Hurthle Cell Thyroid Cancer Research Articles

THU675 A Case Report For Hurthle Cell Neoplasm Suspicious For Carcinoma

Abstract Disclosure: J. Wu: None. P. Rimal: None. S. Ying: None. R. Jasaraj: None. F. Ali: None. A. Havrylyan: None. Hurthle cell carcinoma, also called Hurthle cell thyroid cancer, is an extremely rare type of thyroid tumor. It accounts for approximately 3-4% of all thyroid cancers, [3][19] usually diagnosed when patients present clinically with thyroid nodules or incidental findings on neck imaging. [1][2] In this case, we present a case for suspicious Hurthle cell carcinoma occurring in a 76-year-old male patient. He initially presented with progressive worsening dyspnea. An initial chest CT scan showed multiple pulmonary nodules; meanwhile, it also noted an incidental finding of thyroid nodules on the CT scan. Thyroid function tests, including thyroid-stimulating hormone (TSH) and thyroxine (T4), are mild hypothyroidism, indicating non-thyrotoxic thyroid nodules; ultrasound of the thyroid gland showed one right upper solid isoechoic nodule. Further fine-needle aspiration (FNA) biopsy revealed cells suspicious for hurtle cell neoplasm. The patient was subsequently referred to otolaryngology for thyroid lobectomy or thyroidectomy.Case reports: A 74-year-old male with a past medical history of Hypertension, type2 Diabetes mellitus, Deep vein thrombosis, Atrial fibrillation, Aortic stenosis, and hypothyroidism initially presented with chronic dyspnea caused by severe aortic stenosis, with scheduled aortic valve replacement in August 2022. A pre-procedure chest CT showed multiple 3 -5 mm pulmonary nodules throughout the lungs and an incidental finding of thyroid nodules. The patient was referred to the endocrinology department for his thyroid nodules. The patient was in a clinically euthyroid state, denied compressive symptoms, and denied dysphagia, hoarseness, and past exposure to radiation. The thyroid function test reveals elevated TSH and a high level of thyroid peroxidase antibodies; However, free T4, free T3, and Total T3 are all within normal limits. Subsequently, a thyroid ultrasound revealed one right upper solid isoechoic 2.5 x 1.7 x 2.1 cm nodule (TI-RADS 3). A fine-needle aspiration (FNA) biopsy on 01/23/2023 revealed findings suspicious for hurtle cell neoplasm. This patient was subsequently referred to an otolaryngologist (ENT) for thyroid lobectomy or thyroidectomy to confirm the diagnosis. ENT recommends at least a right thyroid lobectomy. Conclusion: Despite being rare, Hurthle cell carcinoma still affects several patients every year. It is usually diagnosed when patients present clinically with thyroid nodules or incidental findings on imaging of the neck, like in this case. It is characterized by the presence of Hurthle cells in histology. However, FNA cannot distinguish between a benign adenoma and malignant carcinoma. Distinguishing them requires a thyroid lobectomy or thyroidectomy. We hope that highlighting this case report will help clinicians across specialties recognize and diagnose this condition with the appropriate level of care. Presentation: Thursday, June 15, 2023

Abstract 4261: Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies

Abstract Background: Understanding molecular biology of thyroid cancer has revolutionized diagnosis, tumor classifications and identifying effective precision oncology therapies. Methods: Using AACR GENIE database v.12, we cataloged genetic and co-occurring alterations in all thyroid cancers. Results: We identified 2128 cases from 153,834 samples where tumor sub-histologies included Papillary Thyroid Cancer (PTC: 55%; 1162), Poorly Differentiated Thyroid Cancer (PDTC: 12%; 262); Medullary Thyroid Cancer (MTC: 12%; 244), Anaplastic Thyroid Cancer (ATC: 10%; 220); Follicular Thyroid Cancer (FTC: 5%; 111); Hurthle Cell Thyroid Cancer (HCTC: 5%; 95); and others (1; 34). Median age at sequencing was 59 years. Gender distribution was higher in female (54%; n=1104) compared to male (46%; n=933). Ethnicities included 73.2% (n=1,493) White, 8.9% (n=178) Asian, and others.Most frequent genomic mutational alterations overall were BRAF (40.8%; 868) [96% (n=845) V600E, 0.6% (n=5) G469A, 0.6% (n=5) V600_K601delinsE, 0.2% (n=2) K601E, 0.2% (n=2) A404Cfs*9, and 2.7% (n=24) others]; TERT (35%; 624); NRAS (11.6%; 247); TP53 (11.6%; 247) and RET (9.3%; 197) genes. There was variability in genomic alterations between sub-histologies (Table 1). There was statistically significant co-occurrence between BRAF and TERT, TERT and TP53, TERT and NRAS alterations (p<0.001). Mutually exclusive alterations were BRAF and NRAS, BRAF and RET, TERT and RET, NRAS and RET, TP53 and RET, and BRAF and TP53 (p<0.001).Copy number alterations (CNA) were observed in 497 samples and were most frequent in CDKN2A, NKX2-1, CDKN2B, NF2, and CRKL genes (16.5%, 16%, 15.5%, 13.1%, and 13%). 362 oncogenic fusions were noted predominantly in CCDC6-RET, RET-NCOA4, ETV6-NTRK3, BRAF-Intragenic (20%, 7.2%, 3%, 1.6%). Conclusion: Genomic profiling identified full breadth of BRAF, RET and NRAS alterations and co-occurring oncogenic driver alterations. This approach may refine use of targeted therapy in thyroid cancer. Table 1. Histology Most frequent Alterations % n PTC BRAF 62.3% 724 TERT 32.7% 332 PDTC TERT 49% 117 NRAS 28.2% 74 MTC RET 71.3% 174 HRAS 7.8% 19 ATC TP53 58.2% 128 TERT 56.7% 106 FTC TERT 41% 27 NRAS 26.1% 29 HCTC TERT 41% 34 TP53 17.9% 17 Citation Format: Blessie Elizabeth Nelson, Mohammed Gouda, Jason Roszik, Mimi L. Hu, Maria Cabanillas, Vivek Subbiah. Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4261.

RF11 | PSAT234 Deep learning analysis of thyroid nodule ultrasound images has high sensitivity and negative predictive value to rule-out thyroid cancer

Abstract Purpose To evaluate deep learning analysis of thyroid nodule ultrasound images as a rule-out test for thyroid malignancy. Methods Supervised deep learning (DL) classifier of thyroid nodules was trained on 32,545 thyroid US images from 621 nodules representing all major benign and malignant types of thyroid lesions and tested on an independent set of 145 nodules collected at a different healthcare system in the United States. The Big Transfer BiT-M ResNet-50×1 convolutional neural net architecture was modified to contain 3, 4, 6 and 3 PreActBottleneck units per block 1 through 4. Weights pretrained on the ImageNet-21k dataset were loaded and weights for blocks 3 and 4 were fine-tuned for the binary classification task of distinguishing benign and malignant thyroid nodules. Results The deep learning thyroid nodule classifier achieved an area under receiver operating characteristic curve (AUROC) of 0.889 on five-fold cross-validation. The AUROC improved when images were scaled by nodule size and six randomly selected cine clip frames were added to the training set per epoch. GradCAM class activation heatmaps revealed that microcalcifications and spongiform appearance were reliably recognized by the classifier as malignant and benign features, respectively. Spongiform nodules were found to be benign even when microcystic spaces constituted less than 50% of nodule volume. To investigate the clinical relevance of the benign vs. malignant classifier, the binary classification threshold for the probability of malignancy generated by model was set at 7% to achieve sensitivity and negative predictive value (NPV) comparable to that of the fine needle aspiration biopsy (FNA). At this threshold, cross-validated deep-learning model achieved a sensitivity of 90%, specificity of 63%, positive predictive value (PPV) of 46% and negative predictive value of 94%. When tested on an independent image set that includes 18 classic papillary thyroid cancers (PTC), 5 follicular variant PTC, 4 medullary thyroid cancers, 3 follicular thyroid cancers (FTC), and 1 Hurthle cell thyroid cancer, the DL classifier achieved AUROC of 0.88, sensitivity of 97%, specificity of 61%, PPV of 40% and NPV of 99%. A single minimally-invasive FTC that had no suspicious features on thyroid ultrasound was incorrectly classified as benign. Conclusions This study demonstrates that the ultrasound-based deep-learning classifier of thyroid nodules achieves sensitivity and negative predictive value comparable to that of thyroid fine needle aspiration (FNA). Clinicians may use this tool to augment clinical judgment when determining whether to perform FNA procedures. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m., Saturday, June 11, 2022 1:06 p.m. - 1:11 p.m.

PSAT373 Metformin Decreases Serum Thyroglobulin Concentration in Non-Medullary Thyroid Carcinoma

Abstract Background The conventional treatment of non-medullary thyroid carcinoma (NMTC) includes surgical resection, TSH suppression and 131-iodine. Although highly successful, some patients develop persistent/recurrent NMTC requiring alternative therapies, including external radiation and multikinase inhibitors, which may have clinically significant adverse side effects. In vitro studies, in vivo studies in animals, and association studies in humans suggest that metformin, an inexpensive medication with a modest side effect profile, may help prevent or treat NMTC. No interventional metformin trials have been performed in humans. Hypothesis We performed a proof-of-concept intervention trial to test the hypothesis that metformin will decrease serum thyroglobulin concentration (Tg), a surrogate marker for NMTC, in humans with persistent/recurrent NMTC burden. Methods In this IRB approved study, we administered metformin to patients with persistent/recurrent NMTC and analyzed the change in Tg. When available and possible, tumor burden was evaluated by CT imaging. Ten patients with persistent/recurrent well-differentiated NMTC (6 classic papillary thyroid cancer, 1 tall cell variant of papillary thyroid cancer, 2 follicular thyroid cancer, and 1 hurthle cell thyroid cancer) were included. All had exhausted conventional therapies including total thyroidectomy and 131-iodine. All had biochemical evidence of NMTC with Tg > 2 ng/mL, and with non-detectable serum thyroglobulin antibody concentrations. Six had microscopic NMTC not detectable by conventional imaging, and four had NMTC detectable on CT imaging. Five patients elected to be treated with metformin (500 to 2000 mg/d) for two to five months. The remaining five served as untreated controls. Since the Tg variances in the two groups were not equal, the nonparametric Mann-Whitney test was used to determine if the change in Tg was different in the metformin treated and untreated groups. Results Tg decreased in all five patients receiving metformin and increased in all five controls. The mean Tg decrease with metformin therapy was 21.7 ± 8.4%, and the mean Tg increase in the control group was 16.6 ± 12.1%; p < 0.02. TSH was suppressed to < 0.1 mIU/L in both groups at baseline and did not change significantly during the study. Two of the five patients receiving metformin elected to continue the metformin for longer, and the CT imaging studies were evaluable by RECIST criteria. There was no decrease in tumor size in either patient. The progression-free survival was 6 months in one patient and 10 months in the other, which may be longer than that reported for similar historical controls that range from 3.6 to 5.8 months. Summary In summary, metformin caused a TSH-independent decrease of Tg in patients with persistent/recurrent NMTC, but no decrease in tumor size in two evaluable patients. More extensive studies are necessary to determine if metformin slows NMTC progression. Conclusion Metformin decreases Tg in NMTC. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Abstract #1183852: Hurthle cell carcinoma with bone metastasis

Hurthle cell thyroid cancer is usually classified as a type of Follicular thyroid cancer. It comprises about 3-5% of thyroid cancer cases. Hurthle cell thyroid cancers are known for their more aggressive tumor biology; metastases are observed in a minority of cases, and long-term survival can be expected.

Outcomes and Trends of Treatments in High-Risk Differentiated Thyroid Cancer.

To analyze the variant-specific survival benefits and usage patterns of standardized treatment combinations of surgery (S), radioactive iodine ablation (RAI), and thyroid-stimulating hormone suppression therapy (THST) for high-risk differentiated thyroid cancer. Retrospective cohort study. National Cancer Database. The 2004-2017 National Cancer Database was queried for patients receiving definitive surgery for high-risk papillary, follicular, or Hurthle cell thyroid cancer. Cox proportional hazards and Kaplan-Meier analyses assessed for treatment-associated survival. Of 21,076 cases, 18,214 underwent survival analysis with a mean ± SD age of 50.6 ± 17.1 years (71.3% female). When compared with surgery alone, S + RAI was associated with reduced mortality in papillary (hazard ratio [HR], 0.574; P < .001) and follicular (HR, 0.489; P = .004) thyroid cancer. S + RAI + THST was associated with reduced mortality in papillary (HR, 0.514; P < .001), follicular (HR, 0.602; P = .016), and Hurthle cell (HR, 0.504; P = .021) thyroid cancer. In papillary thyroid cancer, S + RAI (91.3%), S + THST (89.2%), and S + RAI + THST (92.7%) were associated with higher 5-year overall survival rates than surgery (85.4%, all P < .001). Papillary thyroid cancer treatments involving THST were associated with higher 5-year overall survival rates than corresponding regimens without THST (all P < .001). In follicular thyroid cancer, S + RAI (73.9%) and S + RAI + THST (78.7%) were associated with higher 5-year overall survival rates than surgery (65.6%, all P < .05). In Hurthle cell thyroid cancer, S + RAI (66.5%) and S + RAI + THST (73.4%) were associated with higher 5-year overall survival rates than surgery (53.7%, all P < .05). On linear regression, THST usage increased by 77.5% (R2 = 0.944, P < .001), while RAI usage declined by 11.3% (R2 = 0.320, P = .035). High-risk differentiated thyroid cancer exhibited varying susceptibilities to different treatment combinations depending on histology, with greatest responses to regimens that included RAI. Physician practices have trended toward decreased RAI and increased THST usage.

Abstract #977955: Lenvatinib use Associated with Multi-organ Adverse Events in Hurthle Cell Thyroid Cancer

The management of metastatic progressive radioiodine-resistant differentiated thyroid cancer has remained a challenge for clinicians. The availability of tyrosine kinase inhibitors (TKIs) within the last decade has expanded the treatment options, but these come with significant adverse effects that may curtail their use.

177Lu-DOTA-EB-TATE, a Radiolabeled Analogue of Somatostatin Receptor Type 2, for the Imaging and Treatment of Thyroid Cancer.

The goal of this study was to analyze the role of somatostatin receptor type 2 (SSTR2) as a molecular target for the imaging and treatment of thyroid cancer through analysis of SSTR2 expression and its epigenetic modulation and testing tumor uptake of different radiolabeled SSTR2 analogues. We analyzed SSTR2 expression by immunostaining of 92 thyroid cancer tissue samples and quantified standard uptake values (SUVmax) of SSTR2 analogue, 68Ga-DOTA-TATE, by PET/CT imaging in 25 patients with metastatic thyroid cancer. We utilized human thyroid cancer cell lines characterized by differential SSTR2 expression (TT, BCPAP, and FTC133) and rat pancreatic cell line (AR42J) with intrinsically high SSTR2 expression for functional in vitro studies. SSTR2-high (AR42J) and SSTR2-low (FTC133) xenograft mouse models were used to test the uptake of radiolabeled SSTR2 analogues and their therapeutic efficacy in vivo. Thyroid cancer had a higher SSTR2 expression than normal thyroid. Hurthle cell thyroid cancer was characterized by the highest 68Ga-DOTA-TATE uptake [median SUVmax, 16.5 (7.9-29)] than other types of thyroid cancers. In vivo studies demonstrated that radiolabeled DOTA-EB-TATE is characterized by significantly higher tumor uptake than DOTA-TATE (P < 0.001) and DOTA-JR11 (P < 0.001). Treatment with 177Lu-DOTA-EB-TATE extended survival and reduced tumor size in a mouse model characterized by high somatostatin (SST) analogues uptake (SUVmax, 15.16 ± 4.34), but had no effects in a model with low SST analogues uptake (SUVmax, 4.8 ± 0.27). A novel SST analogue, 177Lu-DOTA-EB-TATE, has the potential to be translated from bench to bedside for the targeted therapy of patients characterized by high uptake of SST analogues in metastatic lesions.

Role and extent of neck dissection for neck lymph node metastases in differentiated thyroid cancers

Differentiated thyroid cancers (DTC) consist of 95% of thyroid tumors and include papillary thyroid cancer (PTC), follicular thyroid cancer (FTC), and Hurthle cell thyroid cancer (HTC). Rates of lymph node metastases are different depending on histologic subtypes and <5% in FTC and between 5% and 13% in HTC. Lymph node metastasis is more frequent in PTC and while rate of clinical metastasis can be seen approximately 30% rate of routine micrometastasis can be seen up to 80%.Lymph node metastasis of DTC mostly develops first in the Level VI lymph nodes at the central compartment starting from the ipsilateral paratracheal lymph nodes and then spreading to the contralateral paratracheal lymph nodes. Spread to the Level VII is mostly after Level VI invasion. Subsequent spread is to the lateral neck compartments of Levels IV, III, IIA, and VB and sometimes to the Levels IIB and VA. Occasionally skip metastasis to the lateral neck compartments develop without spreading to the central compartments and this situation is more frequent in upper pole tumors.Although application of prophylactic central neck dissection (pCND) in DTC increases the rate of complication, due to its unclear effects on oncologic results and quality of life, the interest to the pCND is decreasing and debate on its surgical extent is increasing. pCND is not essential in DTC and characteristics of patient and tumor and experience of surgeon should be considered when deciding for pCND. Due to lower complication rate of one sided pCND compared to bilateral central neck dissection (CND), low possibility of contralateral central neck metastasis and low risk of recurrence, application of one-sided CND is logical. Although therapeutic CND (tCND) is the standart treatment when there is a clinically involved lymph node, extent of dissection is a matter of debate. A case-based decision for the extent of tCND can be made by considering patient and tumor characteristics and experience of the surgeon.Due to the higher complication risk of bilateral CND, unilateral tCND can be performed if there is no suspicious lymph node on the contralateral side and bilateral tCND can be applied when there is a suspicion for metastasis only on the contralateral side or there are features for risk of metastasis to the contralateral side. In patients with clinical central metastasis owing to intra-operative pathology results by frozen section procedure are compatible with post-operative pathology results, when there is a suspicion for contralateral metastasis, a decision for one- or two-sided dissection can be made using frozen section procedure. In DTC, it can be stated that there is a consensus in the literature about not performing prophylactic lateral neck dissection (LND), but performing therapeutic LND (tLND). In addition, there is a debate on the extent of tLND.In a meta-analysis about lateral metastasis, the rates of metastasis to the Levels IIA, IIB, III, IV, VA, and VB were 53.1%, 15.5%, 70.5%, 66.3%, 7.9%, and 21.5%, respectively. Ultrasonography (USG) is an effective procedure for detection of cervical nodal metastasis on lateral compartment. Pre-operative imaging with USG and/or combination with the fine needle aspiration biopsy (cytology/molecular test/Thyroglobulin test) can allow pre-operative detection and verification of lateral lymph node metastasis.Extent of tLND can be determined to minimize morbidity considering pre-operative USG findings, pre-operative tumor and clinical features of lateral metastasis. Especially in the presence of limited lateral metastases, limited selective LND such as Levels III, IV or Levels IIA, III, IV can be applied according to the patient. Levels IIB and VB should be added to the dissection in the presence of metastases in these regions. In cases that increase the risk of Level IIB involvement, such as presence of metastasis at Level IIA, extranodal tumor involvement, presence of multifocal tumor, and in cases that increase the risk of Level VB involvement such as macroscopic extranodal spread, and simultaneous metastases at Levels II, III, IV; Levels IIB and VB can be added to dissection material. Levels I and VA should be added to the dissection in the presence of clinically detected metastases.

SUN-615 Hurdles in Hurthle Cell Cancer: A Case Report on Hurthle Cell Thyroid Cancer with Vertebral Metastasis

Introduction: Hurthle cell thyroid carcinoma (HCC) is a rare variant of follicular thyroid cancer, exhibiting a different clinical behavior and believed to be more aggressive but with relatively good prognosis. Correct identification of HCC in indeterminate cytological samples is challenging and ultrasound features can be misleading. No specific recommendations exist, making the management of HCC difficult [1]. Clinical Case: A 55-year-old obese woman with history of hypertension and stroke presented with severe back pain, and progressive lower leg motor and sensory weakness over 4 months. Two months prior to consult, a T7 vertebral mass was discovered, and she subsequently underwent decompressive surgery. Histopathology revealed metastatic follicular variant or papillary thyroid carcinoma. The patient was in severe pain and had complete loss of motor and sensory function in lower extremities. Thyroid exam revealed palpable nodules. Neck UTZ showed well-defined calcified nodules in both thyroid lobes, with largest in the mid-section of right lobe measuring 3.3 x 1.6 x 1.9 cm with minimal peripheral vascularity. She was given oxycodone, pregabalin, paracetamol and IV dexamethasone. Palliative radiotherapy was given using external-beam radiotherapy targeting T7 at a dose of 30 Gy in 10 fractions/ 10 days. Urinary tract infection, hypertension and constipation were detected and managed accordingly. She underwent total thyroidectomy 20 days later. Histopathology showed minimally invasive HCC with 4 cm tumor, no extrathyroidal extension, and negative for lymph node involvement. Post-surgical radiotherapy at 150 mCi I-131 was given. Post-ablation whole body scan revealed single island at right thyroid bed with an intense localization to the left of spinal column at the level of T6-T7, suggestive of functioning thyroid metastasis. TSH suppression was initiated. There is significant improvement within 3 months. She regained bladder and bowel control, as well as improvement in motor and sensory strength. Currently there is continuous improvement in function. Conclusion: Early recognition and prompt management should be done to all patients with HCC. UTZ and FNAB suggestive of Hurthle cell morphology can guide us in detecting HCC.

OR19-4 High Prevalence of Primary Hypothyroidism in Patients with Alkaptonuria Eighteen Years of Experience

Background: Alkaptonuria (AKU) is a rare autosomal recessive disorder caused by pathogenic variants in the gene encoding homogentisate-1,2-deoxygenase (HGD). Deficiency of HGD leads to tissue deposition of homogentisic acid (HGA), causing severe osteoarthropathies, aortic and mitral valve degeneration and kidney stones. HGD is vital for the catabolism of tyrosine, which provides the backbone of iodination into thyroxine (T4) within the thyroid gland. The goal of this study was to assess thyroid function (TFT) in patients (pts) with AKU. Methods: We performed a cohort study including pts with AKU followed at our center between 2000 and 2018. All pts had thyroid stimulation hormone (TSH), freeT4 (fT4), anti-thyroid peroxidase antibodies (anti-TPO-abs) measured repeatedly by immunoassay. In addition, a subset of patients underwent a thyroid ultrasound (US). Hypothyroidism (HYPO) was defined as TSH above the reference range (0.27-4.2 mIU/ml) with fT4 below the reference range (0.9-1.7 ng/dl) on two repeated tests or normalization of TSH on levothyroxine (LT4) replacement therapy. Subclinical HYPO (S-HYPO) was defined as TSH above the reference range with normal fT4 on two repeated tests. Results:The study cohort consisted of 130 pts with AKU, majority men (55.4%), aged 59.1±15 years and followed for 36 (range 1-63) months, during which median 10 (range 2-35) TFTs were performed. Twenty-four pts were diagnosed with HYPO, but 3 pts were excluded due to post-thyroidectomy etiology of HYPO, giving a prevalence of HYPO of 16.5% (21/127) - significantly higher than reported 5% of the general population (p=0.006). S-HYPO was diagnosed in 4.7% (6/127) and overt HYPO in 11.8% (15/127) pts, who were treated with a median LT4 dose of 100 mcg daily (1.4 mcg/kg). The median thyroid volume in HYPO pts was 7 cc (range 3.9-13). The prevalence of elevated anti-TPO-abs in the whole cohort was 14% (18/127), while its prevalence in HYPO group was 43% (9/21) - significantly lower than reported 89.8% for HYPO pts in the general population (p<0.001). Among 49 pts who had thyroid US performed, thyroid nodules with a median size of 0.4 (range 0.3-3.2) cm were identified in 59.2% (29/49), similar to prevalence observed in general population (p=0.63). Three pts (6%) were diagnosed with thyroid cancer (TC), 2 - with micro-papillary TC and 1 with Hurthle cell TC. The prevalence of TC was similar to prevalence observed in general population (p=0.77). Conclusions: AKU is associated with high prevalence of primary HYPO. The etiology of HYPO is unclear, given low prevalence of anti-TPO-abs in hypothyroid AKU pts. Further functional studies are needed to assess potential pathologic effect of the accumulation of HGA on thyroid hormone synthesis and function.

Clinicopathological features of differentiated thyroid carcinoma referred to radioiodine therapy at Tripoli Medical Center

Objectives: The objective of this study is to study the demographic, clinicopathological features, and geographical distribution of differentiated thyroid cancer (DTC) among Libyan patients referred from all parts of the country to the nuclear medicine department, for radioactive iodine (RAI) therapy. Materials and Methods: Retrospective review of medical records of 265 patients with differentiated thyroid carcinoma (DTC) referred to RAI therapy in the Nuclear Medicine Branch-Tripoli Medical Center, in the period from May 2005 to October 2010. The data analyzed included sex, age at the time of diagnosis, the city of residence, pathological diagnosis, the extent of disease, and types of treatment. Results: There were 225 (84.9%) females and 40 (15.1%) males giving a sex ratio of 5.6:1. The mean age of males at diagnosis was 51.2 ± 14.8 (range 24–78) years and the mean age of the females was 44.6 ± 15.6 (range 10–95) years. Two hundred and twenty-three (84.2%) had papillary thyroid cancer (PTC), 31 (11.7%) had follicular thyroid cancer, 3 (1.1%) had Hurthle cell thyroid cancer, and 2 (0.8%) had follicular-insular thyroid cancer. About 43 (16.2%) had a history of multinodular goiter, and 3 (1.1%) Hashimoto's thyroiditis. From data collected, cervical lymph node metastases were found in 45 (17.0%), and distal metastases in 27 (10.2%). Conclusions: PTC was the most common type of DTC. DTC was more common among females. The current study showed that the disease tends to occur at an older age, and with less cervical lymph node metastases than previously reported.

TERT promoter mutations in thyroid cancer: a report from a Middle Eastern population.

Telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have recently been described in follicular cell-derived thyroid cancer (TC) in patients from North America and Europe. In this study, we explored whether these findings could be replicated in patients from a different ethnic group. We screened 17 benign thyroid adenomas and 265 TC samples from patients in the Middle East for these mutations by PCR and direct sequencing using DNA isolated from paraffin-embedded tumor tissues. None of the 17 benign adenomas harbored TERT promoter mutations. Of 265 TC, 34 (12.8%) harbored TERT promoter mutations, including 10/153 (6.5%) conventional papillary TC (CPTC), 8/57 (14.0%) follicular variant PTC, 9/30 (30%) tall cell variant PTC, 1/3 (30%) Hurthle cell thyroid cancer (HTC), 1/5 (20%) follicular TC, and 5/13 (38.5%) poorly differentiated TC. C250T mutation was present in only 6/265 (2.3%) cases, while C228T mutation was present in a total of 28/265 (10.6%) cases. These two mutations were mutually exclusive. TERT promoter mutations were significantly more common in older (≥45 years) than younger patients and were associated with larger tumour size, vascular invasion, higher TNM stage (stage III and IV), BRAF(V600E) mutation and persistent/recurrent disease at 6-12 months after initial treatment and at the last follow up. These associations were stronger in non-CPTC. Thus, this study on a large cohort of TC patients from Middle East demonstrates that TERT promoter mutations are relatively common, especially in the non-CPTC, and are associated with more aggressive histopathological features, BRAF(V600E) mutation, and disease persistence/recurrence than the WT TERT.

A phase II study of everolimus in patients with aggressive RAI refractory (RAIR) thyroid cancer (TC).

6023 Background: We present results of an open label phase II study of the mTOR inhibitor Everolimus in patients (pts) with RAIR TC. Methods: Pts with metastatic, incurable RAIR TC who had shown radiographic progression within 6 months prior to enrollment received Everolimus 10mg orally once daily. Responses were monitored by CT's every two months. The primary endpoint was progression free survival. Sequential biopsies were obtained in selected pts. Results: Enrollment to the differentiated TC (DTC) cohort finished in Jan 2013 and included 33 pts, among them 11 with Hurthle cell TC. Exploratory cohorts enrolled 10 pts with medullary [MTC] and 5 with anaplastic [ATC] with 2 added openings remaining for ATC. For the DTC cohort, median time on study to date is 10 months (mo) (&lt;1-23+). 31 pts are evaluable at this time. PFS in the DTC cohort by Kaplan-Meier (K-M) analysis is 16.0 mo (95%CI 10-NR). Currently, disease stability for 6 and 12 mo or more was achieved in 18 and 10/31 pts, respectively, 11 pts remain on study. Median OS was not reached but 1 year survival by K-M analysis was 76%. One pt achieved a PR. 3 pts with DTC underwent sequential biopsies which revealed activation of autophagy while markers for apoptosis were not detected. Among 10 MTC pts, one achieved a PR and 9 pts had stable disease for 6 mo or more (6-33+). Among 5 ATC pts, 3 progressed, one has ongoing disease stability for 5 mo. One patient achieved a complete response that lasted for 18 mo and whole exome sequencing revealed somatic loss of function mutation affecting the Tuberous Sclerosis 2 (TSC2) protein, a negative regulator of mTOR activity [TSC2 (Q1178*) and FLCN (R17fs)]. Most common treatment-related adverse events were as anticipated and included fatigue, stomatitis and infections. Grade (gr) 3 events included infection 5, weight loss 3, leukopenia 3, thrombocytopenia 3, fatigue 3, hypophosphatemia 2, stomatitis 2, pneumonitis 1 and thrombosis 1pts. One pt had gr 4 hypercholesterinemia and one pt had gr 4 leukopenia. Conclusions: Everolimus has significant anti-tumor activity in pts with advanced TC. Activation of autophagy could account for high rate of disease stability. Sequencing may identify mechanistic basis and predictive markers for treatment response. Clinical trial information: NCT00936858.

Tc-99m- and Ga-68-Labeled Somatostatin Analogues in the Evaluation of Hurthle Cell Thyroid Cancer

Tc-99m- and Ga-68-Labeled Somatostatin Analogues in the Evaluation of Hurthle Cell Thyroid Cancer

Renal Metastasis from Hurthle Cell Thyroid Carcinoma and Its Evaluation with Hybrid Imaging

In general, thyroid carcinomas, when they behave aggressively, metastasize to lungs and occasionally to bone and brain. Metastases to other organs are distinctly unusual. Renal metastases have been reported in only 10 patients. Here we report, to the best of our knowledge, the first patient with Hurthle cell thyroid cancer and renal metastasis. The evaluation of this patient was enhanced by utilizing a variety of imaging techniques. The patient was a 75-year-old man who had a history of a total thyroidectomy 9 years previously for a right thyroid lobe Hurthle cell carcinoma. He postoperatively received 150 mCi (5550 MBq) of 131-I therapy and was maintained on thyrotropin suppressive therapy with levothyroxine. He presented to us with a recent history of a progressively enlarging left neck mass. The serum thyroglobulin was elevated to 1183 ng/mL. Multimodality imaging with fluorodeoxyglucose positron emission tomography-computed tomography, magnetic resonance imaging, and Somatostatin receptor scintigraphy with single photon emission computed tomography (SPECT)-computed tomography revealed numerous foci in the skeleton and right kidney. Anatomic imaging characteristics favored a primary renal cell cancer with the additional evidence of renal vein invasion and thrombosis. Histology later revealed a metastatic renal Hurthle cell cancer with positive thyroglobulin stains. Several of the skeletal foci responded partially to cryoablative therapy. The patient refused noncurative Somatostatin analog therapy. He is alive and doing well clinically. The management of thyroid cancers in high-risk groups, such as our patient, frequently requires expert management by the use of novel multimodality imaging and therapeutic techniques.

Well Differentiated Thyroid Cancer

Differentiated thyroid cancer (DTC) accounts for 98 % of thyroid cancer, with neoplasms arising from the follicular cells (papillary, follicular and Hurthle cell thyroid cancer) and parafollicular cells (medullary thyroid cancer). This paper will focus on the well-differentiated thyroid cancers arising from the follicular epithelial cells. By retaining the differentiated features of normal thyrocytes, these tumors usually retain their ability to produce thyroglobulin and to concentrate and organify iodine. Such features facilitate diagnosis, surveillance and treatment of this disease. There is ongoing debate over the management of DTC with respect to the extent of thyroid resection, indications for radioactive iodine treatment and the extent of thyroid hormone suppression therapy. New elements in cancer screening, diagnosis and treatment continue to evolve with the knowledge gained from ongoing research in thyroid cancer molecular genetics, clinical trials for medical treatments and retrospective studies on recurrence, survival and clinical outcomes of current treatment modalities.