bluuebunny/crossref_metadata_2025 huggingface dataset:
What Are the Common Characteristics of Pediatric Patients With Antibody Negative Primary Hypothyroidism?
Authors: Alradadi Rasha , Eugster Erica A
Published: May 2021

Background: The most common cause of acquired primary hypothyroidism is autoimmune thyroiditis which is typically associated with positive anti-thyroid peroxidase and/or anti-thyroglobulin antibodies. However, some children present with primary hypothyroidism and negative antibodies. Whether there are differences between patients with acquired primary hypothyroidism who have positive vs negative anti-thyroid antibodies has not been systematically examined. Aim:To define the characteristics of patients with primary hypothyroidism and negative antibodies. Methods: A retrospective chart review of patients with hypothyroidism seen in the pediatric endocrine clinic at Riley Hospital for Children in Indianapolis, Indiana from August 2016 until December 2019 was performed. Variables examined included age at diagnosis, signs and symptoms at presentation, height, weight, BMI, TSH, FT4, T4, thyroid peroxidase and anti-thyroglobulin antibodies, family history of thyroid disease, physical exam at diagnosis, and associated diseases. Results: Of 173 patients aged 10.6 ± 3.9 years, 128 (74%) had positive antibodies and 44 (26%) had negative antibodies. Of those with positive antibodies, 80 % were female and 20% were male. Of those with negative antibodies, 53% were female and 47% were male. No differences were seen in the incidence of obesity or Down syndrome in patients with positive antibodies compared with those who had negative antibodies. A positive family history of thyroid disease was present in 45% of those with positive antibodies and in 22% of those with negative antibodies, P=0.006 Fifty-eight patients (45%) with positive antibodies reported excessive fatigue and 40 (31%) had a goiter. In contrast, 10 (22.7%) who had negative antibodies reported mild intermittent fatigue, P=0.006 and 7 (15.9 %) had a goiter, P=0.04 The average TSH in the antibody positive group was 129± 230 mcu/ml compared with 48 ± 131 mcu/ml in those with negative antibodies, p=0.04. A trend was also noted for a lower FT4 in those with positive antibodies (0.68±0.37 vs 0.85±0.27, p=0.050) No other differences in baseline characteristics were seen between patients with negative vs positive antibodies. Conclusion: Patients with positive anti-thyroid antibodies had more severe hypothyroidism and were more likely to report extreme fatigue than those with negative antibodies. It is unknown why some children with acquired primary hypothyroidism presumed due to autoimmune thyroid disease have negative antibodies. Long-term follow-up will be needed to determine whether the natural history of thyroid disease in children with primary hypothyroidism is associated with antibody status.
Analysis of Enigma Gene-Signaling Pathways in Thyroid Cancer
Authors: Churdsuwanrak Narudee , Niihara Robert , Rood Kristiana , Yamauchi Celina , Wright Kharl , Adil Md Shafayet , Mirshahidi Saeid , Perez Mia C , Simental Alfred A , Firek Anthony , Khan Salma
Published: May 2021

Fine-needle aspiration (FNA) is one of the most accurate modes of obtaining thyroid nodule biopsies, however, up to 25% of biopsies still yield indeterminate results. There is an increasing number of thyroidectomies due to indeterminate nodules by FNA alone. Therefore, more accurate and time efficient diagnostic approaches for analyzing indeterminate thyroid nodules is required. Recent studies showed that Enigma is associated with different cancer types, including thyroid cancer progression and calcification through its interaction with bone morphogenic protein-1 (BMP-1) and tyrosine kinases linked to mitogen-activated protein kinase (MAPK) signaling pathway. Our published data on Enigma protein analysis with immunohistochemistry showed promising findings to discriminate malignant versus benign nodules. We also showed a thyroid cancer stage-dependent enhancement of Enigma protein expression. In this study, we are investigating Enigma at a gene expression level by quantitative reverse transcription polymerase chain reaction (RT-qPCR), which is more time-efficient, quantitative, and requires less tissue than immunohistochemistry. We extracted mRNA/DNA/proteins from fresh malignant and benign thyroid nodules using a Qiagen AllPrep DNA/RNA/Protein Mini Kit. After verification of the quantity and purity by NanoDrop, isolated mRNA was then run through Enigma-RT-qPCR. MAPK assay was done by western blotting using MAPK-antibody. Our initial results found that Enigma-mRNA expression level was 3-fold higher in malignant compared to benign thyroid tissues. This finding supports our previous protein expression data with a relative quantitative difference in Enigma-mRNA expression level between malignant and benign thyroid nodules. MAPK expression was upregulated in thyroid cancer compared to benign nodules. We conclude that Enigma-RT-qPCR can be used effectively in FNA samples derived from thyroid nodules, which could potentially enhance the diagnostic accuracy of indeterminate nodules and decrease unnecessary thyroidectomies. Furthermore, both Enigma and MAPK were highly expressed in advanced tumor in the same tissues. Future study is needed to establish the functional interaction of Enigma-MAPK activity in thyroid cancer cells.
Association Between Body Mass Index and Aggressive Features of Differentiated Thyroid Cancer
Authors: Almotawa Fahad , Alturki Abdulrahman , AlGhamdi AbdulJabbar , AlEnezi Mohammed , AlJohani Naji , Alhuzaim Omar Nasser
Published: May 2021

Background: Obesity is recognized as a risk factor for several types of cancers, including differentiated thyroid cancer (DTC). However, the association between obesity and aggressiveness of DTC is controversial. The aim of this study was to assess the relationship between body mass index (BMI), aggressive clinicopathological features of DTC and response to therapy in Saudi population. Methods: We evaluated 209 patients retrospectively who underwent total thyroidectomy at a referral center and diagnosed with DTC. Patients were stratified into 2 groups based on their BMI: non-obese (< 30 kg/m2), and obese (≥ 30 kg/m2). Pathological aggressiveness of DTC as well as clinical outcome were evaluated according to the 2015 American Thyroid Association (ATA) guideline. Data were described as mean ± SD and the categorical data as frequency percent. Mann Whitney test measured the difference in medians of all the metric variables and Chi-square test was applied for the categorical data to measure the intergroup difference between obese and non-obese binary dependent variable. All the inferences were carried out at 95% confidence interval in SPSS 25.0 software. Results: One-hundred twenty (57.4%) of our cohort were obese. Obesity was significantly more common in females (61.7%) than males (29.6%); (p=0.002). There were no differences in histopathological features between the non-obese and obese patients, including tumor size (2.3 ± 1.7 cm vs. 2.5 ± 2.1 cm, respectively, P-value = 0.812), extrathyroidal extension (16.9 % vs. 22.4 %, respectively, P-value=0.336), vascular invasions (25 % vs 18.4 %, respectively, P-value= 0.263) and lymph nodes metastasis (N1a 19.3 % vs 11.6 %, N1b 12.0 % vs. 10.7 % respectively, with P-value = 0.289), were shown between the two groups. In addition, no differences were evident in the ATA risk of recurrence (P-value = 0.843), TNM stage (P-value= 0.797), response to therapy (P-value= 0.252) and survival (P-value= 0.389) across the two groups. Conclusion: No association between BMI and DTC aggressiveness were found in our study population of Saudi patients. In addition, no association were demonstrated between BMI and response to therapy in DTC. These findings suggest that BMI may not be an independent risk factor for aggressiveness in DTC and that other traditional clinicopathological factors should be applied for risk assessment.
Malignancy Risk in 18F-FDG-Avid Thyroid Incidentalomas: Controversies and Limitations
Authors: Bukhari Khulood , Haleem Zarah , Munir Kashif
Published: May 2021

Introduction: The prevalence of malignancy in thyroid incidentalomas (TI) discovered on 18F-FDG-PET or PET/CT varies between 0% and 63.6%. The pooled malignancy rate according to three systematic reviews is 33-35%. The 2015 American Thyroid Association (ATA) guidelines recommend that such nodules, when one centimeter or larger in size, should undergo further investigation with thyroid ultrasound (US) and fine-needle aspiration (FNA) cytology. Objectives: The objective of our study was to determine the rate of malignancy amongst TI discovered incidentally on 18F-FDG-PET or PET/CT, examine their clinicopathologic characteristics, and assess the usefulness of maximum standardized uptake values (SUVmax) in differentiating benign and malignant lesions. Methods: We performed an electronic medical record search looking at all 18F-FDG-PET or PET/CT reports during the study period of 12/01/2015 to 05/31/2019 that included the keyword ‘thyroid’ in the impression. Exclusion criteria included a history of thyroid disease or malignancy, known lesion(s) detected on previous clinical or radiological examinations and diffuse radiotracer uptake. Of the 476 reports reviewed, 136 cases were included in the study. Results: Common indications included initial staging or restaging of lymphoma (diffuse large B-cell, mantle-cell, T-cell types) (27.9%), lung adenocarcinoma (18.4%), head and neck cancer (16.9%) and breast cancer (11%). Fifty-eight (42.6%) patients had metabolically inactive lesions; five (8.6%) underwent further investigation with thyroid US and 3 subsequently with FNA (5%). All 3 had benign cytology. Seventy-seven (56.6%) patients had metabolically active lesions and 25 (32.5%) underwent imaging with thyroid US. Twelve (15.6%) had FNA; eight (66.7%) had benign cytology, two (16.7%) revealed atypia of undetermined significance and two (16.7%) were malignant. Biopsy for the two patients with malignant cytology showed follicular cell neoplasm of oncocytic hurtle cell type, and invasive follicular carcinoma with focal insular and papillary features and extensive capsular and vascular invasion. The mean SUVmax in malignant vs benign lesions was 9.05 and 6.41 respectively. Conclusion: The malignancy rate was 2.6% amongst all patients with 18F-FDG-avid TI and 8% amongst patients with metabolically active lesions who were investigated with thyroid US+/- FNA. This is significantly lower than malignancy rates previously reported in the literature. The evident inhomogeneity in the literature is likely multifactorial and may be explained in part by a dissimilarity among studies, and an informed decision by some to avoid invasive testing in the context of poor prognosis from underlying non-thyroidal cancer. Research is needed to determine the cohort of patients who could potentially benefit from further evaluation and treatment.
The Influence of Incidental Detection of Thyroid Nodule on Thyroid Cancer Risk and Prognosis - a Systematic Review
Authors: Chooi Je Ern , Ravindiran Abiramie , Balasubramanian Saba P
Published: May 2021

Clinically unapparent thyroid nodules discovered serendipitously on imaging for non-thyroid indications are termed ‘thyroid incidentalomas’. The increase in the detection of these incidentalomas (which are known to be very common) has been attributed to the widespread use of diagnostic imaging and the increase in sensitivity and resolution of these modalities. It is unclear whether these incidentalomas have a lower prevalence of thyroid cancer or slower tumour progression compared to symptomatic thyroid nodules. This systematic review aimed to determine the risk of malignancy in incidentally detected thyroid nodules and its impact on prognosis in patients with thyroid cancer. PubMed and MEDLINE® on Web of Science databases were searched from inception to March 2020 for English language articles reporting on human studies of thyroid cancer risk and/or prognosis in incidental and non-incidental nodules. Quality of included studies was assessed using the Newcastle-Ottawa Scale (NOS). Seventeen observational studies published between 1998 and 2018 were eligible for analysis; 4 studies reported on risk, 8 studies on prognosis and 5 studies on both risk and prognosis. In the risk review, the odds ratios calculated from the six case-control studies (3246 patients) ranged from 0.64 to 2.86 whilst the relative risks calculated from the three cohort studies (489 patients) ranged from 0.13 to 6.27. NOS score for included risk studies (n=9) ranged from 22.2% to 66.7%. A meta-analysis of the eligible case-control studies (n=3) showed a non-significant summated odds ratio of 1.04 (95% CI=0.63-1.70, p=0.88). In the prognosis review of thirteen studies, three direct and thirteen indirect markers of prognosis were compared between the incidental (1923 patients) and non-incidental (2639 patients) groups. NOS score for included prognosis studies ranged from 66.7% to 100%. Incidentally detected thyroid nodules were significantly more likely to be smaller, have lower rates of extra-thyroidal and extra-nodal extension and lymph node metastasis, and interestingly more likely to have advanced disease. Other indirect prognostic markers were not shown to be significantly different between the two groups. A meta-analysis was not possible but incidentally detected thyroid cancer had better progression-free and overall survival; this finding may be affected by ‘lead time’ bias. Current evidence suggests that the investigation and management of thyroid nodules should not be influenced by the mode of detection.
Ultrasound Guided Percutaneous Ethanol Ablation of Benign Thyroid Nodule: A Study From a Tertiary Hospital in Eastern India
Authors: Baidya Arjun , Faiz Saba , Bhadra Ram Chandra
Published: May 2021

Introduction: Ultrasound guided percutaneous ethanol injection (PEI) of benign thyroid nodule is an easy and effective procedure particularly in cystic and predominantly cystic nodule. Aims: To evaluate efficacy and safety of PEI in managing purely cystic and mixed cystic and solid thyroid nodules. Materials and Methods: Patients of either sex presented with solitary purely cystic benign thyroid nodule, solitary benign mixed with predominantly cystic (>50% of total volume) thyroid nodule, solitary benign mixed with predominantly solid (>50% of total volume) thyroid nodule, solitary solid thyroid nodule were included in this study. Patients who had a nodule BETHESDA 3 and above, pregnancy, patients with critical or terminal illness, patients with other malignancies, multinodular lesions of thyroid, patients with raised T3, T4 and/ or suppressed TSH level were excluded from the study. One hundred sixty patients presenting with thyroid nodule were initially evaluated with thyroid function test and USG. Only those patients with euthyroid solitary thyroid nodules are subjected for fine needle aspiration (FNA). Nodules under BETHESDA 2 are considered for US guided percutaneous ethanol injection (PEI). One hundred twenty-three patients were excluded because of various reasons. Finally ethanol ablation was done in 37 patients. Benign, purely cystic and mixed thyroid nodules were aspirated under ultrasonography guidance. Sterile absolute alcohol (99.99%) (50% of volume aspirated/ maximum 10 ml) was injected and reviewed after 2, 5and 7 months. In case of solid nodule alcohol (50% of nodule volume) was injected. A reduction in volume is calculated at each follow up visit. An adequate response is considered as ≥50 percent reduction in size from baseline after 7 months. If the reduction is <50%, then a second session of absolute ethanol injection is given. Again, patients were similarly followed up after 2, 5 and 7 months. Results: Thirty seven patients underwent PEI. Thirty three patients were considered for final analysis (4 lost to follow up). Response rate of PEI for purely cystic nodule was 100.0% and the overall response rate for mixed nodule was 53.57%. None of the solid nodule responded to PEI even after second session. Among the responder in the mixed nodules, 93.33% responded after first session of PEI. Minor complications like headache occurred in 54.1% patients in the first session. Transient pain at injection site were complained by 86.5% and 37.8% patients in the first and second session respectively. Nausea and vomiting were complained by 18.9% and 16.2% patients in the first and second session respectively.

Conclusions: PEI is an effective and safe for purely cystic and mixed thyroid nodules. It is a relatively safe and less invasive procedure from management of benign solitary cystic and mixed thyroid nodules.
A Tale of Three Cases When Thyroid Cancer Does Not Exist but Metastases Do. A Three-Case Series of Metastatic Follicular Thyroid Carcinoma
Authors: Ziganshina Anna , Brar Rupinder Kaur , Amin Ami , Jennings Timothy , Shawa Hassan
Published: May 2021

Background: Follicular and papillary thyroid carcinomas represent the majority of all malignancies of the thyroid gland. However, follicular thyroid carcinoma (FTC) is much more difficult to diagnose and manage than its papillary counterpart. Among other factors this could be explained by changing diagnostic criteria and by FTC potential for remote distant and often unpredictable metastases sites. Clinical Cases: In our high volume major academic referral center we have encountered three intriguing cases of metastatic FTC with negative surgical thyroid pathology. The first patient is a 61-year-old woman, who at age 50 was diagnosed with 5.4x3.5x4.2 cm left thyroid nodule (TN). FNAB reported hyperplastic nodule versus follicular neoplasm, subsequent surgical pathology report after lobectomy showed hyperplastic nodule. At age 58 she developed a pathological fracture of the 5th thoracic vertebra and pathology report indicated follicular carcinoma of thyroid origin. TG level at this time was 577 ng/ml. Pathology report from completion thyroidectomy again showed nodular hyperplasia, but reexamination of previously resected lobe demonstrated minimally invasive FTC. The second patient is an 83-year-old woman who at age 68 underwent lobectomy for left sided-goiter, pathology report showed benign follicular adenoma. At age 77 she was found to have right-sided skull mass which was determined to be a follicular carcinoma of thyroid origin. Pathology report from completion thyroidectomy was consistent with nodular hyperplasia. At age 82 the patient was noticed to have increased RAI uptake in thyroid bed, sternum, kidneys, and gastroesophageal junction. TG level at this time was 2214 ng/ml. The third patient is a 56-year-old woman initially diagnosed with a 3.5x2.8x2.2cm right TN at age 53. Lobectomy, performed for diagnostic and therapeutic purposes, showed benign follicular adenoma. At age 56 she developed a pathological fracture of the 3rd thoracic vertebra, follicular carcinoma of thyroid origin was shown on pathology report. TG level at this time was 1694 ng/ml. The patient underwent completion thyroidectomy demonstrating multinodular hyperplasia. Conclusion: This case series emphasizes on the pitfalls of follicular neoplasms diagnosis and management. We suggest prolonged clinical and biochemical surveillance of the patients with what appears to be follicular adenoma after lobectomy. Following serum thyroglobulin perhaps represents the most cost-effective surveillance approach of those patients.
Most True Adrenal Incidentalomas Lack Proper Evaluation
Authors: Bell Caitlin , Vinovskis Carissa , Kiseljak-Vassiliades Katja , Wierman Margaret E , Fishbein Lauren Michelle
Published: May 2021

Although the majority of true adrenal incidentalomas are benign and non-functional, appropriate workup is critical to rule out cancers as well as metabolic and cardiovascular diseases such as Cushing’s syndrome, primary aldosteronism (PA), and pheochromocytoma (PCC). The AACE/AAES and ENSAT guidelines recommend that all adrenal incidentalomas be evaluated for worrisome radiographic features and that all patients have initial biochemical work up to evaluate for hypercortisolism and pheochromocytoma as well as primary aldosteronism if hypertensive. Despite this, adrenal incidentalomas often are not evaluated properly leading to delayed diagnoses and potential complications from dysregulated hormone production. To determine if true adrenal incidentalomas are managed properly in our hospital system, we conducted a retrospective chart review. All CT scans (chest or abdomen) of adult patients conducted at the University of Colorado Hospital system between August 2011 and December 2016 were assessed (N=86,771). Of these, 305 scans identified true adrenal incidentalomas. CT scans done for patients with genetic conditions predisposing to adrenal nodules or done for an indication suggestive of adrenal disorder were excluded. From the 305 patient scans, 347 adrenal nodules were identified. Most patients (N=263, 86%) had one adrenal nodule; 42 (14%) had multiple nodules. Mean age of the cohort was 60±12.58 years old (range 21–88), and the majority were female (60.7%). The nodules had a mean size of 2.23±1.42 cm, range 0.5–11.2 cm. Most nodules were identified on CT scans with contrast (79%, N=241). Of the 64 scans (21%) done without contrast, 43% of the nodules had non-contrast enhanced (NCE) Hounsfield units (HU) less than 10, suggesting benign adenomas. Thirty-nine nodules (57%) had NCE HU greater than 10; eight of those were surgically removed (4 metastases from other primary cancers; 2 PCC; 2 lipid poor adrenal cortical adenomas). Most nodules were not biochemically evaluated. Only 64 of the 305 patients (21%) were tested for hypercortisolism (1mg ODST in 35; 24hr UFC in 29). Of those, three (0.1%) were diagnosed with Cushing’s syndrome. Only 82 patients (27%) were evaluated for PCC with plasma and/or 24hr urine metanephrines. Of these, 10 were diagnosed with PCC (3.3%). Only 24 patients (7.9%) were screened for PA with serum aldosterone and plasma renin activity, and four (1.3%) were positive. Taken together, of the 305 patients with adrenal incidentalomas, only 29 (9.5%) met guideline recommendations for biochemical work up for both hypercortisolism and PCC. Of those, 10 had a history of hypertension, yet only 5 were evaluated for PA. In summary, less than 10% of true adrenal incidentalomas had the proper biochemical evaluation. This suggests there are likely missed functional nodules leading to delayed or missed diagnosis possibly contributing to cardiovascular and metabolic consequences.
Birt Hogg Dube Syndrome and Thyroid Cancer - Is There an Association?
Authors: Hehar Jaspreet , Bhan Arti
Published: May 2021

A 71-year-old man presented for evaluation of thyroid nodules. Past medical history includes auricular trichodiscoma/fibrofolliculomas and colon cancer at age 39. He underwent genetic testing revealing mutations of the CHEK2 and FLCN gene, conferring a diagnosis of Birt-Hogg-Dube syndrome (BHD). Subsequently, several family members were diagnosed with this syndrome. He was initially seen for evaluation of chronic cough. A neck ultrasound showed suspicious thyroid nodules and fine needle aspiration revealed suspicion for papillary thyroid cancer. He had molecular testing by AFIRMA and was GSC negative. He underwent right hemithyroidectomy and then completion with findings of a right lobe follicular thyroid carcinoma. Given underlying history of BHD, genetic testing was performed to assess for additional mutations that could predispose to thyroid cancer. This may help to raise awareness of screening for the presence of thyroid nodules and possibly thyroid carcinoma in individuals with BHD. Birt-Hogg-Dube (BHD) syndrome is a rare, autosomal dominant syndrome caused by a germline mutation in the FLCN gene, and is characterized by the presence of fibrofolliculomas, pneumothorax, and renal tumors. Thyroid nodules have been associated with BHD, present in 65% of individuals and 90% of families with this syndrome, however connection between BHD and thyroid cancer has not been established. For our patient, the most significant finding after a 170-gene panel analysis was an NRAS Q61R mutation. Mutations in RAS genes may be found in 15-20% of papillary thyroid cancers, 40-50% of follicular cancers, and 20-40% in follicular adenomas, and indicate poor prognosis. A CHEK2 mutation was also identified, which has been associated with an increased risk of multiple cancers, including thyroid. In addition, he had coding variants in the ATR gene on chromosome 3, as well as the IDH2 gene on chromosome 13. IDH2 may have a role in the development of thyroid cancer, however the contribution of these variants to tumor development or progression is currently unknown. For our patient, there is no published data to our knowledge regarding the findings of his coding variants and their possible association to BHD syndrome. More research needs to be done to assess for additional mutational variations present in those with BHD syndrome that may predispose to the development of thyroid cancer. Hara, H et al. “N-ras mutation: an independent prognostic factor for aggressiveness of papillary thyroid carcinoma.” Surgery vol. 116,6 (1994): 1010-6.
Dabrafenib Induced Pancreatitis: A Rare Event During RAI- Refractory Treatment of Metastatic Papillary Thyroid Cancer
Authors: Edwards Khary , McFadden David , Agosto Salgado Sarimar N
Published: May 2021

Dabrafenib, a BRAF selective tyrosine kinase inhibitor (TKI) has been associated with pancreatitis alone, and in combination with trametinib (a MEK pathway inhibitor). We report a case of dabrafenib induced acute pancreatitis in a patient undergoing treatment for metastatic papillary thyroid cancer (PTC). This adverse event has not been previously reported in thyroid cancer patients using dabrafenib. Case: A 61-year-old female with papillary thyroid cancer status post total thyroidectomy with pathology revealing right 7.6cm PTC with extrathyroidal extension and 13/72 metastatic lymph nodes. She received 100mCi of radioactive iodine (RAI). Ten months post-surgery, she underwent revision neck dissection with 3/36 nodes positive for metastatic disease and neck muscle invasion by PTC. Molecular testing demonstrated AKT1 and BRAFV600E mutations. Due to progressive neck and mediastinal tumors, recommendation was to proceed with systemic therapy. Initially started dabrafenib monotherapy; after 3 doses patient developed burning epigastric pain and fever. Examination revealed abdominal tenderness, elevated lipase at 2266 U/L (8-76U/L), mild hyperbilirubinemia and leukocytosis. CT abdomen/pelvis revealed peripancreatic fat stranding consistent with focal acute pancreatitis. No history of alcohol use. Dabrafenib was assessed to be culprit of pancreatitis; with immediate discontinuation of TKI and supportive management patient improved. At present patient is tolerating Lenvatinib therapy. BRAFV600E mutation occurs in 29-83% of thyroid cancers affecting growth, proliferation, survival, migration, and loss of tissue-specific differentiation via the intracellular MEK/ERK pathway1. RAI offers an important treatment modality for thyroid cancer patients, however patients with BRAFV600E are often poor responders or refractory to RAI1. Dabrafenib, a specific BRAFV600E tyrosine kinase inhibitor in combination with trametinib (a MEK inhibitor) is FDA approved for treatment BRAFV600E mutated anaplastic thyroid cancer; furthermore there is evidence on PTC responses including redifferentiation 2. Pancreatitis has been reported in <1% of dabrafenib treated patients as monotherapy and in combination with trametinib in unresectable or metastatic melanoma clinical trials. It was reported in 4% of patients in a NSCLC when used in combination with trametinib. Recurrent pancreatitis when dabrafenib was re-introduced at a lower dose has also been reported3. Furthermore, it was the cause of pancreatitis in a patient with metastatic melanoma 4 months into the treatment in combination with trametinib4. As this treatment option becomes increasingly utilized for metastatic or locally advanced anaplastic/papillary thyroid cancers, endocrinologists should be aware of the potential for dabrafenib induced pancreatitis during monotherapy use or in combination with trametinib.
Glioblastoma Multiforme and Papillary Thyroid Carcinoma: Rare Combination of Primary Malignancies
Authors: Katkar Rujuta Baban , Vaddepally Raju
Published: May 2021

Introduction: Studies have reported thyroid cancer patients are potentially at 30% increased risk of getting second primary cancer when compared to the general population. We are describing a young Caucasian male patient who was diagnosed with two synchronous cancers, papillary thyroid cancer (PTC) and glioblastoma multiforme (GBM). Case Report: A 52 year old Caucasian male with past medical history of hypertension, partial right thyroidectomy in 1999 for thyroid nodular disease, and postsurgical hypothyroidism on levothyroxine. He underwent FNA of left thyroid nodule found on routine monitoring of thyroid nodules showed to be suspicious for malignancy. He underwent left hemi-thyroidectomy in July 2019, revealing PTC, follicular variant, encapsulated, noninvasive type measuring 0.9 x 0.9 x 0.5 cm, completely excised with negative margins; reminder of the right hemi-thyroidectomy performed in February 2020, revealing cystic adenomatoid nodule and no evidence of malignancy. Postoperative thyroglobulin and thyroglobulin antibodies levels were undetectable. A diagnostic whole body iodine scan didn’t show metastasis hence Iodine-131 treatment was not warranted. A week following the right hemi-thyroidectomy he presents to the ER with apraxia, difficulty with concentration, visual difficulty, headaches. CT scan of the brain revealed left occipital region revealed a 3.7 x 2.3 cm lesion concerning for malignancy. A follow up contrast-enhanced MRI brain showing multiple ring-enhancing lesions identified within the left posterior occipital lobe measuring 1.7 x 1.8 cm, additional occipital lobe lesion measuring 2.7 cm, mid and posterior parietal lobe measuring 3.0 cm extending to collateral sulcus measuring 2 x 3 x 1.9 cm compressing the posterior horn of left lateral ventricle. Patient underwent suboccipital craniotomy, pathology revealing glioblastoma NOS, WHO grade IV; further biomarker analysis was not available. CT of the chest, abdomen, pelvis showed no evidence of metastatic disease. Postoperative MRI of the brain revealed postoperative changes with resection of the left occipital portion of the lesion with additional enhancing regions in the left parietal and temporal lobes and splenium unchanged. Patient underwent concurrent, definitive chemo-radiation with temozolomide, now on maintenance temozolomide and levothyroxine. Conclusion: PTC is the most common thyroid malignancy, affecting young patients less than 45 years old. GBM can occur in people of any age, but they are more frequent in older adults. Physicians should maintain high surveillance for second primary cancers at a variety of sites in patients who have been found or treated for primary cancers, especially at a young age. Further evaluation of genetic and environmental factors between papillary thyroid cancer and glioblastoma multiforme will improve our understanding of the etiology of these malignancies.
Paraneoplastic Eosinophilia (PNE): A Rare Finding in a Patient With Metastatic Medullary Thyroid Carcinoma
Authors: Jara Mark Anthony , Casteel Kelly N , Afshar-Kharghan Vahid , Subbiah Vivek , Wing Shane , Hu Mimi I-Nan
Published: May 2021

Introduction: Medullary thyroid cancer (MTC) is a rare tumor of neuroendocrine origin that co-secretes various peptides leading to diarrhea and vasodilation. Ectopic Cushing syndrome due to production of adrenocorticotropic or corticotrophin-releasing hormone is a well-recognized but uncommon paraneoplastic manifestation of advanced MTC. We report an extremely rare presentation of eosinophilia in a patient with MTC that correlated with disease progression. Case:

A 58-year-old woman with sporadic metastatic MTC harboring somatic RET M918T mutation developed metastatic disease to the liver, lung and bones 2 years after surgery for locally advanced disease. Calcitonin (Ctn) was 123 pg/ml and CEA was 2575 ng/ml. At that time, leukocytosis [WBC 30.8 K/ul (4-11k/ul)] and eosinophilia [eosinophil count 16.01 k/ul (0.04-0.40 k/ul)] were noted. She was asymptomatic. Extensive evaluation of hypereosinophilia ruled out hematological or infectious causes. The patient initiated vandetanib with a partial response (PR) with decrease in lung and liver metastases and a significant improvement of the paraneoplastic eosinophilia [eosinophil count 2.39 k/ul] after 10 weeks of treatment. After a year on treatment, there was progressive disease (PD) with increasing hilar and abdominal lymphadenopathy associated with increased eosinophilia of 4.34 K/ul. Vandetanib was discontinued. She was enrolled on a clinical trial with a highly potent and selective RET inhibitor. The patient achieved PR to study drug by the 2nd month on treatment and durable response for 30 months. The eosinophil count normalized [0.32 k/ul] 4 weeks after starting the new treatment. She developed PD in liver metastases associated with recurrent leukocytosis (WBC 58.6 K/ul) and eosinophilia of 28.13 K/ul. Ctn was 1646 pg/ml. CEA was 8722 ng/ml. Her bone marrow biopsy showed marked eosinophilia, focal MTC metastatic infiltrate, no increased blasts, and was negative for the BCR-ABL1 translocation and the FIP1L1-PDGFRA fusion. She was switched to a different RET Inhibitor but passed away 1 month after starting the new protocol. Discussion: Paraneoplastic eosinophilia should be considered after excluding other causes (e.g. infections, allergy, collagen, vascular or malignant hematopoietic diseases). Thyroid tumors producing colony-stimulating factors, associated with neutrophilia and/or eosinophilia have been described almost exclusively in patients with anaplastic thyroid cancer. This patient had a poorly differentiated MTC as evidenced by the disproportionally high CEA relative to Ctn. The course of the eosinophilia paralleled the clinical behavior of her disease. To our knowledge, this is only the 2nd report of eosinophil trends corresponding with MTC disease course, consistent with a paraneoplastic process. Conclusion: PNE is very rare in MTC and its presence suggests a poor prognosis.
Primary Thyroid Lymphoma: Could Surgery Be Avoided
Authors: Laukiene Romena , Miseviciute Karolina
Published: May 2021

Background: Primary thyroid lymphoma is a rare thyroid disease that makes up only 1 to 5% of all thyroid oncological disorders. The average patient with primary thyroid lymphoma is a woman in her sixth or seventh decade with a history of Hashimoto’s thyroiditis. Clinical Case: 28-year-old woman complained of hoarseness, rapidly enlarging mass of the neck. She was referred to an otorhinolaryngologist by her family physician who suspected upper airway pathology. Otorhinolaryngologist observed swelling of patients’ larynx and prescribed treatment for suspected bacterial larynx infection. Symptoms kept worsening despite of treatment and patient was referred to an endocrinologist for a consultation. Blood lab tests were unremarkable. Ultrasound of the thyroid was performed which revealed a large (4,5 cm), hypoechoic, solid, homogenous node with Doppler signs of increased intranodular vascularity. Additionally, enlarged submandibular salivary gland lymph nodes on both sides of the neck were observed. FNAC (fine-needle aspiration cytology) was performed to diagnose possible thyroid malignancy, however findings showed atypia of undetermined significance (3rd category of Bethesda classification), to differentiate from lymphocytic thyroiditis. Because of high risk of malignancy, it was decided to perform thyroidectomy. During surgery, urgent intraoperative biopsy revealed undifferentiated thyroid carcinoma. As radical tumor extirpation due to prominent surrounding fibrosis was impossible, then only one side lobectomy was performed. Final histological examination revealed large B cell lymphoma, phenotype: CD20+, BCL6+, MuM1+, CD21+, cMyc-, BCL2-, CD10-, CD30-, Ki-67 up to 97%. More accurate disease staging was performed post-operatively, PET scan and computed tomography revealed disseminated primary thyroid lymphoma. Final diagnosis was Stage IV primary large B cell lymphoma of the thyroid. Patient was treated with chemotherapy according to Rx7-CHOP14x6 (Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) protocol. The treatment was tolerated well, 3 months after, complete remission of the disease was observed. During outpatient visits patient remained in remission for all 5 years of planned regular check-ups. Conclusion: This case demonstrates the diagnostic challenge of primary thyroid lymphoma. In the presence of rapidly enlarging thyroid mass, thyroid lymphoma is not usually suspected. FNAC as golden standard of thyroid malignancy often does not allow differentiation of this pathology. In this case, a core biopsy could have helped to make correct preoperative diagnosis and to avoid unnecessary surgery.
Responses to the First Radioactive Iodine Treatment After Targeted Therapy for Aggressive Papillary Thyroid Cancers
Authors: Soe Myat Han , Chiang Janet , Kang Hyunseok , Liu Chienying
Published: May 2021

Introduction: Tall cell variant (TCV) and columnar cell variant (CCV) are aggressive variants of papillary thyroid cancer (PTC) and they are overrepresented in radioactive iodine (RAI) refractory cases. Studies have reported using BRAF and/or MEK inhibitors to restore iodine avidity in patients with iodine refractory disease. There is much less experience of using targeted therapy pre-emptively to enhance iodine uptake for aggressive variants and advanced disease prior to the first RAI treatment (RAI-T). We present three patients with these variants and describe their responses to the first RAI-T after targeted therapy.

Case 1: 64-year-old male with CCV-PTC and areas of poor differentiation (pT3aN1bM1) has somatic BRAF V600E, TERT and AJUBA mutations. Thyroglobulin (TG) 6 weeks post surgery was 21 ug/L, with negative TG antibodies (TGAb). PET-CT revealed FDG avid superior mediastinal lymphadenopathy and lung metastases. He received dabrafenib for 6 weeks followed by his first RAI -T(153 mCi) after thyroid hormone withdrawal (THW). Pre- and post-therapy scans showed uptake in the neck, right superior mediastinum and lung metastases. Three months post RAI, TG decreased to 5.1 ug/L. Chest CT revealed stable mediastinal lymphadenopathy and decreased size of lung metastases.

Case 2: 41-year-old male with TCV-PTC containing areas of focal squamous differentiation and poor differentiation (pT4aN1bM1) has somatic BRAF V600E and TP53 mutations. PET-CT showed FDG avid neck lymph nodes and lung metastases. TG 8 weeks after surgery was 1.5 ug/L, TGAb 31.19 IU/L. He was treated with dabrafenib and trametinib for 4 weeks followed by his first RAI-T (150mCi) after THW. Pretreatment scan showed uptake in the thyroid bed and cervical lymph nodes. Post-therapy scan revealed additional uptake in the lung metastases. Chest CT 3 and 9 months after RAI-T revealed stable paratracheal lymph node and lung metastases. TGAb decreased to 7.04 IU/L; TG was 2.2 ug/L.

Case 3: 33-year-old female with invasive TCV-PTC (pT3bN1aM1) has a somatic BRAF V600E mutation. CT chest showed multiple scattered lung nodules up to 4mm. Ten weeks post surgery, TG was 0.1 ug/L, TGAb 5.21 IU/ml. Patient received 1 month of dabrafenib and trametinib followed by his first RAI-T(125 mCi) after THW. Pre- and post-therapy scans revealed uptake in the neck and left supraclavicular areas, without uptake in lung nodules. Three months post RAI, chest CT revealed stable lung nodules. TG was 0.1 ug/L, and TGAb was 5.16 IU/L. Neck ultrasound showed no disease.

Conclusion: These three patients with aggressive variants of PTC have advanced disease, and all were found to have a BRAFV600E mutation on genomic analysis. They tolerated BRAF targeted inhibition as an attempt to enhance iodine uptake preemptively with various responses to their first RAI-T. More studies will be needed to determine if this strategy will improve outcomes for these patients.
A Case of TSH-Secreting Pituitary Adenoma With Unusual Positive Staining for SF1
Authors: Robinson Kathleen , O’Neill Brian
Published: May 2021

Background: TSH-secreting pituitary adenomas are the rarest functional pituitary tumors. While they are often plurihormonal, SF1 positivity (indicating gonadotroph lineage) is unusual. Here we present the rare case of a patient with TSH-secreting pituitary adenoma with staining positive for TSH, GH, prolactin, SSTR2A, PIT-1, and SF1.

Clinical Case: Patient is a 42 year-old male with a history of hypogonadotropic hypogonadism (lost to follow-up), who presented with a 5 day history of nausea and vomiting. Vitals were notable for tachycardia to 108 BPM, with BMI 14.8 kg/m2. On physical exam he had enlarged right hemi-thyroid and exophthalmos. Labs were notable for TSH 12.55 μIU/mL (0.27-4.20), Free T4 >7.77 ng/dL (0.80-1.80), Free T3 29.02 pg/mL (2.57-4.43), 8am cortisol 0.9 μg/dL (6.0-18.4), FSH 0.6 μIU/ml (1.5-12.4), LH 0.8 μIU/mL (1.7-8.6), PRL 8.5 ng/mL (4.0-15.2), total testosterone <5 ng/dL (249-836), and IGF-1 88.9 ng/mL (94.4-223.0). MRI showed large lobulated pituitary mass extending into the suprasellar region with mass effect and thyroid US showed enlarged almost completely cystic right hemi-thyroid. The patient was started on methimazole 30mg BID, prednisone 40mg daily, and cabergoline 0.5mg weekly (he declined octreotide). FT4 and FT3 remained significantly elevated despite escalation of cabergoline to 0.5mg 5 days weekly, so the patient was admitted two months after his initial presentation for plasmapheresis followed by thyroidectomy. His hospital course was complicated by post-op meningitis and DI, both successfully treated. Surgical pathology was notable for patchy expression of TSH with rare cells expressing GH and prolactin, SSTR2A positivity, strong nuclear positivity for PIT-1 with negative T-PIT staining, and unusual positivity for SF1. At follow-up he is clinically euthyroid and stable without use of LT4 or HC therapy. Repeat TSH, FT4, ACTH, cortisol, and testosterone are pending. He declines chemotherapy, radiation, and octreotide. Conclusion: This is a rare case of TSH-producing adenoma demonstrating SF1 positivity in addition to TSH, GH, PRL, and PIT-1 expression, in the absence of excess gonadotroph secretion. When such tumors secrete multiple hormones, this has been used as evidence to support the argument that such tumors arise from a stem cell population(1). However, the implications for our patient remain unclear.

References: (1) Tordjman et al. Plurihormonal Pituitary Tumor of Pit-1 and SF-1 Lineages, with Synchronous Collision Corticotroph Tumor: a Possible Stem Cell Phenomenon. Endocr Pathol. 2019 Mar;30(1):74-80.
A Rare Case of Anaphylaxis to Methimazole in a Patient With Graves’ Disease
Authors: Garg Dave , Garcia Gonzalo Acosta , Praw Stephanie Smooke
Published: May 2021

We present the case of a patient with Graves’ Disease (GD) who developed anaphylaxis to methimazole (MMI) necessitating hospitalization, emergent treatment and ultimately urgent total thyroidectomy. While the most common adverse reactions to thionamides include hepatotoxicity, agranulocytosis, pruritis, and urticaria, delayed anaphylaxis has been reported.

A 25-year-old woman was diagnosed with GD two years prior to presentation during an admission for syncope. She was started on MMI 10 mg twice a day and propranolol 10 mg three times a day, which she took for roughly one year until she ran out of medication and was lost to follow-up. She remained off MMI until she re-presented several months later grossly thyrotoxic, complaining of fatigue, heat intolerance, unintentional weight loss, blurry vision, and palpitations. Labs were significant for TSH <0.02 mIU/L (normal 0.3-4.7), free T4 >7 ng/dL (normal 0.8-1.7), free T3 >2900 pg/dL (normal 222-383), and thyroid stimulating immunoglobulin (TSI) >500 (normal ≤122).

She was restarted on propranolol and MMI 10 mg twice a day which was quickly increased to 20 mg twice a day. Two weeks after restarting MMI, the patient presented to the ER with a diffuse pruritic rash and was treated with antihistamines and steroids. She clinically improved and was discharged in stable condition. Two days later, her symptoms recurred along with flushing, facial/lip swelling, and dysphagia. She presented to our hospital with evidence of angioedema and difficulty breathing. Based on her presentation, anaphylaxis was diagnosed, and she was given intramuscular epinephrine. She was also started on glucocorticoids, H1/H2 blockers and montelukast and was admitted to the ICU for close monitoring. Over the next few days, her symptoms improved.

As there was no other recent novel exposure, her anaphylactic reaction was attributed to MMI. Given the life-threatening nature of the reaction, there was concern for trialing propylthiouracil (PTU) due to its known cross-reactivity with MMI. Thus, treatment with propranolol, steroids and potassium iodide was initiated with improvement in her thyroid labs. As the patient would be unable to tolerate anti-thyroid agents in the future, it was decided to pursue definitive treatment with total thyroidectomy given the presence of eye disease.

Anaphylaxis secondary to MMI is very rare, and less than a handful of cases have been reported. However, they seem to share two key features: their occurrence with higher doses of MMI (≥40 mg daily), and a delayed onset of presentation (2-4 weeks from exposure). The mechanism is unknown, although it is unlikely to be IgE-mediated given its time course. Current ATA guidelines recommend against using MMI or PTU in patients who have developed serious side effects to the other agent. Our case highlights the importance of close monitoring and timely follow-up after initiating anti-thyroid drugs.