Contribution of Germline Predisposition to Pediatric Thyroid Cancer

Abstract Purpose: Pediatric thyroid carcinoma is a rare cancer for which germline genetic factors remain incompletely understood. To gain further insight, we examined the prevalence and spectrum of pathogenic variants (PV) in cancer-predisposing genes (CPG) in a large cohort of children with thyroid carcinoma at our institution. Experimental Design: This retrospective study included 71 children who presented with thyroid carcinoma as a first (n = 52) or subsequent malignant neoplasm (n = 19) and underwent germline testing. The objectives were to determine the proportion of patients harboring PVs and correlate germline information with clinical features, tumor pathology, and outcome. Results: Eighteen patients (25%; 7 primary and 11 subsequent malignant neoplasm) harbored a PV affecting a CPG. Four of these patients had medullary thyroid carcinoma, whereas 14 had nonmedullary thyroid carcinoma. Children diagnosed with thyroid carcinoma before 11 years of age were significantly more likely to harbor PVs (P < 0.01), as were children with medullary histology tumors (P < 0.05) or a prior cancer history (P < 0.001). Both RB1-associated thyroid carcinomas occurred in children who never received prior chemotherapy or radiotherapy. Seventeen patients remain alive at a median of 3 years since diagnosis (1 month–27 years). Twelve of 18 patients with PVs were treated only with thyroidectomy, whereas six required radioactive iodine therapy or chemotherapy. One patient with multiple endocrine neoplasia type 2 expired. Conclusions: A substantial proportion of children with thyroid carcinoma harbor a CPG PV. Accordingly, genetic counseling and testing should be considered for all affected children, especially those who are young, have medullary thyroid carcinoma, or a prior cancer history.