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.

Differentiated Thyroid Cancer in Children and Adolescents: Long Term Outcome and Risk Factors for Persistent Disease

“…A report from a US referral center on 148 pediatric DTC with DM found a persistent disease rate of 93% after a median follow up of 10.5 years [29], and this striking difference compared to our results, despite a similar median administered cumulative activities of radioiodine, may rely on different evaluation criteria used for treatment response. We have previously shown that in adult patients who had no residual imaging abnormalities after RAI treatment for DM, the residual Tg level (detectable or not) had no predictive role on subsequent progression [16].…”

Prognostic factors in children and adolescents with differentiated thyroid carcinoma treated with total thyroidectomy and RAI: a real-life multicentric study

“…One of the major biases of pediatric DTC guidelines is the paucity of specific data and studies available, despite the fact that the peculiarity of the presentation, prognosis, and management of DTC in children has been clarified [4][5][6]. Thus, extrapolating and applying results from studies of adult population in pediatric field might lead to equivocal conclusions.…”

“…At the onset DTC, pediatric patients have higher risk of cervical lymph node and lung metastases, when compared to the adult counterpart [3]. However, the prognosis is favorable, and the mortality rate is very low [4][5][6]. In this particular setting, customizing the risk of relapse of each patient may avoid unbeneficial treatment.…”

Understanding of Pulmonary Metastases in Pediatric Patients with Differentiated Thyroid Cancer Is Evolving

“…The genomic landscape of pediatric thyroid disease is quickly emerging. Recent literature suggests that fusion mutations are more common in the primary tumor of pediatric thyroid cancer and may portend a more aggressive clinical course (5). The limited genomic data in this cohort support this theory.…”

“…In addition, many patients (n = 148) had persistent disease despite RAI. This finding was echoed in a recent large retrospective study wherein 93% of children and young adults with metastatic thyroid cancer had persistent disease despite RAI (5). Fortunately, patients in both cohorts experienced very low disease-specific mortality.…”