Molecular Profiling of 50 734 Bethesda III-VI Thyroid Nodules by ThyroSeq v3: Implications for Personalized Management.

CONTEXT: Comprehensive genomic analysis of thyroid nodules for multiple classes of molecular alterations detected in a large series of fine needle aspiration (FNA) samples has not been reported. OBJECTIVE: To determine the prevalence of clinically relevant molecular alterations in Bethesda categories III-VI (BCIII-VI) thyroid nodules. METHODS: This retrospective analysis of FNA samples, tested by ThyroSeq v3 using Genomic Classifier and Cancer Risk Classifier at UPMC Molecular and Genomic Pathology laboratory, analyzed the prevalence of diagnostic, prognostic, and targetable genetic alterations in a total of 50 734 BCIII-VI nodules from 48 225 patients. RESULTS: Among 50 734 informative FNA samples, 65.3% were test-negative, 33.9% positive, 0.2% positive for medullary carcinoma, and 0.6% positive for parathyroid. The benign call rate in BCIII-IV nodules was 68%. Among test-positive samples, 73.3% had mutations, 11.3% gene fusions, and 10.8% isolated copy number alterations. Comparing BCIII-IV nodules with BCV-VI nodules revealed a shift from predominantly RAS-like alterations to BRAF V600E-like alterations and fusions involving receptor tyrosine kinases (RTK). Using ThyroSeq Cancer Risk Classifier, a high-risk profile, which typically included TERT or TP53 mutations, was found in 6% of samples, more frequently BCV-VI. RNA-Seq confirmed ThyroSeq detection of novel RTK fusions in 98.9% of cases. CONCLUSION: In this series, 68% of BCIII-IV nodules were classified as negative by ThyroSeq, potentially preventing diagnostic surgery in this subset of patients. Specific genetic alterations were detected in most BCV-VI nodules, with a higher prevalence of BRAF and TERT mutations and targetable gene fusions compared to BCIII-IV nodules, offering prognostic and therapeutic information for patient management.

Autoimmune thyroid disease.

PURPOSE OF REVIEW: Autoimmune thyroid disorders (AITDs) are the most common organ-specific autoimmune disorders. The genetics as well as clinical and laboratory manifestations of AITDs are reviewed. RECENT FINDINGS: We discuss the association between specific rheumatologic disorders and AITDs and manifestations of AITDs that mimic rheumatologic disorders. The recently discovered common molecular pathways involved in these processes are discussed. SUMMARY: AITDs and rheumatologic disorders have significant commonalities both clinically and etiologically. This information is important for rheumatologists and primary care physicians who care for patients with these disorders.

Limitations of preoperative cytology for medullary thyroid cancer: Proposal for improved preoperative diagnosis for optimal initial medullary thyroid carcinoma specific surgery.

BACKGROUND: Preoperative diagnosis of medullary thyroid carcinoma (MTC) is often difficult, given the poor sensitivity of fine-needle aspiration (FNA) cytology for MTC. This study investigates this issue and presents recommendations for improving preoperative diagnostic paradigms in MTC cases. DESIGN/METHOD: Histopathologically confirmed MTC patients with preoperative cytologic assessment of index nodules were enrolled. FNA diagnosis, final pathology, and surgery details were collected. RESULTS: Out of 71 patients, 49 (69%) were diagnosed by FNA as either definitive MTC (35, 49%) or suspected MTC (14, 20%) and 22 (31%) patients had no indication of MTC on FNA. CONCLUSION: In a tertiary-care setting, one-third of subjects had an FNA interpretation that did not suggest the possibility of MTC. The limitations of preoperative diagnosis are especially problematic for MTC as they can cause delayed or incomplete treatment. Additional testing is proposed to improve preoperative diagnosis and surgical care of MTC patients.

The Presence of Hürthle Cells Does Not Increase the Risk of Malignancy in Most Bethesda Categories in Thyroid Fine-Needle Aspirates.

Background: Hürthle cell/oncocytic change is commonly reported on thyroid fine-needle aspiration (FNA) and may be considered an "atypical cell" by clinicians. This study aims to delineate the association between Hürthle cells in preoperative cytology and subsequent pathology of the indexed thyroid nodule and to report rates of malignancy. Methods: Retrospective review of records of 300 patients with Hürthle cell/oncocytic change on FNA and final surgical pathology at a tertiary referral center between 2000 and 2013 was performed and compared with a multi-institutional FNA cohort. The degree of Hürthle cell presence was correlated with histopathologic diagnoses. Results: In the Hürthle cell FNA group, Bethesda System for Reporting Thyroid Cytopathology (BSRTC) categories were as follows: I (nondiagnostic) 14 (4.7%); II (benign) 113 (37.7%); III (atypia of undetermined significance/follicular lesion of undetermined significance) 33 (11%); IV (follicular neoplasm/suspicious for a follicular neoplasm) 125 (41.6%); V (suspicious for malignancy) 12 (4%); and VI (malignant) 3 (1%). When categorized based on the degree of Hürthle cell change, 59 (29%) were classified as mild, 13 (6%) moderate, and 131 (65%) as predominant. When comparing the results with a multi-institutional FNA cohort (all with surgical confirmation), the presence of Hürthle cells was found to be associated with a lower risk of malignancy in all BSRTC categories, with a statistically significant difference in the BSRTC IV and V groups. The sole exception was when Hürthle cell presence was classified as predominant (defined as >75% of the cellular population); the rate of malignancy was significantly elevated in FNAs interpreted as benign/Bethesda II. Conclusions: Although Hürthle cells have been considered by clinicians as an "atypical cell," their presence does not increase the risk of malignancy within BSRTC categories overall. However, when predominant Hürthle cell change is present, the risk of malignancy is increased in the benign cytology/BSRTC category II.

KiSS-1/G protein-coupled receptor 54 metastasis suppressor pathway increases myocyte-enriched calcineurin interacting protein 1 expression and chronically inhibits calcineurin activity.

OBJECTIVE: Tumor metastasis is a critical determinant of death from cancer. Metastin, a product of the KiSS-1 gene, is an endogenously expressed metastasis suppressor that is the ligand for G protein-coupled receptor 54 (GPR54), a Gq/11-coupled receptor. In the present study, our goal was to define the basis of GPR54 action using thyroid cancer cells as a model. DESIGN AND RESULTS: We used GPR54-null thyroid cancer cells to create a stable GPR54 overexpression model. Cell growth and cell migration of the GPR54-expressing lines were inhibited by recombinant metastin, and metastin stimulated the protein kinase C, ERK, and phosphatidylinositol-3-kinase pathways. To identify metastin-regulated genes, we performed microarray analyses using RNA isolated from GPR54 stable transfectants before and after 1 and 24 h of metastin stimulation. Consistent increases in expression of the gene encoding myocyte-enriched calcineurin interacting protein 1 (MCIP-1), an inhibitor of calcineurin, were identified and confirmed using real-time RT-PCR and Western blot. Functionally, metastin treatment of GPR54-expressing cells initially increased calcineurin activity, followed by a prolonged reduction in calcineurin activity for 24 and 48 h, consistent with the pattern of MCIP-1 expression. In addition, treatment with cyclosporin A, a calcineurin inhibitor, blocked cell migration. Lymph node metastasis in papillary thyroid cancers demonstrated loss of MCIP-1 expression in comparison with primary tumors. CONCLUSIONS: These data suggest a role for MCIP-1 and calcineurin inhibition in GPR54-mediated metastasis suppression in human cancers.

Perioperative management of patients with hypothyroidism.

Hypothyroidism is a common disorder affecting the cardiovascular, respiratory, hematopoietic, and renal organ systems--each of which is particularly germane in the management of the surgical patient. In general, treatment of recognized hypothyroidism is recommended before any surgical procedure whenever possible and euthyroidism should be documented by measurement of serum TSH as part of the preoperative evaluation. Such a strategy is likely to result in better surgical outcomes with improved morbidity and mortality. One exception to treating first with thyroid hormone is the patient with angina or coronary artery disease requiring bypass grafting, angioplasty or stenting. In this setting, preoperative thyroid hormone therapy could tax the ischemic myocardium. The coronary blood flow should be addressed first, and thyroid hormone therapy initiated afterwards. The authors have emphasized the need for caution in the interpretation of low serum thyroid hormones in sick or surgical patients because of the importance of distinguishing between hypothyroidism and the "euthyroid sick syndrome." There is no clear evidence at this point to support thyroid hormone replacement in the latter patients, and it may be potentially harmful. Rather, we hold that T3 treatment of various surgical and other patients with nonthyroidal illness should be deferred until proof of its therapeutic efficacy is demonstrated.

Thyroid physiology.

The thyroid gland produces thyroid hormone, which has clinically important actions practically in every system in the human body. Detailed knowledge of the physiology of the thyroid gland is critical for the proper management of thyroid disorders. The molecular biology of thyroid function is being studied in great detail. Clinically important molecules, such as the thyroid-stimulating hormone receptor and the sodium/iodide symporter, have been identified and well characterized. Such discoveries have significantly improved our understanding of thyroid physiology. As a result, new diagnostic and therapeutic approaches for the management of thyroid disorders are now available or in development.

Cinacalcet as alternative treatment for primary hyperparathyroidism: achievements and prospects.

Primary hyperparathyroidism (pHPT), which most frequently occurs asymptomatically, is a common endocrine disease associated with increased morbidity and mortality. The newly introduced management guidelines as well as the recent availability of the first calcimimetic offer a highly promising therapeutic option for patients with pHPT. Cinacalcet, the first available calcimimetic, increases the sensitivity of the calcium-sensing receptor (CaR) to circulating serum calcium, thereby safely reducing serum calcium and PTH concentrations in patients with mild-to-moderate pHPT, intractable disease, and also parathyroid carcinoma. Cinacalcet has proved efficient in short- and long-term controls of hypercalcemia and, though bone mineral density was not improved, the available data point to cinacalcet as the treatment of choice in non-operable patients with pHPT. These results encompass a wide spectrum of disease severity. Results are pending as to whether cinacalcet decreases mortality and morbidity in pHPT, confirmation of which would conclusively recommend this drug as a valid alternative to surgery.

Clinical review: Ectopic cervical thyroid carcinoma--review of the literature with illustrative case series.

CONTEXT: More than 99% of thyroid cancers arise eutopically within the thyroid gland. The most frequent sites of ectopic thyroid tissue are lingual, sublingual, thyroglossal, laryngotracheal, and lateral cervical. Thyroid tissue can also be found in remote structures that were associated with the thyroid anlage during development, including the esophagus, mediastinum, heart, aorta, adrenal, pancreas, gallbladder, and skin. Ectopic thyroid tissue can be subject to the same pathological processes as normal eutopic thyroid tissue such as inflammation, hyperplasia, and tumorigenesis. The aim of this review is to describe aspects of thyroid cancer arising from the ectopic thyroid tissue in the neck in regard to epidemiology, diagnosis, and treatment and to present an illustrative series of cases of ectopic thyroid cancer. DATA ACQUISITION: We have searched the PubMed database for articles including the keywords "ectopic thyroid cancer" published between January 1, 1960, and January 1, 2011. As references, we used clinical case series, case reports, review articles, and practical guidelines focused on ectopic thyroid cancer confined to the neck region. SYNTHESIS AND CONCLUSIONS: The possibility of an ectopic thyroid cancer should be considered in the differential diagnosis of a pathological mass in the neck. Treatment of ectopic cervical thyroid cancer is based predominantly on the surgical excision of the malignant lesion. Management strategies, including performance of total thyroidectomy, neck dissection, and treatment with radioiodine, should be based on individualized risk stratification.