PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications.

The new immunotherapy targeting the programmed cell death 1 (PD-1) receptor and its cognate ligand PD-L1 has renewed hopes of eradicating the most difficult human cancers to treat. Among these, there are the poorly differentiated and anaplastic thyroid cancers, unresponsive to all the therapies currently in use. In the present review we will summarize information regarding the expression of PD-L1 in the different thyroid cancer histotypes, its correlation with clinicopathological features, and its potential prognostic value. Then, we will evaluate the available data indicating the PD-1/PD-L1 axis as a promising target for thyroid cancer therapy.

Cervical lymph node metastases from thyroid cancer: does thyroglobulin and calcitonin measurement in fine needle aspirates improve the diagnostic value of cytology?

BACKGROUND: Measurement of thyroglobulin (Tg) protein in the washout of the needle used for fine needle aspiration biopsy cytology (FNAB-C) has been shown to increase the sensitivity of FNAB-C in identifying cervical lymph node (CLN) metastasis from well-differentiated thyroid cancer (TC). In this study, we evaluated whether routine measurement of Tg protein (FNAB-Tgp), Tg mRNA (FNAB-Tgm) and calcitonin (CT) mRNA (FNAB-CTm) in the FNAB washout of CLN increases the accuracy of FNAB-C in the diagnosis of suspicious metastatic CLN. METHODS: In this prospective study 35 CLN from 28 patients were examined. Histology showed metastatic papillary TC (PTC) in 26 CLN, metastatic medullary TC (MTC) in 3 CLN, metastatic anaplastic TC (ATC) in 3 CLN and 3 metastatic CLN from extra-thyroidal cancers. RESULTS: The overall accuracy of FNAB-C was 84.4%, reaching 95.7% when the analysis was restricted to PTC. Both FNAB-Tgp and FNAB-Tgm compared favorably with FNAB-C and shown diagnostic performances not statistically different from that of FNAB-C. However, FNAB-Tgp and FNAB-Tgm/FNAB-CTm were found useful in cases in which cytology results were inadequate or provided diagnosis inconsistent with patient's clinical parameters. CONCLUSIONS: We demonstrated that FNAB-C, Tg/CT mRNA and Tg protein determination in the fine-needle washout showed similar accuracy in the diagnosis of metastatic CLN from TC. The results of this study suggest that samples for Tg protein and Tg/CT mRNA measurements from CLN suspicious for metastatic TC should be collected, but their measurements should be restricted to cases in which FNAB-C provides uninformative or inconsistent diagnosis with respect to patient's clinical parameters.

Insights on the Association between Thyroid Diseases and Colorectal Cancer.

Benign and malignant thyroid diseases (TDs) have been associated with the occurrence of extrathyroidal malignancies (EMs), including colorectal cancers (CRCs). Such associations have generated a major interest, as their characterization may provide useful clues regarding diseases' etiology and/or progression, with the possible identification of shared congenital and environmental elements. On the other hand, elucidation of the underlying molecular mechanism(s) could lead to an improved and tailored clinical management of these patients and stimulate an increased surveillance of TD patients at higher threat of developing EMs. Here, we will examine the epidemiological, clinical, and molecular findings connecting TD and CRC, with the aim to identify possible molecular mechanism(s) responsible for such diseases' relationship.

Iodized Salt May Not Be Sufficient to Guarantee an Adequate Iodine Intake in Pregnant Women.

Adequate iodine intake is of crucial importance in pregnancy to meet the thyroid hormone needs of both mother and fetus. In the present study, undertaken as a part of the surveillance actions following the introduction in Italy of a national salt iodination program in 2005, the iodine intake was investigated in 123 pregnant women and 49 control women living in the same area of central Italy. All the participants were screened for urinary iodine concentration (UIC), serum level of thyrotropin, free-thyroxine, free-triiodothyronine, and thyroid volume. Moreover, they were provided with a questionnaire on the use of iodine-containing salt or supplements. Control women had a median UIC of 102 µg/L, consistent with an iodine sufficiency, while in pregnant women the median UIC value was 108 µg/L, lower than the endorsed UIC of 150 µg/L. In addition, pregnant women showed a significantly increased median thyroid volume compared to controls. Interestingly, the median UIC did not differ between pregnant women not using iodine-containing salt or supplements and those regularly consuming iodized salt alone, while pregnant women with a daily intake of iodine-containing supplements had an adequate median UIC (168 µg/L). In conclusion, the data reported here showed that pregnant women and their fetuses are still exposed to the detrimental effects of iodine deficiency and that the consumption of iodine-containing supplements should be recommended in pregnancy.

Incidence of Thyroid Cancer in Italian Contaminated Sites.

Some human literature suggests a possible role of endocrine disruptors (EDs) exposure in thyroid cancer (TC) development. We investigated TC incidence in selected Italian National Priority Contaminated Sites (NPCS) with documented presence of EDs considered thyroid carcinogens. Adjusted Standardized Incidence Ratios (SIRs), with their 90% confidence intervals, were computed by gender, and age-specific groups (aged 15-39 years, and 40 years or over) for each NPCS in the period 2006 to 2013. In the age group of 15-39 years, a significant excess of TC risk was found in two NPCSs in males; non-significant excess risks were observed in four NPCSs in males, and in five in females. In the age group of 40 years and over, significant excess risks were found in six NPCSs in males and in seven NPCSs in females; non-significant excess risks were identified in two NPCSs in males and females. The findings of several excesses in incidence, mainly observed in adults aged 40 years or over, are suggestive of a possible adverse effect associated with residence in NPCSs, even if a role of other factors cannot be excluded, due to the adoption of an ecological study design. Future analytical studies are needed to clarify if EDs are a TC risk factor for individuals living in NPCSs.

Evaluation of Clinicopathological and Molecular Parameters on Disease Recurrence of Papillary Thyroid Cancer Patient: A Retrospective Observational Study.

The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan-Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

Malignant Insulinoma with Multiple Liver Metastases and Hypercalcitoninemia in a Patient with Type 2 Diabetes Mellitus Presenting as Recurrent Episodes of Diaphoresis due to Severe Hypoglycemia.

Insulinoma is an insulin-producing pancreatic neuroendocrine tumor that can be malignant in about 10% of cases. Locoregional invasion, lymph node metastases, or remote metastases are the main criteria of malignant insulinoma. Its incidence in patients with pre-existing diabetes mellitus (DM) is exceptionally rare. In this report, we describe a 66-year-old man with long-standing type 2 DM who presented with recurrent episodes of diaphoresis due to severe hypoglycemia despite the withdrawal of insulin therapy, hypercalcitoninemia, and biochemical and radiological findings suggestive of metastatic malignant insulinoma. Unfortunately, after few days of diazoxide treatment, edema, hypotension, oliguria, and water retention were observed, patient's clinical status deteriorated rapidly, and he died in our department from acute renal failure.

Iodine Status in Schoolchildren and Pregnant Women of Lazio, a Central Region of Italy.

The inhabitants of Lazio, similarly to those of other Italian regions, have been historically exposed to the detrimental effects of an inadequate intake of iodine. The latter is a micronutrient essential for the biosynthesis of thyroid hormones (TH). Iodine deficiency is responsible for a number of adverse effects on human health known as iodine deficiency disorders (IDD), the most common of which worldwide are goiter and hypothyroidism. In order to reduce IDD, a national salt iodination program was started in Italy in 2005. In this article we reviewed the available data regarding iodine intake in the Lazio population before and after the introduction of the national salt iodination program, in order to evaluate its efficacy and the eventual problem(s) limiting its success. On the whole, the information acquired indicates that, following the introduction of the program, the dietary iodine intake in the Lazio population is improved. There is, however, still much work ahead to ameliorate the iodine prophylaxis in this region. In fact, although a generally adequate iodine intake in school-age children has been observed, there are still areas where a mild iodine insufficiency is present. Moreover, two independent epidemiological surveys on pregnant women evidenced a low urinary iodine concentration with respect to the reference range conceived by the World Health Organization. These findings demonstrate the need for greater attention to the iodine prophylaxis by health care providers (i.e., obstetricians, gynecologists, pediatricians, etc.), and the implementation of effective advertising campaigns aimed at increasing the knowledge and awareness of the favorable effects of iodine supplementation on population health.

Combined Hepatocholangiocarcinoma Associated with Humoral Hypercalcemia of Malignancy and Chronic Inflammatory Demyelinating Polyneuropathy.

Paraneoplastic syndromes are often a diagnostic challenge to doctors and may have a heterogeneous presentation, including humoral hypercalcemia of malignancy (HHM), most commonly caused by squamous cell cancer and renal, ovarian, endometrial, and breast cancer. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been described in patients affected by several types of cancer, especially hematologic malignancies, and a possible paraneoplastic pathogenesis of this neurological disease has been suggested. This report describes a 56-year-old man with a history of CIDP diagnosed 3 months earlier and persistently elevated aminotransferases for 18 months who was admitted to our internal medicine unit with abdominal pain, fatigue, and severe hypercalcemia with low serum intact parathyroid hormone. Parathyroid hormone-related protein (PTH-rP) was markedly high. Liver imaging showed a large hepatic mass in the right lobe, and percutaneous ultrasound-guided biopsy revealed histopathological findings consistent with a combined hepatocholangiocarcinoma (CHCC). We supposed that both HHM and CIDP could represent a paraneoplastic manifestation of CHCC.

Iodine deficiency in pregnancy: Still a health issue for the women of Cassino city, Italy.

OBJECTIVE: The World Health Organization, the United Nations Children's Fund, and the International Council for the Control of Iodine Deficiency Disorders recommend a median urinary iodine concentration (UIC) in pregnant women between 150 µg/L and 249 µg/L. In the present study, we evaluated whether in the urban area of Cassino (central Italy), after a national salt iodination program (30 mg/kg) was introduced in 2005, the increased demand of iodine during pregnancy was satisfied. METHODS: Between January 2016 and April 2017, 99 pregnant women were enrolled to evaluate UIC in spot urine samples, serum level of thyrotropin, free thyroxine, antithyroglobulin and antithyroperoxidase autoantibodies, and thyroid volume by ultrasonography. Eighty clinically healthy non-pregnant women were evaluated as controls. RESULTS: The median UIC was of 97.7 µg/L and 110.3 µg/L, respectively, in control and pregnant women. A significant increase (P < 0.001) of median thyroid volume was found in pregnant women, relative to control women, being, respectively, 10.4 mL (range 3.68-19.49 mL) and 7.16 mL (range 2.57-14.00 mL). A positive correlation was found between thyroid volume and anthropometric parameters, and an inverse correlation was identified between free thyroxine serum levels and anthropometric parameters. CONCLUSIONS: This observational study found that the majority of pregnant women and their fetuses appear not to be protected from the detrimental consequences of iodine deficiency. Therefore, the identification of new strategies to increase the knowledge and awareness of the general population regarding the beneficial effects of iodine supplementation during pregnancy is highly required.

Vitiligo and Autoimmune Thyroid Disorders.

Vitiligo represents the most common cause of acquired skin, hair, and oral depigmentation, affecting 0.5-1% of the population worldwide. It is clinically characterized by the appearance of disfiguring circumscribed skin macules following melanocyte destruction by autoreactive cytotoxic T lymphocytes. Patients affected by vitiligo usually show a poorer quality of life and are more likely to suffer from depressive symptoms, particularly evident in dark-skinned individuals. Although vitiligo is a non-fatal disease, exposure of affected skin to UV light increases the chance of skin irritation and predisposes to skin cancer. In addition, vitiligo has been associated with other rare systemic disorders due to the presence of melanocytes in other body districts, such as in eyes, auditory, nervous, and cardiac tissues, where melanocytes are thought to have roles different from that played in the skin. Several pathogenetic models have been proposed to explain vitiligo onset and progression, but clinical and experimental findings point mainly to the autoimmune hypothesis as the most qualified one. In this context, it is of relevance the strong association of vitiligo with other autoimmune diseases, in particular with autoimmune thyroid disorders, such as Hashimoto thyroiditis and Graves' disease. In this review, after a brief overview of vitiligo and its pathogenesis, we will describe the clinical association between vitiligo and autoimmune thyroid disorders and discuss the possible underlying molecular mechanism(s).

Thyroid Imaging Reporting and Data System Score Combined with the New Italian Classification for Thyroid Cytology Improves the Clinical Management of Indeterminate Nodules.

The new Italian cytological classification (2014) of thyroid nodules replaced the TIR3 category of the old classification (2007) with two subclasses, TIR3A and TIR3B, with the aim of reducing the rate of surgery for benign diseases. Moreover, thyroid imaging reporting and data system (TI-RADS) score appears to ameliorate the stratification of the malignancy risk. We evaluated whether the new Italian classification has improved diagnostic accuracy and whether its association with TI-RADS score could improve malignancy prediction. We retrospectively analyzed 70 nodules from 70 patients classified as TIR3 according to the old Italian classification who underwent surgery for histological diagnosis. Of these, 51 were available for cytological revision according to the new Italian cytological classification. Risk of malignancy was determined for TIR3A and TIR3B, TI-RADS score, and their combination. A different rate of malignancy (p = 0.0286) between TIR3A (13.04%) and TIR3B (44.44%) was observed. Also TI-RADS score is significantly (p = 0.003) associated with malignancy. By combining cytology and TI-RADS score, patients could be divided into three groups with low (8.3%), intermediate (21.4%), and high (80%) risk of malignancy. In conclusion, the new Italian cytological classification has an improved diagnostic accuracy. Interestingly, the combination of cytology and TI-RADS score offers a better stratification of the malignancy risk.

Deregulated expression of VHL mRNA variants in papillary thyroid cancer.

Recent findings demonstrated that a subset of papillary thyroid cancers (PTCs) is characterized by reduced expression of the von Hippel-Lindau (VHL) tumor suppressor gene, and that lowest levels associated with more aggressive PTCs. In the present study, the levels of the two VHL mRNA splicing variants, VHL-213 (V1) and VHL-172 (V2), were measured in a series of 96 PTC and corresponding normal matched tissues by means of quantitative RT-PCR. Variations in the mRNA levels were correlated with patients' clinicopathological parameters and disease-free interval (DFI). The analysis of VHL mRNA in tumor tissues, compared to normal matched tissues, revealed that its expression was either up- or down-regulated in the majority of PTC. In particular, V1 and V2 mRNA levels were altered, respectively, in 78 (81.3%) and 65 (67.7%) out of the 96 PTCs analyzed. A significant positive correlation between the two mRNA variants was observed (p < 0.001). Univariate analysis documented the lack of association between each variant and clinicopathological parameters such as age, tumor size, histology, TNM stage, lymph node metastases, and BRAF mutational status. However, a strong correlation was found between altered V1 or V2 mRNA levels and DFI. Multivariate regression analysis indicated higher V1 mRNA values, along with lymph node metastases at diagnosis, as independent prognostic factors predicting DFI. In conclusion, the data reported demonstrate that VHL gene expression is deregulated in the majority of PTC tissues. Of particular interest is the apparent protective role exerted by VHL transcripts against PTC recurrences.

Expression and prognostic value of the cell polarity PAR complex members in thyroid cancer.

Establishment and maintenance of the apical-basal cell polarity, required for proper replication, migration, specialized functions and tissue morphogenesis, relies on three evolutionary conserved complexes: PAR, CRUMBS and SCRIBBLE. Loss of cell polarity/cohesiveness (LOP/C) is implicated in cancer progression, and members of the polarity complex have been described as either oncogenes or oncosuppressors. However, no information on their role in thyroid cancer (TC) progression is available. In the present study, we evaluated the gene expression of the PAR complex members aPKCι, PARD3α/ß and PARD6α/ß/γ in 95 papillary TC (PTC), compared to their normal matched tissues and in 12 anaplastic TC (ATC). The mRNA and protein levels of investigated genes were altered in the majority of PTC and ATC tissues. In PTC, univariate analysis showed that reduced expression of aPKCι, PARD3ß and PARD6γ mRNAs is associated with increased tumor size, and the reduced expression of PARD3ß mRNA is associated also with recurrences. Multivariate analysis demonstrated that the presence of lymph node metastasis at diagnosis and the reduced expression of PARD3ß are independent risk factors for recurrences, with hazard ratio, respectively, of 8.21 (p=0.006) and 3.04 (p=0.029). The latter result was confirmed by the Kaplan-Meier analysis, which evidenced the association between decreased PARD3ß mRNA levels and shorter disease-free interval. In conclusion, we demonstrated that the expression of PAR complex components is deregulated in the majority of PTC and there is a general trend towards their reduction in ATC tissues. Moreover, a prognostic value for the PARD3ß gene in PTCs is suggested.

Consumption of iodized salt may not represent a reliable indicator of iodine adequacy: Evidence from a cross-sectional study on schoolchildren living in an urban area of central Italy.

OBJECTIVE: It has been established that iodine prophylaxis prevents endemic goiter. In this study we reported the amount of iodized salt sold by the retailers of Cassino, a city of central Italy. The aim of the study was to evaluate the effects of an iodine prophylaxis program started in 2005 on urinary iodine concentration (UIC) and thyroid volume (TV), and their correlation with anthropometric parameters in a population of schoolchildren. METHODS: The study included 234 schoolchildren (119 girls and 115 boys) ages 13 to 14 y. Each student provided a morning urine sample for UIC determination, and TV was evaluated by ultrasonography. Body weight and height also were measured. Each participant completed a questionnaire reporting the presence of thyroid disease and the consumption of iodized salt and iodine-rich food. RESULTS: The percentage of iodized salt sold by local markets was 42.4%. Median UIC in schoolchildren was 133.9 µg/L (range 33.2-819.5 µg/L), with 71 children having mild (range 50.1-99.9 µg/L) and 10 moderate (range 33.2-48.8 µg/L) iodine deficiency. Eleven children showed excessive iodine intake (range 300.4-819.5 µg/L). Median UIC was higher in children using iodized salt or consuming milk. Goiter prevalence was 3.8%. A positive correlation between TV and body weight, height, and surface was observed. CONCLUSIONS: The data reported may suggest the presence of an adequate iodine intake in the population of Cassino despite the low percentage of iodized salt sold by local retailers. This indicates that silent iodine prophylaxis through the consumption of iodine-rich or iodine-enriched food is of importance in the prevention of iodine deficiency disorders.