Molecular testing for indeterminate thyroid nodules: past, present, and future.

PURPOSE OF REVIEW: To examine the origin, current progress, and future directions of molecular testing in indeterminate Bethesda III and Bethesda IV thyroid nodules. RECENT FINDINGS: The diagnostic performance of current genomic tests shows improved benign call rates, specificity and positive-predictive values over prior test versions. The choice of test platform for clinical use should consider test performance, institutional rate of malignancy, nodule cytology and the potential for prognostication to help guide decision-making. Current challenges include test reliability, defining the optimal duration of surveillance, and improving test performance in challenging cytology, such as oncocytic nodules and NIFTP. Opportunities also remain to optimize cost-effectiveness across multiple clinical and practice settings and to refine the use of molecular testing for dynamic risk stratification, such as with BRAF V600E mutation testing. SUMMARY: Molecular testing of indeterminate thyroid nodules has helped to reduce the burden of diagnostic surgery, associated healthcare costs, and potential complications. Current-generation tests have demonstrated improvement in diagnostic performance, but challenges remain in improving test performance and refining the scope of testing in care. Decision-making for the management of indeterminate thyroid nodules should consider cytology, clinical and sonographic features, patient values and preferences and molecular testing results, whenever available.

Approach to the Patient With a Suppressed TSH.

Subclinical hyperthyroidism (SCH) is a laboratory diagnosis defined by a serum thyrotropin (TSH) concentration below the reference range (< 0.4 mU/L in most assays), and a free thyroxine (FT4) and 3,5,3'-triiodothyronine levels (FT3) in the reference range. Many patients diagnosed with SCH will be clinically euthyroid while others may present with manifestations characteristic of thyroid hormone excess, such as tachycardia, tremor, intolerance to heat, bone density loss, or weight loss. In addition to the laboratory abnormalities, patient factors such as age, symptoms, and underlying heart and bone disease are used to stratify patients for the risk of adverse outcomes and determine the appropriate treatment. Evaluation should include repeat thyroid function tests to document persistent TSH suppression, investigation of the underlying cause, as well as evaluation of the patient's risk of adverse outcomes in the setting of a subnormal TSH. Persistent SCH has been associated with an increased risk of a range of adverse events, including cardiovascular events such as atrial fibrillation and heart failure, bone loss and fracture, and in some studies, cognitive decline. Despite the consistent association of these adverse events with SCH, prospective studies showing improved outcomes with treatment remain limited. Management options include observation without active therapy, radioactive iodine ablation of the thyroid, antithyroid medication, thyroid surgery, or radiofrequency ablation, as appropriate for the patient and clinical setting. The choice of therapy should be guided by the underlying etiology of disease, patient factors, and the risks and benefits of each treatment option.

Changes in Stage Distribution and Disease-Specific Survival in Differentiated Thyroid Cancer with Transition to American Joint Committee on Cancer 8th Edition: A Systematic Review and Meta-Analysis.

BACKGROUND: Recent revision significantly changed the American Joint Committee on Cancer (AJCC) staging criteria for differentiated thyroid cancer (DTC). To quantitatively evaluate resulting changes in patient stage distribution and the associated disease-specific survival (DSS) incorporating diverse populations, we performed a meta-analysis of studies comparing the AJCC 7th edition (AJCC-7) with 8th edition (AJCC-8) staging for DTC. MATERIALS AND METHODS: After PROSPERO registration (#CRD42019123657), publications in English reporting DSS of DTC with AJCC-7 and AJCC-8 from inception to June 2019 were identified by search of MEDLINE and PubMed. Random-effects meta-analyses were conducted to compare differences in survival between AJCC-7 and AJCC-8. Pooled hazard ratios, 10-year DSS, and corresponding interval estimates were calculated for AJCC subgroups. Differences in survival between editions were assessed using subgroup analysis with nonoverlapping confidence intervals indicating statistical significance. RESULTS: Final analysis included six studies with 10,850 subjects and median follow-up from 55 to 148 months. Use of AJCC-8 shifted classification to earlier stages: stage I, from 60% to 81%; stage II, from 5% to 13%; stage III, from 21% to 2%; stage IV, from 10% to 3%. Ten-year DSS was significantly lower in AJCC-8 versus AJCC-7 in patients with stage II (88.6%, 95% confidence interval [CI] 82.7-94.6% vs. 98.1%, 95% CI 96.6-99.6%, respectively) and stage III disease (70.5%, 95% CI 59.1-83.9% vs. 96.8%, 95% CI 94.1-99.64%, respectively). CONCLUSION: Meta-analysis of revised AJCC staging for DTC, incorporating diverse populations, demonstrates redistribution of patients toward earlier clinical stages and better stratification of disease-specific mortality risk, specifically among patients now classified with stage II and III disease. IMPLICATIONS FOR PRACTICE: This study provides updated estimates of disease-specific survival for patients with differentiated thyroid cancer determined by the American Joint Committee on Cancer staging system that are generalizable to broader populations and support improved stratification using the recently revised criteria.

Treatment of Differentiated Thyroid Carcinomas.

Differentiated thyroid cancer (DTC) is the most common thyroid cancer and is frequently encountered in clinical practice. The incidence of DTC has increased significantly over the past three decades. Surgical resection, radioactive iodine (RAI), and levothyroxine suppression therapy remain the primary modalities for DTC treatment. Active surveillance for low-risk thyroid cancer may be an alternative to immediate surgery for appropriately selected patients. Patient characteristics influence treatment selection and intensity. In the subset of patients with progressive distant metastatic disease, not amenable to treatment with surgery or RAI, novel agents, including targeted therapies and immunotherapy, should be considered.

Medical treatment of Cushing's disease: Overview and recent findings.

Cushing's disease, due to pituitary adrenocorticotropic hormone (ACTH) hypersecretion, is the most common etiology of spontaneous excess cortisol production. The majority of pituitary tumors causing Cushing's disease measure <1 cm and the excess morbidity associated with these tumors is mostly due to the effects of elevated, nonsuppressible, ACTH levels leading to adrenal steroid hypersecretion. Elevated circulating cortisol levels lead to abnormal fat deposition, hypertension, diabetes, coronary artery disease, osteoporosis, muscle weakness and psychological disturbances. At experienced centers, initial surgical remission rate via transnasal, transphenoidal resection approaches 80% for tumors less than 1 cm, but may be as low as 30% for larger lesions and long-term recurrence in all groups approaches 25%. Residual disease may be managed with more radical surgery, pituitary-directed radiation, bilateral adrenalectomy, or medical therapy. This paper addresses current and novel therapies in various stages of development for Cushing's disease.