Presentation and outcome of subsequent thyroid cancer among childhood cancer survivors compared to sporadic thyroid cancer:a matched national study

Objective: Childhood cancer survivors (CCS) are at increased risk to develop differentiated thyroid cancer predominantly after radiotherapy (subsequent DTC). It is insufficiently known whether subsequent DTC in CCS has a different presentation or outcome than sporadic DTC. Methods: Patients with subsequent DTC (n = 31) were matched to patients with sporadic DTC (n = 93) on gender, age and year of diagnosis to compare presentation and DTC outcomes. Clinical data were collected retrospectively. Results: Among the CCS with subsequent DTC, all but one had received chemotherapy for their childhood cancer, 19 (61.3%) had received radiotherapy including the thyroid region, 3 (9.7%) 131I-MIBG and 8 (25.8%) had received treatment with chemotherapy only. Subsequent DTC was detected by surveillance through neck palpation (46.2%), as a self-identified mass (34.6%), or by chance. Among sporadic DTC patients, self detection predominated (68.8%). CCS with subsequent DTC tended to have on average smaller tumors (1.9 vs 2.4 cm, respectively, (P = 0.051), and more often bilateral (5/25 (60.0%) vs 28/92 (30.4%), P = 0.024). There were no significant differences in the occurrence of surgical complications, recurrence rate or disease-related death. Conclusion: When compared to patients with sporadic DTC, CCS with subsequent DTC seem to present with smaller tumors and more frequent bilateral tumors. Treatment outcome seems to be similar. The finding that one-third of subsequent DTC cases had been treated with chemotherapy only needs further investigation. These results are important for the development of surveillance programs for CCS at risk for DTC and for treatment guidelines of subsequent DTC

Crystal IS on the move

Introduction: Whether pediatric patients with differentiated thyroid carcinoma (DTC) are at risk of developing treatment-related adverse effects on cardiac function is unknown. We therefore studied in long-term survivors of pediatric DTC the prevalence of cardiac dysfunction and atrial fibrillation in relation to treatment variables, and the association between cardiac dysfunction and plasma biomarkers. Methods: In this nationwide prospective multicenter study, cardiac assessments were performed in 66 adult survivors of pediatric DTC (age at diagnosis 18 years and follow-up 5 years after diagnosis) treated in the Netherlands between 1970 and 2009. Assessment included echocardiography, plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive troponin-T, galectin-3), and 24-hour Holter electrocardiography. Echocardiographic measurements were compared with retrospective data of 66 sex- and age-matched unaffected Dutch controls. Diastolic dysfunction was defined as an early diastolic septal and/or lateral tissue velocity (e) less than 2 SD of mean age-adjusted reference data. Results: The survivors (86.4% women) had at DTC diagnosis a median age of 16 years. Median follow-up was 17 years. Left ventricular ejection fraction <50% was found in one survivor, and median global longitudinal systolic strain was near normal. Diastolic dysfunction was present in 14 asymptomatic survivors (21.2%). Overall, diastolic function of survivors was lower compared with controls (emean 14.5 versus 15.8cm/s, P=0.006). Older attained age and higher waist circumference were associated with decreased diastolic function, whereas thyrotropin levels and cumulative administered radioiodine dose were not. In survivors, biomarkers were not associated with diastolic dysfunction; atrial fibrillation was not observed. Conclusion: While systolic function is unaffected, diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC, which may suggest early cardiac agin

Long-term effects of radioiodine treatment on salivary gland function in adult survivors of pediatric differentiated thyroid carcinoma

Pediatric differentiated thyroid cancer (DTC) is a rare disease. Initial treatment of DTC consists of a (near) total thyroidectomy and radioactive iodine (131I) therapy. Previous studies in adults showed that 131I treatment may result in a reduced salivary gland function. Studies regarding salivary gland function in children treated for DTC are sparse. Our aim was to assess long-term effects of 131I treatment on salivary gland function in survivors of pediatric DTC. Methods: In a nationwide cross-sectional study, salivary gland function of patients treated for pediatric DTC between 1970 and 2013 (>5 years after diagnosis, ≥18 years old at time of evaluation) was studied. Salivary gland function was assessed by sialometry, sialochemistry and a xerostomia inventory. Salivary gland dysfunction was defined as unstimulated whole saliva flow ≤0.2mL/min and/or a stimulated whole saliva flow ≤0.7 mL/min. Results: Sixty-five patients (median age at evaluation 33 [IQR, 25-40] years, 86.2% female, median follow-up period 11 [IQR, 6-22] years) underwent 131I treatment. Median cumulative 131I activity was 5.88 [IQR, 2.92-12.95] GBq, 47.7% underwent multiple 131I administrations. Salivary gland dysfunction was present in 30 (47.6%) patients. Levels of amylase and total protein in saliva were reduced. Moderate to severe xerostomia was present in 22 (35.5%) patients. Stimulated salivary secretion was lower and severity of xerostomia complaints higher in patients treated with higher cumulative 131I activity. Conclusion: In survivors of pediatric DTC, clinically significant salivary gland dysfunction was found in 35.5% and was related to the cumulative 131I activity of the treatment

Increased Global DNA Hypomethylation in Distant Metastatic and Dedifferentiated Thyroid Cancer

Context: Global DNA hypomethylation is a major event for the development and progression of cancer, although the significance in thyroid cancer remains unclear. Therefore, we aimed to investigate its role in thyroid cancer progression and its potential as a prognostic marker. Methods: Global hypomethylation of Alu repeats was used as a surrogate marker for DNA global hypomethylation, and was assessed using the Quantification of Unmethylated Alu technique. Mutations in BRAF and RAS were determined by Sanger sequencing. Results: Ninety primary thyroid tumors were included [28 low-risk differentiated thyroid cancer (DTC), 13 pediatric DTC, 33 distant metastatic DTC, 7 poorly differentiated thyroid cancer (PDTC), and 9 anaplastic thyroid cancer (ATC)], as well as 24 distant metastases and 20 normal thyroid tissues. An increasing hypomethylation was found for distant metastatic DTC [median, 4.0; interquartile range (IQR), 3.1 to 6.2] and PDTC/ATC (median, 9.3; IQR, 7.0 to 12.1) as compared with normal thyroid tissue (median, 2.75; IQR, 2.30 to 3.15), whereas low-risk and pediatric DTC were not affected by hypomethylation. Alu hypomethylation was similar between distant metastases and matched primary tumors. Within distant metastatic DTC, Alu hypomethylation was increased in BRAF vs RAS mutated tumors. Kaplan-Meier and Cox regression analyses showed that thyroid cancer-related and all-cause mortality were associated with tumor hypomethylation, but this association was lost after adjustment for thyroid cancer risk category. Conclusion: Distant metastatic DTC, PDTC, and ATC were increasingly affected by global Alu hypomethylation, suggesting that this epigenetic entity may be involved in thyroid cancer progression and dedifferentiation

Long-Term Effects of Radioiodine Treatment on Salivary Gland Function in Adult Survivors of Pediatric Differentiated Thyroid Carcinoma

Pediatric differentiated thyroid cancer (DTC) is a rare disease. Initial treatment of DTC consists of a total or near-total thyroidectomy and I-131 therapy. Previous studies on adults showed that I-131 treatment may reduce salivary gland function (SGF). Studies regarding SGF in children treated for DTC are sparse. Our aim was to assess the long-term effects of I-131 treatment on SGF in survivors of pediatric DTC. Methods: In a nationwide cross-sectional study, SGF in patients treated for pediatric DTC between 1970 and 2013 (>5 y after diagnosis, >= 18 y old at the time of evaluation) was studied. SGF was assessed by sialometry, sialochemistry, and a xerostomia inventory. Salivary gland dysfunction (SGD) was defined as an unstimulated whole saliva flow of no more than 0.2 mL/min or a stimulated whole saliva flow of no more than 0.7 mL/min. Results: Sixty-five patients underwent I-131 treatment (median age at evaluation, 33 y, with an interquartile range [IQR] of 25-40 y; 86.2% female; median follow-up period, 11 y, with an IQR of 6-22 y). Median cumulative I-131 activity was 5.88 GBq, with an IQR of 2.92-12.95 GBq, and 47.7% underwent multiple I-131 administrations. SGD was present in 30 (47.6%) patients. Levels of amylase and total protein in saliva were reduced. Moderate to severe xerostomia was present in 22 (35.5%) patients. Stimulated salivary secretion was lower and the severity of xerostomia complaints higher in patients treated with higher cumulative I-131 activity. Conclusion: In survivors of pediatric DTC, clinically significant SGD was found in 35.5% and was related to the cumulative I-131 activity of the treatment

Long-Term Effects of Radioiodine Treatment on Female Fertility in Survivors of Childhood Differentiated Thyroid Carcinoma

Background: Differentiated thyroid carcinoma (DTC) during childhood is a rare disease. Its excellent survival rate requires a focus on possible long-term adverse effects. This study aimed to evaluate fertility in female survivors of childhood DTC by assessing various reproductive characteristics combined with anti-Müllerian hormone (AMH) levels (a marker of ovarian reserve). Methods: Female survivors of childhood DTC, diagnosed at ≤18 years of age between 1970 and 2013, were included. Survivors were excluded when follow-up time was less than five years or if they developed other malignancies before or after diagnosis of DTC. Survivors filled out a questionnaire regarding reproductive characteristics (e.g., age at menarche and menopause, pregnancies, pregnancy outcomes, need for assisted reproductive therapy). Survivors aged <18 years during evaluation received an altered questionnaire without questions regarding pregnancy and pregnancy outcomes. These data were combined with information from medical records. AMH levels were measured in serum samples and were compared with AMH levels from 420 women not treated for cancer. Results: Fifty-six survivors with a median age of 31.0 (interquartile range, IQR, 25.1-39.6) years were evaluated after a median follow-up of 15.4 (IQR 8.3-24.7) years. The median cumulative dose of 131I administered was 7.4 (IQR 3.7-13.0) GBq/200.0 (IQR 100.0-350.0) mCi. Twenty-five of the 55 survivors aged 18 years or older during evaluation reported 64 pregnancies, 45 of which resulted in live birth. Of these 55, 10.9% visited a fertility clinic. None of the survivors reported premature menopause. Age at AMH evaluation did not differ between DTC survivors and the comparison group (p = 0.268). Median AMH levels did not differ between DTC survivors and the comparison group [2.0 (IQR 1.0-3.7) μg/L vs. 1.6 (IQR 0.6-3.1) μg/L, respectively, p = 0.244]. The cumulative dose of 131I was not associated with AMH levels in DTC survivors (rs = 0.210, p = 0.130). Conclusions: Female survivors of DTC who received 131I treatment during childhood do not appear to have major abnormalities in reproductive characteristics nor in predictors of ovarian failure