DOI: 10.20452/pamw.16222, Published online: March 03, 2022, Authors: Joanna Klubo-Gwiezdzinska, Leonard Wartofsky

The diagnostic modalities, stratification tools, and treatment options for patients with thyroid cancer have rapidly evolved since the development of the American Thyroid Association (ATA) guidelines in 2015. This review compiles newer concepts in diagnosis, stratification tools and treatment options for patients with differentiated thyroid cancer (DTC), medullary thyroid carcinoma (MTC) and anaplastic thyroid cancer (ATC). Newer developments apply precision medicine in thyroid cancer patients to avoid over-treatment in low risk disease and under-treatment in high risk disease. Among novel patient-tailored therapies are selective RET inhibitors that have shown efficacy in the treatment of MTC with limited systemic toxicity compared with non-specific tyrosine kinase inhibitors. The combination of BRAF and MEK inhibitors have revolutionized management of BRAF V600E mutant ATC. Several immunotherapeutic agents are being actively investigated in the treatment of all forms of thyroid cancer. In this review, we describe the recent advances in the diagnosis and management of DTC, MTC, and ATC, with an emphasis on novel treatment modalities. ^* KAA and SG are first co-authors.

Purpose: Mitochondrial glycerophosphate dehydrogenase (MGPDH) is the key enzyme connecting oxidative phosphorylation (OXPHOS) and glycolysis as well as a target of the antidiabetic drug metformin in the liver. There are no data on the expression and role of MGPDH as a metformin target in cancer. In this study, we evaluated MGPDH as a potential target of metformin in thyroid cancer and investigated its contribution in thyroid cancer metabolism. Experimental Design: We analyzed MGPDH expression in 253 thyroid cancer and normal tissues by immunostaining and examined its expression and localization in thyroid cancer–derived cell lines (FTC133, BCPAP) by confocal microscopy. The effects of metformin on MGPDH expression were determined by qRT-PCR and Western blot analysis. Seahorse analyzer was utilized to assess the effects of metformin on OXPHOS and glycolysis in thyroid cancer cells. We analyzed the effects of metformin on tumor growth and MGPDH expression in metastatic thyroid cancer mouse models. Results: We show for the first time that MGPDH is overexpressed in thyroid cancer compared with normal thyroid. We demonstrate that MGPDH regulates human thyroid cancer cell growth and OXPHOS rate in vitro. Metformin treatment is associated with downregulation of MGPDH expression and inhibition of OXPHOS in thyroid cancer in vitro. Cells characterized by high MGPDH expression are more sensitive to OXPHOS-inhibitory effects of metformin in vitro and growth-inhibitory effects of metformin in vitro and in vivo. Conclusions: Our study established MGPDH as a novel regulator of thyroid cancer growth and metabolism that can be effectively targeted by metformin. Clin Cancer Res; 24(16); 4030–43. ©2018 AACR.

Background: The optimal management of high-risk patients with differentiated thyroid cancer (DTC) consists of thyroidectomy followed by radioiodine (¹³¹I) therapy. The prescribed activity of ¹³¹I can be determined using two approaches: 1) empiric prescribed activity of ¹³¹I (E-Rx); and 2) dosimetry-based prescribed activity of ¹³¹I (D-Rx). Aim: The aim of the study was to compare the relative treatment efficacy and side effects of D-Rx vs. E-Rx. Methods: A retrospective analysis was performed of patients with distant metastases and/or locoregionally advanced radioiodine-avid DTC who were treated with either D-Rx or E-Rx. Response to treatment was based on RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria. Results: The study group consisted of 87 patients followed for 51 ± 35 months, of whom 43 were treated with D-Rx and 44 with E-Rx. Multivariate analysis, controlling for age, gender, and status of metastases revealed that the D-Rx group tended to be 70% less likely to progress (odds ratio, 0.29; 95% confidence interval, 0.087–1.02; P = 0.052) and more likely to obtain complete response (CR) compared to the E-Rx group (odds ratio, 8.2; 95% confidence interval, 1.2–53.5; P = 0.029). There was an association in the D-Rx group between the observed CR and percentage of maximum tolerable activity given as a first treatment of ¹³¹I (P = 0.030). The advantage of D-Rx was specifically apparent in the locoregionally advanced group because CR was significantly higher in D-Rx vs. E-Rx in this group of patients (35.7 vs. 3.3%; P = 0.009). The rates of partial response, stable disease, and progression-free survival, as well as the frequency of side effects, were not significantly different between the two groups. Conclusion: Higher efficacy of D-Rx with a similar safety profile compared to E-Rx supports the rationale for employing individually prescribed activity in high-risk patients with DTC.

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. 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. 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.