Maria Grazia Castagna

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.

Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

OBJECTIVE Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population. METHODS We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres. RESULTS AND CONCLUSIONS The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001). Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

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.

Approach to and treatment of differentiated thyroid carcinoma.

Thyroid cancer is the most common endocrine malignancy, although representing fewer than 1% of all human tumors. Differentiated thyroid carcinoma (DTC) includes the papillary and follicular histotypes and their variants, accounting for more than 90% of all thyroid cancers. Given the changing presentation of DTC in the last years, the aim of DTC management is to ensure the most effective but least invasive treatment, and adequate follow-up for a disease that nowadays is mostly cured just with surgery and is rarely fatal. This review addresses the multiple steps of current management, based on previous assumptions.

Lack of Association between Urinary Iodine Excretion and Successful Thyroid Ablation in Thyroid Cancer Patients

BACKGROUND Low-iodine diet is prescribed before (131)I administration in patients with differentiated thyroid cancer, although no study has properly quantified its clinical benefit. OBJECTIVE Our study aimed to evaluate the association between urinary iodine excretion (UIE) and (131)I ablation by correlating UIE with the rate of successful ablation. PATIENTS We retrospectively studied 201 differentiated thyroid cancer patients who had received (131)I therapy and posttherapy whole-body scan (WBS) for remnant ablation after either thyroid hormone withdrawal (THW group, n = 125) or recombinant human TSH (rhTSH group, n = 76). The outcome of thyroid ablation was assessed using two different criteria: no visible uptake at control WBS 8-12 months after ablation or no visible uptake plus undetectable stimulated serum thyroglobulin (Tg). RESULTS According to the criterion of no visible uptake, 84.6% of the patients were successfully ablated, with no significant difference between THW and rhTSH groups. Mean UIE at the time of ablation was 132 +/- 160 microg/liter, not significantly different between patients of the THW and rhTSH groups. There was no significant difference in UIE between ablated or nonablated patients both in the whole group and the rhTSH or THW groups. According to the criterion of no visible uptake plus undetectable stimulated serum Tg (in anti-Tg negative patients) at control WBS 8-12 months after ablation, UIE was not significantly different in ablated and nonablated patients. CONCLUSIONS Our study indicates that the body iodine content is not an important determinant of thyroid ablation, when preparing the patients with either THW or rhTSH.

Modified-Release Recombinant Human TSH (MRrhTSH) Augments the Effect of 131I Therapy in Benign Multinodular Goiter: Results from a Multicenter International, Randomized, Placebo-Controlled Study

BACKGROUND Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

Diagnostic and therapeutic use of recombinant human TSH (rhTSH) in differentiated thyroid cancer

Traditionally, withdrawal of thyroid hormone to increase serum levels of thyroid-stimulating hormone (TSH) has been used in patients with differentiated thyroid carcinoma (DTC) to optimize radio-iodine uptake and serum thyroglobulin (Tg) stimulation during follow-up and in preparation for radio-iodine therapy. However, this procedure is associated with signs and symptoms of hypothyroidism which negatively affect the patients quality of life. Recombinant human thyrotropin (rhTSH) has provided an effective alternative to thyroid hormone withdrawal. After favourable experimental trials in humans, rhTSH obtained regulatory approval in North America and in Europe as a diagnostic tool, and more recently as a preparation for radio-iodine thyroid remnant ablation. Since then, rhTSH has radically changed the diagnostic and therapeutic management of DTC patients. This review will focus on the clinical application of rhTSH in the management of DTC, highlighting current indications and future perspectives.

Acute exogenous TSH administration stimulates leptin secretion in vivo

TSH-receptor (TSHR) has been found in a variety of cell types, including preadipocytes and adipocytes. In vitro, TSH-mediated preadipocyte and adipocyte responses include proliferation, differentiation, survival, and lipolysis. Objective To measure the response of serum leptin to exogenous administration of recombinant human TSH (rhTSH) in vivo. Patients One hundred patients with differentiated thyroid cancer already treated by total thyroidectomy and (131)I remnant ablation were enrolled. Mean (+/-s.e.m.) body mass index (BMI) was 26.9+/-0.6 kg/m(2). Methods Patients received a standard dose of rhTSH for measurement of thyroglobulin in the follow-up of their disease. Blood samples were taken for the assay of TSH and leptin before the first administration of rhTSH (time 0), and 24 h (time 1), 48 h (time 2), 72 h (time 3), and 96 h (time 4) after the first administration of rhTSH. Results Significant mean serum leptin increments, with respect to basal value, were 16, 13, 18, and 11% at times 1, 2, 3, and 4 respectively. Significant positive correlations of leptin-area under the curve with respect to basal leptin levels (r=0.43; P<0.0001) and BMI (r=0.32; P<0.005) were observed. Conclusions Acute rhTSH administration in hypothyroid subjects under l-thyroxine therapy produces a rise in serum leptin. This increase is proportional to the adipose mass suggesting that a functioning TSHR is expressed on the surface of adipocytes. The role that TSHR activation in adipocytes might play in physiological and pathological conditions remains a matter of investigation.

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.

Long-Term Efficacy of Modified-Release Recombinant Human Thyrotropin Augmented Radioiodine Therapy for Benign Multinodular Goiter: Results from a Multicenter, International, Randomized, Placebo-Controlled, Dose-Selection Study

BACKGROUND Enhanced reduction of multinodular goiter (MNG) can be achieved by stimulation with recombinant human thyrotropin (rhTSH) before radioiodine ((131)I) therapy. The objective was to compare the long-term efficacy and safety of two low doses of modified release rhTSH (MRrhTSH) in combination with (131)I therapy. METHODS In this phase II, single-blinded, placebo-controlled study, 95 patients (57.2 ± 9.6 years old, 85% women, 83% Caucasians) with MNG (median size 96.0 mL; range 31.9-242.2 mL) were randomized to receive placebo (n=32), 0.01 mg MRrhTSH (n=30), or 0.03 mg MRrhTSH (n=33) 24 hours before a calculated (131)I activity. Thyroid volume (TV) and smallest cross-sectional area of trachea (SCAT) were measured (by computed tomography scan) at baseline, six months, and 36 months. Thyroid function and quality of life (QoL) was evaluated at three-month and yearly intervals respectively. RESULTS At six months, TV reduction was enhanced in the 0.03 mg MRrhTSH group (32.9% vs. 23.1% in the placebo group; p=0.03) but not in the 0.01 mg MRrhTSH group. At 36 months, the mean percent TV reduction from baseline was 44 ± 12.7% (SD) in the placebo group, 41 ± 21.0% in the 0.01 mg MRrhTSH group, and 53 ± 18.6% in the 0.03 mg MRrhTSH group, with no statistically significant differences among the groups, p=0.105. In the 0.03 mg MRrhTSH group, the subset of patients with basal (131)I uptake <20% had a 24% greater TV reduction at 36 months than the corresponding subset of patients in the placebo group (p=0.01). At 36 months, the largest relative increase in SCAT was observed in the 0.03 mg MRrhTSH group (13.4 ± 23.2%), but this was not statistically different from the increases observed in the placebo or the 0.01 mg MRrhTSH group (p=0.15). Goiter-related symptoms were reduced and QoL improved, without any enhanced benefit from using MRrhTSH. At three years, the prevalence of permanent hypothyroidism was 13%, 33%, and 45% in the placebo, 0.01 mg, and 0.03 mg MRrhTSH groups respectively. The overall safety profile of the study was favorable. CONCLUSIONS When used as adjuvant to (131)I, enhanced MNG reduction could not be demonstrated with MRrhTSH doses ≤ 0.03 mg, indicating that the lower threshold for efficacy is around this level.