Cases Of Anaplastic Thyroid Carcinoma Research Articles

The frequency of mutations in advanced thyroid cancer in Japan: a single-center study.

We analyzed the outcomes of genetic testing to study the frequency of mutations in advanced thyroid cancer in Japan. Patients (n = 96) with unresectable or metastatic thyroid carcinoma were included for retrospective chart review. Results of gene panel testing, which was performed between May 2020 and April 2023, were analyzed. The median age of the patients was 73.5 years (range, 17-88); 59 were women, and 39 were men. Overall, 17 patients had anaplastic thyroid carcinoma (ATC), 68 had papillary thyroid carcinoma (PTC), 7 had follicular thyroid carcinoma, and 6 had poorly differentiated thyroid carcinoma (PDTC). Of the 81 patients with differentiated thyroid carcinoma (DTC) and PDTC, 88.9% were radioactive iodine-refractory, and 32.7% of all cases had previously been treated with multiple kinase inhibitors. Of ATC cases, 52.9% had BRAF mutations, and 5.9% had RET fusion. Of PTC cases, 83.1% had BRAF mutations, 9.2% had RET fusion, and 1.5% had NTRK fusion. One case each of ATC and PTC had a tumor mutation burden of ≥10. ATC cases had a significantly higher prevalence of TP53 alterations than the other cases (82.3% vs. 11.8%), whereas the frequencies of TERT promoter mutations were 88.2% in ATC cases and 64.7% in the other cases, albeit without a significant difference. In conclusion, 58.8% of ATC, 93.8% of PTC, and 42.9% of PDTC had genetic alterations linked to therapeutic agents. Active gene panel testing is required to increase treatment options.

THU510 The Frequency Of Mutations In Advanced Thyroid Cancer In Japan: A Real Clinical Setting

Abstract Disclosure: S. Toda: None. A. Takahashi: None. K. Masudo: None. H. Iwasaki: None. Background: Thyroid cancer has a high incidence of actionable genetic alterations, but the frequency of mutations in advanced thyroid cancer that requires drug therapy is unknown. Therefore, we examined the outcomes of genetic testing performed in a real clinical setting for the purpose of pharmacotherapy. Methods: In Japan, Oncomine Dx is approved for thyroid cancer that requires drug therapy, and comprehensive genomic profiling is approved for anaplastic thyroid carcinoma and other thyroid carcinomas after the induction of tyrosine kinase inhibitors. We retrospectively reviewed the cases of those who had their tests performed between 2020 and 2022. Results: The study included 65 patients, and the testing methods used were Oncomine Dx in 36 cases, FoundationOne in 25 cases, and FoundationOne Liquid in 4 cases. With a median age of 74 years (range 17–86), 42 were female and 23 were male. Moreover, 13 cases had anaplastic thyroid carcinoma (ATC), 4 follicular thyroid carcinoma (FTC), 42 papillary thyroid carcinoma (PTC), and 6 poorly differentiated thyroid carcinoma (PDTC). Of the PTC examined by Oncomine Dx, 96.8% (30/31) were RAI-refractory; all comprehensive genomic profiling testing cases except ATC had previously been treated with tyrosine kinase inhibitors. In the following cases, actionable mutations were observed. Among 13 ATC cases, 46.2% (6) had BRAF mutation and 7.7% (1) had RET fusion. Of 42 PTC cases, 85.7% (36) had BRAF mutation and 7.1% (3) had RET fusion. Of 6 PDTC cases, 33.3% (2) had BRAF mutation and 16.7% (1) had RET fusion. No actionable mutations were observed in FTC (0/4). We found one case each of ATC and PTC with tumor mutation burden of 10 or higher, both with BRAF mutation. NTRK fusion was not observed in any of the 65 patients studied. There were four PTC cases (9.5%) with iodine accumulation in metastases, two with BRAF mutations, one with RET fusion, and one without detectable mutations. Comparing mutations in ATC and non-ATC, TERT promoter mutations were found in 84.6% of ATC (11/13) vs. 56.2% of non-ATC (9/16), whereas TP53 mutations were found in 76.9% of ATC (10/13) vs. 12.5% of non-ATC (2/16). ATC has a significantly higher prevalence of TP53 mutations. Conclusion: Advanced thyroid cancer is more likely to have actionable mutations. BRAF mutations in advanced PTC may be more common than those previously reported in standard PTC. Moreover, ATC has a higher rate of TP53 mutation than other thyroid carcinomas. Presentation: Thursday, June 15, 2023

Four cases of anaplastic thyroid carcinoma

Four cases of anaplastic thyroid carcinoma

PD-L1 expression in rare and aggressive thyroid cancers: A preliminary investigation for a role of immunotherapy.

Programmed cell death ligand-1 (PD-L1) immunoexpression status determines the response to immunotherapy in many cancers. Limited data exist on PD-L1 status in aggressive thyroid tumors. We investigated PD-L1 expression across thyroid cancers and correlated it with their molecular profile. Sixty-five cases of differentiated thyroid carcinoma, poorly differentiated thyroid carcinoma (PDTC), and anaplastic thyroid carcinoma (ATC) were assessed for PD-L1 expression (clone SP263, VENTANA). The differentiated cases encompassed the aggressive hobnail and tall cell subtypes of papillary thyroid carcinoma (PTC) besides classical PTC and follicular thyroid carcinoma (FTC). Ten nodular goiters (NG) were also evaluated. Tumor proportion score (TPS) and H-score were calculated. BRAFV600E and H-/K-/N-RAS were assessed using allele-specific real-time polymerase chain reaction (PCR). Fisher's exact and Kruskal-Wallis tests were used to investigate the associations between the categorical variables and compare PD-L1 scores with the mutation status. Most PTC (87%) and ATC (73%) cases were PD-L1 positive (TPS ≥1%), with significantly higher positivity rates than NG (20%). TPS >50% was seen in 60% ATC and 7% PTC cases. The median TPS and H-score of ATC were 56 (0-96.6) and 168 (0-275), respectively, and of PTC were 9.6 (4-16.8) and 17.8 (6.6-38.6), respectively. The scores were similar across the PTC subtypes. Only one case each of FTC and PDTC was PD-L1 positive. PD-L1 expression correlated significantly with BRAFV600E, but not with RAS mutation. ATC showed intense and diffuse PD-L1 staining. Although most PTCs were PD-L1 positive, the expression was weaker and patchy, irrespective of the histological subtype. Results of this pilot study indicate that ATC is most likely to respond to immunotherapy. PTC, FTC, and PDTC may be less amenable to immunotherapy. PD-L1 expression correlated significantly with BRAFV600E, allowing for combined targeted therapy.

Anaplastic Transformation of Differentiated Thyroid Carcinoma.

Anaplastic thyroid carcinoma (ATC) is a rare but highly aggressive form of thyroid cancer. Increasingly, patients with ATC present with concurrent foci of well-differentiated thyroid carcinoma (WDTC); however, the significance of these pathologic findings remains unclear. The objective of this study is to determine whether the presence of WDTC within anaplastic tumors is a prognosticator of survival. A retrospective cohort study of all cases of biopsy-proven ATC managed at a tertiary care academic medical center from 2002 to 2020 was performed. Mean age at diagnosis, median survival time, and locations of distant metastases were assessed. The impact of clinical markers such as presence of differentiation, demographic variables, and oncologic information on overall survival was also determined via univariate and multivariate analysis. Forty-five patients were included in this study. The mean age at diagnosis was 69.1 years. Median survival time was 6.1 months after diagnosis. The most common location of distant metastases was the lung (40%). The presence of limited areas of WDTC in patients with predominantly anaplastic thyroid tumors was not significantly associated with improved outcomes (p= 0.509). Smaller tumor size and use of chemotherapy in ATC patients were significantly associated with prolonged survival (p= 0.026 and 0.010, respectively). Clinical outcomes for ATC remain poor. The presence of foci of differentiation within anaplastic thyroid tumors does not appear to improve overall survival-the anaplastic component evidently drives outcomes. Further studies into novel therapies are needed to improve survival in ATC. 4 Laryngoscope, 133:437-442, 2023.

Role of Suprabasin in the Dedifferentiation of Follicular Epithelial Cell-Derived Thyroid Cancer and Identification of Related Immune Markers.

Background: Aberrant regulation of suprabasin (SBSN) is associated with the development of cancer and immune disorders. SBSN influences tumor cell migration, proliferation, angiogenesis, and immune resistance. In this study, we investigated the potential correlation between SBSN expression and immune infiltration in thyroid cancer. Methods: The expression of SBSN in 80 papillary thyroid carcinoma (PTC) specimens was determined using quantitative reverse-transcription polymerase chain reaction, western blotting, and immunohistochemical staining. The expression of SBSN in 9 cases of poorly differentiated thyroid carcinoma (PDTC) and 18 cases of anaplastic thyroid carcinoma (ATC) was evaluated by immunohistochemical staining. Comprehensive bioinformatics analysis of SBSN expression was performed using The Cancer Genome Atlas and Gene Expression Omnibus datasets, and the relationship of SBSN expression with M2 macrophages and T regulatory cells (Tregs) in ATC and PTC was verified by immunohistochemical staining. Results: Compared with those in adjacent normal tissues, the expression levels of SBSN mRNA and protein were significantly higher in PTC tissues. SBSN expression level was correlated with that of cervical lymph node metastasis in PTC patients. Immunohistochemical staining results showed statistically significant differences among high-positive expression rates of SBSN in PTC, PDTC, and ATC. Functional enrichment analysis showed that SBSN expression was associated with pathways related to cancer, cell signaling, and immune response. Furthermore, analysis of the tumor microenvironment (using CIBERSORT-ABS and xCell algorithms) showed that SBSN expression affected immune cell infiltration and the cancer immunity cycle, and immunohistochemistry confirmed a significant increase in M2 macrophage and Treg infiltration in tumor tissues with high-positive SBSN expression. Conclusion: These findings reveal that SBSN may be involved in thyroid carcinogenesis, tumor dedifferentiation progression, and immunosuppression as an important regulator of tumor immune cell infiltration.

PD-L1 expression and immune cells in anaplastic carcinoma and poorly differentiated carcinoma of the human thyroid gland: A retrospective study.

Anaplastic thyroid carcinoma (ATC) and poorly differentiated thyroid carcinoma (PDTC) have limited treatment options, and immune profiling may help select patients for immunotherapy. The prevalence and relevance of programmed death-1 ligand (PD-L1) expression and the presence of immune cells in ATC and PDTC has not yet been well established. The present study investigated PD-L1 expression (clone 22C3) and cells in the tumor microenvironment (TME), including tumor-infiltrating lymphocytes (TILs), tumor-associated macrophages (TAMs) and dendritic cells, in whole tissue sections of 15 cases of ATC and 13 cases of PDTC. Immunohistochemical PD-L1 expression using a tumor proportion score (TPS) with a 1% cut-off was detected in 9/15 (60%) of ATC cases and 1/13 (7.7%) of PDTC cases (P=0.006). PD-L1 expression in TILs was limited to the ATC group (73.3 vs. 0% in ATC and PDTC, respectively). In the ATC group, the TPS for tumor positive PD-L1 expression revealed a non-significant trend towards worse survival, but no difference was observed when investigating PD-L1 expression in TILs and TAMs. In addition to increased PD-L1 expression, all ATC cases exhibited significantly increased CD3+ and CD8+ T cells, CD68+ and CD163+ macrophages, and S100+ dendritic cells compared with the PDTC cases. Loss of mutL homolog 1 and PMS1 homolog 2 expression was observed in one ATC case with the highest PD-L1 expression, as well as in the only PDTC case positive for PD-L1. Notably, the latter was the only PDTC case exhibiting positivity for p53 and a cellular microenvironment similar to ATC. The current results indicated that PD-L1 expression was frequent in ATC, but rare in PDTC. In addition to PD-L1, the present study suggested that microsatellite instability may serve a role in both the TME and the identification of immunotherapy candidates among patients with PDTC.

Gene expression profiling of anaplastic thyroid carcinoma and coexisting differentiated thyroid carcinoma using the NanoString nCounter system.

e18049 Background: Anaplastic thyroid carcinoma (ATC) is one of the worst prognostic malignancies with a 1-year survival rate of 5-20%. ATC is thought to be originated from differentiated thyroid carcinoma (DTC) caused by undifferentiated transformation because ATCs frequently have preexisting or coexisting region of differentiated thyroid carcinoma (co-DTC), but the detailed mechanism is unclear. In this study, we analyzed mRNA expression among ATCs, DTCs and co-DTCs, and compared their molecular characteristics. Methods: Twelve patients with ATC and eight patients with DTC, who were diagnosed at Tsukuba University Hospital between 2009 to 2020, were included in this study. Of 12 ATCs, four cases had co-DTCs. Total RNA was extracted from formalin-fixed paraffin-embedded (FFPE) samples of ATCs, DTCs and co-DTCs. We analyzed mRNA expression profiles among three groups using nCounter PanCancer IO 360 Panel (NanoString Technologies) and nCounter Advanced Analysis (version 2.0.134). The p-values were adjusted using Benjamini-Hochberg method and adjusted p-value < 0.05 was considered as significant. Results: The 1-year survival rate of the 12 ATC cases in this study was 37.5%. Heatmap of pathway revealed that most ATCs showed up-regulation of almost all tumor-related pathways included in the panel except for autophagy while three of ATCs didn’t show immune-related pathways up-regulation, and one co-DTC sample showed similar behavior of pathways to ATCs. The top 10 up-regulated gene in co-DTCs compare to DTCs were BATF3, TDO2, PRF1, BIRC5, MKI67, ANLN, FCGR3A/B, PPARGC1B, C2 and PFKFB3, and gene set enrichment analysis revealed that the genes with differential expression were enriched in gene set of cell proliferation. The top 10 genes with differential expression in ATCs compare to co-DTCs were CXCL5, BRCA2, MMP1, CSCL6, CXCL1, DKK1 and CXCL8, for up-regulation and ID4, ARID1A and EPM2AIP1 for down-regulation. In ATCs, gene sets of cell proliferation, cytokine and chemokine signaling, and myeloid compartment were especially up-regulated. Immune cell profiling showed that ATC had abundant inflammatory cells, especially TILs, neutrophils and macrophages, while co-DTC showed intermediate characteristics between ATC and DTC. Of note, three case of ATCs had lower inflammatory cell scores than the other ATCs except for macrophages and neutrophils, and were clustered as “DTC-like”. Conclusions: These data revealed that co-DTCs showed up-regulation of cell proliferation related genes compare to DTCs, and some ATCs had different immune cell profiles. co-DTCs showed an intermediate immune cell profile between ATC and DTC. Biological profiling of ATCs, DTCs and co-DTCs may help to understand the developmental mechanism of ATCs. In this presentation, we will report the detailed results of mRNA expression analysis with discussion of the previous reports.

Histological features of BRAF V600E-mutant anaplastic thyroid carcinoma.

Treatment with a BRAF inhibitor, alone or in combination with a MEK inhibitor, may be considered for BRAF-mutant anaplastic thyroid carcinoma (ATC). The purpose of this study was to characterise the histology of BRAF V600E-mutant ATC. We identified 28 ATC that were consecutively resected between 2003 and 2019. All tumour slides for each case were evaluated for the presence of a precursor tumour and for ATC morphology (sarcomatoid, pleomorphic giant cell, epithelioid or squamous). BRAF V600E mutation status was determined by BRAF V600E IHC or molecular analysis (OncoPanel NGS). Eighteen (64%) ATC had an associated well-differentiated precursor, including 10 (36%) with associated papillary thyroid carcinoma (PTC) and eight (29%) with associated follicular thyroid carcinoma (FTC) or Hürthle cell carcinoma (HCC). Most ATC (19 cases, 68%) demonstrated a mixed anaplastic morphology. Squamous morphology was present in four cases. Ten (36%) ATC had a BRAF V600E mutation. All ATC that had a PTC precursor had a BRAF V600E mutation (and all ATC with a BRAF V600E mutation had a PTC precursor), whereas no ATC with an FTC or HCC precursor had a BRAF V600E mutation. All four cases of ATC with a squamous morphology had a PTC precursor and a BRAF V600E mutation. In our cohort, the presence of a PTC precursor predicted the presence of the BRAF V600E mutation, whereas ATC with an FTC or HCC precursor lacked a BRAF V600E mutation. A squamous morphology was associated with the presence of a PTC precursor and a BRAF V600E mutation.

Histopathologic Features and Clinical Outcome of Anaplastic Thyroid Carcinoma with a Minor Anaplastic Component.

Although prior studies have reported that patients with anaplastic thyroid carcinoma (ATC) with a focal anaplastic component may have a prolonged survival compared to other ATC patients, the outcome data are limited. We evaluated a cohort of ATC resected between 2003 and 2018. Tumor slides were reviewed to confirm the diagnosis and to identify cases with a minor ATC component (defined as comprising < 10% of the tumor). We evaluated the clinical outcome of these patients compared to that of all other cohort patients (characterized as having conventional ATC). Our cohort was composed of 24 cases of ATC that underwent resection, including 8 (33%) with a minor ATC component. Tumors with a minor ATC component were predominantly associated with papillary thyroid carcinoma. For patients with tumors with a minor ATC component, the 1-year and 2-year survival rates and median survival for patients who died of disease were 88%, 43%, and 17 months (range 6-73 months), respectively. In comparison, for patients with conventional ATC, the 1-year and 2-year survival rates and median survival for patients who died of disease were 56%, 44%, and 7 months (range 2-26 months), respectively. There was no difference in 1- and 2-year survival or overall survival by Kaplan-Meier analysis for patients with tumors with a minor ATC component and those with conventional ATC. In conclusion, the difference in overall survival between ATC groups in our cohort was not significant; however, this could be due to the small cohort size or due to characteristics of our group with a minor ATC component; that is, no tumors in this group were limited to the thyroid (stage IVA), resectability with negative margins was infrequent, and 38% of this group had distant metastases at diagnosis (stage IVC).

PAX8 expression in anaplastic thyroid carcinoma is less than those reported in early studies: a multi-institutional study of 182 cases using the monoclonal antibody MRQ-50.

Anaplastic thyroid carcinoma (ATC) is an aggressive malignant tumor composed of undifferentiated thyroid follicular cells. Pathological diagnosis of ATC can be challenging as the tumor may show morphological overlap with other neoplasms with anaplastic morphology. Immunohistochemical demonstration of thyroid origin facilitates the diagnosis of ATC. Previous studies using the polyclonal anti-PAX8 antibody 10336-1-AP suggested that PAX8 was the most sensitive marker, expressed in up to 80% of ATC. According to a 2018 NordiQC report, the monoclonal anti-PAX8 antibody MRQ-50 has become the most commonly used anti-PAX8 antibody worldwide. However, validation of this antibody in ATC is lacking. In this study, we recruited 182 ATC cases from seven institutions. Pathology slides were subjected to histology review. PAX8 immunohistochemistry using the MRQ-50 antibody was performed in whole tissue slides (n = 147) or tissue microarray sections (n = 35). We found PAX8 expression in 54.4% of the cases, which was significantly lower than those reported in prior studies with the polyclonal antibody. PAX8 expression was positively correlated with the presence of an epithelial pattern (63.6% vs 37.5%, p = 0.0008) and a coexisting differentiated thyroid carcinoma component (71.6% vs 44.3%, p = 0.0004), but was not associated with age, gender, specimen type, or presence of giant cell and sarcomatoid patterns. In conclusion, we demonstrated PAX8 expression using the monoclonal antibody MRQ-50 in only half of the cases in a large ATC series. Pathologists should be aware that PAX8 expression in ATC is less than those reported in early studies to avoid misdiagnosis.

Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing.

To characterise the mutational profiles of poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) and to identify markers with potential diagnostic, prognostic and therapeutic significance. Targeted next-generation sequencing with a panel of 18 thyroid carcinoma-related genes was performed on tissue samples from 41 PDTC and 25 ATC patients. Genetic alterations and their correlations with clinicopathological factors, including survival outcomes, were also analysed. Our results showed that ATC had significantly higher mutation rates of BRAF, TP53, TERT and PIK3CA than PDTC (P=0.005, P=0.007, P=0.005, and P=0.033, respectively). Nine (69%) ATC cases with papillary thyroid carcinoma (PTC) components harboured BRAF mutations, all of which coexisted with a late mutation event (TP53, TERT, or PIK3CA). Nine cases with oncogenic fusion (six RET cases, one NTRK1 case, one ALK case, and one PPARG case) were identified in 41 PDTCs, whereas only one case with oncogenic fusion (NTRK1) was found among 25 ATCs. Moreover, all six cases of RET fusion were found in PDTC with PTC components, accounting for 33%. In PDTC/ATC patients, concurrent TERT and PIK3CA mutations were associated with poor overall survival after adjustment for TNM stage (P=0.001). ATC with PTC components is typically characterised by a BRAF mutation with a late mutation event, whereas PDTC with PTC components is more closely correlated with RET fusion. TERT and concurrent PIK3CA mutations predict worse overall survival in PDTC/ATC patients.

Blockade of the programmed death ligand 1 (PD-L1) as potential therapy for anaplastic thyroid cancer.

Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive form of thyroid cancer (TC) characterized by an aggressive behavior and poor prognosis, resulting in patients' death within a year. Standard treatments, such as chemo and radiotherapy, as well as tyrosine kinase inhibitors, are ineffective for ATC treatment. Cancer immunotherapy is one of the most promising research area in oncology. The PD-1/PD-L1 axis is of particular interest, in light of promising data showing a restoration of host immunity against tumors, with the prospect of long-lasting remissions. In this study, we evaluated PD-L1 expression in a large series of TCs (20 cases) showing a progressive dedifferentiation of the thyroid tumor from well differentiated TC to ATC, employing two different antibodies [R&D Systems and VENTANA PD-L1 (SP263) Rabbit Monoclonal Primary Antibody]. We also tested the anti PD-L1 mAb in an in vivo animal model. We found that approximately 70-90% of ATC cases were positive for PD-L1 whereas normal thyroid and differentiated TC were negative. Moreover, all analyzed cases presented immunopositive staining in the endothelium of vessels within or in close proximity to the tumor, while normal thyroid vessels were negative. PD-L1 mAb was also effective in inhibiting ATC growth in an in vivo model. These data suggest that immunotherapy may be a promising treatment specific for ATC suggesting the need to start with clinical TRIALs.

Prognostic Factors of Anaplastic Thyroid Carcinoma: An Egyptian Single Institution Experience

Background: Anaplastic thyroid carcinoma is an extremely aggressive cancer that has a very poor outcome. We have analyzed predictive factors for overall survival and different therapeutic modalities that could help to determine the optimal therapy for this carcinoma.Methods: We performed a retrospective analysis of data from 54 cases of anaplastic thyroid carcinoma to evaluate demographic, pathological, and clinical characteristics, along with therapeutic modalities that affected survival. The Kaplan-Meier curve was used to visualize the cumulative probability of survival and comparison among/between groups was performed with the log-rank test. A multivariate Cox proportional hazards model was used to examine overall survival.Results: We observed overall survival percentages of 50% (one-year), 25% (2- year), and 5.6% (5-year). The 2-year overall survival was 41.7% for stage IVA, 31.5% for stage IVB, and 7.4% for stage IVC (P= 0.04). The 2-year overall survival rates were 59.3% for patients with negative margins, 30.1% for those with positive margins, and 0.0% in the group without thyroidectomy (P=0.005). Surgery plus postoperative radiotherapy indicated better 2-year overall survival (56%) compared to surgery alone (34.7%, Pone month, no reported metastasis at presentation, negative surgical margins, surgery, radiotherapy, and/or chemotherapy.Conclusion: Anaplastic thyroid carcinoma is an aggressive cancer with a very poor prognosis. Multimodality treatment may improve overall survival in these patients. Duration of symptoms, primary tumor size, distant metastases, surgical treatment, surgical margin status, radiotherapy, and chemotherapy are independent factors that affect prognosis.

Correlation of Reactive Oxygen Species Levels with Resveratrol Sensitivities of Anaplastic Thyroid Cancer Cells.

Anaplastic thyroid carcinoma (ATC) is the most lethal thyroid malignancy without a reliable therapeutic agent. Resveratrol possesses cancer-suppressive effects, while its effect(s) on ATC cells remains unknown. Because oxidative damage caused by increased reactive oxygen species (ROS) is one of the therapeutic effects of anticancer drugs and oxidative stress-caused mitochondria swelling is observed in resveratrol-treated cancer cells, the oxidative statuses and their relevance with resveratrol sensitivities are elucidated using THJ-16T and THJ-11T ATC cells established from two human anaplastic thyroid carcinoma cases. The results revealed that resveratrol-treated THJ-16T rather than THJ-11T cells showed remarkable growth arrest and extensive apoptosis accompanied with the elevated ROS generation and the attenuated superoxide dismutase 2 (SOD2) and catalase (CAT) levels. Mitochondrial impairment and the enhanced caspase-9/caspase-3 activation are found only in resveratrol-sensitive THJ-16T cells. Treatment with the antioxidant N-acetylcysteine (NAC) partly attenuated resveratrol-induced ROS generation and apoptosis of THJ-16T cells. The levels of resveratrol metabolic enzymes (SULT1A1 and SULT1C2) in THJ-16T cells were lower than those in THJ-11T cells and therefore reversely related with resveratrol sensitivities of ATC cells. Our findings demonstrate the ability of resveratrol to increase ROS generation and oxidative-related cellular lesions in resveratrol-sensitive THJ-16T cells presumably through activating the ROS-mitochondrial signal pathway. The levels of SULTs and ROS may reflect the response manners of ATC cells to resveratrol.

EZH2 Overexpression as a Useful Prognostic Marker for Aggressive Behaviour in Thyroid Cancer.

Enhancer of zeste homolog 2 (EZH2) is a member of the polycomb group of genes, which are key factors in the regulation of cell proliferation and differentiation. EZH2 is overexpressed in many malignancies. We analyzed EZH2 protein expression levels in different histological subtypes of thyroid cancer to examine its utility as a prognostic factor. We examined EZH2 protein expression by immunohistochemistry in tissue samples from 67 cases of poorly differentiated (PDTC) and 48 cases of anaplastic thyroid carcinoma (ATC), and in samples of adjacent normal and differentiated thyroid carcinoma (DTC). We examined differences in expression of EZH2 among various histological types of thyroid cancer, and the relationship between EZH2 expression and patient outcome. EZH2 protein was expressed in PDTC and ATC, but not in normal thyroid gland or DTC. EZH-positivity increased in the order of DTC, PDTC, and ATC (p<0.01). Higher EZH2 expression correlated with poorer survival in PDTC (p=0.004), and a similar but non-significant trend was observed in ATC (p=0.166). Multivariate analysis identified EZH2 as an independent prognostic factor similar to metastatic status in the Japanese Society of Thyroid Surgery (JSTS) classification of PDTC. EZH2 overexpression is associated with malignant potential in thyroid cancer, and may thus be a useful prognostic marker of aggressive thyroid cancer.

Comparison of sonographic characteristics of primary thyroid lymphoma and anaplastic thyroid carcinoma.

Although primary thyroid lymphoma (PTL) and anaplastic thyroid carcinoma (ATC) both account for a rare portion of the morbidity of all thyroid malignancies, the therapeutic methods and prognosis for these two diseases are different. The purpose of this study was to investigate the sonographic characteristics of PTL and ATC and to compare the sonographic findings of PTL and ATC. The study included 42 patients with histopathologically proven PTL (n=27) and ATC (n=15). The Clinical characteristics and sonographic findings were retrospectively reviewed and compared between the two groups. The mean age of patients with ATC was not significantly different from that in patients with PTL (P=0.601). The female-to-male ratio of patients with ATC was significantly lower than that of patients with PTL (P=0.029). Both PTL and ATC commonly present as a relatively large, solid mass on sonography with compressive symptoms, in which hoarseness was seen more frequently in ATC group (66.7%) than in PTL group (14.8%) (P=0.001). There is no significant difference in thyroid size, nodular size, margin, shape, echo texture, echogenicity, cystic change, vascularity and local invasion on sonography between ATC and PTL groups. Echogenic strands, markedly hypoechoic and enhanced posterior echo were seen more frequently in PTL group (92.6%, 92.6%, and 85.2%, respectively) than those in ATC group (6.7%, 60.0%, and 33.3%, respectively) (P<0.05), and calcification was seen more frequently in ATC group (80.0%) than in PTL group (0%) (P<0.001). Three ultrasound patterns were observed for PTL including diffuse type (25.9%), nodular type (48.2%) and mixed type (25.9%), while all ATC cases presented with nodular type (100.0%). Associated Hashimoto's thyroiditis occurred more frequently in PTL group (59.3%) than in ATC group (20.0%) (P=0.023). Certain sonographic features as a markedly hypoechogenicity, the presence of an enhanced posterior echo and linear echogenic strands, lack of calcification and associated Hashimoto's thyroiditis were valuable for distinguishing PTL from ATC. In contrast, heterogeneous echogenicity, uncircumscribed margin, irregular shape, and vascular pattern were not specific features for differential diagnosis.

Evaluation of diagnostic accuracy of FNAC and correlation with histopathology in thyroid lesions

Aim: The aim of the study is to evaluate the accuracy of FNAC diagnosis in non neoplastic & neoplastic lesions of thyroid, and correlating with histopathological findings. Materials and Methods: This was a prospective study done in department of Pathology, Tagore medical college for a period of 3 years. 115 cases of thyroid subjected to FNAC where histopathology diagnosis was available were included in the study. The correlation of FNAC diagnosis with histopathology was made and the results were analysed. Results: The range of the age of the patient in this study was 25 to 60 years. The male to female ratio was 18.5:81.5. The maximum cases were colloid goitre (59.2%) in which 12.5% were with features of papillary hyperplasia. Occurrences of dual pathology were seen in our study with one case of Hashimoto’s thyroiditis with focus of papillary carcinoma and the other was medullary carcinoma with papillary carcinoma. 2 cases of anaplastic thyroid carcinoma were also seen. Conclusion: In our study sensitivity of FNAC in detecting thyroid lesions was 93.75%, and the specificity was 97.01%. FNAC of thyroid had a diagnostic accuracy of 95.65% which clearly indicates that FNAC can be used as non invasive, cost effective and a safe diagnostic method for defining thyroid disorders.

Molecular Pathology of Anaplastic Thyroid Carcinomas: A Retrospective Study of 144 Cases.

Anaplastic thyroid carcinoma (ATC) is a rare tumor, with poorly defined oncogenic molecular mechanisms and limited therapeutic options contributing to its poor prognosis. The aims of this retrospective study were to determine the frequency of anaplastic lymphoma kinase (ALK) translocations and to identify the mutational profile of ATC including TERT promoter mutations. One hundred and forty-four ATC cases were collected from 10 centers that are a part of the national French network for management of refractory thyroid tumors. Fluorescence in situ hybridization analysis for ALK rearrangement was performed on tissue microarrays. A panel of 50 genes using next-generation sequencing and TERT promoter mutations using Sanger sequencing were also screened. Fluorescence in situ hybridization was interpretable for 90 (62.5%) cases. One (1.1%) case was positive for an ALK rearrangement with a borderline threshold (15% positive cells). Next-generation sequencing results were interpretable for 94 (65.3%) cases, and Sanger sequencing (TERT) for 98 (68.1%) cases. A total of 210 mutations (intronic and exonic) were identified. TP53 alterations were the most frequent (54.4%). Forty-three percent harbored a mutation in the (H-K-N)RAS genes, 13.8% a mutation in the BRAF gene (essentially p.V600E), 17% a PI3K-AKT pathway mutation, 6.4% both RAS and PI3K pathway mutations, and 4.3% both TP53 and PTEN mutations. Nearly 10% of the cases showed no mutations of the RAS, PI3K-AKT pathways, or TP53, with mutations of ALK, ATM, APC, CDKN2A, ERBB2, RET, or SMAD4, including mutations not yet described in thyroid tumors. Genes encoding potentially druggable targets included: mutations in the ATM gene in four (4.3%) cases, in ERBB2 in one (1.1%) case, in MET in one (1.1%) case, and in ALK in one (1.1%) case. A TERT promoter alteration was found in 53 (54.0%) cases, including 43 C228T and 10 C250T mutations. Three out of our cases did not harbor mutations in the panel of genes with therapeutic interest. This study confirms that ALK rearrangements in ATC are rare and that the mutational landscape of ATC is heterogeneous, with many genes implicated in the follicular epithelial cell dedifferentiation process. This may explain the limited effectiveness of targeted therapeutic options tested so far.

Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions.

Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality. Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC). GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment. CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. The Oncologist 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.