Well-differentiated Thyroid Carcinoma Research Articles

Anaplastic transformation of papillary thyroid carcinoma in the cervical lymph nodes showing a variety of rhabdoid, epithelioid and spindle cell phenotype

Abstract Introduction/Objective Anaplastic thyroid carcinoma (ATC) is a rare undifferentiated tumor of thyroid follicular cells with a dismal prognosis. Most ATCs derive from pre-existing, well-differentiated thyroid carcinomas, most commonly papillary thyroid carcinoma (PTC). In nearly all instances, ATC arises within the thyroid gland. Completely divergent morphologies of this tumor between the bilateral cervical nodes as well as the almost exclusive presence of ATC in the metastatic and nodal locations are very unusual and are reported here. Methods/Case Report A 67-year-old man presented with a rapidly enlarging left cervical mass, hoarseness, dry cough, and drooping left eye. MRI demonstrated bilateral enlarged cervical lymph nodes spanning levels II to V, and nodules in thyroid lobes. Subsequent total thyroidectomy with bilateral radical neck dissection was performed. Histologically, the left lateral cervical masses revealed undifferentiated tumor cells with rhabdoid, epithelioid and spindle cells features. Conversely, the tumor within the thyroid lobes and the right cervical lymph nodes exhibited PTC with tall cell features. All undifferentiated tumor components stained positive with AE1-3, CK7, PAX8, and negative with thyroglobulin, EMA, CD34, S100, Melan-A, Sox 10, desmin, myogenin, and P40. INI-1 staining is retained. Only the spindle cell component stained positive with TTF1. Based on the morphology and immunoprofile, a diagnosis of anaplastic thyroid carcinoma was rendred. Results (if a Case Study enter NA) NA Conclusion Diagnosing anaplastic thyroid carcinoma outside the thyroid lesion can be challenging. In our case, only extensive sampling of the surgical specimen identified a small focus of well-differentiated PTC, staining positive for thyroglobulin, in the left cervical anaplastic carcinoma component, identifying its origin. This case adds to the scarce literature documenting unilateral anaplastic transformation in the left cervical metastatic lymph nodes, while the right cervical lymph nodes contained pure well differentiated PTC. This represents a significant potential pitfall in presurgical fine needle aspiration (FNA) evaluation of patients with ATC.

The Long Journey towards Personalized Targeted Therapy in Poorly Differentiated Thyroid Carcinoma (PDTC): A Case Report and Systematic Review.

Poorly differentiated thyroid carcinoma (PDTC) has an intermediate prognosis between indolent well-differentiated thyroid carcinoma (TC) and anaplastic carcinoma. Herein, we present a case report with a PDTC component, along with a systematic review of the literature. We report a case of a 45-year-old man diagnosed with a PDTC component, along with hobnail and tall-cell variant features positive for BRAFV600E mutation, after a total thyroidectomy and neck dissection. Radioactive iodine (RAI)-131 therapy was applied, but an early recurrence led to complementary surgeries. The anti-Tg rise, the presence of new lymph nodes, and the negative whole-bodyradioiodine scan were suggestive of a radioiodine-resistant tumor. Lenvatinib, sorafenib, dabrafenib/trametinib, cabozantinib and radiotherapy were all administered, controlling the tumor for a period of time before the patient ultimately died post-COVID infection. Systematic Review: We searched PubMed, Scopus, and WebofScience to identify studies reporting clinicopathological characteristics, molecular marker expression, and management of non-anaplastic TC with any proportion of PDTC in adult patients. Of the 2007 records retrieved, 82were included in our review (PROSPERO-ID545847). Our case, together with the systematic review, imply that a combination of molecular-targetedtreatments may be safe and effective in patients with RAI-resistantBRAF-mutated advanced PDTC when surgery has failed to control tumor progression.

A Comprehensive Review and Insights into the New Entity of Differentiated High-Grade Thyroid Carcinoma.

Differentiated high-grade thyroid carcinoma (DHGTC) is a new subset within the spectrum of thyroid malignancies. This review aims to provide a comprehensive overview of DHGTC, focusing on its historical perspective, diagnosis, clinical characteristics, molecular profiles, management, and prognosis. DHGTC demonstrates an intermediate prognosis that falls between well-differentiated thyroid carcinoma and anaplastic thyroid carcinoma. Previously unenumerated, this entity is now recognized for its significant impact. Patients with DHGTC often present at an older age with advanced disease and exhibit aggressive clinical behavior. Molecularly, DHGTC shares similarities with other thyroid malignancies, harboring driver mutations such as BRAFV600E and RAS, along with additional late mutations. The unique behavior and histologic features of DHGTC underscore the necessity of precise classification for prognostication and treatment selection. This highlights the critical importance of accurate diagnosis and recognition by pathologists to enrich future research on this entity further.

The Impact of Race and the Affordable Care Act on Thyroid Carcinoma Outcomes: A National Cancer Database Study.

To assess the impact of race and the Affordable Care Act (ACA) of 2010 on disease presentation and overall survival for patients with well-differentiated thyroid carcinoma. Cross-sectional study of patients (n = 51,078) who underwent partial or total thyroidectomy with or without postoperative radioactive iodine (RAI) for well-differentiated thyroid carcinoma between 2004 and 2018 in the National Cancer Database (NCDB). Cumulative survival (CS) was assessed with Cox proportional hazard regression analyses. There were significant disparities in disease presentation at the time of diagnosis, with Black, Asian/Pacific Islander (API), and Hispanic patients were more likely to have metastatic disease (p < 0.001) and higher TNM stage (p < 0.001) at the time of diagnosis compared to White patients. Black patients had significantly increased risk of death (HR 1.147, 95%CI 1.021-1.289) but API patients had improved CS (HR 0.730, 95% CI 0.608-0.877) compared to White patients. Passage of the ACA was associated with lower risk of mortality, regardless of whether patients lived in states that did not expand Medicaid (HR 0.866, 95% CI 0.823-0.910) or whether they lived in expansion states (HR 0.818, 95% CI 0.758-0.884). Racial disparities significantly impact thyroid carcinoma diagnosis and treatment in the United States but have improved over time. Both expansion and non-expansion states had improved survival outcomes over time, and suggesting analysis of the ACA's long-term impact and ability to address health inequities is still warranted. 3 Laryngoscope, 134:4421-4430, 2024.

Efficacy of Empirical 131 I Radioiodine Therapy in Well-Differentiated Thyroid Carcinoma Patients With Thyroglobulin-Elevated Negative Iodine Scintigraphy Syndrome : A Systematic Review and Meta-analysis.

This study aimed to perform a systematic review and meta-analysis on the efficacy of empirical high-dose radioiodine therapy in treating differentiated thyroid cancer patients with thyroglobulin (Tg)-elevated negative iodine scintigraphy (TENIS) syndrome. We searched PubMed, EMBASE, and the Cochrane Library to identify relevant studies published until April 2022. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist and registered in an international prospective register of systematic reviews (PROSPERO). Meta-analyses of proportions and odds ratios were performed to assess the beneficial effect of empirical high-dose radioiodine therapy in patients with TENIS syndrome. Subgroup analysis was also performed according to the presence of micrometastasis or macrometastasis. We identified 14 studies including 690 patients who received empirical high-dose radioiodine therapy for TENIS syndrome. Those who had micrometastasis exhibited additional lesions not previously observed on diagnostic whole-body scan (prop = 0.64, 95% confidence interval [CI], 0.51-0.77) and had reduced serum Tg levels (prop = 0.69; 95% CI, 0.52-0.84) after empirical radioiodine treatment. No such findings were observed among patients with macrometastasis. Moreover, we found that the empirical radioiodine treatment group had lower serum Tg levels than did controls (odds ratio = 0.27; 95% CI, 0.09-0.87), which suggests a lower risk of disease progression. Our findings indicate that empirical high-dose radioiodine therapy promoted beneficial effects and could be recommended for patients with TENIS syndrome, especially those with micrometastasis.

Clinical and molecular features and survival in thyroid cancer with brain metastases.

2023 Background: Brain metastases (BM) in advanced thyroid cancer are rare; however, they may be underreported as staging brain imaging is not routine. Prognostic features and molecular alterations for this group are poorly described. We characterized the clinical and molecular features of thyroid cancer with BM and evaluated differences in survival. Methods: In this single-center retrospective analysis, patients with metastatic radioactive iodine refractory well-differentiated, poorly-differentiated, or medullary thyroid carcinoma seen at the Princess Margaret Cancer Center from 2007-2022 were included. Electronic medical records were reviewed to collect clinicopathologic and treatment data. All patients had tumor next-generation sequencing (NGS) by a targeted gene panel. Overall survival (OS) from initial medical oncology consultation was analyzed using the Kaplan-Meier method and univariate and multivariate Cox proportional hazards models. Results: Of 248 patients with advanced thyroid cancer, 41(17%) were diagnosed with BM. The median interval from thyroid cancer diagnosis to BM development was 6.49 years (y) (IQR 3.51- 14.35 y). The median age at the time of BM diagnosis was 63.6 y and 23 (56%) were male. Most (76%) were asymptomatic at the diagnosis of BM and 80% had an ECOG of 0-1. Among patients with well-differentiated histology, 27 (18%) developed BM, while 7 (12%) with poorly-differentiated and 7 (19%) with medullary thyroid cancer developed BM. The most common molecular alterations included BRAFV600E (n=19), TERT (n=11), RAS (n=9), RET (n=8), and FANCA (n=3). Patients were treated with surgery (n=5), stereotactic radiation (n=21), whole brain radiation therapy (n=12), or a combination of both (n=2). OS was similar in patients with BM compared to those without (6.05 vs 6.45 y). There were no differences in histology or molecular alterations between patients that developed BM compared to those who did not. The median survival from the time of BM was 3.23 y. Patients with BM with ≥4 lesions had worse survival (0.52 vs 5.09 y, p=0.01). There were no differences in survival based on histology, symptoms, treatment or molecular alterations among those with BM. Conclusions: This is one of the largest reported thyroid BM cohorts and the first with complete NGS. The prevalence of BM in our cohort was higher than previously described, often diagnosed incidentally. Screening for BM in advanced thyroid cancer may detect higher rates, offering prognostic insights. While the number of BM was predictive of survival, molecular alterations did not predict BM development or survival and larger studies are needed.

Diagnostic Accuracy of Ultrasound and Fine-Needle Aspiration Cytology in Thyroid Malignancy.

Introduction: Thyroid nodule incidence is increasing due to the widespread application of ultrasonography. Fine-needle aspiration cytology is widely applied for the detection of malignancies. The aim of this study was to evaluate the predictive value of ultrasonography in thyroid cancer. Methods: This retrospective study included patients that underwent total thyroidectomy for benign thyroid disease or well-differentiated thyroid carcinoma from January 2017 to December 2022. The study population was divided into groups: the well-differentiated thyroid cancer group and the control group with benign histopathological reports. Results: In total, 192 patients were enrolled in our study; 159 patients were included in the well-differentiated thyroid cancer group and 33 patients in the control group. Statistical analysis demonstrated that ultrasonographic findings such as microcalcifications (90.4%), hypoechogenicity (89.3%), irregular margins (92.2%) and taller-than-wide shape (90.5%) were correlated to malignancy (p < 0.001). Uni- and multivariate analysis revealed that both US score (OR: 2.177; p < 0.001) and Bethesda System (OR: 1.875; p = 0.002) could predict malignancies. In terms of diagnostic accuracy, the US score displayed higher sensitivity (64.2% vs. 33.3%) and better negative predictive value (34.5% vs. 24.4%) than the Bethesda score, while both scoring systems displayed comparable specificities (90.9% vs. 100%) and positive predictive values (97.1% vs. 100%). Discussion: The malignant potential of thyroid nodules is a crucial subject, leading the decision for surgery. Ultrasonography and fine-needle aspiration cytology are pivotal examinations in the diagnostic process, with ultrasonography demonstrating better negative predictive value.

Effectiveness and safety of lenvatinib in a series of advanced well-differentiated thyroid carcinomas from a single tertiary cancer center and literature review.

Treatment of advanced differentiated thyroid carcinoma (DTC) remains a challenge as 25-50% of patients with locally invasive or distant metastatic disease become refractory to radioiodine (RAI) therapy. Tyrosine kinase inhibitors (TKI) are increasingly used in this setting. The SELECT trial demonstrated that lenvatinib, a multikinase inhibitor, significantly improved progression free survival (PFS) compared to placebo. Our aim was to report the effectiveness and safety of lenvatinib in our series of patients with advanced DTC. A total of 25 patients with advanced DTC followed at a single tertiary center from January of 2016 to January of 2022 were retrospectively reviewed. Patients were treated with a mean daily dose of lenvatinib of 16.9 mg for a mean of 9.1 months. Median estimated PFS was 31.3 months. One patient achieved complete response. The objective response rate (ORR) was 40% and the disease control rate was 84%. The mean change in summed longest diameter of target lesions from baseline to nadir was -36.9%. Lenvatinib prolonged the tumor volume doubling time in 86.7% patients. Interestingly, we found that patients treated with a lower dose of lenvatinib (<16.9 mg daily) had a significantly higher PFS and ORR than patients treated with higher dosages (>16.9 mg). Adverse events were frequently reported. Our results confirm the effectiveness of lenvatinib in the management of patients with advanced DTC and support the need to adjust the dosage of lenvatinib to patient´s performance status and comorbidities.

Quality of Life in Patients With Well-Differentiated Thyroid Carcinoma After Total Thyroidectomy in Greece.

Well-differentiated thyroid cancer is among the most common types of endocrine cancer. Despite its increasing prevalence, the prognosis of thyroid cancer is rather good, with a five-year survival rate ranging between 80% and 90%, depending on the histological type. Not only the post-treatment complications and the side effects of the lifelong medicationbut also the possibility of a recurrence may have a negative impact on the patient's quality of life (QoL). The aim of this study is to investigate the impact of total thyroidectomy on the QoL of patients with well-differentiated thyroid carcinoma. A prospective study was performed in patients who underwent total thyroidectomy due to well-differentiated thyroid carcinoma in the Otolaryngology-Head and Neck Surgery Department at the University Hospital of Larissa, Greece. The QoL was evaluated based on the "Quality of Life (Thyroid Version)" questionnaire. One hundred patients participated in the study, with a mean age of 51.24±15.33 years. Of these, 63 (63%) were females and 37 (37%) were males. Social concerns, physical well-being, and psychological well-being presented a gradual positive alteration during the first 12 months after the surgery, with psychological well-being reporting the most significant progress of 15.3%. However, spiritual well-being appeared to decline over time. The younger patients progressively improved their physical, psychological, and mental well-being; however, the older patients showed an amelioration of their social skills. Female patients reported higher levels of spiritual well-being, whereas males developed better social skills. In the long term, total thyroidectomy can ameliorate patients' physical status, psychological well-being, and social concerns. However, it might have a negative effect on their mental health during the first 12 months postoperatively. In addition, QoL is directly influenced by demographic characteristics such as age and gender.

Pathogenesis and signaling pathways related to iodine-refractory differentiated thyroid cancer.

Thyroid cancer is the most common malignant neoplasm within the endocrine system and the field of head and neck surgery. Although the majority of thyroid cancers, more than 90%, are well-differentiated thyroid carcinomas with a favourable prognosis, the escalating incidence of this disease has contributed to an increasing number of patients with a propensity for recurrent disease, rapid disease progression, and poor or no response to conventional treatments. These clinical challenges are commonly attributed to alterations in key thyroid oncogenes or signaling pathways, thereby initiating tumour cell dedifferentiation events, accompanied by reduced or virtually absent expression of the sodium/iodine symporter (NIS). As a result, the disease evolves into iodine-refractory differentiated thyroid cancer (RAIR-DTC), an entity that is insensitive to conventional radioiodine therapy. Despite being classified as a differentiated thyroid cancer, RAIR-DTC has an extremely poor clinical prognosis, with a 10-year survival rate of less than 10%. Therefore, it is of paramount importance to comprehensively elucidate the underlying pathogenesis of RAIR-DTC and provide specific targeted interventions. As the pathogenic mechanisms of RAIR-DTC remain elusive, here we aim to review recent advances in understanding the pathogenesis of RAIR-DTC and provide valuable insights for the development of future molecularly targeted therapeutic approaches.

Update on current diagnosis and management of anaplastic thyroid carcinoma.

Well-differentiated thyroid carcinoma has a favorable prognosis with a 5-year survival rate of over 95%. However, the undifferentiated or anaplastic type accounting for < 0.2%, usually in elderly individuals, exhibits a dismal prognosis with rapid growth and disappointing outcomes. It is the most aggressive form of thyroid carcinoma, with a median survival of 5 mo and poor quality of life (airway obstruction, dysphagia, hoarseness, persistent pain). Early diagnosis and staging are crucial. Diagnostic tools include biopsy (fine needle aspiration, core needle, open surgery), high-resolution ultrasound, computed tomography, magnetic resonance imaging, [(18)F]fluoro-D-glucose positron emission tomo-graphy/computed tomography, liquid biopsy and microRNAs. The BRAF gene (BRAF-V600E and BRAF wild type) is the most often found molecular factor. Others include the genes RET, KRAS, HRAS, and NRAS. Recent management policy is based on surgery, even debulking, chemotherapy (cisplatin or doxorubicin), radiotherapy (adjuvant or definitive), targeted biological agents and immunotherapy. The last two options constitute novel hopeful management modalities improving the overall survival in these otherwise condemned patients. Anti-programmed death-ligand 1 antibody immunotherapy, stem cell targeted therapies, nanotechnology achievements and artificial intelligence imple-mentation provide novel promising alternatives. Genetic mutations determine molecular pathways, thus indicating novel treatment strategies such as anti-BRAF, anti-vascular endothelial growth factor-A, and anti-epidermal growth factor receptor. Treatment with the combination of the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib has been approved by the Food and Drug Administration in cases with BRAF-V600E gene mutations and is currently the standard care. This neoadjuvant treatment followed by surgery ensures a two-year overall survival of 80%. Prognostic factors for improved outcomes have been found to be younger age, earlier tumor stage and radiation therapy. A multidisciplinary approach is necessary, and the therapeutic plan should be individualized based on surveillance and epidemiology end results.

Prevalence of Differentiated High-Grade Thyroid Carcinoma Among Well-Differentiated Tumors: A Systematic Review and Meta-Analysis.

Background: The current edition of the World Health Organization (WHO) classification of endocrine tumors introduced grading for follicular cell-derived thyroid cancer. Tumors with necrosis and/or high mitotic count but not fulfilling the Turin criteria for poorly differentiated carcinoma will be reclassified as differentiated high-grade thyroid carcinoma (DHGTC). However, the impact of this reclassification has not been evaluated. In this study, we performed a systematic review and meta-analysis to estimate the prevalence of this new entry across thyroid tumor subtypes. Methods: In this systematic review and meta-analysis, studies reporting data on necrosis and/or mitoses in well-differentiated thyroid carcinoma (WDTC) were used to estimate the prevalence of DHGTC. Heterogeneity and potential publication bias were also evaluated. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed, and quality assessment was performed using a modification of the Newcastle-Ottawa scale. The study has been registered in the International Prospective Register of Systematic Reviews (PROSPERO, ID: CRD42022378716). Results: In clinically unselected patients, the prevalence of DHGTC in WDTC was 0.072 [95% confidence interval, CI, = 0.045-0.113]. The proportion of high-grade tumors greatly varied across growth patterns and subtypes. Overall, the prevalence of DHGTC was higher in follicular thyroid carcinoma (FTC; 0.146 [CI = 0.101-0.205]) than in papillary thyroid carcinoma (PTC; 0.059 [CI = 0.036-0.097]). Diffuse sclerosing, follicular, and classic subtype PTC had the lowest rates of high-grade features (i.e., 0.018 [CI = 0.004-0.084]; 0.036 [CI = 0.010-0.124]; and 0.042 [CI = 0.027-0.066], respectively), while a greater proportion of solid trabecular and histologically aggressive PTC could be reclassified as DHGTC (i.e., 0.154 [CI = 0.067-0.314] and 0.168 [CI = 0.108-0.252], respectively). Similar proportions were obtained for minimally and widely invasive FTC (i.e., 0.136 [CI = 0.058-0.287] and 0.152 [CI = 0.086-0.254], respectively). Finally, in a cohort of patients with poor prognosis (i.e., fatal cases, metastatic and radioiodine resistant tumors, cases with biochemical recurrence), the proportion of DHGTC was 0.287 [CI = 0.155-0.469]. Conclusions: Following the current WHO indications, some tumors will be reclassified as DHGTC. The proportion of tumors with high-grade features is relevant in FTC, solid trabecular, and histologically aggressive PTC subtypes. A remarkable enrichment in DHGTC among patients with poor prognosis confirms the negative impact of high-grade features on outcome.

Bilateral axillo-breast approach (BABA) robotic neck dissection for papillary thyroid carcinomas

Papillary thyroid carcinoma (PTC), the most commonly diagnosed thyroid malignancy, frequently presents with lymph node metastases. Effective management of metastatic lymph nodes is crucial due to the disease's high recurrence rates. Herein, we present our approach to robotic thyroidectomy and central/lateral neck node dissection, which has shown comparable oncologic outcomes, reduced complications, and improved cosmetic results compared to open surgeries. We detail the surgical procedure, from patient positioning and flap dissection, through central and lateral neck dissection, to closure. The BABA robotic modified radical neck dissection (MRND) is primarily recommended for patients with well-differentiated thyroid carcinoma, predominantly PTC, presenting with suspected or pathologically confirmed lateral neck metastasis. We also discuss the application of the da Vinci robot settings in performing precise procedures and preserving critical anatomical structures. This comprehensive review provides insights into the effectiveness of BABA robotic thyroid surgery and central/lateral neck node dissection in managing PTC.

Lymph node imaging for thyroid cancer.

Cervical lymph nodes (LNs) in the central (level VI) and lateral (levels II-V) compartments of the neck are the most common sites of locoregional metastases associated with thyroid cancer. Prophylactic nodal dissections are uncommon in modern thyroid surgery and are not routinely performed due to concern for increased morbidity and do not offer improved survival. Therefore, a selective approach for LN dissections is increasingly important. Preoperatively, this is most frequently assessed with cervical ultrasound (US). Contrast-enhanced computed tomography (CT) of the neck can also be used for preoperative assessment. Both US and CT imaging can be used to characterise LNs in levels II-VI and their risk of malignancy based on size, morphology, and growth. US-guided fine-needle aspiration of equivocal LN with thyroglobulin (Tg) washout can also determine if a LN harbours malignancy. For postoperative surveillance after total thyroidectomy, both US and CT continue to play an important role at 6-12 months intervals. These patients may also benefit from additional biochemical data such as Tg levels in addition to LN and thyroid bed imaging. Thyroid uptake scans may also play a role in LN surveillance postoperatively for well-differentiated thyroid carcinoma in certain clinical contexts. Less commonly, positron emitted tomography may play a role, but is typically reserved for patients with aggressive or radioactive iodine refractory disease.

CDK4 phosphorylation status and rational use for combining CDK4/6 and BRAF/MEK inhibition in advanced thyroid carcinomas.

CDK4/6 inhibitors (CDK4/6i) have been established as standard treatment against advanced Estrogen Receptor-positive breast cancers. These drugs are being tested against several cancers, including in combinations with other therapies. We identified the T172-phosphorylation of CDK4 as the step determining its activity, retinoblastoma protein (RB) inactivation, cell cycle commitment and sensitivity to CDK4/6i. Poorly differentiated (PDTC) and anaplastic (ATC) thyroid carcinomas, the latter considered one of the most lethal human malignancies, represent major clinical challenges. Several molecular evidence suggest that CDK4/6i could be considered for treating these advanced thyroid cancers. We analyzed by two-dimensional gel electrophoresis the CDK4 modification profile and the presence of T172-phosphorylated CDK4 in a collection of 98 fresh-frozen tissues and in 21 cell lines. A sub-cohort of samples was characterized by RNA sequencing and immunohistochemistry. Sensitivity to CDK4/6i (palbociclib and abemaciclib) was assessed by BrdU incorporation/viability assays. Treatment of cell lines with CDK4/6i and combination with BRAF/MEK inhibitors (dabrafenib/trametinib) was comprehensively evaluated by western blot, characterization of immunoprecipitated CDK4 and CDK2 complexes and clonogenic assays. CDK4 phosphorylation was detected in all well-differentiated thyroid carcinomas (n=29), 19/20 PDTC, 16/23 ATC and 18/21 thyroid cancer cell lines, including 11 ATC-derived ones. Tumors and cell lines without phosphorylated CDK4 presented very high p16CDKN2A levels, which were associated with proliferative activity. Absence of CDK4 phosphorylation in cell lines was associated with CDK4/6i insensitivity. RB1 defects (the primary cause of intrinsic CDK4/6i resistance) were not found in 5/7 tumors without detectable phosphorylated CDK4. A previously developed 11-gene expression signature identified the likely unresponsive tumors, lacking CDK4 phosphorylation. In cell lines, palbociclib synergized with dabrafenib/trametinib by completely and permanently arresting proliferation. These combinations prevented resistance mechanisms induced by palbociclib, most notably Cyclin E1-CDK2 activation and a paradoxical stabilization of phosphorylated CDK4 complexes. Our study supports further clinical evaluation of CDK4/6i and their combination with anti-BRAF/MEK therapies as a novel effective treatment against advanced thyroid tumors. Moreover, the complementary use of our 11 genes predictor with p16/KI67 evaluation could represent a prompt tool for recognizing the intrinsically CDK4/6i insensitive patients, who are potentially better candidates to immediate chemotherapy.

Excellent Response to Therapy Occurs for Most Patients With Thyroid Cancer Treated With Lobectomy

IntroductionAmerican Thyroid Association (ATA) Guidelines for Management of Thyroid Nodules and Thyroid Cancer indicate that thyroid lobectomy (TL) or total thyroidectomy (TT) are appropriate surgery for low- and intermediate-risk well-differentiated thyroid carcinoma. We sought to determine outcomes of TL or TT by ATA response to therapy (RTT) classification. MethodsThis is a single-institution retrospective cohort study of adults with unilateral suspicious or malignant thyroid nodules under 4 cm from January 2016 through December 2021. Our primary outcome was ATA RTT. ResultsDuring the study period, 118 met inclusion criteria: 37 (31%) underwent TL and 81 (69%) TT. Of the TL patients, 7 (19%) underwent completion thyroidectomy. Response to therapy (RTT) was similar with TT versus TL: excellent response 56 (69%) versus 30 (81%), indeterminate response 20 (25%) versus 5 (14%), and biochemically incomplete response 5 (6%) versus 2 (5%), P = 0.20. There were no differences between the groups for age, sex, race or ethnicity, tumor size, histologic type, or complications. Thyroidectomy (TT) was associated with multiple nodules 47% versus 22% for TL (P = 0.009), bilateral nodules 43% versus 16% (P = 0.004), central neck lymph nodes removed median 3 (interquartile range [IQR] 1-8) versus 0 (IQR 0-2) P < 0.001, lymph node metastases median 0 (IQR 0-1) versus 0 (0-0) P = 0.02. Median follow-up was 32.5 mo (IQR 17-56 mo) and was similar between the groups. ConclusionsPatients with TL for well-differentiated thyroid carcinoma without high-risk features have an RTT similar to patients undergoing TT. In this cohort, 81% of patients treated with TL have not required additional intervention.

HHV-6A Infection of Papillary Thyroid Cancer Cells Induces Several Effects Related to Cancer Progression.

Recent studies have shown that thyrocytes are permissive to HHV-6A infection and that the virus may contribute to the pathogenesis of autoimmune thyroiditis. Thyroid autoimmune diseases increase the risk of papillary cancer, which is not surprising considering that chronic inflammation activates pathways that are also pro-oncogenic. Moreover, in this condition, cell proliferation is stimulated as an attempt to repair tissue damage caused by the inflammatory process. Interestingly, it has been reported that the well-differentiated papillary thyroid carcinoma (PTC), the less aggressive form of thyroid tumor, may progress to the more aggressive follicular thyroid carcinoma (FTC) and eventually to the anaplastic thyroid carcinoma (ATC), and that to such progression contributes the presence of an inflammatory/immune suppressive tumor microenvironment. In this study, we investigated whether papillary tumor cells (BCPAP) could be infected by human herpes virus-6A (HHV-6A), and if viral infection could induce effects related to cancer progression. We found that the virus dysregulated the expression of several microRNAs, such as miR-155, miR-9, and the miR-221/222 cluster, which are involved in different steps of carcinogenesis, and increased the secretion of pro-inflammatory cytokines, particularly IL-6, which may also sustain thyroid tumor cell growth and promote cancer progression. Genomic instability and the expression of PTEN, reported to act as an oncogene in mutp53-carrying cells such as BCPAP, also increased following HHV-6A-infection. These findings suggest that a ubiquitous herpesvirus such as HHV-6A, which displays a marked tropism for thyrocytes, could be involved in the progression of PTC towards more aggressive forms of thyroid tumor.

SAT552 Thyroid Mass With Both Anaplastic, Papillary Carcinoma Treated With Surgery, Radiation Therapy, Paclitaxel Chemotherapy

Abstract Disclosure: T.H. Hoang: None. D. Whiteman: None. P. Luceri: None. V. Del Signore: None. Introduction: Anaplastic thyroid carcinoma, while rare, is extremely aggressive and overall survival is poor. Median survival is a mere 4 months from time of diagnosis and mortality approaches 100%. We present a case of anaplastic thyroid carcinoma in the setting of differentiated thyroid carcinoma that has shown response to total thyroidectomy, radiation, and chemotherapy over the course of several months. Case Presentation: A 58 year old female who originally presented with the sensation of a lump in her throat in 2012. Thyroid ultrasound at that time revealed a thyroid mass (3 x 2 x 2 cm, mixed echogenicity) of the right thyroid lobe. Two thirds of the mass was solid with increased vascularity; the remaining was cystic. Originally, cytology revealed benign follicular cells, colloid, Hurthle cells and macrophages, and was negative for malignancy. She was diagnosed with a nodular goiter and she was lost to follow up. She again complained of a 15 pound weight loss associated with a lump in her neck in 2021. A repeated thyroid ultrasound revealed a 7cm right sided thyroid nodule with mass effect on the trachea. Repeated cytology showed atypia of undetermined significance. Molecular analysis was positive for EIF1AX, NRAS, &amp; TERT mutations. ENT recommended a total thyroidectomy due to the molecular mutations and the patient’s compressive symptoms. Surgical pathology was consistent with a right-sided, anaplastic thyroid carcinoma arising from an encapsulated, well-differentiated thyroid carcinoma confined to the thyroid and measuring 5.5 cm (Stage IV CT3a, cN0, cM0). Interestingly, the anaplastic component of the tumor was only 15% of the overall mass with the other portion being well-differentiated papillary thyroid carcinoma. She received 6000cGy of external beam radiation with concurrent paclitaxel (60mg/m2) for 6 weekly cycles. A PET/CT four months later showed no evidence of local or distant metastatic disease. CT Chest, Abdomen, Pelvis with contrast did not reveal metastatic disease either. Later, CT soft tissue of her neck showed no residual or recurrent tumor. MRI Brain was negative for acute findings, including metastatic disease. At the current time, she is 18 months from her original diagnosis of anaplastic thyroid carcinoma. She continues to follow with medical oncology and endocrinology and there has been no evidence of recurrent disease. Discussion: When present, it is common for anaplastic thyroid carcinoma to be associated with both papillary and follicular thyroid carcinoma. Regardless of association, anaplastic thyroid carcinoma remains aggressive and median survival is measured in months. Treatment includes surgery, radiation and chemotherapy which can contribute to an increase in 2 year survival to 42% from 18% without treatment. Advancements in the treatment of anaplastic thyroid carcinoma are needed as the recurrence of aggressive disease is unfortunately expected. Presentation Date: Saturday, June 17, 2023

SAT576 Change Is Not Always For The Best! A Transformation of Papillary Into Metastatic Anaplastic Thyroid Carcinoma

Abstract Disclosure: J. Syeda: None. R. Zafar: None. K. Rajamani: None. INTRODUCTION: Anaplastic thyroid carcinoma (ATC) can occur de-novo or from preexisting well-differentiated thyroid carcinoma (1). The presence or absence of certain driver mutations can help predict the likelihood of this transformation process. We present a case of an elderly female with an initial diagnosis of well-differentiated papillary thyroid cancer (PTC) with a transformation into metastatic anaplastic thyroid carcinoma (ATC). CASE PRESENTATION: An 81-year-old female patient was initially seen 8 years ago with a 35-year history of goiter. At the initial presentation, she felt well and did not have any symptoms. Physical examination revealed an enlarged thyroid gland with left lobe nodularity. A thyroid ultrasound showed a multinodular thyroid gland including a 2x1.7x1.2 cm solid nodule with macro calcifications in the right lobe, 2.8x2.6x2.5 cm solid nodule, and 1.6x1.3x1.6 cm heterogeneous solid nodule with calcifications and irregular margins in the left lobe. She had a fine needle aspiration of these three nodules. The right nodule was non-diagnostic and both left nodules were positive for PTC. She underwent a total thyroidectomy and central lymph node dissection. Radioactive iodine treatment with 163mCi was administered after surgery. One and a half years after surgery, her thyroglobulin levels started trending upward. This led to a further workup including a PET/CT scan, which showed a hyper metabolic 6 mm left supraclavicular lymph node. Needle biopsy of this lymph node disclosed metastatic PTC. The pathologic diagnosis following surgical resection was positive for metastatic poorly differentiated thyroid carcinoma. A subsequent PET/CT scan and a thyroid ultrasound showed an abnormal uptake of the left neck lymph node and additional metastatic nodes in the left neck respectively. A core needle biopsy of these lesions was positive for ATC. Foundation One CDx testing was positive for BRAF V600E, TP53, and TERT promoter mutations. Cellblock from the initial thyroidectomy was reevaluated by pathology and confirmed no evidence of ATC. Foundation One CDx testing of the thyroidectomy specimen was positive for BRAF V600E and TERT promoter mutations. Surveillance imaging shows mediastinal adenopathy, left pleural thickening, and bone and liver metastases. DISCUSSION: Anaplastic transformation is not uncommon (1). This case supports the evidence that TERT promoter mutations may not trigger anaplastic transformation but may predispose to the aggressive PTC phenotype prone to conversion to ATC when one of the ATC-related “second hit” genetic events occurs (2). This case suggests that the “second hit” event is a TP53 mutation. The detection of a TP53 mutation in PTC with an aggressive phenotype may help predict anaplastic transformation. REFERENCES: 1-Endocrine Pathology. 2021 Mar; 32(3):347-356. 2- Semin Cancer Biol. 2020 Apr; 61: 23-29. Presentation: Saturday, June 17, 2023

Aerodigestive Tract Invasion by Well-differentiated Thyroid Carcinoma presenting as Anemia: A Case Report

Aerodigestive Tract Invasion by Well-differentiated Thyroid Carcinoma presenting as Anemia: A Case Report