Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.

OBJECTIVE: Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. METHODS: We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. RESULTS: We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). CONCLUSION: The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.

Application of the American Thyroid Association Risk Assessment in Patients with Differentiated Thyroid Carcinoma in a German Population.

BACKGROUND: The American Thyroid Association (ATA) uses criteria to assess the risk for persistent disease in differentiated thyroid carcinoma (DTC) after radioiodine therapy (RAI). There are no data available showing that this classification can be adopted unadjusted by Germany. AIM: The aim of our study is to investigate whether the ATA classification can be applied to a German population for short-term prognosis. Furthermore, we investigated the influence of an age cutoff value. METHODS: We retrospectively analyzed 121 patients who were referred to our tertiary referral center. Patients were classified into risk categories, and the therapy response was determined according to ATA. RESULTS: A total of 73/83 (88%) ATA low-risk patients and 12/19 (63%) intermediate-risk patients showed an excellent response; 2/19 (11%) high-risk patients had a biochemical, and 6 (31%) had a structural incomplete response. Of all 39 patients ≥55 years, 84% had an excellent response. Using a cut off of 50 years, 50/62 (81%) of the older patients showed an excellent response. CONCLUSION: The ATA risk classification is able to estimate the response to RAI therapy in a German population. A shift from 55 to 50 years as an age cutoff value does not result in any relevant change in the treatment response.

Responsivity of the Striatal Dopamine System to Methylphenidate-A Within-Subject I-123-ß-CIT-SPECT Study in Male Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods: Thirteen adolescent male patients (9-16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-ß-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results: On-MPH status was associated with a highly significant change (-29.9%) of striatal DAT BP as compared to off-MPH (t = -4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion: Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.

Second primary malignancies induced by radioactive iodine treatment of differentiated thyroid carcinoma - a critical review and evaluation of the existing evidence.

PURPOSE: Concern is growing about long-term side effects of differentiated thyroid cancer treatment, most notably radioactive iodine (RAI) therapy. However, published studies on the subject have had heterogeneous cohorts and conflicting results. This review seeks to provide an updated evaluation of published evidence, and to elucidate the risk of second primary malignancies (SPMs), especially secondary hematologic malignancies (SHMs), attributable to RAI therapy. METHODS: An extensive literature search was performed in Ovid MEDLINE, Ovid MEDLINE and In-Process & Other Non-Indexed Citations, Ovid MEDLINE Epub Ahead of Print, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Studies regarding RAI-induced SPMs or a dose-response relationship between RAI therapy and SPMs were identified, 10 of which were eligible for the analysis. We evaluated risk of bias in each study and judged quality of evidence (QOE) across all studies using the Grading of Recommendations, Assessment, Development and Evaluations approach. RESULTS: For the outcome "SPM", the relative effect (relative risk, hazard ratio, or odds ratio) of RAI vs. no RAI ranged from 1.14 to 1.84 across studies, but most results were not statistically significant. For the outcome "SHM", reported relative effects ranged from 1.30 to 2.50, with 2/3 of the studies presenting statistically significant results. In 7/8 of the studies, increased risk for SPM was shown with increasing cumulative RAI activity. QOE was "very low" regarding SPM after RAI and regarding a dose-response relationship, and "low" for SHM after RAI. CONCLUSION: Based on low quality evidence, an excess risk for the development of SPM cannot be excluded but is expected to be small.

Individualized treatment of differentiated thyroid cancer: The value of surgery in combination with radioiodine imaging and therapy - A German position paper from Surgery and Nuclear Medicine. / Individualisierte Behandlung von differenziertem Schilddrüsenkrebs: Der Wert der Operation in Kombination mit Radiojodbildgebung und -therapie ­ Ein deutsches Positionspapier aus der Chirurgie und Nuklearmedizin.

A consensus statement about indications for post-surgical radioiodine therapy (RIT) in differentiated thyroid cancer patients (DTC) was recently published by the European Thyroid Association (ETA) 1. This publication discusses indications for RIT on the basis of an individual risk assessment. Many of the conclusions of this consensus statement are well founded and accepted across the disciplines involved. However, especially from the perspective of nuclear medicine, as the discipline responsible for indicating and executing RIT, some of the recommendations may require further clarification with regard to their compatibility with established best practice and national standards of care. Assessment of the indications for RIT is strongly dependent on the weighing up of benefits and risks. On the basis of longstanding clinical experience in nuclear medicine, RIT represents a highly specific precision medicine procedure of proven efficacy with a favorable side-effect profile. This distinguishes RIT significantly from other adjuvant oncological therapies and has resulted in the establishment of this procedure as a usually well-tolerated, standard safety measure. With regard to its favorable risk/benefit ratio, this procedure should not be unnecessarily restricted, in the interest of offering reassurance to the patients. Both patients' interests and regional/national differences need to be taken into account. We would therefore like to comment on the recent consensus from the perspective of authors and to provide recommendations based on the respective published data.

Evaluating the use of a two-step age-based cutoff for the UICC/AJCC TNM staging system in patients with papillary or follicular thyroid cancer.

BACKGROUND: The joint Union International Contre le Cancer and American Joint Committee on Cancer (UICC/AJCC) Tumor, Node, Metastasis (TNM) staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomization of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of our study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease-specific survival (DSS). METHODS: We retrospectively studied two cohorts of adult DTC patients from The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV. RESULTS: We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. However, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small. CONCLUSIONS: The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although these two-step age-based cutoffs were marginally better from a statistical point of view, from a clinical point of view, the recently defined optimal single age cutoffs of 50 years for PTC and 40 years for FTC might be preferable.

High-dose radiation exposure and hypothyroidism: aetiology, prevention and replacement therapy.

Without any doubt, high dose radiation exposure can induce hypothyroidism. However, there are open questions related to the mechanisms of its induction, corresponding dose thresholds and possible countermeasures. Therefore, this review addresses the aetiology, prevention and therapy of radiation induced hypothyroidism. External beam radiotherapy with several 10 Gy to the head and neck region and radioiodine therapy with several 100 Gy thyroid absorbed dose can destroy the thyroid gland and can induce autoantibodies against thyroid tissue. According to recent literature, clinical hypothyroidism is observed at threshold doses of ∼10 Gy after external beam radiotherapy and of ∼50 Gy after radioiodine therapy, children being more sensitive than adults. In children and adolescents exposed by the Chernobyl accident with mean thyroid absorbed doses of 500-800 mGy, subclinical hypothyroidism has been detected in 3%-6% of the cases with significant correlation to thyroid absorbed doses above 2.5 Gy. In case of nuclear emergencies, iodine thyroid blocking (ITB) is the method of choice to keep thyroid absorbed doses low. Large doses of stable iodine affect two different steps of internalization of radioiodine (transport and organification); perchlorate affecting the transport only may be an alternative to iodine. Administered before radioiodine incorporation, the effect of 100 mg iodide or more is still about 90% after 1 days, 80% after 2 days, and 50% or less after 3 days. If administered (too) late after exposure to radioiodine, the theoretically expected protective effect of ITB is about 50% after 6 h, 25% after 12 h, and about 6% after 24 h. In case of repeated or continuous exposure, repeated administration of 50 mg of iodide daily is indicated. If radiation-induced hypothyroidism cannot be avoided, thyroid hormone replacement therapy with individualized dosing and regular monitoring in order to maintain thyroid-stimulating hormone levels within the normal range ensures normal life expectancy.

A Search for Causes of Rising Incidence of Differentiated Thyroid Cancer in Children and Adolescents after Chernobyl and Fukushima: Comparison of the Clinical Features and Their Relevance for Treatment and Prognosis.

The incidence of differentiated thyroid cancer (DTC) is steadily increasing globally. Epidemiologists usually explain this global upsurge as the result of new diagnostic modalities, screening and overdiagnosis as well as results of lifestyle changes including obesity and comorbidity. However, there is evidence that there is a real increase of DTC incidence worldwide in all age groups. Here, we review studies on pediatric DTC after nuclear accidents in Belarus after Chernobyl and Japan after Fukushima as compared to cohorts without radiation exposure of those two countries. According to the Chernobyl data, radiation-induced DTC may be characterized by a lag time of 4-5 years until detection, a higher incidence in boys, in children of youngest age, extrathyroidal extension and distant metastases. Radiation doses to the thyroid were considerably lower by appr. two orders of magnitude in children and adolescents exposed to Fukushima as compared to Chernobyl. In DTC patients detected after Fukushima by population-based screening, most of those characteristics were not reported, which can be taken as proof against the hypothesis, that radiation is the (main) cause of those tumors. However, roughly 80% of the Fukushima cases presented with tumor stages higher than microcarcinomas pT1a and 80% with lymph node metastases pN1. Mortality rates in pediatric DTC patients are generally very low, even at higher tumor stages. However, those cases considered to be clinically relevant should be followed-up carefully after treatment because of the risk of recurrencies which is expected to be not negligible. Considering that thyroid doses from the Fukushima accident were quite small, it makes sense to assess the role of other environmental and lifestyle-related factors in thyroid carcinogenesis. Well-designed studies with assessment of radiation doses from medical procedures and exposure to confounders/modifiers from the environment as e.g., nitrate are required to quantify their combined effect on thyroid cancer risk.

Finding the Optimal Age Cutoff for the UICC/AJCC TNM Staging System in Patients with Papillary or Follicular Thyroid Cancer.

Background: Differentiated thyroid cancer (DTC) is the only cancer entity for which the UICC/AJCC (Union for International Cancer Control and American Joint Committee on Cancer) TNM (tumor-node-metastasis) staging system involves an age cutoff as a prognostic criterion. However, the optimal age cutoff has not yet been determined in detail. The aim of our study was therefore to investigate the optimal age cutoff for the TNM staging system to predict disease-specific survival (DSS) with a focus on differences between patients with papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Methods: We retrospectively studied two large well-described cohorts of adult DTC patients from a Dutch and a German university hospital. DSS was analyzed for DTC overall, and for PTC and FTC separately, using several age cutoffs (per 5-year increment between 20 and 85 years and subsequently 1-year increments between 35 and 55 years), employing the histopathological criteria from the TNM staging system, eighth edition. Results: We included 3074 DTC patients (77% PTC and 23% FTC; mean age at diagnosis was 49 years). Median follow-up was seven years. For DTC and for PTC and FTC separately, the majority of the age cutoffs had a better statistical model performance than a model with no age cutoff. For DTC overall and for PTC, an age cutoff of 50 years had the best statistical model performance, while it was 40 years for FTC. Conclusions: In this large European population of DTC patients, when employing the histopathological criteria of the TNM system (eighth edition), the optimal age cutoff to predict DSS is 50 years rather than the 55 years currently in use. With the optimal age cutoff being 50 years for PTC and 40 years for FTC, there was a substantial difference in age cutoff for the respective histological entities. Therefore, implementation of different age cutoffs for PTC and FTC could improve the predictive value of the TNM staging system.

Feasibility Study Shows Multicenter, Observational Case-Control Study Is Practicable to Determine Risk of Secondary Breast Cancer in Females With Differentiated Thyroid Carcinoma Given Radioiodine Therapy in Their Childhood or Adolescence; Findings Also Suggest Possible Fertility Impairment in Such Patients.

Objective: This single-center, observational case-control feasibility study sought to test key elements of a protocol for an eventual long-term international observational case-control study of a larger patient cohort, to evaluate the risk of breast cancer as a second primary malignancy in females with differentiated thyroid cancer (DTC) given radioiodine therapy (RAI) during childhood or adolescence. Patients: Females developing DTC after the Chernobyl accident in Belarus and ≤19 years old at the time of thyroid surgery were enrolled: patients given RAI (n = 111) and controls of similar age not given RAI (n = 90). Results: One case of breast cancer was newly diagnosed among the RAI patients, but none in controls. Patients given RAI significantly less frequently needed 2nd surgeries than did controls (23%, 26/111 vs. 39%, 35/90, P < 0.05); the main indication for such procedures usually is suspicion of local recurrence. RAI patients appeared to have had more frequent reproductive difficulties than did controls: 78% (87/111) of the former vs. 93% (84/90) of the latter had a history of pregnancy (P < 0.01), and the mean number of pregnancies was 1.5 ± 1.2 in RAI patients vs. 1.9±1.1 in controls (P < 0.05). Most notably, infertility was observed in 23% (26/111) of RAI patients vs. 4% (4/90) of controls (P < 0.01). In conclusion, a international observational case-control study on breast cancer after DTC in patients given RAI vs. not given RAI appears to be feasible. Additional research and everyday clinical attention should be devoted to reproductive function after RAI in young females.

Hypothyroidism after radiation exposure: brief narrative review.

The thyroid gland is among the organs at the greatest risk of cancer from ionizing radiation. Epidemiological evidence from survivors of radiation therapy, atomic bombing, and the Chernobyl reactor accident, clearly shows that radiation exposure in childhood can cause thyroid cancer and benign thyroid nodules. Radiation exposure also may induce hypothyroidism and autoimmune reactions against the thyroid, but these effects are less well-documented. The literature includes only a few, methodologically weak animal studies regarding genetic/molecular mechanisms underlying hypothyroidism and thyroid autoimmunity after radiation exposure. Rather, evidence about radiation-induced hypothyroidism and thyroid autoimmunity derives mainly from follow-up studies in patients treated with external beam radiotherapy (EBRT) or iodine-131, and from epidemiological studies in the atomic bombing or nuclear accident survivors. Historically, hypothyroidism after external irradiation of the thyroid in adulthood was considered not to develop below a 10-20 Gy dose threshold. Newer data suggest a 10 Gy threshold after EBRT. By contrast, data from patients after iodine-131 "internal radiation therapy" of Graves´ disease indicate that hypothyroidism rarely occurs below thyroid doses of 50 Gy. Studies in children affected by the Chernobyl accident indicate that the dose threshold for hypothyroidism may be considerably lower, 3-5 Gy, aligning with observations in A-bomb survivors exposed as children. The reasons for these dose differences in radiosensitivity are not fully understood. Other important questions about the development of hypothyroidism after radiation exposure e.g., in utero, about the interaction between autoimmunity and hypofunction, and about the different effects of internal and external irradiation still must be answered.

Breast Cancer After Treatment of Differentiated Thyroid Cancer With Radioiodine in Young Females: What We Know and How to Investigate Open Questions. Review of the Literature and Results of a Multi-Registry Survey.

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case-control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial "misdiagnosis."

Clinical considerations for the treatment of secondary differentiated thyroid carcinoma in childhood cancer survivors.

The incidence of differentiated thyroid carcinoma (DTC) has increased rapidly over the past several years. Thus far, the only conclusively established risk factor for developing DTC is exposure to ionizing radiation, especially when the exposure occurs in childhood. Since the number of childhood cancer survivors (CCS) is increasing due to improvements in treatment and supportive care, the number of patients who will develop DTC after surviving childhood cancer (secondary thyroid cancer) is also expected to rise. Currently, there are no recommendations for management of thyroid cancer specifically for patients who develop DTC as a consequence of cancer therapy during childhood. Since complications or late effects from prior cancer treatment may elevate the risk of toxicity from DTC therapy, the medical history of CCS should be considered carefully in choosing DTC treatment. In this paper, we emphasize how the occurrence and treatment of the initial childhood malignancy affects the medical and psychosocial factors that will play a role in the diagnosis and treatment of a secondary DTC. We present considerations for clinicians to use in the management of patients with secondary DTC, based on the available evidence combined with experience-based opinions of the authors.

The time point of completion thyroidectomy has no prognostic impact in patients with differentiated thyroid cancer.

BACKGROUND: After partial resection of the thyroid gland, a second operation referred to as "completion thyroidectomy" may be required if histopathological analysis indicates the presence of differentiated thyroid cancer (DTC). Although there is little evidence, it is assumed that the time point of completion thyroidectomy is not critical for oncological prognosis of patients with DTC. We assessed whether patients with total thyroidectomy (TTx) in a two-step procedure have an equal long-term prognosis with regard to disease-specific survival (DSS) compared to patients immediately undergoing total thyroidectomy in a one-step procedure. METHODS: A database study using the Würzburg thyroid cancer database with 2258 patients with pT1a-pT4b tumours DTC who were operated between 1980 and 2016 was carried out. RESULTS: A total of 277 patients with papillary microcarcinoma pT1aN0M0 were treated by hemithyroidectomy. TTx as one-step procedure was performed in 1114 patients compared to 867 with TTx as a two-step procedure. Patients with papillary thyroid cancer more frequently had a TTx as one-step procedure than follicular thyroid cancer patients (59.4% vs 47%; P < 0.001). Compared to a one-step thyroidectomy, overall complication rate was not different compared to patients undergoing a single operation. Multivariate analysis showed that the presence of distant metastases, T-stage and age at diagnosis were the only independent determinants for DTC-specific survival, regardless of a one- or two-time thyroidectomy. CONCLUSION: The present study on the largest of such patient collectives provides evidence that a delayed completion operation does not affect DSS in DTC, nor does it lead to a significant increase in complication rates.