Unraveling the significance of TSHR mutations in indeterminate thyroid cytology specimens

Abstract

Objectives: We investigated the clinical significance of thyroid-stimulating hormone receptor (TSHR) mutations detected in thyroid fine needle aspiration (FNA) specimens.

Methods: The pathology archives at our institution were reviewed between 2018 and 2021 for indeterminate (Bethesda category III and IV) specimens with Thyroseq® analysis showing TSHR mutations.

Results: A total of 2184 cases diagnosed as atypia/follicular lesion of undetermined significance (AUS/FLUS), and 2625 diagnosed as follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) were identified. A total of 1735 AUS/FLUS and 2339 SFN/FN underwent Thyroseq® analysis; 69 showed TSHR mutations (1.6%, 59 female, 10 male, average age: 55 years). Ten cases showed oncocytic features. Twelve patients underwent radionuclide scans within 1 year of FNA:11 were hyperfunctioning. Nodule size and TSH levels were weakly correlated. Twenty-two different TSHR mutations were identified (most common: M453T). A second mutation was found in five cases (EZH1 n = 2, and EIF1AX n = 3). The expression of sodium-iodide transporter (NIS) mRNA was in the range of 0.01%-62.43% out of all sequencing reads, and was elevated in 49 (71%) cases. Surgical pathology follow-up was available in five cases (all benign except one). On follow-up available for 38 cases (mean: 24 months; range: 7-47 months), 34 (89.5%) nodules remained stable and 3 (8%) increased in size.

Conclusions: TSHR mutations in thyroid FNA samples classified as indeterminate are rare, generally benign, and commonly associated with autonomy on scan if performed.

Keywords: Bethesda; TSHR; ThyroSeq®; fine needle aspiration; thyroid.

FIGURE 1

A composite figure of two cases with TSHR mutation. Case 1: The FNA sample was diagnosed as “Atypia of Undetermined Significance,” it was cellular and showed monolayer sheets and cohesive groups of follicular cells with oncocytic cytoplasm and random nuclear atypia. No nuclear features of papillary carcinoma were seen (A: Diff-Quik^® stain. B: Papanicolaou stain. C: ThinPrep^® preparation). The surgical pathology follow-up was diagnosed as follicular adenoma (D–E: hematoxylin and eosin stains at 50× and 200×). Case 2: The FNA samples from this case show monotonous populations of follicular cells arranged in cohesive groups and microfollicles with round nuclei, with evenly distributed nuclear chromatin pattern. No nuclear features of papillary carcinoma were seen 2 (A: Diff-Quik^® stain. B: Papanicolaou stain. C: ThinPrep^® preparation). The surgical pathology follow-up was follicular adenoma (D–E at 50× and 200× hematoxylin and eosin stains). [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

A composite figure of cytologic features of cases with TSHR mutation. Follicular cells arranged in loosely cohesive groups with marginal vacuoles, also known as “fire flares” (air-dried smear stained with Diff-Quik stain A–C, 50×, 100× and 200×). The alcohol fixed smears stained with Papanicolaou stain demonstrate follicular cells with round nuclei with even chromatin pattern, moderate amount of cytoplasm containing paravacoular granules (D–F, 50× and 200×). [Color figure can be viewed at wileyonlinelibrary.com]