bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Thrombotic Risk in Thyroid Cancer
Authors: Akamnonu Chukwuka , Cohen David A
Published: May 2021

Introduction: Current guidelines from the International Society of Thrombosis and Hemostasis recommend limited screenings for deep vein thrombosis (DVT) or pulmonary embolism (PE) with no identifiable precipitating factor (termed unprovoked). There is paucity of data with regards to thyroid cancer screening in the setting of an unprovoked VTE. Studies from Europe have shown an association between VTE and thyroid cancer; however, these studies do not account for differences in iodine availability, thus the need for studies in the United States. Understanding the risk of thyroid cancer as a provocative factor in developing a deep venous thrombosis (DVT) or pulmonary embolism (PE) may be able to facilitate case detection of disease and prevent future morbidity and mortality from thyroid cancer and/or VTE. Objectives: The primary objective of this study is to understand the risk of developing VTE in the setting of thyroid cancer. Methods: In this retrospective chart review study, we reviewed electronic medical records of patients with a history of DVT or PE between ages 18-99, presenting to all outpatient clinics at a single academic medical center in New Jersey between October 1, 2015, and Dec 31, 2018. We screened for coexistent cancer history among this group, and from this sample we further isolated cases of thyroid cancer. Results: 345 patients were found to have a history of VTE. 187 were female (54%) and 113 (29%) had a history of malignancy. The most common cancers were breast (19%), colorectal (9%), leukemia (9%), prostate (8%), and lymphoma (8%). Thyroid cancer accounted for 2% of all discovered cases. Conclusion: In this retrospective analysis, 2% of all patients with VTE and cancer carried a diagnosis of thyroid cancer. Although this suggests a relatively low risk, given the medical burden of a venous thromboembolism and the comparable proportion of thyroid cancer in all new cancer cases, thyroid cancer should be considered a provoking factor in unprovoked VTE.
Histological Study on the Thyroid Tissue Adjoining the Noninvasive Thyroid Follicular Neoplasm With Papillary-Like Nuclear Features, Seeking a Possible Association With Hashimoto’s Thyroiditis
Authors: Pereira Paola N
Published: May 2021

Papillary thyroid carcinoma (PTC) is the most frequent type of thyroid cancer (TC), and advances in ultrasound methods resulted in better and higher detection of this tumor. Thus, the increase in the incidence of PTC is due to the detection of microcarcinomas by ultrasound, as well as partially, due to the increased diagnosis of the encapsulated and/or well-defined non-invasive follicular variant of thyroid papillary carcinoma (NIEFVPTC). Recently, there was a change in the histological classification of NIEFVPTC, currently known as non-invasive follicular thyroid neoplasm with papillary-like features (NIFTP), thus the clinical evidence leads to an excellent prognosis once its a indolent neoplasia, dismissing additional treatments as lymphadenectomy and radioiodotherapy, therefore reducing psychological impact. This study was approved by the ethics and research committee and addressed the analysis and review of histological slides of thyroid neoplasia that currently meet the criteria for NIFTP. Furthermore, the study sought to evaluate the concomitant existence of NIFTP with histological findings consistent with Hashimoto’s Thyroiditis (HT). Underlying studies evoke a possible increase in the imperil of developing PTC when associated with HT. It should be noted that this morphological correlation is poorly described in the literature. Accordingly, a retrospective study was carried out by histological review of 232 cases diagnosed as PTC from total thyroidectomies with cervical lymphadenectomy from 1993 to 2014, previously diagnosed as NIEFVPTC. The histological slides of these cases came from the Surgical Pathology files of the Pathology Department of UNICAMP, Brazil. After histological review, 14 cases reclassified as NIFTP were selected, all referring to female patients, of which 6 presented histological criteria of NIFTP associated with HT. Additionally, a histological and laboratory correlation of the 14 selected cases was performed through the dosages of relevant serum titers of antithyroid antibodies (anti-TPO and TgAb). Out of the 6 patients detected with association of NIFTP and TH, 5 had significant titers above 65IU/ml for anti-TPO and 120IU/ml for TgAb. Additional data from thyroid ultrasonography were collected and showed that cases of NIFTP without association with HT, presented nodules ranging from 1.5 cm to 5.1 cm, predominantly hypoechoic, solid, with regular contours, peripheral vascularization and located predominantly in the right lobe. In conclusion, 14 cases of NIFTP were detected, among 232 cases of PTC, with 6 cases being histologically associated with HT. Of these, 5 cases had laboratory tests with positive antithyroid antibody titers, proving this association, from a clinical point of view. All cases of NIFTP with and without HT association were female, with nodules ranging from 0.3cm to 5.0cm to ultrasound, predominantly in the right lobe.
Indeterminate Thyroid Nodules With RAS Mutations Have Higher Rates of Malignancy When Multiple Non-Cystic Nodules or Irregular Borders Are Present
Authors: Bernuy Mario Carlos C Rivera , Tessnow Alex , Hussain Iram
Published: May 2021

Background: There is heterogeneity in positive predictive value for cancer in RAS-mutated cytologically indeterminate nodules and paucity of data with regards to specific ultrasound features that are associated with malignancy in these nodules. The goal of this study is to assess the ultrasonographic characteristics, in relation to clinical and histopathologic outcomes of thyroid nodules known to have a RAS mutation. Design and Methods: Cases were identified using our institutional Afirma® Genetic Sequence Classifier (GSC) database, and a retrospective review of electronic medical records for thyroid nodules biopsied between January 2018 and August 2020. Nodules categorized as Bethesda III or IV and harboring a RAS mutation by Xpression Atlas® were included. Thyroid ultrasound images were reviewed by the authors and were risk stratified according to the 2015 American Thyroid Association Thyroid Nodule and Differentiated Thyroid Cancer Guidelines (ATA Guidelines) and the 2017 ACR TIRADS system (ACR Guidelines). The nodules were divided into benign or malignant categories based on surgical pathology. Noninvasive follicular thyroid neoplasms with papillary like nuclear features (NIFTP) were categorized as benign. Results: A total of 22 nodules were identified to have a RAS mutation. NRAS mutated nodules, all with the same point mutation (pQ61R c.182A>G), were most common 14/22 (63.6%). There was no significant difference in clinical features, ultrasonographic appearance or histopathologic outcomes between NRAS- and HRAS-mutated nodules. 12/22 (54.4%) were low risk by ATA Guidelines and 11/22 (50%) were TIRADS 4 (moderately suspicious) by ACR Guidelines. There was no significant difference in predictive value of ATA Guidelines vs ACR Guidelines. The prevalence of malignancy was 45.4% (only slightly lower than the general risk for a suspicious GSC). Invasive follicular variant papillary thyroid cancer (FVPTC), was the most common malignancy, 4/10 (40%). 6/10 (60%) were classified as low risk of recurrence post-operatively. All malignant RAS-mutated nodules (10/10) had at least one other non-cystic nodule present on ultrasonography whereas only 4/9 (44%) of RAS-mutated benign nodules did [P=.006]. RAS-mutated malignant nodules had significantly more nodules with irregular borders compared to RAS-mutated benign nodules (4/10 and 0/10, 40% and 0% respectively) [P=.03]. Conclusions: This is the first study to observe higher rates of malignancy in RAS-mutated indeterminate nodules when other non-cystic nodules are present. A lobectomy is the preferred surgical approach for RAS-mutated nodules, however a total thyroidectomy may be considered in patients with other non-cystic nodules or irregular nodules borders. Overall, RAS-mutated nodules have a low risk of recurrence post-operatively.
Macrophage-Tumor Crosstalk in the Pathogenesis of Follicular Thyroid Cancer
Authors: Caperton Caitlin , Franco Aime T
Published: May 2021

Thyroid cancer is the most common endocrine malignancy and one of the fastest growing cancers in the United States. Follicular thyroid carcinoma (FTC) represents the second most common form of thyroid cancer diagnosed in the US and is most often tied to mutations in the RAS protein family of the MAP kinase pathway. In addition to driver mutations, FTC is characterized by a unique tumor microenvironment (TME) composed of cellular and non-cellular components that impact tumorigenesis and disease progression. Preliminary data from our lab has shown that CD45+ immune cells account for approximately 68% of all cells found in whole tumors collected from mouse models of RAS-driven disease. Macrophages account for the largest portion of known immune cell populations. Further experiments have demonstrated that tumor cell lines isolated from our RAS-driven models secrete cytokines known to impact the recruitment and activation state of cells of the myeloid lineage, particularly macrophages. However, it’s unclear what type of functional characteristics are induced by these secreted factors and how the resulting macrophage phenotype affects disease progression. Here, we sought to determine how bidirectional communication between macrophages and thyroid cancer cell lines could contribute to the development of a protumorigenic microenvironment. First, we began by defining how RAS-driven thyroid cancer cell lines affected the functional phenotype of previously unstimulated macrophages. Through gene expression analysis encompassing several markers of macrophage activation states, we determined that tumor cell-secreted factors induced the expression of multiple genes associated with tumor associated macrophages (TAM). In particular, we observed consistent upregulation of IL-10 and TNF-alpha, factors that have been associated with worsening disease. These results were further validated through quantification of protein secretion. In addition, we determined the role of activated macrophages in the progression of thyroid cancer, and specifically the effect of macrophage-secreted factors on tumor cell proliferation. Through direct and indirect assays of proliferation, we determined that factors secreted by classically-activated M1 macrophages inhibited cell proliferation. Surprisingly, secretions from alternatively-activated M2 macrophages reduced in vitro cell growth in some cell lines. Further analysis demonstrated that reduced cell proliferation was not associated with cell death, but rather was a result of delayed progression through the cell cycle. These results help to further define the macrophage phenotype within our model of FTC and will identify potential therapeutic targets to reduce the activity of protumorigenic cell populations.
Management of Papillary Thyroid Cancer Metastatic to the Central Nervous System: A Narrative Review of the Literature
Authors: Zambrano Jose Leonel , Ramos Andrés Felipe García , Pico Víctor Manuel Blanco , García Franco Alejandro Vallejo , Arboleda Marcela Patiño , Valencia Carlos Mario Balcázar , Chaparro Jose Mauricio Ocampo
Published: May 2021

Introduction: Brain metastases (BM) associated with papillary thyroid cancer (PTC) occur with an approximate frequency of 0.15% to 1.3% of PTC cases. There is little evidence regarding the treatment of this association (PTC and BM). A narrative review of the literature is presented. We assessed multiple treatment options and its effectiveness in this vulnerable population. Methods: The data were collected using the PubMed search engine and Google Scholar. There were selected all studies that included: << thyroid carcinoma >> << brain metastases >> << radiotherapy >> << surgery >> << iodine-131 >> << papillary carcinoma >> << differentiated carcinoma >>. Once the relevant works had been listed and compared, the main findings of each one were related and analyzed. Results: We found 15 studies between the years 1990 and 2019 that describe 187 patients with thyroid cancer and brain metastases; of which 138 presented PTC, and 62% (58/93) were women. The average age was 59 years. Patients who received multimodal treatment (association of 2 or more therapies; one of them, brain metastasis resection) had a longer survival, with an average of 54 months, compared to monotherapy. Discussion: Patients with PTC who also present BM require a multimodal therapy approach: when it is associated with brain metastasis resection, better results are evident; in contrast, when monotherapy is used, a limited performance is observed, with poor results. Conclusion: Patients with PTC who also present BM have better outcomes and higher survival rate with a multimodal therapy approach, including brain metastasis resection.
Machine Learning-Based Models for Prediction of Subtype Diagnosis of Primary Aldosteronism Using Blood Test
Authors: Kaneko Hiroki , Umakoshi Hironobu , Ogata Masatoshi , Wada Norio , Iwahashi Norifusa , Fukumoto Tazuru , Yokomoto-Umakoshi Maki , Nakano Yui , Matsuda Yayoi , Miyazawa Takashi , Sakamoto Ryuichi , Ogawa Yoshihiro
Published: May 2021

Context: Primary aldosteronism (PA) is a common cause of secondary hypertension and is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who can be cured by unilateral adrenalectomy and should be referred to specialized centers. The use of machine learning has been introduced in some fields of clinical prediction. Combining machine learning with clinical data could lead to the development of new models for predicting unilateral subtype of PA. Objective: The aim of this study was to develop a predictive model of subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Design and setting: This was a retrospective cross-sectional study in referral centers. Patients: We retrospectively analyzed 91 patients with unilateral and 138 patients with bilateral subtype of PA diagnosed according to adrenal venous sampling findings, and stratified randomly split to the training (80%) and test cohorts (20%). Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop prediction models from 21 clinical variables. Classifiers were trained using stratified 10 fold cross-validation of the training cohort and hyperparameters of each classifier were adjusted using grid search to optimize the accuracy in the training cohort. Main Outcome Measures: The accuracy and the area under the receiver operating characteristic curve (AUC) for subtype prediction in the test cohort were compared among the optimized classifiers. Results: Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7% and 0.990, respectively. Serum potassium levels, plasma aldosterone concentrations, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1% and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF. Conclusions: Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.
Navigating the Debate on Large (4+cm) Thyroid Nodules: Local Insight on a Persisting Problem
Authors: Steinmetz-Wood Samantha , Kennedy Amanda , Tompkins Bradley , Gilbert Matthew Philip
Published: May 2021

Background: Thyroid nodules are a common clinical finding, however discordant practice guidelines for managing large nodules may result in unnecessary surgeries and excess costs. Recent data suggest similar false negative rates in fine needle aspiration (FNA) biopsies between small (<4cm) and large (4+ cm) nodules, indicating that monitoring rather than surgery may be appropriate for large nodules. Evaluating current management strategies may reveal insights regarding excess surgeries, costs and opportunities for improvement.

Objectives: The goal of this project was to describe the patients at our institution with large thyroid nodules and determine the proportion of potentially unnecessary surgeries and the associated predictors.

Methods: This was a retrospective cohort study that included patients who received a FNA of nodule (s) ≥4cm between 11/1/2014 and 10/31/2019 at our tertiary care institution. Patient demographics, sonographic nodule size, fine needle aspiration cytology, molecular testing results, final surgical pathology, history of neck irradiation, family history of thyroid cancer, presence of compressive symptoms or presence of a toxic nodule or toxic multinodular goiter, were compared between patients who had surgery and those who did not. A surgery was considered inappropriate if the FNA result was benign in the absence of any of the following: a suspicious result on molecular testing, compressive symptoms, family history of thyroid cancer in a first degree relative, history of neck irradiation, toxic nodule or toxic multinodular goiter or substernal extension. Continuous variables were evaluated using Wilcoxon rank-sum test while categorical variables were tested using chi-square or Fisher’s exact test.

Results: A total of 177 patients had a 4+ cm nodule during the timeframe. Half of patients (54.2%)with 4+ cm nodules had surgery. Patients who underwent surgery were significantly younger (51.5 years vs 62 years; P<0.001), more likely to report obstructive symptoms (34.4% vs 12.1%; P=0.001) and have a larger nodule size (5.0 cm vs 4.7 cm; P=0.26) than patients who did not have surgery. Forty-one patients with benign (Bethesda II) FNA results went on to have surgery. All 41 patients were found to be negative at surgery, yielding a false negative rate of 0.0% in our cohort. Twenty-three surgeries (24.0%) were considered inappropriate and overall 13% (23/177) of patients with 4+cm nodules had unnecessary surgery. The median charge for these surgeries was $13,183.

Conclusion: Approximately half of our patients with 4+ cm nodules had surgery, especially patients who are younger, report obstructive symptoms, and have larger nodule sizes. Overall 13% of our patients with 4+cm nodules had unnecessary surgery revealing opportunities for improving care and costs.
Prevalence and Spectrum of DICER1Mutations in Adult-Onset Thyroid Nodules
Authors: Chong Anne-Sophie , Nikiforov Yuri E , Condello Vincenzo , Wald Abigail , Nikiforova Marina , Foulkes William , Rivera Barbara
Published: May 2021

Context: DICER1 mutations are found in multinodular goiter and differentiated thyroid carcinoma in children, and can be a manifestation of DICER1 syndrome, but the prevalence of DICER1 mutations and their significance in adult-onset thyroid nodules is unknown.

Objective: Determine 1) the prevalence of DICER1 hotspot mutations in thyroid nodules; 2) the frequency of a second DICER1 pathogenic variant in thyroid nodules with DICER1 hotspot mutations; 3) the prevalence of other thyroid cancer driver mutations in thyroid nodules with and without DICER1 hotspot mutations.

Design: Population-based study of 14,993 consecutive fine needle aspiration biopsies of thyroid nodules evaluated by ThyroSeq v3. From 214 DICER1 hotspot-positive cases, we selected 61, matched to DICER1 hotspot-negative nodules. We performed full sequencing of all exons and exon-intron boundaries of DICER1.

Setting: Commercial and university-based laboratories in the United States and Canada

Results: Among 14,993 thyroid nodules, 214 (1.4%) revealed a DICER1 hotspot mutation. A second pathogenic/likely pathogenic variant in DICER1 was found in 45/59 (76%) DICER1 hotspot-positive nodules studied while no other DICER1 variant was identified in the DICER1 hotspot-negative group by full DICER1 sequencing. Other alterations in thyroid-related genes were significantly more frequent in DICER1 hotspot-negative nodules (32/61) than in DICER1 hotspot-positive nodules (4/59) (p<0.0001).

Conclusions: DICER1 alterations occur in a proportion of adult thyroid nodules and appear mutually exclusive with alterations in other thyroid cancer-related genes. DICER1 hotspot mutations occur with a second hit in most cases and could suggest occult DICER1 syndrome in adults with thyroid nodules.
MiR-122-5p: A Novel Biomarker of Glucocorticoid Action
Authors: Chantzichristos Dimitrios , Svensson Per-Arne , Garner Terence , Glad Camilla A M , Walker Brian Robert , Bergthorsdottir Ragnhildur , Ragnarsson Oskar , Trimpou Penelope , Stimson Roland H , Borresen Stina Willemoes , Feldt-Rasmussen Ulla , Jansson Per-Anders , Skrtic Stanko , Stevens Adam , Johannsson Gudmundur
Published: May 2021

Background: Glucocorticoids are among the most prescribed medications for various indications, and treatment with glucocorticoids is associated with increased morbidity and mortality. A biomarker allowing quantification of glucocorticoid action could improve treatment safety and efficacy. Objective: To identify and validate circulating biomarkers of glucocorticoid action using a clinical experimental study and multi-omic network analysis. Methods: In a randomized, controlled, crossover, single-blind trial, 10 subjects without endogenous glucocorticoid production (Addison’s disease) received intravenous hydrocortisone infusion in a circadian pattern (physiological glucocorticoid exposure) or isotonic saline (glucocorticoid withdrawal) over 22 hours. Food intake and sample collections were standardized during both treatment periods. The transcriptomes of peripheral blood mononuclear cells and adipose tissue, plasma miRNAome and serum metabolome were collected at 7 AM (end of infusion). These multi-omic data were compared between the two interventions, within and between subjects, using network analysis of higher order interactions along with statistical and machine learning approaches. Samples from 120 subjects with varying glucocorticoid exposure from independent studies were used for the replication of the miRNA findings. The study was pre-registered at ClinicalTrials.gov with identifier NCT02152553. Results: We identified a transcriptomic profile derived from both peripheral blood mononuclear cells and adipose tissue, and a multi-omic signature including genes, miRNAs and metabolites that were associated with glucocorticoid exposure. Within the multi-omic signature we identified a single microRNA (miR-122-5p, p=0.009) regulated by glucocorticoid exposure, which we then replicated as a novel biomarker of glucocorticoid action in 120 subjects from independent studies (0.01 ≤ p ≤ 0.05). Conclusions: The discovery of miR-122-5p as a novel circulating biomarker of glucocorticoid action may have a significant impact on clinical practice. Our data also improves the understanding of glucocorticoid action and may have impact on future studies on the mechanistic understanding for the role of glucocorticoids in the etiology of common diseases, such as cardiovascular disease and obesity.
Ultrasensitive Detection of BRAF Mutations in Circulating Tumor DNA of Patients With Metastatic Thyroid Cancer
Authors: Gouda Mohamed A , Ong Emily , Huang Helen J , McPhaul Laron , Yoon Steve , Janku Filip , Gianoukakis Andrew G
Published: May 2021

Background: Liquid biopsy is a promising technology that can offer various advantages for molecular testing over tissue-based approaches. Most studies trying to address the utility of liquid biopsy in thyroid cancer have failed so far to achieve satisfactory rates of detection of relevant mutations. In this study, we examined a newly developed approach for ultrasensitive detection of oncogenic mutations in thyroid cancer using BRAF mutation as a proof-of-concept. In an exploratory analysis, we also correlated our findings with clinical outcomes and with levels of standard of care biomarkers. Methods: We included a group of patients with metastatic thyroid carcinoma. Cell free DNA (cfDNA) was isolated from an average of 2 ml of plasma and from matched formaldehyde fixed paraffin tissue blocks (FFPB) that were obtained from prior surgery. Extracted DNA was subject to preamplification of mutant copies using Q5 High-Fidelity PCR kit. Digital droplet PCR was performed on pre-amplified purified DNA where BRAF mutated allele frequencies (AF) were measured using BioRad ddPCR Qx200. Results: Thirty-three patients were included in our study with a median age at diagnosis of 62. Our method achieved a sensitivity of detection of 47.6% and a specificity of 80%. Mutant BRAF V600E was detected in cfDNA of 54.5% of patients (n=18) compared to 80.8% in isolated DNA from matched FFPB. Median overall survival (OS) was shorter in patients with wild type (WT) BRAF in both ctDNA and tissue (127m vs 218m, p=0.015; 116m vs 223m, p=0.004). Thyroglobulin (Tg) levels did not correlate with BRAF mutations either quantitatively or qualitatively. In the papillary thyroid carcinoma-classic variant cohort (n=20), however, patients with cfDNA mutant BRAF were more likely to have elevated Tg (90.9% versus 44.4% respectively, p=0.05). Conclusions: Our study provided a proof of concept for a newly developed technique to provide high sensitivity of mutation detection in thyroid cancer. The achieved sensitivity of detection is the highest to date using liquid biopsy in this tumor type. While we addressed only BRAF mutations in our study, the same approach can potentially be used for other mutations as well, likely changing the paradigm for use of liquid biopsy in thyroid cancer.
Cepharanthine Blocks the Presentation of Thyroid & Islet Peptides in a Novel Humanized Autoimmune Polyglandular Syndrome Type 3 Variant (APS3v) Mouse Model
Authors: Li Cheuk Wun , Osman Roman , Menconi Francesca , Concepcion Erlinda , Tomer Yaron
Published: May 2021

Introduction: There is a strong genetic association between autoimmune thyroiditis (AITD) and Type 1 diabetes (T1D), and the co-occurrence of AITD and T1D in the same individual is referred to as Autoimmune Polyglandular Syndrome type 3 variant (APS3v). We previously discovered a unique amino acid signature of the HLA-DR pocket (designated APS3v HLA-DR pocket) that predisposes to APS3v, and we found that both thyroid (Tg.1571, TPO.758) and islet (GAD.492) peptides can bind to this flexible APS3v HLA-DR pocket. The goal of the present study is to identify small molecules that can block the presentation of these thyroid and islet peptides by the APS3v HLA-DR pocket as a potential therapeutic approach for APS3v. Methods: We screened a panel of small molecules using an in vitro screening assay we developed using Baculovirus-generated recombinant APS3v-DR. To validate “hit” compounds discovered by the in vitro assay in a mouse model we established a novel mouse model of APS3v. The APS3v mouse model was established by immunizing humanized NOD-DR3 mice with Tg.1571, TPO.758 and GAD.492 combined, together with adjuvant. We then validated hit small molecules for their effectiveness in blocking stimulation of T-cell responses in the APS3v mouse model. Results: Our screen identified 4 small molecules (S5, S9, S15, S53) that showed more than 50% inhibition in our in vitro assay. We were also able to establish a novel APS3v mouse model. Immunized mice showed an increase in cytokine production in response to all 3 thyroidal and islet peptides. The immunized mice also developed antibody responses against each peptide. When we tested the 4 “hit” compounds, only Cepharanthine (S53) which we previously identified as a small molecule blocking AITD immune responses, could block all 3 thyroidal/islet peptides in the APS3v mouse model. Treating with Cepharanthine prior to inducing APS3v in the mice also reduced T-cell proliferation in the immunized mice. Conclusions: We established a novel humanized APS3v mouse model by co-immunizing 3 thyroidal and islet peptides. We also identified Cepharanthine as a small molecule that can block thyroid and islet specific T-cell responses in this model. Cepharanthine can be further tested in APS3v patients carrying the specific APS3v-DR pocket as a potential therapeutic treatment.
A Case of Paraneoplastic Erythropoietin Secretion Secondary to Medullary Thyroid Cancer
Authors: Pare Aurelie , Tamilia Michael
Published: May 2021

Background: Paraneoplastic erythropoietin (EPO) secretion is a well-described phenomenon that is classically seen in renal cell carcinoma. It has also been described in parathyroid adenoma and in pheochromocytoma. Additionally, follicular thyroid cancer cells, papillary thyroid cancer cells, and anaplastic thyroid cancer cells have all been found to express EPO in vitro. To our knowledge, EPO expression by medullary thyroid cancer has not previously been studied. Here, we describe a case of suspected paraneoplastic EPO secretion in the setting of advanced medullary thyroid cancer.

Clinical Case: A 46 year-old woman presented to our clinic with hoarseness and was proven to have a medullary thyroid cancer with enlarged lymph nodes on the right at levels IV, V and VI. Genetic testing was negative for a germline RET mutation. She underwent total thyroidectomy with bilateral lymph node dissection and was subsequently treated with external beam radiation therapy. Pathology confirmed the diagnosis of medullary thyroid cancer, with extension beyond the thyroid capsule and bilateral lymph node involvement. Rising calcitonin and CEA were noted over the following years. A MRI of the abdomen showed indeterminate subcentimetric liver lesions. A Gallium-68 Dotatate PET scan confirmed the suspicion of liver metastases. Five years after the initial surgery, the patient developed rising hemoglobin levels, despite a long-standing history of iron deficiency anemia. JAK2 testing was negative. EPO levels were elevated (43.45 mU/mL, reference range 2.59 - 18.5 mU/mL) suggesting secondary polycythemia. The patient had a negative smoking history and a pulse oximetry of 98%; there was no evidence of hypoxia that could cause an elevation in EPO. Other differential diagnoses including pheochromocytoma, Cushing’s syndrome from ectopic ACTH production, and renal and brain tumors were excluded. Biopsy of the liver lesions is not technically feasible at this time. Since discovery of the erythrocytosis, the patient has undergone repeated therapeutic phlebotomies, to maintain acceptable hematocrit levels.

Conclusion: We believe that our patient’s case may be the first reported case of ectopic EPO production from medullary thyroid cancer causing polycythemia. We encourage other clinicians to report similar clinical cases in order to better understand this rare clinical entity.
A Rare Case of Aggressive Ectopic Thyroid Cancer in a Patient With Graves Disease
Authors: Mahmood Ejaz , Anastasopoulou Catherine , Blocher Nissa
Published: May 2021

Background: Ectopic thyroid tissue is a rare entity with a prevalence of 1 per 300,000 persons. Malignancy in ectopic thyroid tissue is reported in <1% of these cases.[1] We report a case of aggressive papillary carcinoma in ectopic thyroid gland in a patient with Graves’ disease.

Case: A 65-year old woman was incidentally found to have a 3.1 cm mass with coarse calcifications in the superior mediastinum on CT scan of chest. Ultrasound confirmed the presence of hypoechoic mass which was separate from thyroid. Additionally, a 0.5cm TI-Rad 4 left thyroid lobe nodule was found. FNA of the mediastinal mass was suspicious for follicular thyroid neoplasm. Thyramir testing was positive for BRAF V600E and TERT c-124C>T mutations. Thyroid function tests showed frank hyperthyroidism and elevated thyroid stimulating immunoglobulins. Thyroid uptake and scan showed diffuse uptake of 67% at 24 hours.

The patient underwent simultaneous excision of mediastinal mass and total thyroidectomy. The pathology of mediastinal mass showed papillary thyroid cancer with tall and sclerosis features with one involved lymph node. The pathology of thyroid gland did not show any malignancy. She was treated with 100 mCi I-131. Post treatment Whole Body Nuclear Scan after treatment revealed metastatic disease in left lower lung area.

Discussion: Ectopic thyroid gland is usually found anywhere between forman caecum and mediastinum. It is rare to find ectopic thyroid tissue in the presence of eutopic thyroid gland which can create a diagnostic dilemma. Only a very few case reports of thyroid cancer arising from ectopic thyroid tissue have been reported. Our case is unique as the eutopic thyroid gland had Graves’ disease with no malignancy but the ectopic thyroid tissue developed aggressive papillary thyroid cancer. There are no specific guidelines for the management of carcinoma in ectopic thyroid glands, possibly due to the rarity of the condition. Our case has a clear metastasis to the lungs. However, it is important to differentiate ectopic thyroid tissue with carcinoma from thyroid cancer metastasis which can be difficult at times. Without specific guidelines for the management of cancer in ectopic thyroids, an individualised approach can be taken using the same therapeutic principals used in the management of eutopic thyroid cancer. Additionally, a finding of a normal thyroid gland or a benign condition in the thyroid gland should not exclude the diagnosis of malignancy in ectopic thyroid tissues.

1) Vázquez, Oscar R., et al. “Ectopic papillary thyroid cancer with distant metastasis.” Case reports in endocrinology 2018 (2018).
A Rare Case of Classical Hodgkin Lymphoma of the Thyroid Gland
Authors: Chandran Chandriya , Prater Janna , Mayrin Jane Valerie , Young Nancy A , Lytle Andrew , Bhattacharyya Siddharth
Published: May 2021

Background: Hodgkin lymphoma (HL) classically occurs in the lymph nodes and only in about 5% of cases occurs in extra-nodal sites. Primary thyroid lymphomas, most of which are non-Hodgkin lymphomas, comprise less than 5% of all thyroid malignancies. Only a few cases of HL of the thyroid have been reported in the literature, and in most of these cases, fine-needle aspiration biopsy (FNAB) was unreliable for diagnosis. We present a case of classical Hodgkin lymphoma of the thyroid that was falsely negative from both FNAB and core needle biopsy specimens and was diagnosed after surgery.

Clinical Case: A 51-year-old female was seen for a rapidly enlarging neck mass associated with progressive dyspnea and dysphagia. Despite being a telemedicine visit due to the COVID-19 pandemic, significant enlargement and deformity of the neck were startling. The patient was clinically and biochemically euthyroid with a TSH of 2.49 mIU/L (0.5-5.0 mIU/L) and normal FT4. She denied a personal or family history of thyroid disease and neck irradiation. Thyroid ultrasound revealed a 5.3 cm hypoechoic, wider than tall nodule with smooth margins in the left lobe, and a 1.9 cm hypoechoic and taller than wide nodule in the right lobe of the thyroid. A CT scan of the neck also revealed a 1.2 cm lymph node in the left lateral aspect of the thyroid. FNAB of the nodules showed Hurthle cells in a background of crushed lymphocytes with occasional large atypical lymphoid cells. Flow cytometry performed on a repeat FNAB specimen revealed no evidence of lymphoma. A repeat CT scan of the neck performed 2 weeks later due to worsening symptoms demonstrated middle mediastinal lymphadenopathy and a large 8x4.7x4.7 cm mass contiguous with the thyroid with a 3.8 cm cystic collection within. The patient was scheduled for an oncology consultation due to the high likelihood of lymphoma but was admitted to another institution with symptoms. She underwent a thyroid core biopsy and flow cytometry, which again failed to reveal her diagnosis. She then underwent left partial thyroidectomy, and pathology demonstrated infiltrates of small lymphocytes with histiocytes, interspersed with clusters of large, irregular, multilobate cells consistent with Reed-Sternberg cells. She was diagnosed with nodular sclerosing variant of classical HL. Chemotherapy was instituted with rapid improvement in symptoms.

Clinical Lesson: Primary HL of the thyroid is extremely rare and most often presents as a rapidly enlarging neck mass with or without compressive symptoms. Diagnosis with FNAB is challenging and can be misinterpreted as lymphocytic thyroiditis. In our patient, flow cytometry was performed twice and was falsely negative. The treatment of HL differs entirely from that of other primary thyroid cancers and thyroiditis. Hence, in patients presenting with classic symptoms, a high index of suspicion is needed to make an accurate and prompt diagnosis of HL.
Brain Metastases in a Patient With Papillary Thyroid Carcinoma. Clinical Case Report
Authors: Ramos Andrés Felipe García , Zambrano Urbano Jose Leonel , Pico Víctor Manuel Blanco , García Franco Alejandro Vallejo , Arboleda Marcela Patiño , Valencia Carlos Mario Balcázar , Chaparro Jose Mauricio Ocampo
Published: May 2021

Introduction: Papillary thyroid carcinoma (PTC) is the most common neoplasm of the endocrine system and the least aggressive, representing between 70% and 80% of thyroid neoplasms. This is characterized by slow growth and a low risk of progression to metastasis. Brain Metastases (BM) associated with PTC occur with a incidence rate of 0.15%. Tyrosine kinase inhibitors (TKI) are a very promising alternative for managing these patients. Here is described the case of a patient with PTC with brain and lung metastases, her respective management and evolution. Clinical Case Report: A 64-year-old patient with a history of controlled hypothyroidism, who was recently diagnosed with high cell variant PTC, positive for BRAF V600E mutation. Neck CT revealed a thyroid mass extending to the superior mediastinum, with associated lung metastases. We started by suppressing TSH with levothyroxine. Brain MRI was done due to persistent and as safety precaution before starting thyrotropin alfa This showed multiple intra-parenchymal lesions compatible with BM. Patient received management with gamma Knife radiosurgery for BM and with lenvatinib 24mg day. The patient presented a decrease in tumor size by more than 50% in the neck, with disappearance of the majority of BM at 90 days. After 18 months of treatment, she was still alive. Discussion and Conclusion: PTC associated with BM has a very poor life expectancy, and there are not guidelines for its management and the treatment is based on case reports and expert opinions. Radiosurgery plus ITK combined therapy could provide better outcomes to these patients
Cardiac Metastasis From Anaplastic Thyroid Carcinoma
Authors: Gonzalez Michelle N Garcia , Palomo Antonio Segovia , Torres Juanita H Lastra
Published: May 2021

Background: Anaplastic thyroid carcinoma represents 2% of all thyroid carcinomas. The most common metastatic sites are lung and neck lymph nodes. Cardiac metastasis is extremely rare. Autopsy studies of patients with thyroid cancer have documented a frequency of metastatic cardiac involvement of 0%–2%. Clinical Case: A 57- year- old woman was admitted to the emergency room with a rapidly expanding neck mass of 3 months duration. She complained of pain in the anterior neck, dysphagia, dyspnea, palpitations and hemoptoic sputum. She further reported history of weight loss. She denied medical history of cancer in the family. Prior medical history was described as non- significant. On clinical examination, vital signs were normal. General swelling around the thyroid region was noted. A hard, tender, immobile mass was palpated. A superficial lymph node of about 5 cm in diameter was palpated in level II A and IIB. The patient was admitted to the hospital for further workup. Laboratory work up revealed, hemoglobin 7.6 g/dL, hematocrit 22.5%, white blood cells 15,000/mm3, fasting plasma glucose 135 mg/dL and urea 59 mg/dL. Thyroid function tests revealed TSH 2.46 mUI/ml (normal range: 0.38-5.33 mUI/ ml), fT3 1.69 pg/ml (normal range: 2.39-6.79 pg/ml), fT4 0.57 ng/dl (normal range: 0.58-1.64 ng/dl). A fine needle aspiration cytology from the thyroid lesion described a poorly differentiated thyroid carcinoma. CT scan of the neck and chest revealed a large heterogeneous mass with hypointense areas involving the thyroid gland of 9 x 8 x 7 cm that surrounded the vertebral bodies and displaced and infiltrated the neck vessels, trachea and esophagus. In the right atrium and right ventricle three well- circumscribed ovoid masses were observed, the largest one measured approximately 21 x 17 mm, suggestive of cardiac metastases. Bilateral adrenal masses were also observed the largest one measuring 69 x 51 mm. Diagnosis of anaplastic thyroid cancer stage IVC was established with a large thyroid mass, widespread metastasis and poorly differentiated metastatic carcinoma on fine needle aspiration biopsy. During her hospitalization she presented both atrial tachycardia and atrial fibrillation and was started on amiodarone. A week later, the patient′s condition deteriorated and she died of respiratory arrest without having any further treatment for the tumor. Conclusion: In patients with established thyroid malignancy who develop cardiac arrhythmias, cardiac metastasis should be considered.
Coexistence of Pituitary Adenoma Causing Acromegaly and Medullary Thyroid Cancer
Authors: Pare Aurelie , Tamilia Michael
Published: May 2021

Background: We present a case of coexisting acromegaly and medullary thyroid cancer. As both conditions are rare, the association raises the possibility of causality (non-genomic) as opposed to pure coincidence.

Clinical Lesson: A 73 year-old man presented to our clinic with an incidental finding of a left thyroid nodule. The patient underwent an ultrasound-guided fine needle aspiration biopsy which revealed medullary thyroid carcinoma. Shortly afterward, the patient underwent a total thyroidectomy with bilateral cervical lymph node dissection. The patient tested negative for mutations involving RET exons 8, 10, 11, 13, 14, 15, and 16.

On initial presentation, the patient was also noticed to have an appearance typical of acromegaly, with spade-like hands and characteristic acromegalic facial features, including prognathism and macroglossia. These findings were long-standing. He was found to have elevated IGF-1 (121.4 nmol/L, reference range 6.1 - 26.9 nmol/L) and hyperprolactinemia (78.2 mcg/L, reference range 2.7 - 16.9 mcg/L). His growth hormone (GH) levels did not suppress following a 75 g oral glucose tolerance test. Magnetic resonance imaging of the sella turcica revealed a prominent pituitary gland and stalk with a rightward deviated infundibulum, with a suspected 1.1 cm left-sided pituitary macroadenoma. The patient declined surgical management, and he was instead managed medically with octreotide.

Conclusion: Coexistance of GH-producing pituitary adenoma and medullary thyroid cancer is a rare occurrence. We identified ten cases previously described in the literature. Specifically, this is the second reported case of a patient presenting with both medullary thyroid cancer and pituitary adenoma causing acromegaly.

The advanced acromegalic phenotype suggested long standing disease and therefore prolonged tissue exposure to elevated levels of IGF-I. Although acromegaly is more commonly associated with nodular goiter of follicular-cell origin, the possibility of a thyroidal C-cell neoplasm must be entertained especially if GLP-1 agonist therapy is being considered for the treatment of hyperglycemia.
Paragangliomas the Forgotten Neuroendocrine Neoplasms: A Retrospective Review of 237 Cases From 2 Centers in 2 Years
Authors: Ramirez-Renteria Claudia , Albarran-Sanchez Alejandra , Hernandez-Calderon David Enrique , Cardenas Pattsy Etual Espinosa , Sosa Ernesto , Lopez-Juarez Nitzia , Irisson Irene Mora , Noyola-Garcia Maura E , Portocarrero-Ortiz Lesly A , Moreno-Jimenez Sergio , Melgar-Manzanilla Virgilio , Almeida-Gutierrez Eduardo , Mercado Moises
Published: May 2021

Background: paragangliomas (PGN) (including adrenal PGN or pheochromocytomas) are uncommon neuroendocrine neoplasias. Their ubiquity and lack of uniform nomenclature has resulted in systematic sub-registry and limited resources for patients and clinicians. However, 40% of them are hereditary, 10–20% are hormonally active and 50% result in treatment-related complications.

Objectives: to describe the clinical and biochemical characteristics of PGN in two referral centers in a 2-year period.

Materials and Methods: a retrospective review of the files of patients evaluated in the Centro Medico Nacional Siglo XXI or the Instituto Nacional de Neurología y Neurocirugia between June 2018 and May 2020, even if diagnosis was prior to those dates. The search was performed using ICD-10 terms in the outpatient registries. Data is described using non-parametric statistics, including medians (interquartilic ranges, IQR). According to the reported incidences we expected to find 35 new cases per year in each hospital.

Results: 237 patients, 86.4% female with a median age at diagnosis of 54 years (IQR 45–64) were found. The tumors were located in the head 23.9%, neck 63.3%, thorax 0.4%, adrenal in 11.1%, other sites in the abdomen 1.3%. The most common symptoms in head PGN were hypoacusia (85.2%) and cranial nerve palsies (39.3%), in the neck, a visible mass and pain (30.6%) while the “classic” catecholaminergic symptoms were more common in thoracic and abdominal tumors (>50%). Tumors were large or invasive in 50.1% of the cases and at least one hormone was above the upper limit of normal (ULN) in 40.6% of the 64 evaluated cases, mostly urinary dopamine (70% of cases tested, 1.1–2.1 ULN) and plasma and urine metanephrines (60% of cases tested, 1.1- 33.7 ULN and 50% cases, 1.1–22 ULN, respectively). Severe systolic hypertension was more frequent in male patients <30 years of age and 41.6% were candidates to genetic testing due to the tumor characteristics or patient history. Surgery was performed in 55.6%, radiotherapy in 25.2% and 12.1% are under surveillance or pending surgery, 7.1% were lost to follow up. Only 5 cases with metastasis were documented in 1215 patient-years of follow-up. Treatment-related complications were reported in 14.7% and persistence in 32.2%.

Conclusions: despite the retrospective nature of the study and sub registry, we found more tumors than expected. The frequency of hormonal production was high, but it is likely related to patient selection bias (mostly symptomatic cases studied). Dopamine and metanephrines are useful in the evaluation of PGN. Endocrinologists should be aware of these common tumors and be part of the multidisciplinary team.