncertain PPV ranging from 15% to 70%.…”

“…RAS mutations are the most common to indeterminate nodules and have been found in both benign and malignant nodules, presenting an uncertain PPV ranging from 15% to 70%. 8,[22][23][24][25] Other mutations and fusions can occur at a much lower frequency, making their PPV difficult to study and consequently not well understood. Rare BRAF mutations, excluding BRAFV600E, have RAS-like properties rather than BRAFV600E-like properties, and have been found in both benign and malignant thyroid nodules.…”