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Background: Metastatic disease to the thyroid gland is uncommon but well-described. Metastatic disease to a concurrent primary thyroid neoplasm is a rare phenomenon. We sought to study patients with metastasis to the thyroid with a focus on the histopathologic and clinical features in tumor-to-tumor metastasis., Methods: We identified a series of patients with metastatic disease to the thyroid, with or without a concurrent primary neoplasm, through a search of the files of the Department of Pathology. All relevant slides were retrieved and reviewed, including routine HE and immunohistochemical stains. We performed a detailed English language literature search (1962-2022) and review to identify tumor-to-tumor metastasis involving the thyroid., Results: We identified 14 patients with metastasis to the thyroid over a 22-year period. Four patients exhibited papillary thyroid carcinoma, with metastatic spread of a different malignancy seeding into the thyroid cancer. We describe the histopathologic diagnostic process and findings, clinical management, and the clinical course of tumor-to-tumor metastasis in greater detail for these 4 patients., Conclusion: Tumor-to-tumor metastasis to the thyroid is a rare event with unique histopathologic features. Our findings suggest that the phenomenon of tumor-to-tumor metastasis serves to highlight broader mechanisms of metastatic disease in general. We provide the largest-to-date and comprehensive review of the literature to identify all previous reported instances of tumor-to-tumor metastasis involving the thyroid., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Multidisciplinary Tumor Boards (MDT) are used to obtain input regarding cancer management. This study assessed the impact of our institutional Endocrine MDT., Methods: MDT notes on patients with thyroid cancer treated during 2012-2018 were abstracted retrospectively from the electronic medical record. Management change (MC) was prospectively collected by the MDT coordinator. Biannual evaluations reviewed the impact of the MDT as observed by attendees., Results: MC was recommended in 47 (15%) of 286 presentations, with additional imaging being the most frequent (43%). Presentation of recurrences were more likely to result in MC (24% vs. 13% initial, p = 0.03). Overall, 98% of attendees found the conference exceeded educational expectations. About 24% reported intending to use a more evidence/guideline-based approach after attending and this trend increased over time (p = 0.002)., Conclusion: MDT presentations led to a higher rate of MC particularly in recurrent TC patients and increased evidenced-based practice for attendees., (Copyright © 2021. Published by Elsevier Inc.)

Background: This study aims to analyze changes in characteristics, practice and outcomes of pediatric differentiated thyroid cancer (DTC) at our tertiary care institution., Methods: Patients <21 years of age diagnosed between 1973 and 2013 were identified. Clinicopathological data, treatment and outcomes were obtained by a retrospective review., Results: Thirteen males and 68 females were divided into Group A (n=35, diagnosed before July 1993) and Group B (n=46, diagnosed after July 1993). Group B was more likely to undergo neck ultrasound (US) (70% vs. 23%, p<0.0001) and fine-needle aspiration (FNA) biopsy (80% vs. 26%, p<0.0001). Patients in Group B more often underwent total thyroidectomy as a definitive surgical treatment (87% vs. 69%, p=0.04). There was no difference in radioactive iodine use. Recurrence-free survival was similar., Conclusions: Increased use of US and FNA has affected initial surgical management in the latter part of the study, possibly due to extension of adult DTC guidelines. The effects of the new pediatric DTC guidelines need further study.

Background: EphA2 is a tyrosine kinase receptor that is overexpressed in many cancers and is associated with poor prognosis and increased metastasis. Phosphorylated Akt (pAkt) plays a role in the regulation of thyroid cancer invasion and metastasis. We investigated the role of EphA2 and Akt in FTC-133 and FTC-238, 2 closely related human cell lines with differing invasive phenotypes., Methods: Western blot was used to measure the total protein expression in cell lines, and immunohistochemistry was performed on thyroid tissue microarrays. Thyroid cell lines were transfected with siRNA or cDNA. Invasion assays were performed using Matrigel chambers, and invaded cells were assayed with (3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT)., Results: EphA2 protein was expressed in thyroid cancer cell lines and in benign and malignant human thyroid tumors but not in normal thyroid. Compared with FTC-133, FTC-238 expressed fivefold more EphA2 protein and had a fivefold increase in invasion (P < .001). In FTC-238, EphA2 siRNA decreased EphA2 levels and reduced invasion, with a decrease in pAkt protein. Overexpression of EphA2 in FTC-133 increased invasion and increased pAkt protein. Akt siRNA and Akt inhibitors decreased pAkt levels and invasion without changing EphA2 levels., Conclusion: EphA2 is expressed in human thyroid cancer and mediates invasion in the follicular thyroid cell lines FTC-133 and -238. Phosphorylated Akt (pAkt), an important regulator of thyroid cancer metastasis, is attenuated by EphA2 knockdown, providing evidence that EphA2 may act through pAkt to mediate invasion. EphA2 and pAkt may be candidates for targeted therapy against metastatic thyroid cancer., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Purpose: To evaluate the risk of a subsequent primary thyroid cancer (SPTC) in patients with common invasive cancers, with attention to latency trends and histology associations., Methods: Patients with one of 10 common invasive cancers were followed from 1975 to 2008 in 9 registries participating in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Standardized incidence ratios (SIRs) for SPTC were determined by the multiple primary-SIR program in SEER*Stat., Results: A total of 2502 SPTCs were observed. Greatly elevated SIRs for SPTC were noted for 9 of 10 evaluated cancers in the 12 months after initial diagnosis. The SIRs remained elevated 12-59 months after diagnosis for all cancers except leukemia, uterine, and bladder cancers. Increased risks persisted 60-119 months beyond diagnosis for renal (SIR 2.56) and breast cancer (SIR 1.16); and 120+ months for renal cancer (SIR 2.46). Increased SPTC risk after renal and female breast cancers was mostly seen in nonirradiated patients. The principal histology association was between papillary thyroid cancer and renal cell carcinomas., Conclusions: Many common cancers are associated with increased risk of SPTC beyond 12 months of initial diagnosis. Although this can be explained partly by continued surveillance bias, radiation effects, and known rare familial associations for some tumors, these factors alone are unlikely to explain the persistent, significant two-way association with renal and breast cancers. Additional research is needed to further define the biological and environmental mechanisms underlying these associations.

Background: After thyroid lobectomy, many patients require ongoing care. This study sought to quantify the rates of surveillance and intervention after thyroid lobectomy., Methods: One hundred one consecutive patients who underwent a thyroid lobectomy for nodular disease were evaluated. Clinical and follow-up data were obtained by a review of patient charts and included an evaluation of resource utilization related to thyroid disease., Results: Nineteen patients required completion thyroidectomy for thyroid cancer, and 11 had hypothyroidism before lobectomy. Of the remaining evaluable patients, 30 (42.2%) of 71 required thyroid hormone replacement after lobectomy, with 24 patients having elevated thyroid-stimulating hormone and 6 suppression of nodules in the contralateral lobe. The likelihood of thyroid hormone replacement demonstrated a trend with a contralateral nodule (9 of 14 vs. 21 of 57, P = 0.06) and a significant association with thyroiditis on surgical pathology (10 of 11 vs. 20 of 60, P < 0.001). Of the 82 patients who did not undergo completion lobectomy, 10 (12%) of 82 underwent postoperative fine-needle aspiration of the contralateral lobe, and 25 (30%) of 82 were followed with ultrasound surveillance. Only 27% of patients treated with lobectomy required no further surveillance or intervention. There were no instances of permanent recurrent laryngeal nerve injury., Conclusions: After thyroid lobectomy, most patients require continued surveillance and intervention. With a near-zero complication rate, total thyroidectomy may be a more effective and efficient option for management of nodular thyroid disease.

Background: Integrated positron emission tomography (PET)-computed tomography (CT) may have advantages over conventional imaging in localizing recurrent or persistent differentiated thyroid cancer., Methods: A retrospective review of patients who underwent PET-CT scans was performed. Results were compared with contrast CT, magnetic resonance imaging, ultrasonography, and radioactive iodine (RAI) scans., Results: Thirty patients (mean age, 49.9 ± 17 years) underwent 36 PET-CT scans, mostly for elevated thyroglobulin levels and negative RAI scans (30 scans). Fifty percent (18/36) of PET-CT scans showed increased uptake in the neck, 11 of 36 (31%) in the chest, 3 of 36 (8.3%) in bone, and 6 of 36 (16.6%) in other areas. PET-CT had overall sensitivity, specificity, and positive predictive values of 73.9%, 61.5%, and 77.3% respectively. To assess the added value of PET-CT, we focused on the 21 scans performed after conventional imaging in 20 patients. PET-CT provided additional information in 2 (10%) patients, both of whom were spared interventions. However, PET-CT underestimated extent of disease in 3 (15%) patients and led to unnecessary interventions in 3 (15%) additional patients., Conclusion: PET-CT has reasonable sensitivity in the detection of recurrent thyroid cancer. However, the added value of PET-CT may be seen only in a limited number of patients after good quality, conventional imaging. Further studies are needed to determine the most cost-effective approach to managing these patients., (Copyright © 2010 Mosby, Inc. All rights reserved.)

Background: Mutations in the RET proto-oncogene cause multiple endocrine neoplasia type 2A (MEN2A), and prophylactic thyroidectomy has generally been recommended before the age of 5 years. Patients with codon 609 mutations develop MTC at a later age and therefore the timing of prophylactic thyroidectomy is less clear. We report a three-generation family with C609Y RET mutation where members having prophylactic or therapeutic thyroidectomy call the current recommendations for age at thyroidectomy into question., Methods: Sixteen family members underwent thyroidectomy, for which clinical, laboratory, and pathological data were analyzed. A literature review of RET codon 609 mutations was carried out., Results: Data were collected from 16 patients from this 38-member kindred. None of these affected members had pheochromocytoma, and one had a parathyroid adenoma. Nine of 16 patients had MTC (mean age 44.7 years, range 29-59 years) and elevated basal calcitonin levels; 6 of these 9 had lymph node metastases. Two patients had C-cell hyperplasia (CCH) at ages 18 and 37 years, and five patients had normal thyroid pathology (mean age 16 years, range 5-37 years). In the literature, a family with C609Y mutation was reported, with 15 members having MTC (mean age 42 years, range 21-59 years), and 6 with CCH (mean age 24 years, range 15-37 years)., Conclusion: The youngest patient with C609Y RET mutation and MTC was 21 years old, and the youngest patient with CCH was 15 years old at diagnosis. These data suggest that patients with RET C609Y mutations can delay thyroidectomy until 10-15 years of age, with annual calcitonin screening prior to thyroidectomy.

Background: Increased extracellular matrix 1 (ECM1) expression, as determined by real-time reverse transcriptase-polymerase chain reaction (RT-PCR), has been recently proposed as a novel and independent diagnostic marker for malignant thyroid nodules. However ECM1 protein expression has not been previously evaluated in thyroid tumors. Real-time RT-PCR is not widely available and this has important implications for the widespread use of the expression of this gene for diagnosis. The purpose of the current study is to evaluate and compare ECM1 expression by real-time RT-PCR with immunohistochemistry (IHC) as diagnostic aids in thyroid neoplasms., Materials and Methods: ECM1 expression was studied in normal thyroid tissues (n = 14) and primary thyroid tumors (19 benign, 30 malignant) using both techniques. The performance characteristics of ECM1 expression were examined with receiver operating characteristic curves and the resulting area under the curve., Results: ECM1 was highly expressed in thyroid carcinomas, compared with benign thyroid tissues, both at the mRNA (P < 0.01) and protein (P = 0.06) levels. However, ECM1 mRNA expression appeared to be a more sensitive marker of thyroid malignancy than IHC (AUC = 0.77 and 0.65, respectively). ECM1 expression by both methods was useful in identifying malignant follicular, but not Hürthle cell neoplasms., Conclusions: We confirm that ECM1 expression has potential utility as an independent diagnostic marker for thyroid cancer, although, performance characteristics were lower than previously published. Furthermore, IHC was not as sensitive as real-time RT-PCR in identifying malignant lesions. Prospective studies are needed to further clarify the role of ECM1 expression as a diagnostic marker.

Increased 14-3-3sigma expression has been observed by immunohistochemistry in papillary and anaplastic tumors, but not follicular thyroid cancers. 14-3-3sigma mRNA expression and methylation status was examined in tumor cell lines and primary thyroid tissues using real-time RT-PCR, bisulfite sequencing and methylation-specific PCR. Most of the 27 CpG's in the gene's CpG island were methylated in normal thyroid, TPC-1, NPA, FTC-238 and 2-7, which did not express 14-3-3sigma. In contrast, they were unmethylated in KAK-1 and anaplastic lines KAT4 and DRO-90. 14-3-3sigma expression was not increased in thyroid carcinomas, the majority of which had a methylated CpG island. In addition, 5-aza-dC treatment increased 14-3-3sigma expression in the FTC-238 and NPA cell lines, which had low baseline expression. We conclude 14-3-3sigma expression in thyroid carcinomas is regulated by CpG island hypermethylation.

Background: Allelotype studies have suggested that chromosome 1p is frequently lost in thyroid cancers, thus suggesting that there is an important tumor suppressor at this location. RIZ1 (PRDM2), located on 1p36, is a recently described tumor suppressor gene and is a member of the protein methyltransferase superfamily. RIZ1 expression is lost in a variety of tumors, primarily by means of epigenetic mechanisms that involve promoter hypermethylation., Methods: RIZ1 expression was examined in a panel of thyroid tumor cell lines and primary thyroid tissues (14 normal, 19 benign, and 31 cancerous) by using real-time polymerase chain reaction (PCR). Methylation status of the RIZ1 promoter was studied using bisulfite sequencing and methylation-specific PCR., Results: The authors demonstrated that RIZ1 expression is lost in thyroid tumor cell lines and is also significantly reduced in thyroid carcinomas, when compared with normal thyroid tissues (P < .0001) and benign tumors (P = .0003). The current study results also showed that loss of RIZ1 is mediated by aberrant cytosine methylation of the RIZ1 promoter. One hundred percent of carcinomas were methylated, compared with 33% of normal thyroid tissues (P = .001). RIZ1 mRNA expression was significantly higher (P = .02) in unmethylated (1.22 +/- 1.2, mean +/- standard deviation [SD]), compared with methylated tissues (0.37 +/- 0.42, mean +/- SD). Last, treatment with a DNA methyltransferase inhibitor led to reactivation of RIZ1 expression in cell lines that had negligible RIZ1 expression at baseline., Conclusions: The current study suggested an important role for RIZ1 expression in thyroid tumorigenesis and identified a potential novel therapeutic target for tumors unresponsive to other therapies., (Copyright 2006 American Cancer Society.)

Medullary thyroid cancers account for approximately 7% of primary thyroid malignancies and are often associated with paraneoplastic syndromes. We discuss the case of a 59-year-old man who presented with a hypercoagulable state, nonbacterial endocarditis, and recurrent strokes in the setting of widespread medullary thyroid cancer. The patient was anticoagulated and underwent thyroidectomy, modified radical neck dissection, and subsequent axillary lymphadenectomy. Despite no recurrent thromboembolic events, the patient ultimately succumbed to his disease 8 months after diagnosis and 6 months after initial thyroidectomy. This is the first report, to our knowledge, of this unique presentation in a patient with thyroid cancer. The literature pertaining to the diagnosis and management of hypercoagulability states in patients with cancer, in general, and thyroid cancer, in particular, is reviewed.