Positive Papillary Thyroid Carcinoma Research Articles

Thyroglobulin Antibodies and Tumor Epitope-Specific Cellular Immunity in Papillary Thyroid Cancer.

Papillary thyroid carcinoma (PTC) is characterized by T cell infiltration and frequently by the presence of anti-thyroglobulin antibodies (TgAbs). The role of cellular immunity and of TbAbs in this context is a matter of debate. The aim of our study was to correlate the presence of TgAbs, tumor epitope-specific T cells and the clinical outcome of PTC patients. We studied n=183 consecutive patients with a diagnosis of PTC which were treated with total thyroidectomy plus 131I ablation. During a follow-up of in mean 97 months, most of the PTC patients had no signs of tumor relapse (n=157 patients). In contrast, one patient had serum Tg levels above the detection limit and<1 ng/ml, two patients Tg serum levels≥1 ng/ml and<2 ng/ml and n=23 patients had Tg serum levels≥2 ng/ml. Morphological signs of tumor recurrence were seen in 14 patients; all of these patients had serum Tg levels≥2 ng/ml. Importantly, with the exception of one patient, all TgAb positive PTC patients (n=27) had no signs of tumor recurrence as the serum Tg levels were below the assays functional sensitivities. Tetramer analyses revealed a higher number of tumor epitope-specific CD8+T cells in TgAb positive patients compared to TgAb negative PTC patients. In summary, we show that the occurrence of TgAbs may have an impact on the clinical outcome in PTC patients. This might be due to a tumor epitope-specific cellular immunity in PTC patients.

Larotrectinib Before Initial Radioactive Iodine Therapy in Pediatric TRK Fusion-Positive Papillary Thyroid Carcinoma: Time to Reconsider the Treatment Paradigm for Distantly Metastatic Disease?

Larotrectinib Before Initial Radioactive Iodine Therapy in Pediatric TRK Fusion-Positive Papillary Thyroid Carcinoma: Time to Reconsider the Treatment Paradigm for Distantly Metastatic Disease?

Is Completion Thyroidectomy Necessary in Patients with Papillary Thyroid Carcinoma who Underwent Lobectomy?

Background/Objectives: Although thyroid lobectomy recently is considered as sufficient for low-risk papillary thyroid carcinoma (PTC), completion thyroidectomy is required due to the insufficiency of the preoperative evaluation. The aim of this study was to investigate recurrence rate and disease free survival depending on the gross extrathyroidal extension (gETE) or the number of metastatic lymph node identified in patients with PTC.Materials &amp; Methods: We assessed 3373 patients with PTC who underwent lobectomy at Seoul St. Mary’s Hospital (Seoul, Korea) between January 2009 and December 2014. Clinicopathological characteristics and long-term surgical outcomes were retrospectively analyzed through complete chart reviews. The mean follow-up duration was 97.1 ± 21.4 months.Results: The rate of recurrence was higher in gETE group (1.8% vs. 6.0%, p=0.004), leading to decreased disease free survival in Kaplan-Meier analysis (log-rank p&lt;0.001). N1 group (n=1389) was analyzed into two groups whether the number of positive nodes is more than 5 or less. For the group of the more metastatic nodes, the recurrence rate higher compared to the other group (3.0% vs. 9.3%, p&lt;0.001). DFS was longer in the group that had lesser metastatic nodes (log-rank p&lt;0.001). However, in terms of N1 group over 1cm (n=492), No statistical difference was observed according to the number of positive lymph nodes (4.5% vs. 9.1%, p=0.092)Conclusion: When it comes to node positive PTC, Despite the number of positive lymph nodes was over 5, follow-up with no further surgery can be an option.

NTRK-rearranged papillary thyroid carcinoma demonstrates frequent subtle nuclear features and indeterminate cytologic diagnoses.

The studies on the cytomorphologic features of NTRK-rearranged papillary thyroid carcinoma (PTC) are limited and some reported characteristics, such as frequent indeterminate diagnoses and presence of fibrotic fragments, are inconsistent in literature. NTRK gene rearrangements were detected in thyroidectomy specimens of PTC by either fluorescence in situ hybridization or next-generation sequencing. All the cytologic slides of NTRK-rearranged PTC were reviewed to evaluate the cytomorphologic features. The preoperative cytologic diagnoses of NTRK-rearranged PTC were compared with those of NTRK/BRAF wild-type and BRAFV600E -positive PTC. Fourteen PTC cases were identified to harbor NTRK gene rearrangements. Most of them showed a mixed architectural pattern of cell fragments (n = 13, 92.9%) and microfollicles (n = 9, 64.3%) with relatively rare papillary structures (n = 4, 28.6%). Nuclear grooving was frequently present (n = 11, 78.6%) but was mostly subtle and limited. Seven cases (50.0%) showed rounded nuclei without discernible nuclear elongation, and only 3 (21.4%) cases presented with nuclear pseudoinclusions. Among these cases, 7 (50.0%) were diagnosed as The Bethesda System for Reporting Thyroid Cytopathology (TBS) category III, 2 (14.3%) were diagnosed as TBS IV, and 5 (35.7%) were diagnosed as TBS V. The rate of TBS III-IV diagnoses for NTRK-rearranged PTCs was significantly higher (64.3%) than that for the 25 consecutive NTRK/BRAF wild-type PTCs (20.0%, P = .013) and the 70 consecutive BRAFV600E -positive PTCs (7.1%, P < .001) as selected. NTRK-rearranged PTC demonstrated intermediate nuclear features, such as subtle nuclear grooving, infrequent nuclear elongation, and rare pseudoinclusions, resulting in a significantly higher rate of TBS III-IV diagnoses compared to PTC with other molecular alterations.

Snail-1 Overexpression Correlates with Metastatic Phenotype in BRAFV600E Positive Papillary Thyroid Carcinoma.

The ability of cancer to metastasize is regulated by various signaling pathways, including transforming growth factor β (TGFβ), also implicated in the upregulation of Snail-1 transcription factor in malignant neoplasms. B-type Raf kinase gene (BRAF)V600E, the most common driving mutation in papillary thyroid carcinoma (PTC), induces epithelial to mesenchymal transition (EMT) in thyroid cancer cells through changes in the Snail-1 level, increasing cell migration and invasion. However, little is known about the mechanism of Snail-1 and BRAFV600E relations in humans. Our study included 61 PTC patients with evaluated BRAFV600E mutation status. A total of 18 of those patients had lymph node metastases—of whom 10 were BRAFV600E positive, and 8 negative. Our findings indicate that the expression of Snail-1, but not TGFβ1, correlates with the metastatic phenotype in PTC. This is the first piece of evidence that the upregulation of Snail-1 corresponds with the presence of BRAFV600E mutation and increased expression of Snail-1 in metastatic PTC samples is dependent on BRAFV600E mutation status.

Elevated BANCR expression levels have different effects on papillary thyroid carcinoma progression depending on the presence of the BRAFV600E mutation

IntroductionThe role of BRAF-activated non-protein coding RNA (BANCR) in papillary thyroid carcinoma (PTC) is controversial, its clinical significance is unclear and no study has correlated the presence of the BRAFV600E mutation in PTC with BANCR expression. MethodsBANCR levels in PTC and matched nonmalignant thyroid epithelial tissues from 85 patients were determined using quantitative RT-PCR. BRAFV600E was detected by mutant allele-specific PCR amplification. The results were correlated with clinicopathological characteristics of the patients. ResultsThe presence of BRAFV600E associates with lower relative BANCR expression (RBE) in PTC (p = 0.008). RBE is down-regulated in BRAFV600E positive PTC, while it is unchanged or up-regulated in BRAFV600E negative PTC compared to the levels in paired nonmalignant tissue (p = 0.001). At the cut-off of 31.3%, sensitivity of fold change of BANCR for the presence of BRAFV600E is 68.0% and specificity is 67.2%. In BRAFV600E positive PTC up-regulated BANCR predicts lymph node metastasis (p = 0.001), while in BRAFV600E negative PTCs high RBE predicts thyroid capsule invasion (p = 0.028). ConclusionsDepending on the presence of BRAFV600E, elevated BANCR levels demonstrated different effects on lymphatic spreading and local PTC invasion. Therefore, BANCR could be a useful prognostic biomarker in risk stratification of PTC patients.

Utility of Activated Carbon Nanoparticle (CNP) During total Thyroidectomy for Clinically Nodal Positive Papillary Thyroid Carcinoma (PTC).

Activated carbon nanoparticle (CNP) is a novel tracer that may facilitate nodal dissection in clinically nodal positive (cN1) papillary thyroid carcinoma (PTC). The present study compared the nodal yield and surgical outcomes between surgery with CNP and without CNP. Patients who underwent total thyroidectomy with therapeutic nodal dissection for cN1 PTC were given the option of intraoperative CNP injection. Among those who received CNP, 0.2mL CNP suspension was injected in both thyroid lobes before dissection. Study endpoints included number of total and metastatic lymph nodes, inadvertently removed parathyroid glands (PGs), postoperative parathyroid hormone, calcium, and post-6-month thyroglobulin (Tg). Biochemical complete response (BCR) was defined as Tg ≤ 1ng/mL and/or stimulated Tg ≤ 2ng/mL. One-hundred and twenty patients (58.3%) received CNP, while 86 (41.7%) had surgery without CNP. Demographics, tumor characteristics, and operative time were comparable between the two groups. However, total mean number of normal and metastatic lymph nodes retrieved were significantly greater in CNP group (10.0 vs. 8.1, p = 0.032 and 4.5 vs. 2.7, p = 0.002, respectively). Rate of inadvertently removed PG was significantly less in CNP group (13.3% vs. 23.3%, p = 0.042). Postoperative Tg level and BCR were significantly lower in CNP group (9.9ng/mL vs. 14.7ng/mL, p = 0.297 and 82.4% vs. 72.9%, p = 0.002, respectively). However, large-sized ( ≥ 3cm) PTCs had a significantly lower nodal staining rate than smaller-sized PTCs (10.3% vs. 69.4%, p < 0.001). CNP injection can facilitate therapeutic central nodal dissection by increasing the nodal yield rates and reducing inadvertent PG removal. To enhance its utility, a greater volume of CNP might be necessary in larger-sized (> 3cm) PTCs.

Simultaneous Hodgkin lymphoma and BRAF V600E -positive papillary thyroid carcinoma

Rationale:Papillary thyroid carcinoma (PTC) is the most common endocrine malignancy. However, the simultaneous occurrence of PTC and Hodgkin Lymphoma (HL) was rarely reported.Patient concerns:We present a case of simultaneous BRAFV600E-positive PTC and HL in a 17-year-old female.Diagnosis:She was referred to our clinic with a painless lump in her left neck. A highly suspicious thyroid nodule and multiple enlarged lymph nodes in the neck were found by ultrasonography examination. The suspicious nodule was diagnosed as PTC by fine needle aspiration cytology.Interventions:A total thyroidectomy with bilateral lymph node dissection was performed and the microscopic examination revealed a 2-cm PTC with BRAFV600E mutation and HL (mixed cellularity) in the bilateral lymph nodes. PTC was postoperatively considered as T1bN0M0. Levothyroxine (125 μg/d) was administered to the patient for thyrotropin suppression therapy. Then the patient was referred to the Department of Hematology to receive 4 cycles of ABVD followed by 30 Gy involved-site radiotherapy and radioactive iodine (RAI) therapy for thyroid cancer.Outcomes:After two cycles of ABVD, multiple enlarged lymph nodes showed a significant response to the chemotherapy in the patient.Lessons:Simultaneous HL and BRAFV600E-positive PTC is extremely rare. Biopsy of the suspicious lymph nodes should be performed to confirm malignancy metastasizing from PTC or other lesions. Similarly, in HL patients with suspicious thyroid nodule, ultrasound-guided fine needle aspiration of thyroid nodule should be performed to exclude thyroid malignancy.

Presurgical Screening of Fine Needle Aspirates from Thyroid Nodules for BRAF Mutations: A Prospective Single Center Experience.

Objective:Analysis of BRAF V600E mutation in thyroid fine needle aspirates (FNA) is an important adjunct to cytology, particularly among FNA placed in the “indeterminate category.” However, such a prospective evaluation of FNA obtained from patients with thyroid nodules has been lacking from India.Material and Methods:FNA from 277 patients were prospectively evaluated for BRAF mutations by Sanger's sequencing. A subset of 30 samples was also analyzed by pyrosequencing using the PyroMark BRAF mutation kit.Results:Overall, 27.2% of FNA samples were positive for mutations including 19 (35.8%) of the 53 histologically confirmed papillary thyroid carcinoma (PTC), 2 of the 25 follicular variants of PTC, and 1 anaplastic thyroid carcinoma. Only 1 (2.7%) of the 37 samples in the atypia of undetermined significance/follicular lesion of unknown significance category was BRAF positive. The sensitivity of cytology improved marginally from 67.1% to 68.3% when evaluated with BRAF. Further, a comparison of the clinicopathological characteristics of BRAF positive and negative PTCs showed a significant association (P = 0.05) between lymph node metastasis and BRAF positivity.Conclusion:BRAF positivity was lower than that reported from East Asia with the test being useful in confirming malignancies among the suspicious of malignancy and malignant categories.

Programmed Death-Ligand 1 Expression and Its Correlation with Lymph Node Metastasis in Papillary Thyroid Carcinoma.

BackgroundThe immunotherapeutic role of programmed death-ligand 1 (PD-L1) in life expectancy in many cancers has been highlighted. However, data regarding PD-L1 expression in papillary thyroid carcinoma (PTC) are limited. In this study, we describe the PD-L1 and programmed cell death protein 1 (PD-1) expressions in PTC and analyze their correlation with lymph node (LN) metastasis.MethodsClinicopathological data were obtained from 116 patients with PTC who were treated in Gyeongsang National University Hospital, Jinju, Korea in 2009. Tissue microarray blocks were made using representative paraffin blocks of classical PTCs excluding follicular variants. Two pathologists graded the proportion and intensity of PD-L1 and PD-1 expression in both tumor and inflammatory cells. According to their proportions, positive PTC cells were scored as negative (0%), grade 1 (1%–50%), and grade 2 (51%–100%). Similarly, positive inflammatory cells were graded as negative (0%), grade 1 (1%–10%), and grade 2 (11%–20%). The intensity of each protein expression was simplified as positive or negative.ResultsA statistically significant correlation exists between the proportions of PD-1 and PD-L1 expression both in papillary carcinoma (p=.001) and peritumoral lymphoid cells in the thyroid (p<.001). In addition, the proportion of PD-L1 expression in PTC cells was closely related to metastatic LNs (p=.036).ConclusionsPD-L1 is a valuable predictive marker for LN metastasis in PTC. Immunomodulating therapies that inhibit PD-L1 might be an option for patients with LN metastasis.

EWSR1 rearrangement is a frequent event in papillary thyroid carcinoma and in carcinoma of the thyroid with Ewing family tumor elements (CEFTE).

Carcinomas of the thyroid with Ewing family tumor element (CEFTEs) are small-cell thyroid tumors with epithelial differentiation that disclose p63 expression and EWSR1-FLI1 rearrangement, carry a favorable prognosis and may co-exist with papillary thyroid carcinoma (PTC) foci. Two histogenetic hypotheses have been advanced regarding the origin of CEFTEs: arising in PTCs or in solid cell nests (SCN). A total of 3 CEFTEs, 54 PTCs, and 10 SCNs were reviewed, and fluorescence in situ hybridization (FISH) technique was performed in all cases to search for the presence of EWSR1 rearrangements. The three CEFTEs disclosed the EWSR1-FLI1 rearrangement both in the small cell and in the PTC component. Out of the 54 PTC cases, 28 (51.9%) were positive, 20 (37.0%) were negative, and 6 (11.1%) were inconclusive for EWSR1 rearrangement; in two of the positive PTC cases, the EWSR1-FLI1 rearrangement was detected. Classic PTC disclosed more often the EWSR1 rearrangement than other PTC variants (p=0.031). PTCs with EWSR1 rearrangement disclosed a lower percentage of nuclei with EWSR1 polysomy than those without EWSR1 rearrangement (p=0.001). Out of the 10 SCNs, 7 (70.0%) were negative and 3 (30.0%) were inconclusive for the EWSR1 rearrangement. Monosomic nuclei were more frequent (mean of 44.3%) in SCNs than in PTCs (p<0.001). The presence of the EWSR1-FLI1 rearrangement in PTC component of all studied CEFTEs and the existence of the EWSR1 rearrangement in some PTCs favor the origin of CEFTE from PTC. The high frequency of EWSR1 rearrangements in PTC may represent a new diagnostic marker of these tumors.

Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model.

BRAF(V600E) mutation exerts an essential oncogenic function in many tumors, including papillary thyroid carcinoma (PTC). Although BRAF(V600E) inhibitors are available, lack of response has been frequently observed. To study the mechanism underlying intrinsic resistance to the mutant BRAF(V600E) selective inhibitor vemurafenib, we established short-term primary cell cultures of human metastatic/recurrent BRAF(V600E)-PTC, intrathyroidal BRAF(V600E)-PTC, and normal thyroid (NT). We also generated an early intervention model of human BRAF(V600E)-PTC orthotopic mouse. We find that metastatic BRAF(V600E)-PTC cells elicit paracrine-signaling which trigger migration of pericytes, blood endothelial cells and lymphatic endothelial cells as compared to BRAF(WT)-PTC cells, and show a higher rate of invasion. We further show that vemurafenib therapy significantly suppresses these aberrant functions in non-metastatic BRAF(V600E)-PTC cells but lesser in metastatic BRAF(V600E)-PTC cells as compared to vehicle treatment. These results concur with similar folds of down-regulation of tumor microenvironment-associated pro-metastatic molecules, with no effects in BRAF(WT)-PTC and NT cells. Our early intervention preclinical trial shows that vemurafenib delays tumor growth in the orthotopic BRAF(WT/V600E)-PTC mice. Importantly, we identify high copy number gain of MCL1 (chromosome 1q) and loss of CDKN2A (P16, chromosome 9p) in metastatic BRAF(V600E)-PTC cells which are associated with resistance to vemurafenib treatment. Critically, we demonstrate that combined vemurafenib therapy with BCL2/MCL1 inhibitor increases metastatic BRAF(V600E)-PTC cell death and ameliorates response to vemurafenib treatment as compared to single agent treatment. In conclusion, short-term PTC and NT cultures offer a predictive model for evaluating therapeutic response in patients with PTC. Our PTC pre-clinical model suggests that combined targeted therapy might be an important therapeutic strategy for metastatic and refractory BRAF(V600E)-positive PTC.

Langerhans cell histiocytosis and Erdheim-Chester disease, both with cutaneous presentations, and papillary thyroid carcinoma all harboring the BRAF(V600E) mutation.

Langerhans cell histocytosis (LCH) and Erdheim-Chester disease are two rare histiocytic disorders. Their occurrence in the same patient is more infrequent, but has been described. We report a case of a 38-year-old woman who presented with a diagnosis of single system cutaneous LCH. Subsequently, she developed multiple papules on her extremities consistent with a non-LCH xanthogranuloma type lesion. BRAF(V600E) mutation immunostain, VE1 was positive in the skin lesion, which was confirmed by molecular polymerase chain reaction (PCR) studies, initiating a complete systemic workup for Erdheim-Chester disease. Systemic involvement was confirmed with bilateral sclerotic bone lesions and retroperitoneal and pelvic fibrosing disease. She was also found to have a BRAF(V600E) mutation positive papillary thyroid carcinoma. New suspicious cutaneous lesions presenting in patients with a history of LCH need to be biopsied. A BRAF(V600E) mutation in a non-LCH histiocytic lesion with a xanthogranuloma phenotype (CD163/CD68/CD14/fascin/Factor 13a) should prompt an Erdheim-Chester disease workup. This is a unique case of a woman with BRAF(V600E) mutation positive Erdheim-Chester disease and cutaneous LCH, while also being, to our knowledge, the first reported case in the English literature of it occurring in a patient with a BRAF(V600E) mutation positive papillary thyroid carcinoma.

Expression of BIM gene in papillary thyroid carcinoma and its association with the BRAFV600E mutation

To study the link between BRAFV600E status and the expression of BIM gene in papillary thyroid carcinoma(PTC) tissues and to analyze the association of these factors with clinicopathological characteristics. BRAFV600E status was determined by MASA-PCR, and qPCR was applied to detect the expression of BIM gene. Finally, the associations of these factors with clinicopathological characteristics were analysed. The rate of mutant BRAFV600E in PTC was 54.1%, and the expression of BIM gene was lowered in BRAFV600E positive PTC tissues. Additionally, there was significant association(P<0.05)between BRAFV600Epositiveness and raised TNM Staging(Ⅲ/Ⅳ), and lowered BIM expression was significantly associated(P<0.05)with the tumor size and raised TNM Staging(Ⅲ/Ⅳ). These findings may help us to know more about the mechanism of PTC and to develop new diagnostic biomarkers or prognostic indicators of PTC. Key words: Papillary thyroid carcinoma; BRAFV600E; BIM gene

BRAF V600E positive papillary thyroid carcinoma is associated with suspicious ultrasound features

BRAF V600E positive papillary thyroid carcinoma is associated with suspicious ultrasound features

Association of HLA-B*51:01 with Papillary Thyroid Carcinoma in the Chinese Han Population of the Shandong Coastal Areas

A lot of work has been done to study the association between human leukocyte antigen (HLA) and papillary thyroid carcinoma (PTC) in various populations. But the results of the currently available studies are not consistent. The aim of this study was to evaluate the association of HLA-A, -B, -C, -DRB1, and -DQB1 with PTC in the Chinese Han population of the coastal areas of Shandong Province with respect to age and sex. A total of 154 patients diagnosed with PTC were analyzed for HLA-A, -B, -C, -DRB1, and -DQB1 alleles by using a polymerase chain reaction sequence-based typing (PCR-SBT) method. Two hundred unrelated healthy individuals were typed as controls. Compared with the controls, the HLA-B*51:01 (8.8% vs. 4.5%, p=0.029, OR 2.039 [CI 1.101-3.775]) and HLA-C*07:06 (2.6% vs. 0.5%, p=0.024, OR 5.307 [CI 1.119-25.171]) allele frequencies were higher in the PTC patients, while the HLA-C*07:01 (1.3% vs. 6.0%, p=0.001, OR 0.206 [CI 0.071-0.601]) allele frequency was lower in the PTC patients that did not persist after Bonferroni correction for multiple tests. This showed no statistically significant correlation of the HLA-A, -DRB1, and -DQB1 alleles and PTC. The incidence of PTC was more frequent in females between 30 and 60 years old. There were no significant differences in the age and sex distributions between the total and the HLA-B*51:01 positive PTC patients. The HLA associations in this Chinese Han population differ markedly from studies done in Europeans and Caucasians. The results reveal that HLA-B*51:01 is more likely to be a susceptible allele for PTC in addition to age and sex in the coastal areas of Shandong Province.

Clinical significance of the BRAFV600E mutation in multifocal papillary thyroid carcinoma in Korea

We examined the frequency of the BRAF(V600E) mutation and compared the clinicopathologic features based on the BRAF(V600E) mutation status in multifocal papillary thyroid carcinoma (PTC). A total 85 patients who were diagnosed with multifocal PTC were enrolled. We confirmed the status of the BRAF(V600E) mutation in each tumor focus by the real-time polymerase chain reaction technique. Among the 85 patients, 49 (57.6%), 34 (40.0%), and 2 (2.4%) patients were determined to have all BRAF(V600E)-positive, mixed BRAF(V600E), and all BRAF(V600E)-negative in their tumor foci, respectively. When we compared clinicopathologic features according to the BRAF(V600E) mutation status of the dominant tumor, the BRAF(V600E) -positive group (n = 70) showed more extrathyroidal invasion in the dominant tumor (32.9% vs 6.7%, P = .041) and more lymph node metastasis (67.2% vs 40.0%, P = .049) than the BRAF(V600E) -negative group (n = 15). Considering all tumor foci, the all BRAF(V600E) mutation group exhibited a younger population (P = .039), showed increased extrathyroidal invasion (38.8% vs 14.7%, P = .017) and lymph node metastasis (71.4% vs 48.4%, P = .038), and received more radioactive iodine therapy (79.2% vs 52.9%, P = .012) than the mixed BRAF(V600E) mutation group. A larger tumor size and heavier preoperative body weight was positively correlated with the relative expression of BRAF(V600E) mutation calculated by 2(-△△Ct) method. Most of the Korean patients with multifocal PTC had the BRAF(V600E) mutation in one or more tumor foci, and all BRAF(V600E)-positive multifocal PTC showed more aggressive features.

BRAF mutation positive papillary thyroid carcinoma is less advanced when Hashimoto's thyroiditis lymphocytic infiltration is present

Concomitant papillary thyroid cancer (PTC) and Hashimoto's thyroiditis (HT) is a frequent occurrence. Whether these two conditions are linked and whether PTC with concurrent HT has distinct clinicopathological characteristics are still debated issues. Lymphocytic infiltration is abundant in HT and might be relevant in the pathogenesis and progression of PTC. BRAF(V600E) mutation is associated with a more advanced PTC at diagnosis; however, its role in the clinicopathological characteristics of PTC with concurrent HT is unknown. We enrolled 146 patients with histological diagnosis of PTC. Microscopic assessment of histology samples was performed to identify the presence of lymphocytic infiltration. Detection of BRAF(V600E) was performed on cytology samples by both direct sequencing and pyrosequencing, and results were correlated with clinical parameters. Concurrent HT lymphocytic infiltration was associated with the female gender, smaller tumour size, a less frequent extracapsular extension and a lower grade of TNM staging. BRAF(V600E) was more frequent in PTC with concomitant lymphocytic infiltration. In PTC harbouring BRAF(V600E) , concurrent lymphocytic infiltration was still associated with the female gender, a less frequent extracapsular extension and a lower TNM staging. These results suggest that lymphocytic infiltration of HT is a protective factor against PTC progression, and it is independent of BRAF mutational status.

An Ep-ICD Based Index Is a Marker of Aggressiveness and Poor Prognosis in Thyroid Carcinoma

BackgroundNuclear accumulation of the intracellular domain of epithelial cell adhesion molecule (Ep-ICD) in tumor cells was demonstrated to predict poor prognosis in thyroid carcinoma patients in our earlier study. Here, we investigated the clinical significance of Ep-ICD subcellular localization index (ESLI) in distinguishing aggressive papillary thyroid carcinoma (PTC) from non-aggressive cases.MethodsUsing domain specific antibodies against the intracellular (Ep-ICD) and extracellular (EpEx) domains of epithelial cell adhesion molecule, 200 archived tissues from a new cohort of patients with benign thyroid disease as well as malignant aggressive and non aggressive PTC were analyzed by immunohistochemistry (IHC). ESLI was defined as sum of the IHC scores for accumulation of nuclear and cytoplasmic Ep-ICD and loss of membranous EpEx; ESLI = [Ep-ICDnuc + Ep-ICDcyt + loss of membranous EpEx].ResultsFor the benign thyroid tissues, non-aggressive PTC and aggressive PTC, the mean ESLI scores were 4.5, 6.7 and 11 respectively. Immunofluorescence double staining confirmed increased nuclear Ep-ICD accumulation and decreased membrane EpEx expression in aggressive PTC. Receiver-operating characteristic (ROC) curve analysis showed an area under the curve (AUC) of 0.841, 70.2% sensitivity and 83.9% specificity for nuclear Ep-ICD for differentiating aggressive PTC from non-aggressive PTC. ESLI distinguished aggressive PTC from non-aggressive cases with improved AUC of 0.924, 88.4% sensitivity and 85.5% specificity. Our study confirms nuclear accumulation of Ep-ICD and loss of membranous EpEx occurs in aggressive PTC underscoring the potential of Ep-ICD and ESLI to serve as diagnostic markers for aggressive PTC. Kaplan Meier survival analysis revealed significantly reduced disease free survival (DFS) for ESLI positive (cutoff >10) PTC (p<0.05), mean DFS = 133 months as compared to 210 months for patients who did not show positive ESLI.ConclusionESLI scoring improves the identification of aggressive PTC and thereby may serve as a useful index for defining aggressiveness and poor prognosis among PTC patients.

The prognostic significance of the V600E B-Raf mutation in papillary thyroid carcinoma: data from an Australian population

Aims B-Raf V600E mutation in the thyroid is a specific marker of papillary thyroid carcinoma (PTC) and correlates with poorer survival and rates of recurrence. 1 , 2 We assessed the prevalence of this mutation in a series of PTCs from an Australian population, its association with aggressive clinicopathological features, recurrence and mortality. Methods 82 patients with a median follow up of 6 years were studied. V600E mutation status was determined by PCR on DNA extracted from paraffin blocks. Clinicopathological parameters, recurrence and mortality were analysed according to V600E mutation status. Results The V600E mutation was demonstrated in 44 of 82 (54%) tumours. Up to 58% of patients with V600E positive PTCs suffered a recurrence compared to 12% of patients with V600E negative PTCs ( p =0.005). Up to 15% of patients with V600E positive PTCs died during the follow-up period compared to 5% of patients without the mutation ( p =0.19). The V600E mutation was associated with male sex ( p =0.0002) and the classic subtype ( p =0.005). Discussion The prevalence of B-Raf V600E mutation in PTCs in this study is similar to other series. We confirmed that this mutation was associated with a poorer prognosis, specifically higher rates of recurrence.