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Introduction: The personalized management of differentiated thyroid cancer (DTC) is currently based on the postoperative TNM staging system and the ATA risk stratification system (RSS), both updated in 2018 and 2015, respectively., Purpose: We aimed to evaluate the impact of the last two editions of TNM and ATA RSS in the prediction of persistent/recurrent disease in a large series of DTC patients., Patients and Methods: Our prospective study included 451 patients undergone thyroidectomy for DTC. We classified the patients according to TNM (both VIII and VII ed.) and stratified them according to the ATA RSS (both 2015 and 2009). We then evaluated the response to the initial therapy after 12-18 months according to the ATA "ongoing" risk stratification, and analyzed the variables associated with persistent/recurrent disease by multivariate analysis., Results: The performance of the last two ATA RSSs was not significantly different. By staging patients according to the VIII or VII TNM editions, we found significant differences only in the distribution of patients with structural disease classified in stages III and IV. At multivariate analysis, only T-status and N-status were independently associated with persistent/recurrent disease. Overall, ATA RSSs and TNMs showed low predictive power in terms of persistent/recurrent disease (by Harrell's test)., Conclusions: In our series of DTC patients, the new ATA RSS as well as the VIII TNM staging provided no additional benefit compared to the previous editions. Moreover, the VIII TNM staging system may underestimate disease severity in patients with large and numerous lymph node metastases at diagnosis., 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 © 2023 Sapuppo, Grasso, Di Benedetto, Belfiore and Pellegriti.)

Background: Differentiated thyroid cancer (DTC) is generally associated with an excellent prognosis. However up to 20% of DTC patients have disease events during subsequent follow-up; rarely patients present an aggressive disease with distant metastases (DM), mainly in the lung and bone. Metastases at unusual sites may also occur, generally in patients with disseminated disease. Orbital localization is rare and only few cases have been described so far., Case Description: A 36 years-old man, treated with chemo and radiotherapy during childhood for non-Hodgkin lymphoma, was referred for suspicious lymph node (LN) and multiple lung metastases. Total thyroidectomy and latero-cervical (LC) lymphadenectomy were performed: papillary thyroid cancer (PTC), 25 mm, 11/17 LN metastases; pT2N1bM1. Post-treatment total body scan with I-131 showed LN and lung uptake. Eighteen months from diagnosis he presented progressive diplopia, proptosis and right exophthalmos due to an 18 mm orbital metastasis. Hence, due to I-131 refractoriness for structural disease progression despite I-131 therapy, he started therapy with Lenvatinib for 6 months, with initial partial response followed by disease progression, and then with Cabozantinib, which he stopped after 6 months for adverse events and disease progression after therapy reduction. Currently, the patient is receiving Lenvatinib, rechallenge therapy, with disease stabilization and biochemical response. Molecular analysis, performed on both primary and relapsed tumor didn't show any significant pathogenic alteration., Conclusions: This case of DTC with an unusual metastasis in the orbit, may suggest that patient's exposure to chemo- and radiotherapy during pediatric age might have played a role in the subsequent development of this unusually aggressive tumor, reinforcing the recommendation of long-term and intensive follow-up of these patients.

Introduction: Multifocality in papillary thyroid cancer (PTC) is a common event, ranging from 18% to 87%. Additional multiple foci are frequently very small and generally detected in pathology specimens. The mechanisms of intrathyroidal spread, and its correlation with age, gender, tumour size, and lymph node metastases remain unclear. Moreover, studies assessing the prognostic impact of PTC multifocality have yielded non-univocal results. We aimed to evaluate the following: a) the histopathological and clinical characteristics associated with multifocal PTC; and b) the impact of multifocality on the long-term outcome., Material and Methods: We analysed a consecutive series of 2814 PTC patients without evidence of microscopic extrathyroidal extension (T1a, T1b, and T2), all of whom had undergone total thyroidectomy and were followed-up (median 4.7 years) in our thyroid clinic. Females comprised 81.3% and males 18.7% (F/M = 4.4/1), with a median age at diagnosis of 45.0 years. Patients were subdivided into 2 groups: 72.7% unifocal tumour and 27.3% multifocal tumour. Post-surgical radioiodine ablation (RAI) (30-100 mCi of 131-I) was performed in 1425 (50.6%) patients. All patients were periodically followed with thyroglobulin and anti-thyroglobulin antibodies measurements and with neck ultrasonography under L-thyroxine therapy and subjected to additional radioiodine administration or another therapeutic measure if not cured., Results: Patients in the multifocal group were older (median age 46.4 vs. 44.5 years, respectively, p < 0.05) and presented a lower F/M ratio (F/M = 3.7/1 and 4.7/1; p = 0.01). T1a and T1b tumours showed no significant difference in multifocality rate whereas T2 tumours were less frequently multifocal (14.2% vs. 10.9%, p < 0.05). Multifocal tumours were more frequent in N1b (11.3% vs. 7.8%, p < 0.01) and less frequent in Nx (50.5% vs. 56.8%, p < 0.01), with no difference between the N0 and N1a groups. The clinical outcome was similar in the 2 group of patients (88.2 % in the unifocal group vs. 90.2% in the multifocal group)., Conclusions: Multifocality is more frequent in older and male patients, in smaller tumours, and in N1b. However, multifocality "per se" was not associated, in our study, with worse clinical outcome in PTC patients.

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

Thyroid cancer incidence is significantly increased in volcanic areas, where relevant non-anthropogenic pollution with heavy metals is present in the environment. This review will discuss whether chronic lifelong exposure to slightly increased levels of metals can contribute to the increase in thyroid cancer in the residents of a volcanic area. The influence of metals on living cells depends on the physicochemical properties of the metals and their interaction with the target cell metallostasis network, which includes transporters, intracellular binding proteins, and metal-responsive elements. Very little is known about the carcinogenic potential of slightly increased metal levels on the thyroid, which might be more sensitive to mutagenic damage because of its unique biology related to iodine, which is a very reactive and strongly oxidizing agent. Different mechanisms could explain the specific carcinogenic effect of borderline/high environmental levels of metals on the thyroid, including (a) hormesis, the nonlinear response to chemicals causing important biological effects at low concentrations; (b) metal accumulation in the thyroid relative to other tissues; and (c) the specific effects of a mixture of different metals. Recent evidence related to all of these mechanisms is now available, and the data are compatible with a cause-effect relationship between increased metal levels in the environment and an increase in thyroid cancer incidence.

Background: Despite a large amount of data, the optimal surgical management of differentiated thyroid cancer remains controversial. Current guidelines recommend total thyroidectomy if primary thyroid cancer is >4 cm, while for tumors that are between 1 and 4 cm in size, either a bilateral or a unilateral thyroidectomy may be appropriate as surgical treatment. In general, total thyroidectomy would seem to be preferable because subtotal resection can be correlated with a higher risk of local recurrences and cervical lymph node metastases; on the other hand, total thyroidectomy is associated with more complications., Methods: This is a retrospective study conducted on 359 patients with differentiated thyroid cancer, subjected to total thyroidectomy. Our aim was to correlate clinical and pathological features (extrathyroid tumor growth, bilaterality, nodal and distant metastasis) with patient (gender and age) and tumor (size and histotype) characteristics. Moreover, we recorded postoperative complications, including hypoparathyroidism and laryngeal nerve damage., Results: In our study, we found a high occurrence of pathological features indicating cancer aggressiveness (bilaterality, nodal metastases, and extrathyroid invasion). On the other hand, total thyroidectomy was associated with relatively low postsurgical complication rates., Conclusions: Our data support the view that total thyroidectomy remains the first choice for the routine treatment of differentiated thyroid cancer., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2019 Dario Giuffrida et al.)

Background: Lenvatinib is a multi-kinase inhibitor approved for patients with radioactive iodine (RAI)-resistant differentiated thyroid cancer (DTC). Before the drug approval from the Italian National Regulatory Agency, a compassionate use programme has been run in Italy. This retrospective study aimed to analyse data from the first series of patients treated with lenvatinib in Italy., Methods: The primary aim was to assess the response rate (RR) and progression-free survival (PFS). Secondary end-points include overall survival (OS) and toxicity data., Results: From November 2014 to September 2016, 94 patients were treated in 16 Italian sites. Seventeen percent of patients had one or more comorbidities, hypertension being the most common (60%). Ninety-eight percent of patients were treated by surgery, followed by RAI in 98% of cases. Sixty-four percent of patients received a previous systemic treatment. Lenvatinib was started at 24 mg in 64 subjects. Partial response and stable disease were observed in 36% and in 41% of subjects, respectively; progression was recorded in 14% of patients. Drug-related side-effects were common; the most common were fatigue (13.6%) and hypertension (11.6%). Overall, median PFS and OS were 10.8 months (95% confidence interval [CI], 7.7-12.6) and 23.8 months (95% CI, 19.7-25.0) respectively., Conclusion: Lenvatinib is active and safe in unselected, RAI-refractory, progressive DTC patients in real-life setting. RR and PFS seem to be less favourable than those observed in the SELECT trial, likely due to a negative selection that included heavily pretreated patients or with poor performance status., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Thyroid cancer incidence is increased in volcanic areas where environment pollution biocontaminates residents. Tungsten (W) is the most increased heavy metal in drinking water of Mount Etna volcanic area where it exceeds the normal range in the urine of 27% inhabitants. The possible connection between increased tungsten and thyroid cancer has never been studied. We investigated in vitro the effect tungsten on both human thyrocytes in primary culture, thyrospheres (aggregates of stem/precursor thyroid cells) and thyrocytes differentiated from tungsten-exposed thyrospheres. Chronic exposure to low-dose (nanomolar range, as in the urines of volcanic area residents) soluble tungsten had major biological effects on thyroid stem/precursor cells, promoting growth with a biphasic (hormetic) dose-response and reducing apoptosis. No such effects were observed in mature thyrocytes. In addition, tungsten-exposed thyrospheres had abnormal expression of genes commonly altered also in thyroid cancer and increased activation of the DNA-repair proteins H2AX and 53BP1. Moreover, exposure to tungsten decreased thyrosphere differentiation, as indicated by the reduced expression of thyroid-specific genes in derived thyrocytes that also showed preneoplastic changes such as increased anchorage-independent growth, clonogenic growth and migration capacity. The mechanism of action of tungsten on thyroid stem/precursor cells is unclear but involves membrane G-proteins and activation of the ERK signaling pathway. These data indicate that chronic exposure to slightly increased tungsten, harmless for mature thyrocytes, importantly affects the biology of stem/precursor thyroid cells and of their progeny, inducing characteristics of preneoplastic transformation.

Context: Differentiated thyroid cancer (DTC) has an excellent prognosis, but up to 20% of patients with DTC have disease events after initial treatment, indistinctly defined as persistent/recurrent disease., Objective: To evaluate the prevalence and outcome of "recurrent" disease (relapse after being 12 months disease-free) compared with "persistent" disease (present ab initio since diagnosis)., Design: Retrospective analysis of persistent/recurrent disease in patients with DTC (1990 to 2016) with 6.5 years of mean follow-up., Setting: Tertiary referral center for thyroid cancer., Patients: In total, 4292 patients all underwent surgery ± 131I treatment of DTC., Main Outcome Measures: DTC cure of disease persistence or recurrence., Results: A total of 639 of 4292 (14.9%) patients had disease events after initial treatment, most (498/639, 78%) with persistent disease and 141 (22%) with recurrent disease. Relative to patients with recurrent disease, patients with persistent disease were significantly older (mean age 46.9 vs 45.7 years) and with a lower female to male ratio (1.9/1 vs 4.8/1). Moreover, in this group, structured disease was more frequent (65.7% vs 41.1%), and more important, distant metastases were significantly more frequent (38.4% vs 17.0%). At multivariate analysis, male sex (OR = 1.7), age (OR = 1.02), follicular histotype (OR = 1.5), T status (T3; OR = 3), and N status (N1b; OR = 7.7) were independently associated with persistent disease. Only the N status was associated with recurrent disease (N1b; OR = 2.5)., Conclusions: In patients with DTC not cured after initial treatment, persistent disease is more common and has a worse outcome than recurrent disease. Postoperative status evaluated during first-year follow-up may have important clinical implications for planning tailored treatment strategies and long-term follow-up procedures.

Purpose: Papillary thyroid cancer (PTC) has good prognosis with a very low chance of mortality. The prognostic role of metastatic lymph node location was judged controversial and more recently (TNM VIII ed.) was considered to have no impact on the prognosis of older patients. The aim of the study was to evaluate the role of metastasized node location on PTC-related mortality., Methods: PTC-related mortality was analysed in a consecutive retrospective series of 1653 PTC patients followed at our Thyroid Clinic (mean follow-up 5.9 years)., Results: Sixteen out of 1653 patients (0.96%) died because of PTC. Average age was 68 years at presentation and 74.7 at death. F/M ratio was 1:1. The death rate increased in relation to the lymph node status: 0.2% in N0, 0.3% in N1a and 3.0% in N1b., Conclusions: The presence of lymph node metastases in the N1b compartment should be considered as a risk factor for distant metastatic spread and for cancer-related death and included in post-surgery evaluation.

Objective: To correlate clinical and pathological characteristics at diagnosis with patient long-term outcomes and to evaluate ongoing risk stratifications in a large series of paediatric differentiated thyroid cancers (DTC)., Study Design: Retrospective analysis of clinical and pathological prognostic factors of 124 paediatric patients with DTC (age at diagnosis <19 years) followed up for 10.4 ± 8.4 years. Patients with a follow-up >3 years (n = 104) were re-classified 18 months after surgery on the basis of their response to therapy (ongoing risk stratification)., Results: Most patients had a papillary histotype (96.0%), were older than 15 years (75.0%) and were diagnosed because of clinical local symptoms (63.7%). Persistent/recurrent disease was present in 31.5% of cases during follow-up, but at the last evaluation, only 12.9% had biochemical or structural disease. The presence of metastases in the lymph nodes of the lateral compartment (OR 3.2, 95% CI, 1.28-7.16, P = 0.01) was the only independent factor associated with recurrent/persistent disease during follow-up. At the last evaluation, biochemical/structural disease was associated with node metastases (N1a, N1b) by univariate but not multivariate analysis. Ongoing risk stratification compared to the initial risk classification method better identified patients with a lower probability of persistent/recurrent disease (NPV = 100%)., Conclusions: In spite of the aggressive presentations at diagnosis, paediatric patients with DTC show an excellent response to treatment and often a favourable outcome. N1b status should be considered a strong predictor of persistent/recurrent disease which, as in adults, is better predicted by ongoing risk stratification., (© 2018 Wiley Periodicals, Inc.)

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent., Methods: Six scientific Italian societies entitled to cure thyroid cancer patients (the Italian Thyroid Association, the Medical Endocrinology Association, the Italian Society of Endocrinology, the Italian Association of Nuclear Medicine and Molecular Imaging, the Italian Society of Unified Endocrine Surgery and the Italian Society of Anatomic Pathology and Diagnostic Cytology) felt the need to develop a consensus report based on significant scientific advances occurred in the field., Objective: The document includes recommendations regarding initial evaluation of thyroid nodules, clinical and ultrasound criteria for fine-needle aspiration biopsy, initial management of thyroid cancer including staging and risk assessment, surgical management, radioiodine remnant ablation, and levothyroxine therapy, short-term and long-term follow-up strategies, and management of recurrent and metastatic disease. The objective of this consensus is to inform clinicians, patients, researchers, and health policy makers about the best strategies (and their limitations) relating to the diagnosis and treatment of differentiated thyroid cancer.

Purpose: Papillary thyroid carcinoma (PTC), the most common thyroid cancer histotype, has a good prognosis even when spread to the neck lymph node (LN). The prognostic role of LN metastases' location is still controversial. The aim of the present study was to evaluate the clinical relevance of the number and location of LN metastases at presentation in PTCs., Methods: This retrospective study included a consecutive series of 1653 PTC patients followed for a mean period of 5.9 years in a referral thyroid cancer clinic. All patients have undergone thyroidectomy with the dissection of at least six LNs. According to the LN status, patients were subdivided into 569 N0 (34.4%), 644 N1a (39.0%, central compartment) and 440 N1b (26.6%, latero-cervical compartment)., Results: Age at diagnosis was significantly lower in N1b (39.8, IQR 30.7-51.6) and N1a (40.1, IQR 31.3-50.1) than in N0 (44.7, IQR 36.6-55.0 yrs). The male gender was more prevalent in N1b than in N1a and N0 (F/M = 1.9/1, 4.0/1 and 5.5/1, respectively). Persistent/recurrent disease at last control was significantly more frequent in N1b (29.8%) than in N1a (14.3%), and in N1a than in N0 (4.2%) (p < 0.01 for all). Also, distant metastases were significantly (p < 0.001) more frequent in N1b (14.1%) than in N1a (4.3%) and N0 (1.6%). LN metastases' number (>5) was a significant risk factor for persistent/recurrent disease only for N1a patients., Conclusions: These data indicate that persistent/recurrent disease and distant metastases are significantly more frequent in patients with latero-cervical LN (N1b) metastases and that the LN location should be used for a better postsurgical risk stratification.

Purpose: Tall cell (TCV) and diffuse sclerosing (DSV) variants are aggressive variants of papillary thyroid cancer (PTC). We compared the risk of recurrent/persistent disease in patients with TCV, DSV and classical PTC (cPTC) and evaluated the prognostic accuracy of initial vs. ongoing risk stratification., Methods: A consecutive series of DSV (n = 54), TCV (n = 72) and cPTC (n = 184) patients was retrospectively analyzed. TCV and DSV patients were first risk stratified for recurrent/persistent disease without considering the histotype as a risk factor and subsequently, 6-24 months after initial treatment, re-classified on the basis of the response to therapy (ongoing risk stratification)., Results: Extrathyroidal extension was more frequent in DSV than in TCV and cPTC patients (p < 0.05); moreover, only DSV tumors had a higher rate of recurrent/persistent disease when compared to cPTC treated with the same protocol (total thyroidectomy followed by 131 I treatment) (p < 0.01). After initial treatment, 54.2% of TCV and 20.4% of DSV patients were classified at low risk, while at ongoing risk stratification, the excellent response (low risk) was higher for both TCV (77.8%) and DSV (50.0%) patients relative to initial stratification (both p < 0.01). Using ongoing risk classification, positive predictive value (PPV) for persistent/recurrent disease was higher relative to initial risk stratification for both TCV (PPV = 93.8 vs. 39.4%) and DSV (PPV = 63.0 vs. 34.9%), p < 0.05 for both., Conclusions: In our series DSV, but not TCV patients, had poorer outcome than cPTC treated with the same protocol. Moreover, the ongoing risk stratification predicted outcome better than the initial classification in both TCV and DSV patients.

Background/aim: Pediatric thyroid cancer (TC) is rare but its incidence is increasing. We analyzed incidence and characteristics of pediatric TC in Sicily and comparatively evaluated data from the volcanic and non-volcanic areas., Materials and Methods: All incident pediatric (0-19 years) TCs in Sicily between 2002-2009 were analyzed for the area of residence and compared to data for adults., Results: A total of 54 differentiated TCs (DTC) and nine medullary TCs were diagnosed in Sicily in children between 2002-2009. DTC age standardized rate for the world population (ASRw) was 0.8/10 5 in females and 0.2/10 5 in males, with a higher incidence in the volcanic area (ASRw=1.4/10 5 in females, 0.5/10 5 in males) vs. the rest of Sicily (ASRw=0.6/10 5 in females, 0.1/10 5 in males). Pediatric TCs were larger in size and more frequently with extrathyroid extension and lymph-node involvement in comparison to TCs in adults., Conclusion: In the volcanic environment of Sicily, TC incidence is markedly increased in children, suggesting a short-term effect of unidentified carcinogens of volcanic origin., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: The diffuse sclerosing variant (DSV) of papillary thyroid cancer (PTC) is considered an aggressive histotype associated with poor prognosis. However, the available data for both the outcome and best management of this disease are inconsistent., Methods: This study reviewed the current literature by searching PubMed up to November 30, 2015, using the search terms "diffuse sclerosing variant" and "papillary thyroid cancer (or carcinoma)" and selecting only studies evaluating recurrent/persistent disease and cancer-related mortality in both DSV and classic PTC (cPTC). The association with some features of aggressiveness at diagnosis, the risk of recurrence or persistence, and the risk of cancer-related death were reported as odds ratio (OR) with confidence intervals (CI). Meta-regression analysis was used to assess the effect of covariates across the studies., Results: Ten studies met the eligibility criteria and contributed 585 DSV and 64,611 cPTC patients. Relative to patients with cPTC, patients with DSV exhibited a higher risk of extrathyroidal extension and lymph node and distant metastases. The risk of persistent/recurrent disease was three times higher in patients with DSV than it was in cPTC patients (OR = 3.19 [CI 1.86-5.49]). This risk was not different when only studies where post-surgical (131)I was routinely administered were considered (OR = 2.07 [CI 0.88-4.90]). The risk of cancer-related mortality was not different between DSV and cPTC (OR = 1.34 [CI 0.76-2.38])., Conclusions: This meta-analysis confirms the aggressive biological behavior of DSV thyroid cancer. When preoperatively suspected, total thyroidectomy with lymph node excision followed by radioiodine therapy should be the correct management for DSV.

Unlabelled: Post-surgical ablation of thyroid remnant with radioactive iodine (RAI) in differentiated thyroid cancer (DTC) is aimed to destroy any thyroid remnant in the thyroid bed (remnant ablation) and any microscopic foci of cancer cells eventually present within the thyroid remnant (adjuvant therapy). The present text is an attempt to offer practice guidelines for the indication of thyroid ablation and the preparation of DTC patients considering the latest achievement in the field and the changing epidemiology of DTC observed in the last 10 years., Methodology: The executive committee of the Italian Society of Endocrinology appointed a task force of thyroid cancer expert including Nuclear Medicine Physicians and Endocrinologists to provide a consensus on the post-surgical ablation in thyroid cancer patients. The task force had no conflict of interest and had no commercial support. A number of specific topics were selected and the members selected relevant papers by searching in the Pubmed for articles published from 2000 to January 2015. Selected studies were categorized by level of evidence, and the recommendations were graded according to the level of evidence as high (A), moderate (B), or low (C).

Most epidemiological studies concerning differentiated thyroid cancers (DTC) indicate an increasing incidence over the last two decades. This increase might be partially explained by the better access to health services worldwide, but clinicopathological analyses do not fully support this hypothesis, indicating that there are carcinogenetic factors behind this noticeable increasing incidence. Although we have undoubtedly understood the biology and molecular pathways underlying thyroid carcinogenesis in a better way, we have made very little progresses in identifying a risk profile for DTC, and our knowledge of risk factors is very similar to what we knew 30-40 years ago. In addition to ionizing radiation exposure, the most documented and established risk factor for DTC, we also investigated the role of other factors, including eating habits, tobacco smoking, living in a volcanic area, xenobiotics, and viruses, which could be involved in thyroid carcinogenesis, thus, contributing to the increase in DTC incidence rates observed., (© 2014 Society for Endocrinology.)

Introduction: The prognostic usefulness of BRAF(V600E) evaluation in papillary thyroid cancer (PTC) has been analyzed in many studies, with controversial conclusions., Aim: To analyze the clinical relevance of BRAF(V600E) measurement in a homogenous series of PTC patients followed in a single institution., Methods: One hundred three classical variant PTC patients who underwent total thyroidectomy in the 3-year period between 2005 and 2008 were retrospectively selected, and BRAF(V600E) assessment was performed using paraffin-embedded archival specimens in 2013. All patients were actively followed at our medical center, with an average follow-up of 55±13 months., Results: BRAF(V600E) mutation-positive cancers (55.3%) were more frequently associated with lymph node metastasis (p=0.01) and advanced TNM stage (III-IV) (p=0.03). These findings were also confirmed in the subset of 42 microcarcinomas. BRAF(V600E)-positive patients were also at a higher risk of persistent disease (OR 3.5 [95% confidence interval {CI} 1.2-10.3], p=0.03) in univariate but not multivariate analysis (OR 2.8 [CI 0.7-11.8], p=0.2). Lymph node involvement was an independent predictor of persistent disease (OR 30.9 [CI 6.0-159.0], p<0.0001). Kaplan-Meier curves confirmed a higher percentage of persistent/recurrent disease in BRAF(V600E)-positive patients (p=0.02). However, the BRAF(V600E) mutation did not change the recurrence rate of PTC in subgroup analyses on the basis of other established risk factors (p=0.2)., Conclusions: BRAF(V600E)-positive tumors were at higher risk of developing more aggressive behavior and were associated with less favorable outcomes in the short and medium term, but the BRAF(V600E) mutation was not an independent predictor of unfavorable outcome. Therefore, its use as a prognostic marker in clinical practice is not advisable.

Context: Papillary thyroid microcarcinoma (PTMC) is an indolent neoplasia, often asymptomatic and discovered incidentally. Some PTMCs, however, exhibit a more aggressive behavior, frequently recur, and can even cause cancer-related death., Objective: The aim of this study was to evaluate the prevalence of PTMCs and the associated risk factors at presentation in 2 thyroid cancer registries from areas with different genetic and environmental characteristics., Design and Patients: We conducted a retrospective, observational study of all incident cases of PTMCs recorded over a 5-year period in the Sicilian Regional Registry for Thyroid Cancer (SRRTC) and in the Surveillance Epidemiology and End Results (SEER) US registry., Setting: The study took place at an academic hospital., Results: The incidence of PTMCs was much higher in Sicily (1777 PTMC diagnosed in 2002-2006; age-standardized incidence rate for the world population [ASRw] = 5.8 per 100 000) than in the United States (14 423 PTMC in the period 2004-2008; ASRw = 2.9 per 100 000). Within the SRRTC, a significantly higher incidence was observed in the volcanic area (ASRw = 10.4 vs 4.6 in the rest of Sicily). In Sicily, the female to male ratio was higher, and PTMC patients were younger. In both registries, a significant inverse correlation was observed between age and tumor size. Young patients (≤45 y) exhibited a higher frequency of nodal metastases., Conclusions: PTMC incidence is twice as high in Sicily compared with the United States, and within Sicily, the incidence is twice as high in the volcanic area. In young patients, PTMCs are larger at presentation and exhibit more risk factors. In both registries, more than 35% of PTMCs exhibited 2 or more risk factors, suggesting that they may require surgery and follow-up similar to that of larger carcinomas.

Background: The tall cell variant (TCV) is a relatively rare variant of papillary thyroid cancer. Since a controversy exists whether or not the TCV has a worse outcome, the aim of our study was to retrospectively compare the clinicopathological features and outcomes in a group of TCV patients and a larger group of patients with classical papillary thyroid carcinoma (cPTC)., Subjects and Methods: Data from 30 TCV and 293 cPTC patients were analyzed. Among the 293 cPTC, we also selected a "high-risk" cPTC group (no.=103) that was treated with the same protocol used for the TCV patients. All data were managed by Cox analysis., Results: Compared to all cPTC patients, TCV subjects displayed only a significantly higher rate of extrathyroid extension. At multivariate analysis, TCV was not an independent variable for the prediction of a high risk of persistent/recurrent disease. At the last follow-up observation, there was no difference in the disease status between the TCV and all cPTC patients. Moreover, "high-risk" cPTC patients had a significant increase in persistent/recurrent disease., Conclusions: In our study, although the TCV histotype is associated with a higher prevalence of extrathyroid extension, it is characterized by an outcome that is not significantly different from that of all cPTC patients and is more favorable than that of "high-risk" cPTC patients. Only those TCV patients classified as "high risk" based on specific pathological and clinical features, according to current guidelines, should be treated aggressively, such as with a total thyroidectomy, neck lymph node dissection or ablative radioiodine treatment.

Context: We previously reported that differentiated thyroid cancer (DTC) has higher aggressiveness and poorer prognosis in patients with Graves' disease (GD) than DTC in euthyroid control patients. Subsequent studies on this issue reached controversial conclusions. Genetic and environmental factors, as well as the lack of appropriate control subjects and/or inadequate patient follow-up, may account for these discrepancies., Objective: The aim of this study was to investigate the long-term disease-specific mortality of nonoccult DTCs occurring in patients with GD compared with DTCs in matched euthyroid control patients., Patients and Design: The previously described cohorts of nonoccult DTCs occurring in either patients with GD (DTC-GD, n = 21) or matched euthyroid DTC control patients (n = 70) were compared again after a longer follow-up (50-363.6 months; median, 165.6 months) to compare the major clinical endpoints of persistent/recurrent disease and overall survival. Both cohorts were recruited in 1982-1994 at a single institution. All patients had undergone total thyroidectomy and were followed up according to a standardized protocol., Results: Persistent/recurrent disease was more frequent in DTC-GD patients than in control patients (P = .0119). Disease-specific mortality was also significantly higher in DTC-GD patients (6 of 21, 28.6%) than in euthyroid control patients (2 of 70, 2.9%) (P = .0001). At the last visit, the percentage of disease-free patients was 57.1% (12 of 21) in the DTC-GD group vs 87.1% (61 of 70) in the control group (P = .0025)., Conclusions: Nonoccult DTCs occurring in patients with GD cause increased disease-specific mortality compared with DTCs in matched euthyroid control patients. These findings emphasize the need for early diagnosis and aggressive treatment of nonoccult DTCs in patients with GD.

Context: Differentiated thyroid cancer (DTC) in thyroglossal duct cysts is uncommon. The requirement of total thyroidectomy and lymph node dissection is still controversial., Setting: The study was performed in a referral thyroid cancer center at an academic hospital., Patients: We conducted a single center retrospective study of a consecutive series of 26 patients with DTC in thyroglossal duct cyst, all having undergone cyst resection and total thyroidectomy., Main Outcome Measures: Diagnostic modalities, surgical treatment, histopathological features, and clinical outcome were included in the study., Results: Thyroglossal duct cyst cancer histotype was papillary in 23 of 26 patients (88.5%) and follicular-Hurthle in 3 of 26 cases (11.5%). A concomitant papillary DTC in the thyroid gland was found in 16 of 26 cases (61.5%), and it was multifocal in 8 of 16 cases (50%). At presentation, the patients with cancer in both the thyroglossal duct cyst and the thyroid were older than the patients who only had cancer in the thyroglossal duct cyst (44.9 ± 7.6 vs 32.0 ± 12.7; P = .006). Lymph node dissection, performed in 17 of 26 patients (65.4%), indicated that the central compartment was involved in 6 patients (35.3%, all having cancer also in the thyroid), the laterocervical compartments in 10 patients (58.8%), and the submental in 4 (23.5%). Six patients (23.1%) had persistent disease at 6-year median follow-up., Conclusions: DTC in thyroglossal duct cysts occurs at a younger age and with more aggressive features at presentation. Concomitant cancer in the thyroid and lymph node metastases is present in most cases. Lymph node compartment involvement is different from that of cancers in the thyroid gland. Therefore, surgical treatment should include both thyroglossal duct cyst resection and total thyroidectomy, with individualized surgical nodal dissection. Subsequent management should follow current DTC guidelines.

Surgery and radioiodine therapy are usually effective for most patients with differentiated thyroid cancer. However, poorly differentiated and anaplastic thyroid carcinomas represent a challenge to physicians on the basis of the current cancer treatment modalities. These cancer subtypes are often lethal and refractory to radioiodine therapy as well as most of the common chemotherapy drugs. Several kinase inhibitors are promising targeted therapies for these malignancies; however, clinical trials involving these drugs have provided controversial results and their clinical use is still under debate. Advanced medullary thyroid carcinomas may also be refractory to conventional therapies and novel kinase inhibitors may also be useful to control tumor progression in certain patients. Novel evidence is emerging that thyroid cancer is a stem cell disease, thereby implying that the driving force of thyroid cancers is a subset of undifferentiated cells (thyroid cancer stem cells) with unlimited growth potential and resistance to conventional therapeutic regimens. Thyroid cancer stem cells have been proposed as responsible for tumor invasiveness, metastasis, relapse and differentiation. Therefore, drugs that selectively target these cells could serve as a cornerstone in the treatment of poorly differentiated thyroid cancer.

Context: Treatment and follow-up of patients thyroidectomized for differentiated thyroid carcinoma (DTC) mainly depends on the identification of the patient's risk of recurrence. Thyroglobulin (Tg) is the most important marker of persistent/recurrent disease. The recent introduction of a new, more sensitive Tg measurement allows for the early detection of the disease by measuring the basal (under L-T(4) therapy) serum Tg level without TSH stimulation., Objective: The goal of this study is to identify the basal serum Tg threshold value that indicates recurrent disease by using a second-generation Tg assay., Design and Patients: A continuous series of 425 DTC patients, all thyroidectomized and treated with (131)I after surgery and having basal Tg of no more than 1.0 ng/ml, negative anti-Tg antibodies, and a recombinant human TSH-stimulated Tg measurement was retrospectively analyzed., Setting: The study took place at an academic hospital., Results: The most accurate basal Tg value for predicting the presence of recurrent/residual disease was more than 0.15 ng/ml (sensitivity 87%, specificity 91%, negative predictive value 98.6%, and positive predictive value 47.8%). When the basal Tg level was no more than 0.15 ng/ml, the risk of disease presence was very low, even in patients classified at an intermediate or high risk. In contrast, when the basal Tg level was more than 0.15 ng/ml, the percentage of recurrent disease was relatively high (12.5% or one in eight cases) in low-risk patients., Conclusions: Basal Tg, measured using a second-generation Tg assay allows for the identification of DTC patients who are likely to remain disease free with great accuracy. This simple measurement, therefore, may be sufficient to assess the risk-adapted management of DTC patients.

Background: The steadily increasing incidence of thyroid cancer has been attributed mostly to more sensitive thyroid nodule screening. However, various environmental factors, such as those associated with volcanic areas, cannot be excluded as risk factors. We evaluated thyroid cancer incidence in Sicily, which has a homogenous population and a province (Catania) that includes the Mt Etna volcanic area., Methods: In a register-based epidemiological survey, we collected all incident thyroid cancers in Sicily from January 1, 2002, through December 31, 2004. The age-standardized incidence rate for the world population (ASR(w)) was calculated and expressed as the number of thyroid cancer diagnoses per 100 000 residents per year. The association of thyroid cancer incidence rate with sex, age, tumor histotype, and various environmental factors was evaluated by modeling the variation of the ASR(w). All statistical tests were two-sided., Results: In 2002-2004, 1950 incident thyroid cancers were identified in Sicily (among women, ASR(w) = 17.8, 95% confidence interval [CI] = 16.9 to 18.7; and among men, ASR(w) = 3.7, 95% CI = 3.3 to 4.1). Although the percentage of thyroid cancers that were microcarcinomas (ie, < or = 10 mm) and ratio of men to women with thyroid cancer were similar in all nine Sicilian provinces, thyroid cancer incidence was statistically significantly higher in the province of Catania (among women, ASR(w) = 31.7, 95% CI = 29.1 to 34.3; and among men, ASR(w) = 6.4, 95% CI = 5.2 to 7.5) than in the rest of Sicily (among women, ASR(w) = 14.1, 95% CI = 13.2 to 15.0; and among men, ASR(w) = 3.0, 95% CI = 2.6 to 3.4) (all P values < .001). Incidence of papillary, but not follicular or medullary, cancers was statistically significantly increased in Catania province, and papillary tumors from patients in Catania more frequently carried the BRAF V600E gene mutation (55 [52%] of 106 tumors) than tumors from patients elsewhere in Sicily (68 [33%] of 205 tumors) (relative risk = 1.7, 95% CI = 1.0 to 2.8, P = .02). Cancer incidence was statistically significantly lower in rural areas than in urban areas of Sicily (P = .003). No association with mild iodine deficiency or industrial installations was found. Levels of many elements (including boron, iron, manganese, and vanadium) in the drinking water of Catania province often exceeded maximum admissible concentrations, in contrast to water in the rest of Sicily., Conclusion: Residents of Catania province with its volcanic region appear to have a higher incidence of papillary thyroid cancer than elsewhere in Sicily.

BRAF((V600E)) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. We evaluated the relationship between BRAF((V600E)) and tumor, host, and environmental factors in PTCs from all geographical areas of Sicily. By PCR, BRAF((V600E)) was investigated in a series of 323 PTCs diagnosed in 2002-2005. The correlation between clinicopathological tumor, host, and environmental characteristics and the presence of BRAF((V600E)) were evaluated by both univariate and multivariate analyses. BRAF((V600E)) was found in 38.6% PTCs, with a 52% frequency in the classical PTCs and 26.4% in the tall cell variant. Univariate analysis indicated that BRAF((V600E)) was associated with greater tumor size (P=0.0048), extra-thyroid invasion (P<0.0001), and cervical lymph nodal metastases (P=0.0001). Multivariate logistic regression analysis confirmed that BRAF((V600E)) was an independent predictor of extra-thyroid invasion (P=0.0001) and cervical lymph nodal metastasis (P=0.0005). The association between BRAF((V600E)) and extra-thyroid invasion was also found in micro-PTCs (P=0.006). In 60 classical PTCs, BRAF((V600E)) was positively correlated with matrix metalloproteinase-9 expression (P=0.0047), suggesting a possible mechanism for BRAF((V600E)) effect on PTC invasiveness. No association was found between BRAF((V600E)) and patient age, gender, or iodine intake. In contrast, a strong association was found with residency in Eastern Sicily (P<0.0001 compared with Western Sicily). These results indicate that BRAF((V600E)) mutation is a marker of aggressive disease in both micro- and macro-PTCs. Moreover, for the first time, a possible link between BRAF((V600E)) mutation and environmental carcinogens is suggested.

To investigate predictors of relapse in small (

Imaging-detected relapses are observed in a significant proportion of patients with medullary thyroid carcinoma (MTC) with normal postoperative imaging studies. The aim of this study was to search for prognostic factors of imaging-detected relapse. This retrospective study was performed in 63 consecutive MTC patients with normal postoperative medical imaging. After surgery, the basal calcitonin (CT) level was undetectable in 35 patients and elevated in 28. During follow-up, 18 patients developed a clinical or imaging-detected relapse (29%) in the neck and/or at distant sites: 15 had an elevated postoperative basal CT level and three had an undetectable postoperative basal CT level. At multivariate analysis, the significant parameters predictive of imaging-detected relapse were the postoperative plasma CT level and the tumour extension (pT). The 3- and 5-year relapse-free survival rates were 94 and 90% in patients with an undetectable postoperative basal CT level, and 78 and 61% in patients with a detectable basal CT level (P<0.05). The 3- and 5-year relapse-free survival rates were 92 and 85% in the pT1-3 patients, and 57 and 46% in the pT4 patients (P<0.01). These results show that postoperative CT level and tumour extension are critical prognostic factors for the identification of patients at a high risk of relapse.

Background: Serum thyroglobulin (Tg) measurement after TSH stimulation, by either thyroid hormone withdrawal or recombinant human TSH (rhTSH) administration, is the most sensitive method for early detection of patients with persistent or recurrent differentiated thyroid cancer (DTC) after total thyroidectomy and 131I ablation. The use of rhTSH is now increasing because it avoids thyroid hormone suppressive therapy (THST) withdrawal and the consequent symptoms of severe hypothyroidism. Current guidelines suggest measurement of serum Tg 4 days after starting a 2-day course of rhTSH injections, and assumes that Tg reaches maximum serum levels at that time., Objective: The present study was carried out to evaluate the accuracy of rhTSH/thyroglobulin test in DTC patients with persistent disease and low thyroglobulin levels., Patients and Measurements: A series of 13 DTC patients was selected because they had proven persistent disease associated with low Tg levels (< 2.0 micro g/l) under l-thyroxine treatment. In all of them, serum Tg was > 5.0 micro g/l at the last THST withdrawal. We measured serum Tg and TSH levels on days 0.5, 1, 1.5, 2, 4, 7, 10 and 15 after the first of a 2-day course of intramuscular rhTSH injections., Results: Serum Tg values were variable in terms of both peak and time-course. Detectable serum Tg levels were recorded on day 4 in all patients. However, among these 13 patients, the peak Tg value was reached earlier than day 4 in three patients and later in two others. In one patient, Tg level at day 2 was higher (3.0 micro g/l) than at day 4 (1.8 micro g/l). In six of the 13 patients studied we compared Tg values after rhTSH to those subsequently obtained after THST withdrawal: in five of them Tg values were two to three times higher after the latter stimulation. Serum Tg value variability after rhTSH was partially accounted for by variability of serum TSH levels, which were inversely related to patient body surface., Conclusions: In DTC patients with persistent disease and low Tg levels, optimization of the diagnostic use of Tg measurement after rhTSH may require rhTSH dose adjustment to the patient body surface area and repeated blood sampling, in order to improve diagnostic accuracy. In these patients not even a TSH-stimulated serum Tg cut-off of 2.0 micro g/l on day 4 provides 100% accuracy, whereas a cut-off of 1.0 micro g/l seems more appropriate. Therefore, in this subset of patients, if any detectable Tg level >or= 1.0 micro g/l is found after rhTSH, re-evaluation after THST should be advised.

Background: Insular thyroid carcinoma was described originally as a tumor with aggressive behavior. However, whether a predominant insular component is an independent factor for poor prognosis is unclear., Methods: The authors compared the clinical behavior of tumors in three groups of patients with thyroid carcinoma--13 patients with insular thyroid carcinoma, 18 patients with follicular thyroid carcinoma, and 26 patients with papillary thyroid carcinoma--who were selected based on similar tumor size and similar age. Disease free survival and disease specific deaths were assessed in the three groups with a Kaplan-Meier analysis and were compared using the log-rank test. Cox regression analysis was used to evaluate the influence of histotype and other prognostic factors on the occurrence of distant metastases and disease specific death., Results: Patient follow-up ranged from 5.2 months to 190.0 months. At last follow-up, only 1 of 13 patients (7.7%) with insular carcinoma, compared with 8 of 18 patients (44.4%) with follicular carcinoma and 12 of 26 patients (46.1%) with papillary carcinoma, were disease free. The disease specific death rate was 61.5% among patients in the insular carcinoma group compared with 16.7% and 15.4% among patients in the follicular carcinoma group (P = 0.006) and the papillary carcinoma group (P = 0.025), respectively. At multivariate analysis, the insular histotype was the only variable that was related independently to disease specific death (hazard ratio = 4.27; P = 0.005). Distant metastases occurred in 84.6% of patients in the insular carcinoma group compared with 50% and 19.2% of patients in the follicular carcinoma group (P = 0.039) and the papillary carcinoma group (P = 0.0003), respectively. All metastases from patients with insular carcinomas (n = 11 patients) showed radioiodine uptake, but a clinical benefit from this treatment was observed only in 1 patient., Conclusions: Patients with insular thyroid carcinoma have a poorer outcome compared with patients of similar age who have differentiated types of thyroid carcinoma with tumors of a similar size. Because radioiodine rarely is effective in the treatment of patients with metastatic insular thyroid carcinoma, novel and possible multimodal therapies should be explored for the treatment of patients with these aggressive tumors., (Copyright 2002 American Cancer Society.)

In this retrospective study we analyzed cancer characteristics and outcome in a consecutive series of 48 young patients (< or =20 yr of age) with a differentiated thyroid cancer (DTC), observed during the period 1977-1998. In none of them was thyroid cancer related to ionizing radiation. The median age was 18.1 yr, range 7-20, and the female/male ratio was 2.5/1. Papillary thyroid cancer (PTC) occurred in 83% and follicular thyroid cancer (FTC) in 17% of cases. All patients underwent total or near total thyroidectomy plus pre- and/or paratracheal lymphnode dissection. Surgery complication rate was low (4% permanent hypoparathyroidism; no permanent lesion of recurrent laryngeal nerve). Extrathyroid disease was present in 52% of patients with PTC and in 50% of patients with FTC, while nodal metastases were present in 62.5% of patients with PTC and in 12.5% of patients with FTC. Lung metastases occurred in 10 patients with PTC (25%) and in none with FTC. Twenty-one patients required radioiodine treatment for metastatic disease: 11 patients for relapsing lymph-node metastases, 4 patients for lung metastases, 6 patients for both lymph-node and lung metastases. After a mean follow-up of 85+/-12 months all patients followed regularly (no.=47) were alive; 37 patients (79%) were free of disease and 10 (21%) had residual disease. Our results indicate that non-radiation-related DTC occurring in young patients often presents at an advanced stage. For this reason, although the prognosis is usually good in these patients, we believe that total or near total thyroidectomy with lymphadenectomy is always the required initial surgical treatment.

Treatment of persistent/recurrent differentiated thyroid cancer is based on surgery, when feasible, and malignant tissue ablation by 131I administration. This procedure requires levothyroxine withdrawal to obtain high levels of endogenous thyrotropin (TSH) to stimulate radioactive iodine uptake by the malignant tissue. Levothyroxine withdrawal may cause severe adverse effects and complications in patients with concomitant illness or advanced metastatic disease. The recent availability of recombinant human thyrotropin (rhTSH) allows diagnostic whole-body scan (WBS) and thyroglobulin testing without levothyroxine withdrawal. We describe six patients with metastatic differentiated thyroid cancer (DTC) and concomitant illness in whom the use of rhTSH was effective in preventing the complications that patients had previously experienced during hypothyroidism consequent to levothyroxine withdrawal. Our results indicate that rhTSH can be particularly advantageous to avoid signs and symptoms of hypothyroidism and complications because of associated diseases in view of 131I treatment of DTC metastases in selected cases in which levothyroxine withdrawal may be dangerous. Its efficacy to treat advanced metastatic disease should be further investigated.

The receptor for hepatocyte growth factor (Met) is not expressed in the normal thyroid but it is overexpressed in most thyroid carcinomas. We evaluated whether Met immunostaining of cytological smears from fine-needle aspiration biopsy (FNAB) may be useful for the preoperative diagnosis of thyroid cancer. Notably, routine cytological examination often fails to distinguish well-differentiated follicular carcinomas and a proportion of papillary carcinomas (low-grade papillary carcinomas and papillary carcinomas follicular variant [FVPTC]) from benign lesions: all these lesions are usually classified as suspicious. We examined 80 thyroid lesions diagnosed as suspicious at cytology that had subsequently undergone surgery. The histologic diagnosis had been: papillary carcinomas (n = 14), FVPTC (n = 11), follicular carcinomas (n = 25), atypical follicular adenomas (n = 5), follicular adenomas (n = 20), and nodular goiters (n = 5). We also studied typical papillary carcinomas (n = 30) and nodular goiters (n = 10), all correctly diagnosed at cytology. In lesions classified suspicious at routine cytology, Met immunostaining was positive in 12 of 14 (85.7%) papillary carcinomas, 8 of 11 (72.7%) FVPTC, 7 of 25 (28%) follicular carcinomas, and 5 of 5 atypical adenomas. In contrast, none of the 25 lesions cytologically suspicious but benign at histology were positive. These data suggest that Met immunostaining of suspicious cytological smears are useful for identifying malignant lesions, especially those with a papillary histotype.

Combinations of doxorubicin and streptozocin and 5-FU and dacarbazine were given alternately to 20 patients with metastatic medullary thyroid carcinoma. Three partial responses and 10 long-term stabilizations were observed. No unexpected toxicity occurred., (Copyright 2000 Cancer Research Campaign.)

Background: The surgical approach to Differentiated Thyroid Carcinoma (DTC) is controversial. Aim of this study is to evaluate the opportunity of total thyroidectomy as treatment of choice for DTC in children., Methods: We examined the tumor features at diagnosis, the complications of surgery and the clinical outcome in a consecutive series of 33 young patients, (age range 7-19 yrs), who underwent total thyroidectomy for DTC as compared to a consecutive series of 181 adult patients operated for DTC (age range 20-64 yrs)., Results: Histopathological examination has shown that bilateral foci of the tumor and extrathyroidal extension, were present with similar frequency in both groups of patients (15 vs 18% and 39 vs 48% respectively); node metastases and distant metastases were more frequent in young patients than in adult patients. Complications of total thyroidectomy were not frequent with 6% of permanent hypoparathyroidism. No case of laryngeal nerve damage was observed. In 7/8 patients with lung metastases the radioiodine treatment was effective: in four patients we observed a complete remission of disease, and in three patients a partial response with a decrease of Tg levels and a reduction of the radioiodine uptake areas., Conclusions: Thyroid carcinoma is not less aggressive in children than in adults. Total thyroidectomy plus lymph node dissections appears to be the treatment of choice as routine surgical treatment of DTC in children. Radioiodine therapy gives good results for the treatment of lung metastases.

Neuroendocrine tumors (NET) of the thyroid gland are rare. Apart from medullary thyroid carcinoma (MTC), metastases of gastroenteropancreatic (GEP) NET may also occur. Features of six patients (five men, one female: age range, 39-67 years) with thyroid metastases from a GEP-NET are described. Thyroid metastases were bilateral in all patients and were associated with enlarged neck lymph nodes in five. In four cases, the thyroid tumor was either the first sign of the disease (n = 2) or was an isolated site of recurrence (n = 2). The tumors were well (n = 3) or poorly differentiated (n = 3). Five tumors for which the primary site could be determined corresponded to foregut-derived tumors (3 lungs, 1 thymus and 1 pancreatic NET). One tumor demonstrated calcitonin (CT) production as shown by immunohistochemistry and elevated plasma CT levels. However, the disease history and the clinical features strongly favored a metastasizing GEP-NET. No tumoral RET proto-oncogene mutation was found in this patient. The differential diagnosis between metastatic GEP-NET and MTC is crucial because prognosis, work-up, and treatment differ greatly.

The clinical behavior and outcome was evaluated in 21 nonoccult differentiated thyroid carcinomas occurring in Graves' patients during the period 1982-94 and compared with that of matched tumors occurring in euthyroid controls (n = 70). At surgery, patients with Graves' disease showed distant metastases more frequently than euthyroid patients (3/21 = 14.3% vs. 1/70 = 1.4%, P = 0.0556). Graves' patients also showed a significantly higher cumulative risk of recurrent/progressive distant metastases or total adverse events (odd ratios = 3.14 and 2.07, respectively) as compared with euthyroid patients. At the last follow-up visit, persistence of distant metastases was also more frequent in the Graves' group (P = 0.007), although the cumulative individual dose of radioiodine administered was higher than in the control group (median dose = 805 mCi vs. 350 mCi). Two patients died in the Graves' group vs. none in the control group. Circulating thyroid stimulating antibodies were present in all patients but one and persisted as long as signs of disease were evident. These findings indicate that differentiated thyroid carcinomas in patients with Graves' disease are more aggressive than those occurring in matched euthyroid controls and should, therefore, be managed accordingly.

A radioiodine accumulation at Total Body Scan (TBS) in patient who has been thyroidectomized for a differentiated thyroid cancer is usually a reliable indicator of recurrent or metastatic functioning thyroid tissue. Radioiodine uptake may be usually observed at TBS in areas such as the intestinal tract, liver, salivary glands, bladder, and also in case of blood vessel ectasia. This report describes a patient with a bilaterally significant 131I uptake in upper abdomen. By ultrasound and radionuclide imaging the 131I uptake was proven to be due to radioiodine accumulation caused by bilateral polycystic renal disease.

We report the case of a patient who developed Graves' disease and a papillary thyroid cancer only 5 years after irradiation and adjuvant chemotherapy for Hodgkin's disease. This case is peculiar for the very short latency time between Hodgkin's disease treatment and thyroid cancer development, an event possibly related to Graves' disease with elevated serum levels of TSAb. We conclude that, in patients treated for Hodgkin's disease, continued follow-up by clinical examination and sonography of the thyroid is needed, especially if they develop Graves' disease.