Benign thyroid nodules with RAS mutation grow faster.

CONTEXT: The management of a benign thyroid nodule includes follow-up until its size requires a surgical or alternative treatment. To date, it is difficult or impossible to predict the size changes of a benign nodule in a given patient because no specific growth parameters exist. RAS mutations have been described in thyroid adenomas and hyperplastic benign nodules. OBJECTIVE: The aim of this study was to establish whether the volume changes of benign nodules are associated with the presence of RAS mutation. PATIENTS AND METHODS: Genomic DNA obtained by fine-needle aspiration of 78 thyroid nodules with benign cytology was analysed by pyrosequencing for the presence of NRAS(61) and KRAS(13) mutations. Ultrasonographic features were obtained. The volume of nodules at baseline and their changes after a mean follow-up of 25 months were evaluated according to the presence of RAS mutation. RESULTS: A RAS mutation was found in 24 thyroid aspirates (30·8%, 8 NRAS(61) and 16 KRAS(13) ). RAS mutation was not associated with ultrasonographic features, but was significantly associated with a larger size at baseline (P = 0·017). After a 25-month mean follow-up, RAS mutation-positive nodules displayed faster growth (RAS mutation-positive vs RAS mutation-negative % annual growth 27·6% ±32·2% vs 1·0% ±17·0%, P < 0·001). CONCLUSIONS: Benign thyroid nodules bearing RAS mutation grow more rapidly than those with wild-type RAS. Searching for RAS mutations in thyroid nodules with benign cytology might be useful to the clinician in choosing a more appropriate and timely surgical management.

Prognostic role of the CDNK1B V109G polymorphism in multiple endocrine neoplasia type 1.

CDKN1B encodes the cyclin-dependent kinase inhibitor p27/Kip1. CDKN1B mutations and polymorphisms are involved in tumorigenesis; specifically, the V109G single nucleotide polymorphism has been linked to different tumours with controversial results. Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome, characterized by the development of different types of neuroendocrine tumours and increased incidence of other malignancies. A clear genotype-phenotype correlation in MEN1 has not been established yet. In this study, we assessed whether the CDKN1B V109G polymorphism was associated with the development of aggressive tumours in 55 consecutive patients affected by MEN1. The polymorphism was investigated by PCR amplification of germline DNA followed by direct sequencing. Baseline and follow-up data of tumour types and their severity were collected and associated with the genetic data. MEN1-related aggressive and other malignant tumours of any origin were detected in 16.1% of wild-type and 33.3% of polymorphism allele-bearing patients (P = NS). The time interval between birth and the first aggressive tumour was significantly shorter in patients with the CDKN1B V109G polymorphism (median 46 years) than in those without (median not reached; P = 0.03). Similarly, shorter was the time interval between MEN1 diagnosis and age of the first aggressive tumour (P = 0.02). Overall survival could not be estimated as 96% patients were still alive at the time of the study. In conclusion, CDKN1B V109G polymorphism seems to play a role in the development of aggressive tumours in MEN1.

Evolution of benign thyroid nodules under levothyroxine non-suppressive therapy.

BACKGROUND: Non-suppressive or partially suppressive L-T4 treatment demonstrated to be effective in reducing the volume of the nodules. However, studies with long follow-up are lacking and significant controversy exists regarding the efficacy of non-suppressive L-T4 treatment in benign nodular goiter. AIM: The goal of this study was to determine the evolution of thyroid nodules in subjects treated with a non-suppressive levothyroxine (L-T4) dose, compared to untreated subjects. DESIGN AND PATIENTS: We followed for a period of 1-9 years the thyroid nodule size in 356 female patients in the age range 19-45 at study entry, of which 201 untreated (Group 0) and 165 treated with a non-suppressive L-T4 dose (Group L-T4). MEASUREMENTS: We determined the volume of thyroid nodules by ultrasonography. RESULTS: The initial mean nodule volume in Group 0 and Group L-T4 was 3.91 ± 6.87 and 4.01 ± 7.35 mL, respectively. Nodule volume increase was inversely correlated to the initial volume. The final volume was slightly higher in untreated than in L-T4 treated subjects (5.37 ± 8.49 and 4.39 ± 6.72 mL). In both groups, the mean of annual fold increase of nodule volume was inversely correlated with the follow-up duration (P < 0.0046), indicating a slower growth as time advances. In the subjects treated with L-T4, the mean annual increase of nodule volume was significantly minor compared to untreated subjects. Concomitant nodules in ten multinodular goiters exhibited totally independent evolution, demonstrating that intranodular factors are more important for the nodule behavior than extra nodular factors. CONCLUSIONS: Our study demonstrates that the growth of benign thyroid nodules is inversely correlated to their size, benign nodules naturally growth slowly as time advances, and that a chronic treatment with L-T4 at a non-TSH-suppressive dose significantly reduces their growth.

GH provocative tests stimulate the growth in children with idiopathic short stature.

CONTEXT: Growth hormone (GH) deficiency in a child with short stature is diagnosed by GH secretion provocative tests. When the test response is considered adequate, the short stature is considered idiopathic (ISS). OBJECTIVE: To determine the effect of GH provocative tests on the growth rate in children with idiopathic short stature. DESIGN: Children with short stature with a normal response to at least one GH provocative test were enrolled. Height and growth velocity were measured prior to and after stimulus tests during the follow-up. METHODS: Height, mid-parental height, body weight, and body mass index were measured. The height and growth rate were converted to percentiles and Standard Deviation Scores (SDS) using reference ranges standardized by age and sex. GH provocative tests employed arginine or clonidine as secretagogues. RESULTS: Fourty-six children of both genders were enrolled. In thirty-six children, height was measured at the time of testing and on an average time prior to and after the tests of 210 days and 180 days respectively. After testing the children displayed a 3.4-fold increase in their estimated 90-day growth rate. The median (inter-quartile range, IQR) 90 days growth of children pre-and post-tests were 0.7 (0.2-1.0) cm and 2.4 (1.7-3.1) cm respectively with a mean 3,4-fold increase (p < 0.0001). The median (IQR) 90 days growth of children pre- and post-tests calculated as standard deviation scores (SDS) were -4.0 (-5.4--2.1) SDS and 0.1 (-1.9-1.4) SDS respectively (p < 0.0001). Ten children with ISS were observed for about 5 months before the GH provocative tests. A small increase in the growth rate was seen only in 2 out of 10 children before testing while it increased in all of them after the tests. The difference in the median growth rate at the first and the second observation was not significant (p = 0.219). CONCLUSIONS: Two sequential somatotropic axis provocative tests increase the growth rate in children with idiopathic short stature. The duration of this effect is yet to be determined.

Survival predictors of radioiodine-refractory differentiated thyroid cancer treated with lenvatinib in the real-life.

CONTEXT: Lenvatinib is approved for the treatment of radioiodine-refractory differentiated thyroid cancer (RR-DTC). The definition of predictive factors of survival is incomplete. OBJECTIVE: To identify pre- and post- treatment survival predictors in a real-life cohort of RR-DTC treated with lenvatinib. DESIGN: Multicenter, retrospective, cohort study. SETTING: Three Italian thyroid cancer referral centers. PARTECIPANTS: 55 RR-DTC treated with lenvatinib. MAIN OUTCOME MEASURES: Progression-free survival (PFS) and overall survival (OS). RESULTS: Lenvatinib was the first-line kinase-inhibitor in 96.4% of subjects. Median follow-up was 48 months. Median PFS and OS were 26 (95% CI 19.06-32.93) and 70 months (95% CI 36-111.99), respectively. Pre-treatment setting: Eastern Cooperative Oncology Group (ECOG) performance status was independently related to PFS (p < 0.001; HR 18.82; 95% CI 3.65-97.08: score 0-1 as reference) and OS (p = 0.001; HR 6.20; 95% CI 2.11-18.20; score 0-1 as reference); radioactive iodine (RAI)-avidity was independently related to PFS (p = 0.047; HR 3.74; 95% CI 1.01-13.76; avid disease as reference). Patients with good ECOG status (0-1) and RAI-avid disease obtained objective response in 100% of cases and achieved a median PFS of 45 months without any death upon a median follow-up of 81 months. Post-treatment setting: best radiological response independently predicted PFS (p = 0.001; HR 4.6; 95% CI 1.89-11.18; partial/complete response as reference) and OS (p = 0.013; HR 2.94; 95% CI 1.25-6.89; partial/complete response as reference). CONCLUSIONS: RR-DTC with good performance status and RAI-avid disease obtain the highest clinical benefit from lenvatinib. After treatment initiation, objective response was the only independent survival predictor.

BRAF mutation positive papillary thyroid carcinoma is less advanced when Hashimoto's thyroiditis lymphocytic infiltration is present.

BACKGROUND: Concomitant papillary thyroid cancer (PTC) and Hashimoto's thyroiditis (HT) is a frequent occurrence. Whether these two conditions are linked and whether PTC with concurrent HT has distinct clinicopathological characteristics are still debated issues. Lymphocytic infiltration is abundant in HT and might be relevant in the pathogenesis and progression of PTC. BRAF(V600E) mutation is associated with a more advanced PTC at diagnosis; however, its role in the clinicopathological characteristics of PTC with concurrent HT is unknown. DESIGN AND PATIENTS: We enrolled 146 patients with histological diagnosis of PTC. Microscopic assessment of histology samples was performed to identify the presence of lymphocytic infiltration. Detection of BRAF(V600E) was performed on cytology samples by both direct sequencing and pyrosequencing, and results were correlated with clinical parameters. RESULTS: Concurrent HT lymphocytic infiltration was associated with the female gender, smaller tumour size, a less frequent extracapsular extension and a lower grade of TNM staging. BRAF(V600E) was more frequent in PTC with concomitant lymphocytic infiltration. In PTC harbouring BRAF(V600E) , concurrent lymphocytic infiltration was still associated with the female gender, a less frequent extracapsular extension and a lower TNM staging. CONCLUSIONS: These results suggest that lymphocytic infiltration of HT is a protective factor against PTC progression, and it is independent of BRAF mutational status.

Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET.

CONTEXT: Radioactive iodine is a crucial tool for treatment of differentiated thyroid cancer (DTC). In 5% of cases, DTCs lose I-131 avidity and assume an aggressive behaviour. Treatment options for iodine-refractory DTC are limited. We report the experience of off-label use of the tyrosine kinase inhibitor sorafenib for treatment of advanced iodine-refractory DTC. DESIGN: Patients with progressive DTC refractory to radioactive iodine were treated with sorafenib used off-label independently from their performance status. Primary study end-points were radiological response, progression-free survival (PFS) and safety. Secondary end-points were site-specific radiological response and overall survival (OS). An exploratory analysis of the role of serum thyroglobulin (Tg) and fluorodeoxyglucose (FDG) positron emission tomography (PET) was performed. RESULTS: A total of 17 patients were included in the study. Median follow-up was 15·5 months. Clinical benefit was obtained in 71% of subjects (30% partial response and 41% stable disease). Sorafenib was mostly well tolerated, but a high incidence of fatal events was reported (three patients died from severe bleeding events and two from cardiac arrest). Median PFS was 9 months. Median OS was 10 months. The best responses were observed in lymph nodes and lung. Baseline Tg levels and the Tg response to treatment were correlated to both radiological response and PFS. Baseline FDG-PET assessment and early FDG-PET response were correlated to radiological response. CONCLUSIONS: Sorafenib allows morphological disease control in the majority of patients with iodine-refractory DTC. Progression-free survival and overall survival were lower than in previous studies as a consequence of the worse clinical condition of our patients. Sorafenib is mostly well tolerated but could have been responsible for the reported fatal events. Baseline Tg and the Tg response to treatment could be useful for predicting morphological response and clinical outcome. Early FDG-PET response could be helpful for the timely identification of nonresponding patients.

Exposure to Bisphenol A increases malignancy risk of thyroid nodules in overweight/obese patients.

Bisphenol A (BPA) is a widespread thyroid disruptor, but evidence about an association with thyroid cancer is weak. Excess body weight is a risk factor for thyroid cancer and affects activity of endocrine disruptors. Aim of the study was to investigate the association between BPA exposure and thyroid cancer, verifying the effect modification related to body weight. We performed a multicentre, cross-sectional study including consecutive patients referring for nodular goiter. The quantitative determination of BPA in serum samples was performed through high performance liquid chromatography system, coupled in tandem with ultraviolet and fluorescence detection. Ninety-six patients were included: 55 benign nodules, 41 thyroid cancers, 28 normal weight, and 68 overweight/obese. BPA was detected in 79 subjects. In the overall study population and in the group with BMI<25 kg/m2 BPA exposure was not significantly correlated to thyroid cancer (p = 0.08 and 0.759, respectively). In the group with BMI≥25 kg/m2, BPA-exposed subjects showed significantly higher risk of malignancy (OR: 5.3, p = 0.028). At multivariate analysis, such association was independent of smoking, alcohol consumption, occupational exposure, and phthalates exposure (p = 0.021 and 0.016, respectively), but was lost after adjustment for the presence of metabolic syndrome (p = 0.089). In overweight/obese subjects, BPA exposure was significantly associated with higher thyroid stimulating hormone levels. Our study suggests that BPA exposure is a risk factor for thyroid cancer in overweight/obese subjects.

A Prospective Multicenter Study Examining the Relationship Between Thyroid Cancer Treatment Outcomes and the Presence of Autoimmune Thyroiditis.

Background: There is some controversy on the potential relationship between autoimmune processes and clinicopathologic features as well as prognosis of differentiated thyroid cancer (DTC), and the evidence is limited by its largely retrospective nature. We examined the relationship between the presence of autoimmune thyroiditis (AT) and 1-year thyroid cancer treatment outcomes in a large multicenter study using prospectively collected data. Methods: We included data from consecutive DTC patients enrolled in the Italian Thyroid Cancer Observatory (ITCO) database (NCT04031339). We divided the groups according to the presence (AT) or absence (no autoimmune thyroiditis [noAT]) of associated AT. We used propensity score matching to compare the clinical features and outcomes between the two groups at 1-year follow-up. Results: We included data from 4233 DTC patients, including 3172 (75%) females. The American Thyroid Association (ATA) risk levels were as follows: 51% (2160/4233) low risk, 41.3% (1750/4233) intermediate risk, and 7.6% (323/4233) high risk. There were 1552 patients (36.7%) who had AT. Before propensity score matching, AT patients were significantly younger and had a smaller and bilateral tumor (p < 0.0001). Patients with AT more frequently fell into the low- and intermediate-risk categories, while the ATA high risk was more frequent among noAT patients (p = 0.004). After propensity score matching, patients with AT more frequently showed evidence of disease (structural/biochemical incomplete response) versus excellent/indeterminate response, compared with patients without AT (7.3% vs. 4.5%, p = 0.001), with an odds ratio of 1.86 ([confidence interval: 1.3-2.6], p = 0.0001). However, when considering only structural persistence as the outcome, no statistically significant differences were observed between patients with or without AT (3.4% vs. 2.7%, p = 0.35). The elevated risk associated with the ATA intermediate and high risk at diagnosis remained consistently statistically significant. Conclusions: In this large prospective series, biochemical persistence was more frequent, at 1-year follow-up, in AT patients. However, there was no significant association between the presence of AT and structural persistence of disease. These findings may be explained by the presence of a residual thyroid tissue.

Limitations of Chromogranin A in clinical practice.

CONTEXT: Usefulness of circulating Chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (NEN) is controversial. The aim of the present study was to assess the actual role of this marker as diagnostic tool. METHODS: Serum blood samples were obtained from 42 subjects affected with NEN, 120 subjects affected with non-endocrine neoplasias (non-NEN) and 100 non-neoplastic subjects affected with benign nodular goitre (NNG). Determination of CgA was performed by means of immunoradiometric assay. RESULTS: The CgA levels among NEN-patients were not significantly different from NNG and non-NEN subjects. The Receiver operating characteristic (ROC) curves analysis failed to identify a feasible cut-off value for the differential diagnosis between NEN and the other conditions. CONCLUSION: Serum CgA is not helpful for the first-line diagnosis of NEN.

Cell-Free DNA Analysis within the Challenges of Thyroid Cancer Management.

Thyroid cancer is the most frequent endocrine malignancy with an increasing incidence trend during the past forty years and a concomitant rise in cancer-related mortality. The circulating cell-free DNA (cfDNA) analysis is a patient's friendly and repeatable procedure allowing to obtain surrogate information about the genetics and epigenetics of the tumor. The aim of the present review was to address the suitability of cfDNA testing in different forms of thyroid cancer, and the potential clinical applications, as referred to the clinical weaknesses. Despite being limited by the absence of standardization and by reproducibility and validity issues, cfDNA assessment has great potential for the improvement of thyroid cancer management. cfDNA may support the pre-surgical definition of thyroid nodules by complementing invasive thyroid fine needle aspiration cytology. In addition, it may empower risk stratification and could be used as a biomarker for monitoring the post-surgical disease status, both during active surveillance and in the case of anti-tumor treatment.

Prevalence of RET/PTC rearrangement in benign and malignant thyroid nodules and its clinical application.

Fine-needle aspiration cytology (FNAC) is the primary means to distinguish benign thyroid nodules from malignant ones. About 20% of FNAC yields indeterminate results leading to unnecessary or delayed surgery. Many studies of tissue samples, the majority of which are retrospective advocate testing for RET rearrangements as a diagnostic adjunctive tool in thyroid nodules with indeterminate cytological findings. Because of the uncertain prevalence of RET rearrangements, its utility as a tumor marker is still controversial. The goal of this study was to establish the prevalence and the utility of testing for RET rearrangements in FNAC suspicious of cancer in a clinical setting. In this prospective study, we analysed a large series of thyroid aspirates by RT-PCR only and Southern blot on RT-PCR products for type 1 and 3 RET rearrangements. Results were compared with clinical findings, cytological diagnosis and final histopathology. By the higher sensitive Southern-blot on RT-PCR method, RET rearrangements were present in 36% of papillary thyroid carcinomas (RET/PTC-1, 12%; RET/PTC-3, 20%; both, 4%) and of 13.3% of benign nodules. By means of RT-PCR only, RET rearrangements were disclosed only in 14.3% of PTC and in 3.6% of benign nodules. No significant correlation was found between RET rearrangements and clinicopathological features of patients. These results indicate that molecular testing of thyroid nodules for RET/PTC must take into account of its high prevalence in benign nodules, inducing false positive diagnoses when the highly sensitive assay Southern-blot on RT-PCR is used. Its searching by means of RT-PCR only, has a specificity superior of conventional cytology and can be used to refine inconclusive FNAC.

Significance of RAS Mutations in Thyroid Benign Nodules and Non-Medullary Thyroid Cancer.

Thyroid nodules are detected in up to 60% of people by ultrasound examination. Most of them are benign nodules requiring only follow up, while about 4% are carcinomas and require surgery. Malignant nodules can be diagnosed by the fine-needle aspiration cytology (FNAC), which however yields an indeterminate result in about 30% of the cases. Testing for RAS mutations has been proposed to refine indeterminate cytology. However, the new entity of non-invasive follicular thyroid neoplasm, considered as having a benign evolution and frequently carrying RAS mutations, is expected to lower the specificity of this mutation. The aggressive behavior of thyroid cancer with RAS mutations, initially reported, has been overturned by the recent finding of the cooperative role of TERT mutations. Although some animal models support the carcinogenic role of RAS mutations in the thyroid, evidence that adenomas harboring these mutations evolve in carcinomas is lacking. Their poor specificity and sensitivity make the clinical impact of RAS mutations on the management of thyroid nodules with indeterminate cytology unsatisfactory. Evidence suggests that RAS mutation-positive benign nodules demand a conservative treatment. To have a clinical impact, RAS mutations in thyroid malignancies need not to be considered alone but rather together with other genetic abnormalities in a more general context.

Kinase-inhibitors for iodine-refractory differentiated thyroid cancer: still far from a structured therapeutic algorithm.

The kinase-inhibitors (KIs) sorafenib and lenvatinib demonstrated efficacy in iodine-refractory DTC upon phase III studies. However, evidence allowing a punctual balance of benefits and risks is poor. Furthermore, the lack of a direct comparison hampers to establish the proper sequence of administration. However, some insights may provided: a) indirect comparison between phase III trials showed milder toxicity for sorafenib, which should be preferred in case of cardiovascular comorbidities; b) prospective evidence of efficacy in KIs pre-treated patients is available only for lenvatinib, which should be used as second-line. Promising activity was found for the majority of other tested KIs, but no placebo-controlled trials are available. Emerging, but still early, frontiers include the restoration of iodine-sensitivity and the selective activity on pathogenic mutations. In conclusion, the use of KIs in iodine-refractory DTC is far from a structured therapeutic algorithm.

Growing thyroid nodules with benign histology and RET rearrangement.

Some benign thyroid nodules are stationary in size over time while others grow progressively, indicating that there is a broad individual variability within benign nodules. To date, it is very difficult to predict if a benign thyroid nodule will grow in size and which will be its trend over time. While BRAF(V600E) is a highly specific marker of thyroid cancer, RET rearrangements have been disclosed also in non malignant thyroid lesions and their biological significance is debated. We compared the clinical history of three histologically benign thyroid nodules harboring RET rearrangements with that of 6 benign nodules bearing wild type RET. The nodules negative for RET rearrangements were followed for 10 years by ultrasonographic evaluation, showing a slow, constant enlargement. Three patients with benign nodules diagnosed at FNAC, were followed for 11, 9 and 7 years by annual ultrasonographic evaluation. After several years of latency, the nodules had an unexpected and gradual increase in their dimensions, reaching a large final size. A second FNAC confirmed the previous cytologic diagnosis of benign lesion. Because of the increasing size of the nodules, the patients were advised to surgery. Before undergoing thyroidectomy, we performed molecular diagnostic tests that revealed the absence of BRAF(V600E) and the presence of RET/PTC-1 in one nodule and RET/PTC-3 in the two others. Despite the presence of this oncogene, the samples were histologically classified as benign hyperplastic nodules. These findings lead us to speculate that histologically benign hyperplastic thyroid nodules containing RET rearrangements might represent a subgroup of nodules with a rapid size increase.

Fathoming the link between anthropogenic chemical contamination and thyroid cancer.

Incidence and mortality of thyroid cancer are increasing, thus making mandatory to improve the knowledge of disease etiology. The hypothesis of a role for anthropogenic chemicals is raising wide consideration. A series of occupational studies revealed that job exposures with high risk of chemical contamination were usually more prone to thyroid cancer development. These include shoe manufacture, preserving industry, building activities, pulp/papermaker industry and the wood processing, agricultural activities, and other work categories characterized by contact with chemicals, such as chemists and pharmacists. However, such epidemiological analyses cannot define a causal relationship. Thyroid-disrupting activity has emerged for a broad set of anthropogenic chemicals, with the best evidence being gained for polychlorinated biphenyls, polybrominated diphenyl ethers, dioxins, bisphenols, phthalates, pesticides, and heavy metals. A series of case-control studies, assessing exposure to thyroid-disrupting agents, as measured on biological matrices, have been recently performed providing the following insights: a) positive relationship with thyroid cancer was found for phthalates, bisphenols, the heavy metals cadmium, copper, and lead; b) polybrominated diphenyl ethers exposure showed no relationship with thyroid cancer c) controversial results were reported for polychlorinated biphenyls and pesticides. However, such studies cannot demonstrate the causal link with disease occurrence, as exposure is assessed after tumour development. Studies with different methodological approach are therefore required for defining the role of anthropogenic environmental chemicals in thyroid carcinogenesis.

Human exposure to bisphenol AF and diethylhexylphthalate increases susceptibility to develop differentiated thyroid cancer in patients with thyroid nodules.

Pollutants represent potential threats to the human health, being ubiquitous in the environment and exerting toxicity even at low doses. This study aims at investigating the role of fifteen multiclass organic pollutants, assumed as markers of environmental pollution, most of which exerting endocrine-disrupting activity, in thyroid cancer development. The increasing incidence of differentiated thyroid cancer (DTC) may be related to the rising production and environmental dissemination of pollutants. Fifty-five patients, twenty-seven with diagnosis of benign thyroid nodules and twenty-eight suffering from differentiated thyroid cancer, were enrolled and the concentration levels of seven bisphenols, two phthalates (i.e. di(2-ethylhexyl) phthalate (DEHP) and its main metabolite, mono-(2-ethyl-hexyl) phthalate) (MEHP)), two chlorobenzenes, (1,4-dichlorobenzene and 1,2,4,5-tetrachlorobenzene), and 3 phenol derivatives (2-chlorophenol, 4- nonylphenol, and triclosan) were determined in their serum by using a validated analytical method based on high performance liquid chromatography with ultraviolet tandem fluorescence detection. A significant relationship was found between malignancy and the detection in the serum of both bisphenol AF and DEHP. Indeed, their presence confers a more than fourteen times higher risk of developing differentiated thyroid cancer. Relationship between these two pollutants and the risk of malignancy was dose-independent and not mediated by higher thyroid stimulating hormone levels. Even if a conclusive evidence cannot still be drawn and larger prospective studies are needed, the exposure to low doses of environmental endocrine-disrupting contaminants can be considered consistent with the development of thyroid cancer.

Chromogranin A as circulating marker for diagnosis and management of neuroendocrine neoplasms: more flaws than fame.

Owing to the heterogeneity of neuroendocrine neoplasms (NENs), the availability of reliable circulating markers is critical for improving diagnostics, prognostic stratification, follow-up and definition of treatment strategy. This review is focused on chromogranin A (CgA), a hydrophilic glycoprotein present in large dense core vesicles of neuroendocrine cells. Despite being long identified as the most useful NEN-related circulating marker, clinical application of CgA is controversial. CgA assays still lack standardization, thus hampering not only clinical management but also the comparison between different analyses. In the diagnostic setting, clinical utility of CgA is limited as hampered by (a) the variety of oncological and non-oncological conditions affecting marker levels, which impairs specificity; (b) the fact that 30-50% of NENs show normal CgA, which impairs sensitivity. Regarding the prognostic phase, there is prospective evidence which demonstrates that advanced NENs secreting CgA have poorer outcome, as compared with those showing non-elevated marker levels. Although the identification of cut-offs allowing a proper risk stratification of CgA-secreting patients has not been performed, this represents the most important clinical application of the marker. By contrast, based on prospective studies, the trend of elevated circulating CgA does not represent a valid indicator of morphological evolution and has therefore no utility for the follow-up phase. Ultimately, current knowledge about the role of the marker for the definition of treatment strategy is poor and is limited by the small number of available studies, their prevalent retrospective nature and the absence of control groups of untreated subjects.

Great veins invasion in follicular thyroid cancer: single-centre study assessing prevalence and clinical outcome.

PURPOSE: Great veins invasion is considered as a rare and prognostically unfavourable event in thyroid cancer. However, current knowledge about this issue is mainly based on single case reports. Follicular thyroid cancer (FTC) represents the histotype with the most pronounced angioinvasive feature. This study is aimed at assessing the actual prevalence of great veins invasion in FTC and providing information about prognosis and the proper clinical management of these patients. METHODS: Clinico-pathological and radiological data of patients with thyroid cancer undergoing thyroidectomy in our institution were retrospectively retrieved. Inclusion criteria were as follows: (a) histological diagnosis of FTC; (b) instrumental and histological evidence of great veins invasion and (c) documented follow-up entirely performed at our institution. Pre-surgical assessment of great veins status was performed in all patients by means of Doppler ultrasonography. RESULTS: Out of 637 patients operated from 2003 to 2013, four subjects, all affected with FTC, showed great veins involvement (0.62% of the overall cohort and 7.85% of the FTC group). One of them was lost at follow-up. All three patients with available follow-up were subjected to aggressive surgery obtaining a complete eradication of neck disease. All of them achieved the 5-year survival target (60, 63 and 96 months of survival for patients 1, 2 and 3, respectively). CONCLUSIONS: Great veins invasion may not be uncommon in FTC and preoperative detection and characterisation of such condition may optimise surgical approach and improve survival.