Subtype Of Papillary Thyroid Cancer Research Articles

Radioiodine Therapy Does Not Impact Survival in Tall-Cell Subtype of Papillary Thyroid Cancer

Radioiodine Therapy Does Not Impact Survival in Tall-Cell Subtype of Papillary Thyroid Cancer

Papillary Thyroid Cancer Trends in the Wake of the COVID-19 Pandemic: Is There a Shift toward a More Aggressive Entity?

Globally, the incidence of papillary thyroid cancer (PTC) has been increasing over the last few decades and it has become the second most common cancer in women in the UAE. There is some evidence to suggest that COVID-19 infection might be directly linked to the development of aggressive variants of PTC. The primary goal of this study was to compare the clinical and pathologic characteristics of thyroid cancer patients treated at the largest endocrine surgery center in Abu Dhabi before and after the COVID-19 pandemic outbreak. This retrospective cohort analysis included patients who underwent elective thyroid surgery at Burjeel Hospital between January 2018 and December 2022. Patients were divided into two groups based on when the COVID-19 outbreak started: group one, comprising patients who had surgery between January 2018 and December 2019 (the "pre-pandemic group"), and group two, comprising patients who had surgery between January 2021 and December 2022 (the "post-pandemic group"). In addition to demographic data, clinicopathological factors, such as aggressive cell type, multifocality, tumor size and location, laterality, lympho-vascular invasion, and extrathyroidal extension, were assessed. We utilized the t-paired test for parametric variables and the Chi-square test for the cross-table analysis. During the study, 1141 people had thyroid surgery, with an annual average of 285 procedures. PTC cases recorded in the final histopathological samples rose from 111 in the pre-pandemic era to 182 in the post-pandemic era. Neither the female-to-male gender ratio, which was 90:21 in the pre-pandemic group and 142:40 in the post-pandemic group (p = 0.532), nor the median age, which was 39.1 and 40.1 years, respectively, varied significantly between the two groups. However, there was a significant increase between pre-pandemic and post-pandemic in the aggressive PTC variants (3% vs. 11.5%, p = 0.001), increased poor prognostic factors such as bilateral multifocality (10.8% vs. 32.4%, p = 0.000), as well as increased capsule-vascular tumor invasion (19.8% vs. 27%); on the other hand, the size of the single foci was 17 mm in the pre-pandemic group compared to 13 mm in the post-pandemic group (p = 0.001). A significant rise in unfavorable prognostic markers and aggressive subtypes of PTC was seen post-pandemic in thyroidectomy patients operated on at a leading endocrine surgery center in the United Arab Emirates.

Clinical and morphological features and unsolved issues in diagnosis of aggressive forms of papillary thyroid carcinoma

Differentiated thyroid cancer (DTC) is a disease with a favorable clinical course and high survival rate compared to other epithelial tumors. The majority of DTC (up to 85 %) is represented by various subtypes of papillary thyroid cancer (PTC). Aggressive forms of PTC characterized by early lymphogenous and hematogenous metastasis, low avidity to radioiodine therapy (RIT), low relapse-free survival rates and high mortality rate compared to other types of PTC occur among them. Preoperative diagnosis of PTC is based on the results of ultrasound (US) examination and fine-needle aspiration biopsy (FNA) with cytological examination of the aspirate. At the same time, the capabilities of cytological examination in determining the histological type of PTC are limited and it does not allow to predict its aggressiveness and plan adequate treatment. Molecular genetic tests of the tumor cytological and morphological material are effective in prognosis of aggressiveness of PTC due to the determination of specific mutations in the BRAF, TERT, RAS genes and the quantitative expression of oncogenic and tumor suppressive microRNAs. Some of these indicators are already used in the morphological classification of tumors of the endocrine system.
 At the same time, there are contradictory data concerning the connection of the molecular genetic portrait of PTC, the clinical manifestations of its aggressiveness (extrathyroidal invasion, early metastasis, and radioiodine resistance) and its pathomorphological structure. We tried to summarize and analyze the literature data regarding the diagnosis of aggressive variants of PTC.

Molecular Profiling for Bethesda III to VI Nodules: Results of a Multicenter International Retrospective Study

ObjectiveMolecular testing is a well-established tool that assists in the management of thyroid nodules. We describe our experience using molecular testing of thyroid nodules with Bethesda III to VI cytology. MethodsThis is a retrospective multicenter, multinational study of thyroid nodules that underwent preoperative molecular profiling with ThyGenX/ThyGeNEXT or ThyroSeq V3 between 2015 and 2022. The clinical characteristics and mutational profiles of tumors were compared. Collected data included demographics, cytology results, surgical pathology, and molecular alterations. Molecular alterations were categorized into 3 main phenotypes: BRAF-like, RAS-like, and non-BRAF-non-RAS (NBNR). ResultsOverall, 784 patients who had surgery were included, of which 603 (76.2%) were females. The most common histologic type was papillary thyroid cancer (PTC) with 727 (91.9%) cases. In total, 205 (28.2%) cases showed an aggressive subtype of PTC (eg, tall cell and hobnail). BRAF-like alterations were most likely to be found in Bethesda V and VI nodules and show extrathyroidal extension (ETE), nodal disease, and/or aggressive subtypes of PTC (P < .001 for all). RAS-like alterations were more commonly found in Bethesda III and IV nodules and were less likely to show ETE, nodal disease, and/or aggressive histology (P < .001 for all). NBNR alterations were more commonly found in Bethesda III and IV nodules and were less likely to show ETE, nodal disease, and/or aggressive subtypes of PTC. However, they were rarely but significantly associated with poorly differentiated thyroid cancer (P < .005). ConclusionMolecular testing of thyroid nodules can help determine the likelihood of malignancy and classify nodules into several tumor phenotypes, predicting their behaviors and potentially allowing for a more tailored treatment. NBNR alterations should be managed with caution.

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.

HISTOLOGICAL AND MOLECULAR GENETIC CHARACTERISTICS OF CLINICALLY AGGRESSIVE VARIANTS OF PAPILLARY THYROID CARCINOMA: A LITERATURE REVIEW

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer; this cancer presents relatively low malignancy, good prognosis, and a 10-year survival rate of over 90 %. However, the clinical behaviors of this cancer are complex and varied. PTC is easy to spread via lymphatic ducts, which results in recurrence, metastases, and even death [1]. Differentiated thyroid cancer has a favorable prognosis in terms of relapsefree and overall survival. However, some cases of differentiated thyroid cancer (TC) are characterized by aggressive course with distant metastases. Identification of histological subtypes of papillary thyroid cancer (PTC) and detection of specific mutations may have some prognostic value in the prediction of the disease course and clinical response to treatment. The severity of the disease depends on multiple clinical characteristics, morphological and molecular features of the tumor. Several histological variants of PTC with varying degrees of malignancy have been described so far: from well-differentiated PTC to radioiodine refractory undifferentiated anaplastic carcinoma with a high mitotic index and high probability of relapses. Recurrent PTC mainly refers to localized and distant recurrence, including recurrence of the primary tumor, lymph node metastases, invasion of the esophagus and trachea, invasion of muscles, soft tissues and nerves, and distant metastases. Many factors can affect the recurrence of thyroid cancer, and final conclusion has not yet been reached. Aim: to summarize the available literature data on the molecular genetic characteristics of aggressive variants of papillary thyroid carcinoma. Methods: We conducted a literature review of scientific papers over the past decade using PubMed search engine resources. In addition, a search was conducted using the data of the scientific electronic library eLIBRARY for the above keywords. For this meta-analysis, we used articles containing clinical evidence on the most recent issues regarding aggressive variants of papillary thyroid carcinoma. Results: The highest frequency of BRAF V600E among PTC is shown by the high-cell variant of PTC (90%), also significantly higher with «shoe nail» cells than in classical PTC and varies from 40-90%. In a columnar cell, PTC, mutations in the BRAF V600E gene are much less common than in classic PTC. The diffuse sclerosing type of PTC is characterized by the presence of a RET/PTC translocation, and the percentage of the BRAF V600E mutation is 0-60 in various studies. Conclusion: In the presented work, the morphological and clinical features of patients with prognostic unfavorable variants of PTC are considered. Correct recognition of these variants is an important component in the diagnosis of tumor pathology of the thyroid gland, except for accidentally detected microcarcinomas without signs of invasion into the tissues and into the capsule of the thyroid gland and into the lymphatic vessels. The most aggressive forms of PTC include diffuse sclerosing, tall cell, and insular variants of PTC. Various genetic abnormalities, such as BRAF mutation, can be detected in this case. Thus, in some cases these markers can help to predict the course of TC and to provide adequate and timely treatment.

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.

A nomogram and risk classification system for predicting cancer-specific survival in tall cell variant of papillary thyroid cancer: a SEER-based study.

Tall cell variant (TCV) of papillary thyroid cancer (PTC) is the most common aggressive subtype of PTC. The factors that affect survival of patients with TCV remain unclear. We aimed to develop a model to predict the cancer-specific survival (CSS). A total of 1615 patients diagnosed with TCV between 2004 and 2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database and randomized into training and validation cohorts (7:3). A predictive nomogram for predicting CSS was constructed by Cox proportional hazards regression and validated by concordance index (C-index), calibration curve, and decision curve analyses (DCA). A risk classification system was built based on the total nomogram scores of each case. A nomogram was constructed including five independent prognostic factors (age, tumor size, T stage, M stage, and extent of surgery) associated with CSS in TCV patients. Various validations proved that the nomogram model had good consistency and discrimination for TCV prognosis. The risk classification system could perfectly classify TCV patients into three risk groups with significantly different CSS. Compared with traditional AJCC TNM staging system, the nomogram could better predict CSS in TCV patients. A nomogram and corresponding risk classification system were developed for predicting CSS in TCV patients. The model has excellent performance and can be used to help clinicians make accurate prognostic assessment and individualized treatment.

Dissection of molecular and histological subtypes of papillary thyroid cancer using alternative splicing profiles

Despite growing evidence of the relevance of alternative splicing (AS) to cancer development and progression, the biological implications of AS for tumor behaviors, including papillary thyroid cancer (PTC), remain elusive. With the aim of further understanding the molecular and histological subtypes of PTC, we in this study explored whether AS events might act as new molecular determinants. For this purpose, AS profiles were analyzed in RNA-sequencing data from The Cancer Genome Atlas (TCGA) and from a Korean patient dataset. A total of 23 distinct exon-skipping (ES) events that correlated significantly with PTC oncogenic activity and differentiation scores were identified. The two top-ranked ES events, NUMA1_17515 in exon 18 of NUMA1 and TUBB3_38175 in exon 6 of TUBB3, showed high correlations with oncogenic activities and discriminated histological and molecular subtypes of PTC. Furthermore, two novel intron-retention (IR) events for TUBB3 were uncovered. All ES and IR events for the TUBB3 gene were predicted to induce nonsense-mediated mRNA decay. The relative abundances of intron reads in the PTC dataset from TCGA showed IR levels to differ significantly among PTC subtypes, possibly reflecting their different tumor behaviors. This study provides a landscape of AS changes among PTC subtypes and identified two significant AS events, NUMA1_17515 and TUBB3_38175, as potential AS biomarkers for PTC subclassification and characterization. The AS events identified in this study may be involved in the development of phenotypic differences underlying the functional characteristics and histological differentiation of PTCs.

Papiller Karsinomda PD-L1’in Aşırı Ekspresyonu ve Klinikopatolojik Değişkenlerle İlişkisi

Aim: Standard treatment may not be sufficient in patients with metastatic papillary thyroid cancer (PTC), and it may be beneficial to add PD-1 agents to the treatment. Therefore, this study was conducted to compare and evaluate the expression of PD-L1 in patients with nodular goiter (NG) and Hashimoto's thyroiditis (HT) within the scope of PTC carcinoma. Material and Methods: Thirty-five patients from each group who underwent thyroidectomy for NG, HT, and PTC, between January 2011 and December 2017 were identified. Immunohistochemically, an anti-PD-L1 stain was applied by taking new sections from the tissue samples of 105 patients. The histological type, tumour diameter, capsule invasion (CI), and lymphovascular invasion (LVI) were evaluated. Results: Nine (25.7%) of the patients with PTC were defined as classic, 10 (28.6%) as follicular, 6 (17.1%) as oncocytic, 5 (14.3%) as encapsulated, 2 (5.7%) as solid, 1 (2.9%) tall cell, and 2 (5.7%) as Warthin-like. The expression of PD-L1 in the patients with PTC was significantly higher than in the patients with NG and HT (p&amp;lt;0.001). There was a significant relationship between the increased PD-L1 expression and staining intensity and presence of thyroid LVI in the patients with PTC (p=0.047). In addition, the PD-L1 expression and LVI were observed to be more severe in patients with follicular, tall cell, and oncocytic subtype PTC (p=0.011, p=0.026, respectively). Conclusion: It was observed that the PD-L1 expression increased in patients with PTC. PD-L1 expression and LVI were more severe in patients with follicular, tall cell, and oncocytic subtype of PTC.

Characterization of Subtypes of BRAF-Mutant Papillary Thyroid Cancer Defined by Their Thyroid Differentiation Score.

The BRAFV600E mutation has been associated with more advanced clinical stage in papillary thyroid cancer (PTC) and decreased responsiveness to radioiodine (RAI). However, some BRAF mutant PTCs respond to RAI and have an indolent clinical behavior suggesting the presence of different subtypes of BRAF mutant tumors with distinct prognosis. To characterize the molecular and clinical features of 2 subtypes of BRAF-mutant PTCs defined by their degree of expression of iodine metabolism genes. 227 BRAF-mutant PTCs from the Cancer Genome Atlas Thyroid Cancer study were divided into 2 subgroups based on their thyroid differentiation score (TDS): BRAF-TDShi and BRAF-TDSlo. Demographic, clinico-pathological, and molecular characteristics of the 2 subgroups were compared. Compared to BRAF-TDShi tumors (17%), BRAF-TDSlo tumors (83%) were more frequent in blacks and Hispanics (6% vs 0%, P = 0.035 and 12% vs 0%, P = 0.05, respectively), they were larger (2.95 ± 1.7 vs 2.03 ± 1.5, P = 0.002), with more tumor-involved lymph nodes (3.9 ± 5.8 vs 2.0 ± 4.2, P = 0.042), and a higher frequency of distant metastases (3% vs 0%, P = 0.043). Gene set enrichment analysis showed positive enrichment for RAS signatures in the BRAF-TDShi cohort, with corresponding reciprocal changes in the BRAF-TDSlo group. Several microRNAs (miRs) targeting nodes in the transforming growth factor β (TGFβ)-SMAD pathway, miR-204, miR-205, and miR-144, were overexpressed in the BRAF-TDShi group. In the subset with follow-up data, BRAF-TDShi tumors had higher complete responses to therapy (94% vs 57%, P < 0.01) than BRAF-TDSlo tumors. Enrichment for RAS signatures, key genes involved in cell polarity and specific miRs targeting the TGFβ-SMAD pathway define 2 subtypes of BRAF-mutant PTCs with distinct clinical characteristics and prognosis.

Clinical implication of xenotropic and polytropic retrovirus receptor 1 in papillary thyroid carcinoma.

To investigate the expression of xenotropic and polytropic retrovirus receptor 1 （） in papillary thyroid cancer （PTC） and its clinical implication. The HPA and UALCAN databases were used to explore the expression of XPR1 in PTC and normal tissues. The cBioPortal database was used to obtain the clinical data of PTC patients and gene expression profile. The correlation of expression with gender，age，sub-types，T stage，N stage，M stage and clinical stage of patients were analyzed. Cox regression was conducted to analysis the factors affecting the prognosis of PTC patients. The mutation of was assessed through cBioPortal database. GO and KEGG analyses were used to explore the related biological pathway of involved in PTC. HPA database analysis showed that XPR1 was highly expressed in PTC tissue compared with normal tissues. UALCAN analysis displayed that expression was significantly higher in PTC tissue compared with normal tissues （<0.01），and the highest and lowest expressions of were observed in tall cell and follicular sub-type of PTC，respectively. The expression of was correlated with age，sub-types，T stage，N stage and disease stage of PTC patients （<0.05 or <0.01），but was not correlated with gender and M stage （all >0.05）. Cox regression analysis showed that was an independent prognostic factor of PTC patients （=2.894，<0.05）. The cBioPortal database indicated that the mutation appeared in 6% PTC patients; the mutation type mainly was missense and the mutation point was located at the E615K. Enrichment analysis indicated that might affect the PTC progression through involvement in metabolic pathway. is highly expressed in PTC tissues，which is associated with the prognosis of patients. Metabolic pathway associated with might play an important role in PTC progression，indicating that might be a novel biomarker for diagnosis and treatment of PTC.

Characterization of TERT and BRAF copy number variation in papillary thyroid carcinoma: An analysis of the cancer genome atlas study.

Alterations in the genome, including mutations and copy number variation (CNV), can drive cancer progression. The Cancer Genome Atlas (TCGA) project studying papillary thyroid cancer (PTC) identified a number of recurrent arm-level copy number amplifications, some spanning genes that are also commonly mutated in thyroid cancer. Herein, we focus on the role of TERT and BRAF CNV in PTC, including its relation to mutation status, gene expression, and clinicopathological characteristics. Utilizing TCGA CNV data, we identified focal amplifications and deletions involving the TERT and BRAF loci. TERT amplifications are more frequent in later stage thyroid tumors; in contrast, BRAF amplifications are not associated with stage. Furthermore, TERT amplifications are more frequently found in tumors also harboring TERT mutations, the combination further increasing TERT expression. Conversely, BRAF amplifications are more frequently found in BRAF wildtype tumors, and are more common in the follicular subtype of PTC as well as classic PTCs associated with a high follicular component and a RAS-like expression profile (assessed by the BRAF/RAS score). This is the first study to examine the TCGA thyroid dataset for gene-level CNV of TERT and BRAF, and their relationship with mutation status, tumor type and tumor stage. Assessing the differences in patterns of TERT and BRAF amplifications in the context of the mutation status of these genes may provide insight into the differing roles CNV can play depending on tumor type, and may lead to a better understanding of cancer drivers in thyroid cancer.

Are Bethesda III Thyroid Nodules More Aggressive than Bethesda IV Thyroid Nodules When Found to Be Malignant?

Simple SummaryThe Bethesda classification system is a widespread tool used in the initial screening test for thyroid nodules. The system classifies the biopsy of the nodule into 6 categories, each with its associated malignancy risk and recommendations for management. Nodules classified as Bethesda III and IV are considered intermediate risk, and although Bethesda III nodules are more likely to be benign than Bethesda IV, our hypothesis is that out of those that are malignant, a subset may be more aggressive given their diverse cellular features. In this study we looked at 628 individuals who underwent surgery with a Bethesda III or IV nodule and compared the number of aggressive features found in those with confirmed malignancy. We discovered that Bethesda III nodules that were found to be malignant were more likely to have aggressive features, such as aggressive sub-types of thyroid cancer, spread of cancer beyond the thyroid capsule, and spread of cancer to the lymph nodes. Our results suggest that Bethesda III thyroid nodules may not as indolent as they seem, and these findings may affect management decisions in individuals with indeterminate thyroid nodules.The Bethesda classification system for thyroid fine needle aspirate (FNA) is used to predict the risk of malignancy and to guide the management of thyroid nodules. We postulated that thyroid malignancies characterized as Bethesda III on FNA have more aggressive features than those classified as Bethesda IV. A retrospective chart review was performed to identify those who underwent thyroid surgery at a single tertiary hospital setting between 2015 and 2020. Associations between Bethesda category, molecular genetic test results, and histopathologic findings were examined. Out of 628 surgeries that were performed, 199 (54.2%) Bethesda III nodules and 216 (82.8%) Bethesda IV nodules were malignant. Of those that were malignant, 37 (18.6%) and 22 (10.2%) Bethesda III and Bethesda IV nodules showed aggressive features, respectively (p value = 0.014). There was a proportionally increased number of aggressive features in extra-thyroidal extension, lymph nodes metastasis, and all aggressive subtypes of papillary thyroid cancer in the Bethesda III category. Although Bethesda IV nodules are much more likely to be malignant (p value = 0.002), our study suggests that Bethesda III nodules that are resected are more likely to have aggressive features than Bethesda IV nodules, with a statistically significant increase in the solid variant of papillary thyroid cancer and lymph node metastasis.

MON-533 Diffuse Sclerosing Variant Papillary Thyroid Cancer: Clinical and Histopathological Features, Mutational Profile, Management and Outcome

Diffuse sclerosing variant (DSV) is a rare subtype of papillary thyroid cancer (PTC). Whether it represents a higher grade subtype than conventional PTC is not quite clear. Furthermore, there are limited data on its long-term outcome and its molecular genetics. In this report, we studied all cases of DSV PTC seen at our center during the last 20 years. Out of more than 6000 patients (pts) with differentiated thyroid cancer, only 37 were DSV. We reviewed the clinical and histopathological features, management and outcome of these cases. In addition, molecular genetics is partially achieved; 17 out of these 37 cases have been genotyped for BRAFV600E, TERT promotor mutations, NRAS, HRAS and KRAS mutations. The molecular profiling of the other 20 cases is being done. A total of 37 pts were studied {(12 Males:25 Females, median age 21 years (8-89)}. One pt had lobectomy and the other 36 pts (97.3%) had a total thyroidectomy. Central only (4 pts) or central/lateral lymph node dissection (29 pts) were performed. The median tumor size was 4.5 cm (1.5-8.1). The tumor was multifocal in 27 cases (73%), with extrathyroidal invasion in 27 (73%) and lymphovascular invasion in 24 pts (64.8%). A background lymphocytic thyroiditis was present in 12 pts (32.4%). Lymph node metastases were present in 34 pts (92%) and distant metastases in 13 pts (35%). The sites of metastasis are lungs in 12 pts (32.4%) and lungs and bone in 1 pt. Twenty pts (54.1%) were in TNM8 stage 1, 10 pts (27%) in stage 2, 1 (2.7%) in stage 4a, 3 (8.1%) in stage 4b and 3 unstageable. The ATA risk classification for these pts was 4 pts (10.8%) in low, 12 (32.4%) in intermediate, 19 (51.4%) in high-risk groups and 2 could not be assessed. I-131 was administered to 33 pts (89.2%). The median administered activity was 136 mCi (46-218). Fifteen pts (40.5%) received additional therapies (3 surgeries, 7 RAI, 5 surgeries, and RAI). In 17 pts (46%) which were genotyped, only 3 tumors (8.1%) had BRAFV600E mutation, 1 (2.7%) had TERT promotor C228T mutation and none had RAS mutations. At the last follow up, 15 pts (40.5%) achieved an excellent response, 9 (24%) an indeterminate response, 6 (16.2%) with a structural disease, and 7 (19%) were lost for follow up.Conclusion: DSV PTC is a rare variant, occurs mostly in adolescent and young pts, characterized by aggressive histopathological features and high rates of lymph node and distant metastases but the commonly reported mutations in PTC are rare in DSV and mortality is absent.

SUN-482 A Very Rare Case of Thyroid Cancer

Background: Cribriform-Morular variant of Papillary Thyroid Cancer (PTC-CMV) is an exceedingly rare subtype of thyroid cancer that predominantly affects younger females. As the name implies, it is a papillary thyroid carcinoma with predominantly cribriform and morular pattern of carcinoma cells on cytopathology. While completion thyroidectomy is usually recommended for larger and higher-risk Papillary Thyroid Cancer (PTC), surveillance may be acceptable with PTC-CMV, which tends to be a less aggressive malignancy. Clinical Case: A 46-year-old Guyanese woman presented with a three week history of an enlarging right-sided neck mass associated with a globus sensation while swallowing food. She denied any history of radiation exposure. Her exam findings were positive for a tender, right-sided neck mass. CT neck without contrast revealed a 4.1 x 4.0 x 5.9cm heterogeneous mass within the right thyroid lobe causing mild tracheal deviation to the left. Ultrasound of thyroid gland showed a solid heterogeneous hypoechoic 4.22 x 2.39 x 2.46cm right lobe nodule with no microcalcifications, border irregularity or taller-than-wider morphology. Fine Needle Aspiration of the nodule came back as Atypia of Undetermined Significance. The patient then underwent a core needle biopsy. The resultant pathology was negative for thyroid carcinoma or medullary thyroid carcinoma but was suggestive of a bronchial cleft cyst versus bronchogenic cyst with atypical glandular proliferation. She subsequently underwent a right hemithyroidectomy which revealed a final pathological diagnosis of a 3.5cm PTC-CMV. Such pathology warranted the patient to undergo a colonoscopy which was negative for Familial Adenomatous Polyposis (FAP). Given her negative GI workup and non-contributory family history for colonic polyposis or carcinoma the decision was made to continue surveillance rather than performing completion thyroidectomy as the disease was presumed to be sporadic. Discussion: PTC-CMV accounts for 0.2% of all PTC. It is associated with FAP in more than 50% of cases but can also occur sporadically. This subtype of PTC generally follows a less aggressive course. Review of current literature revealed several case series of CMV-PTC patients. In the largest one, 32 cases were observed over a 19 year period and only two out of twelve patients with FAP-associated PTC-CMV initially treated with hemithyroidectomy developed recurrence to the contralateral lobe. Interestingly, none of the remaining patients with the sporadic type developed recurrence suggesting that completion thyroidectomy may not be mandatory in this group. It is, therefore, critical to identify these patients and screen them with a colonoscopy to avoid the potentially unnecessary resection of the contralateral lobe and the consequent need for thyroid hormone replacement.

Papillary thyroid carcinoma with prominent myofibroblastic stromal component: clinicopathologic, immunohistochemical and next-generation sequencing study of seven cases.

Papillary thyroid carcinoma with desmoid-type fibromatosis or nodular fasciitis-like stroma is an extremely unusual and poorly understood subtype of papillary thyroid cancer. Although prior studies have demonstrated alterations in the Wnt/β-catenin signaling pathway in some of these tumors, controversy still exists regarding the nature of the stromal spindle component. We have studied seven cases of papillary thyroid carcinoma with prominent myofibroblastic stroma, including six men and one woman aged 20-65 years (mean age = 44). All cases displayed areas consistent with conventional papillary thyroid carcinoma embedded in abundant myofibroblastic-like stroma. The myofibroblastic stroma in six cases resembled desmoid-type fibromatosis and in one case it more closely resembled nodular fasciitis. By immunohistochemical staining, the stromal spindle component showed positivity for SMA and low MIB1 proliferation index in all cases, and there was at least patchy strong nuclear positivity for beta-catenin in six/seven cases. Stains for cytokeratin AE1/AE3 and PAX8 were positive in the epithelial elements but negative in the stromal component. Next-generation sequencing was performed on six of seven cases. CTNNB1 gene mutations were identified in six/seven cases. The epithelial component showed BRAF mutations in two cases and an NRAS mutation in one case. The case with fasciitis-like stroma was negative for beta-catenin by sequencing and immunostaining as well as negative for USP6 gene rearrangement. Our findings indicate that papillary thyroid carcinoma with prominent myofibroblastic stroma may represent more than one category of lesions.

A meta-analysis evaluating the relationship between B-type Raf kinase mutation and cervical lymphatic metastasis in papillary thyroid cancer.

Background:B-type Raf kinase (BRAF) mutation is proved to be a critical predictive factor in papillary thyroid cancer (PTC) with aggressive characteristics. However, the association between BRAF mutation and cervical lymphatic metastasis in PTC is controversial.Methods:We searched papers on the study of BRAF mutation and cervical lymphatic metastasis in PTC patients through PubMed, Web of Science, Embase, and Cochranelibrary. The BRAF (+) cases, BRAF (–) cases, and cervical lymphphatic metastatic cases in both BRAF (+) and BRAF (–) groups were collected. After Quality assessment, statistical Analysis (funnel plot and Harbord evaluation, Random-effect model, heterogeneity, subgroup analysis, sensitivity analysis, and metacum analysis) were done by the Review Manager (RevMan) 5.3 and stata14 statistical software.Results:There were 78 cross-section studies which met our inclusion criteria. And all of them had no selection bias, publication bias, or any other bias. A significant association existed between BRAF mutation and cervical lymph node metastasis (LNM) (odds ratio [OR] = 1.63; 95% confidence interval [CI]: 1.44–1.84; P < .05). Overall, 46 studies were conducted among East Asians. Twenty four articles had provided the data of central lymph node metastasis (CLNM), 11 articles with the data of lateral lymph node metastasis (LLNM), and classic/conventional PTC (CPTC) was analyzed in 10 studies. Subgroup analyses were performed based on ethnicity, metastatic site, and subtype of PTC. Significant association between BRAF (+) mutation and cervical LNM were indicated in East Asians (OR = 1.73; 95% CI: 1.49–2.02; P < .05), in non-East Asians (OR = 1.57; 95% CI: 1.26–1.96; P < .05), and in CLNM (OR = 1.80; 95% CI: 1.56–2.07; P < .05). While no significant association was found in LLNM (OR = 1.37; 95% CI: 0.76–2.48; P = .29 > .05) and in CPTC (OR = 1.32; 95% CI: 0.97–1.80; P = .08 > .05). We did not find any other major changes when sensitivity analysis was performed. The metacum analysis showed no significant association existed before 2012. While a significant association began to exist between BRAF mutation and LNM from 2012, and this association became stable from 2017.Conclusions:We consider that a significant association exists between BRAF mutation and cervical LNM. Further meta-analysis on subgroup may reveal some valuable factors between BRAF gene mutation and LNM. And we do not recommend that BRAF (+) as the biomarker for LNM in PTC.

Prognostic risk factors for rare oncocytic variantin 101 cases of papillary thyroid carcinoma.

Oncocytic variant (OV) is an unusual subtype of papillary thyroid cancer whose histopathologic diagnostic criteria, clinicopathologic features and biological behavior are different and have not been comprehensively studied, characterized in literature. Previous studies present conflicting results upon its prognosis. We investigated demographic and clinicopathologic risk factors affecting its prognosis while presenting our clinical experience. This is a retrospective cohort study reviewing 101 patients of OV from an archive of 4500 well-differentiated thyroid cancer patients treated with iodine-131 (131I) between 1991 and 2017. Predefined parameters of age, gender, tumor size (TS), total 131I dose, time to recurrent disease, overall survival, extrathyroidal extension, multifocality, vascular invasion, accompanying other variants, capsular status of thyroid gland, initial cervical lymph node (LN) metastases, preablation stimulated thyroglobulin level, background thyroiditis and stage were evaluated by statistical comparison between metastatic and nonmetastatic groups. Seventeen cases (17%) developed metastases/recurrence, 70% of the recurrences occured before 24 months. Four patients (4%) died during the follow-up. Metastatic sites were usually cervical LN, local recurrence in thyroid bed and lungs. Multivariate analysis revealed stage (IV) and TS were the main parameters impacting recurrence/metastases. In the follow-up, isolated cervical LN metastases were found in 41% of metastatic cases, while 12% had sole recurrence in thyroid bed. Eighty eight percent of the metastatic disease included locoregional (cervical) and/or remote LN. The recurrences were associated with initial thyroid masses greater than 3.5cm in diameter. We found that the prognosis of OV is not poor in our series. Stage (IV) and tumor size are the main risk factors in metastatic development.

Abstract 4234: Computational analysis of immune-associated genomic and transcriptomic elements differentiating papillary thyroid cancer subtypes

Abstract Approximately 600,000 patients live with papillary thyroid cancer (PTC) in the United States, with its incidence rising from 4.8 to 14.9 cases per 100,000 people from 1975 to 2012. Despite being the fastest growing cancer, the therapeutic options for PTC has remained unchanged and are primarily limited to surgery, radioactive iodine, and chemotherapy. Considering the untapped potential of immunotherapy for thyroid cancer, this study explores the genomic and transcriptomic features of PTC subtypes in order to identify dysregulated immune-associated (IA) genes and IA pathways that may serve as therapeutic targets. Using data from The Cancer Genome Atlas (TCGA), the three most common histological subtypes of PTC, including the classical (CPTC), the follicular variant (FVPTC), and the tall cell (TCPTC), were analyzed computationally and compared to normal tissue to identify differentially expressed IA genes. These dysregulated IA genes were further filtered for prognostic significance using MACIS scores. To investigate the molecular mechanism for their dysregulation and explore the possibility of genome-based patient stratification, we profiled the correlation of genomic alterations, including mutation and copy number variation, in the various PTC subtypes to IA gene expression using the information theory-based algorithm REVEALER. Our analyses revealed that the expression profiles of CPTC and TCPTC were the most similar from an immunological perspective, with 360 IA genes similarly dysregulated in both of those subtypes. Additionally, TCPTC had the most unique immunological profile, with 300 IA genes dysregulated exclusively in TCPTC, compared to 107 in FVPTC and 22 in CPTC. Specifically, gene such as RAET1E, FGFR11, and MUC1, which are associated with innate and adaptive immune responses, cell survival and proliferation, and TP53-transcription respectively, were dysregulated only in TCPTC. We also studied gene expression regulators and determined that microRNAs had a limited role in the gene dysregulation we observed. However, the regulatory pathways and mutational features unique to certain subtypes were indicative of pathways differentiating cancer prognosis between PTC subtypes. Most notably, genes in the glycosylation pathway mediated by MUC1 and B3GNT3 are upregulated in TCPTC but are downregulated in the less aggressive FVPTC and CPTC subtypes, suggesting a possible mechanism for the aggressive progression of TCPTC. In summary, our findings indicate that subtypes of PTC have both common and unique dysregulated IA genes and pathways, which may be exploited to develop novel immunotherapy targets or biomarkers predictive of prognosis for the different subtypes. Citation Format: Jaideep Chakladar, Megan Chu, Aditi Gnanasekar, Kristen F. Rosenberg, Joseph C. Tsai, Lindsay M. Wong, Weg M. Ongkeko. Computational analysis of immune-associated genomic and transcriptomic elements differentiating papillary thyroid cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4234.