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Introduction: The 2015 American Thyroid Association guidelines recommend to de-escalate treatment such as Thyroid lobectomy instead of total thyroidectomy for 1-4 cm papillary thyroid cancer (PTC). Dutch guidelines endorse restricted work-up for thyroid incidentalomas recommending only fine needle aspiration in case of a 'palpable thyroid nodule'. This diagnostic work-up algorithm may result in the identification of less indolent PTCs and may lead to a patient population with relatively more aggressive PTCs. This study aims to retrospectively analyze recurrence rates of low-risk 1-4 cm PTC in the Netherlands., Methods: From the national cancer registry, patients with low-risk 1-4 cm PTC between 2005 and 2015 were included for analysis. Disease free survival (DFS) and overall survival were compared between patients who underwent TT ± RAI and TL without RAI. Post-hoc propensity score analysis was performed correcting for age, sex, T-stage, and N-stage., Results: In total 901 patients were included, of which 711 (78.9%) were females, with a median follow-up of 7.7 years. TT was performed in 893 (94.8%) patients. Recurrence occurred in 23 (2.6%) patients. Multivariable analysis showed no significant correlation between extent of surgery and DFS (p = 0.978), or overall survival (p = 0.590). After propensity score matching, multivariable analysis showed no significant difference on extent of surgery and recurrence., Conclusion: Low-risk PTC patients with 1-4 cm tumor who underwent TL showed similar recurrence rates as those who underwent TT ± adjuvant RAI, which suggests that TL can be sufficient in treating low-risk 1-4 cm PTC, possibly reducing morbidity of these patients in the Netherlands., (© 2022. The Author(s).)

Background: The rising demand for 18 F-fluorodeoxyglucose positron emission tomography with computed tomography ( 18 F-FDG PET/CT) has led to an increase of thyroid incidentalomas. Current guidelines are restricted in giving options to tailor diagnostics and to suit the individual patient., Objectives: We aimed at exploring the extent of potential overdiagnostics by performing a systematic review and meta-analysis of the literature on the prevalence, the risk of malignancy (ROM) and the risk of inconclusive FNAC (ROIF) of focal thyroid incidentalomas (FTI) on 18 F-FDG PET/CT., Data Sources: A literature search in MEDLINE, Embase and Web of Science was performed to identify relevant studies., Study Selection: Studies providing information on the prevalence and/or ROM of FTI on 18 F-FDG PET/CT in patients with no prior history of thyroid disease were selected by two authors independently. Sixty-one studies met the inclusion criteria., Data Analysis: A random effects meta-analysis on prevalence, ROM and ROIF with 95% confidence intervals (CIs) was performed. Heterogeneity and publication bias were tested. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool., Data Synthesis: Fifty studies were suitable for prevalence analysis. In total, 12,943 FTI were identified in 640,616 patients. The pooled prevalence was 2.22% (95% CI = 1.90% - 2.54%, I 2 = 99%). 5151 FTI had cyto- or histopathology results available. The pooled ROM was 30.8% (95% CI = 28.1% - 33.4%, I 2 = 57%). 1308 (83%) of malignant nodules were papillary thyroid carcinoma (PTC). The pooled ROIF was 20.8% (95% CI = 13.7% - 27.9%, I 2 = 92%)., Limitations: The main limitations were the low to moderate methodological quality of the studies and the moderate to high heterogeneity of the results., Conclusion: FTI are a common finding on 18 F-FDG PET/CTs. Nodules are malignant in approximately one third of the cases, with the majority being PTC. Cytology results are non-diagnostic or indeterminate in one fifth of FNACs. These findings reveal the potential risk of overdiagnostics of FTI and emphasize that the workup of FTI should be performed within the context of the patient's disease and that guidelines should adopt this patient tailored approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 de Leijer, Metman, van der Hoorn, Brouwers, Kruijff, van Hemel, Links and Westerlaan.)

Background: Currently, there are no European recommendations for the management of pediatric thyroid cancer. Other current international guidelines are not completely concordant. In addition, medical regulations differ between, for instance, the US and Europe. We aimed to develop new, easily accessible national recommendations for differentiated thyroid carcinoma (DTC) patients <18 years of age in the Netherlands as a first step toward a harmonized European Recommendation., Methods: A multidisciplinary working group was formed including pediatric and adult endocrinologists, a pediatric radiologist, a pathologist, endocrine surgeons, pediatric surgeons, pediatric oncologists, nuclear medicine physicians, a clinical geneticist and a patient representative. A systematic literature search was conducted for all existing guidelines and review articles for pediatric DTC from 2000 until February 2019. The Appraisal of Guidelines, Research and Evaluation (AGREE) instrument was used for assessing quality of the articles. All were compared to determine dis- and concordances. The American Thyroid Association (ATA) pediatric guideline 2015 was used as framework to develop specific Dutch recommendations. Discussion points based upon expert opinion and current treatment management of DTC in children in the Netherlands were identified and elaborated., Results: Based on the most recent evidence combined with expert opinion, a 2020 Dutch recommendation for pediatric DTC was written and published as an online interactive decision tree (www.oncoguide.nl)., Conclusion: Pediatric DTC requires a multidisciplinary approach. The 2020 Dutch Pediatric DTC Recommendation can be used as a starting point for the development of a collaborative European recommendation for treatment of pediatric DTC.

Objective: The SELECT trial showed progression-free survival (PFS) benefit for lenvatinib for advanced radioiodine-refractory differentiated thyroid cancer (RAI-refractory or RR-DTC) patients, on which current clinical practice is based. We assessed whether the effectiveness and toxicity of lenvatinib in real-life clinical practice in the Netherlands were comparable to the pivotal SELECT trial., Methods: From three Dutch centres Electronic Health Records (EHRs) of patients treated in the lenvatinib compassionate use program or as standard of care were reviewed and checked for SELECT eligibility criteria. Baseline characteristics, safety, and efficacy measures were compared and PFS and overall survival (OS) were calculated. Furthermore, PFS was compared to estimates of PFS reported in other studies., Results: A total of 39 DTC patients with a median age of 62 years were analysed. Of these, 27 patients (69%) did not fulfil the SELECT eligibility criteria. The most common grade ≥3 toxicities were hypertension (n = 11, 28%), diarrhoea (n = 7, 18%), vomiting (n = 4, 10%), and gallbladder disease (n = 3, 8%). Median PFS and median OS were 9.7 (95% confidence interval (CI): 4.0-15.5) and 18.3 (95% CI: 4.9-31.7) months, respectively, response rate was 38% (95% CI: 23-54%). PFS in the Dutch real-life situation was comparable to previous real-life studies, but inferior to PFS as shown in the SELECT trial (P = 0.04)., Conclusions: PFS in our non-trial population was significantly shorter than in the SELECT trial population. In the interpretation of results, differences in the real-life population and the SELECT study population regarding patient characteristics should be taken into account.

Objective Gene alterations leading to activation of the MAPK pathway are of interest for targeted therapy in patients with advanced radioactive iodine refractory (RAI-R) thyroid carcinoma. Due to technical reasons gene fusion analysis in RNA isolated from formalin-fixed tumor tissues has till now been limited. The objective of the present study was to identify targetable gene rearrangements in RNA isolated from formalin-fixed RAI-R thyroid carcinomas. Design Retrospective study in 132 patients with RAI-R thyroid carcinoma (59 papillary-, 24 follicular-, 35 Hürthle cell- and 14 anaplastic thyroid carcinoma). Methods Total nucleic acid (undivided DNA and RNA) was isolated from formalin-fixed tissue. Extensive gene fusion analysis was performed in all samples that tested negative for pathogenic BRAF, NRAS, HRAS and KRAS variants. Results Seven targetable gene fusions were identified in the remaining 60 samples without known DNA variants. This includes frequently reported gene fusions such as CCDC6/RET (PTC1), PRKAR1A/RET (PTC2) and ETV6/NTRK3 , and gene fusions that are less common in thyroid cancer (TPM3/NTRK1, EML4/ALK and EML4/NTRK3). Of note, most gene fusions were detected in papillary thyroid carcinoma and MAPK-associated alterations in Hürthle cell carcinomas are rare (2/35). Conclusion Targetable gene fusions were found in 12% of RAI-R thyroid carcinoma without DNA variants and can be effectively identified in formalin-fixed tissue. These gene fusions might provide a preclinical rationale to include specific kinase inhibitors in the treatment regimen for these patients. The latter intends to restore iodine transport and/or take advantage of the direct effect on tumor cell vitality once progressive disease is seen.

Radiation exposure to the thyroid gland during treatment of childhood, adolescent and young adult cancer (CAYAC) may cause differentiated thyroid cancer (DTC). Surveillance recommendations for DTC vary considerably, causing uncertainty about optimum screening practices. The International Late Effects of Childhood Cancer Guideline Harmonization Group, in collaboration with the PanCareSurFup Consortium, developed consensus recommendations for thyroid cancer surveillance in CAYAC survivors. These recommendations were developed by an international multidisciplinary panel that included 33 experts in relevant medical specialties who used a consistent and transparent process. Recommendations were graded according to the strength of underlying evidence and potential benefit gained by early detection and appropriate management. Of the two available surveillance strategies, thyroid ultrasound and neck palpation, neither was shown to be superior. Consequently, a decision aid was formulated to guide the health care provider in counseling the survivor. The recommendations highlight the need for shared decision making regarding whether to undergo surveillance for DTC and in the choice of surveillance modality., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Everolimus is a mTOR inhibitor used for the treatment of different solid malignancies. Many patients treated with the registered fixed 10 mg dose once daily are in need of dose interruptions, reductions or treatment discontinuation due to severe adverse events. This study determined the correlation between systemic everolimus exposure and toxicity. Additionally, the effect of different covariates on everolimus pharmacokinetics (PK) was explored., Methods: Forty-two patients with advanced thyroid carcinoma were treated with 10 mg everolimus once daily. Serial pharmacokinetic sampling was performed on days 1 and 15. Subsequently, a population PK model was developed using NONMEM to estimate individual PK values used for analysis of an exposure-toxicity relationship. Furthermore, this model was used to investigate the influence of patient characteristics and genetic polymorphisms in genes coding for enzymes relevant in everolimus PK., Results: Patients who required a dose reduction (n = 18) due to toxicity at any time during treatment had significant higher everolimus exposures [mean AUC0-24 (SD) 600 (274) vs. 395 (129) µg h/L, P = 0.008] than patients without a dose reduction (n = 22). A significant association between everolimus exposure and stomatitis was found in the four-level ordered logistic regression analysis (P = 0.047). The presence of at least one TTT haplotype in the ABCB1 gene was associated with a 21 % decrease in everolimus exposure., Conclusion: The current study showed that dose reductions and everolimus-induced stomatitis were strongly associated with systemic everolimus drug exposure in patients with cancer. Our findings confirm observations from another study in patients with cancer and show us that everolimus is a good candidate for individualized dosing in patients with cancer. CLINICALTRIAL., Gov Number: NCT01118065.

Background: Treatment of differentiated thyroid carcinoma (DTC) often involves administration of radioactive iodine (I-131) for remnant ablation or adjuvant therapy. As DTC has favorable outcome and the incidence is increasing, concerns have been raised about the possible adverse effects of I-131 therapy. We systematically reviewed the literature to examine the risk of intermediate and long-term adverse effects of I-131 therapy in DTC patients., Methods: Multiple electronic databases were searched up to November 2014 for English-language, controlled studies that reported on the risk of salivary gland dysfunction, lacrimal gland dysfunction, gonadal dysfunction, female reproductive outcomes or second primary malignancies (SPM) after I-131 exposure. The certainty of the evidence found was assessed using GRADE., Results: In total, 37 articles met all inclusion criteria, no studies reporting on adverse effects after I-131 treatment focused solely on children. After exposure to I-131 for DTC, patients experienced significantly more frequently salivary gland dysfunction (prevalence range: 16-54%, moderate-level evidence), lacrimal gland dysfunction (prevalence: 11%, low-level evidence), transient male gonadal dysfunction (prevalence: 35-100%, high-level evidence), transient female gonadal dysfunction (prevalence: 28%, low-level evidence) and SPM (prevalence: 2.7-8.7%, moderate-level evidence) compared to unexposed patients. I-131 therapy seems to have no deleterious effects on female reproductive outcomes (very-low level evidence). The prevalence and severity of adverse effects were correlated to increasing cumulative I-131 activity., Conclusion: Treatment with I-131 for DTC may have significant adverse effects, which seem to be dose dependent. These adverse effects of treatment must be balanced when choosing for I-131 therapy in patients with DTC., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Context: Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients., Methods: All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported., Results: In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity., Conclusion: The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity., (© 2015 European Society of Endocrinology.)

Background: There is no international consensus on surveillance strategies for differentiated thyroid carcinoma (DTC) after radiotherapy for childhood cancer. Ultrasonography could allow for early detection of DTC, however, its value is yet unclear since the prognosis of DTC is excellent. We addressed the evidence for the question: 'is outcome of DTC influenced by tumor stage at diagnosis?'., Methods: A multidisciplinary working group answered the sub-questions: 'is recurrence or mortality influenced by DTC stage at diagnosis? Does detection of DTC at an early stage contribute to a decline in adverse events of treatment?' The literature was systematically reviewed, and conclusions were drawn based on the level of evidence (A: high, B: moderate to low, C: very low)., Results: In children, level C evidence was found that detection of DTC at an early stage is associated with lower recurrence and mortality rates. No evidence was found that it influences morbidity rates. In adults, clear evidence was found that less advanced staged DTC is a favorable prognostic factor for recurrence (level B) and mortality (level A). Additionally, it was found that more extensive surgery increases the risk to develop transient hypoparathyroidism (level A) and that higher doses of radioiodine increases the risk to develop second primary malignancies (level B)., Conclusion: Identification of DTC at an early stage is beneficial for children (very low level evidence) and adults (moderate to high level evidence), even considering that the overall outcome is excellent. These results are an important cornerstone for the development of guidelines for childhood cancer survivors at risk for DTC., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Thyroid cancer is the most prevalent endocrine malignancy. Based on the increased understanding of thyroid tumourigenesis, novel therapeutic agents have been identified. However, given the low incidence, the good prognosis of the majority of these tumours and the limited evidence of different treatment modalities, a wide variety of treatment strategies are available. These are mostly based on small studies, data from retrospective analyses and the particular experiences of treating physicians. We discuss the recent developments in the treatment of advanced differentiated thyroid cancer., Case Description: Three cases demonstrate the considerations involved in treatment decisions for patients with advanced thyroid cancer. The first patient achieved stable disease for over five years with different targeted therapies. The second patient shows the potential (severe) toxicity of these drugs and the third patient illustrates the indolent nature of this disease., Conclusion: The treatment of patients with extensively metastasised thyroid cancer is very complicated. The timing of initiation of therapy and the potential toxicity of targeted therapies are important in the clinical decision to treat or not to treat because of the slowly progressive course of differentiated thyroid cancer. When targeted therapy is considered, it remains of great importance to enrol patients in clinical studies in order to further determine the position of these therapies, to develop more effective (combination) treatment schemes, and above all, to identify those patients that truly benefit.

¹⁸F-fluorodeoxyglucose positron emission tomography (¹⁸FDG-PET) scintigraphy is a useful imaging technique in the evaluation of metastasised thyroid carcinoma. Administration of recombinant human thyrotropin (rhTSH, Thyrogen®) increases the diagnostic yield of this procedure. Here we present a 64-year-old male who was followed for Hürthle cell carcinoma of the thyroid with several intrapulmonary metastases. He developed sudden complaints of neck pain following rhTSH administration as part of the routine preparation for a diagnostic ¹⁸FDG-PET÷CT procedure. This investigation subsequently revealed a previously undetected metastatic lesion in the first cervical vertebra, with no signs of spinal cord compression. Treatment with a nonsteroidal anti-inflammatory drug reduced the symptoms sufficiently, and a few weeks later the neurosurgeon performed a complete resection of the metastasis. It is likely that the symptoms were caused by oedema and÷or increased blood flow to the lesion. Physicians should be aware that rhTSH administration to patients with disseminated thyroid carcinoma may lead to sudden onset of symptoms caused by previously occult metastases.

Objective: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients., Design: Retrospective multicenter study in eight University Medical Centers in The Netherlands., Methods: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease., Results: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification., Conclusions: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

Objective: To assess the prognostic value of detectable thyroglobulin (Tg) after initial surgery and radioactive iodine (¹³¹I) therapy by comparing patients with a negative post-therapeutic whole body scan (WBS) with either detectable or undetectable Tg., Background: Differentiated thyroid cancer has a good prognosis. However, recurrences can occur up to 30 years after initial treatment. Because life-long follow-up is necessary, it is important to explore possible risk factors associated with recurrence and mortality., Design, Patients and Measurements: We studied 539 patients who were treated between 1980 and 2007. After the last therapeutic dosage of 5550 MBq ¹³¹I, 72 patients had negative post-therapeutic WBS and positive Tg levels (Tg+ group) and 399 patients had negative post-therapeutic WBS and negative Tg (Tg- group). The 68 remaining patients had proven residual macroscopic disease. We investigated recurrences and overall mortality in the Tg+ and Tg- group compared with the Dutch population., Results: In the Tg+ group, detectable recurrences occurred significantly earlier and more frequently than in the Tg- group (19%vs 13%, P = 0·024). Survival between these groups was comparable, but shorter than the general Dutch population [Standardised Mortality Rate (SMR) 1·38 (95% CI 1·12;1·63) (P = 0·003)]. Disease-free survival in the Tg groups was comparable and not significantly different from the Dutch population [SMR = 1·09 (95% CI 0·81;1·34) (P = 0·569)]., Conclusion: Patients with detectable Tg during the last ¹³¹I treatment and a negative post-therapeutic WBS have significant earlier and more recurrences than patients without detectable Tg. Survival in both groups is comparable. After initial therapy, the combination of a negative high dose post-therapeutic WBS with detectable Tg is a valuable predictor for earlier and more recurrences, but is not associated with survival., (© 2010 Blackwell Publishing Ltd.)

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

In 4 patients, an incidentaloma of the thyroid was found on 18-fluoro-deoxyglucose positron-emission tomography (FDG-PET). In the first patient, a 73-year-old man, a medullary thyroid carcinoma was discovered during the staging procedure ofa laryngeal carcinoma. In the second patient, an 81-year-old woman, a follicular thyroid carcinoma was found as a result of a FDG-PET evaluation of an adenocarcinoma of the lung. In the third patient, a 64-year-old woman, a papillary thyroid carcinoma was found during dissemination investigation after curative removal of an adrenocortical carcinoma. The last patient, a 78-year-old man, was found to have a thyroid incidentaloma on FDG-PET scan during staging ofa recurrence of a gastrointestinal stromal tumour. Thyroid incidentalomas are present on 1.2-2.3% of FDG-PET scans. Further diagnostic work-up of these lesions by fine needle aspiration is warranted since up to 50% are malignant. However, whether these malignant thyroid lesions are relevant is not always clear. Treatment depends on the primary disease for which the FDG-PET scan was initially made. This requires good evaluation and discussion with the patient.

Context: Medullary thyroid carcinoma (MTC) metastasizes early in its clinical course. No effective systemic therapy is available. Generally (somatic or germline), mutations in the rearranged during transfection gene are considered essential in the pathogenesis of MTC., Objective: We investigated imatinib, a tyrosine kinase inhibitor, as a potential treatment in patients with disseminated MTC., Design: A phase II study was initiated using 600 mg imatinib daily with a possible dose increase to 800 mg in case of progression. Standard Response Evaluation Criteria in Solid Tumors were used using computed tomography or magnetic resonance imaging every 2 months., Results: There were 15 patients with disseminated MTC treated for up to 12 months. No objective responses were observed. Four patients had stable disease over 24 months. Three patients stopped treatment due to toxic effects [fatigue (n = 2) and nausea (n = 1)]. In four cases the dose of imatinib was decreased because of toxicity [rash and malaise (n = 2) and laryngeal swelling (n = 2)]. Emergency tracheotomy was performed in two cases due to mucosal swelling of the larynx in patients with recurrent nerve palsy and a narrow vocal cleft. In nine patients with a history of a thyroidectomy, the dose of supplemental thyroid hormone was increased because of serious hypothyroidism., Conclusions: Imatinib therapy yielded no objective responses and induced considerable toxicity in patients with MTC. A minority of patients had stable disease. Patients with supplemented hypothyroidism or with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.

Differentiated thyroid carcinoma is a rare disease. Appropriate diagnosis, treatment and follow-up are complex but greatly influence treatment outcomes and patient quality of life. Patients with differentiated thyroid carcinoma present in many hospitals throughout the Netherlands, underscoring the need for uniformity in diagnosis and treatment. This prompted the Dutch Society of Nuclear Medicine and the Dutch Endocrine Society to develop an evidence-based guideline that emphasises not only new scientific developments but also the organisation of care. Thyroid-stimulating hormone (TSH) assessment and fine needle aspiration cytology play a central role in the diagnostic assessment of a patient with a thyroid nodule. Ablation of residual thyroid tissue with radioiodine (1-131) is recommended for all patients who have undergone total thyroidectomy. Follow-up protocols distinguish between patients with a low risk of thyroid-carcinoma recurrence and those with a non-low risk of recurrence.

Objective: Evaluation of treatment of children who are proven carriers of a multiple endocrine neoplasia type 2 (MEN 2)-associated rearranged during transfection (RET) gene mutation., Design: Retrospective case study and review of the literature., Method: Between 1976 and 2005, 6 boys and 14 girls with a proven RET mutation or biochemical indication of MEN 2 had thyroid surgery at the University Medical Center, Groningen, The Netherlands. The median age was 10 years (range: 0-08). Preoperative assessment, surgical procedure, pathological findings, postoperative complications and treatment results were studied and compared with data from the literature., Results: All 20 children underwent total thyroidectomy. In 17 children with preoperatively abnormal basal or stimulated calcitonin levels, total thyroidectomy was combined with tracheo-oesophageal exploration (n = 6) or central compartment dissection (n = 11). C-cell hyperplasia was found in 19 cases (95%) and medullary thyroid carcinoma in 14 (70%; aged 3-18 years). Lymph-node metastases were found in 3 children (15%), all over the age of 10. They underwent additional selective lateral neck dissection, unilateral in 2 cases and bilateral in 1. Two children developed hypoparathyroidism postoperatively, no recurrent laryngeal-nerve palsy was observed. All patients are clinically free of disease after a median follow-up of 9 years (range: 0.6-27). The patients with node metastases still have biochemical evidence of disease. The literature indicates that the progression of the malignant transformation to medullary thyroid carcinoma is connected to the type of RET-mutation. The treatment plan depends on the type of mutation., Conclusion: Medullary thyroid cancer occurs at a very young age in carriers ofgermline RET mutations. In patients with high-risk mutations prophylactic thyroidectomy is likely to be recommended before the child reaches the age of 2. Elective central lymph-node dissection can be omitted in this instance. After this age, however, the risk of lymph-node metastases increases and, for cases with increased basal or stimulated calcitonin levels, total thyroidectomy with central compartment dissection is indicated.

In differentiated thyroid carcinoma 10-year survival rates amount to 80-95%. Because age at diagnosis varies widely, these survival rates strongly depend on age at presentation. The aim of the present study was to analyse the attributable risk factors, including therapy per se, on survival in thyroid cancer after proper adjustment for the baseline mortality rate in the general population and to elucidate the adverse treatment effects on survival. Initial treatment in 504 patients consisted of thyroidectomy and 131I ablation. High-dose 131I was administered for residual disease. Patients in complete remission underwent an annual physical examination and thyroglobulin measurements during TSH suppression. Survival time was studied after transformation to standardised survival time to adjust for the baseline mortality rate in the general population. Median follow-up since diagnosis was 9 years. The 10-year overall survival was 83% and disease-specific survival 91%. After initial treatment, persistent disease occurred in 75 patients (15%). In univariate analysis, T4, N1, M1 status and Hürthle cell type were prognostic for persistent and recurrent disease. Age was not prognostic for recurrent disease in multivariate analysis. The standardised survival time was not altered in disease-free patients. However, patients with persistent disease had a median standardised survival time of only 0.60 (95% confidence interval 0.47;0.72), ranging from 0 to above 1, independent of initial tumour status or age. The cumulative proportion of persistent disease was at least 20% of the whole group. Disease-free patients after thyroid carcinoma have a normal residual life span. In contrast, in cases of persistent disease the life expectancy ranges widely with its median being reduced to 60%. Overall, treatment including radioiodine is safe but unsuccessful in 20% of the patients. Age is not a disease-specific risk factor and should not be used as an independent factor in treatment algorithms.

Background: Management of patients with differentiated thyroid carcinoma with negative diagnostic radioiodide scanning and increased serum thyroglobulin (Tg) concentrations is a widely debated problem. High-dose iodine-131 treatment of patients who have a negative (131)I diagnostic whole-body scan (WBS) is advocated. However, the therapeutic benefit of this "blind" treatment is not clear., Objective: To investigate the course of serum Tg during thyroid hormone suppression therapy (Tg-on) and clinical outcome in patients with negative diagnostic (131)I scanning and increased serum Tg concentrations during thyroid hormone withdrawal (Tg-off), after treatment with high-dose (131)I., Design: Retrospective single-center study., Methods: Fifty-six patients were treated with a blind therapeutic dose of 150 mCi (131)I. Median follow-up from this treatment until the end of observation was 4.2 Years (range 0.5-13.5 Years)., Results: The post-treatment WBS revealed (131)I uptake in 28 patients, but none in the remaining 28 patients. In this study the Tg-on values did not change after treatment in either the positive or the negative post-treatment WBS group. During follow-up, 18 of the 28 patients with a positive post-treatment WBS achieved complete remission, compared with 10 of the 28 patients with a negative post-treatment WBS. Nine patients in the negative group died, but no patients died in the positive post-treatment group (P=0.001)., Conclusions: High-dose iodine treatment in diagnostically negative patients who have a negative post-treatment scan seems to confer no additional value for tumor reduction and survival. In patients with a positive post-treatment scan, high-dose iodine treatment can be used as a diagnostic tool to identify tumor location, and a therapeutic effect may be present in individual cases.

Differentiated thyroid cancer is a rare disease and until recently was considered to be sporadic. However, increasing evidence has been found for a genetic basis of this disease. In approximately 5% of patients the differentiated thyroid cancer is dominantly inherited. Several families with different syndromes, of which differentiated thyroid cancer is a feature, have already been described. However, until now, single genes explain only a minority of cases. We hypothesize that differentiated thyroid cancer is a polygenic disease. Data from epidemiologic studies, about occult and multifocal carcinomas and the different response to specific risk factors contribute to this hypothesis.

The overall prognosis of patients with differentiated thyroid cancer is excellent, but the prognosis is rapidly worsening, when the disease is diagnosed in elderly patients. Old patients more often present with poor prognostic features, such as large tumors, follicular or Hürthle cell subtypes, extrathyroidal growth and distant metastases. Therefore, an optimal therapeutic approach is recommended. Current therapy includes a total thyroidectomy, if necessary combined with a lymph node dissection and followed by high dose radioiodine ablation. Radioiodine therapy in elderly patients meets specific problems, concerning thyroid hormone withdrawal, side effects of 131I and nursing problems. Additional treatment of residual, recurrent or metastatic disease must be tailored, according to the stage of the disease, and should not be denied on the basis of chronological age. Lifelong treatment with suppressive thyroid hormone therapy does not lead to important long-term side effects at old age.

Treatment options in patients with bone metastases of differentiated thyroid carcinoma are limited and mostly aimed at palliation. Conventional treatment modalities are: radioiodine therapy, surgery or external irradiation. A lesser known option is selective embolization of tumour metastases. During selective catheterization of the arteries that feed the metastases embolization material (e.g. polyvinyl alcohol particles) is injected into the local vasculature under radiographic control. The embolization is immediately evaluated angiographically. This therapy was used in three patients with differentiated thyroid carcinoma, a 60-year-old man suffering from back ache, paresis and afterwards paralysis of the lower body parts with incontinence, and in two women aged 59 years (suffering from diplopia and a pelvic metastasis) and aged 27 years (suffering from neurological symptoms or pain of the right leg due to a pelvic metastasis). In all three the symptoms disappeared after the embolization and ensuing treatment with radioactive iodine. Due to recurrent increase in serum thyroglobulin concentration repeated re-embolization was necessary, but during a follow-up period of 3-5 years the palliation remained adequate. Selective embolization appears to be a safe and efficacious treatment, with good tolerability for the patient. Embolization alone or preferably preceded by radioiodine therapy may lead to decreased tumour progression and often gives rise to immediate relief of symptoms.

Background: The outcome for patients with bone metastases from differentiated thyroid carcinoma is worse compared to the overall prognosis of patients with differentiated thyroid carcinoma. The aim of this study is to evaluate the effect of embolization with concomitant radioiodine treatment on the serum thyroglobulin (Tg) level, pain and neurological symptoms in patients with large bone metastases from differentiated thyroid carcinoma., Patients and Methods: Five symptomatic patients, who presented with a large unresectable bone metastasis of differentiated thyroid carcinoma were treated with radioiodine and embolization. The effect of this combined treatment was compared to the effect of radioiodine without embolization in a previously treated control group of 6 patients. Serum Tg levels, pain and neurological symptoms were scored. Both groups were treated similarly with total thyroidectomy followed by ablation with 5.55 GBq 131I and a second dose of 5.55 GBq 131I three months later, except for embolization in the embolization group, which took place between the 2 radioiodine treatments., Results: In the embolization group, serum Tg at the second 131I therapy had decreased by 88.7% (median, range: 77.1-99.3%), which was significantly more compared to the decrease of serum Tg in the control group (18.6%, range: -4.7-95%, P < 0.05). CT-scanning showed a median volume reduction of the metastasis after radioiodine treatment combined with embolization of 52.5% (range: 39-80%). Both strategies resulted in a rapid relief of pain and neurological symptoms. Embolization was not accompanied with severe complications., Conclusions: This preliminary study suggests that embolization of bone metastases of differentiated thyroid carcinoma in combination with radioiodine treatment results in a significant initial reduction of serum Tg level compared to radioiodine treatment alone. This suggests a beneficial reduction in tumour burden. In this patient category, embolization appears to be a safe and well tolerated procedure.