Contemporary Management of Thyroid Nodules.

Thyroid nodules are common in the general population, with higher prevalence in women and with advancing age. Approximately 5% of thyroid nodules are malignant; the majority of this subset represents papillary thyroid cancer. Ultrasonography is the standard technique to assess the underlying thyroid parenchyma, characterize the features of thyroid nodules, and evaluate for abnormal cervical lymphadenopathy. Various risk stratification systems exist to categorize the risk of malignancy based on the ultrasound appearance of a thyroid nodule. Nodules are selected for fine-needle aspiration biopsy on the basis of ultrasound features, size, and high-risk clinical history. Cytology results are classified by the Bethesda system into six categories ranging from benign to malignant. When cytology is indeterminate, molecular testing can further risk-stratify patients for observation or surgery. Surveillance is indicated for nodules with benign cytology, indeterminate cytology with reassuring molecular testing, or non-biopsied nodules without a benign sonographic appearance.

Hypercalcemia of Malignancy Attributed to Cosecretion of PTH and PTHRP in Lung Adenocarcinoma.

INTRODUCTION: Hypercalcemia of malignancy (HCM) portends a very poor prognosis, and no established guidelines exist regarding its management. Most instances of HCM are due to local osteolysis or secretion of parathyroid hormone related-peptide, while less than 1% of all cases are due to ectopic secretion of parathyroid hormone. CASE REPORT: We present an unusual case of HCM due to proposed cosecretion of both parathyroid hormone and parathyroid hormone-related protein in a 36-year-old man with a poorly differentiated lung adenocarcinoma. The patient's hypercalcemia was refractory to conventional measures, including intravenous bisphosphonate therapy (zoledronic acid), and was improved with administration of denosumab. CONCLUSION: This is the youngest and first case of hypercalcemia of malignancy attributed to cosecretion of PTH and PTHrP from an adenocarcinoma. In refractory cases of HCM, denosumab is a potential option when other conventional measures are unsuccessful.

Macrocalcifications Do Not Alter Malignancy Risk Within the American Thyroid Association Sonographic Pattern System When Present in Non-High Suspicion Thyroid Nodules.

Background: The American Thyroid Association Sonographic Pattern System (ATASPS) depicts five levels of suspicion for malignancy based on the sonographic appearance of a thyroid nodule. However, 3-37% of nodules are non-classifiable when the combination of grayscale findings is not depicted by the ATASPS. The only calcifications included in the ATASPS are in solid hypoechoic high suspicion (HS) nodules and include both microcalcifications and peripheral interrupted calcifications with soft tissue extrusion. Non-hypoechoic nodules with these and other calcification patterns, which we defined as non-high suspicion calcifications (NHSC), are not classifiable by ATASPS. We assessed the effect of assigning an ATASPS risk level to nodules with NHSC based on analysis of their other grayscale features. Methods: A retrospective review of 728 consecutively biopsied nodules was performed. Nodules were classified by ATASPS as HS, intermediate suspicion (IS), low suspicion (LS), or very low suspicion (VLS); other nodules with patterns not described by ATASPS were non-classifiable (NC). If NC was due to NHSC, the nodule was assigned an ATASPS by analysis of grayscale features alone. Cytology and pathology results were correlated with assigned ATASPS level. Results: A NC pattern was observed in 144 of the 728 nodules (20%). Of these, 101/144 (70%) had NHSC and the assigned ATASPS was IS (n = 18), LS (n = 62) and VLS (n = 21). The distribution of cytology diagnoses within this group was similar to classifiable nodules (IS p = 0.13, LS p = 0.55, VLS p = 0.44). The majority of NHSC (n = 92, 91%) were macrocalcifications (large central or linear dystrophic calcifications); however, 9 LS pattern nodules had punctate echogenic foci, possibly representing microcalcifcations, with an estimated cancer prevalence of 19% (vs. 10% for total LS group, p = 0.24). The remaining NC nodules (43/144, 30%) included solid nodules with heterogeneous echogenicity (n = 30) or presence of a complete circumferential rim calcification, limiting further sonographic assessment (n = 13). Malignancy was identified in 11 out of 43 (26%) of these [9/30 (30%) heterogeneous solid and 2/13 (15%) with complete rim calcifications]. Conclusions: Macrocalcifications accounted for the majority of NHSC and these did not alter the expected ATASPS malignancy risk based on grayscale features.

Akt isoform-specific effects on thyroid cancer development and progression in a murine thyroid cancer model.

The Akt family is comprised of three unique homologous proteins with isoform-specific effects, but isoform-specific in vivo data are limited in follicular thyroid cancer (FTC), a PI3 kinase-driven tumor. Prior studies demonstrated that PI3K/Akt signaling is important in thyroid hormone receptor ßPV/PV knock-in (PV) mice that develop metastatic thyroid cancer that most closely resembles FTC. To determine the roles of Akt isoforms in this model we crossed Akt1-/-, Akt2-/-, and Akt3-/- mice with PV mice. Over 12 months, thyroid size was reduced for the Akt null crosses (p < 0.001). Thyroid cancer development and local invasion were delayed in only the PVPV-Akt1 knock out (KO) mice in association with increased apoptosis with no change in proliferation. Primary-cultured PVPV-Akt1KO thyrocytes uniquely displayed a reduced cell motility. In contrast, loss of any Akt isoform reduced lung metastasis while vascular invasion was reduced with Akt1 or 3 loss. Microarray of thyroid RNA displayed incomplete overlap between the Akt KO models. The most upregulated gene was the dendritic cell (DC) marker CD209a only in PVPV-Akt1KO thyroids. Immunohistochemistry demonstrated an increase in CD209a-expressing cells in the PVPV-Akt1KO thyroids. In summary, Akt isoforms exhibit common and differential functions that regulate local and metastatic progression in this model of thyroid cancer.

Gelsolin: a novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer.

Follicular thyroid cancer (FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant thyroid hormone receptor-beta (TRbeta(PV/PV) mouse) that spontaneously develops thyroid cancer with metastasis similar to humans has provided new opportunities to study contributors to FTC metastasis. This study evaluates the role of gelsolin, an actin-regulatory protein, in modulating the metastatic potential of FTC. Gelsolin was previously found by cDNA microarray analysis to be down-regulated in TRbeta(PV/PV) mice as compared with wild-type mice. This study found an age-dependent reduction of gelsolin protein abundance in TRbeta(PV/PV) mice as tumorigenesis progressed. Knockdown of gelsolin by small interfering RNA resulted in increased tumor cell motility and increased gelsolin expression by histone deacetylase inhibitor (trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that gelsolin physically interacted with TRbeta1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of gelsolin and the DNA binding domain of TR. The physical interaction of gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local tumor progression and metastatic potential of thyroid carcinogenesis.

Overview of Hypothyroidism in Pregnancy.

Overt hypothyroidism in pregnancy, defined as an elevated serum thyroid-stimulating hormone (TSH) and reduced serum free thyroxine or a TSH >10 mIU/L, is known to have adverse effects on pregnancy. Subclinical hypothyroidism is typically defined as an elevated TSH and normal FT4 levels. There remains much controversy on the benefit of starting levothyroxine for mothers diagnosed with subclinical hypothyroidism. Recent studies are redefining the normal range for TSH in pregnancy, and the data on whether treatment of subclinical hypothyroidism improves outcomes for the mother and fetus are unclear. One confounding variable is the presence of thyroid peroxidase antibodies, as it may be a surrogate marker for other autoimmune disorders detrimental to pregnancy. If levothyroxine treatment is initiated, the dosing and monitoring strategy is different from nonpregnant individuals. Randomized clinical trials are underway that may better elucidate whether treatment of subclinical hypothyroidism is warranted.

AKT activation promotes metastasis in a mouse model of follicular thyroid carcinoma.

The phosphatidylinositol 3-kinase/AKT pathway is crucial to many cell functions, and its dysregulation in tumors is a common finding. The molecular basis of follicular thyroid cancer metastasis is not well understood but may also be influenced by AKT activation. We previously created a knockin mutant mouse that expresses a mutant thyroid hormone receptor-beta gene (TRbetaPV mouse) that spontaneously develops thyroid cancer and distant metastasis similar to human follicular thyroid cancer. In this study, we investigated whether our mouse model exhibits similar AKT activation as human follicular thyroid cancer. Western blot analysis on thyroids from both wild-type and TRbeta(PV/PV) mice revealed elevation of activated AKT in TRbeta(PV/PV) mice. Immunohistochemistry and confocal microscopy reveal activated AKT in both the thyroid and metastatic lesions of TRbeta(PV/PV) mice. Whereas all three AKT isoforms were overexpressed in primary tumors from TRbeta(PV/PV) mice in the cytoplasm of thyroid cancer cells, only AKT1 was also found in the nucleus, matching the localization of activated AKT in a pattern similar to human follicular thyroid cancer. In the metastases, all AKT isoforms correlated with phosphorylated AKT nuclear localization. We created primary thyroid cell lines derived from TRbeta(PV/PV) mice and found reduction of phosphorylated AKT levels or AKT downstream targets diminishes cell motility. Activated AKT is common to both human and mouse follicular thyroid cancer and is correlated with increased cell motility in vitro and metastasis in vivo. Thus, TRbeta(PV/PV) mice could be used to further dissect the detailed pathways underlying the progression and metastasis of follicular thyroid carcinoma.

Zonisamide effective for weight loss in women.

Zonisamide (Zonegran), in conjunction with a reduced-calorie diet (deficit of 500 kcal/d), resulted in an additional mean 5-kg (11-pound) weight loss compared with diet alone. This regimen was well-tolerated in obese female patients. Further evaluation of long-term side effects and continued weight loss beyond 32 weeks is needed.

Thyroid nodule and thyroid cancer management pre- and post-cardiac transplantation.

Thyroid nodules are common in the adult population. Widespread use of sensitive imaging studies often leads to their incidental discovery. Recent guidelines recommend thyroid-stimulating hormone determination and ultrasonography during initial nodule evaluation. Fine-needle aspiration is often performed to detect malignancy. However, the management of thyroid nodules in cardiac transplantation patients has not been directly addressed by recent guidelines. Confounding medications such as amiodarone and anti-coagulants present a management dilemma. The timing of fine-needle aspiration is crucial because (1) malignancy diagnosed pre-operatively usually precludes organ transplantation, and (2) patients undergoing solid-organ transplantation are at increased risk of developing de novo malignancies, including thyroid. With the rising incidence of thyroid cancer, donor-related malignancy will likely become a more prominent issue. This review addresses thyroid nodule management in the cardiac transplant population and provides recommendations for organ donation and transplantation in donors and recipients with thyroid cancer.

Lessons from mouse models of thyroid cancer.

BACKGROUND: Thyroid cancer is the most common endocrine tumor and is increasing in incidence. The aim of this study was to review mouse models of differentiated thyroid cancer and how they elucidate human thyroid cancer biology. SUMMARY: Differentiated thyroid cancer, primarily papillary and follicular, comprises the majority of thyroid cancers. There has been tremendous growth in the cross-talk between basic science and clinical practice for thyroid cancer management. Insight into the framework of genes responsible for differentiated thyroid cancer has been gained through the use of mouse models. Common genetic alterations found in human papillary thyroid cancer such as RET/PTC rearrangements or the BRAF(V600E) mutation have genetically modified mouse counterparts. These and other preclinical mouse models have validated the importance of the cyclic adenosine monophosphate (cAMP)/protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways in papillary thyroid cancer (PTC). RAS mutations have a role in both papillary and follicular thyroid cancer development. Mice with overactivation of the phosphatidylinol-3-kinase (PI3K)-AKT and/or thyrotropin-regulated signaling pathways have been found to develop follicular thyroid cancer. Additional mouse models of thyroid cancer that utilize inducible expression systems are in development or are being characterized and will better reflect the majority of human thyroid cancers which are non-hereditary. Advances in in vivo imaging of mice allow for earlier detection of metastasis and the ability to follow tumor growth or regression which may be used in evaluation of pharmaceutical agents. CONCLUSIONS: Mouse models have expanded our understanding of the altered signaling pathways that contribute to thyroid cancer tumorigenesis and provide a powerful tool to develop novel diagnostic approaches and therapies.

Myositis associated with the decline of thyroid hormone levels in thyrotoxicosis: a syndrome?

BACKGROUND: Musculoskeletal complaints are common in patients with thyroid dysfunction. Both thyrotoxic and hypothyroid myopathy have been well described, and there are distinct presentations, laboratory findings, and clinical outcomes between the two groups. Myopathy has also been reported in hyperthyroid patients only after beginning treatment, suggesting that relative hypothyroidism may also contribute to musculoskeletal disease. A confounding factor in these cases was that these patients were on antithyroid drugs that may also have direct effects on the muscle, irrespective of the rate of decline in thyroid hormone levels. SUMMARY: We report a patient with Graves' disease who developed myalgias with elevated creatine kinase levels after total thyroidectomy. Addition of triiodothyronine quickly resolved her symptoms and creatine kinase levels, whereas discontinuation of triiodothyronine, despite having normal to elevated total thyroxine levels, led to a relapse. CONCLUSION: Myositis after correction of thyrotoxicosis may constitute a syndrome that should be assessed for in hyperthyroid patients complaining of myalgias after starting treatment.

The pituitary tumor-transforming gene promotes angiogenesis in a mouse model of follicular thyroid cancer.

Overexpression of the pituitary tumor-transforming gene (PTTG) has been associated with tumorigenesis. In a mouse model that spontaneously develops follicular thyroid cancer (FTC) with distant metastasis (TRbetaPV mouse), PTTG is overexpressed, similar to human thyroid cancer. To evaluate the role of PTTG in thyroid carcinogenesis, we studied the offspring of TRbetaPV mice with mice lacking PTTG (PTTG(-/-) mice). The thyroids of TRbeta(PV/PV) PTTG(-/-) mice were significantly smaller than TRbeta(PV/PV) mice. Ki-67 staining showed a decrease in thyroid proliferation in TRbeta(PV/PV) PTTG(-/-) mice. Our evaluation of the Rb-E2F pathway, a central mediator of cell growth, found that TRbeta(PV/PV) PTTG(-/-) mice exhibited a decrease in protein levels of phosphorylated Rb along with an elevation of the cdk inhibitor p21. Histological examination documented no difference in FTC occurrence between TRbeta(PV/PV) and TRbeta(PV/PV) PTTG(-/-) mice, which indicates that PTTG removal does not prevent the initiation of FTC. However, TRbeta(PV/PV) PTTG(-/-) mice had a significant decrease in vascular invasion and less development of lung metastasis as they progressively aged. CD31 staining also showed a decrease in vessel density in TRbeta(PV/PV) PTTG(-/-) versus TRbeta(PV/PV) thyroids. Given the decreased vascular invasion in the PTTG knockout mice, we studied genes involved in angiogenesis. Real-time reverse transcription-polymerase chain reaction showed a consistent decrease in pro-angiogenic factors, fibroblast growth factor (FGF2), its receptor FGFR1 and vascular endothelial growth factor. Our results highlight the dual roles of PTTG as a regulator of thyroid growth and contributor to tumor progression. The separation of the pathways regulating cell proliferation, tumor initiation and tumor progression should direct future therapeutic options.