Fabio Maino

Delayed risk stratification, to include the response to initial treatment (surgery and radioiodine ablation), has better outcome predictivity in differentiated thyroid cancer patients

INTRODUCTION After initial treatment, differentiated thyroid cancer (DTC) patients are stratified as low and high risk based on clinical/pathological features. Recently, a risk stratification based on additional clinical data accumulated during follow-up has been proposed. OBJECTIVE To evaluate the predictive value of delayed risk stratification (DRS) obtained at the time of the first diagnostic control (8-12 months after initial treatment). METHODS We reviewed 512 patients with DTC whose risk assessment was initially defined according to the American (ATA) and European Thyroid Association (ETA) guidelines. At the time of the first control, 8-12 months after initial treatment, patients were re-stratified according to their clinical status: DRS. RESULTS Using DRS, about 50% of ATA/ETA intermediate/high-risk patients moved to DRS low-risk category, while about 10% of ATA/ETA low-risk patients moved to DRS high-risk category. The ability of the DRS to predict the final outcome was superior to that of ATA and ETA. Positive and negative predictive values for both ATA (39.2 and 90.6% respectively) and ETA (38.4 and 91.3% respectively) were significantly lower than that observed with the DRS (72.8 and 96.3% respectively, P<0.05). The observed variance in predicting final outcome was 25.4% for ATA, 19.1% for ETA, and 62.1% for DRS. CONCLUSIONS Delaying the risk stratification of DTC patients at a time when the response to surgery and radioiodine ablation is evident allows to better define individual risk and to better modulate the subsequent follow-up.

Post-surgical thyroid ablation with low or high radioiodine activities results in similar outcomes in intermediate risk differentiated thyroid cancer patients

BACKGROUND In differentiated thyroid cancer (DTC) patients at intermediate risk of recurrences, no evidences are provided regarding the optimal radioactive iodine (RAI) activity to be administered for post-surgical thyroid ablation. METHODS This study aimed to evaluate the impact of RAI activities on the outcome of 225 DTC patients classified as intermediate risk, treated with low (1110-1850  MBq) or high RAI activities (≥3700  MBq). RESULTS Six to 18 months after ablation, remission was observed in 60.0% of patients treated with low and in 60.0% of those treated with high RAI activities, biochemical disease was found in 18.8% of patients treated with low and in 14.3% of patients treated with high RAI activities, metastatic disease was found in 21.2% of patients treated with low and in 25.7% of patients treated with high RAI activities (P=0.56). At the last follow-up (low activities, median 4.2 years; high activities, median 6.9 years), remission was observed in 76.5% of patients treated with low and in 72.1% of patients treated with high RAI activities, persistent disease was observed in 18.8% of patients treated with low and in 23.5% of patients treated with high RAI activities, recurrent disease was 2.4% in patients treated with low and 2.1% in patients treated with high RAI activities, deaths occurred in 2.4% of patients treated with low and in 2.1% of patients treated with high RAI activities (P=0.87). CONCLUSION Our study provides the first evidence that in DTC patients at intermediate risk, high RAI activities at ablation have no major advantage over low activities.

Nodules in autoimmune thyroiditis are associated with increased risk of thyroid cancer in surgical series but not in cytological series: evidence for selection bias

BACKGROUND The association of thyroid cancer and autoimmune thyroiditis (AIT) has been widely addressed, with conflicting results in surgical and cytological series, likely affected by selection bias. OBJECTIVE The objective of the study was to evaluate the association between the cytological features suggestive or indicative of malignancy and AIT in 2504 consecutive patients (2029 females and 475 males, mean age 58.3 ± 14.1 y) undergoing fine-needle aspiration cytology for thyroid nodules. PATIENTS Based on the clinical diagnosis, patients were divided into four groups: AIT with nodules (N-AIT, 14.9%); nodular Graves disease (N-GD, 2.8%); nodular goiter and negative thyroid antibodies (NGAb-, 68.4%); and nodular goiter with positive thyroid antibodies (NGAb+, 13.9%). RESULTS The prevalence of patients with cytological features suggestive (Thy4) or indicative of malignancy (Thy5) was 4.5 % in the N-AIT group, not different compared with the other groups (N-GD, 5.6%; NGAb-, 5.0%; NGAb+, 4.3%). No difference was also found in the other categories (Thy2 and Thy3). When the same analysis was performed in the subgroup of patients (14.3%) with a histological confirmation, we found that the prevalence of differentiated thyroid cancer was significantly higher (P = .01) in the N-AIT group (67.8%) compared with the other groups (N-GD, 40.0%; NGAb-, 37.2%; NGAb+, 36.9%). CONCLUSIONS The results of our cytological series do not support a link between N-AIT and thyroid cancer. The association between cancer and N-AIT found in the histology-based series is likely due to a selection bias represented by the fact that the prevalent indication for surgery in the N-AIT group was suspicious cytology (60.7% of patients) more frequently than in the other groups.

DIO2 Thr92Ala Reduces Deiodinase-2 Activity and Serum-T3 Levels in Thyroid-Deficient Patients

Context A substantial proportion of athyreotic levothyroxine (LT4)-treated patients experience hypothyroid-like symptoms. During LT4 replacement, levels of the active hormone triiodothyronine (T3) strictly depend on type 2-deiodinase (D2)-mediated activation of LT4. The Thr92Ala polymorphism and the 258 G/A in the DIO2 gene have been associated with various clinical conditions. Objectives To investigate the effects of DIO2 polymorphisms in thyroid hormone homeostasis. Design We compared the presurgical hormonal status of thyroidectomized LT4-treated patients who had a similar thyroid-stimulating hormone (TSH) level with their postsurgery status and analyzed their DIO2 genotype in a subgroup of 102/140 (72.8%) of patients. We measured the enzymatic properties of Thr92Ala in living cells and in relevant generated mouse models. Subjects and methods A total of 140 thyroidectomized subjects were included. Serum free T3 (FT3), free thyroxine, and TSH levels were directly measured. Immunohistochemistry and immunoblotting were performed for D2 protein. Results The DIO2 genotyping revealed an association between low FT3 values and Thr92Ala. Specifically, the mean postsurgery FT3 levels were significantly lower in patients carrying the mutated allele(s) than in wild-type patients, in whom FT3 postsurgical levels were similar to presurgery levels. The -258 G/A variation was not associated with hormonal alteration. We found that endogenous wild-type D2 and Thr92Ala share the same subcellular localization but differ in protein stability. Importantly, Thr92Ala reduced D2-mediated thyroxine to T3 conversion. Conclusions Thyroidectomized patients carrying Thr92Ala are at increased risk of reduced intracellular and serum T3 concentrations that are not adequately compensated for by LT4, thus providing evidence in favor of customized treatment of hypothyroidism in athyreotic patients.

Reference Range of Serum Calcitonin in Pediatric Population

BACKGROUND Children belonging to the multiple endocrine neoplasia type 2 (MEN 2) pedigree and carrying germline RET mutations are candidates for prophylactic thyroidectomy, the timing of which is based on the mutation-associated risk and the calcitonin (CT) levels. DESIGN The aim of this study was to establish the reference range for serum CT in a pediatric population. The study included 2740 subjects (1339 females and 1401 males) ranging in age from 1 day to 16 years and undergoing blood testing for any medical condition not affecting serum CT. RESULTS Overall, serum CT was undetectable in 61.5% of the samples and detectable in 38.5%. Detectable samples were more frequent in the first 2 years of life. Thereafter, undetectable samples became more frequent, particularly in females. Mean serum CT concentrations were higher in the first year of life (9.81 ± 8.8 pg/mL; range, 2.0-48.9 pg/mL) and the second year of life (4.56 ± 2.64 pg/mL; range, 2.0-14.7 pg/mL). A significant decrease of serum CT levels was observed thereafter (P < .001), and starting from the third year of life serum CT levels were similar to those found in adults. No gender difference was found in any age group. Based on these results, age-specific CT reference ranges are needed in the pediatric population, and especially in the first 2 years of life. CONCLUSIONS This is the first study defining the reference range for serum CT in the pediatric population and large enough to be statistically meaningful. Our proposal may facilitate the process of decision making when dealing with gene carriers of MEN 2.

Obesity Does Not Modify the Risk of Differentiated Thyroid Cancer in a Cytological Series of Thyroid Nodules

Background: A possible impact of obesity on the risk of thyroid cancer has been postulated in some studies, but it remains controversial. Objective: To investigate the association between obesity and differentiated thyroid carcinoma in a population of unselected patients subjected to fine-needle aspiration cytology (FNAC) for thyroid nodules. Methods: We retrospectively evaluated the results of FNAC of thyroid nodules in 4,849 patients (3,809 females and 1,040 males; mean age 55.9 ± 14.1 years). Patients were stratified according to their body mass index (BMI). There were 1,876 (38.7%) normal-weight patients (BMI 18-24.9), 1,758 (36.2%) overweight (BMI 25-29.9), 662 (13.7%) grade 1 obese (BMI 30-34.9), 310 (6.4%) grade 2 obese (BMI 35-39.9) and 243 (5.0%) grade 3 obese (BMI >40). Results: The prevalence of suspicious or malignant nodules (Thy4/Thy5) did not differ across the 5 BMI groups, i.e. it was 6.8% in normal-weight patients, 6.3% in overweight patients, 6.3% in grade 1 obese patients, 4.0% in grade 2 obese patients and 4.2% in grade 3 obese patients (p = 0.29). The prevalence of Thy4/Thy5 nodules did not differ when males and females were evaluated separately (p = 0.22 and p = 0.12, respectively). A significant, lower rate of Thy4/5 cytology was observed in female patients with grade 2-3 obesity (odds ratio 0.51; 95% confidence interval 0.284-0.920; p = 0.009). Conclusions: The results of this study, in a retrospective series of patients with thyroid nodules, do not confirm previous findings reporting an association between obesity and differentiated thyroid carcinoma. Thus, obese patients with nodular thyroid disease should be managed the same as normal-weight patients.

Prospective Validation of ATA and ETA Sonographic Pattern Risk of Thyroid Nodules Selected for FNAC

Context Recently, the American Thyroid Association (ATA) and the European Thyroid Association (ETA) have proposed that thyroid ultrasound (US) should be used to stratify the risk of malignancy in thyroid nodules and to aid decision-making about whether fine-needle aspiration cytology (FNAC) is indicated. Objective To validate and to compare the ATA and ETA US risk stratification systems of thyroid nodules in a prospective series of thyroid nodules submitted to FNAC. Setting We prospectively evaluated 432 thyroid nodules selected for FNAC from 340 patients. Cytology reports were based on the five categories according to the criteria of the British Thyroid Association. Results The proportion of Thy2 nodules decreased significantly, whereas the proportion of Thy4/Thy5 nodules significantly increased with increasing US risk class (P < 0.0001). The ability to identify benign and malignant nodules was similar between ATA and ETA systems. According to ATA and ETA US risk stratification systems, 23.7% and 56.0% nodules did not meet the criteria for FNAC, respectively. Considering only categories at lower risk of malignancy, the cumulative malignancy rate in these nodules was 1.2% for ATA and 1.7% for ETA US risk stratification systems. Conclusions ETA and ATA US risk stratification systems provide effective malignancy risk stratification for thyroid nodules. In clinical practice, using this approach, we should be able to reduce the number of unnecessary FNAC without losing clinically relevant thyroid cancer.

Prognostic indicators for papillary thyroid carcinoma

ABSTRACT Introduction: Differentiated thyroid cancer (DTC) includes more than 90% of all thyroid carcinoma and its incidence is growing, mainly due to an increase in the incidence of papillary thyroid cancer (PTC) for the widespread use of neck ultrasonography. Areas covered: Several prognostic factors should be considered during the management of PTC in order to provide the most effective treatment. The most important prognostic factors in PTC include personal and pathological features such as patient’s age, gender, hystotype, tumor size, extrathyroidal extension, lymph node involvement, presence of local or distant metastases and molecular analyses. We performed a search in the PubMed database for studies published in English since 1960 using the terms: ‘thyroid cancer’, ‘prognostic factors’, ‘age’, ‘gender’, ‘hystotype’, ‘tumor size’, ‘extrathyroidal extension’, ‘lymph node’, ‘metastases’ and ‘molecular analyses’. Expert commentary: Prognostic factors can guide clinicians during the treatment and follow-up of DTC patients, but it is now evident that the risk of recurrence or death must be evaluated periodically, on the basis of individual risk, according to the response to initial therapy or the subsequent therapy required during follow-up.

Clinical significance of type 2 iodothyronine deiodinase polymorphism

ABSTRACT Introduction: Biological activity of thyroid hormones (TH) is regulated by enzymes known as deiodinases. The most important is represented by the type 2 deiodinase (D2), which is the main T4-activating enzyme, ubiquitous in human tissues and therefore essential in many metabolic processes. A single nucleotide polymorphism (SPN) of D2, known as Thr92Ala (rs225014), has been reported in the general population while other polymorphisms are less frequently described. Areas covered: Several authors investigated the potential metabolic effect of these polymorphisms in the general population and in specific groups of patients. Thr92Ala polymorphism was mainly studied in patients with autoimmune or surgical hypothyroidism and in patients with physical/psychological disorders that could be related to an overt hypothyroidism. Susceptibility to develop more severe type 2 diabetes or insulin resistance has also been evaluated. Commentary: There is an increasing evidence that the presence of D2 polymorphisms may play a pivotal role in a better definition and customized therapeutic approach of patients with hypothyroidism and/or type 2 diabetes, suggesting that these patients should be screened for D2 polymorphisms. Nevertheless, further research should be performed in order to clarify the association between D2 polymorphisms, metabolic alterations and clinical conditions of the carrier patients.