Classic Papillary Thyroid Cancer Research Articles

12327 Presenting Features of Papillary Thyroid Cancer with Hobnail Histology and Factors Associated with Advanced Disease at Presentation

Abstract Disclosure: S.K. Majumdar: None. J. Sinard: None. The Hobnail subtype of papillary thyroid cancer (PTC) is reported to be a rare form of PTC that manifests with higher rates of extrathyroidal extension, metastases, disease recurrence, and mortality, when compared to classic PTC. We set out to characterize the clinical manifestations and initial pathologic findings of patients with PTC and hobnail histology at our institution. A retrospective search of pathology records from 1/2014 through 1/2024 was conducted to identify rare thyroid cancer variants including those with hobnail histology. An electronic medical record review was then performed to collect clinical information. The study was approved by our institutional IRB. A total of 15 patients with PTC of the hobnail subtype (≥ 30% features) or with hobnail features (< 30%) were identified: 8 hobnail subtype, 5 having hobnail features, 1 had hobnail and oncocytic features, 1 had hobnail and tall cell features. Sixty percent were female, mean age 50.6 years (SD 16.4), 67% white, 27% Hispanic, 6% black. Mean BMI was 29.4 kg/m^2 (SD 5.4), 33% had a history of prior or current smoking. Cancers were found incidentally in 33% of cases (3 after physical exam noting goiter or nodule), 53% presented with a newly noticed neck lesion, one of these presented with hoarseness and cough from tracheal invasion which was found later at surgery. Mean tumor size 2.65 cm (SD 1.7), 13 patients had 1 or more lymph nodes removed with at least one node being positive in 77% of cases. Rates of lymphatic invasion were 73% (33% extensive), vascular invasion 13%, and 13% had gross extrathyroidal extension. After initial surgery 60% had stage 1 disease, 27% stage 2, and 13% stage 3. One patient was changed to stage 4 upon the later discovery of lung metastases and this patient had 30% tall cell features on pathology. Three patients had T3 or T4 tumors, all of whom were from minority and vulnerable populations (2 non-English speaking Hispanic, 1 Black with mental illness), had significantly higher BMI than others (36.2 ± 4 vs 27.2 ± 4.5, p = 0.01), and tended to be older (67 ± 9.5 vs 46.5 ± 16, p = 0.057 ns). Long term follow up was limited since hobnail histology was only found in reports beginning in 2017 and became more frequent in 2022 and 2023. Although limited by case number, our findings show that patients who presented with the most advanced disease were from vulnerable populations, were older, and had higher BMI’s than those with lower stage disease. Also, coexistence of other variants, like tall cell changes, may impact presentation. Therefore, while PTC with hobnail histology is typically associated with more advanced disease presentations, psychosocial and other factors appeared to explain higher stage disease at presentation in our series. Presentation: 6/3/2024

Clinicopathological Features of CCDC6-RET and NCOA4-RET Fusions in Thyroid Cancer: A Single-Center Retrospective Cohort Study in a Chinese Population.

Background: The rearranged during transfection (RET) proto-oncogene fusion is common in papillary thyroid cancer (PTC), varying across ethnic groups. However, comprehensive comparisons of RET fusion types are limited. This study aims to identify predominant RET fusions and analyze their clinicopathological characteristics in a cohort of Chinese thyroid cancer cases. Methods: This single-center retrospective cohort study analyzed thyroid cancer data, utilizing next-generation sequencing on formalin-fixed, paraffin-embedded tissue samples. Detailed clinicopathological data of thyroid cancer cases with RET fusions were collected. Results: Among 2300 thyroid cancer cases, RET fusions were exclusively found in PTC or differentiated high-grade thyroid carcinoma (DHGTC) cases (2234 cases), absent in other types (66 cases). Of the 2234 PTC or DHGTC cases, 113 (5.06%) exhibited RET fusions, including 100 primary cases. Coiled-coil domain containing 6 (CCDC6)-RET fusions predominated (78.0%, 78/100), with nuclear receptor coactivator 4 (NCOA4)-RET fusions representing 22.0% (22/100). NCOA4-RET fusions were more prevalent in patients aged 45 years and older (54.5% vs. 28.2%, p = 0.021) and DHGTC cases (p < 0.05) and associated with higher rates of lymph node metastases (90.9% vs. 67.9%, p = 0.032). CCDC6-RET fusion exhibited a higher prevalence of Hashimoto's thyroiditis (HT) (67.9% vs. 22.7%, p < 0.001) and elevated thyroglobulin antibody levels (14.11 [1.86-174.32] IU/mL vs. 2.01 [1.14-15.41] IU/mL, p = 0.018). Moreover, CCDC6-RET fusion predominantly occurred in classical PTC (56.4%, 44/78) and infiltrative follicular PTC (17.9%, 14/78), whereas NCOA4-RET fusion was more frequent in classical PTC (36.4%, 8/22), solid PTC (27.3%, 6/22), and DHGTC (27.3%, 6/22). RET fusions with compound mutations were associated with older age (≥45 years) and bilateral thyroid involvement. Follow-up data showed a higher recurrence rate in the RET fusion group compared with the BRAFV600E mutation group (5.0% vs. 0.0%, p = 0.018). Although the NCOA4-RET group showed a numerically higher recurrence rate compared with CCDC6-RET (9.1% vs. 3.8%), this difference was not statistically significant (p = 0.559). Conclusions: RET fusions are specific to PTC or DHGTC cases among Chinese thyroid cancer cases. CCDC6-RET and NCOA4-RET fusions exhibited distinct clinicopathological features, with NCOA4-RET being more aggressive.

Organochlorine pesticides and risk of papillary thyroid cancer in U.S. military personnel: a nested case-control study

BackgroundThe effects of organochlorine pesticide (OCP) exposure on the development of human papillary thyroid cancer (PTC) are not well understood. A nested case-control study was conducted with data from the U.S. Department of Defense Serum Repository (DoDSR) cohort between 2000 and 2013 to assess associations of individual OCPs serum concentrations with PTC risk.MethodsThis study included 742 histologically confirmed PTC cases (341 females, 401 males) and 742 individually-matched controls with pre-diagnostic serum samples selected from the DoDSR. Associations between categories of lipid-corrected serum concentrations of seven OCPs and PTC risk were evaluated for classical PTC and follicular PTC using conditional logistic regression, adjusted for body mass index category and military branch to compute odds ratios (OR) and 95% confidence intervals (CIs). Effect modification by sex, birth cohort, and race was examined.ResultsThere was no evidence of associations between most of the OCPs and PTC, overall or stratified by histological subtype. Overall, there was no evidence of an association between hexachlorobenzene (HCB) and PTC, but stratified by histological subtype HCB was associated with significantly increased risk of classical PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 1.61, 95% CI, 1.09, 2.38; p for trend = 0.05) and significantly decreased risk of follicular variant PTC (third tertile above the limit of detection (LOD) vs. <LOD, OR = 0.38, 95% CI, 0.16, 0.91; p for trend = 0.04). Further stratified by sex, risk of classical PTC was higher for females (third tertile above LOD vs. <LOD, OR = 2.23, 95% CI: 1.23, 4.06; p-trend = 0.02) than for males (OR = 1.22, 95%CI: 0.72–2.08; p-trend = 0.56), though the test for interaction by sex was not statistically significant (p-interaction = 0.30). Similarly, β-hexachlorocyclohexane (β-HCCH) was associated with a higher risk for classical PTC for women with concentrations ≥LOD versus <LOD (OR = 1.76, 95% CI: 1.07, 2.89), while the effects were null for men. There were no consistent trends when stratified by race or birth year. ConclusionsThe U.S. Environmental Protection Agency has classified HCB and other OCPs we studied here as probable human carcinogens. Our findings of increased risks for classical PTC associated with increased concentrations of HCB and β-HCCH, which were stronger among females, should be replicated in future studies of other populations.

Improved cancer risk stratification of isoechoic thyroid nodules to reduce unnecessary biopsies using quantitative ultrasound.

Gray-scale ultrasound (US) is the standard-of-care for evaluating thyroid nodules (TNs). However, the performance is better for the identification of hypoechoic malignant TNs (such as classic papillary thyroid cancer) than isoechoic malignant TNs. Quantitative ultrasound (QUS) utilizes information from raw ultrasonic radiofrequency (RF) echo signal to assess properties of tissue microarchitecture. The purpose of this study is to determine if QUS can improve the cancer risk stratification of isoechoic TNs. Patients scheduled for TN fine needle biopsy (FNB) were recruited from the Thyroid Health Clinic at Boston Medical Center. B-mode US and RF data (to generate QUS parameters) were collected in 274 TNs (163 isoechoic, 111 hypoechoic). A linear combination of QUS parameters (CQP) was trained and tested for isoechoic [CQP(i)] and hypoechoic [CQP(h)] TNs separately and compared with the performance of conventional B-mode US risk stratification systems. CQP(i) produced an ROC AUC value of 0.937+/- 0.043 compared to a value of 0.717 +/- 0.145 (p >0.05) for the American College of Radiology Thyroid Imaging, Reporting and Data System (ACR TI-RADS) and 0.589 +/- 0.173 (p >0.05) for the American Thyroid Association (ATA) risk stratification system. In this study, CQP(i) avoids unnecessary FNBs in 73% of TNs compared to 55.8% and 11.8% when using ACR TI-RADS and ATA classification system. This data supports that a unique QUS-based classifier may be superior to conventional US stratification systems to evaluate isoechoic TNs for cancer and should be explored further in larger studies.

Warthin-like variant of papillary thyroid carcinoma with lymph node metastases: a case report and review of the literature

BackgroundWe present a rare case of thyroid lesion marked as the Warthin-like variant of papillary thyroid carcinoma (WLV-PTC) with lymph node metastases. A proper preoperative identification is difficult because of unspecific cytology features and common ultrasound characteristics of this malignant tumor. The long-term prognosis cannot be thoroughly described due to the scarcity of data. The purpose of the presentation is to show common characteristics and long-term survival rates of an uncommon variant of differentiated thyroid cancer (DTC). Therefore, the data represented in this article can make a significant contribution to future investigations.Case presentationA 40-year-old Ukrainian woman had a lesion in the thyroid gland, which was accidentally diagnosed during medical checkup. Ultrasound (US) features were similar to the common suspicious nodule. It had typical signs of suspicion for malignancy (TI-RADS-4) on the background of thyroiditis. A thorough investigation of the neck showed lymph nodes with nonspecific US features on both lateral compartments. Lymph nodes were hypoechoic, oval-shaped and 10 mm wide, with regular contours, low central vascularity, with preserving hilar fat, without cystic formation. The patient did not have any complaints or changes in the hormone status. No hereditary findings linked with cancer were discovered. The woman had been living for a long time in the country with a high level of insolation, which was atypical for the ordinary environment of the patient. Fine-needle aspiration (FNA) of the lesion was done and the Bethesda system 6 result was obtained. Total thyroidectomy with central lymph node dissection was accomplished. The histological conclusion was WLV-PTC on the background of lymphocytic infiltration of the gland with metastasis to the lymph nodes. The inpatient radioactive iodine (RAI) ablation (100 mCi) was subsequently performed. Hormone withdrawal was used followed by RAI. In one year after the surgery the level of thyroglobulin (Tg) was 0.2 ng/ml. Up to the present time the five-year follow-up has not demonstrated any signs of recurrence relying on a level of Tg (< 0.04 ng/ml), Tg antibodies (< 14 IU/ml), neck US without any structural disease.ConclusionWLV-PTC resembles salivary gland tumors with similar histological features. This variant is not well known, but often associated with a stroma lymphocytic infiltration and a low risk of lymph node metastases. It is regarded that this rare subtype has similar long-term survival rates as classic papillary thyroid cancer (PTC).

The Impact of BRAF V600E Mutation Allele Frequency on the Histopathological Characteristics of Thyroid Cancer.

A BRAF V600E mutation in papillary thyroid cancer (PTC) has been shown to be associated with aggressive behavior. Nevertheless, not all BRAF V600E PTCs behave aggressively. Allele frequency (AF) is the number of mutated molecules divided by the total number of wild-type molecules at a specific location in the genome. The relationship between BRAF V600E AF and the histopathological features of thyroid malignancies is not well understood. We hypothesized that the BRAF V600E AF will correlate directly with aggressive histopathological behavior. The aim of this study was to examine this relationship. A retrospective chart review was performed for patients treated for BRAF V600E thyroid malignancies from 2019 to 2022 at McGill University tertiary care hospitals (n = 317). Patients with BRAF V600E-positive malignancies that included information on AF were included (n = 44). The correlation between AF and tumor histopathological features was analyzed. Out of the 44 nodules with a BRAF V600E mutation, those with aggressive features of PTC had a mean AF of 25.8%, which was significantly higher than the non-aggressive group with a mean AF of 10.25% (p = 0.020). Additionally, there was a statistically significant difference in mean AF between patients with a positive sentinel LN (29%) and those with a negative sentinel LN (17.8%) (p = 0.021). Classical PTC was present in 29.5% (13/44) of nodules, with a mean AF of 15.6%. The tall cell subtype was found in 64% (28/44) of nodules, with a mean AF of 23%. Solid and hobnail subtypes were less common in this study, and there was no statistically significant relationship between AF and histopathological subtypes (p = 0.107). Nodules smaller than 1cm had a mean AF of 13.3%, while nodules ranging from 1 2cm had a mean AF of 20.6%, and those larger than 2cm had a mean AF of 27.7%. However, no statistical difference was observed between AF and nodule size (p = 0.160). In this study, BRAF V600E mutations in conjunction with AF help to determine whether thyroid malignancies will display aggressive behavior. This pre-operative finding can help thyroid specialists to determine the extent of thyroidectomy and whether lymph node dissection is required.

Role of ST6GAL1 in Thyroid Cancers: Insights from Tissue Analysis and Genomic Datasets.

Thyroid cancer is the predominant endocrine-related malignancy. ST6 β-galactoside α2,6-sialyltransferase 1 (ST6GAL1) has been studied in various types of cancers; however, the expression and function of ST6GAL1 in thyroid cancer has not been investigated so far. Previously, we conducted two genome-wide association studies and have identified the association of the ST6GAL1 gene with plasma thyroglobulin (Tg) levels. Since Tg levels are altered in thyroid pathologies, in the current study, we wanted to evaluate the expression of ST6GAL1 in thyroid cancer tissues. We performed an immunohistochemical analysis using human thyroid tissue from 89 patients and analyzed ST6GAL1 protein expression in papillary thyroid cancer (including follicular variant and microcarcinoma) and follicular thyroid cancer in comparison to normal thyroid tissue. Additionally, ST6GAL1 mRNA levels from The Cancer Genome Atlas (TCGA, n = 572) and the Genotype-Tissue Expression (GTEx) project (n = 279) were examined. The immunohistochemical analysis revealed higher ST6GAL1 protein expression in all thyroid tumors compared to normal thyroid tissue. TCGA data revealed increased ST6GAL1 mRNA levels in both primary and metastatic tumors versus controls. Notably, the follicular variant of papillary thyroid cancer exhibited significantly higher ST6GAL1 mRNA levels than classic papillary thyroid cancer. High ST6GAL1 mRNA levels significantly correlated with lymph node metastasis status, clinical stage, and reduced survival rate. ST6GAL1 emerges as a potential cancer-associated glycosyltransferase in thyroid malignancies, offering valuable insights into its diagnostic and prognostic significance.

Prognostic impact of lymph node characteristics after therapeutic neck dissection for classic N1 papillary thyroid cancer.

The impact of lymph node characteristics on mortality and recurrence remains controversial. This study evaluated the prognostic impact of lymph node characteristics in a large, homogenous cohort of patients with therapeutic neck dissection for clinically N1 classic papillary thyroid cancer (PTC). All consecutive adult patients with therapeutic central and lateral neck dissection for PTC at a French referral centre were prospectively enrolled from January 2000 until June 2021. The primary outcome was the impact of lymph node characteristics in predicting a disease event (persistence or recurrence), using univariable and multivariable logistic regression modelling. A total of 462 patients were included. Lymph node capsular rupture was seen in 260 patients (56.3 per cent). Median maximum lymph node size was 15 (i.q.r. 9-23) mm. The median central, lateral, and total lymph node ratio (LNR) was 0.50 (i.q.r. 0.22-0.75), 0.15 (i.q.r. 0.07-0.29), and 0.26 (i.q.r. 0.14-0.41), respectively. After a median follow-up of 93 (i.q.r. 50-149) months, 182 (39.4 per cent) patients had a disease event. After multivariable analysis, the number of harvested lymph node >35 (OR 2.33 (95 per cent c.i. 1.10-4.95)), presence of lymph node capsular rupture (OR 1.92 (1.17-3.14)), and total LNR >0.20 (OR 2.37 (1.08-5.19)) and >0.40 (OR 4.92 (1.61-15.03)) predicted a disease event. An LNR of 0.20 predicted a disease event with a sensitivity of 80.8 per cent and a specificity of 50.4 per cent. Disease persistence or recurrence after thyroidectomy with therapeutic neck dissection for classic PTC with preoperative nodal disease appears to depend on number of harvested lymph node, presence of lymph node capsular rupture, and total LNR.

SAT556 An Unusual Case of Papillary Thyroid Carcinoma With Biallelic MEN1 Variants In a Patient With MEN1

Abstract Disclosure: E. Chuki: None. M. Raffeld: None. J. Klubo-Gwiezdzinska: None. S. Gubbi: None. S. Jha: None. Introduction: Multiple endocrine neoplasia (MEN1) syndrome is caused by germline variants in MEN1. Papillary Thyroid Cancer (PTC) is not regarded as a canonical MEN1-related endocrine tumor. Pathogenic variants in MEN1 are rare in PTC. Herein, we report an MEN1 patient with biallelic loss of MEN1 in PTC.Clinical case: A 59-year-old Hispanic female presented with asymptomatic hypercalcemia due to primary hyperparathyroidism [serum calcium: 13.9 mg/dl (8.4-10.2), PTH: 314 pg/ml (15-65) and 25 hydroxy vitamin D: 15 ng/ml (33 – 100)]. Physical examination was unrevealing for any neck mass or lymph nodes. Kidney function was normal with no history of or imaging evidence of kidney stones or calculi. Bone densitometry revealed osteoporosis [lowest T-score of -2.7 in spine]. Germline genetic testing was performed given large size of the parathyroid tumor and biochemical presentation suspicious for parathyroid cancer. A pathogenic MEN1 p.Ile54Serfs*65 was identified. A neck sonogram and 99-technetium sestamibi scan showed a 4.1 cm left parathyroid adenoma and incidental 3.5 cm, heterogeneous right thyroid lobe nodule having smooth margins without microcalcifications, and no cervical lymphadenopathy. Thyroid function studies were normal. Fine needle aspiration of right thyroid nodule revealed epithelial neoplasia containing many atypical cells with enlarged nuclei, nuclear grooves, fine chromatin, and moderate amounts of granular to oxyphilic cytoplasm. Patient underwent left inferior parathyroidectomy and right thyroid lobectomy. Histology was consistent with parathyroid adenoma and a hyperplastic adenomatous thyroid nodule with a 1.1 cm focus of classic PTC with minor follicular and oncocytic components, limited to the thyroid with clear margins and no lymphovascular invasion (pT1bNxMx). Genetic sequencing of the PTC (TSO500 gene panel) revealed two pathogenic frameshift variants in MEN1 p.I54fs*65 and p.D33fs*82 at variant allele frequency (VAF) of 53% and 42% respectively, TERT promoter (TERTp) variant [C228T (c.-124C&amp;gt;T)] at VAF of 44.8% and an NRAS p.Q61K variant at VAF of 39%. The two MEN1 variants were in trans to each other on opposite alleles, suggestive of a second-hit leading to a loss of biallelic function of MEN1.Conclusion: PTC in MEN1 has been rarely reported in the literature [1]. However, per our knowledge, this is the first report of a PTC with second-hit in the MEN1 gene. Somatic MEN1 pathogenic variants have been reported in occasional cases of thyroid oncocytic tumors and NRAS is more frequently associated with follicular or oncocytic thyroid tumors. Thus, whether this tumor should be regarded as a rare manifestation of the MEN1 syndrome is unclear. The histopathologic and molecular characteristics of thyroid tumors in MEN1 warrant further investigation. Reference: 1. Desai et al. Ann Surg Oncol 2001;8(4):342-6. Presentation Date: Saturday, June 17, 2023

Differentiated Thyroid Cancer in Adolescents: Single Center Experience and Considerations for Surgical Management and Radioiodine Treatment

Differentiated thyroid cancer (DTC) in adolescents rare but with a favorable outcome, despite higher rates of cervical lymph node and pulmonary metastasis compared to adults. The aim of this study was to critically evaluate treatment of adolescents with DTC at a single center. Patients receiving postoperative radioiodine treatment (RAIT) for DTC between 2005 and 2020 at our institution were screened to identify adolescents according to the World Health Organization definition (10-19 years of age). Demographics, clinico-pathological characteristics, treatment and outcome were analyzed. Among 1,897 DTC patients, 23 (1.3%) were adolescents with a median (range) age of 16 (10-18) years. The female to male ratio was 3.6:1. Sixty percent had classic papillary thyroid cancer, with follicular variant in 40%, which was higher than previously reported (15-25%) for this age group. pT-status was pT1 in 9 (39.2%), pT2 in 8 (34.8%), pT3 in 3 (13%) and pT4 in 3 (13%) patients. In 19 (82.6%) patients, central lymphadenectomy was performed and metastasis was seen in 57%. All patients received RAIT with initial activities of 1.2 (n=1, 4.3%), 2 (n=12, 52.2%) or 3.7 GBq (n=10, 43.5%). Eighteen (78.2%) patients were free of biochemical and radiologic disease at a median follow-up of 60.7 months. Second-line surgery for lymph node relapse was necessary in 3 (13%) cases. There was one disease-associated death. Despite high rates of metastasis, most patients were cured, and second-line surgery was rarely required. Further prospective studies are needed to determine whether less aggressive surgical management or omitting adjuvant RAIT are feasible in patients with limited stages at diagnosis.

Primary leiomyosarcoma of the thyroid with concurrent papillary thyroid cancer: a rare case report and a review of literature

BackgroundLeiomyosarcoma (LMS) is a soft tissue malignant tumor that has a predilection to the abdominopelvic and limb smooth muscles. LMS of the thyroid is exceptionally rare. Papillary thyroid cancer (PTC) is the most common thyroid malignancy and originates from the thyroid epithelial layer. To our knowledge, the presence of both tumors in the same patient has not been reported previously.Case presentation & literature reviewA 42-year-old woman presented with a progressively enlarging neck mass for a few months. She underwent left thyroid lobectomy, and the histology showed high-grade primary LMS of the thyroid. She subsequently underwent a complete thyroidectomy, which identified a classical PTC on her right lobe.Our comprehensive literature review identified 39 published cases of primary LMS of the thyroid. The average tumor size was 5.88 cm and occurred more in women. The most common presentation was neck mass, followed by compressive symptoms. Recurrence and metastasis were uncommon at 15% and 10–25%, respectively.ConclusionThyroid LMS is a rare malignancy with a worse prognosis than PTC. A thorough workup must be done to rule out metastasis before labeling it as primary thyroid cancer.

Utilizing Dynamic Risk Stratification in Patients With Tall Cell Variant Papillary Thyroid Cancer.

Tall cell variant (TCV) papillary thyroid cancer (PTC) is a subtype of PTC associated with aggressive tumor behavior, advanced stage, and higher rates of recurrence and mortality. The present study aimed to test an established dynamic risk stratification tool in the TCV population, with the goal of better predicting the postoperative course of these patients. Retrospective chart review. A total of 94 patients with TCV who underwent total thyroidectomy with radioactive iodine ablation were retrospectively reviewed from 1998 through 2020. Biochemical, structural, and overall response to treatment was determined for each patient, based on postoperative thyroglobulin levels and imaging findings. Primary outcomes were locoregional and distant recurrence, presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. Patients with TCV who were stratified as having an excellent overall response to treatment had lower rates of locoregional recurrence than indeterminate, biochemical incomplete, and structural incomplete responses (2.0%, 33.3%, 55.0%, and 85.7% at 5 years respectively, p < 0.001). The same was true for distant recurrence as well (2.0%, 9.0%, 35.1%, and 42.9%, p < 0.001). An excellent response was also associated with lower rates of presence of disease at final follow-up, need for additional intervention, and disease-specific mortality. Although TCV is an aggressive subtype associated with worse clinical outcomes than classical PTC, patients with an excellent overall response to treatment have significantly improved outcomes when compared to indeterminate, biochemical incomplete, and structural incomplete responses. 3 Laryngoscope, 133:2430-2438, 2023.

Molecular and clinical features of papillary thyroid cancer in adult patients with a non-classical phenotype.

Genotyping is fundamental in papillary thyroid cancer (PTC) and helps to enhance diagnosis and prognosis and determine appropriate treatments. The phenotype-genotype association in PTC was previously studied, with BRAF V600E characterizing classic PTC and tall-cell PTC and RAS mutations characterizing follicular-variant PTC. In clinic, some non-classical histological subtypes of PTC were also identified, however, their genotype remains unclear. In this study, we collected samples of these non-classical PTC after the exclusion of classic phenotypes and examined their phenotypes, genotype and the relationship between phenotype and genotype. We screened out non-classical PTC by excluding classical PTC from 1,059 different thyroid samples, and a total of 24 cases was obtained and described from the morphological features, which is rare in differentiated PTC. DNA/RNA sequencing was performed using 18 available samples to describe the genetic features. PTC with the non-classical phenotype were characterized cuboidal to low columnar tumor cells with subtle nuclear features of PTC and without discernible nuclear elongation, concurrently with dense microfollicles, delicate papillae or solid nodules with delicate fibrovascular cores. They were associated with lymphatic vessel invasion (P<0.001) but not with a worse prognosis (P=0.791). Gene fusions were identified in 14 of 18 (77.8%) cases, including eight fusions of NTRK and six fusions of RET. The high percentage of fusions in this papillary thyroid cancer subgroup suggested a correlation of gene fusions with the phenotype that does not belong to the BRAF V600E-mutant or RAS-mutant group. Our study retrospectively screened a large cohort of different thyroid tissue samples, and presented the histopathological and genetic features of a non-classical phenotype of PTC from 24 patients. It may contribute to diagnose in PTC, and patients of these non-classical phenotype may benefit from targeted therapy, compared to a natural patient cohort without selection.

Complicated papillary thyroid cancer in young women: Case report

Abstract Introduction Despite papillary thyroid cancer (PTC) almost has a favorable prognosis, some patients for whom standard care is not sufficient due to the aggressive nature of their disease may exist. Here, we try to present a case report of young woman with a complicated PTC. Clinical Case A 32-year-old woman presented with a suspicious left lobe thyroid nodule, when a fine needle aspiration (FNA) cytology revealed classical PTC then underwent thyroidectomy with suppressive levothyroxine therapy was performed. During surveillance, a left supraclavicular lymph node (LN) was detected and an excisional biopsy was revealed metastatic PTC so that a total thyroidectomy with neck dissection was done, but unfortunately it was complicated by permanent tracheostomy. Two sessions of therapeutic radioactive iodine (RAI) were initiated at 150 mCi and then treated by suppressive levothyroxine therapy. One year later on, another palpable cervical LN (area IV) with evidence of non-sizable thyroid tissue were discovered. A stimulated thyroglobulin level=150.8 (3.5–77) ng/ml, anti-thyroglobulin=18.41 (&amp;lt;115) IU/mL and thyroid scintigraphy showed an intense radioiodine uptake in the thyroid bed (relatively large remnant thyroid tissue +/- residual disease), with no evidence of discrete RAI-avid cervical, mediastinal LN, or distant metastases. The patient is refusing further surgical intervention and Tyrosine kinase inhibitors may be a chance. Early wise approach and prediction the highly prevalent factors for aggressive PTC can judge the management plan. Conclusion Meticulous preoperative evaluation of LN metastasis is required for PTC patients with certain criteria to assess the management plan.

Vascularity depicted by contrast-enhanced ultrasound predicts recurrence of papillary thyroid cancer

PurposeAlthough angiogenesis is crucial for the occurrence and development of solid tumors, the prognostic value of vascularity remains unclear in papillary thyroid cancer (PTC), due to the lack of effective techniques to evaluate vascularity. Contrast-enhanced ultrasound (CEUS) is an effective technique to evaluate vascularity. This study aimed to investigate whether vascularity depicted by CEUS was associated with structural recurrence in classic PTC. Methods512 consecutive patients who underwent total thyroidectomy and central lymph node dissection for classic PTC larger than 1 cm between January 2015 and December 2018 and who were followed up for 12 months or longer were retrospectively enrolled. For this study, iso- and hyperenhancement were considered hypervascularity, whereas hypovascularity referred to hypoenhancement. Kaplan-Meier cumulative event curves for structural recurrence were compared using the log-rank test. The multivariate Cox proportional hazard regression analysis was used to estimate hazard ratios (HRs) of hypervascularity depicted by CEUS for structural recurrence. Results61 (11.9 %) of 512 patients had structural recurrence. Hypervascular PTCs had a shorter recurrence-free survival rate than hypovascular PTCs (P < 0.001). In the multivariate analysis, hypervascularity (HR, 2.069; 95 % confidence interval [CI]: 1.087, 3.937), larger size (HR, 1.279; 95 % CI: 1.011, 1.618), multifocality (HR, 1.976; 95 % CI: 1.150, 3.396), extrathyroidal extension (HR, 2.276; 95 % CI: 1.026, 5.046), and lymph node metastasis (HR, 3.631; 95 % CI: 1.515, 8.701) were independently associated with structural recurrence. ConclusionHypervascularity depicted by CEUS was independently associated with structural recurrence in patients with classic PTC.

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 &amp;gt; 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 &amp;lt; 0.02. TSH was suppressed to &amp;lt; 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.

ODP532 Fractionated Radioactive Iodine Therapy in Management of Differentiated Thyroid Cancer

Abstract Introduction Management of differentiated thyroid cancer (DTC) requires individualized treatment plans that are tailored to the risk of disease recurrence. Radioactive iodine treatment (RIT) remains a treatment modality that is valuable in certain patients with DTC. The lack of institutional availability and travel bans imposed by the COVID-19 pandemic did not allow a subset of our patients to get intermediate or high-dose RIT. As an alternative, fractionated low-dose RITs given over a short time interval have been used. We aim to study the response to therapy in this patient population. Materials and methods This retrospective study was performed at a tertiary care hospital in Qatar. Between 2015-2020, patients who completed at least 2 doses of low-dose RIT within 6-12 months with at least one staging visit 3-6 months after their last treatment were included in the study. Results 69 patients met our inclusion criteria, 30 (43.5%) of whom were males and 39 (56.5%) females. The mean age at diagnosis was 40.7 +/- 9.35 years. Classic papillary thyroid cancer was the predominant histological variant (76.6%). Based on surgical pathology, the initial risk of disease recurrence was high in 24 (34.8%) patients, intermediate in 21 (30.4%) patients, and low in 21 (30.4%) patients. 3 (4.3%) patients did not have complete data for classification. Lymphatic invasion was noted in 16 (23.2%), vascular invasion in 15 (21.7%), positive margins in 30 (43.5%) and extra-nodal invasion in 10 (14.5%) patients. Patients underwent between 2-6 fractionated RITs, with the majority having undergone 2. In the low-risk group, 9 (42.9%) patients had an excellent response to therapy at last follow-up, 3 (14.3%) had the persistent structural disease, and 9 (42.8%) patients had an indeterminate response. In the intermediate-risk group, 7 (33.4%) patients had excellent response, 2 (9.5%) had the biochemically persistent disease, 8 (38.1%) had the structurally persistent disease, and 4 (19%) had an indeterminate response. In the high-risk group, 5 (20.8%) patients had excellent response, 13 (54.2%) had a structurally persistent disease, and 6 (25%) patients had an indeterminate response to therapy. Conclusion A similar response to therapy has been reported in the literature in the low and high-risk recurrence groups, suggesting that additional RIT may not be beneficial. In the intermediate risk of recurrence group, there is a higher percentage of patients with structural evidence of disease compared to what is reported in the literature, suggesting that perhaps a single intermediate or high dose RIT may be more beneficial. Either way, the c urrent management of DTC should be based on dynamic risk assessment to guide the need for further therapies. Presentation: No date and time listed

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.

ODP466 Case of Sporadic Medullary Thyroid Cancer Detected by Serum Calcitonin Measurement

Abstract Introduction Thyroid nodules are common and their prevalence has increased with more widespread neck sonography. While most thyroid nodules are benign their evaluation and surveillance is centered around identifying nodules that harbor malignant growths. While secular trends suggest progressively increasing prevalence of thyroid cancer, it is largely an indolent generally curable disease. Medullary thyroid cancer (MTC) is comparatively rare (3-5% of all thyroid cancer) and significantly more virulent than the common papillary thyroid cancer. Guidelines regarding screening for potential MTC remain controversial. We describe the case of a patient with sporadic MTC detected by routine serum calcitonin measurement. Clinical case; The patient is a 52 yr old Caucasian man referred after a serendipitous finding of thyroid calcifications found on Neck and Chest CT done for radiculopathy evaluation. He had no neck symptoms and no anomalies on clinical neck examination nor history of radiation exposure nor relevant family neoplastic history. The neck ultrasound showed a multinodular goiter with a dominant hypoechoic 1.4 cm nodule in the right hemi-thyroid with microcalcifications (TIRADS 5). The nodule biopsy showed pauci-cellular specimen with abundant colloid and the patient had opted for repeat serial sonography rather repeat biopsy because of his unpleasant experience with the first biopsy. Routine initial endocrine evaluation included thyroid function tests (normal) and a random serum calcitonin; 267 (n; &amp;lt;15pg/ml). This degree of elevation was confirmed on repeated measures. A calcitonin stimulation test with calcium gluconate showed a peak stimulated calcitonin of 786 pg/ml. Total thyroidectomy and central neck dissection, confirmed a diagnosis of MTC (T1a N1a Mx). Only one of six sampled neck lymph nodes showed metastatic disease. RET mutation testing was -ve and 4 months post surgery his calcitonin is 97pg/ml with no radiologic evidence of any residual or recurrent disease. Discussion The patient's clinical presentation is typical of sporadic MTC (found serendipitously) which while uncommon is more prevalent than familial MTC and has a significantly more virulent clinical course than the much more prevalent classic papillary thyroid cancer. It also has significantly less cure potential and greater morbidity and mortality risk making early detection and aggressive management even more vital. Despite not being included in many guidelines for standard evaluation of thyroid nodules the random calcitonin obtained in the patient was central to the prompt and correct diagnosis of the patient. Conclusions Despite the limitations and caveats to its interpretation, our case highlights the potential utility of routine serum calcitonin measurement as part of the routine screening work up of thyroid nodules even in so called "low risk" clinical presentations with no clinical flags suggestive of possible familial MTC or MEN 2. Presentation: No date and time listed

Active Surveillance of Small Metastatic Lymph Nodes as an Alternative to Surgery in Selected Patients with Low-Risk Papillary Thyroid Cancer: A Retrospective Cohort Study.

Background: It has been suggested that small metastatic lymph nodes (LNs) detected after initial surgery in patients with differentiated thyroid cancer (DTC) can be managed with active surveillance (AS). However, there is still concern regarding the clinical outcomes of these patients. The main aims of our study were as follows: (1) to assess the frequency of growth and the need of additional treatment in a group of patients with LN recurrences selected for AS, and (2) to determine predictive factors of LN progression. Methods: We retrospectively reviewed 856 clinical records from our DTC patient's database (May 2010 to January 2022). Eighty patients had suspicious cervical LNs on consecutive ultrasound (US) after initial surgery, but we included 50 patients with cytological confirmation of metastatic disease and at least 12 months follow-up. Exclusion criteria were as follows: any LN ≥2 cm or multiple LNs ≥1.5 cm in size, proximity to vital structures, PET-positive disease (standard uptake value ≥5), aggressive histology, and distant metastasis. Patients were followed with thyroglobulin (Tg) and thyroglobulin antibodies measurements on suppressive therapy and neck US every 6-12 months. LN growth was defined as an increase of ≥3 mm in any of its diameters. Results: A total of 50 patients had a median age of 41 years (range, 18-75). Most patients were women (80%) and had classical papillary thyroid cancer (86%). The mean size of the LNs was 10.1 ± 4.4 mm. After a median follow-up of 29 months (range, 12-144), 12 patients (24%) had an increase in size of the metastatic LN, 7 (58%) of whom were surgically removed. None of these seven patients had a structural incomplete response at the end of follow-up. The only variable that predicted an increase in LN size was a rise in Tg levels ≥0.5 ng/mL (p = 0.016). Based on a multivariate analysis, patients with increase in Tg levels ≥0.5 ng/mL had a significantly higher chance of developing LN growth (odds ratio [OR] 16.2 [confidence interval, CI 1.5-120.2], p = 0.020). The median progression-free survival rate was 6.6 years [CI 5.6-9.5]. Conclusion: AS of small LNs could be a feasible alternative to immediate surgery in properly selected patients.