Tall Cell Research Articles

Frank Invasion in Tall Cell Carcinoma with Reversed Polarity of the Breast: Report of Two Cases.

Tall cell carcinoma with reversed polarity (TCCRP) is a rare neoplasm of the breast composed of columnar tumor cells arranged in solid and solid papillary nests with evidence of apical nuclear polarity. No frank invasion is evident despite the lack of a myoepithelial cell layer throughout the tumor. TCCRP has a triple negative or hormone receptor-low immunophenotype. Recurrent IDH2 R172 hotspot mutation coexisting with genetic alterations in the PI3K pathway characterize this tumor. Here, we report on two postmenopausal patients with TCCRPs with frank stromal invasion. IDH2 R172 mutations were detected in both tumors by immunohistochemistry. Targeted sequencing of case 2 demonstrated the presence of IDH2 R172T and RTEL1 E839K mutations. Both patients underwent breast conservation surgery, radiation therapy and adjuvant endocrine therapy with anastrozole and show no evidence of disease at 65 and 25 months, respectively. This study suggests that tall cell carcinoma with reversed polarity may give rise to frank invasive carcinoma, the prognostic significance of which is yet unknown.

Interplay and clinicopathological correlates of tumor size, multifocality and aggressive variants in patients with operated differentiated thyroid carcinoma: A retrospective cohort study

Objectives: To investigate the interplay and clinicopathological correlates of tumor size, cancer foci (multifocality/bilaterality), and aggressive variants in patients with operated differentiated thyroid cancer (DTC). Methods: A total of 596 patients with operated DTC (median age: 47.0 (range: 18.0-87.0 years, 77.5% were females) were included in this retrospective cohort study. Data on patient demographics, cancer foci, concomitant Hashimoto's thyroiditis, surgery type, DTC subtype (papillary thyroid cancer [PTC], follicular thyroid cancer [FTC]) and variants, tumor size, lymph node metastasis, tumor invasion were recorded. Results: PTC aggressive variant (21.9%, P=0.045), extrathyroidal invasion (24.6%, P=0.012), tall cell PTC variant (60.3%, P=0.043), and widely invasive FTC variants (60.0% P=0.002) rates were significantly higher in the bilateral multifocal tumors than in the unifocal and unilateral multifocal tumors. The rates of Hashimoto's thyroiditis (59.8%, P<0.001) and PTC subtype (99.6%, P<0.001) were significantly higher, while the rates of lymph node metastasis (5.8%, P<0.001), capsule invasion (11.6%, P<0.001), vascular invasion (0.4%, P<0.001) and extrathyroidal invasion (4.5%, P<0.001) were significantly lower in <10 mm than in >10 mm tumors. Presence vs. absence of PTC aggressive variant was associated with significantly higher greatest tumor size (12 mm, P=0.013) and higher rates of multifocal tumor (50.5%, P=0.013) and extrathyroidal invasion (33.0%, P<0.001). Conclusions: Our findings revealed the presence of bilaterality/multifocality and aggressive variants in a considerable proportion of patients with operated DTC, and a multifaceted interplay between bilaterality/multifocality, tumor size, and PTC aggressive variants, in addition to their individual effects on increased risk of tumor invasion, particularly the extrathyroidal invasion.

A lasso-based model to predict lateral lymph node metastasis in unifocal papillary thyroid carcinoma with central lymph node metastasis.

To screen the risk factors for lateral lymph node metastasis (LLNM) in unifocal papillary thyroid carcinoma (PTC) with central lymph node metastasis (CLNM) and create a corresponding model. A retrospective analysis of 362 patients from our hospital was performed. All patients were randomized into training and validation groups in a ratio of 7:3. Risk factors were screened using the least absolute shrinkage and selection operator (LASSO) and logistic regression analysis. The analysis indicated that upper location, number of CLNM ≥ 3, rate of CLNM ≥ 0.172, prelaryngeal LNM, pretracheal LNM, and tall cell variant of papillary thyroid carcinoma (TCV-PTC) are independent risk factors. Visualizing the model with a nomogram, receiver operating characteristic (ROC) curves revealed an area under the curve (AUC) of 0.773 for the training group and 0.779 for the validation group. This confirms the stability and outstanding accuracy of the model. Also, the calibration curves and clinical descision curves reflect strong calibration,offering potential clinical benefits. The risk factors for LLNM include metastasis to the prelaryngeal lymph nodes, metastasis to the pretracheal lymph nodes, location in the upper level, number of metastases ≥3 in CLNM, TCV-PTC and metastasis rate ≥0.172. A nomogram incorporating these factors exhibits excellent predictive value and stability.

Targeting Non-Apoptotic Pathways with the Cell Permeable TAT-Conjugated NOTCH1 RAM Fragment for Leukemia and Lymphoma Cells.

Targeting nonapoptotic cell death offers a promising strategy for overcoming apoptosis resistance in cancer. In this study, we developed Tat-Ram13, a 25-mer peptide that fuses the NOTCH1 intracellular domain fragment RAM13 with a cell-penetrating HIV-1 TAT, for the treatment of T-cell acute lymphoblastic leukemia with aberrant NOTCH1 mutation. Tat-Ram13 significantly downregulated NOTCH1-target genes in T-ALL cell lines. Furthermore, the peptide had potent cytotoxic effects on various human leukemia and lymphoma cell lines. However, it did not affect normal lymphocytes and monocytes, some subsets of leukemia cells, or adherent tumor cells. This cell-selective cytotoxic activity was closely correlated with the peptide uptake via macropinocytosis in leukemia cells. In leukemia cells, Tat-Ram13 triggered rapid cell death. This cell death involved mitochondrial membrane depolarization and extracellular release of lactate dehydrogenase and high-mobility group box-1 protein without activation of caspase-3 or cleavage of PARP-1. These results suggest that Tat-Ram13 cell death is nonapoptotic and mediated by rapid plasma membrane rupture. Moreover, alanine scanning analysis identified four critical hydrophobic amino acids in the RAM13 domain essential for its cytotoxicity. Consequently, these results suggest that Tat-Ram13 is a tumor-selective, nonapoptotic cell death-inducing agent for treating refractory leukemia and lymphomas with apoptosis resistance.

Tall cell carcinoma with reversed polarity: a care report of a rare subtype of triple negative breast cancer

Tall cell carcinoma with reversed polarity: a care report of a rare subtype of triple negative breast cancer

CALML6 as a potential diagnostic marker for thyroid cancer promotes thyroid cancer cell proliferation via modulating the immune microenvironment

PurposeCALML6 is an inflammation-related gene, and its expression may be associated with cancer. Here we evaluated the role of CALML6 expression in papillary thyroid carcinoma (PTC). MethodsWe utilized databases such as The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression Project (GTEx) and UALCAN to evaluate the relationship between CALML6 expression and clinicopathological features in thyroid cancer. Immunohistochemical assays were used to observe CALML6 expression in thyroid cancer tissues. The role of CALML6 in PTC cells was investigated using RNA interference. ResultsWe found CALML6 expression was lower than normal and associated with extrathyroidal extension, lymph node metastasis, pathological T stage, tall cell PTC and the expressions of immune checkpoint genes CD274 and PDCD1LG2 in THCA. Additionally, Immunohistochemical staining showed that CALML6 expression was significantly upregulated in thyroid cancer tissues. RNAi analysis showed that CALML6 knockdown significantly reduced cell growth and blocked the cell cycle of PTC cells. Conclusions: Our results suggest that CALML6 may be a novel diagnostic marker for PTC that is closely associated with the invasive and tall cell subtypes, and it may be a potential target for immunotherapy.

Cytologic hallmarks and differential diagnosis of papillary thyroid carcinoma subtypes.

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, characterized by a range of subtypes that differ in their cytologic features, clinical behavior, and prognosis. Accurate cytologic evaluation of PTC using fine-needle aspiration is essential but can be challenging due to the morphologic diversity among subtypes. This review focuses on the distinct cytologic characteristics of various PTC subtypes, including the classic type, follicular variant, tall cell, columnar cell, hobnail, diffuse sclerosing, Warthin-like, solid/trabecular, and oncocytic PTCs. Each subtype demonstrates unique nuclear features, architectural patterns, and background elements essential for diagnosis and differentiation from other thyroid lesions. Recognizing these distinct cytologic patterns is essential for identifying aggressive subtypes like tall cell, hobnail, and columnar cell PTCs, which have a higher risk of recurrence, metastasis, and poorer clinical outcomes. Additionally, rare subtypes such as diffuse sclerosing and Warthin-like PTCs present unique cytologic profiles that must be carefully interpreted to avoid diagnostic errors. The review also highlights the cytologic indicators of lymph node metastasis and high-grade features, such as differentiated high-grade thyroid carcinoma. The integration of molecular testing can further refine subtype diagnosis by identifying specific genetic mutations. A thorough understanding of these subtype-specific cytologic features and molecular profiles is vital for accurate diagnosis, risk stratification, and personalized management of PTC patients. Future improvements in diagnostic techniques and standardization are needed to enhance cytologic evaluation and clinical decision-making in thyroid cancer.

Reduced expression of FOXE1 in differentiated thyroid cancer, the contribution of CPG methylation, and their clinical relevance.

Forkhead box E1 (FOXE1) is a transcription factor with a crucial role in thyroid morphogenesis and differentiation. Promoter hypermethylation downregulates FOXE1 expression in different tumor types; nevertheless, its expression and relationship with methylation status in differentiated thyroid cancer (DTC) remain unclear. A total of 33 pairs of matched samples of PTC tumors and non-tumors were included. Tumor cell cultures were treated with either 5-Aza-2'-deoxycytidine demethylating agent or dimethyl sulfoxide (DMSO). A real-time polymerase chain reaction (RT-PCR) and Western blotting were performed to assess FOXE1 expression. The methylation status was quantified using bisulfite sequencing. A luciferase gene assay was used to determine CpG-island functionality. Gene expression and promoter methylation of FOXE1 and FOXE1-regulated genes were also analyzed with data from The Cancer Genome Atlas (TCGA) thyroid samples. After demethylating treatment, increased FOXE1 mRNA was observed concomitantly with reduced promoter methylation of CpGisland2. A negative correlation between mRNA downregulation and an increased methylation level of CpGisland2 was observed in tumors. Diminished protein expression was also detected in some DTC cell lines and in some tumor samples, suggesting the involvement of post-transcriptional regulatory mechanisms. CPGisland2 was proved to be an enhancer. TCGA data analysis showed low FOXE1 mRNA expression in tumors with a negative correlation with methylation status and a positive correlation with the expression of most of its target genes. Reduced FOXE1 expression, accompanied by a high methylation level, was associated with PTC aggressiveness (tall cell variant, advanced extra thyroid extension, T4 American Joint Committee on Cancer (AJCC) classification), age at diagnosis (over 45 years old), and presence of a BRAFV600E mutation. FOXE1 mRNA was downregulated in DTC compared with non-tumors, followed by high CpGisland methylation. A coupling of low mRNA expression and high methylation status was related to characteristics of aggressiveness in DTC tumors.

Establishment and Characterization of T-ALL Cell Line with KMT2A::Afdn and T/My Mpal Cell Line with ETV6::NCOA2- the First Reports

Establishment and Characterization of T-ALL Cell Line with <i>KMT2A::Afdn</i> and T/My Mpal Cell Line with <i>ETV6::NCOA2</i>- the First Reports

Sumoylation As a Novel Target for T-Cell Neoplasms

Despite breakthroughs in our understanding of peripheral T-cell lymphoma (PTCL) through studies such as genetic profiling, this disease has proven to be difficult to manage compared to it B-cell counterparts. There have been few advances in treatment regimens since the initial trials with CHOP-based chemotherapy (Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone) for many decades. In recent years, there have been more targeted therapies such as Brentuximab-Vedotin, however this is not applicable to most PTCL. Given the persistent poor outcomes in this patient population, novel therapeutic options are needed. Similar to B-cell lymphomas, a subset of PTCL lymphomas exhibit alterations in cMYC expression. Recent studies have demonstrated a unique susceptibility of cMYC-driven B-cell lymphomas to the inhibition of SUMOylation. SUMOylation is a process of post translational modification (PTM), similar as ubiquitination. However, SUMOylation results in alteration of protein function, rather than explicit changes such as targeting for destruction. Using a recently descript PTCL model, LM-23, which overexpresses cMYC, we found that inhibition of SAE-1/2 with SB-4826, which are necessary for SUMOylation, led to decreased tumor growth in a subcutaneous tumor model, as well as cell death in in vitro models. Here, we demonstrate a susceptibility of T-cell neoplasms (PTCL and T-lymphoblastic leukemia) to the inhibition of SUMOylation by targeting SAE-1/2 with SB-4826. Using multiple neoplastic T-cell lines, we demonstrate a low micromolar ICI50 for SB-4826 for neoplastic T-cell lines including LM-23 and Jurkat, similar to B-cell lymphoma cells lines. This ICI50 value is significantly lower than non-neoplastic T-cells, suggesting decreased effects on non-neoplastic counterparts of the functional immune system. Additionally, LM-23 tumor bearing mice treated with SB-4826 showed significant reductions in tumor volume compared to CHOP treated mice. Additional studies on murine and human PTCL and T-ALL cell lines will be presented. While further preclinical studies are necessary, these studies identify SUMOylation as a novel therapeutic target in PTCL and T-ALL, especially cMYC- driven T-cell neoplasms.

Construction and validation of a nomogram for predicting cervical lymph node metastasis in tall cell variant of papillary thyroid carcinoma.

To analyze the risk factors associated with the occurrence of cervical lymph node metastasis (LNM) in patients with tall cell variant of papillary thyroid carcinoma (TCV-PTC) and to establish a nomogram. Clinical data of 727 patients with TCV-PTC from SEER database were obtained, and they were randomly divided into the training group (n = 508) and validation group (n = 219). The clinicopathological characteristics were analyzed by logistic regression, including age, marital status, race, gender, tumor size(cm), T stage, M stage, bilaterality, capsular invasion, extrathyroidal extension (ETE), vascular invasion and multifocality. The C-index, calibration curves, and DCA were utilized to validate the model from the differentiation and calibration of the nomogram, respectively. Tumor size, extrathyroidal extension, and multifocality were independent risk factors for the development of LNM in patients with TCV-PTC (P < 0.05). In the training and validation groups, the C-index of internal validation of the nomogram were 0.727 (95% CI: 0.571-0.785) and 0.712 (95%CI: 0.700-0.714). The calibration curves indicated that the model was in good agreement, and the DCA indicated that the nomogram model had good clinical utility. Tumor size, extrathyroidal extension, and multifocality are independent risk factors for developing LNM in TCV-PTC. The nomogram model can predict the risk of developing LNM in TCV-PTC patients and provide clinical guidance.

Clinically aggressive follicular cell-derived thyroid carcinoma: A comprehensive series with histomolecular characterization and discovery of novel gene fusions

Thyroid cancer rates are increasing, mostly with a good prognosis and less than 2 % of cases are more aggressive. Recent efforts focus on understanding molecular events predicting tumor aggressiveness and treatment targets in advanced thyroid cancer. This study concerned 57 patients with aggressive metastatic, and/or radioiodine-refractory thyroid carcinomas, excluding anaplastic cases. Molecular profiling, including next-generation sequencing and RNA sequencing, was conducted to dissect the complex molecular landscape of these aggressive tumors. Histopathological analysis indicated that papillary carcinomas and high-grade thyroid carcinomas were predominant. The molecular analysis revealed a spectrum of mutations, with prevalent occurrences of BRAF V600E, TERT promoter, and RAS mutations. RNA sequencing identified ten gene fusions, such as NTRK and RET fusions. Three novel fusions were discovered: UGGT1::TERT, BTBD9::TERT, and TG::IGF1R, potentially driving aggressive behavior. UGGT1::TERT was linked to radioiodine-refractory tall cell PTC, BTBD9::TERT to high-grade follicular PTC, and TG::IGF1R to oncocytic carcinoma. These findings underscore the importance of TERT alterations in aggressive phenotypes and offer insights into molecular mechanisms guiding targeted therapies. Further research is necessary to confirm their significance as diagnostic and prognostic markers in thyroid cancer.

Single-chain nanobody inhibition of Notch and avidity enhancement utilizing the β-pore forming toxin Aerolysin.

Notch plays critical roles in developmental processes and disease pathogenesis, which has led to numerous efforts to modulate its function with small molecules and antibodies. Here we present a nanobody inhibitor of Notch signaling, derived from a synthetic phage-display library targeting the notch Negative Regulatory Region (NRR). The nanobody inhibits Notch signaling in a luciferase reporter assay and in Notch-dependent hematopoietic progenitor cell differentiation assay, despite a modest 19uM affinity for Notch. We addressed the low affinity by fusion to a membrane-associating domain derived from the β-Pore forming toxin Aerolysin, resulting in a significantly improved IC50 for Notch inhibition. The nanobody-aerolysin fusion inhibits proliferation of T-ALL cell lines with similar efficacy to other Notch pathway inhibitors. Overall, this study reports the development of a Notch inhibitory antibody, and demonstrates a proof-of-concept for a generalizable strategy to increase the efficacy and potency of low-affinity antibody binders.

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.

12210 Prognostic Determinants of Aggressive Histology Papillary Thyroid Carcinoma: A Pathway to Personalized Treatment

Abstract Disclosure: M. Almaghrabi: None. G. Sindi: None. H. Sasseville: None. S. Radi: None. M. Tamilia: None. Background: Papillary thyroid carcinoma (PTC), the most common form of thyroid malignancy, generally presents with a favorable prognosis. However, aggressive variants of Papillary Thyroid Carcinoma (AV-PTC), such as tall cell, hobnail, columnar, and solid forms, pose significant challenges in prognosis and treatment, due to their unique pathological behaviors and increased risks of recurrence and mortality. The management debate for AV-PTC without invasive characteristics is ongoing. It's argued that aggressive histology alone should not dictate the clinical management of PTC patients lacking aggressive features. Objectives: This study aims to investigate the prognostic impact of invasive features in AV-PTC and their implications on clinical outcomes. Methods: We conducted a retrospective cohort study of AV-PTC patients treated from 2008 to 2022, analyzing medical records to identify prognostic factors related to disease recurrence, persistence, and overall survival. This involved distinguishing between groups with invasive characteristics—identified as one of the following: extrathyroidal extension, lymphovascular invasion, the presence of positive lymph nodes, or the detection of distant metastases upon diagnosis, and non-invasive AV-PTC groups. Results: Key findings from our comparison between invasive and non-invasive groups of AV-PTC highlighted significant factors associated with poorer outcomes in the invasive group. These included multifocality (P=0.001), larger tumor size (P=0.047), extra thyroid extension (P=0.002), lymph vascular invasion (P&amp;lt;0.001), the presence of contralateral nodules (P=0.018), and positive surgical margins (P=0.003). Moreover, advanced tumor stage and increased lymph node involvement were more common in invasive cases (P=0.012, P=0.040). Despite no significant differences in genetic mutations between groups (P=0.396), the Ki-67 index was numerically higher in the invasive group. Hemithyroidectomy followed by completion thyroidectomy, performed in 12 patients (22.2%). Survival analysis further highlighted the significance of these invasive features, with Kaplan-Meier curves indicating a 5-year freedom from recurrence rate of 77.18% and a 10-year rate of 68.61%. Univariable Cox regression revealed that the tumor size, positive margins, and tumor stage predicted recurrence. Seven patients had distant metastasis, and all were in the invasion group (18.92%) p= 0.088. Conclusion: Our study emphasizes the critical role of certain invasive features in determining the prognosis of AV-PTC. The adoption of more extensive treatments for patients without invasive features highlights the complexity of treating AV-PTC and the importance of personalized treatment plans. This research advances our understanding of AV-PTC, advocating for individualized approaches to enhance patient outcomes. Presentation: 6/3/2024

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 (&amp;lt; 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

8549 A Pre-ablative Stimulated Thyroglobulin Value That Predicts ATA High Risk Patients and Their Treatment Response

Abstract Disclosure: H. Gondaliya: None. N. Nangadda: None. D. Bhat: None. K.S. Khadilkar: None. S. Kumbenahalli Siddegowda: None. B.G. Sooragonda: None. A. Shetty: None. S. Kannan: None. In ATA risk stratification system for differentiated thyroid cancer (DTC), one of the variables placing patients in ATA high risk category is thyroglobulin (Tg) suggestive of distant metastases. However there is no defined cut-off Tg level for guiding the clinicians. We aimed to determine pre-ablative stimulated Tg (psTg) value that predicts ATA high risk patients (based on non-Tg parameters) and their treatment response on follow up. This was an ambispective observational study of 285 patients with DTC treated at our centre from April 2017 to November 2022. psTg was measured in all patients 3-4 weeks after surgery and they were subjected to RAIA depending on clinician’s discretion and followed up using the ATA dynamic risk stratification every 6 months. The cohort was divided into two groups: ATA high risk and ATA non-high risk (Low and intermediate risk). Patients among high risk group were divided based on response to treatment into structural incomplete group and non-structural incomplete group (Excellent, Indeterminate and Biochemically incomplete response). The mean age of the study population was 41±15 years and 68% (n=194) were female and 87% (n=249) were papillary thyroid cancer (PTC) and 13% (n=36) were Follicular Thyroid Cancer (FTC). Median duration of follow up was 2.95 years (IQR: 1.42 - 5.12). Among those with PTC, 75% were Classic, 15% Follicular variant and 10% aggressive variants that included tall cell, hobnail, diffuse sclerosing and columnar variant. On ATA risk stratification, 81.75% (n=233) patients were in non-high risk group with median psTg 3.4 ng/ml (IQR 0.5-12.2) and 18.25% (n=52) were in high-risk group with median psTg 150.5 ng/ml (IQR 7.15-439.5). On ROC analysis of all the patients, a psTg value &amp;gt;53.3 ng/ml was predictive of ATA high risk group with PPV of 64%; NPV of 93.5% and AUC 0.81. In ATA high-risk group, there were 73% (n=38) of patients with structural incomplete response on follow up and their median psTg was 287 ng/ml (IQR 95-500) and there were 27% (n=14) with non-structural incomplete response and their median psTg level of 6.2 ng/ml (IQR 2.3-110). A psTg value &amp;gt;53 ng/ml discriminated structural incomplete from non-structural incomplete response with PPV of 77%; NPV 87% and AUC 0.83. A psTg value &amp;gt;53 ng/ml not only predicts ATA high risk patients but also indicates those who are likely to remain with structural residual disease at follow up of 3 years. Presentation: 6/1/2024

7962 Transformation of Poorly Differentiated Papillary Thyroid Carcinoma to Anaplastic Thyroid Carcinoma, an Atypical Course!

Abstract Disclosure: T. Altaweel: None. S. Makadsi: None. M. Hussein: None. J. Samantray: None. Introduction: Anaplastic thyroid cancers are undifferentiated, rare and aggressive. The transformation of papillary thyroid cancer to anaplastic thyroid cancer is documented in literature, however, rare. In this report, we present a case of Anaplastic thyroid carcinoma likely arising from a co-existing poorly differentiated Papillary carcinoma. Case Presentation: A 74-year-old male with past medical history of tobacco smoking who presented with the onset of voice hoarseness for 6 months. He has also noticed a left neck mass that is in the mid supraclavicular region. A Neck CT neck was performed at the time of presentation and was significant for a 4.6x3.4x5.9 cm left thyroid mass with displacement of the trachea. FNA biopsy showed papillary carcinoma with focal features of Tall Cell Variant. Poorly differentiated components with fragments of stroma and muscle were seen and suggested invasion. These findings raised the possibility of anaplastic thyroid carcinoma in the setting of papillary carcinoma and poorly differentiated carcinoma. BRAF V600E pathogenic variant mutation along with TERT mutation were found. Patient underwent direct laryngoscopy, bronchoscopy with biopsies, and tracheostomy with surgical pathology confirming papillary thyroid cancer with muscles invasion. Combination dabrafenib and trametinib were started. No surgical resection of thyroid tissue was planned. A follow up CT showed a significant decrease in the low-density soft tissue involving the medial thyroid gland bilaterally, consistent with interim positive response to therapy. Three months later, CT neck showed near complete resolution of low-density soft tissue involving the medial thyroid and parathyroid glands and subglottic trachea consistent with further interim positive response to therapy. Six months post initiation of therapy, CT Neck showed focal low density in the mid and inferior right thyroid gland which may represent residual and/or recurrent thyroid carcinoma. That density was further demonstrated on a repeat CT neck as a 1.8 cm hypodense nodule in the inferior right thyroid gland and concerning for recurrent thyroid tumor with possible infiltration of the trachea. Conclusion: ATC prognosis is affected by many factors such as metastasis, age, treatment strategies, socioeconomic status and the presence of BRAF V600E and TERT mutations. Diagnosis can be challenging. Our patient presented months after his symptoms started and this is an atypical course of Anaplastic Thyroid Carcinoma as it usually progresses aggressively and rapidly. Given the pathology reports and the more slow presentation of this patient’s carcinoma, it can be suggested that this is a case of papillary carcinoma with a later transformation to ATC. In these cases, surgical resection Presentation: 6/2/2024

8788 Implications of NTRK gene fusion in Papillary thyroid cancer

Abstract Disclosure: W. Medina-Torres: None. L. El Musa Penna: None. J. Segarra-Villafane: None. L.R. Sepulveda-Garcia: None. Z. Maisonet -Feliciano: None. I.C. Arroyo: None. M. Ramirez: None. M. Alvarado: None. L.A. Gonzalez-Rodriguez: None. V.J. Carlo: None. Thyroid cancer (TC) is the most common endocrine cancer. Papillary thyroid carcinoma (PTC) is the predominant contributor of this occurrence, comprising approximately 80% of all thyroid carcinomas. PTC has a good prognosis with a 5-year survival rate of more than 90% after resection. Nonetheless, factors such as tumor size, multifocality, nodal and distant metastases, characterize more aggressive cases including tall cell variant, columnar cell variant, and hobnail variant Aside from staging parameters, PTC behavior is mostly determined by morphologic variant. This is the case of 31 y/o female without known past medical history who was evaluated at endocrinology clinic due to a fine needle thyroid aspiration (FNA) positive for PTC, tall cell variant. Total thyroidectomy with central compartment dissection was performed. Pathology report presented a main tumoral mass of 3 cm but permeating multinodular pattern involving the entire gland with focal extrathyroidal extension, positive margins and six level VI positive lymph nodes. As per report, the tumor presented both papillary and follicular patterns of growth and other findings including oncocytic change, foci of clear cell change, low mitotic rate, and most notably "reverse polarization”. This pattern has the pathological features suggestive of the novel NTRK gene fusion mutation. The patient was treated with radioactive iodine (RAI) and one year post treatment there was evidence of elevated Thyroglobulin level at 904 ng/mLand thyroglobulin Ab at 2.48 IU/mL. A WBS +SPECT was done resulting in small uptake at left posterior thyroid bed and pulmonary intake. A chest CT revealed multiple bilateral sub centimeter nodules. Based on this result, a second course of RAI was given. Follow up neck ultrasound and chest CT presented persistent left level VI lymph nodes, increased amount of bilateral sub-centimeter pulmonary nodules and new thoracic(T11) lesion. FNA of left neck lymph nodes were positive for metastatic PTC for which left neck dissection was performed. Evaluation for actionable somatic mutations was requested based on resistance behavior, remarkable for TRIM33-NTRK1 chromosomal rearrangement. Patient was evaluated by Oncology service who started Larotrectinib treatment since it was approved for NTRK driven malignancies. Six-month post therapy patient achieved clinical and biochemical improvement. In the thyroid, NTRK-driven malignancies are rare and aggressive but treatable, in the evolving genomic era. As reviewed in the literature, NTRK fusion-positive TC exhibits distinctive clinicopathological features that could aid in identifying potential patients. Thus, in such patients who have PTC with non-classic pathologic patterns, specific molecular profile of the main tumor may have significant prognostic value that must be integrated into stratification system in order to provide target therapy on time. Presentation: 6/3/2024

Prognostic factors of papillary and follicular carcinomas based on pre-, intra-, and post-operative findings.

Papillary and follicular thyroid carcinomas (PTC and FTC) are prominent malignancies that originate from thyroid follicular cells. PTC is usually diagnosed via preoperative cytology, and large tumor size, clinical node metastasis, and distant metastasis constitute preoperative prognostic factors. Gross extrathyroidal and extranodal tumor extensions have a significant prognostic impact, are evaluated intraoperatively, and are useful for determining the extent of surgery. Aggressive variants, such as tall cell and hobnail variants, a high Ki-67 labeling index (LI), and somatic gene mutations are prognostic factors in postoperative pathological and molecular examinations. In contrast, FTC is generally diagnosed based on postoperative pathology. Large tumor size and M factors have prognostic value; however, the findings of pathological examinations are very important. FTCs are classified as minimally invasive, encapsulated angioinvasive, and widely invasive FTCs. Widely invasive FTC with vascular invasion (VI) and encapsulated angioinvasive FTCs with extensive VI have a poor prognosis, whereas widely invasive FTC without VI has an excellent prognosis, which is similar to that of minimally invasive FTC. This indicates that VI is a considerably more important prognostic marker than capsular invasion. For postoperative follow-up, dynamic markers such as the thyroglobulin-doubling rate (DR), metastatic tumor volume-DR, and change in the neutrophil-to-lymphocyte ratio are important and are useful for evaluating the effectiveness of treatments, such as radioactive iodine therapy and molecular targeted therapy, for recurrent lesions. For clinicians, it is important to accurately evaluate prognostic markers of PTC and FTC in the pre-, intra-operative, and post-operative phases.