Epithelial Thyroid Cancer Research Articles

LDL, HDL and endocrine-related cancer: From pathogenic mechanisms to therapies.

Cholesterol is essential for a variety of functions in endocrine-related cells, including hormone and steroid production. We have reviewed the progress to date in research on the role of the main cholesterol-containing lipoproteins; low-density lipoprotein (LDL) and high-density lipoprotein (HDL), and their impact on intracellular cholesterol homeostasis and carcinogenic pathways in endocrine-related cancers. Neither LDL-cholesterol (LDL-C) nor HDL-cholesterol (HDL-C) was consistently associated with endocrine-related cancer risk. However, preclinical studies showed that LDL receptor plays a critical role in endocrine-related tumor cells, mainly by enhancing circulating LDL-C uptake and modulating tumorigenic signaling pathways. Although scavenger receptor type BI-mediated uptake of HDL could enhance cell proliferation in breast, prostate, and ovarian cancer, these effects may be counteracted by the antioxidant and anti-inflammatory properties of HDL. Moreover, 27-hydroxycholesterol a metabolite of cholesterol promotes tumorigenic processes in breast and epithelial thyroid cancer. Furthermore, statins have been reported to reduce the incidence of breast, prostate, pancreatic, and ovarian cancer in large clinical trials, in part because of their ability to lower cholesterol synthesis. Overall, cholesterol homeostasis deregulation in endocrine-related cancers offers new therapeutic opportunities, but more mechanistic studies are needed to translate the preclinical findings into clinical therapies.

MON-LB77 Inhibitors of XIAP as Novel Therapeutic Agents in Thyroid Cancer

Treatment options for radioiodine-refractory epithelial thyroid cancer (ETC) are limited to tyrosine kinase inhibitors (TKIs), which are associated with significant adverse effects and are not curative. The inhibitors of apoptosis (IAP) family have oncogenic properties and overexpression of X-linked IAP (XIAP) in papillary thyroid carcinoma (PTC) is associated with a poor prognosis. Our group has previously reported a synergistic interaction between SMAC mimetics (SM) (IAP antagonists with XIAP and cIAP1 specificity), and PPARgamma agonists in granulosa cell tumors (1). Such an approach has not been explored in ETC.We hypothesize that SM may be efficacious alone or in combination with a secondary agent to inhibit proliferation, induce cell death and/or promote differentiation to resensitize cells to radioiodine.Four ETC-derived cell lines (K1, Nthy-ori 3-1, TPC-1 and SW-1736) were examined for cIAP1, cIAP2 and XIAP expression by RT-PCR. The K-1 and TPC-1 cell lines (PTC origin, BRAFV600E and PI3KCA mutation positive) were chosen to investigate the effects of an SM in combination with either a PPARgamma agonist (rosiglitazone) or a broad-spectrum TKI (sorafenib). Cell proliferation was examined using xCELLigence Real-Time Cell Analysis. Viability was assessed using total cell counts at 24 and 48 hours.In the four cell lines, we found abundant cIAP1 and XIAP expression and low cIAP2 expression. When an SM was used in combination with either rosiglitazone or sorafenib, we observed significant impairment of cell proliferation and viability with a clear morphological response. These effects appear SM-dependent, as SM treatment alone also showed significant effects on proliferation. However, these effects were enhanced when combined with sorafenib, which was ineffective alone. Markers of differentiation are currently being examined.Our findings suggest a novel role for SM in treating or redifferentiating radioiodine-refractory ETC. Clinically, this may involve lower doses of individual agents than when used alone, thereby reducing adverse effects.

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.

CTLA-4 and PD-1 Ligand Gene Expression in Epithelial Thyroid Cancers.

The dysregulation of PD-1 ligands (PD-L1 and PD-L2) and CTLA-4 ligands (CD80 and CD86) represents a tumor strategy to escape the immune surveillance. Here, the expression of PD-L1, PD-L2, CD80, and CD86 was evaluated at the mRNA level in 94 patients affected by papillary thyroid carcinoma (PTC) and 11 patients affected by anaplastic thyroid carcinoma (ATC). Variations in the mRNAs in PTC patients were then correlated with clinicopathological features. The expression of all genes was deregulated in PTC and ATC tissues compared to normal tissues. In particular, the downregulation of CD80 was observed above all in ATC. In addition, the increased expression of CD80 associated with longer disease-free survival in PTC. Higher expression of PD-L1 associated with the classical histological variant and with the presence of BRAFV600E mutation in PTC. The increased PD-L2 expression correlated with BRAFV600E mutation and lymph node metastasis, while its lower expression correlated with the follicular PTC variant. The latter was also associated with the CD80 downregulation, which was also related to the absence of lymph node metastasis. In conclusion, we documented the overall dysregulation of PD-1 and CTLA-4 ligands in PTC and ATC tissues and a possible prognostic value for CD80 gene expression in PTC.

Encapsulated Follicular Variant of Thyroid Papillary Carcinoma - Case Report and Differential Diagnosis Discussion

Abstract Papillary carcinoma is the most common type of epithelial thyroid cancer in women, especially in the reproductive period, accounting for about 75-80% of well-differentiated cancers at this level. One of its variants, follicular encapsulated thyroid carcinoma, is a well-differentiated malignant tumor with good prognosis which, despite the presence of vascular and capsular invasion, rarely causes metastasis, if fully resected. We present the case of a young patient who presented with dysphagia and a painless cystic nodular lesion of the thyroid, and underwent thyroidectomy. The histopathological diagnosis of the lesion was a challenge, being based on the correlation of clear criteria, given the existence of numerous lesions with follicular pattern in the thyroid.

Nodular thyroid disease in the elderly: novel molecular approaches for the diagnosis of malignancy.

Epithelial thyroid cancers (TC) comprise two differentiated histotypes (DTC), the papillary (PTC) and the follicular (FTC) thyroid carcinomas which, following dedifferentiation, are assumed to give rise to the poorly differentiated thyroid carcinomas and the rare, but highly aggressive and invariably fatal, anaplastic thyroid carcinomas. Although thyroid cancer mortality has not been changed, its annual incidence has increased over the last two decades, mainly because of the improved ability to diagnose malignant transformation in small non-palpable thyroid nodules. Despite DTC patients have a favorable prognosis, aggressive disease is more frequently observed in the elderly showing a higher disease-specific mortality. Of relevance is the high prevalence of nodular thyroid disease in aged patients being higher than 90%, in women older than 60year, and 60% in men older than 80year. This implies a careful evaluation of thyroid nodules in this group of patients in order to exclude malignancy. In fact, despite the tremendous progress in the comprehension of the underlying molecular mechanisms deregulated in DTC progression, several aspects of their clinical management remain to be solved and novel diagnostic strategies are sorely needed. Here, we will attempt to review new molecular approaches, which are currently being exploited in order to ameliorate the diagnosis of thyroid nodules.

Selective Antitumoral Effect of Sorafenib Loaded PLGA Nanoparticles Conjugated with Cetuximab on Undifferentiated/Anaplastic Thyroid Carcinoma Cells

Drug targeting represents a challenging approach with promising potential to circumvent some problems associated with many toxic effects of antineoplastics drugs. The objective of the present study was to develop PLGA nanoparticles surface modified with cetuximab to deliver in a targeted fashion sorafenib into undifferentiated/anaplastic thyroid carcinoma cell line as an efficient in vitro model Sorafenib loaded nanoparticles were obtained by the single emulsion evaporation method and characterized in terms of size (252 nm), charge (-14.6 mV), morphology (spherical), drug entrapment efficiency (58%) and in vitro drug release. Resulted nanoparticles were surface conjugated with monoclonal antibody cetuximab by EDC/Sulfo-NHS cross linking chemistry, without affecting significantly to their physicochemical properties. 51% of the cetuximab was incorporated into the surface of PLGA nanoparticles. Cellular uptake studies were performed with fluorescent (6-coumarin) PLGA nanoparticles and cetuximab conjugated fluorescent PLGA nanoparticles in both thyroid anaplastic (CAL-62) and normal thyroid cells (Nthy-ori 3-1). Confocal microscopy assays revealed that the capture of immunonanoparticles over the time showed a different pattern depending on the cell and the nanoparticles studies. In vitro antiproliferation assay based on MTT showed that sorafenib incorporated nanoparticles had a more cytotoxic effect on normal thyroid Nthy-ori 3-1 cells than on anaplastic thyroid CAL-62 cells. However, cetuximab conjugated nanoparticles reverted the cytotoxicity profile, showing a lower cytotoxic effect on normal thyroid Nthy-ori 3-1 cells when compared with anaplastic thyroid CAL-62 cells. These data suggest that sorafenib-PLGA nanoparticles surface modified with cetuximab represent a new and promising targeting approach for the treatment of epithelial thyroid cancer.

Emerging molecular markers for the prognosis of differentiated thyroid cancer patients

Epithelial thyroid cancers are represented by the differentiated papillary and follicular thyroid carcinomas which, following dedifferentiation, are thought to give rise to the highly aggressive and incurable anaplastic thyroid carcinomas. Although derived from the same cell type, the different thyroid tumors show specific histological features, biological behavior and degree of differentiation as a consequence of different genetic alterations. Over the last few years, our knowledge regarding the molecular alterations underlying thyroid cell malignant transformation and cancer progression has considerably increased; however, the prognosis of differentiated thyroid cancer patients still relies on high-risk clinic-pathological variables. In particular, the actual staging systems provides only a rough prediction for cancer mortality and risk of recurrences, including in each risk group patients with highly different tumor-specific progression, disease-free interval and survival time. In order to improve DTC patient's risk stratification, both the European and the American Thyroid Associations proposed practical guidelines to integrate the actual staging systems with additional clinical features such as the tumor histological variant, the results of post-ablative whole body scan and the serum thyroglobulin levels. Despite that, patients within the same risk group still show a very heterogeneous behavior in terms of disease-free interval. As a consequence, the identification of new prognostic molecular biomarkers able to testify tumor aggressiveness is highly required. Here we'll review recently characterized new molecular markers potentially able to ameliorate the prognosis in DTC patients.

Germline Alterations in RASAL1 in Cowden Syndrome Patients Presenting with Follicular Thyroid Cancer and in Individuals with Apparently Sporadic Epithelial Thyroid Cancer

RASAL1 has recently been identified as an important tumor suppressor for sporadic thyroid tumorigenesis, particularly for follicular thyroid cancer (FTC) and anaplastic thyroid cancer. Thyroid cancer is an important component of Cowden syndrome (CS). Patients with germline PTEN mutations have an overrepresentation of FTC over other histological subtypes. To determine the prevalence of germline RASAL1 mutations in PTEN mutation-positive and wild type CS patients. We reviewed our prospective database of more than 3000 CS/CS-like patients and retrospectively identified a subset of patients who presented with thyroid cancer for RASAL1 mutation analysis. We reviewed data from The Cancer Genome Atlas (TCGA) sporadic papillary thyroid cancer (PTC) database with germline data for RASAL1 mutations to determine the prevalence of germline RASAL1 mutations in CS-related thyroid cancer patients. We scanned 155 CS/CS-like patients with thyroid cancer for germline RASAL1 mutations. Of the 155 patients, 39 had known germline pathogenic PTEN mutations (PTEN(mut+)) and 116 were PTEN mutation negative (PTEN(WT)). Among these 155 patients, we identified RASAL1 germline alterations suspected as being deleterious in two patients. Both were patients with PTEN(WT) who had FTC (2/48, 4.1%). This was in contrast to patients with PTEN(mut+) who had thyroid cancer (0/39). Of 339 sporadic patients with PTC from the TCGA study, 62 (18%) had germline RASAL1 variants predicted to be deleterious. TCGA patients with follicular-variant PTC were statistically overrepresented (21/62, 34%) among patients with deleterious RASAL1 variants compared with those without (57/277, 21%). Germline RASAL1 alterations are uncommon in patients with CS but may not be infrequent in patients with apparently sporadic follicular-variant PTC.

Follicular Thyroid Cancers Demonstrate Dual Activation of PKA and mTOR as Modeled by Thyroid-Specific Deletion of Prkar1a and Pten in Mice

Thyroid cancer is the most common form of endocrine cancer, and it is a disease whose incidence is rapidly rising. Well-differentiated epithelial thyroid cancer can be divided into papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Although FTC is less common, patients with this condition have more frequent metastasis and a poorer prognosis than those with PTC. The objective of this study was to characterize the molecular mechanisms contributing to the development and metastasis of FTC. We developed and characterized mice carrying thyroid-specific double knockout of the Prkar1a and Pten tumor suppressor genes and compared signaling alterations observed in the mouse FTC to the corresponding human tumors. The study was conducted at an academic research laboratory. Human samples were obtained from academic hospitals. Deidentified, formalin-fixed, paraffin-embedded (FFPE) samples were analyzed from 10 control thyroids, 30 PTC cases, five follicular variant PTC cases, and 10 FTC cases. There were no interventions. Mouse and patient samples were analyzed for expression of activated cAMP response element binding protein, AKT, ERK, and mammalian target of rapamycin (mTOR). Murine FTCs were analyzed for differential gene expression to identify genes associated with metastatic progression. Double Prkar1a-Pten thyroid knockout mice develop FTC and recapitulate the histology and metastatic phenotype of the human disease. Analysis of signaling pathways in FTC showed that both human and mouse tumors exhibited strong activation of protein kinase A and mTOR. The development of metastatic disease was associated with the overexpression of genes required for cell movement. These data imply that the protein kinase A and mTOR signaling cascades are important for the development of follicular thyroid carcinogenesis and may suggest new targets for therapeutic intervention. Mouse models paralleling the development of the stages of human FTC should provide important new tools for understanding the mechanisms of FTC development and progression and for evaluating new therapeutics.

Utility of PTEN Protein Dosage in Predicting for Underlying GermlinePTENMutations among Patients Presenting with Thyroid Cancer and Cowden-Like Phenotypes

Thyroid cancer is a major component of Cowden syndrome (CS). CS patients with an underlying PTEN mutation (PTEN(mut+)) have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, less than 1% of sporadic epithelial thyroid cancer patients carry a germline PTEN mutation. Cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. Our objective was to analyze the utility of patient blood phosphate and tensin homolog deleted on chromosome 10 (PTEN) protein levels in predicting germline PTEN mutations. We conducted a 5-yr, multicenter prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared blood PTEN protein levels between PTEN(mut+) patients and those with variants of unknown significance or wild-type PTEN (PTEN(wt/vus)). We assessed the utility of PTEN protein levels in predicting germline PTEN mutations. Of 2792 CS/CS-like patients, 721 patients had thyroid cancer; 582 of them (81%) had blood PTEN protein analyzed. PTEN germline pathogenic mutations were present in 27 of 582 patients (4.6%). Ninety-six percent (26 of 27) of PTEN(mut+) patients had blood PTEN protein levels in the lowest quartile as compared with 25% (139 of 555) of PTEN(wt/vus) patients (P < 0.001). Low blood PTEN levels predicted for PTEN(mut+) cases with a 99.76% negative predictive value (95% confidence interval = 98.67-99.96) and a positive test likelihood ratio of 3.84 (95% confidence interval = 3.27-4.52). Our study shows that low blood PTEN protein expression could serve as a screening molecular correlate to predict for germline PTEN mutation in CS and CS-like presentations of thyroid cancer.

Thyroid cancer genetics: how close are we to personalizing clinical management?

Author for correspondence: Genomic Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, NE-50, Cleveland, OH 44195, USA and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Thyroid Cancer Center, Endocrinology & Metabolism Institute, Cleveland Clinic, Cleveland, OH 44195, USA and Stanley Shalom Zielony Institute of Nursing Excellence, Cleveland Clinic, Cleveland, OH 44195, USA and Department of Genetics, & CASE Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA Tel.: +1 216 444 3440 Fax: +1 216 636 0655 engc@ccf.org Thyroid cancer genetics: how close are we to personalizing clinical management?

Use of PTEN protein dosage to predict for underlying germ-line PTEN mutations among patients presenting with thyroid cancer and Cowden-like phenotypes.

1508 Background: Thyroid cancer is a major component of Cowden Syndrome (CS), a heritable syndrome characterized also by breast, uterine and kidney cancers. CS patients with an underlying germline PTEN mutation have a 70-fold increased risk of developing epithelial thyroid cancer. In contrast, &lt;1% of sporadic epithelial thyroid cancer harbor a germline PTEN mutation. Thus, cost-efficient markers capable of shortlisting thyroid cancers for CS genetic testing would be clinically useful. Here, we analyzed the relationship of patient PTEN protein levels in predicting the presence of germline PTEN mutations. Methods: We conducted a 5-year, multi-center prospective study of 2792 CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Analysis of PTEN and downstream proteins by immunoblotting was performed on total protein lysates from patient-derived lymphoblast lines. We compared PTEN protein expression levels between patients with pathogenic PTEN mutations (PTENmut+), and those with variants of unknown significance (VUS) or wildtype PTEN. PTEN immunohistochemistry (IHC) was performed on available thyroid samples. Results: Of 2792 CS/CS-like patients, 722 had thyroid cancer. PTEN germline pathogenic mutations were present in 36/722 (5%) patients. PTENmut+ cases presented at an earlier age (35 vs 42 years; p=0.02). PTEN frameshift and truncation mutations accounted for 55% of mutations. 95% (19/20) of PTENmut+ patients had blood-PTEN protein levels in the lowest quartile as compared to 27% (90/330) of PTEN wildtype/PTEN VUS patients (p&lt;0.001). Low blood-PTEN levels predicted for PTENmut+ cases with a 99.6 % NPV (95%CI 97.7- 99.9) and a positive test likelihood ratio of 3.5 (95%CI 2.8-4.3). Affected thyroid tissues (n=22) from PTENmut+ cases showed loss of PTEN protein by IHC, correlating with patient blood PTEN levels (r2=0.30, p=0.016). Conclusions: Our study shows that PTEN protein dosage could serve as a molecular correlate predicting for germline PTEN mutation in CS and CS-like presentations of thyroid cancer. The clinical utility of PTEN IHC in identifying thyroid cancer patients for germline PTEN testing should be further explored.

Off-Label Use of Sunitinib in Patients with Advanced, Epithelial Thyroid Cancer: A Retrospective Analysis

Tyrosine kinase receptors play an important role in tumor angiogenesis and, their implication in epithelial thyroid tumor growth has been highlighted. Sunitinib is a novel tyrosine kinase inhibitor, approved in 2006 by Food and Drug Administration for the treatment of advanced renal cell and gastrointestinal stromal tumors. Preliminary promising results have been also obtained in patients with RAI-resistant thyroid neoplasia. In the current study, our experience on 9 patients with advanced thyroid epithelial cancer is analyzed and discussed in relation to the new patents in this field. According to RECIST criteria, partial response was obtained in 5/9 (55.5%) patients at 3 months and in 6/9 (66.6%) at 6 months. Median treatment follow-up was 13.0 months and median overall survival and progression-free survival were 20 [95% confidence interval (CI) 9.3 - 30.6] and 21 months (95% CI 6.9 - 35.1), respectively. One case of severe thoracic hemorrhage was observed, the most common adverse events being represented by fatigue, (44.4% ), skin rash (33.3% ), headache (33.3% ), and one case each of hypertension, macrocytosis and acute pneumonia. These results confirm sunitinib as a potential useful tool for the treatment of advanced thyroid cancers and may open the way for new patents of molecules with more specific target selectivity.

Mouse Models of Follicular and Papillary Thyroid Cancer Progression

A significant number of well-differentiated thyroid cancers progress or recur, becoming resistant to current therapeutic options. Mouse models recapitulating the genetic and histological features of advanced thyroid cancer have been an invaluable tool to dissect the mechanisms involved in the progression from indolent, well differentiated tumors to aggressive, poorly differentiated carcinomas, and to identify novel therapeutic targets. In this review, we focus on the lessons learned from models of epithelial cell-derived thyroid cancer showing progression from hyperplastic lesions to locally invasive and metastatic carcinomas.

Incidence and Clinical Characteristics of Thyroid Cancer in Prospective Series of Individuals with Cowden and Cowden-Like Syndrome Characterized by Germline PTEN, SDH, or KLLN Alterations

Thyroid cancer is believed to be an important component of Cowden syndrome (CS). Germline PTEN and SDHx mutations and KLLN epimutation cause CS and CS-like phenotypes. Despite the established association, little is known about the incidence and clinical features of thyroid cancer found in CS/CS-like patients. The aim of the study was to compare incidence, clinical, and histological characteristics of epithelial thyroid cancers in CS/CS-like individuals, in the context of PTEN, SDHx, and KLLN status. The study encompassed a 5-yr, multicenter, prospective accrual of 2723 CS and CS-like patients, all of whom had comprehensive PTEN analysis. SDHx mutation analysis occurred in those without PTEN mutations/variations and elevated manganese superoxide dismutase (MnSOD) levels. KLLN epimutation analysis was performed in the subset without any PTEN or SDHx mutation/deletion/ variant/polymorphism. Gene-specific thyroid cancer histologies, demographic and clinical information, and adjusted standardized incidence rates were studied. Of 2723 CS/CS-like patients, 664 had thyroid cancer. Standardized incidence rates for thyroid cancer were 72 [95% confidence interval (CI), 51-99; P < 0.001] for pathogenic PTEN mutations, 63 (95% CI, 42-92; P < 0.001) for SDHx variants, and 45 (95% CI, 26-73; P < 0.001) for KLLN epimutations. All six (16.7%) diagnosed under age 18 yr carried pathogenic PTEN mutations. Follicular thyroid cancer was overrepresented in PTEN mutation-positive cases compared to those with SDHx and KLLN alterations. PTEN frameshift mutations were found in 31% of patients with thyroid cancer compared to 17% in those without thyroid cancer. CS/CS-like patients have elevated risks of follicular thyroid cancer due to PTEN pathogenic mutations and of papillary thyroid cancer from SDHx and KLLN alterations. Children presenting with thyroid cancer should be tested for PTEN mutations.

The Emerging Role of Sunitinib in the Treatment of Advanced Epithelial Thyroid Cancer: Our Experience and Review of Literature

Tyrosine kinase receptors have been shown to play an important role in epithelial thyroid tumor growth and angiogenesis. Thyroid cancers commonly present oncogene mutations involved in MAPK kinase pathway like BRAF and RET; they are also frequently dependent on VEGF stimuli. Preliminary clinical experiences suggest a promising role of sunitinib (a tyrosine kinase inhibitor) for the treatment of advanced thyroid cancers. This review deals with the available data on the effect of sunitinib in the treatment of metastatic, radioiodine refractory thyroid cancers. We also report our experience with the off-label use of sunitinib in such patients.

Cardiac Metastasis from Thyroid Carcinoma

Cardiac metastasis from epithelial thyroid cancer is a very rare and potentially serious complication. We have identified only 54 reported cases over a 130-year period. Here we review this literature. Cardiac metastases are frequently asymptomatic, but when symptoms develop these tend to be severe and often fatal. The prognosis of cardiac metastases from thyroid cancer is unclear as survival data are often missing or absent in reported cases. However, as many patients died suddenly from cardiac complications, the prognosis seems poor. Of those patients who survived, all underwent surgical intervention. Trans-thoracic echocardiography is the diagnostic modality of choice as it allows dynamic evaluation of intracardiac masses. Metastatic involvement of the heart from thyroid cancer is uncommon. Left untreated this complication seems likely to be fatal. Therefore, in patients with established thyroid malignancy who develop cardiac arrhythmias, new murmurs, or signs of cardiac decompensation, we suggest that cardiac metastases be considered. Echocardiography should be performed in patients with advanced thyroid cancer and cardiac symptoms or signs. If a cardiac metastasis is present, we recommend surgical intervention if possible.

Mendelian genetics of rare—and not so rare—cancers

Mendelian genetics forms the basis for gene-informed risk assessment and management for the patient and family, and should be at the very foundation of 21st century personalization of healthcare. Yet this is an underutilized commodity. Identification and characterization of germline mutations in the RET proto-oncogene, encoding a receptor tyrosine kinase, as causing >90% of multiple endocrine neoplasia type 2 (MEN 2), an autosomal dominant disorder characterized by medullary thyroid cancer, pheochromocytoma, and hyperparathyroidism, heralded the era of evidence-based molecular diagnosis, predictive testing, genetic counseling, gene-informed cancer risk assessment, and preventative medicine. Since then, many syndromic endocrine neoplasias have proven to fall under this clinically utile and actionable model, such as those caused by mutations in RET, VHL, or SDHB-D. The familial risk associated with epithelial (nonmedullary) thyroid carcinoma is among the highest of all solid tumors, yet only a few highly penetrant heritable epithelial thyroid cancer syndrome exist. This is illustrated by Cowden syndrome, a difficult-to-recognize autosomal dominant disorder characterized by breast, thyroid, and other cancers, caused by germline mutations in PTEN, encoding a phosphatase, and minorly, SDHB/SDHD variants.

Decreased 1-25 Dihydroxyvitamin D 3 Concentration in Peripheral Blood Serum of Patients with Thyroid Cancer

Vitamin D(3), in addition to its role in calcium homeostasis, has been recognized as playing a role in human cancer development. However, little is known about the association between vitamin D status and the development of thyroid cancer. This study aimed to investigate vitamin D metabolism by measuring 25(OH) D(3), 1-25 (OH)(2) D(3), PTH and calcium concentrations in the peripheral blood of patients with different forms of thyroid tumors. The 25-hydroxyvitamin D(3) ,1-25- dihydoxyvitamin D(3), PTH and calcium serum levels of 50 consecutive patients with epithelial thyroid cancer 27 cases of papillary cancers (PTC), 16 follicular cancers (FTC), and seven cases of anaplastic cancers (ATC) and 34 multinodular nontoxic goiter (MNG) were measured by specific immunoassay. The control group consisted of 26 healthy volunteers. Our results revealed significantly lower 1-25 (OH)(2) D(3) concentration in the PTC group (22.67 pg/mL +/- 8.12; p <0.05), FTC group (16.09 pg/mL +/- 6.15; p <0.02) and ATC group (9.48 pg/mL +/- 5.18; p <0.02). Levels of 1-25 (OH)(2) D(3) varied by cancer stage and were also significantly different. A significant decrease in circulating 1-25 (OH)(2) D(3) concentration was found in patients with stage I (24.12 pg/mL +/- 6.77; p <0.05), stage II (16.93 pg/mL +/- 4.55; p <0.05), stage III (12.44 +/- 8.98; p <0.02) and in stage IVa (6.18 +/- 2.22; p <0.01). There were no significant differences when comparing serum levels of 25(OH) D(3), PTH or calcium concentrations among individuals with multinodular goiter, thyroid cancer and age- and sex-matched control volunteers. Our study revealed that impaired vitamin D(3) metabolism may play an important role in thyroid follicular cell oncogenesis.