Concetto Regalbuto

Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors.

Background. In the last decades, thyroid cancer incidence has continuously and sharply increased all over the world. This review analyzes the possible reasons of this increase. Summary. Many experts believe that the increased incidence of thyroid cancer is apparent, because of the increased detection of small cancers in the preclinical stage. However, a true increase is also possible, as suggested by the observation that large tumors have also increased and gender differences and birth cohort effects are present. Moreover, thyroid cancer mortality, in spite of earlier diagnosis and better treatment, has not decreased but is rather increasing. Therefore, some environmental carcinogens in the industrialized lifestyle may have specifically affected the thyroid. Among potential carcinogens, the increased exposure to medical radiations is the most likely risk factor. Other factors specific for the thyroid like increased iodine intake and increased prevalence of chronic autoimmune thyroiditis cannot be excluded, while other factors like the increasing prevalence of obesity are not specific for the thyroid. Conclusions. The increased incidence of thyroid cancer is most likely due to a combination of an apparent increase due to more sensitive diagnostic procedures and of a true increase, a possible consequence of increased population exposure to radiation and to other still unrecognized carcinogens.

Cancer risk in patients with cold thyroid nodules: Relevance of iodine intake, sex, age, and multinodularity☆

PURPOSE We evaluated the frequency of thyroid cancer in patients with cold thyroid nodules in relation to iodine intake, sex, age, and multinodularity in a consecutive series of patients with nodular thyroid diseases. PATIENTS In the period from 1980 to 1990, 5,637 patients were studied: 4,176 patients were from an iodine-sufficient area (ISA) and 1,461 from an adjacent iodine-deficient area (IDA). Surgery was performed in 792 patients on the basis of a suspicious or malignant finding at fine-needle aspiration biopsy. RESULTS The overall thyroid cancer frequency was 4.6% (259 patients had cancer). Iodine intake affected the cancer rate in patients with cold nodules. The frequency of cancer in patients with cold thyroid nodules was 5.3% in the ISA and 2.7% in the IDA. This difference, however, was significant only in females. Sex had a major influence on the malignant rate of cold nodules; although female patients were more frequently observed (n = 5,028) than male patients (n = 609), the frequency of cancer was significantly lower in female patients with cold nodules (4.2%) than in males (8.2%). Age was an important factor in both sexes. The proportion of nodules that were malignant was smallest in patients of the 4th decade and was greatest in patients younger than 30 years or older than 60 years. Multivariate analysis showed that sex and age interact in determining the cancer risk in patients with thyroid nodules. Finally, the frequency of thyroid cancer in patients with a solitary nodule was not different from the frequency in patients with multiple nodules. CONCLUSION Our study indicates that thyroid cancer risk in a patient with a nodular goiter varies markedly according to iodine intake, sex, and age but not in relation to multinodularity, as assessed by clinical examination. The knowledge of these epidemiologic aspects of thyroid cancer may increase the accuracy of the preoperative selection of patients with cold nodules of the thyroid.

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.

Papillary Thyroid Microcarcinomas: A Comparative Study of the Characteristics and Risk Factors at Presentation in Two Cancer Registries

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.

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.

Genetics of Specific Phenotypes of Congenital Hypothyroidism: A Population-Based Approach

Congenital hypothyroidism (CH) may cause severe and irreversible neurologic and developmental abnormalities when not recognized early. Many millions of newborns have now been screened and many thousands of patients with CH have been identified. Approximately 80%-85% have defects of thyroid gland development, while 15%-20% have congenital errors of thyroid hormone biosynthesis. An entire population screened for CH over a long period of time, was studied in the present report, using a population-based approach. In particular, two CH phenotypes, both presenting with in situ thyroid gland (patients with either goiter or with thyroid gland volume ranging from normal to hypoplasic) were analyzed. Mutations were searched in some of the most likely candidate genes: thyroperoxidase (TPO) in patients with CH goiter, Pax8 and thyrotropin receptor (TSHR) in the other group. In the former group (n = 8), four TPO gene mutations were identified in three patients. One patient was a compound heterozygous. In two cases an already described mutation (1277(insGGCC)) was present; in two other cases mutations not previously described (1996(G-->T) and 2295(G-->A)), which induced aminoacid variations with a Glu --> Stop and Val --> Ile changes, respectively, were identified. In all patients mutations were inherited from one of the parents. In the case of the compound heterozygous patient, one mutation was inherited from the mother (1277(insGGCC)) and the other from the father (1996(G-->T), Glu --> Stop). In the latter group (n = 8), a patient with a 16-base pair C(T)(13)CC deletion in TSHR gene intron 8, 42-bp distal to exon/intron 8 splice junction, was identified. No mutation was identified in Pax8 gene.

Update on thyroid cancer treatment

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.

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.

Acute changes in clinical parameters and thyroid function peripheral markers following L-T4 withdrawal in patients totally thyroidectomized for thyroid cancer

After total thyroidectomy, differentiated thyroid cancer (DTC) patients have to undergo L–T4 withdrawal for measuring serum thyroglobulin and 131I whole-body scan (131I WBS) to evaluate residual/recurrent malignant disease. The aim of the present work was to study in these patients the effects of acute thyroid hormone deficiency on various target organs and tissues. Clinical parameters and thyroid function peripheral markers were evaluated in 20 DTC patients, both before and after L–T4 withdrawal. A 24-h urine collection, a fasting blood sample for laboratory examinations, a clinical score for hypothyroidism and cardiovascular, neurological and neuropsy-chological evaluations were carried out. After L–T4 withdrawal, the clinical score significantly increased, as well as total cholesterol, triglycerides, creatine kinase, lactate dehydrogenase, aspartate aminotransferase and alanine aminotransferase, whereas SHBG, osteocalcin and urine hydroxyproline levels significantly decreased. The acute thyroid hormone deficiency caused a systolic dysfunction of the left ventricle associated with an increase in systemic vascular resistance without cardiac contractility alterations. A significant increase in the left ventricular mass and thickness was also observed. Carpal tunnel syndrome appeared in 30% of patients and a significant reduction in the immediate auditive memorization and in attentive performance was also detected. These observations indicate that acute hypothyroidism causes significant clinical alterations of peripheral tissue function. In the follow-up of DTC patients, therefore, L–T4 withdrawal procedure should be restricted to cases where the cost/benefit ratio is favorable. Alternative procedures, such as the use of recombinant human TSH, should be used whenever possible.

Longitudinal study on goiter prevalence and goitrogen factors in northeastern Sicily

A longitudinal study was carried out in an area of endemic goiter of north-eastern Sicily. Three different surveys (in 1977, 1983 and 1994) evaluated the epidemiological prevalence of goiter in schoolchildren of the endemic area (towns of Bronte, Troina and Maniaci) in comparison to an iodine sufficient control area (Catania). Biochemical studies were also performed on urinary iodine and thiocyanate (SCN) excretion and 131I thyroid uptake. In the town of Troina an experimental program of active iodine prophylaxis was carried out from 1979 to 1987 by iodinating the municipal water supply. The aim of this study was to evaluate the effect of an active iodine prophylaxis program in comparision to the “silent iodoprophylaxis” due to improved economic conditions and widespread introduction of industrially produced food. In the 1977–94 period a significant decrease of goiter prevalence in schoolchildren was observed in all areas where no active iodoprophylaxis had been introduced. An abnormal prevalence of goiter, however, was still present in Bronte (12.1%) and Maniaci (25.9%) schoolchildren in respect to Catania (0.7%). In Troina, goiter prevalence decreased from 52.2 to 6.1% after only five years of active iodine prophylaxis (1983). It increased to 8.4% seven years after the program was discontinuated (1994). In all areas studied average urinary iodine excretion increased by 70–100 μg/day except in the more rural area at Maniaci. During the same period urinary SCN values decreased by 30–40% and were lower in Troina (non volcanic soil) than in other towns studied. The balance beetween iodine and SCN intake appears a relevant factor in the etiology of endemic goiter in these areas and the iodine/SCN ratio inversely correlated with goiter prevalence. The persistence of endemic goiter in spite of the important changes in life style and socio-economic conditions if compared to the dramatic amelioration obtained by an active iodine prophylaxis program, confirms the inadequacy of the silent iodine prophylaxis, and further supports the need of an immediate introduction of active iodine prophylaxis in the areas of endemic goiter in Sicily.