Faculty Bibliography

Introduction: Molecular tests such as ThyroSeq are recommended in the workup of cytologically indeterminate thyroid nodules (ITN). While repeat molecular testing is often performed after repeat fine needle aspiration (FNA) yields persistently indeterminate cytology, ThyroSeq's inter-test reliability is unclear. We assessed consistency of initial and repeat ThyroSeq analyses performed on samples from the same thyroid nodules.
Method(s): All thyroid nodules diagnosed as ITN on consecutive FNAs that received ThyroSeq with both biopsies from 2014-2018 at our institution, were reviewed. Initial analysis was ThyroSeq v2 while repeat was v2 or v3. Nodules with gene mutations, fusions, or copy number alterations (CNA) were considered ThyroSeq-positive.
Result(s): During the study period, 30 patients underwent ThyroSeq analysis on initial and repeat FNA samples (median interval=21 months). On initial testing, 27 (90%) nodules were ThyroSeq-negative and 3 (10%) low-risk mutations (RAS, EIF1AX, TSHR) were identified. Repeat ThyroSeq re-identified these 3 nodules and also interpreted 9 initially ThyroSeq-negative nodules as positive (kappa=0.286). All 9 molecular alterations were low-risk, most were identified on v3 (7, 77.8%), and CNA was the most common change (6, 66.7%). Of 12 patients with ThyroSeq-positive nodules, 8 underwent lobectomy. Final pathology identified low-risk malignancy in 3 nodules; the remainder were benign.
Conclusion(s): New findings on repeat ThyroSeq are possible. Whether these findings were detected by expanded panel or are the result of de-novo changes is unknown. The risk of missing high-risk changes appears to be low. More studies are needed to characterize the concordance of ThyroSeq analyses and natural evolution of ITNs.
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The majority of malignancies identified in indeterminate thyroid nodules (ITN) are low risk. Therefore, the need for total thyroidectomy or adjuvant treatment such as completion thyroidectomy or radioactive iodine (RAI) therapy in the treatment of ITNs is uncertain. This study aimed to analyze the likelihood of a need for total thyroidectomy and RAI therapy in the management of ITNs. All ITNs diagnosed on FNA cytology from 2014-2018 at NYU Langone Health were reviewed. ITNs managed with surgery were selected. Demographics, nodule characteristics, final pathology, treatment detail, and clinical outcomes were recorded. During the study period, 218 patients with surgically excised ITNs were identified. One hundred forty-two (65.1%) patients underwent thyroid lobectomy (TL), and 76 (34.9%) had total thyroidectomy (TT) upfront. In the lobectomy group, 26 (18.3%) had a malignant nodule on final surgical pathology, 8 (5.6%) underwent completion thyroidectomy, and 5 (3.5%) received RAI. In the total thyroidectomy group, 26 (34.2%) were diagnosed as malignant, and 14 (18.4%) received RAI. Follicular variant of papillary thyroid carcinoma (FVPTC) was the most common malignant diagnosis in both groups (TL: 20, 76.9%; TT: 12, 46.2%). Adenomatous nodule was the most common benign diagnosis (TL: 55, 72.5%; TT: 15, 51.2%). NIFTP accounted for 28.2% (40) of nodules treated with lobectomy and 27.6% (21) of nodules treated with upfront total thyroidectomy. In the entire cohort, only two (1%) patients had significant pathology in the contralateral lobe (1 [0.5%] with papillary thyroid carcinoma [PTC] and 1 [0.5%] with multifocal micro-PTC). Of all 218 ITNs, only 19 patients (8.7%) received RAI. With a median follow-up of 31.5 months (interquartile range = 21-39.5), no recurrences or progression was seen. The need for completion thyroidectomy or adjuvant RAI therapy in the treatment of ITN was low in our series. These data suggest that initial management of ITNs with lobectomy might be sufficient in the majority of cases

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Extracardiac rhabdomyoma is an uncommon benign striated muscle tumor with a predilection for the head and neck region. However, it is extremely rare for extracardiac rhabdomyoma to present as a thyroid nodule. We report a case of rhabdomyoma diagnosed by thyroid fine-needle aspiration (FNA) in a patient with Birt-Hogg-Dubé (BHD) syndrome. A 60-year-old man with BHD syndrome presented for recurrent pneumothorax. Chest CT incidentally identified a thyroid nodule. Subsequent sonography confirmed a 4.44 × 2.28 × 2.82 cm solid, hypoechoic nodule with smooth margins in the right upper pole. Ultrasound-guided FNA revealed many clusters and scattered isolated large polygonal cells with abundant granular cytoplasm and small peripherally located nuclei. Vague striations in the cytoplasm were focally identified. No follicular cells or colloid was present. Immunocytochemistry on one direct smear slide demonstrated diffuse positivity for desmin, supporting muscular differentiation. Subsequent surgery identified an adult rhabdomyoma originating from the inferior constrictor muscle of the neck and anteriorly displacing the thyroid. Because the mass was intimately associated with the thyroid gland, it was initially mistaken for a thyroid nodule on ultrasound. Diagnosis of rhabdomyoma on FNA is challenging, especially when rhabdomyoma mimics a thyroid nodule on imaging. The differential diagnosis includes Hurthle cell neoplasm, granular cell tumor, colloid nodule, and normal striated skeletal muscle. Adequate radiologic data and familiarity with the cytologic features of rhabdomyoma are critical for an accurate diagnosis.

DICER1 encodes an endoribonuclease involved in microRNA maturation and therefore has an important role in gene transcript regulation. Germline mutations scattered along DICER1 are associated with DICER1 syndrome which prominently features thyroid nodules. The tumors typically carry a second, somatic mutation in the RNase IIIb catalytic domain, referred to as "hotspot." These hotspot mutations occur in*1-2% of thyroid papillary carcinomas (PTC). The incidence of the hotspot mutations in thyroid nodules in adults, their association with malignancy and with other, germline DICER1 mutations remain largely unknown. We analyzed 6,734 consecutive clinical FNA samples from typically indeterminate cytology thyroid nodules for hotspot DICER1mutations using ThyroSeq v3 targeted next generation sequencing (NGS) assay from 11/2017-05/2018. Available follow-up was collected. A subgroup of cases underwent full DICER1 coding region and exon-intron boundaries analysis using a custom Fluidigm Access Array followed by NGS on Illumina MiSeq. Somatic DICER1 hotspot mutations were identified in 135 (2.0%) of nodules, with D1810H/V/Y and D1709G/E/N being most common. Median patient age was 37 years (range 19-79 y), 93% were females. Follow-up was available for 27 patients: 15 underwent surgery with benign diagnoses in 9 cases, NIFTP in 5 and follicular variant PTC in 1. Twelve patients were managed non-surgically, including one with a stable nodule harboring DICER1mutation at an allele frequency unchanged over 10 years between FNAs. A subset of 11 positive cases was tested for alteration in the entire DICER1 gene, which confirmed the hotspot mutations in 10 and detected additional alterations in 9 (90%), including non-hotspot mutations in 8 and LOH in 1 case. We report for the first time that likely somatic hotspot DICER1 mutations are relatively common and found in*2% of thyroid nodules in adults, who are typically mid-age women. At surgery, most of these nodules are benign, with*33% risk of NIFTP and*7% risk of follicular variant PTC. Our analysis also shows that somatic hotspot mutations are usually accompanied by a second, loss of function DICER1 mutation, which may in some cases be germline in nature

BACKGROUND:Thyroid-stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%-82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied. METHODS:To examine the association of TSHR mutations with the functional status and surgical outcomes of thyroid nodules, we evaluated 703 consecutive thyroid FNA samples with indeterminate cytology for TSHR mutations using next-generation sequencing. Testing for EZH1 mutations was performed in selected cases. The molecular diagnostic testing was done as part of standard of care treatment, and did not require informed consent. RESULTS:TSHR mutations were detected in 31 (4.4%) nodules and were located in exons 281-640, with codon 486 being the most common. Allelic frequency ranged from 3% to 45%. Of 16 cases (12 benign, 3 FTC, 1 PTC) with surgical correlation, 15 had solitary TSHR mutations and 1 PTC had comutation with BRAF V600E. Hyperthyroidism was confirmed in all 3 FTC (2 overt, 1 subclinical). Of 5 nodules with solitary TSHR mutations detected at high allelic frequency, 3 (60%) were FTC. Those at low allelic frequency (3%-22%) were benign. EZH1 mutations were detected in 2 of 4 TSHR-mutant malignant nodules and neither of 2 benign nodules. CONCLUSION/CONCLUSIONS:We report that TSHR mutations occur in ∼5% thyroid nodules in a large consecutive series with indeterminate cytology. TSHR mutations may be associated with an increased cancer risk when present at high allelic frequency, even when the nodule is hyperfunctioning. Benign nodules were however most strongly correlated with TSHR mutations at low allelic frequency.