Thyroid and Parathyroid Tumors

Current and future directions for the treatment of advanced thyroid cancer

Genetics of thyroid cancer and effects of thyroid hormone on tumor progress in vivo

IntroductionLenvatinib is approved in Japan for treating patients with all histological subtypes of unresectable thyroid cancer, including differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC), and anaplastic thyroid cancer (ATC). However, safety and effectiveness data are limited in Japanese patients. Therefore, this prospective, post-marketing observational study evaluated, in daily clinical practice, the safety and effectiveness of lenvatinib in Japanese patients with unresectable thyroid cancer.MethodsAll patients with unresectable thyroid cancer first treated with lenvatinib between May and November 2015 were registered. Patients were orally administered lenvatinib and followed up for 12 months. The endpoints included adverse drug reactions (ADRs), overall survival (OS), overall response rate (ORR), and time-to-treatment failure. Post hoc Cox multivariate analyses were performed to assess prognostic factors associated with the 12-month OS rate.ResultsOf 629 registered patients, 594 were included in the analysis. A total of 442 patients (74.4%) had DTC, 28 (4.7%) had MTC, and 124 (20.9%) had ATC. Hypertension, proteinuria, and palmar-plantar erythrodysesthesia syndrome were the most frequently reported ADRs across all histological subtypes. The median OS was 101.0 days in patients with ATC which was not reached in patients with DTC and patients with MTC, with 12-month OS rates of 15.6%, 75.7%, and 83.0%, respectively. The ORRs were 59.2%, 45.0%, and 43.8% among 368 patients with DTC, 20 with MTC, and 105 with ATC, respectively. Multivariate analyses revealed that Eastern Cooperative Oncology Group performance status (ECOG PS), tumor size, the presence of tumor invasion, and body weight were baseline prognostic factors affecting OS in patients with DTC, while ECOG PS and the presence of liver metastasis were prognostic factors in patients with ATC.ConclusionLenvatinib demonstrated an acceptable safety profile for patients with thyroid cancer in a real-world setting in Japan. The safety profile and effectiveness findings for lenvatinib in this study were consistent with those from previous clinical trials, irrespective of histological subtype.Electronic Supplementary MaterialThe online version of this article (10.1007/s12325-020-01433-8) contains supplementary material, which is available to authorized users.

The thyroid gland is composed of follicular cells, parafollicular cells, and connective tissue with occasional lymphocytes. Each of these cell types can give rise to histologically distinct tumors that differ significantly in behavior, prognosis, and response to treatment. The commonest tumors by far are those derived from follicular epithelial cells; these tumors are classified as differentiated (papillary and follicular), poorly differentiated (insular), and undifferentiated (anaplastic). Medullary thyroid cancers are derived from parafollicular cells. Tumors derived from lymphocytes and connective tissue cells are similar to such lesions elsewhere in the body, but a detailed discussion of those entities is beyond the scope of this chapter. In one of the earliest studies on prognostic factors in thyroid cancer, the multivariate analysis of the European Organization for Research and Treatment of Cancer (EORTC) Thyroid Cancer Co‐operative Group, all histologies were combined. The 5‐year survival ranged from 80% in differentiated carcinoma (papillary and follicular), to 55% in medullary thyroid carcinoma (MTC), to 10% in anaplastic carcinoma. Most subsequent studies of prognostic factors in thyroid cancer were developed for individual histologic types [differentiated papillary–follicular, poorly differentiated (insular), medullary, and anaplastic thyroid carcinomas] and they will be considered separately in this review. Some studies combine papillary and follicular, while others do not. The focus of this chapter is a review of the tumor‐, host‐ and environment‐related prognostic factors in differentiated thyroid cancer, with an additional discussion of prognostic factors in other thyroid histologies.

Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient.

&lt;div&gt;Abstract&lt;p&gt;&lt;b&gt;Purpose:&lt;/b&gt; Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Experimental Design:&lt;/b&gt; This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. &lt;i&gt;PI3K/mTOR/Akt&lt;/i&gt;–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Conclusions:&lt;/b&gt; Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. &lt;i&gt;Clin Cancer Res; 24(7); 1546–53. ©2018 AACR&lt;/i&gt;.&lt;/p&gt;&lt;/div&gt;

Thyroid cancer is the most common endocrine malignancy. Differentiated thyroid cancer (DTC) with the two subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC), is the most frequent subtype of thyroid cancer; more rare subtypes are medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC). The incidence of DTC has increased rapidly in recent years due to the more frequent use of imaging methods such as ultrasound of the neck and fine-needle aspiration (FNA) of thyroid nodules. After total thyroidectomy and radioiodine treatment, DTC remains an indolent and curable disease in most patients, whereas the cure rate in MTC is lower and depends on early diagnosis. Most ATCs are incurable. In recent years, there has been great progress in identifying genetic changes in thyroid cancer, and genetic testing of FNA samples or blood samples provides useful information for clinical decision making. Tumor staging, either postoperatively or by imaging, and measuring the tumor markers thyroglobulin for DTC and calcitonin for MTC, allow for dynamic risk-adapted stratification for follow-up procedures. In advanced metastatic thyroid cancer, molecular targeted therapy using tyrosine kinase receptor inhibitors, including sorafenib, lenvantinib, vandetanib, and cabozantinib, helps control tumor progression and prolongs progression-free survival. Using a dynamic risk-stratified approach to manage thyroid cancer, the outcomes for most thyroid cancer patients are excellent compared with those for other cancers. The major challenge in the future is to identify high-risk patients and to treat and monitor them appropriately. Clin Cancer Res; 22(20); 5012-21. ©2016 AACR SEE ALL ARTICLES IN THIS CCR FOCUS SECTION, "ENDOCRINE CANCERS REVISING PARADIGMS".

Targeted Therapy in Thyroid Cancer: State of the Art

Thyroid hyperplasia/multinodular goiter, characterized by cellular and follicular overgrowth, is a very common endocrine condition, resulting in various functional and structural consequences and certain malignant potential. Its genetic background is completely unknown. Given previous genetic and epigenetic data suggesting that RASAL1 might be a thyroid tumor suppressor gene, particularly in follicular thyroid neoplasm, we hypothesized that the RASAL1 gene could play a fundamental role in the development of thyroid hyperplasia/multinodular goiter. To explore the role of the RASAL1 gene in the development of thyroid hyperplasia/multinodular goiter, we developed a novel Rasal1 knockout mouse model using the CRISPR/Cas9 approach and the C57BL/6J zygotes, followed by observing the pathological changes in the thyroid gland of the knockout mice in comparison with the wildtype mice. We successfully created a novel Rasal1 knockout mouse model with establishment of several generations of mice carrying the heterozygous and homozygous knockout of the Ra-sal1 gene at exon 2, which was confirmed by genetic testing and by Western blotting of the Rasal1 protein. All the mice with Rasal1 knockout, whether heterozygous or homozygous, developed grossly visible multinodular goiter with microscopic confirmation of follicular cell hyperplasia, with occasional case showing thyroid cancer. In contrast, only occasional case of aged wild-type mice developed thyroid hyperplasia and no wild-type mice developed thyroid malignancy. These data demonstrate that defect of Rasal1 can cause full and complete development of thyroid hyperplasia/multinodular goiter in mice. Given the striking similarity of thyroid hyperplasia/multinodular goiter in these Rasal1 knockout mice with that in humans, it is plausible to suggest that RASAL1 is a master gene involved in the development and pathogenesis of human thyroid hyperplasia/ multinodular goiter. This project also provides a new genetic knockout mouse model for future study of thyroid neoplasm.

Phase Ii Study of Lenvatinib (Len), a Multi-Targeted Tyrosine Kinase Inhibitor, in Patients (Pts) with All Histologic Subtypes of Advanced Thyroid Cancer (Differentiated, Medullary and Anaplastic)

55 - Thyroid Cancer: 18F-Fluoro-2-Deoxy-D-Glucose Positron Emission Tomography (An Overview)

Thyroid cancer is the commonest endocrine malignancy but represents only 1% of all cancers. Although the prognosis of differentiated thyroid cancer is good, the survival time of anaplastic and of medullary thyroid cancer is still very short. More precise diagnosis with better stratification of patients and identification of risk patients may improve the prognosis of thyroid cancer. Treatment of thyroid cancer is multidisciplinary and involves endocrinologists, nuclear medicine specialists, and surgeons. The spectrum of contributions to this special issue in International Journal of Endocrinology is well reflecting this situation. The contributions to this special issue, two reviews and three studies, report mainly on laboratory and imaging techniques to improve diagnosis in thyroid cancer. J. Hannallah et al. emphasize the multimodal approach in diagnosis and managing patients with poorly differentiated thyroid cancer in their review. The identification of poorly differentiated thyroid cancer has been complicated by the lack of clear criteria for diagnosis. A panel of histological, immunohistochemical, and genetic markers and clinical parameters is listed which are typical for this thyroid carcinoma entity. The value of current treatment possibilities is critically discussed. In the paper review by G. Treglia et al. the role of Fluorine-18-Fluorodeoxyglucose positron emission tomography in aggressive subtypes of different thyroid cancer types (Hurthle cell, anaplastic, poorly differentiated, more aggressive histological subtypes of differentiated thyroid cancer, and metastases) is discussed. FDG-PET-positivity in radio-iodine-refractory differentiated thyroid cancer appears to predict more aggressive tumor progression. Data on imaging of medullary thyroid carcinoma lesions using glucagon-like peptide 1 by [Lys40(Ahx-HYNIC-99mTc/EDDA)NH2]-exendin-4 are presented by D. Pach et al. Radioactively labeled GLP-1 analogues are successfully used in patients with insulinoma but the diagnostic value in medullary thyroid cancer is not clear. According to the first preliminary data, the analogues may possess a confirmatory role in lesions where inconsistent results are obtained with other imaging procedures. S. H. Hsieh et al. in their study identified male gender as prognostic parameter for higher recurrence in papillary thyroid cancer in stages II–IV. The study by B. C. Ahn et al., by contrast, deals with a very established clinical test, the measurement of serum thyroglobulin levels, for the identification of recurrent lesions in differentiated thyroid cancer. The importance of patients' antithyroglobulin levels in the calculation of thyroglobulin levels is addressed. The identification of potentially aggressive subtypes of thyroid cancer and the early detection of recurrent lesions play key roles in the managing of the patient. By compiling these papers, we hope to add some knowledge with respect to screening and postoperative care particularly of the more aggressive thyroid cancer types. Eleonore Frohlich Richard Wahl Barbara Czarnocka Leonidas Duntas

PurposeThis study aimed to evaluate the MRI features of the main histological subtypes of thyroid cancer and enable differentiation between anaplastic thyroid carcinoma (ATC), poorly differentiated thyroid carcinoma (PDTC), and papillary thyroid carcinoma (PTC).Materials and methodsThis study included 79 patients with histopathologically proven thyroid cancer (14 ATCs, 8 PDTCs, and 57 PTCs) who underwent neck MRI. MRI images were retrospectively reviewed and compared between the three pathologies.ResultsThe maximum diameter was larger in ATCs and PDTCs than in PTCs (65.2 mm and 38.4 mm vs. 26.0 mm, p < 0.01). The signal intensity ratio of the solid components on T2-weighted images (T2WIs) was higher in ATCs than in PTCs (1.13 vs. 0.89, p < 0.05). The predominant signal intensity of the solid components on T2WI exhibited hyperintensity relative to the spinal cord in ATCs more frequently than in PTCs (71% vs. 30%, p < 0.01), whereas hypointensity was more frequent in PTCs than in ATCs and PDTCs (60% vs. 0% and 13%, p < 0.01). Intratumoral ring-shaped hypointensity on T2WI was more frequent in ATCs than in PDTCs and PTCs (64% vs. 13% and 18%, p < 0.01). An ill-defined margin was more frequent in ATCs and PDTCs than in PTCs (93% and 63% vs. 25%, p < 0.01). Extrathyroidal extension, tracheal invasion, esophageal invasion, vascular invasion, and venous thrombosis were more frequently observed in ATCs than in PTCs (p < 0.05).ConclusionsMRI could characterize the differences between ATCs, PDTCs, and PTCs.

IntroductionLocally advanced thyroid cancer refers to thyroid cancer that invades important structures of the neck, with poor prognosis. Neoadjuvant targeted therapy has the potential to increase the R0/1 resection rate in locally advanced thyroid cancer and improve the outcome in these patients.MethodsWe conducted a systematic review of studies that reported neoadjuvant targeted therapy in locally advanced thyroid cancer. Individual patient data was extracted from eligible studies. Objective response rate (ORR) and R0/1 resection rate were calculated.ResultsSixteen studies and 32 patients were included into analysis, including 18 differentiated thyroid cancer (DTC), 3 medullary thyroid cancer (MTC), 8 anaplastic thyroid cancer (ATC) and 3 poor-differentiated thyroid cancer (PDTC). Most patients were stage T4a (53.1%) and T4b (28.1%). 81.3% patients had regional lymph node metastasis and 37.5% had distant metastasis. RET mutated MTC and BRAF mutated ATC were treated with selective RET inhibitor and selective BRAF/MEK inhibitors. Other treatment regimens were multitarget tyrosine kinase inhibitors (mTKIs). The average duration of treatment was 4.3 months (SD = 4.1). The overall ORR was 78.1% (95%CI: 60.0%–90.7%), and the R0/1 resection rate for the intention to treat population was 78.1% (95%CI: 60.0%–90.7%). With a median follow-up time of 12.1 months, 1 DTC patient and 3 ATC patients died of the disease.ConclusionsNeoadjuvant targeted therapy was a new treatment option for locally advanced thyroid cancer and might improve the R0/1 resection rate in selective cases. However, more clinical trials with longer follow-up time are awaited to confirm the clinical benefit of neoadjuvant targeted treatment.

A new study points to disparities in thyroid cancer incidence between specific age and ethnic groups, but the authors and others say that its findings tell only part of the story and that more research needs to be performed.The study, presented in Orlando, Florida, at ENDO 2017, the annual scientific meeting of the Endocrine Society, shows that the incidence of thyroid cancer is rising among young people and among Hispanics and African Americans.Although the incidence of the disease appears to be increasing at a slower rate now than it was a few years ago, that slowing has occurred mainly among non-Hispanic whites and older populations, whereas the rate of thyroid cancer has continuously increased in young and Hispanic and black populations according to Anupam Kotwal, MBBS, a clinical fellow in the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at the Mayo Clinic in Rochester, Minnesota.Kotwal has been working with Mayo Clinic endocrinologist Juan Brito Campana, MBBS, to examine how sex, racial, and age disparities play a role in the diagnosis of thyroid cancer, access to care, and its management.The study may have implications for disease-specific outcomes as well as societal and economic costs, he notes."[Thyroid cancer] is the most common cancer in Hispanic females, female adolescents, and young adults.