Distant Metastases From Childhood Differentiated Thyroid Carcinoma: Clinical Course and Mutational Landscape

Abstract

Context: Distant metastases (DM) from childhood differentiated thyroid carcinoma (DTC) are uncommon and published studies are limited.

Objective: This work aimed to describe the outcomes of patients with DM from childhood DTC and to evaluate the molecular landscape of these tumors.

Methods: A retrospective study was conducted at a tertiary cancer center including patients with pediatric DTC (diagnosed at age ≤ 18 years from 1946 to 2019) and DM.

Results: We identified 148 patients; 144 (97%) had papillary thyroid carcinoma (PTC) and 104 (70%) were female. Median age at DTC diagnosis was 13.4 years (interquartile range [IQR], 9.9-15.9 years). Evaluable individuals received a median of 2 (IQR, 1-3) radioactive iodine (RAI) treatments at a median cumulative administered activity of 238.0 mCi (IQR, 147.5-351.0 mCi). The oncogenic driver was determined in 64 of 69 PTC samples: RET fusion (38/64; 59%), NTRK1/3 fusions (18/64; 28%), and the BRAF V600E mutation (8/64; 13%). At last evaluation, 93% had persistent disease. The median overall and disease-specific survival after DTC diagnosis were 50.7 and 52.8 years, respectively. Eight (5%) PTC patients died of disease after a median of 30.7 years (IQR, 20.6-37.6 years).

Conclusion: Childhood DTC with DM persists in most patients despite multiple courses of RAI, but disease-specific death is uncommon, typically occurring decades after diagnosis. Fusion genes are highly prevalent in PTC, and all identified molecular alterations have appropriate targeted therapies. Future studies should focus on expanding genotype-phenotype correlations, determining how to integrate molecularly targeted therapy into treatment paradigms, and relying less on repeated courses of RAI to achieve cure in patients with DM from childhood DTC.

Keywords: fusion gene; lung metastasis; pediatric thyroid cancer; prognosis; somatic mutation; stage II.

Figure 1.

Kaplan-Meier survival curves of patients diagnosed with distant metastases from childhood differentiated thyroid carcinoma. A, Overall survival (OS; n = 148). Sixteen patients died during follow-up. The median OS was 50.7 years. The 5-, 10-, 15-, 20-, 25-, and 30-year OS rates were 98.5%, 97.7%, 96.1%, 93.5%, 90.6%, and 86.8%, respectively. B, Disease-specific survival (DSS; n = 145). Eight patients died of papillary thyroid carcinoma (PTC); no follicular thyroid carcinoma–related deaths occurred. The median DSS was 52.8 years. The 5-, 10-, 15-, 20-, 25-, and 30-year DSS rates were 99.2%, 99.2%, 99.2%, 96.3%, 93.0%, and 93.0%, respectively. Patients with an unknown cause of death (n = 3) were excluded from the DSS analysis.