Newbern, Dorothee

Background: Childhood cancer survivors and bone marrow transplant recipients treated with radiation therapy (RT) are at increased risk for subsequent thyroid cancer. However, the genetic landscape of pediatric thyroid cancer, both primary and RT-induced, remains poorly defined, as pediatric papillary thyroid carcinoma (PTC) has been understudied compared with adults and data on pediatric follicular thyroid carcinoma (FTC) are virtually nonexistent. The objective of this study was to characterize and compare the molecular profiles of pediatric RT-induced PTC and FTC cases with primary pediatric thyroid cancers. Methods: A total of 41 differentiated thyroid carcinomas (11 RT cases and 30 primary cases) from 37 patients seen at Phoenix Children's Hospital between January 1, 2010 and December 31, 2019 were evaluated by targeted next-generation sequencing and/or BRAF immunohistochemistry. Results: Eighty-six percent (6/7) of RT-PTC harbored a gene fusion (GF) compared with 56% (14/25) of primary PTC; 14% (1/7) of RT-PTC had a single-nucleotide variant (SNV; specifically, a point mutation in the DICER1 gene ) compared with 44% (11/25) of primary PTC (all of the latter had the BRAF V600E mutation). An exceedingly rare ROS1 fusion was identified in a child with RT-PTC. With respect to FTC, copy number alterations (CNAs) were seen in 75% (3/4) of RT cases compared with 40% (2/5) of primary cases. None of the RT-FTC had SNVs compared with 100% (5/5) of primary FTC. Conclusions: In children, the molecular profile of subsequent RT-induced thyroid cancers appears to differ from primary (sporadic and syndromic) cases, with a high prevalence of GFs in RT-PTC (similar to PTC occurring after the Chernobyl nuclear reactor accident) and CNAs in RT-FTC. A better understanding of the molecular mechanisms underlying these cancers may lead to more accurate diagnosis, prognosis, and treatment, as some of the genomic alterations are potentially targetable.

e21528 Background: Thyroid cancer is a common secondary malignancy among childhood cancer survivors who have received radiation to the head, neck and/or upper thorax. The optimal strategy for surveillance for thyroid carcinoma in childhood cancer survivors remains controversial. Current Children’s Oncology Group recommendations are limited to physical exam. The objective of this study was to determine the sensitivity and specificity of thyroid ultrasound versus neck exam by a pediatric endocrinologist in the diagnoses of thyroid cancer in a cohort of high-risk childhood cancer survivors. Methods: Medical records of childhood cancer survivors who received radiotherapy to the head, neck and/or upper thorax were reviewed. These patients were seen in a comprehensive childhood cancer survivorship clinic from 01/01/2010 to 12/31/2017. Patient populations included oncology, bone marrow transplant and brain tumor patients. Results: 226 patients received radiation to the head, neck and/or upper thorax. Of those, 129 patients were male (57%). Sixteen (7.1%) of patients developed a secondary thyroid malignancy including 4 patients previously treated for an oncological malignancy, 9 patients treated with bone marrow transplantation, and 3 patients with a CNS malignancy. Median radiation dose was 1800 cGy (range 400-5940 cGy). Time to thyroid carcinoma diagnosis occurred at a median of 12 years (range 4-19 years) from treatment with radiation. Screening ultrasounds were obtained in 146 (65%) patients while 226 (100%) had a physical exam. Two cases were identified by abnormalities on physical exam. The sensitivity of US was 100% (CI 80.6-100) compared to a sensitivity of 12.5% (CI 3.5-36) using physical exam (P < 0.0001). Screening ultrasound had a specificity of 73% (CI 65.1-80.1) while physical exam yielded a specificity of 100% (CI 98.2-100). Conclusions: Regular screening with ultrasounds provide the greatest sensitivity for detection of secondary thyroid carcinomas after head, neck and upper thorax radiation in childhood cancer survivors. If screening ultrasounds were not routinely utilized in our clinic, 14 of the 16 patients (87.5%) would have had a delay in their diagnosis of a secondary thyroid malignancy. Screening ultrasounds may lead to earlier detection of thyroid carcinomas, with the potential to decrease the need for aggressive surgery, radioiodine therapy and, ultimately, to decrease recurrence risk.