Clinicopathologic and molecular characterization of NTRK-rearranged thyroid carcinoma (NRTC)

Abstract

Primary thyroid neoplasms with actionable NTRK rearrangements are rare, and their clinical behavior, histologic characteristics, and molecular landscape are not well understood. We report an institutional series of eleven NTRK-rearranged thyroid carcinomas (NRTC) by performing clinicopathologic review and next-generation sequencing for targeted mutations and gene rearrangements. The NRTC encompass a histomorphologic spectrum of ten papillary thyroid carcinomas (PTC), including one with high-grade features, and one secretory carcinoma (SC), in ten adults and one adolescent. All NRTC were characterized by an unusual multinodular growth pattern, extensive lymphovascular invasion, and cervical lymph node metastases at initial presentation. Immunophenotypically, while most cases were positive for TTF1 and PAX8, the SC case was negative/weak for these markers and instead diffusely expressed GATA3, mammaglobin and S100. Observed gene rearrangements included ETV6-NTRK3 (n = 4, including the SC), TPR-NTRK1 (n = 2), RBPMS-NTRK3 (n = 2), SQSTM1-NTRK1 (n = 1), SQSTM1-NTRK3 (n = 1), and EML4-NTRK3 (n = 1). Mutation profiling revealed a concurrent TERT promotor mutation C228T in two (22%) patients and a novel frameshift MEN1 deletion in one. All patients received total thyroidectomy and radioactive iodine. Despite frequent development of persistent/recurrent disease (9 cases, 82%) and distant metastases (6 cases; 55%), no tumor-related death occurred over a median (range) follow-up of 44 (11 to 471) months. Three patients received NTRK inhibitor therapy, with the SC case showing complete resolution and two other patients experiencing 33% and 69.7% decrease of disease burden. Although the range of features is variable, NRTC appear to be clinically aggressive tumors with high metastatic rate but relatively low mortality with NTRK inhibitor therapy. The histologic findings of multinodular growth and extensive lymphovascular spread, seen in all NRTC, including PTC and SC, may serve as useful histomorphologic clues to prompt NTRK status testing. We also present the first report of concurrent TERT promotor activating mutation which did not appear to confer entrectinib resistance to NRTC.

Fig. 1. Observed NTRK rearrangements in the cases.

Numbers in parentheses indicate the exons involved at fusion breakpoints. The tyrosine kinase domain of NTRK1/3 remained intact in all the cases.

Fig. 2. NRTC with predominantly follicular pattern associated with ETV6-NTRK3 and RBPMS-NTRK3 fusions.

a–c Papillary thyroid carcinomas with ETV6-NTRK3 fusion showed multiple irregularly shaped tumor nodules infiltrating the thyroid (a). Growth pattern was mainly follicular with isolated foci of true papillae (black arrowhead) and hyperplasia-like epithelial folding (white arrowhead) (b). Tall cell features were focally seen in case 4 (c). d Papillary thyroid carcinomas with RBPMS-NTRK3 fusion had similar histologic appearance composed of well-formed neoplastic follicles and scattered papillae.

Fig. 3. Primary thyroid secretory carcinoma with ETV6-NTRK3 fusion (case 11).

The tumor demonstrated a lobulated appearance with prominent intratumoral fibrosis (a). Admixed microcystic and tubulopapillary patterns were seen, and the cells showed elongated, often grooved nuclei with finely speckled chromatin and central nucleoli (b, inset). The cytoplasm was abundant and vacuolar, frequently containing intracytoplasmic eosinophilic globules in a signet ring-like appearance (b, inset). By immunohistochemistry, there was diffuse expression of mammaglobin (c) and S100 (d), and focal weak TTF1 (e). PAX8 was negative (f).

Fig. 4. NRTC with predominantly papillary pattern associated with TPR-NTRK1 and SQSTM1-NTRK1 fusions.

TPR-NTRK1 fusion thyroid carcinoma, showing multiple infiltrative nodules of well-formed papillae (a) and scattered glomeruloid structures (b). SQSTM1-NTRK1 fusion thyroid carcinoma exhibited multinodular growth (c) and a labyrinthine pattern formed by coalescent true and abortive papillae with glomeruloid structures (d, inset).

Fig. 5. NRTC with predominantly insular pattern associated with SQSTM1-NTRK3 fusion (case 8).

The tumor is multinodular and divided by fibrous septa (a). There is extensive extrathyroidal extension into the strap muscle (b). Higher magnification revealed an insular growth pattern with scattered microfollicles (c). The tumor cells are oncocytic, with convoluted nuclei, finely granular chromatin, and increased mitotic activity (up to 4 mitoses per 10 high-power fields) (d).

Fig. 6. Brain metastasis from an EML4-NTRK3 fusion thyroid carcinoma (case 1).

Tumor cells were oncocytic with finely stippled nuclei and occasional nuclear grooves, forming microfollicles and papillae.