Claudia Scollo

Papillary Thyroid Cancer Incidence in the Volcanic Area of Sicily

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.

High prevalence of differentiated thyroid carcinoma in acromegaly

Objective Acromegaly is a chronic disease caused by increased GH secretion and associated with a greater risk of developing both benign and malignant tumours. In the present study we evaluated the prevalence of thyroid disorders and thyroid malignancies in a series of acromegalic subjects.

Risk-Adapted Management of Differentiated Thyroid Cancer Assessed by a Sensitive Measurement of Basal Serum Thyroglobulin

CONTEXT Treatment and follow-up of patients thyroidectomized for differentiated thyroid carcinoma (DTC) mainly depends on the identification of the patients 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.

Differentiated thyroid cancer in children and adolescents

In this retrospective study we ana-lyzed cancer characteristics and outcome in a consecutive series of 48 young patients (≦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 thy-roidectomy plus pre- and/or paratracheal lymph-node 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 pa-tients with PTC (25%) and in none with FTC. Twenty-one patients required radioiodine treat-ment for metastatic disease: 11 patients for re-lapsing 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 thyroidecto-my with lymphadenectomy is always the required initial surgical treatment.

Usefulness of Recombinant Human Thyrotropin in the Radiometabolic Treatment of Selected Patients with Thyroid Cancer

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 diagnostic use of the rhTSH/thyroglobulin test in differentiated thyroid cancer patients with persistent disease and low thyroglobulin levels.

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.

Descriptive Epidemiology of Human Thyroid Cancer: Experience From a Regional Registry and The “Volcanic Factor”

Thyroid cancer (TC), the most common endocrine tumor, has steadily increased worldwide due to the increase of the papillary histotype. The reasons for this spread have not been established. In addition to more sensitive thyroid nodule screening, the effect of environmental factors cannot be excluded. Because high incidences of TC were found in volcanic areas (Hawaii and Iceland), a volcanic environment may play a role in the pathogenesis of TC. In January 2002, the Regional Register for TC was instituted in Sicily. With a population of approximately five million inhabitants with similar genetic and lifestyle features, the coexistence in Sicily of rural, urban, industrial, moderate-to-low iodine intake, and volcanic areas provides a conducive setting for assessing the environmental influences on the etiology of TC. In Sicily, between 2002 and 2004, 1,950 new cases of TC were identified, with an age-standardized rate (world) ASR(w) = 17.8/105 in females and 3.7/105 in males and a high female/male ratio (4.3:1.0). The incidence of TC was heterogeneous within Sicily. There were 2.3 times more cases in the Catania province (where most of the inhabitants live in the volcanic area of Mt. Etna): ASR(w) = 31.7/105 in females and 6.4/105 in males vs. 14.1 in females and 3.0 in males in the rest of Sicily. Multivariate analysis documented that residents in the volcanic area of Mt. Etna had a higher risk of TC, compared to the residents in urban, industrial, and iodine deficient areas of Sicily. An abnormally high concentration of several chemicals was found in the drinking water of the Mt. Etna aquifer, which provides water to most of the residents in the Catania province. Our data suggest that environmental carcinogen(s) of volcanic origin may promote papillary TC. Additional analyses, including cancer biological and molecular features, will allow a better understanding of risk factors and etiopathogenetic mechanisms.

Thyroid cancer in thyroglossal duct cysts requires a specific approach due to its unpredictable extension.

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.

Appearance of anti TSH-receptor antibodies and clinical Graves’ disease after radioiodine therapy for hyperfunctioning thyroid adenoma

Radioiodine treatment use is frequent in patients with benign hyperfunctioning thyroid diseases and the side-effects are rare. In this paper we described the appearance of TSH-receptor antibodies and the concomitant development of persistent hyperthyroidism in a patient with hyperfunctioning thyroid adenoma after 131I treatment. A 70-year-old man presented a hyperfunctioning thyroid adenoma with suppressed uptake in the adjacent normal gland. Antibodies against the thyroglobulin (TgAb), thyroid peroxidase (TPOAb) and TSH-receptor (TRAb) were absent. One year after remission by radioiodine therapy the patient developed severe and persistent hyperthyroidism associated with diffuse 131I uptake in the gland. TgAb and TPOAb remained absent, but TRAb were present. Although spontaneous development of Graves’ disease cannot be excluded, the time sequence and the negative familial and personal history for autoimmune diseases suggest a possible connection between the two phenomena. The release of TSH-receptor antigen from follicular cells damaged by 131I may have triggered the autoimmune response turning a toxic nodular goiter patient into a Graves’ disease patient.

Cardiac Arrest After Intravenous Calcium Administration for Calcitonin Stimulation Test

Medullary thyroid cancer (MTC) is an aggressive tumor, deriving from the parafollicular C-cells of the thyroid. Screening, diagnosis, and follow-up of MTC require evaluation of serum calcitonin (CT), a highly sensitive and specific marker of this cancer. When basal CT levels are nondiagnostic (mildly elevated), a stimulation test is useful to differentiate a neoplastic (MTC) or preneoplastic (C-cell hyperplasia) hypercalcitoninemia from nonmalignant conditions. Measurement of a stimulated CT is also helpful to decide the timing of prophylactic thyroidectomy in RET gene mutation carriers in familial MTC and in postsurgical follow-up of MTC patients (1,2). CT stimulation can be obtained by either pentagastrin injection or by short intravenous calcium gluconate infusion (2– 2.5 mg/kg of elemental calcium administered at 10 mL/min) (1,3). The calcium stimulation test is preferred to pentagastrin (which is currently unavailable) because it is causing less patient discomfort. The main reported adverse effects are paresthesia of the extremities and/or lips, feeling of warmth, flushing, and a chalky taste sensation (1,3). We describe a severe adverse event that occurred in a healthy volunteer during a pilot study designed to assess the reference ranges for calcium-stimulated serum CT levels in our Medical Center. A 28-year-old man in good health, without any known chronic or acute illness, cardiac disease, or thyroid abnormality volunteered for a calcium stimulation test. He did not smoke and took no medication, and his weight was 60 kg. Pretest evaluation indicated that electrolytes, liver enzymes, glucose, creatinine, blood pressure, and ECG were normal. The subject gave written informed consent. Two mg/kg of elemental calcium (calcium gluconate 10%; B. Braun, 10 mL vials; B. Braun, Melsungen, Germany) was infused intravenously at 10 mL/minute while the subject was in a supine position. A few seconds after completion of the infusion, the subject became unresponsive, his pulse was not present, and an electrocardiogram (ECG) revealed asystolia. Cardiopulmonary resuscitation was immediately executed, and the heart rate was restored. The patient quickly regained consciousness, was able to answer questions, and did not complain of any discomfort. Further evaluation did not reveal any cardiac abnormality (QT interval was in normal range and an echocardiogram showed no pathological findings) and after three hours of observation, he was discharged. This clinical case indicates that the CT stimulation test with calcium gluconate infusion, performed according to the currently indicated procedures, may have severe adverse effects. Previously, a case of atrial fibrillation after combined administration of calcium gluconate (2 mg/kg in 1 min) and pentagastrin (0.5 lg/kg over 5 sec) has been reported. The patient was converted to normal sinus rhythm with digoxin. In that case, the agent responsible for the adverse reaction could not be determined (4). More recently, persistent atrial fibrillation has been observed in a patient after a calcium stimulation test (5). In our case, the calcium infusion caused a severe adverse effect (cardiac arrest) in a healthy young man. The adverse event could have caused more severe consequences if the test had not been carried out under continuous cardiac monitoring inside a medical center. It is well known that rapid intravenous calcium injection may cause vasodilatation, decreased blood pressure, bradycardia, cardiac arrhythmias, syncope, and cardiac arrest (6). Even if rare, these possible adverse effects of this diagnostic test must be considered because they are potentially life-threatening. Therefore, appropriate procedures (including continuous cardiac monitoring) should be followed to guarantee rapid intervention in case of an adverse cardiovascular event. A slower calcium infusion procedure should be evaluated and the calcium stimulation test use should be limited to conditions such as the evaluation of RET gene mutation carriers (2) and suspicious MTC patients with CT values mildly elevated. Its use in the postoperative follow-up of MTC patients with undetectable basal serum CT should be avoided, as suggested in the ATA guidelines (7). In these patients, the risk of persistent or recurrent disease is low and the improved sensitivity of basal serum CT measurements has reduced the role of stimulation testing (7).