Pathologic diagnosis of thyroid nodules with preoperatively detected tumor protein 53 mutations: A tricenter series of 32 cases.

Abstract

BACKGROUND: Mutations in the tumor protein 53 gene (TP53 mutation) in thyroid nodules are quoted to confer a high (80%) probability of malignancy when detected on the ThyroSeq v3 genomic classifier if associated with other molecular alterations. However, TP53 mutation also occurs in benign and low-risk thyroid neoplasms. Thus, the risk of malignancy in nodules harboring TP53 mutation is not well characterized. METHODS: Of 4,575 molecularly profiled preoperative fine-needle aspiration samples, 36 (0.8%) were identified harboring TP53 mutation. The study included 32 cases in which the pathology diagnosis was obtained from surgical specimens. RESULTS: The reviewed diagnosis was benign/low-risk neoplasms in 11 (34%), carcinoma-American Thyroid Association low risk of recurrence in 7 (22%), carcinoma-American Thyroid Association low-intermediate risk in 6 (19%), and carcinoma-American Thyroid Association high risk in 8 (25%). In the entire cohort and the indeterminate fine-needle aspiration category (Bethesda III-IV), the risk of malignancy was 66% and 56%, respectively. All 11 cases with a reviewed diagnosis of benign or low-risk neoplasms had their tumor capsule submitted entirely for histologic examination, and 64% had total thyroidectomy. In 30 cases comprehensively molecularly profiled, the molecular alterations were substratified into 4 groups: TP53 mutation alone (n = 5, 17%), TP53 mutation with copy number alteration (n = 9, 30%), TP53 mutation with other mutations but no copy number alteration (n = 9, 30%), and TP53 mutation with other mutations and copy number alteration (n = 7, 23%). The risk of malignancy for each group was 40%, 44%, 67%, and 100%, respectively. The frequency of American Thyroid Association-high-risk malignancy, which would often lead to a recommendation for total thyroidectomy, was 20%, 11%, 22%, and 43%, respectively. The risk of malignancy was higher in cases with additional mutations and copy number alteration (7/7, 100%) than in those with TP53 alone or with concomitant copy number alteration only (6/14, 43%) (P = .018). CONCLUSION: Thirty four percent of nodules with TP53 mutation with or without concomitant molecular alterations were benign/low-risk thyroid neoplasms and treated by total thyroidectomy in the majority of cases. Risk of malignancy increased significantly to 100% when TP53 mutation co-occurred with other mutations and copy number alterations. Since American Thyroid Association high-risk carcinomas were found in only 25% of TP53-mutated nodules, thyroid lobectomy may be considered as the initial treatment, in the appropriate clinical context.