Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma: A Review and Multidisciplinary 2023 Update.

Importance: Oncocytic (Hürthle cell) thyroid carcinoma is a follicular cell-derived neoplasm that accounts for approximately 5% of all thyroid cancers. Until recently, it was categorized as a follicular thyroid carcinoma, and its management was standardized with that of other differentiated thyroid carcinomas. In 2022, given an improved understanding of the unique molecular profile and clinical behavior of oncocytic thyroid carcinoma, the World Health Organization reclassified oncocytic thyroid carcinoma as distinct from follicular thyroid carcinoma. The International Thyroid Oncology Group and the American Head and Neck Society then collaborated to review the existing evidence on oncocytic thyroid carcinoma, from diagnosis through clinical management and follow-up surveillance. Observations: Given that oncocytic thyroid carcinoma was previously classified as a subtype of follicular thyroid carcinoma, it was clinically studied in that context. However, due to its low prevalence and previous classification schema, there are few studies that have specifically evaluated oncocytic thyroid carcinoma. Recent data indicate that oncocytic thyroid carcinoma is a distinct class of malignant thyroid tumor with a group of distinct genetic alterations and clinicopathologic features. Oncocytic thyroid carcinoma displays higher rates of somatic gene variants and genomic chromosomal loss of heterozygosity than do other thyroid cancers, and it harbors unique mitochondrial DNA variations. Clinically, oncocytic thyroid carcinoma is more likely to have locoregional (lymph node) metastases than is follicular thyroid carcinoma-with which it was formerly classified-and it develops distant metastases more frequently than papillary thyroid carcinoma. In addition, oncocytic thyroid carcinoma rarely absorbs radioiodine. Conclusions and Relevance: The findings of this review suggest that the distinct clinical presentation of oncocytic thyroid carcinoma, including its metastatic behavior and its reduced avidity to radioiodine therapy, warrants a tailored disease management approach. The reclassification of oncocytic thyroid carcinoma by the World Health Organization is an important milestone toward developing a specific and comprehensive clinical management for oncocytic thyroid carcinoma that considers its distinct characteristics.

A Pilot Nonrandomized Controlled Trial Examining the Use of Artificial Tears on the Radioactivity of Tears After Radioactive Iodine Treatment for Thyroid Cancer.

Background: Nasolacrimal duct obstruction (NLDO) is an adverse effect of high dose radioactive iodine (RAI) therapy for thyroid carcinoma. There are currently no established preventive measures. This study assesses whether preservative free artificial tears (PFATs) can decrease the 131I sodium iodide (131I) activity in the tears of patients following RAI therapy for thyroid carcinoma, and potentially serve as a preventive measure for RAI-associated NLDO. Methods: This non-randomized prospective pilot clinical trial recruited contact-lens wearing patients undergoing RAI therapy for thyroid cancer to self-administer PFATs into the right eye for four days starting on the day of RAI ingestion. Left eyes were the controls. While wearing contacts, patients self-administered PFATs per the following-Day 1: every 15 minutes for 2 hours, then every 30 minutes until bedtime, day 2: every hour for at least 12 hours, day 3: four times a day, and day 4: two times a day. Contact lenses were changed daily, and all lenses were collected one week later. Levels of 131I activity were measured by a well counter, decay-corrected, and converted to units of becquerel. Statistical analyses were performed to compare the 131I activities of the experimental and control eyes. Results: Sixteen eyes of eight patients treated with an average of 145.7 mCi (range 108-159) of 131I for papillary thyroid cancer were included. On day 1, artificial tears decreased the geometric mean 131I activity by 26% in the experimental eyes (p = 0.008). Artificial tears also decreased the geometric mean area under the curve over four days by 23% (p = 0.002). Conclusions: 131I is present in the tears following RAI therapy for thyroid carcinoma. Frequent PFATs starting on the day of RAI ingestion may decrease the level of 131I in the tears. This finding could have implications for lowering the risk of NLDO. Future multi-center clinical trials are needed to determine whether the use of artificial tears after RAI therapy may decrease the risk of NLDO. Clinical Trial Registration: NCT04327999.

Molecular signature incorporating the immune microenvironment enhances thyroid cancer outcome prediction.

Genomic and transcriptomic analysis has furthered our understanding of many tumors. Yet, thyroid cancer management is largely guided by staging and histology, with few molecular prognostic and treatment biomarkers. Here, we utilize a large cohort of 251 patients with 312 samples from two tertiary medical centers and perform DNA/RNA sequencing, spatial transcriptomics, and multiplex immunofluorescence to identify biomarkers of aggressive thyroid malignancy. We identify high-risk mutations and discover a unique molecular signature of aggressive disease, the Molecular Aggression and Prediction (MAP) score, which provides improved prognostication over high-risk mutations alone. The MAP score is enriched for genes involved in epithelial de-differentiation, cellular division, and the tumor microenvironment. The MAP score also identifies aggressive tumors with lymphocyte-rich stroma that may benefit from immunotherapy. Future clinical profiling of the stromal microenvironment of thyroid cancer could improve prognostication, inform immunotherapy, and support development of novel therapeutics for thyroid cancer and other stroma-rich tumors.

Factors Associated With Radioactive Iodine Therapy-Acquired Nasolacrimal Duct Obstruction.

OBJECTIVE: To identify factors associated with radioactive iodine (RAI)-acquired nasolacrimal duct obstruction (NLDO). METHODS: Retrospective chart review and telephone surveys of patients who received RAI therapy for thyroid carcinoma at an academic institution were conducted. Telephone surveys were used to screen for post-RAI NLDO diagnoses. Databases were reviewed for documented NLDO, demographics, RAI dose, total number of RAI treatments, and sialadenitis. Routine post-RAI whole-body scintigraphy (WBS) images were analyzed for the presence or absence of 131I sodium iodide (I-131) in the nasolacrimal duct. Intranasal I-131 activity was graded as none, low, moderate, and high; those with moderate or high activity were considered to have "increased" activity. Logistic and ordinal logistic regression models were used to evaluate the associations with NLDO while adjusting for I-131 dose. RESULTS: Of the 209 patients who completed the survey, 15 (7%) had NLDO diagnoses. Increased intranasal I-131 activity on WBS, presence of nasolacrimal I-131 WBS activity, presence of documented post-RAI sialadenitis, and history of >1 RAI treatment were associated with the development of NLDO from univariate analyses (P ≤ .013). After adjusting for the administered dose of I-131, the presence of sialadenitis and nasolacrimal I-131 activity on WBS were the remaining 2 factors significantly associated with NLDO development (P < .001 and P = .01, respectively). CONCLUSIONS: The presence of sialadenitis and nasolacrimal I-131 activity on WBS are I-131 dose-independent correlative factors for RAI-associated NLDO. Patients with these characteristics should be counseled on their increased risk of NLDO after RAI therapy for thyroid carcinoma.

Approach to the Patient With Thyrotoxicosis Using Telemedicine.

CONTEXT: The potential for endocrine care via telemedicine has been recognized since the early 2000s when clinical outcome data demonstrated improvements in glycemic control with telemedicine. The widespread use of telemedicine during the COVID-19 pandemic has pushed telemedicine beyond diabetes care and into clinical areas with a paucity of published data. The evaluation and treatment of thyrotoxicosis heavily relies on laboratory assessment and imaging with physical exam playing a role to help differentiate the etiology and assess the severity of thyrotoxicosis. CASE DESCRIPTION: We describe a patient presenting for evaluation of new thyrotoxicosis via telemedicine, and describe modifications to consider for thorough, safe evaluation via telemedicine. CONCLUSION: Telemedicine may be an ideal way to assess and treat patients with thyrotoxicosis who are not able to physically attend a visit with an endocrinologist but still have access to a laboratory for blood draws. Potential challenges include access to imaging and high-volume surgeons if needed. Clinical and economic outcomes of telemedicine care of thyrotoxicosis should be studied so that standards of care for endocrine telemedicine can be established.

Wnt Signaling in Thyroid Homeostasis and Carcinogenesis.

The Wnt pathway is essential for stem cell maintenance, but little is known about its role in thyroid hormone signaling and thyroid stem cell survival and maintenance. In addition, the role of Wnt signaling in thyroid cancer progenitor cells is also unclear. Here, we present emerging evidence for the role of Wnt signaling in somatic thyroid stem cell and thyroid cancer stem cell function. An improved understanding of the role of Wnt signaling in thyroid physiology and carcinogenesis is essential for improving both thyroid disease diagnostics and therapeutics.

Management of Hyperthyroidism during the Preconception Phase, Pregnancy, and the Postpartum Period.

Hyperthyroidism can occur during pregnancy and the postpartum period, and the treatment of hyperthyroidism should be considered in the preconception phase. Pregnancy has multiple normal physiologic effects on thyroid hormone, which is a separate process distinct from syndromes such as transient hyperthyroidism of hyperemesis gravidarum. The rationale regarding antithyroid drug use during different stages of pregnancy is reviewed, including the literature regarding adverse neonatal outcomes such as aplasia cutis and methimazole embryopathy in the setting of first trimester maternal methimazole use. The use of treatment modalities for hyperthyroidism during pregnancy such as surgery is also discussed. Studies of maternal, fetal, and neonatal complications of hyperthyroidism are examined in this article. Moreover, the evidence regarding antithyroid drugs, specifically methimazole and propylthiouracil, during lactation is considered. Other disease conditions that can take place during pregnancy and the postpartum period such as hyperemesis gravidarum, subclinical hyperthyroidism, gestational trophoblastic disease, and postpartum thyroiditis and their treatments are also presented.

Thyroid Cancer in Pregnancy.

Owing to the young median age of diagnosis, thyroid cancer in women can coincide with pregnancy and affect its management. The evaluation of a thyroid nodule in pregnant women is similar to that in nonpregnant women, but special consideration must be taken for the impact of a cancer diagnosis and its sequelae in pregnancy. The initial comprehensive exam for pregnant and nonpregnant women includes evaluation of the biochemical function and structure of the thyroid gland, and then fine-needle aspiration biopsy of any suspicious nodule. Management diverges after biopsy and diagnosis, as pregnancy affects timing of thyroidectomy and radioiodine exposure. Owing to the indolent nature of differentiated thyroid cancers, surgery can often be delayed to the immediate postpartum period without change in recurrence or mortality rate. However, for more aggressive thyroid cancers or if the patient wishes to pursue surgery during pregnancy, a discussion about maternal health, fetal risk, and disease prognosis is needed between the physician and patient. This review serves to discuss the evaluation of the thyroid nodule and management of thyroid cancers in the pregnant population, as well as address thyroid cancer surveillance in pregnant women with a previous history of thyroid cancer.

Is above age 45 appropriate for upstaging well-differentiated papillary thyroid cancer?

OBJECTIVE: Age greater than 45 years old is a prognostic marker in well-differentiated papillary thyroid cancer (PTC) using the American Joint Cancer Committee/Union Internationale Contre le Cancer Tumor Nodes Metastasis (AJCC/UICC TNM) staging system. Our clinical observation has been that patients aged 45 to 64 years have similar outcomes when compared to patients younger than 45 years, and we questioned the origin and accuracy of this prognostic variable. METHODS: Using SEERstat software, we analyzed the Surveillance, Epidemiology, and End Result (SEER) database for PTC using the following International Classification of Diseases for Oncology (ICD-O) codes: 8050, 8260, 8340, 8341, 8342, 8243, and 8344. Data were stratified in 5-year categories by age at diagnosis from 20 to 84 years old, with patients 85 years old and above categorized together. Survival is reported as cause specific. RESULTS: A total of 53,581 patients were identified. The 5-year survival rate decreased with each increasing age category with no inflection point at age 45 in the survival curve. While the prognosis was less favorable in each advancing age group, survival remained above 90% for all age groups under 65 years. CONCLUSION: A review of the literature reveals a lack of data supporting the use of age 45 as a prognostic variable. Our SEER database review revealed a continuum of disease-specific mortality for each incremental 5-year time period above age 45. We conclude that the current use of age 45 as a single prognostic age marker does not accurately reflect the progressive mortality risk that is apparent with each 5-year increment in age.