BRAF V600E and risk stratification of thyroid microcarcinoma: a multicenter pathological and clinical study.

Studies from single institutions have analyzed BRAF in papillary microcarcinomas, sometimes with contradictory results. Most of them have provided limited integration of histological and clinical data. To obtain a comprehensive picture of BRAF V600E-mutated microcarcinomas and to evaluate the role of BRAF testing in risk stratification we performed a retrospective multicenter analysis integrating microscopical, pathological, and clinical information. Three hundred and sixty-five samples from 300 patients treated at six medical institutions covering different geographical regions of Italy were analyzed with central review of all cases. BRAF V600E statistical analysis was conducted on 298 microcarcinomas from 264 patients after exclusion of those that did not meet the required criteria. BRAF V600E was identified in 145/298 tumors (49%) including the following subtypes: 35/37 (95%, P<0.0001) tall cell and 72/114 (64%, P<0.0001) classic; conversely 94/129 follicular variant papillary microcarcinomas (73%, P<0.0001) were BRAF wild type. BRAF V600E-mutated microcarcinomas were characterized by markedly infiltrative contours (P<0.0001) with elongated strings of neoplastic cells departing from the tumor, and by intraglandular tumor spread (P<0.0001), typically within 5 mm of the tumor border. Multivariate analysis correlated BRAF V600E with specific microscopic features (nuclear grooves, optically clear nuclei, tall cells within the tumor, and tumor fibrosis), aggressive growth pattern (infiltrative tumor border, extension into extrathyroidal tissues, and intraglandular tumor spread), higher American Thyroid Association recurrence risk group, and non-incidental tumor discovery. The following showed the strongest link to BRAF V600E: tall cell subtype, many neoplastic cells with nuclear grooves or with optically clear nuclei, infiltrative growth, intraglandular tumor spread, and a tumor discovery that was non-incidental. BRAF V600E-mutated microcarcinomas represent a distinct biological subtype. The mutation is associated with conventional clinico-pathological features considered to be adverse prognostic factors for papillary microcarcinoma, for which it could be regarded as a surrogate marker. BRAF analysis may be useful to identify tumors (BRAF wild type) that have negligible clinical risk.

The natural history of benign thyroid nodules.

IMPORTANCE: Detection of asymptomatic thyroid nodules has increased. Consensus is lacking regarding the optimal follow-up of cytologically proven benign lesions and sonographically nonsuspicious nodules. Current guidelines recommend serial ultrasound examinations and reassessment of cytology if significant growth is observed. OBJECTIVE: To determine the frequency, magnitude, and factors associated with changes in thyroid nodule size. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter, observational study involving 992 consecutive patients with 1 to 4 asymptomatic, sonographically or cytologically benign thyroid nodules. Patients were recruited from 8 hospital-based thyroid-disease referral centers in Italy between 2006 and 2008. Data collected during the first 5 years of follow-up, through January 2013, were analyzed. MAIN OUTCOMES AND MEASURES: Baseline nodule growth (primary end point) was assessed with yearly thyroid ultrasound examinations. Size changes were considered significant for growth if an increase of 20% or more was recorded in at least 2 nodule diameters, with a minimum increase of 2 mm. Baseline factors associated with growth were identified. Secondary end points were the sonographic detection of new nodules and the diagnosis of thyroid cancer during follow-up. RESULTS: Nodule growth occurred in 153 patients (15.4% [95% CI, 14.3%-16.5%]). One hundred seventy-four of the 1567 original nodules (11.1% [95% CI, 10.3%-11.9%]) increased in size, with a mean 5-year largest diameter increase of 4.9 mm (95% CI, 4.2-5.5 mm), from 13.2 mm (95% CI, 12.1-14.2 mm) to 18.1 mm (95% CI, 16.7-19.4 mm). Nodule growth was associated with presence of multiple nodules (OR, 2.2 [95% CI 1.4-3.4] for 2 nodules; OR, 3.2 [95% CI, 1.8-5.6 for 3 nodules; and OR, 8.9 [95% CI, 4.4-18.0] for 4 nodules), main nodule volumes larger than 0.2 mL (OR, 2.9 [95% CI, 1.7-4.9] for volumes >0.2 to <1 mL and OR, 3.0 [95% CI, 1.8-5.1] for volumes ≥1 mL), and male sex (OR, 1.7 [95% CI, 1.1-2.6]), whereas an age of 60 years or older was associated with a lower risk of growth than age younger than 45 years (OR, 0.5 [95% CI 0.3-0.9]). In 184 individuals (18.5% [95% CI, 16.4%-20.9%]), nodules shrank spontaneously. Thyroid cancer was diagnosed in 5 original nodules (0.3% [95% CI, 0.0%-0.6%]). Only 2 had grown. An incidental cancer was found at thyroidectomy in a nonvisualized nodule. New nodules developed in 93 patients (9.3% [95% CI, 7.5%-11.1%]), with detection of one cancer. CONCLUSIONS AND RELEVANCE: Among patients with asymptomatic, sonographically or cytologically benign thyroid nodules, the majority of nodules exhibited no significant size increase during 5 years of follow-up and thyroid cancer was rare. These findings support consideration of revision of current guideline recommendations for follow-up of asymptomatic thyroid nodules.

Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer.

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.

Minimal Extrathyroidal Extension in Predicting 1-Year Outcomes: A Longitudinal Multicenter Study of Low-to-Intermediate-Risk Papillary Thyroid Carcinoma (ITCO#4).

Background: The role of minimal extrathyroidal extension (mETE) as a risk factor for persistent papillary thyroid carcinoma (PTC) is still debated. The aims of this study were to assess the clinical impact of mETE as a predictor of worse initial treatment response in PTC patients and to verify the impact of radioiodine therapy after surgery in patients with mETE. Methods: We reviewed all records in the Italian Thyroid Cancer Observatory database and selected 2237 consecutive patients with PTC who satisfied the inclusion criteria (PTC with no lymph node metastases and at least 1 year of follow-up). For each case, we considered initial surgery, histological variant of PTC, tumor diameter, recurrence risk class according to the American Thyroid Association (ATA) risk stratification system, use of radioiodine therapy, and initial therapy response, as suggested by ATA guidelines. Results: At 1-year follow-up, 1831 patients (81.8%) had an excellent response, 296 (13.2%) had an indeterminate response, 55 (2.5%) had a biochemical incomplete response, and 55 (2.5%) had a structural incomplete response. Statistical analysis suggested that mETE (odds ratio [OR] 1.16, p = 0.65), tumor size >2 cm (OR 1.45, p = 0.34), aggressive PTC histology (OR 0.55, p = 0.15), and age at diagnosis (OR 0.90, p = 0.32) were not significant risk factors for a worse initial therapy response. When evaluating the combination of mETE, tumor size, and aggressive PTC histology, the presence of mETE with a >2 cm tumor was significantly associated with a worse outcome (OR 5.27 [95% confidence interval], p = 0.014). The role of radioiodine ablation in patients with mETE was also evaluated. When considering radioiodine treatment, propensity score-based matching was performed, and no significant differences were found between treated and nontreated patients (p = 0.24). Conclusions: This study failed to show the prognostic value of mETE in predicting initial therapy response in a large cohort of PTC patients without lymph node metastases. The study suggests that the combination of tumor diameter and mETE can be used as a reliable prognostic factor for persistence and could be easily applied in clinical practice to manage PTC patients with low-to-intermediate risk of recurrent/persistent disease.

Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients.

Background: One of the most widely used risk stratification systems for estimating individual patients' risk of persistent or recurrent differentiated thyroid cancer (DTC) is the American Thyroid Association (ATA) guidelines. The 2015 ATA version, which has increased the number of patients considered at low or intermediate risk, has been validated in several retrospective, single-center studies. The aims of this study were to evaluate the real-world performance of the 2015 ATA risk stratification system in predicting the response to treatment 12 months after the initial treatment and to determine the extent to which this performance is affected by the treatment center in which it is used. Methods: A prospective cohort of DTC patients collected by the Italian Thyroid Cancer Observatory web-based database was analyzed. We reviewed all records present in the database and selected consecutive cases that satisfied inclusion criteria: (i) histological diagnosis of DTC, with the exclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features; (ii) complete data of the initial treatment and pathological features; and (iii) results of 1-year follow-up visit (6-18 months after the initial treatment), including all data needed to classify the estimated response to treatment. Results: The final cohort was composed of 2071 patients from 40 centers. The ATA risk of persistent/recurrent disease was classified as low in 1109 patients (53.6%), intermediate in 796 (38.4%), and high in 166 (8.0%). Structural incomplete responses were documented in only 86 (4.2%) patients: 1.5% in the low-risk, 5.7% in the intermediate-risk, and 14.5% in the high-risk group. The baseline ATA risk class proved to be a significant predictor of structural persistent disease, both for intermediate-risk (odds ratio [OR] 4.67; 95% confidence interval [CI] 2.59-8.43) and high-risk groups (OR 16.48; CI 7.87-34.5). Individual center did not significantly influence the prediction of the 1-year disease status. Conclusions: The ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC in real-world clinical settings characterized by center heterogeneity in terms of size, location, level of care, local management strategies, and resource availability.

Mitotane Concentrations Influence Outcome in Patients with Advanced Adrenocortical Carcinoma.

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

Mitotane Concentrations Influence the Risk of Recurrence in Adrenocortical Carcinoma Patients on Adjuvant Treatment.

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28-62) with a median maintenance dose of 2.0 g/day (IQR 1.5-2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5-19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7-M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88-0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

Type 2 deiodinase polymorphism (threonine 92 alanine) predicts L-thyroxine dose to achieve target thyrotropin levels in thyroidectomized patients.

CONTEXT: Type 2 deiodinase (D2) converts T4 in T3 in several human tissues, including hypothalamus and pituitary, and, therefore, plays a pivotal role in the negative feedback regulation of TSH secretion. A common variant of the gene, threonine (Thr) 92 alanine (Ala), has been identified and associated with decreased D2 enzymatic activity. OBJECTIVE: Our objective was to investigate whether this polymorphism predicts the T4 dosage needed to obtain target TSH levels in thyroidectomized patients. SETTING: Ambulatory patients were included in the study. PATIENTS: A total of 191 consecutive thyroid cancer patients, previously treated by near total thyroidectomy and radioiodine ablation, were studied. They were on stable T4 dose treatment aimed at obtaining either suppressed (supp) (n=117, <0.1 mU/liter) or near-supp (n=74, >or=0.1<0.5 mU/liter) serum TSH levels. MAIN OUTCOME MEASURES: DNA genotyping for D2 Thr92Ala variant and evaluation of T4 dose (microg/kg) needed to obtain target TSH levels were determined. RESULTS: Ala/Ala homozygous patients needed a higher T4 dose as compared with patients carrying the Thr92 variant (X/Thr patients) according to a recessive genetic model (2.08+/-0.43 vs. 1.90+/-0.35 microg/kg; P<0.05). This difference was observable in the near-supp group (P=0.002), but not in the supp group (P=0.4). CONCLUSIONS: D2 Thr92Ala polymorphism seems to predict the need for higher T4 intake in thyroidectomized patients. If this finding is confirmed in additional studies, it may predict the T4 requirement to suppress TSH on the basis of the individual genetic background.

Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules.

CONTEXT: Routine serum calcitonin (CT) measurement in patients with thyroid nodules for diagnosis of medullary thyroid carcinoma (MTC) is controversial. OBJECTIVE: The objective of this study was to evaluate the diagnostic accuracy of systematic CT measurement in non-multiple endocrine neoplasia type 2 patients with nodular thyroid disease. SETTINGS: This study was conducted at a national healthcare system hospital (outpatient and inpatient sectors). SUBJECTS: Consecutive patients with nodular thyroid disease (n = 5817) were studied. MAIN OUTCOME MEASURES: Serum CT levels were measured under basal conditions, and when basal values were more than or equal to 20 and less than 100 pg/ml, testing was repeated after pentagastrin stimulation. Basal or stimulated levels more than 100 pg/ml were indication for surgery. RESULTS: Fifteen cases of MTC and seven of C cell hyperplasia (CCH) were identified. MTCs were diagnosed in all patients with basal CT more than 100 pg/ml. The four patients with basal CT more than or equal to 50 and less than 100 pg/ml included two diagnosed with MTC and two with CCH. In 10 patients with basal levels more than or equal to 20 and less than 50 pg/ml, histology confirmed the presence of MTC in four, four others had CCH, and the remaining two were negative for thyroid malignancy. Positive predictive values for basal CT levels in the preoperative diagnosis of MTC were: 23.1% for values more than or equal to 20 pg/ml, 100% for values more than 100 pg/ml, 25% for levels more than or equal to 50 and less than 100 pg/ml, and 8.3% for values more than or equal to 20 and less than 50 pg/ml. Positive predictive values for the pentagastrin test (>100 pg/ml) were 40% in the entire series. CONCLUSIONS: CT screening of thyroid nodules is a highly sensitive test for early diagnosis of MTC, but confirmatory stimulation testing is necessary in most cases to identify true positive increases.

Age influences TSH serum levels after withdrawal of l-thyroxine or rhTSH stimulation in patients affected by differentiated thyroid cancer.

Recombinant human TSH (rhTSH) has been recently suggested for radioiodine ablation in patients with differentiated thyroid cancer (DTC). To date, studies are still not available about the effectiveness of rhTSH stimulation depending on the age, since serum TSH clearance may be different in younger and in older patients. The aim of this study was to investigate the influence of age to serum TSH levels after rhTSH stimulation and thyroid hormone withdrawal (THW). We retrospectively evaluated two groups of consecutive DTC patients: group 1 (311 patients, age 49.0+/-13.6 years, ranging 15-86) underwent rhTSH stimulation 6-12 months after thyroid ablation (rhTSH-group); group 2 (84 patients, age 46.9+/-13.5 years, ranging 20-77) was followed by THW (THW-group). The influence of age, gender, body mass index and body surface area to serum TSH levels were evaluated in both groups. RhTSH-group: on day 5 (d5), TSH levels were 32.7+/-21.4 microU/ml (range 0.8-136.6). By univariate analysis, d5-TSH was positively related to age (r=0.27, p=0.0001) and no correlations were found with the other parameters. At multivariate analysis, both age and gender (female) were independently associated with d5-TSH levels. THW-group: after thyroid hormone withdrawal, TSH levels were 71.1+/-36.4 microU/ml (range 8.5-200). At univariate analysis, only age was significantly and negatively related to serum TSH levels (r=-0.31, p=0.004). Our data indicate that age and gender seem to positively influence serum TSH levels after rhTSH stimulation. An opposite effect of age on serum TSH levels has been observed after THW. Therapeutic implications ((131)I-treatment) of these findings have to be better investigated in prospective studies.

[Laparoscopic adrenalectomy: analysis of 65 cases]. / Surrenalectomia laparoscopica: analisi di 65 procedure.

The aim of this study was to present our experience with laparoscopic adrenalectomy. Over the period from January 2000 to January 2007, 60 patients (40 M, 20 F; mean age: 52.5 years; range: 16-77 years) underwent adrenalectomy in our department. Five patients were submitted to bilateral adrenalectomy, thus making a total of 65 cases. The indications were the following: non-secreting masses in 21 cases and secreting masses in 44; 29% were incidentalomas. The operation was performed with a transperitoneal lateral approach. The parameters evaluated were operative time, blood loss, and postoperative course. The mean operative time was 140 minutes, with a tendency towards reduced times in the later cases. In 3 cases (5%), conversion to laparotomy proved necessary. We observed only one major complication, consisting in a pancreatic fistula due to removal of tissue from the pancreatic tail. The mean blood loss was estimated at about 49 +/- 50 ml. The mean postoperative stay was 4.5 days. On the basis of our analysis of the results we feel that we can safely claim, in agreement with the literature, that laparoscopic cholecystectomy is the treatment of choice for benign disease and that lesions measuring > 6 cm can be dealt with by surgical teams with good laparoscopic experience.

Temporal Changes in Thyroid Nodule Volume: Lack of Effect on Paranodular Thyroid Tissue Volume.

BACKGROUND: The term "nodular goiter" has long been used to refer to a nodular thyroid gland, based on the assumption that nodule growth may be associated with hyperplasia of the surrounding non-nodular tissue. The aim of this prospective, multicenter, observational study was to determine whether nodule growth is accompanied by growth in the non-nodular tissue. METHODS: Eight Italian thyroid-disease referral centers enrolled 992 consecutive patients with one to four benign nodules. Nodular and non-nodular thyroid tissue volumes were assessed for five years with annual ultrasound examinations. RESULTS: In participants whose nodules remained stable (n = 839), thyroid volumes did not change (baseline 15.0 mL [confidence interval (CI) 14.5-15.6]; five-year evaluation 15.1 mL [CI 14.5-15.7]). In participants with significant growth of one or more nodule (n = 153), thyroid volumes increased and by year 5 were significantly greater than those of the former group (17.4 mL [CI 16-18.7]). In 76 individuals with unilateral nodules that grew, the mean nodular lobe volume significantly exceeded that of the contralateral lobe (8.6 mL [CI 7.4-9.8] vs. 6.7 mL [CI 6-7.4]). The unaffected lobe volumes remained stable over time, while nodular lobes grew steadily and were significantly greater at the end of follow-up (10.1 mL [CI 8.9-11.3]). Excluding the volume of the largest growing nodule in these cases, the remaining volume of the affected lobe remained virtually unchanged with respect to its baseline value. Furthermore, there was no significant difference in the non-nodular tissue volume between the unaffected lobe and the affected lobe (with the largest growing nodule volume subtracted), both at baseline and at the end of follow-up. CONCLUSIONS: The growth of thyroid nodules is a local process, not associated with growth of the surrounding non-nodular tissue. Therefore, a normal-sized thyroid containing nodules should be referred to as a "uni- or multinodular thyroid gland" and considered a distinct entity from "uni- or multinodular goiter."

Are Evidence-Based Guidelines Reflected in Clinical Practice? An Analysis of Prospectively Collected Data of the Italian Thyroid Cancer Observatory.

OBJECTIVES: The goal of evidence-based practice guidelines is to optimize the management of emerging diseases, such as differentiated thyroid cancer (DTC). The aim of this study was to assess therapeutic approaches for DTC in Italy and to see how closely these practices conformed to those recommended in the 2009 American Thyroid Association (ATA) guidelines. METHODS: The Italian Thyroid Cancer Observatory was established to collect data prospectively on thyroid cancers consecutively diagnosed in participating centers (uniformly distributed across the nation). Data on the initial treatment of all pathologically confirmed DTC cases present in the database from January 1, 2013 (database creation) to January 31, 2016, were analyzed. RESULTS: A total of 1748 patients (77.2% females; median age 48.1 years [range 10-85 years]) were enrolled in the study. Most (n = 1640; 93.8%) were papillary carcinomas (including 84 poorly differentiated/aggressive variants); 6.2% (n = 108) were follicular and Hürthle cell carcinomas. The median tumor diameter was 11 mm (range 1-93 mm). Tumors were multifocal in 613 (35%) and presented extrathyroidal extension in 492 (28%) cases. Initial treatments included total thyroidectomy (involving one or two procedures; n = 726; 98.8%) and lobectomy (n = 22; 1.2%). A quarter of the patients who underwent total thyroidectomy had unifocal, intrathyroidal tumors ≤1 cm (n = 408; 23.6%). Neck dissection was performed in 40.4% of the patients (29.5% had central compartment dissection). Radioiodine remnant ablation (RRA) was performed in 1057 (61.2%) of the 1726 patients who underwent total thyroidectomy: 460 (41.2%) of the 983 classified by 2009 ATA guideline criteria as low-risk, 570 (87.1%) of the 655 as intermediate-risk, and 82 (93.1%) of the 88 as high-risk patients (p < 0.001). RRA was performed in 44% of the cases involving multifocal DTCs measuring ≤1 cm. CONCLUSIONS: The treatment approaches for DTCs used in Italy display areas of inconsistency with those recommended by the 2009 ATA guidelines. Italian practices were characterized by underuse of thyroid lobectomy in intrathyroidal, unifocal DTCs ≤1 cm. The use of RRA was generally consistent with risk-stratified recommendations. However, its frequent use in small DTCs (≤1 cm) that are multifocal persists, despite the lack of evidence of benefit. These data provide a baseline for future assessments of the impact of international guidelines on DTC management in Italy. These findings also illustrate that the dissemination and implementation of guideline recommendations, and the change in practice patterns, require ongoing education and time.

Impaired caspase-3 expression by peripheral T cells in chronic autoimmune thyroiditis and in autoimmune polyendocrine syndrome-2.

CONTEXT: Activation-induced cell death (AICD) is a major mechanism in the regulation of peripheral tolerance, and caspase-3 represents its major executioner. AICD impairment contributes to the persistence of autoreactive T cells, and defective AICD has been reported in autoimmune thyroiditis as well as in type 1 diabetes mellitus. OBJECTIVE: The objective of this study was to evaluate the involvement of caspase-3 in the regulation of AICD resistance in thyroid and polyendocrine autoimmunity. DESIGN/SETTINGS/PATIENTS/INTERVENTION: Caspase-3 expression was analyzed in peripheral blood lymphocytes from 26 adults (A-AT) and 25 children (Y-AT) affected by autoimmune thyroiditis and 13 individuals affected by chronic autoimmune thyroiditis plus Addison's disease [autoimmune polyendocrine syndrome-2 (APS-2)] in comparison with 32 age-matched normal control subjects (NC). OUTCOME MEASURES: Caspase-3 mRNA expression in peripheral T cells was evaluated by quantitative real-time PCR; protein expression of both procaspase-3 and activated caspase-3 by Western blot analysis was followed by scanning densitometry. RESULTS: Caspase-3 mRNA expression was significantly reduced in resting lymphocytes from both A-AT (P = 0.001) and Y-AT (P = 0.016) compared with NC. After lymphocyte activation, protein levels of caspase-3 active form were significantly reduced in A-AT (P = 0.023) and Y-AT (P = 0.001) compared with NC. The APS-2 group displayed characteristics similar to the A-AT group because both caspase-3 mRNA and protein active form levels were significantly reduced compared with NC (P = 0.004 and 0.002, respectively). CONCLUSION: Our data show that peripheral lymphocytes of subjects affected by thyroid autoimmunity or APS-2 show defective expression of the major executioner of AICD, thus potentially contributing to AICD resistance and to the development of autoimmunity.

Comparative evaluation of recombinant human thyrotropin-stimulated thyroglobulin levels, 131I whole-body scintigraphy, and neck ultrasonography in the follow-up of patients with papillary thyroid microcarcinoma who have not undergone radioiodine therapy.

CONTEXT: Although the prognosis of papillary thyroid microcarcinoma (PTMC) is usually excellent, the optimal follow-up strategy has never been investigated. OBJECTIVE: The objective of the study was to investigate the role of neck ultrasonography (US), whole-body scintigraphy (WBS), and serum thyroglobulin levels (Tg) after recombinant human (rh) TSH in the follow-up of very low-risk PTMC patients. DESIGN: The study was a 5-yr observational study based on a 6- to 12-month follow-up after near total thyroidectomy. SETTING: The study population consisted of ambulatory patients. PATIENTS: Eighty consecutive patients diagnosed with PTMC, who had not undergone postoperative radioiodine treatment because of unifocal tumor without lymph node metastases and who did not have anti-Tg antibodies, were included. MAIN OUTCOME MEASURES: WBS and Tg after both rhTSH and neck US were measured. RESULTS: rhTSH-Tg was 1 ng/ml or less in 45 (Tg-) and more than 1 in 35 (Tg+) patients. WBS showed no pathological uptake in any patient. US identified node metastases in two Tg (+) and one Tg (-) patients. rhTSH-Tg levels positively correlated with thyroid bed iodine uptake (r = 0.40, P < 0.0001). To date (32 +/- 13 months after surgery), all node-negative patients have undetectable Tg levels on LT(4) treatment and negative US. CONCLUSIONS: For the initial follow-up of PTMC patients without risk factors and anti-Tg antibodies and who did not undergo radioiodine treatment: 1) WBS is useless; 2) US is highly sensitive in detecting node metastases; and 3) detectable rhTSH-Tg levels mainly depend on small normal tissue remnants. In this subgroup of PTMC patients, neck US might be regarded as a primary tool for the initial follow-up.

Papillary thyroid carcinomas with biochemical incomplete or indeterminate responses to initial treatment: repeat stimulated thyroglobulin assay to identify disease-free patients.

Papillary thyroid cancer (PTC) patients treated with thyroidectomy and radioiodine remnant ablation (RRA) often have detectable TSH-stimulated thyroglobulin (Tg) levels without localizable disease after primary treatment. To assess the value of repeat stimulated Tg assays in these patients' follow-up, we retrospectively analyzed 86 cases followed in 5 Italian thyroid-cancer referral centers. We enrolled 86 patients with PTCs treated with total/near-total thyroidectomy plus RRA between January 1,1990 and January 31, 2006. In all cases, the initial postoperative visit revealed stimulated serum Tg ≥1 ng/mL, negative Tg antibodies, and no structural evidence of disease. None received empiric radioiodine therapy. Follow-up (median: 9.6 years) included neck ultrasound and basal Tg assays (yearly) and at least 1 repeat stimulated Tg assay. Of the 86 patients analyzed (initial risk: low 63 %, intermediate 35 %, high 2 %), one (1 %) had ultrasound-detected lymph node disease and persistently elevated stimulated Tg levels at 3 years. In 17 (20 %), imaging findings were consistently negative, but the final stimulated Tg levels was still >1 ng/mL (median 2.07 ng/mL, range 1.02-4.7). The other 68 (80 %) appeared disease-free (persistently negative imaging findings with stimulated Tg levels ≤1 ng/mL). Mean intervals between first and final stimulated Tg assays were similar (5.2 and 4.8 years) in subgroups with versus without Tg normalization. Reclassification as disease-free was significantly more common when initial stimulated Tg levels were indeterminate (<10 ng/mL). In unselected PTC cohorts with incomplete/indeterminate biochemical responses to thyroidectomy and RRA, periodic remeasurement of stimulated Tg allows most patients to be classified as disease-free.

Association of subclinical hypercortisolism with type 2 diabetes mellitus: a case-control study in hospitalized patients.

OBJECTIVE: Subclinical hypercortisolism (SH) may play a role in several metabolic disorders, including diabetes. No data are available on the relative prevalence of SH in type 2 diabetes (T2D). In order to compare the prevalence of SH in T2D and matched non-diabetic control individuals, we performed a case-controlled, multicenter, 12-month study, enrolling 294 consecutive T2D inpatients (1.7% dropped out the study) with no evidence of clinical hypercortisolism and 189 consecutive age- and body mass index-matched non-diabetic inpatients (none of whom dropped out). DESIGN AND METHODS: Ascertained SH (ASH) was diagnosed in individuals (i) with plasma cortisol after 1 mg overnight dexamethasone suppression >1.8 microg/dl (50 nmol/l), (ii) with more than one of the following: (a) urinary free cortisol >60.0 microg/24 h (165.6 nmol/24 h), (b) plasma ACTH <10.0 pg/ml (2.2 pmol/l) or (c) plasma cortisol >7.5 microg/dl (207 nmol/l) at 24:00 h or >1.4 microg/dl (38.6 nmol/l) after dexamethasone-CRH (serum cortisol after corticotrophin-releasing hormone stimulus during dexamethasone administration) test, and (iii) in whom the source of glucocorticoid excess was suggested by imaging and by additional biochemical tests (for ACTH-dependent ASH). RESULTS: Prevalence of ASH was higher in diabetic individuals than in controls (9.4 versus 2.1%; adjusted odds ratio, 4.8; 95% confidence interval, 1.6-14.1; P = 0.004). In our population the proportion of T2D which is statistically attributable to ASH was approx. 7%. Among diabetic patients, the presence of severe diabetes (as defined by the coexistence of hypertension, dyslipidaemia and insulin treatment) was significantly associated with SH (adjusted odds ratio, 3.8; 95% confidence interval, 1.4-10.2; P = 0.017). CONCLUSIONS: In hospitalized patients, SH is associated with T2D.

TERT Promoter Mutations in Papillary Thyroid Microcarcinomas.

BACKGROUND: Small papillary thyroid carcinomas have contributed to the worldwide increased incidence of differentiated thyroid cancer observed over the past decades. However, the mortality rate has not changed over the same period of time, raising questions about the possibility that thyroid cancer patients, especially those with small tumors, are overdiagnosed and overtreated. Molecular prognostic marker able to discriminate aggressive thyroid cancers from those with an indolent course would be of great relevance to tailor the therapeutic approach and reduce overtreatment. Mutations in the TERT promoter were recently reported to correlate strongly with aggressiveness in advanced forms of thyroid cancer, holding promise for a possible clinical application. The occurrence and potential clinical relevance of TERT mutations in papillary thyroid microcarcinomas (mPTCs) is currently unknown. This study aimed to analyze the occurrence of two TERT promoter mutations (-124C>T and -146C>T) and their potential association with unfavorable clinical features in a large cohort of mPTCs. METHODS: A total of 431 mPTCs cases were collected from six Italian institutions, and TERT promoter mutational status was assessed by a next-generation sequencing approach. RESULTS: TERT promoter mutations were found in 4.7% of the analyzed mPTCs, showing that even microcarcinomas carry mutations in this gene. Correlation analysis showed that TERT promoter mutations are not associated with aggressive features or clinical outcome in the cohort analyzed. CONCLUSIONS: TERT mutations are present but uncommon in mPTCs. Apparently, in mPTCs, the occurrence of TERT mutations is not correlated with unfavorable clinical features.

Spinal volumetric bone mineral density and vertebral fractures in female patients with adrenal incidentalomas: the effects of subclinical hypercortisolism and gonadal status.

Although adrenal incidentalomas (AI) are not associated with clinically evident syndromes, some patients display biochemical features of subclinical hypercortisolism (SH). Previous studies indicated a negative effect of SH on bone in AI patients, but the prevalence of vertebral fractures and the roles of SH and gonadal status in volumetric bone mineral density are unknown. In 70 female AI patients and 84 controls, the prevalence of vertebral fractures and spinal bone mineral density (by quantitative computed tomography) were evaluated. Subjects were subdivided according to menopausal status into groups Pre (21 patients and 23 controls) and Post (49 patients and 61 controls); there were 14 and 35 patients without SH (SH(-)) and 7 and 14 patients with SH (SH(+)) in groups Pre and Post, respectively. The prevalence of fractures was higher in SH(+) than in controls and in SH(-) subjects in both groups Pre [SH(+), 42.9%; controls, 0% (P = 0.001); SH(-), 7.1% (P = 0.049)] and post [SH(+), 78.6%; controls, 37.7% (P = 0.006); SH(-) 42.9% (P = 0.024)]. In group Post, the mean z-score quantitative computed tomography values were lower in SH(+) patients (-0.78 +/- 0.29) than in controls (0.06 +/- 0.14; P = 0.011) and SH(-) patients (0.02 +/- 0.19; P = 0.034). Evaluation of spinal bone is indicated in female AI patients with SH.

Follow-up of low risk patients with papillary thyroid cancer: role of neck ultrasonography in detecting lymph node metastases.

Persistent or recurrent disease is rare in low risk patients with papillary thyroid cancer, and follow-up of these patients is a matter of debate. Neck ultrasonography (US), serum thyroglobulin (Tg), and whole body scan (WBS) after T(4) withdrawal were performed in 456 patients, followed up to 5 yr. At the end of the first year, 335 patients were Tg negative, and 121 were Tg positive; 65 of 96 patients with Tg levels between 1 and 10 ng/ml became spontaneously Tg negative after 2 yr. During follow-up, WBS discovered node metastases in 13 subjects, and US discovered node metastases in 38 subjects (31 Tg positive and 7 Tg negative). WBS did not add any information, because all WBS-positive patients were also US and Tg positive. Fifty percent of metastases were less than 1 cm and not palpable. Finally, the negative predictive value of both negative Tg and US at first follow-up was 98.8%. We suggest a first follow-up based upon US assessment and stimulated (after T(4) withdrawal or recombinant human TSH) serum Tg determination; subsequently, 1) US should not be mandatory at each examination in initially Tg- and US-negative subjects, but is strongly suggested in all other cases; 2) Tg determination should be repeated 1 yr later, after exogenous or endogenous TSH stimulation only in initially Tg-positive patients without any other evidence of residual disease; and 3) Tg measurement during therapy should be sufficient in all other cases.