New Findings on Presentation and Outcome of Patients With Adrenocortical Cancer: Results From a National Cohort Study.

CONTEXT: Because of the rarity of adrenocortical cancer (ACC), only a few population-based studies are available, and they reported limited details in the characterization of patients and their treatment. OBJECTIVE: To describe in a nationwide cohort the presentation of patients with ACC, treatment strategies, and potential prognostic factors. METHODS: Retrospective analysis of 512 patients with ACC, diagnosed in 12 referral centers in Italy from January 1990 to June 2018. RESULTS: ACC diagnosed as incidentalomas accounted for overall 38.1% of cases, with a frequency that increases with age and with less aggressive pathological features than symptomatic tumors. Women (60.2%) were younger than men and had smaller tumors, which more frequently secreted hormones. Surgery was mainly done with an open approach (72%), and after surgical resection, 62.7% of patients started adjuvant mitotane therapy. Recurrence after tumor resection occurred in 56.2% of patients. In patients with localized disease, cortisol secretion, ENSAT stage III, Ki67%, and Weiss score were associated with an increased risk of recurrence, whereas margin-free resection, open surgery, and adjuvant mitotane treatment were associated with reduced risk. Death occurred in 38.1% of patients and recurrence-free survival (RFS) predicted overall survival (OS). In localized disease, age, cortisol secretion, Ki67%, ENSAT stage III, and recurrence were associated with increased risk of mortality. ACCs presenting as adrenal incidentalomas showed prolonged RFS and OS. CONCLUSION: Our study shows that ACC is a sex-related disease and demonstrates that an incidental presentation is associated with a better outcome. Given the correlation between RFS and OS, RFS may be used as a surrogate endpoint in clinical studies.

Differentiated thyroid carcinoma presentation may be more aggressive in children and adolescents than in young adults.

BACKGROUND: The available studies concerning the influence of age on the phenotypical expression of differentiated thyroid carcinoma (DTC) have hitherto compared DTC presentation either between pre-pubertal and pubertal children or between pediatric patients and aged adults; aim of this study was to ascertain for the first time whether presentation of DTC may significantly vary according to age, even within a peculiar study population covering only young patients aged less than 30 years. METHODS: The main clinical, biochemical and pathologic data at DTC diagnosis were retrospectively recorded in 2 selected cohorts including, respectively, 18 children and adolescents aged less than 18 years (Group A) or 45 young adults aged between 20 and 29.8 years (Group B). RESULTS: The statistical distribution of DTC cases in the different age ranges was found to progressively increase with increasing age; furthermore, the patients of Group A exhibited at diagnosis a more severe clinical involvement and a higher rate of extra-regional metastases; finally, also the association with both autoimmune thyroid diseases (AITDs) and a biochemical hypothyroid pattern was more common in Group A patients. CONCLUSIONS: In a study population younger than 30 years: a) the risk of developing DTC increases with age, achieving its zenith during the 3rd decade of life; b) clinical presentation is more severe in children and adolescents younger than 18 years than in the patients aged between 20 and 30; c) in the cohort of children and adolescents DTC is more often associated with AITDs, which might play some role in conditioning the more aggressive phenotypical presentation of DTC in this patient group.

Differentiated thyroid carcinoma in lingual thyroid.

The lingual thyroid is the most common form of thyroid ectopy. The ectopic tissue may display any disease affecting the thyroid, including malignancies, which have an estimated incidence of less than 1%. To date only 51 cases of lingual thyroid cancer were reported. Analogously to what observed in orthotopic thyroid, papillary carcinoma is the predominant histotype in lingual thyroid carcinoma. The higher frequency of lingual follicular thyroid carcinoma previously reported is possibly related to histological misclassification in some early reports, prior to the standardization of histological typing of differentiated thyroid carcinomas. Nonetheless, the frequency of the follicular histotype is not negligible, accounting for about one-third of the reported cases. Both natural history and prognosis of lingual thyroid carcinoma are poorly known, likely because of the rarity of the disease and the heterogeneity in the therapeutic approach. However, among the cases more recently reported, surgical excision of the mass, either alone or followed by radioiodine ablation, is the first-line approach, with only two cases treated by radioiodine alone. The nonsignificant rate of neoplastic transformation in lingual thyroid should encourage efforts to obtain a widely accepted consensus for the management of this rare condition, along with standardization of either diagnostic or therapeutic handling of malignancies arising in ectopic thyroid.

Radioiodine ablation of postsurgical thyroid remnants after treatment with recombinant human TSH (rhTSH) in patients with moderate-to-severe graves' orbitopathy (GO): a prospective, randomized, single-blind clinical trial.

CONTEXT: Recent evidence suggests thyroidectomy (Tx) followed by radioiodine remnant ablation to be beneficial to Graves' orbitopathy (GO) patients. OBJECTIVE: The aim of the study was to evaluate the effect of (131)I thyroid ablation after recombinant human TSH stimulation in patients with moderate-to-severe GO. DESIGN, PATIENTS, AND INTERVENTIONS: The study was prospective, randomized, and single-blind, and it included 40 consecutive patients with moderate-to-severe GO randomized into: 1) a Tx-radioactive iodine (RAI) group (20 subjects who underwent total-Tx and (131)I ablation after recombinant human TSH stimulation); and 2) a Tx group (20 subjects who underwent total-Tx alone). OUTCOME MEASURES: The overall GO outcome 12 months after Tx/radioiodine ablation was the main measure. RESULTS: GO evaluation at the end of iv glucocorticoids showed eye disease to be improved in 65% of the Tx-RAI group and 60% of the Tx group patients. At 6 and 12 months, no further changes in the GO outcome could be observed in the Tx-RAI group. Conversely, five patients from the Tx group exhibited a deterioration in GO. At 12 months, GO was found to be improved in 70% of the Tx-RAI and 20% of the Tx group patients, the latter being found to be stable (55%) or worse (25%) than at baseline evaluation. At 12 months, GO was found to be inactive in a significantly higher percentage of patients in the Tx-RAI than in the Tx group (75 vs 30%; P < .01). CONCLUSIONS: Postoperative radioiodine ablation proved more effective than Tx alone in inducing earlier and steadier GO improvement in patients with moderate-to-severe GO treated with iv glucocorticoids over a 24-month follow-up period.

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) = 17.8/10(5) in females and 3.7/10(5) 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) = 31.7/10(5) in females and 6.4/10(5) 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.

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.

Iodine prophylaxis using iodized salt and risk of maternal thyroid failure in conditions of mild iodine deficiency.

CONTEXT: Mild to moderate iodine deficiency during pregnancy can cause transient maternal hypothyroidism and impaired mental development of the progeny. These unfavorable effects are preventable by iodine supplementation. In Europe, however, less than 50% pregnant women receive iodine-containing supplements, thus representing dietary iodized salt the only carrier of iodine for most women in this life stage. OBJECTIVE/DESIGN: This longitudinal study is aimed to investigate the effects of long-term iodized salt consumption on maternal thyroid function during gestation. PARTICIPANTS/OUTCOME MEASURES: We prospectively evaluated thyroid function in 100 consecutive thyroperoxidase antibody-negative pregnant women from a mildly iodine-deficient area. Sixty-two women who had regularly used iodized salt for at least 2 yr prior to becoming pregnant and 38 who commenced iodized salt consumption upon becoming pregnant were classified as long-term (LT) and short-term (ST) iodine supplemented, respectively. RESULTS: Long-term iodized salt consumption resulted in a very low prevalence of maternal thyroid failure (MTF) in LT women. Conversely, short-term iodine prophylaxis does not seem to protect against the risk of MTF, the prevalence of which was almost 6-fold higher in ST than LT women (36.8% vs. 6.4%; chi(2) 14.7, P < 0.0005; relative risk 5.7, 95% confidence interval 2.03-16.08, P < 0.001). The relative risk reduction amounted to 82.5%, this measure indicating the extent to which long-term iodine prophylaxis using iodized salt would reduce the risk of MTF in ST women. CONCLUSIONS: Prolonged iodized salt significantly improves maternal thyroid economy and reduces the risk of maternal thyroid insufficiency during gestation, probably because of a nearly restoring intrathyroidal iodine stores.

antiphospholipid antibodies syndrome associated with hyperhomocysteinemia related to MTHFR Gene C677T and A1298C heterozygous mutations in a young man with idiopathic hypoparathyroidism (DiGeorge syndrome).

CONTEXT: Antiphospholipid syndrome (APS, or Hughes' syndrome) is a systemic autoimmune disorder characterized by antiphospholipid antibody positivity, which may lead to arterial and/or venous thrombosis. Hyperhomocysteinemia (HHcy), variously associated with 5,10-methylene tetrahydrofolate reductase (MTHFR) gene point mutations, is also implicated in thromboembolic events. The association of APS and HHcy has already been described but has never been reported in patients with DiGeorge syndrome (DGS), the most common contiguous-gene deletion syndrome (22q11.2) in humans, whose phenotype conversely includes bleeding disorders. DATA ACQUISITION: In this report, we present the case of a 19-yr-old patient with a past medical history of learning disability and obesity affected with idiopathic hypoparathyroidism, metabolic syndrome, and diffuse vasculitis disorders. He was referred to our endocrinology clinic for the management of severe hypocalcemia. At the time of presentation he had been taking antiepileptic drugs for 2 wk and displayed facial dysmorphism (short neck, micrognathia, a small mouth, hypoplastic nasal alae, eye hypertelorism, and low-set simple ears). DGS was suspected and confirmed by both fluorescence in situ hybridization analysis and single nucleotide polymorphism-array analysis, which revealed contiguous gene microdeletion of the chromosome 22q11.2 in the minimal DiGeorge critical region, specifically at the gene locus D22S75 (N25). CONCLUSIONS: APS, revealed by anti-beta-2-glycoprotein and anti-prothrombin antibodies positivity, and moderate HHcy related to heterozygous C677T and A1298C point mutations of the MTHFR gene were identified as a possible cause of thrombotic disorder responsible for the widespread presence of cutaneous and cerebral lesions.

Effects of thyroidectomy alone or followed by radioiodine ablation of thyroid remnants on the outcome of graves' ophthalmopathy.

Fifty-five patients with Graves' disease (GD) and mild to moderate Graves' ophthalmopathy (GO) underwent near-total thyroidectomy (Tx). In 16 patients this was followed by a standard ablative dose of (131)I because of the hystologic evidence of differentiated thyroid carcinoma. We retrospectively evaluated whether or not GO activity could be affected by thyroid surgery alone or followed by complete ablation of thyroid tissue. Accordingly, on the basis of clinical activity score (CAS) values prior to thyroidectomy, we identified two groups: group A with active GO (CAS > or = 3; n = 31) and group B with inactive GO (CAS < or = 2; n = 24). CAS values were then recorded at 6, 12, and 24 months after surgery/(131)I ablation. Over the course of the follow-up period, GO became inactive in approximately 70% of group A patients (CAS 4.2 +/- 0.8 at baseline, 2.1 +/- 2.0 at 24 months, p < 0.0001) and became active in 37.5% patients from group B. When we examined GO activity according to the type of treatment used (Tx or Tx and (131)I), the prevalence of inactive GO both short- and long-term, was significantly higher in the group of patients who underwent Tx and (131)I ablation. Therefore, this seems to be a more effective means of inducing and maintaining inactive GO.

Changes in both size and cytological features of thyroid nodule after levothyroxine treatment.

OBJECTIVE: We prospectively evaluated the effects of 12 months thyrotropin suppressive levo-thyroxine (L-T4) therapy in terms of changes in both thyroid nodule size and cytological features and considered whether thyroid nodule size changes actually resulted in (or were the result of) cytological changes. DESIGN AND PATIENTS: We studied 142 consecutive patients with benign 'cold' solitary thyroid nodules. For the purposes of the study, we divided our patients into three groups according to their initial cytological nodule classification as follows: group 1, including 88 colloid nodules (CN); group 2, including 30 hyperplastic nodules (HN); and group 3, including 24 adenomatous nodules (AN). MEASUREMENTS: The effects of TSH suppressive L-T4 treatment on both nodule volume and cytological characteristics were evaluated by ultrasonography and fine-needle aspiration (FNA) before and 12 months after the onset of therapy. RESULTS: Twelve months of TSH suppressive L-T4 treatment were effective in shrinking about one-third to one-quarter (31.8% CN, 26.7% HN and 25% AN) of thyroid nodules, irrespective of their initial cytological characteristics. Similarly, there was no difference in the prevalence of 'non-responders' (increasing nodules) to L-T4, which accounted for about one-fifth or less (20.5% CN, 13.3% HN and 20.8% AN) of all nodules. We found also that cytological features changed in 33.8% nodules after 12 months of L-T4 treatment. These changes were most commonly observed in HN and AN and consisted largely ( approximately 80%) of cytological characteristics resembling colloid features, not only in shrinking but also in stable nodules, thus indicating that cytology changes might be the very first indicator of nodule sensitivity to L-T4 therapy even in the continued absence of nodule shrinkage. When nodules were divided into three subgroups according to variations in size (shrinking, stable and increasing nodules), we observed that the distribution of the three cytological types showed a trend towards colloid lesions in shrinking nodules (chi2 3.8, P < 0.005) and towards an augmentation of hypercellular, adenomatous and suspicious characteristics in increasing nodules (chi2 3.6, P < 0.005). CONCLUSION: The frequency of shrinking nodules was not different between colloid, hyperplastic and adenomatous nodules. Repeat FNA should be advisable for thyroid nodules which increase in volume despite L-T4 therapy and might also provide useful information about nodule sensitivity to L-T4 treatment for both HN and AN, even where nodule size remains stable.