ResearchPad - thyroid-neoplasia-and-cancer Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[MON-513 Suppressing the Growth of Human Medullary Thyroid Cancer Cells Using FDA-Approved Drug]]> Medullary thyroid carcinoma (MTC) is a solid tumor of the parafollicular cells in the thyroid gland. MTC has worse prognosis, when compared with other differentiated thyroid cancers, and MTC patients with distant metastases have a low survival rate unless thyroidectomy is performed at an early stage. Furthermore, conventional treatments have only marginal benefits. Therefore, there is a need to develop novel therapeutics for MTC. Several drugs that are developed and tested in preclinical trials fail in clinical trials. Therefore, repurposing the already US Food and Drug Administration (FDA)-approved drugs towards the treatment of cancers may have potential benefits, like saving the lives of cancer patients and lowering the investment cost of drug development. Here, we explored a novel precision treatment for thyroid cancers by repurposing the FDA-approved small molecule anti-parasitic drug Nitazoxanide (NTZ). In our study, we examined the anticancer effects of NTZ on human MTC cells using the TT cell line. We treated the TT cells with different concentrations of NTZ and assessed the cell proliferation by water-soluble tetrazolium salt (WST-1) assay and oxygen consumption rate (OCR) by Seahorse extracellular flux analysis (Seahorse XFe24 Analyzer). Additionally, we determined the effects of NTZ on the protein expression of key signaling molecules that regulate MTC cell growth by western blot analysis. Our results indicated that NTZ significantly suppressed the growth of TT cells at 24 h treatment. Very importantly, NTZ reduced the basal OCR demonstrating the inhibition of mitochondrial respiration. Moreover, protein expression studies revealed that NTZ markedly reduced the key Hippo signaling pathway effector molecule TAZ and the oncogene c-myc. Interestingly, NTZ decreased the expression of epidermal growth factor receptor (EGFR) that plays an important role for RET activation in MTC. Importantly, NTZ increased the expression of p53 upregulated modulator of apoptosis (Puma). Taken together, our findings demonstrate for the first time that NTZ inhibits the growth of MTC cells and decreases the cancer cell metabolism. The mechanisms by which NTZ targets the MTC cells involve the suppression of key oncogenic proteins and upregulation of tumor suppressor molecule. Thus, our study highlights that repurposing this FDA-approved currently used drug may have a greater advantage of being tested in preclinical models of MTC, and therefore, for the rapid consideration of NTZ as a potential therapeutic drug to treat MTC patients in the near future.

<![CDATA[MON-508 Clinicopathological Features of Papillary Thyroid Cancer After Fukushima and Chernobyl Accidents]]> The phenomenon of a sharp increase in the incidence of thyroid cancer worldwide is now under debate. Screening activity, diagnostic improvements or real rise in incidence as a result of unknown carcinogens are discussed. Studies in Belarus after Chernobyl showed that the synergistic influence of radiation and nitrates might lead to an increased thyroid cancer (TC) risk in children. For better understanding of the etiology, we compared the published clinical data of pediatric TC patients after the nuclear emergency of Fukushima with the observations we made after the Chernobyl accident.

In a large-scale survey after the Fukushima accident, 300,476 subjects were screened and by September 2018, 191 subjects were diagnosed with thyroid malignancy or suspected malignancy by fine needle aspiration. Mean age of TC patients was 17.8 years at presentation. Mean tumor size was 14.9 mm. Postoperative lymph node metastasis, extra-thyroidal invasion, and pulmonary metastasis were detected in 79%, 45%, and 2.1% of all cases, respectively. Only 4.8% TC cases were staged as low risk pT1aN0M0 (Suzuki et al. 2018). For comparison, in Belarus patients mean age was 13.0 years at presentation (1078 cases), mean tumor size 14.4 mm. Lymph node metastases were observed in 74%, pulmonary metastasis in 11% and extra-thyroidal extension in 48.5 - 64.1% (with respect to latency period). The low risk (pT1aN0M0) TC patients were diagnosed in 19.2% cases.

The most of TC cases from Japan and Belarus were clinically significant, not “overdiagnosed” and screened on time. Given that the accidental thyroid doses were very low in Japanese cases, it would be very important to evaluate and compare the exposure to endocrine disruptors as e.g. nitrates and low radiation doses from diagnostic procedures (dental X-ray examination and computed tomography).


Suzuki S, Matsumoto Y, Ookouchi C, Nakano K, Iwadate M, Suzuki S, Nakamura I, Fukushima T, Mizunuma H, Yamashita S, Takenoshita S. The clinicopathological features of childhood and adolescent thyroid cancer in Fukushima after the Fukushima Daiichi nuclear power plant accident. Thyroid. 2018; Supplement 1, (Poster 136).

<![CDATA[MON-490 Calcitonin-Based Thyroidectomy Is a Safe Approach in Patients with Germline RET Mutation and Permits to Delay Surgery in Children]]> Introduction: Medullary thyroid cancer (MTC) arises from C cells secreting calcitonin. In familial MTC cases, a germline RET mutation is discovered in 98% of cases. Nowadays, an early diagnosis and radical surgery are the only curative approach. However, thyroidectomy in children is associated with a higher rate of surgical adverse events, compared to surgery in adults. The best clinical approach in patient harboring germline RET mutation (gene carriers, GC) is still undefined. Methods and materials: since 1994 to 2018 we identified 174 GC by RET screening. 56 GC underwent total thyroidectomy and lymph node dissection for the evidence of high calcitonin levels at the first clinical evaluation, whereas 27 GC underwent surgery for high stimulated calcitonin levels during the active surveillance (median 16 months, range 13-118). 90 GC are still in follow up. Results: In the group of 27 GC patients who underwent surgery during the active surveillance, 15 GC had only C cells hyperplasia (CCH) foci and 12 were affected by MTC. These carcinomas were all confined to the thyroid, without any lymph node and distant metastasis. All these patients are still in clinical remission, after a median follow-up of 4 years (range 1-11). At time of the surgery, the patients affected by MTC were significantly older than patients harboring only CCH (median 49 vs 30 years old, respectively). Among these 27 GC, 7 were diagnosed as GC when they were younger than 18 years (median 7 years old, range 2-18) and they underwent surgery after a median period of 3 years (range 1-10 years), when they were all older than 7 years. In this group, 6 of 7 were affected by CCH and only one case by a microMTC. There were not any persistent surgical adverse events and all of them are still in clinical remission. 41 of 90 GC, who are still in active surveillance, were younger than 18 years at time of RET screening: nowadays, 10/41 are older than 18 years and 15/41 are older than 14 years, all with calcitonin still in the normal range. Conclusions: we demonstrated that the calcitonin-based thyroidectomy is a safe approach in GC. Intriguingly, this approach seems to be interesting especially in children in order to perform still an early and safe surgery but when they are older, possibly adults.

<![CDATA[MON-532 Characterization of the Angiogenic Factor SFRP2 in Papillary Thyroid Carcinoma]]> Over the last decade, there has been an average annual increase of 3.1% in thyroid cancer diagnosis in the U.S. Papillary thyroid carcinoma (PTC) accounts for 80% of all thyroid cancer diagnoses. However, few molecular markers exist to identify clinically aggressive phenotypes. The angiogenic factor, secreted frizzled-related protein 2 (SFRP2), is associated with a poor prognosis in several malignancies including breast cancer and melanoma. The role of SFRP2 in PTC has yet to be investigated. The aims of this study were to determine the differential expression of SFRP2 in PTC, benign thyroid adenomas, normal thyroid tissue (from patients without cancer), and normal adjacent tissue (NAT) (non-cancerous tissue from patients with PTC) and investigate the role of SFRP2 in tumor development in two PTC cell lines, PTC classical variant (PTC-CV) and PTC follicular variant (PTC-FV), upon treatment with a humanized anti-SFRP2 monoclonal antibody (hSFRP2 mAb). Immunohistochemistry (IHC) was performed using human tissue protein microarrays including 226 PTC, 79 benign adenomas, 112 NAT, and 30 normal thyroid tissue samples. In-vitro proliferation and apoptosis experiments were performed on MDA-T41 (PTC-CV) and MDA-T68 (PTC-FV) cell lines by treating with hSFRP2 mAb, Xolair IgG control, and a vehicle control. SFRP2 expression was significantly higher in PTC compared with benign adenomas and normal thyroid (mean expression scores 9, 6, and 1, respectively; p<0.05). SFRP2 expression was significantly higher in NAT than normal thyroid (mean expression score 4 and 0, respectively, p<0.05). Apoptotic rates were increased by 40% and 62% in the PTC-CV hSFRP2 mAb treatment group compared with the Xolair and vehicle treatment groups, respectively (p<0.05). Apoptotic rates were increased by 126% and 59% in the PTC-FV hSFRP2 mAb treatment group compared with the Xolair and vehicle treatment groups, respectively (p<0.05). Treatment with hSFRP2 mAb had no significant effect on proliferation in either cell line. In conclusion, SFRP2 expression is significantly higher in PTC than in benign adenomas and normal thyroid tissue. SFRP2 expression in NAT is significantly higher than in normal thyroid tissue and not significantly different from benign adenomas. SFRP2 expression in nonmalignant tissue adjacent to PTC could be due to expression in the tumor microenvironment. Treatment with a novel hSFPR2 mAb increases apoptotic rates in two different PTC cell lines. These data suggest that SFPR2 is involved in tumorigenesis of PTC.

<![CDATA[MON-499 Nivolumab-Induced Hypothyroidism Is Irreversible in Most Patients]]> Background Thyroid dysfunction caused by the immune checkpoint inhibitor (ICPI) is common, however mild dysthyroidism could occur easily in cancer patients due to other causes. The aim of this study was to investigate the incidence and clinical course of ICPI-induced hypothyroidism requiring thyroid hormone replacement. Patients and methods We analyzed baseline and follow up thyroid function tests of cancer patients treated with nivolumab between March 2016 and March 2019 at Chonnam University Hwasun Hospital retrospectively. Results Among 265 cancer patients treated with nivolumab therapy, six patients were excluded from the study because they were on thyroid hormone replacement therapy before starting nivolumab therapy. Twenty-one patients (8.1%) newly developed thyroid dysfunction during nivolumab therapy and sixteen patients (6.2%) required thyroid hormone replacement therapy due to drug-induced hypothyroidism. Cancer diagnoses included lung cancer (n=7), renal cell carcinoma (n=4), malignant melanoma (n=2), hepatocellular carcinoma (n=2), and esophageal cancer (n=1). Six patients (37.5%) showed thyrotoxic phase prior to overt hypothyroidism and the others (n=10, 62.5%) revealed hypothyroidism without thyrotoxic phase. Most ICPI-induced hypothyroidism was irreversible, only one patient was able to discontinue thyroid hormone replacement after quitting nivolumab therapy. Conclusion A significant number of patients treated with nivolumab developed ICPI-induced hypothyroidism requiring thyroid hormone replacement and its clinical course was irreversible in most patients.

<![CDATA[MON-LB86 The Sensitivity and Specificity of Various Thyroid Nodule Ultrasound Characteristics and the Diagnostic Accuracy of the ATA Guidelines and ACR TI-RADS for Predicting Thyroid Cancer at an Urban Endocrinology Clinic]]> Introduction: Several current guidelines assess sonographic features to guide management of thyroid nodules. The ACR uses an additive point system to assign the level of risk to various sonographic features, whereas the ATA groups sonographic features together to determine the level of risk. The purpose of this study is to compare the performance of the ATA guidelines and ACR TI-RADS at an urban endocrinology clinic in risk stratifying thyroid nodules by their specific sonographic features.

Methods: This retrospective, chart-review study includes adult patients who met sonographic criteria for fine needle aspiration (FNA) biopsy based on ATA or ACR TI-RADS at an outpatient endocrinology practice in San Francisco, CA between December 2011 and August 2019. Patients with a prior history of thyroid malignancy (anaplastic and medullary thyroid carcinoma or thyroid lymphoma) were excluded. The reference standard for the diagnosis of malignancy was surgical pathology or FNA cytology Bethesda category V or VI when surgical pathology was unavailable. Analysis of guideline performances and specific sonographic features included: sensitivities (Sn), specificities (Sp), positive predictive values (PPV), negative predictive values (NPV), and area-under-the-curve (AUC) using Fisher’s exact test.

Results: Two hundred seventy-five nodules among 195 adults (86.2% were women) were included in the analysis. Twelve nodules were malignant, with an associated malignancy rate of 4.4%. TI-RADS had higher accuracy based on AUC of 0.710 compared to 0.623 using ATA guidelines. TI-RADS also had a higher PPV of 21.4% among nodules with 9 points, versus 5.8% among nodules in the ATA “high suspicion” category. Ultrasound characteristics with the highest Sp, relative PPV and NPV were: microcalcifications (84.5%, 4.3%, 96.0%, respectively), taller-than-wide (81.7%, 7.1%, 96.7%), irregular margins (77.7%, 6.0%, 96.5%); the characteristic with the highest Sn was hypoechogenicity (83.3%), however this had relatively low Sp (25.4%) and PPV (4.5%).

Conclusions: TI-RADS performed better with higher overall accuracy and PPV when applied to nodules classified as having the highest malignancy risk. Taller-than-wide shape, irregular margins, and microcalcifications were the characteristics most useful for malignancy risk stratification. Limitations of this study include: interobserver bias, small sample size, referred patient population (which may differ from other institutions), and inability in some cases to confirm malignant FNA cytology with surgical pathology.

<![CDATA[MON-537 Primary Adrenal Insufficiency During Tyrosine Kinase Inhibitors Treatment in Advanced Thyroid Cancer Patients]]> Objective: Tyrosine kinase inhibitors (TKIs) are used for the treatment of metastatic differentiated (DTC), poorly differentiated (PDTC) and medullary (MTC) thyroid cancer. Several adverse events (AEs) have been reported in almost all patients (pts) treated with TKIs. One of the less known AE related to the use of these drugs is the primary adrenal insufficiency (PAI).

Methods: We analyzed the basal and stimulated adrenal function, ACTH levels, adrenal antibodies and electrolytes levels in 82 thyroid cancer pts treated with TKIs (vandetanib and cabozantinib in MTC pts, lenvatinib and sorafenib in DTC and PDTC pts) and we correlated these results with the clinical-pathological features of our pts.

Results: In our series, 25/82 (30.5%) pts showed a PAI after stimulation test with a progressive ACTH increase in 14/25 (56%) pts. Thirteen/25 (52%) pts with PAI were DTC, 8/25 (32%) pts were MTC and 4/25 (16%) pts were PDTC. Sixteen/25 (64%) pts were treated with lenvatinib, 8/25 (32%) were treated with vandetanib and 1/25 (4%) was treated with cabozantinib at the time of stimulation test. In 5/25 (20%) pts PAI occurred within 12 months from the TKIs treatment initiation, in 9/25 (36%) within 36 months and in 11/25 (44%) after 36 months of treatment. Eighteen/25 pts with PAI were older than 55 years. Twenty/25 (80%) of these pts were treated with cortisone acetate replacement therapy with the improvement of fatigue in a small part of these while other 5 pts were untreated due to the mild degree of PAI and the absence of specific symptoms (i.e fatigue). Moreover, in our pts the evaluation of adrenal antibodies was negative and the electrolytes levels were in the normal range. We also correlated the presence of PAI with the clinical-pathological features of our pts but we didn’t observe any significant correlation.

Conclusions: We observed that PAI, mainly subclinical, can occur during TKIs treatment in thyroid cancer pts. The appearance of fatigue, the typical symptom of PAI, could be multifactorial in these pts due also to the direct effect of TKIs treatment. Thus, in these cases is very difficult to recognize the cause of fatigue and to decide the appropriate treatment (cortisone acetate replacement therapy vs TKIs dose reduction). Moreover, the time of PAI appearance is variable since it can be early (<12 months) or late (>36 months) after TKIs treatment initiation and the adrenal function must be monitored during all TKIs treatment period. More studies are needed to know the pathophysiology of this “adverse event” during TKIs treatment and to improve the acknowledgments regarding the differential diagnosis and treatment of these pts, regardless of symptoms.

<![CDATA[MON-506 Assessment of Quality of Life in Persons with Thyroid Cancer and Thyroid Nodules: A Single Center Experience]]> INTRODUCTION: Despite an excellent prognosis and survival rate, quality of life (QOL) in thyroid cancer is lower than expected. QOL in thyroid cancer survivors is similar to persons with colon and gynecologic cancers, but worse than breast cancer.1 The SF-36 QOL questionnaire has shown to be a valid tool for assessing QOL in thyroid cancer subjects.2 We evaluated QOL in both thyroid nodule and thyroid cancer patients in an institutional cancer registry.

METHODS: The Short Form-36 data version 2 (SF-36) QOL data was obtained from single institution prospective bioinformatics thyroid cancer and benign nodule registry. Physical and mental health scores from the SF-36 questionnaire were obtained from both thyroid cancer and nodule patients. Physical and mental QOL responses were scored on a scale from 20-80 and categorized as either “the same or better than the average population,”; “below average,”; or “well below average.” A two sample Wilcoxon rank sum test and a chi-squared test were used to compare QOL between thyroid cancer and nodule subjects, using QOL as a continuous or categorical variable. Univariate descriptive statistics and bivariate analyses were performed using a Wilcoxon Rank Sum and Chi-squared test for categorical QOL data and Kruskal-Wallis for continuous QOL data.

RESULTS: We analyzed 321 thyroid cancer and 32 nodule subjects who completed the SF-36 at a single point in time after diagnosis. There was no difference between the groups with regard to sex, age or QOL scores overall. Average age was 43 and 48 years in cancer and nodule groups respectively. Average Physical QOL score was 50.8 (standard deviation SD + 8.8) and 29.6 (SD+ 12.1), respectively (p=0.42). Average Mental QOL score was 48.9 (SD + 9.9) and 48.3 (SD + 8.1) respectively, p=0.16. Physical QOL score was significantly decreased as cancer stage increased when evaluating results as a continuous variable: Stage 1: 51.8 + 8.7; Stage 2: 50.6 +9.5; Stage 3: 48.7 + 7.2; Stage 4: 47.4 + 9.2. Results for mental QOL as a continuous variable by cancer stage showed improvement in reported QOL with increasing cancer stage: Stage 1: 48 (SD+ 9.9); Stage 2: 50.6 (SD + 11.1); Stage 3: 51.1 (SD + 9.13); Stage 4: 53 (SD+ 6.4), p=0.03.

CONCLUSIONS: We found no overall difference in physical nor mental QOL between patients with thyroid cancer or benign thyroid nodules. Overall, QOL was in the “same or better than average” for all respondents, but low cancer stage was associated with higher physical and lower mental QOL scores.


1. Barbus, Elena & Peştean, Claudiu & Iulia Larg, Maria & Piciu, Doina. (2016). Quality of life in thyroid cancer patients: A literature review. Clujul Medical. 90. 10.15386/cjmed-703

2. Lubitz CC, De Gregorio L, Fingeret AL, et al. Measurement and Variation in Estimation of Quality of Life Effects of Patients Undergoing Treatment for Papillary Thyroid Carcinoma. Thyroid. 2017;27(2):197-206. doi:10.1089/thy.2016.0260

<![CDATA[MON-509 RET Mutations in the MEN1 Syndrome: Is It an Innocent Bystander?]]> Introduction

MENIN and RET mutations in MEN1 families, are rare, and, when they co-exist either mutation may predominate the clinical picture.

We report a family, with both mutations, and, suspect that the RET mutation may not be an innocent bystander.

Clinical Cases

GM (36M): 2009: Presented with skin lesions and a lactotroph adenoma causing chiasmal compression. Treatment: Hypophysectomy and Cabergoline. This resulted in restoration of sexual function and fertility.

2013: Developed hyperparathyroidism [Calcium 10.6mg% (8.5-10.5); PTH 610pg/ml (10-65); MIBG Scan: parathyroid adenomas]. Treatment: Subtotal parathyroidectomy with allotransplant.

2015: Developed Zollinger-Ellison Syndrome [multiple gastric ulcers; S Gastrin: 516pg/ml; (0-180)]. Treatment: Pantoprazole.

MRI Abdomen: Calcific atrophic pancreas and bilateral non-functioning adrenal adenomas.

HM (32M): 2008: Skin lesions and Lactotroph adenoma. Treatment with Cabergoline resulted in restoration of sexual function and a reduction in breast and tumour size.

2013: Hyperparathyroidism [Calcium 10.9mg%; PTH: 166pg/ml; Calcium excretion: 1160mg/24hrs (100-250); BMD: Osteopenia. MIBG 123 Scan: Avid uptake in Right Inferior parathyroid gland]. He underwent a subtotal parathyroidectomy with allotransplant.

2015: Recurrent Hyperparathyroidism (Calcium 10.7mg%; PTH: 116pg/ml; MIBG 123 scan: Hyperfunction of the transplanted gland). Stable on treatment with Cinacalcet.

Their mother, AM (42F): 1980: Detected to have a lactotroph adenoma when investigated for primary infertility and galactorrhoea. She was treated with Bromocriptine and delivered the boys in 1980 and 1984 respectively. She had recurrent renal calculi and hydronephrosis (? hyperparathyroidism). She succumbed to renal failure following surgery for a benign pancreatic cystadenoma in 1990.


Whole exome sequencing of GM and HM showed pathogenic mutations of both, MENIN and RET gene. The precise mutation was a stop gain mutation at exon 3 MENIN.C511T:p.Q171X . They (GM/HM) also harboured a mutation in the RET gene at exon 14 c. G2492T: p.G831V; g. chr10. This may be the first family in which the rare combination of these two mutations has been reported.

The genomics and the clinical presentation suggest that the MENIN mutation predominates in the family, but the presence of bilateral adrenal adenomas in GM are significant on account of RET mutation. The latter may be a harbinger of serious disease in the future. The situation is further compounded by the recurrence of hyperparathyroidism in the allograft of HM. This may be caused due to chance or an unknown genetic/ epigenetic phenomenon in the two MEN mutated genes and RNA sequencing of the tumour tissue may explain the genetic phenomenon. The latter two events suggest that the RET mutations in MEN1 may not be an innocent bystander.

<![CDATA[MON-520 How Does the American Joint Committee on Cancer 8<sup>th</sup>Edition Tumor, Node, Metastasis Staging System Perform in Patients Evaluated at a Major Middle Eastern Medical Center?]]> The American Joint Committee on Cancer (AJCC) Tumor Node Metastasis (TNM) Classification of Cancer 8th edition (AJCC8) was officially introduced in January 2018 as a replacement for the previous version (AJCC7). Validation studies using data obtained from large cancer registries in North America demonstrated the superiority of AJCC8 over AJCC7 for prediction of survival. Subsequent studies from Europe and East Asia have mostly shown similar findings. However, these data may not be generalizable to other parts of the world. In this first study from the Middle East (Saudi Arabia), we compared these two versions of AJCC staging for their concordance and prediction of outcome in a large unselected sample of patients (pts) with DTC managed at a major referral medical center. We also compared the AJCC staging systems with the American Thyroid Association (ATA) Risk Classification.

Of 814 consecutive pts seen during this period, 94 were excluded either due to their diagnosis being medullary or anaplastic thyroid cancer (37) or because of deficient data. The remaining 720 pts (149 males (20.7%), 571 females (79.3%) were included. The median age at the diagnosis was 37 yrs (range, 6-83). Total thyroidectomy was performed in 693 pts (96.3%) and central and/or lateral lymph node dissections in 487 pts (67.6%). I-131 was administered to 626 pts (87%). The tumors were classic PTC in 519 pts (72%), follicular variant PTC in 100 (13.9%), Tall cell PTC in 22 (3.1%), diffuse sclerosing PTC in 10 (1.4%), follicular thyroid cancer in 21 (2.9%) and other rare subtypes in 48 pts (6.8%).

The number (%) of pts within each stage group by AJCC7 and AJCC8 respectively are as follows: Stage 1: 514 (71.4%) vs. 597 (82.9%), Stage 2: 46 (6.4%) vs. 75 (10.4%), Stage 3: 63 (8.8%) vs. 11 (1.5%), Stage 4: 97 (13.5%) vs. 37 (5.1%).

Comparing AJCC8 with the ATA risk stratification system in 709 pts in which data were available, we found a high correlation with 96.8% of ATA low risk group being stage 1 in AJCC8, 2.9% stage 2 and 0.3% stage 3 and none in stage 4. The ATA intermediate risk group was 87.4% AJCC8 stage 1, 12.3% stage 2, 0.4% stage 3 and none in stage 4. The ATA high risk group was 19.1% in AJCC8 stage 1, 33% in stage 2, 9.6% in stage 3 and 38.3% in stage 4.

In addition, AJCC8 was more predictive of the outcome with 80% of pts with evidence of disease (biochemically and structurally incomplete) being in AJCC8 stage 3 or 4 compared with 60% in AJCC7. For ATA staging, 8.6%, 22.4% and 67.7% of low, intermediate and high risk groups had evidence of disease at the last follow up, respectively.

Conclusion: In this Middle Eastern population, AJCC8 downstaged a significant percentage of pts with DTC from higher stages in AJCC7. It also correlated better with the outcome and with the ATA risk classification system.

<![CDATA[MON-524 Prospective Evaluation of Patients with Encapsulated Classical Variant of Papillary Thyroid Cancer and Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): Have They A Similar Prognosis?]]> Background: Our previous retrospective study demonstrated that the absence of tumor capsule or, if present, its invasion were independent risk factors for the persistence of the disease (OR 6.75, CI 1.97-23.08 and OR 7.89, CI 1.78-34.94, respectively) in papillary thyroid cancer (PTC). This data was confirmed also analyzing separately the most frequent PTC variants [follicular variant (FVPTC) and classical variant (CVPTC)]. Moreover, we demonstrated that the absence of tumor capsule was significantly more frequent in FVPTC BRAF V600E mutated than FVPTC wild-type for BRAF gene or with rare-BRAF mutations (e.g., BRAF K601E, BRAF V600_K601delinsE). These data confirmed the importance of the integrity of the tumor capsule in FVPTC which led in 2016 to the definition of a new thyroid neoplasm entity named NIFTP. According to these retrospective data, we have assumed that the integrity of the tumor capsule in CVPTC could have a prognostic role similar to that confirmed in the NIFTP group.

Methods: we have prospectively collected data of patients (pts) underwent total thyroidectomy or lobectomy for encapsulated-CVPTC (E-CVPTC) or NIFTP. In both cases the tumor was accurately analyzed by the pathologists according to the criteria used for the NIFTP (in particular with one capsule sample every 1 mm). All pts performed at least one clinical control and neck US within 6 months from surgery.

Results: From January 2018 to June 2019, 144 E-CVPTC and 177 NIFTP were prospectively collected. 83/144 (57.6%) E-CVPTC and 106/177 (59.8%) NIFTP cases were included. The others were excluded due to the presence of other thyroid tumors associated in the same gland. No differences in epidemiological and pathological features were found between E-CVPTC and NIFTP except for the tumor size, significantly bigger in NIFTP than E-CVPTC [22±16mm (2-68) vs 8±11mm (1-80), p<0.00]. A significantly higher rate of NIFTP’ pts underwent lobectomy respect to E-CVPTC pts (34%vs14.5%, p=0.02). After a mean of 9 months of follow-up all pts had an excellent response according to ATA guidelines.

Conclusions: These prospective data demonstrated that NIFTP and E-CVPTC have a similar clinical behavior in a short-term follow-up, thus suggesting that the presence of an intact tumor capsule is predictive of a good outcome. A longer follow up is needed to confirm these initial interesting findings.

<![CDATA[MON-LB76 Impact of Age on Survival and Prognostic Factors in Radioiodine Refractory Differentiated Thyroid Cancer Patients]]> BACKGROUND

Age has been identified as a major prognostic factor in differentiated thyroid cancer (DTC). Prognostic factors of radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) are poorly described. The objectives of our study were to analyze the influence of age on the survival of patients with RAIR-DTC and to determine their prognostic factors according to age.


This single centre, retrospective study enrolled 155 patients diagnosed with a RAIR-DTC between 1991 and 2017. The primary end point was overall survival (OS). Secondary endpoints were progression free survival (PFS) and prognostic factors.


Median OS was 8.2 years (95% IC: 5.3-9.6). There was no difference according to age (P = 0.47) with median OS at 8.3 years in patients < 65 (95% IC: 4.9-10), and 7.5 years in patients > 65 (IC: 4,9-11,3). PFS after RAIR-diagnosis was 2.1 years (95% IC: 0.8-3) in patients < 65, and 1 year in patients > 65 (95% IC: 0.34-0.68). In both groups, progressive disease despite 131I reduced OS, in comparison with other RAIR criteria. In patients < 65, an interval between the initial diagnosis of DTC and the diagnosis of RAIR metastatic disease more than 3 years was protective from poor OS (HR: 2.12; 95% CI: 1.05-4.27). In patients > 65, presence of a mediastinum metastasis at RAIR-diagnosis was a significant factor for decreased OS (HR: 0.22; 95% CI: 0.11-0.44).

No difference was found between groups regarding therapeutic management. One third of patients received tyrosine kinase inhibitors in both groups (< 65 years: 20 patients (28%), ≥ 65 years: 28 (33%), P = 0.49). They were also similar regarding the number of lines received or the median duration of treatment (< 65 years: 19.5 months (2-59), ≥ 65 years: 19 months (1-64), p= 0.35). At least one line of TKI was transitorily or definitively withdrawn due to toxicity in 40% of patients (< 65 years: 8/20 patients (40%), ≥ 65 years: 13/28 (46%), p= 0,037).


In RAIR-DTC patients, age was not predictive of the outcome. In our study, older patients seem to have benefited from intensive therapeutic management. Continual progress made in the management of RAIR-DTC, especially with the implementation of systemic therapies should probably make reconsider the natural history and conventional prognostic factors of RAIR-DTC.

<![CDATA[MON-495 Influence of Lymphocytic Thyroiditis at Histology and Serum Thyroglobulin Autoantibodies on the Course of Papillary Thyroid Carcinoma]]> PURPOSE Papillary thyroid carcinoma (PTC) is frequently associated with diffuse lymphocytic thyoiditis (LT) at histology and serum autoantibodies to thyroglobulin (TgAb) and to thyroperoxidase (TPOAb). The influence of LT and thyroid autoantibodies on the prognosis of PTC is debated. We evaluated the clinical course of a large group of PTC patients according to the presence or absence of LT (LT+ and LT-) and thyroid autoantibodies. METHODS We evaluated 194 consecutive and non-selected PTC patients treated with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009, followed for 7.2 years (mean). 72 patients had follicular variant of PTC, 97 classic, 16 tall cells and the remaining 9 others variants (solid or oxyphilic cells). LT was diagnosed in presence of >10 lymphocytes/field (40x). At the time of ablation, all patients underwent measurement of Tg, TgAb and TPOAb, neck ultrasound and whole body scan. After ablation, patients underwent Tg (Beckman Coulter), TgAb and TPOAb (Tosoh) measurement and neck ultrasound (associated with other imaging if required) every 6-12 months. PTC was considered in remission according to the following criteria: un-stimulated Tg <0.2 ng/mL or stimulated Tg <1 ng/mL with TgAb <8 IU/mL and no evidence of structural disease. PTC was considered as persistent when un-stimulated Tg was ≥0.2 ng/mL or stimulated Tg was ≥1 ng/mL, or when TgAb were ≥8 IU/mL, or there was evidence of structural disease. RESULTS LT was found in 47% of patients, with a F/M ratio of 6.6/1, and was associated with a hypoechoic pattern at thyroid ultrasound (p = 0.05). At the end of follow-up 44/194 (22.7%) had persistent disease. Among them, 17/72 (23.6%) were follicular, 19/97 (19.6%) classic, 6/16 (37.5%) tall cells and 2/9 (22.2%) other variants. The time to remission was longer in the LT+ compared to the LT- patients (19.5 vs 7.5 months) (median) (p <0.001), in TgAb positive compared to TgAb negative patients (28.5 vs 7.5 months) (p <0.001) and in TPOAb positive compared to TPOAb negative patients (28.0 vs 8.0 months) (p = 0.005). At multivariate analysis TgAb were the only independent factor influencing the time to remission (0.54; 0.35-0.83; HR and confidence interval) (p = 0.001). However, evaluating only the 111 TgAb negative patients, the time to remission (undetectable un-stimulated or stimulated Tg and no evidence of structural disease) was similar in the LT+ and LT- groups (8.0 months for both). At variance, in 83 TgAb positive patients the time to remission was longer in LT+ than in LT- patients (29.3 vs 13.0 months) (p=0.01). CONCLUSIONS The time to remission is longer in LT+ compared to LT- PTC patients treated with total thyroidectomy plus ¹³¹I ablation. This is due to the frequent association of LT with TgAb, because undetectable TgAb is required to define the remission of PTC. Indeed, coexistent LT does not influence the time to remission when the analysis is restricted to TgAb negative patients.

<![CDATA[MON-486 Polygenic Susceptibility to Papillary Thyroid Cancer in Italian Subjects]]> INTRODUCTION AND AIM. Thyroid cancer is the most common endocrine neoplasia, with an estimated age-standardized incidence rate of 6.7 per 100000 worldwide in 2018 [1]. This rate is rapidly increasing and papillary thyroid carcinoma (PTC) is the main histotype. PTC susceptibility is the result of genetic predisposition, environmental factors and lifestyle. We studied the genetic combination that characterizes PTC affected subjects, differentiating them from healthy controls.

METHODS AND RESULTS. We considered the genetic variants (SNPs) significantly associated with PTC on the PubMed database. 184 informative SNPs were selected, considering linkage disequilibrium. Then, SNPs data were extracted from the online 1000 Genomes database, comprising genome of 2504 unselected individuals collected worldwide. The combination of 184 SNPs associated with PTC was used to group individuals in different risk-clusters according to their genetic structure, calculated by Bayesian statistics, as previously performed for polycystic ovary syndrome [2]. Individuals were distributed among 7 groups worldwide, indicating different degree of genetic predisposition to PTC. We then considered genetic data from about 1200 individuals (697 PTC versus 497 healthy controls) of Central/South Italian origin registered in a GWAS, specific for PTC [3]. This first analysis was refined using the 33 SNPs reasonably most causative of genetic clustering (26 with p<0.05 at trend test in GWAS and 7 with p<0.05 in the model of recessive inheritance). At multivariate logistic regression analysis, PTC and healthy controls resulted genetically different (ODDS RATIO 188.6, 95%CI 64.35-552.8), revealing diverse predisposition to develop cancer. Afterwards, these results have been confirmed in an independent cohort of Italian subjects (234 PTC and 100 controls). Then, the genetic structure of each subject was indicated as a percentage of affinity to each risk-cluster and re-analyzed together with other risk factors: sex, body-mass index, area of origin and familiarity (quantified in a growing score as the degree of kinship increases). These data were analyzed together by principal component analysis and clustering of the two groups was even more pronounced. The most contributive factors to the diversity between PTC and healthy controls were genetics and familiarity.

CONCLUSION. We demonstrated that PTC affected subjects are genetically different from healthy controls, and that the difference is identifiable in a peculiar combination of genetic variants.


1. Bray F et al. CA: a cancer journal for clinicians. 2018; 68 (6):394-424

2. Casarini and Brigante. JCEM. 2014; 99:E2412-20

3. Köhler et al. Genome-wide association study on differentiated thyroid cancer. J Clin Endocrinol Metab. 2013;98:E1674-81.

<![CDATA[MON-489 Comorbidity of Primary Hyperparathyroidism and Papillary Thyroid Cancer. A Single Center Outcomes]]> Introduction Concurrence of primary hyperparathyroidism in patients with thyroid disease has been previously reported by several studies. However, comorbidity between primary hyperparathyroidism (PHPT) and papillary thyroid cancer (PTC) has been sparsely described by previous, mostly case-series studies, and is considered rare. Since pathophysiological mechanisms behind the two diseases are supposed to be different, any link between these diseases has not been explained as yet. Hypothesis: Aim of the study was to investigate the possible concurrence for the two diseases in people who underwent thyroidectomy for suspected thyroid nodules. Methodology Retrospective observational study that included 2913 patients (24% men with mean age 49.82 yrs, 76% women mean aged 47.73 yrs), who underwent total thyroidectomy during the last 13 years (2005-2018) at the Department of Endocrine Surgery, Euroclinic Hospital, in Greece. The patient-groups were categorised according to histopathology criteria of the thyroid and/ or parathyroid glands (in case of comorbidity of primary hyperparathyroidism (PHPT) diagnosed prior to surgery). Results: Statistical analysis revealed benign histopathology findings in 1945 patients (64%), while papillary cancer was found in 978 (32%). Among patients with non-malignancy, 16 (11 women/5 men) had PHPT, but in those with papillary cancer, PHPT was diagnosed in 38 (33 women/5 men) individuals. The relative risk for the concurrence of PHPT and PTC was 2.033 (95%CI 1.69 to 2.43, P<0.0001). Age groups between 30 and 60 yrs were associated with the highest relative frequency of comorbidity (82%). A significant positive correlation was observed between less aggressive PTC histopathology findings and PHPT concurrence (P<0.0001). Interestingly, no patient with PTC and PHPT had either capsular invasion or regional/distant metastases. Moreover, most patients with comorbidity (92%) had a tumour diameter smaller (mean 6.3 mm) than those with PTC alone (mean 18 mm). Conclusions: Our study found that the comorbidity between primary hyperparathyroidism and PTC may be considered as possible. Endocrinologist’s diagnostic approach may add serum calcium and parathormone levels in patients who undergo evaluation for suspected thyroid nodules. Patients with PHPT and PTC had mostly microcarcinomas, and histopathology findings showed a less aggressive PTC pattern. Further large cohorts as well as genetic studies, are needed to duplicate our results and further highlight possible common pathogenetic pathways behind PHPT and PTC concurrence.

<![CDATA[MON-522 In Silico Analysis of Polymorphism rs2228638 in Neuropillin-1 Demonstrated That This Variant May Hinder EBV Entry into Epithelial Cells]]> The Epstein-Barr virus (EBV) is the first herpesvirus identified to be associated with human cancers and our group has demonstrated its association to thyroid cancer. It infects the vast majority of the world population causing latent and persistent infection, interfering in the metabolism of the host cells and triggering tumorigenic processes. Neuropillin-1 (NRP-1) is a type I transmembrane glycoprotein distributed on the cell surface of the virus, and considered vital for tumorigenesis. It has been demonstrated that EBV infection was increased by NRP1 expression. However, a conformational alteration of NRP1 could interfere with virus internalization into epithelial cells. The rs2228638 polymorphism of NRP1 may modify the molecule tridimensional configuration. In order to better understand the role of this polymorphism, based on NCBI dbSNP and UniProt databases, we evaluated the effect of the amino acid change in the protein structure using bioinformatics tools including SIFT, Align GVGD, PolyPhen-2, SNAP, PANTHER, PredictSNP, nsSNPAnalyzer, PROVEAN, SNP&GO, PMut and MuPRO. PANTHER prediction indicated that the polymorphic variant could produce a change in function. MuPRO indicated that the amino acid exchange produced by the polymorphism decreases protein stability. However, none of these tools showed conformational alteration. In conclusion, the presence of the rs2228638 polymorphism of NRP-1 may cause functional but not morphological changes that hinder EBV entry into the epithelial cells.

<![CDATA[OR21-07 The 2015 American Thyroid Association Risk Stratification System Is a Predictor of Persistent Disease in Real-World Clinical Practice]]> Background. Management and follow-up of differentiated thyroid cancer (DTC) are guided by the likelihood of disease persistence or recurrence. The American Thyroid Association (ATA) practice guidelines provide a risk-estimation system based on data mainly derived by retrospective, single-center, and small cohorts.

Aim. To validate the ATA risk-stratification system in predicting persistent structural disease.

Methods. We analyzed data from the Italian Thyroid Cancer Observatory’s observational, web-based database, which prospectively enrolls newly diagnosed DTC patients in 40 Italian centers. For the present study we selected consecutive cases satisfying the inclusion criteria: 1) histological diagnosis of DTC, including papillary, follicular, and poorly differentiated tumors; 2) registration in the ITCO database between January 1, 2013 and April 23, 2019; 3) clinical evaluation between 6 and 18 month after primary treatment, including enough data to estimate the response to the initial treatment. Exclusion criteria were: histological diagnosis of NIFTP, medullary, or anaplastic thyroid cancer. The response to the initial treatment was categorized as excellent, biochemical incomplete, structural incomplete, or indeterminate based on imaging findings (neck ultrasound and other imaging studies, if performed), basal or stimulated serum thyroglobulin levels, and anti-Tg antibody levels. To model the response to treatment, we used a cumulative link model; given the hierarchical structure of the data, with patients nested within centers, we used a mixed-effect model, with a center-specific intercept summarizing unobserved center-specific characteristics.

Results. Complete data about initial treatment and response to treatment after 6-18 months since initial treatment was available for 2071 patients. According to the ATA system, 1109 patients (53.6%) were classified as low-risk, 796 (38.4%) as intermediate, and 166 (8.0%) as high-risk. Excellent response was recorded in 1576 (76.1%) patients, indeterminate in 376 (18.2%), biochemical incomplete in 33 (1.6%), and structural incomplete in 86 (4.2%).The ATA risk stratification system is a significant predictor of response to treatment after 6-18 months: classification as intermediate- and high-risk increased the likelihood of a response worse than excellent (OR 1.68 [95% confidence intervals, CI 1.34-2.10] and 3.23 [95% CI 2.23-4.67], respectively), and a persistent structural disease (OR 4.67 [95% CI 2.59-8.43] and 16.48 [95% CI 7.87-34.5], respectively. In both analyses, the effect of the center (taking into account center-specific features) was negligible and not statistically significant.

Conclusion. The 2015 ATA risk stratification system is a reliable predictor of short-term outcomes in patients with DTC, also if applied in a real-world setting consisting of several different clinical sites.

<![CDATA[MON-488 Technologies of Diffuse Optics in the Diagnosis of Thyroid Cancer]]> BACKGROUND:

The most common tool to test malignancy in the study of thyroid nodules (NT) is ultrasound and fine needle aspiration biopsy (FNAB). However, the sensitivity and specificity of the method and the effectiveness in thyroid cancer are limited; therefore new methods to study thyroid nodules are required. In this way our goal is to introduce hybrid diffuse optical instruments that are capable to measure and discriminate altered microvascular blood flow, blood volume and tissue scattering coefficients of TN. Near-infrared diffuse optical technologies aim to overcome the shortcomings of present techniques while screening for malignant thyroid nodules for early and fast diagnosis of cancer. This idea was based on the previous experience in breast cancers with diffuse optical techniques.


We have developed a device based on near-infrared diffuse correlation spectroscopy (DCS), which is a technology aimed at retrieving the microvascular flow of a certain region of tissue by mean of low power near-infrared laser light, and used in combination with a commercial ultrasound system (US). In order to combine these devices, we have developed a probe enabling multimodal data acquisition and subsequently we have analyzed the optical properties and the blood flow index in the thyroid lobes of eleven subjects who presented a thyroid nodule.


Four subjects have required FNAB: P4 and P7 were reported as being malignant (Bethesda VI and IV respectively) while P6 and P8 were evaluated as being benign (Bethesda II). Surgical removal confirmed papillary thyroid carcinoma in P4, while denied the result of FNAB for P7 (Multinodular thyroid hyperplasia). We have considered the contralateral lobe as intra-subject reference to validate the feasibility of the DCS system in a very absorbing tissue as thyroid is. The difference between the blood flow index of the nodule and the contralateral lobe is maximum for subject P4, while the difference in benign subjects is lower. T-test showed no significant difference between benign nodules and contralateral lobes. Subject P7 showed a small difference as for other benign subjects despite the FNAB results indicating presence of malignancy.


Apparently diffuse optics technologies would be able to differentiate malignant thyroid nodules from benign thyroid nodules, but more measurements require confirming our preliminary results as that diffuse optical technology can complement the current techniques such as US and FNAB.

A new measurement campaign is being scheduled with a completed, fully integrated device that was developed within the LUCA project (

<![CDATA[MON-498 Thyroseq V3 GC for Bethesda III and IV: An Institutional Experience]]> Background:

Molecular testing of thyroid nodules classified as indeterminate on fine-needle aspiration (FNA) is used for patient management. ThyroSeq® v3 genomic classifier is a commercially available test that examines a wide spectrum of genomic alterations in a thyroid FNA sample based on algorithmic analysis and reports test results as either negative (including currently negative) or positive. This study reviews our institutional experience with Thyroseq® V3 to distinguish between benign disease versus cancer in thyroid nodules diagnosed as Bethesda III or IV on cytology.


Thyroid nodules with Bethesda III or IV cytology diagnoses and available Thyroseq® V3 results from 12/17 to 8/19 were retrieved from the pathology database. Cytopathology diagnoses were correlated with molecular testing and histopathology.


416 cases (Bethesda III n=252, Bethesda IV n=164) were retrieved: 295 (71%) were reported as Thyroseq® V3 negative and 121 (29%) as positive. The 82.1% (207/252) benign call rate (BCR) of Thyroseq® v3 for Bethesda III was significantly higher (p<0.001) than that for Bethesda IV, BCR 54% (88 /164). Histopathologic follow-up was available for 128 cases (96 ThyroSeq® v3 positive, 32 ThyroSeq® v3 negative): 57 benign and 71 malignant (including NIFTP). For Bethesda III and IV diagnoses respectively, the test demonstrated 91.7 % (95% Cl 73%-99%) and 91.5% (95% Cl 80%-98%) sensitivity, 94% (95% Cl 90%-97%) and 82.4% (95% Cl 74%-89%) specificity, 99% (95% Cl 96%-99%) and 95% (95% Cl 89%-98%) negative predictive value and 63% (95% Cl 50%-74%) and 70.5% (95% Cl 61%-79%) positive predictive value, given malignancy rates 10% Bethesda III; 32% Bethesda IV. 45 unique combinations of genetic alterations were detected in the 96 operated ThyroSeq® v3 positive cases—34 combinations (76%) were present in <2 cases and only 3 combinations occurred 7 or more cases. Forty-six (48%) nodules had RAS mutations, either combined with other mutations 31% (23/30, 77% malignant) or alone, 17% (10/16, 63% malignant), followed by

THADA/IGF2BP3 gene fusion changes,11.5% (10 /11 malignant). Three cases with BRAF mutations (1 V600E, 1 K601E, 1 K601N) were malignant. Copy numbers alterations alone were present in 10 (5/ 10 malignant) and the gene expression profile alone was positive in 5 cases (all malignant). Mutations that were associated with benign pathology were PTEN, DICER1, E1F1AX and TP53. There were 6 false negative cases, 5 low risk cancers by American Thyroid Association criteria and 1 NIFTP.


The high BCR of Thyroseq® v3 for Bethesda III category avoids surgery for majority of patients. A more comprehensive mutational and fusion panel reveals the complexity of the genetic signature of indeterminate nodules. Future larger and likely multicenter studies will be required to define the associated cancer risk and potential prognosis associated with adjunct molecular testing.

<![CDATA[MON-510 Patients with Large Multinodular Goiters Operated for Presumed Benign - Large or Growing Thyroid Nodules, Have a High Likelihood of Significant Synchronous Thyroid Cancers]]> Introduction: Despite the current state of evidence suggesting that thyroid nodules’ size should not be the sole criterion for the decision to undergo thyroidectomy, many patients are still operated for large, or growing nodules. In order to ascertain whether this is a justifiable approach, we performed the present study.

Methods/ Subjects: We reviewed the data from two prospectively collected databases of patients undergoing thyroid surgery in two tertiary referral centers, one in the USA (A) and the other one in Greece (B) over 14 consecutive years. We collected data on the preoperative surgical indication, FNA cytology and surgical pathology. We included subjects with multinodular goiters, operated solely for large or growing thyroid nodules, who did not have any known or presumed thyroid cancer, or indications of high risk for malignancy (FNA suspicious for thyroid cancer, follicular neoplasm, suspicious for follicular neoplasm, FLUS/AUS, cellular specimen), family history of thyroid cancer or prior neck radiation exposure.

Results: We reviewed 5523 consecutive cases of thyroid surgery (A:2711, B:2812). After excluding n=3059 subjects, we included n=2464 subjects in the present analysis. Overall 535 thyroid cancers were identified (21.7%): 349 (65.2%) were microcarcinomas (<1cm), 161 (30.0%) were macrocarcinomas (≥1cm) and 25 of undetermined size. The histology was consistent with papillary cancer (PTC) n=500, follicular cancer (FTC) n=14, Hurthle cell cancer (HCC) n=9, medullary cancer (MTC) n=4, thyroid lymphoma n=1 and mixed histology cancers n=4. In n=68 (2.75%) cases, a thyroid cancer was found in the large or growing thyroid nodule, which was the original indication for surgery. The cancers were multifocal in n=165 subjects; there was extrathyroidal extension in n=61, capsular invasion was present in n=80, lymph node involvement in n=35 and bone metastasis in n=2 subjects.

Conclusions: Although the likelihood of identifying a clinically relevant thyroid cancer in a large or growing nodule, in the absence of risk enhancing features, is low; the risk of synchronous, clinically important, thyroid cancers is high in patients with large multinodular goiters. Therefore, more precise screening strategies are urgently needed to identify the patients, who would clearly benefit from thyroid surgery and protect those who do not need to be operated on.