Detection and evaluation of the presence of the BRAF V600E mutation in ameloblastomas in an Indian population

Introduction: Ameloblastoma is a benign epithelial odontogenic neoplasm that constitutes approximately 1% of all oral tumors and about 9 to 11% of all odontogenic tumors. They are slow-growing, locally invasive, and demonstrate a potential for metastasis and malignant transformation. The molecular pathogenesis of ameloblastoma is attributed to aberrant activity of the signal transduction pathways relating to developmental stages of odontogenesis including the mitogen-activated protein kinase (MAPK) pathway. The BRAF V600E mutation was identified as the most frequently mutated gene in this neoplasm. Studies have shown that use of BRAF inhibitors in patients diagnosed with ameloblastomas led to a significant reduction in tumor volume. Aims: To detect the expression of BRAF V600E mutation in ameloblastomas in an Indian population using immunohistochemistry. To compare the difference in the occurrence of the BRAF V600E mutation between mandibular and maxillary cases. Materials and Methods: Thirty-three formalin-fixed paraffin-embedded tissues of histopathologically proven cases of ameloblastoma were assessed for the BRAF V600E mutation by immunohistochemistry using the BRAF V600E monoclonal antibody. Patient data such as age, sex, anatomical site, recurrence were documented. Statistical Analysis: The statistical analysis was performed using the Pearson Chi-square test and Student's t-test. Results: The present study revealed a high expression of the BRAFV600E mutation in mandibular cases of ameloblastoma among Indians irrespective of the age, sex, site, recurrence or histological pattern. Conclusions: The identification of this driver mutation opens the possibility of an adjuvant therapeutic modality to reduce the significant facial disfigurement and morbidity following surgical management.

Diagnostic value of thyroid imaging report and data system combined with BRAF V600E mutation detection for thyroid fine needle puncture cytological uncertain nodules / 肿瘤研究与临床

Objective:To investigate the diagnostic value of thyroid imaging report and data system (TIRADS) combined with BRAF V600E mutation detection in differentiating uncertain thyroid nodules by using fine needle aspiration cytology (FNAC), and to analyze the role of TIRADS classification in screening the nodules needed to be routinely detected for BRAF V600E mutation.Methods:The clinicopathological data of 337 thyroid nodules patients diagnosed with TIRADS classification, FNAC Bethesda classification, BRAF V600E mutation detection and postoperative histopathology from the Second Hospital of Hebei Medical University between January 2018 and August 2021 were retrospectively analyzed. The role of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation detection alone and the combined detection in the differentiation of benign and malignant thyroid nodules was also analyzed.Results:The postoperative histopathological result was regarded as the gold standard. The sensitivity of TIRADS classification, FNAC Bethesda classification and BRAF V600E mutation for thyroid cancer diagnosis was 76.0%, 88.1% and 80.4% respectively, and the corresponding specificity was 84.0%, 96.0% and 100.0%, respectively. Histologically, 37 (62.7%) of 59 nodules with FNAC uncertainty were malignant nodules after the surgery. The sensitivity and accuracy of BRAF V600E mutation detection in the diagnosis of FNAC uncertain nodules were 51.4% and 69.5%, respectively, while the sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were 86.5% and 84.7%, respectively. The sensitivity and accuracy of BRAF V600E mutation detection combined with TIRADS classification were both improved ( P values were 0.002 and 0.049, respectively). The positive rate of BRAF V600E mutation in thyroid nodules increased step by step with the rise of risk degree in TIRADS classification, and the type 3 cases were lower than those in type 4a cases [14.3% (1/7) vs. 68.6% (24/35), P = 0.012], and there were no statistically significant differences among the adjacent groups above 4a (all P > 0.05). Conclusions:TIRADS combined with BRAF V600E mutation detection can improve the sensitivity and accuracy in the diagnosis of FNAC uncertain thyroid nodules. The BRAF V600E mutation rate of TIRADS 4a and above nodules is high, so routine detection is recommended.

Diagnostic value of BRAF(V600E) mutation analysis in fine needle aspiration for evaluation of thyroid nodules / 고신대학교의과대학학술지

OBJECTIVES: Ultrasound-guided fine-needle aspiration (FNA) is routinely used in the evaluation of thyroid nodules. However, it has several pitfalls, as has been noted in nondiagnostic and indeterminate cases. This study aims to investigate the value of BRAF(V600E) mutation co-testing in FNA cytology. METHOD: A total of 310 patients underwent BRAF(V600E) mutation co-testing in FNA cytology on thyroid nodules between June 2013 and June 2014. Of the 310 patients, 69 patients who had undergone a surgery for thyroid nodules were included in this study. The presence of the BRAF(V600E) mutation was determined by allele-specific polymerase chain reaction amplification of exon 15 of the BRAF gene. RESULTS: Of 69 cases, 33 (47.8%) were BRAF(V600E) mutation positive. The BRAF(V600E) mutation was not significantly associated with high-risk features such as tumor size, lymph node metastasis, and pathological stage. The respective diagnostic performance of FNA (P = 0.02), BRAF(V600E) mutation (P = 0.03), and ultrasonographic (P = 0.00) findings was statistically significant. The sensitivity, specificity and positive predictive value of FNA was 64.9%, 83.3%, and 94.8%. The sensitivity, specificity and positive predictive value of BRAF(V600E) mutation was 56.1%, 91.7%, and 96.9% and the US features was 91.2%, 91.7%, and 98.1% respectively. However, sensitivity of FNA with BRAF(V600E) mutation (77.2%) was lower than FNA with US (92.9%) and combination all together (92.9%). CONCLUSION: In this study, we found that US features were the most useful in preoperative differential diagnosis of thyroid nodules. BRAF(V600E) mutation co-testing in FNA cytology was also useful for diagnosis of thyroid tumors.

Expression of Sodium-Iodide Symporter Depending on Mutational Status and Lymphocytic Thyroiditis in Papillary Thyroid Carcinoma

BACKGROUND AND OBJECTIVES: Sodium-iodine symporter (NIS) is a marker for the degree of differentiation in thyroid cancer. The genetic factors or microenvironment surrounding tumors can affect transcription of NIS. In this study, we investigated the NIS mRNA expression according to mutational status and coexistent lymphocytic thyroiditis in papillary thyroid cancer (PTC). MATERIALS AND METHODS: The RNA expression levels of NIS in the samples from database of The Caner Genome Atlas (TCGA; n=494) and our institute (n=125) were analyzed. RESULTS: The PTCs with the BRAFV600E mutation and the coexistence of BRAFV600E and TERT promoter mutations showed significantly lower expression of NIS (p < 0.001, respectively), and those with BRAF-like molecular subtype also had reduced expression of NIS (p < 0.001). NIS expression showed a positive correlation with thyroid differentiation score (r=0.593, p < 0.001) and negative correlations with expressions of genes involved in ERK signaling (r=−0.164, p < 0.001) and GLUT-1 gene (r=−0.204, p < 0.001). The PTCs with lymphocytic thyroiditis showed significantly higher NIS expression (p=0.013), regardless of mutational status. CONCLUSION: The NIS expression was reduced by the BRAFV600E mutation and MAPK/ERK pathway activation, but restored by the presence of lymphocytic thyroiditis.

The value of ultrasound-guided fine needle aspiration combined with detection of BRAF V600E in diagnosis of benign and malignant thyroid nodules / 中华超声影像学杂志

Objective@#To evaluate the value of ultrasound-guided fine needle aspiration(US-FNA) combined with detection of BRAF V600E and thyroid imaging reporting and data system(TI-RADS) in diagnosis of benign and malignant thyroid nodules.@*Methods@#In this study, 123 operative thyroid nodules from 114 patients who underwent US-FNA and detection of BRAF V600E were enrolled. TI-RADS was apply for the classification of each nodule before surgery. Specimens from each nodule were subjected for hematoxylin and eosin (HE) staining and cytological diagnosis and detection of BRAF V600E mutation.@*Results@#①BRAF V600E mutation was found in 71 (71/123) nodules with histologic confirmation of papillary-thyroid carcinoma, 58 of which were cytologically diagnosed as carcinoma and 13 were indeterminate. Compared with the postoperative pathological results, US-FNA combined with BRAF V600E could improve the sensitivity and accuracy of diagnosis to thyroid nodules compared with individual US-FNA, and the difference was statistically significant(P<0.001). ②The mutation rate of BRAF V600E was associated with thyroid capsular invasion(χ2=8.44, P=0.004), and combined with TI-RADS could indicate the high-risk of this invasion. ③Among 123 operative nodules, 18 nodules were BRAF V600E negative and cytologically diagnosed as indetermination, 10 of which were TI-RADS 3b or above. After thyroidectomy, 6 nodules were confirmed as papillary-thyroid carcinoma, 1 nodule was thyroid follicular carcinoma, and 3 nodules were benign ones.@*Conclusions@#US-FNA combined with detection of BRAF V600E and TI-RADS can improve the diagnostic accuracy and decrease the misdiagnosis in indeterminate nodules.

Correlation of BRAF V600E mutation with the clinicopathological features of papillary thyroid carcinoma / 肿瘤研究与临床

Objective To discuss the BRAF V600E mutation rate in papillary thyroid carcinoma (PTC) and its relationship with the clinicopathological features. Methods Two hundred and sixty-five PTC patients(including 226 cases of classical type,29 cases of follicular type, 3 cases of high cell type, 2 cases of diffuse sclerosis type, 2 cases of eosinophilic type, 3 cases of cystic type) from August 2014 to October in Shanxi Provincial Cancer Hospital, were collected with completely clinical and pathological information. The BRAF V600E mutation was detected by real-time polymerase chain reaction (RT-PCR) method. Pearson χ 2 test and the exact probability method were used to analysis the relationship between gene mutations and clinicopathological data. Results BRAF V600E mutation rate in PTC patients was 73.21 %(194/265). There was no significant difference in the mutation rate of BRAF V600E among patients with different age, gender, tumor location,tumor number and extravaginal invasion(all P>0.05),but the mutation rates of BRAF V600E gene in patients with different tumor size, histopathological subtypes, lymph node metastasis and clinical stage were significantly different(all P<0.05).Conclusion The PTC patients with positive BRAF V600E mutation have poor clinicopathological features,and BRAF V600E mutation may be a predictor of advanced PTC.

Expression and correlation of phosphorylation extracellular signal-regulated kinase and monopolar spindle 1 in colorectal cancer with wild type or BRAF V600E mutation / 肿瘤研究与临床

Objective To determine the correlation between phosphorylation extracellular signal-regulated kinase (p-Erk) and monopolar spindle 1 (Mps1) in colorectal cancer patients with the BRAF V600E mutation or not, and to explore the relationship between the expression of p-Erk and Mps1 with the clinicopathological features and prognosis of colorectal cancer patients. Methods Two hundred and eighty-eight paraffin-embedded tissue sections containing both the carcinoma and its adjacent non-neoplastic colorectal tissue were collected from January 2009 to June 2015 in the First Hospital of Shanxi Medical University. BRAF mutation was detected by Sanger sequencing. Kaplan-Meier survival analysis was used to analyze the correlation between BRAF V600E and prognosis. Immunohistochemistry was used to detect the expression level of p-Erk and Mps1 in colorectal cancer with wild type or BRAF V600E mutation. The correlation between p-ERK and Mps1 expression was analyzed by using linear regression analysis. Results The BRAF V600E mutation rate was 5.2 % in colorectal carcinomas. In addition, the poorly differentiated tumours and mucinous tumours had higher incidence of BRAF mutations than well differentiated tumours and non-mucinous tumours respectively [14.3 % (9/63) vs. 2.7 % (6/225),χ 2= 11.208,P = 0.001; 25.0 % (6/24) vs. 3.4 %(9/264),χ 2=16.630,P <0.001). The positive rate of p-Erk and Mps1 in colorectal carcinomas with BRAF V600E was significantly higher than that in colorectal carcinomas with BRAF WT (14/15 vs. 3/15, P <0.05; 15/15 vs. 3/15, P < 0.05]. It was found that the p-Erk expression correlated positively to the Mps1 expression (R2= 0.419,P < 0.001). The expressions of p-Erk protein in poorly differentiated adenocarcinoma was significantly higher and mucinous adenocarcinoma than those in high differentiated adenocarcinoma and non-mucinous adenocarcinoma (χ 2= 6.679, P = 0.01; χ 2= 5.735, P = 0.017), as well as in the group with lymph node metastasis than without lymph node metastasis (χ 2=5.436, P =0.02). Positive rate of Mps1 in poorly differentiated carcinoma was higher than that in well differentiated adenocarcinoma of colorectal carcinomas (χ 2=7.950, P =0.009). The Kaplan-Meier survival analysis indicated that patients with BRAF V600E had a worse survival rate than BRAF WT patients. Conclusions BRAF V600E may play an important role in specific pathological kinds of colorectal carcinomas, which is expected to be an independent prognostic factor. The expression of p-Erk is significantly correlated with Mps1 in colorectal carcinomas, suggesting that Mps1 may become a new potential target for targeted therapy.

Analysis of BRAF V600E mutation in bilateral well-differentiated thyroid carcinoma / 临床与实验病理学杂志

Purpose To investigate the correlation between BRAF V600E mutation and clinicopathologic parameters in bilateral welldifferentiated thyroid carcinoma.Method Collected 80 patients with papillary thyoid carcinoma (PTC) (67 patients with classical type,8 patients with follicular variant,3 patients with oncocytic variant,2 patients with tall cell variant),5 patients with follicular carcinoma and 30 normal tissues near the tumor,BRAF V600E mutation was detected via polymerase chain reaction.Result The presence of BRAF V600E mutation was found in 52 patients with PTC (65.0％),the mutation was not in the 5 patients with ollicular carcinoma as well as in the 30 normal tissues near the tumor.The BRAF V600E mutation was positively correlated with age,capsule invasion,lymph node metastasis,tumor clinical stage.In the histological variant of PTC,the BRAF V600E mutation rate of classical type and tall cell variant is very high (70.1％,100.0％),but the BRAF V600E mutation rate of follicular variant is very low (33.3％).Conclusion The BRAF V600E mutation rates are different in different age groups.The BRAF V600E mutation was positively correlated with capsule invasion,lymph node metastasis,tumor clinical stage.The BRAF V600E mutation rate of classical type and tall cell variant is very higher than follicular variant.

Clinical and Histopathological Profile Of BRAF V600E Mutation In Conventional Papillary Thyroid Carcinoma in A Filipino Population

BRAF V600E is a possible biomarker for risk stratification and prognostication in papillary thyroid carcinoma. Studies on its association with aggressive clinicopathological features among East Asian populations are limited. This study examines the clinical and histopathological features of this mutation in Filipinos with conventional papillary thyroid carcinoma. Methods: Formalin-fixed, paraffin embedded thyroid tissue blocks of papillary carcinoma for the study period January 2010 to December 2012 were retrieved. Slides were reviewed and described according to tumour size, variant type, sclerosis, multifocality, subcapsular location, extra-thyroidal extension, nodal metastasis, and nodal extracapsular spread. Medical records were reviewed for patient demographics and characteristics. Mutation status was determined using realtime polymerase chain reaction and sequencing. Results: Sixty-five patients were included in this study. BRAF V600E mutation prevalence was 38.46%. The mutation positive group was predominantly female, young (mean age 36 years), with tumour size less than 4 cm, and late-stage disease. Extra-thyroidal extension (60%), significant sclerosis (96%), and subcapsular tumour location (72%) were the most frequent findings. Eighty-three percent of patients with nodal metastasis had extracapsular spread. Conclusions: Compared to some Asian populations, this study of Filipino patients shows a lower prevalence of BRAF V600E mutation. The clinical and histopathological features of mutation positive patients raise important issues regarding extent of surgical excision and appropriate management of neck metastasis for this group.

BRAF(V600E) Test for Suspicious Lateral Lymph Nodes in Papillary Thyroid Cancer / 대한내분비외과학회지

PURPOSE: This study evaluates the BRAF(V600E) test with fine-needle aspiration cytology (FNAC) for lateral lymph node (LN) metastasis in papillary thyroid carcinoma (PTC). METHODS: Ninety-one patients, including 95 lateral LNs with possible PTC metastasis, were consecutively entered into the study. We analyzed the accuracy of results for the BRAF(V600E) test and FNAC for lateral LN metastasis in PTC. RESULTS: Modified radical neck dissection was performed for 34 cases due to lateral LN metastasis. The sensitivity of FNAC was 88.2% , and the LN-BRAF(V600E) test 64.7%. The specificity and positive predictive value (PPV) were 100% for both tests. The negative predictive values (NPV) were FNAC, 93.8%, and LN-BRAF(V600E), 83.6%. For samples positive with either the BRAF(V600E) test or FNAC, the sensitivity was 94.1%, specificity 100%, PPV value 100%, and NPV 96.8%. CONCLUSION: This study suggests that the complementary LN-BRAF(V600E) test with FNAC is a supportive diagnostic method for PTC patients with indeterminate or non-diagnostic suspicious lateral LNs.

Clinicopathological Implications of the BRAF(V600E) Mutation in PTC with Concurrent Hashimoto Thyroiditis

BACKGROUND AND OBJECTIVES: The relationship between Hashimoto thyroiditis (HT) and papillary thyroid cancer (PTC) is still controversial. Some studies suggested that molecular basis of the association between HT and PTC. BRAF(V600E) mutation is the most common genetic alteration founded in PTC. This study was to determine a role of BRAF(V600E) mutation in PTC with concurrent HT and their association with other clinicopathological factors. MATERIALS AND METHODS: We enrolled 452 patients who underwent thyroid surgery between 2009 and 2012 for classical PTC. The status of BRAF(V600E) mutation was evaluated by direct sequencing. HT was defined as presence of lymphocytic thyroiditis in pathology or positive serum anti-thyroid peroxidase antibody. RESULTS: Total 139 patients (30%) with PTC had coexistence HT. HT was significantly associated female (p=0.006), and younger age (p=0.045). BRAF(V600E) mutation was confirmed in 264 patients (58%). The frequency of BRAF(V600E) mutation was significantly lower in PTC with coexistence HT (48.2%) compared by PTC without HT (62.9%, p=0.004). However, there was no significant difference in clinicopathological feature of PTC according to the presence of HT in patients with BRAF(V600E) mutated PTC. BRAF(V600E) mutation was less frequent in PTC with coexistence HT. CONCLUSION: These findings suggested that HT and BRAF(V600E) mutation might be independent factors in development and progression of PTC.

Dysembryoplastic Neuroepithelial Tumors

Dysembryoplastic neuroepithelial tumor (DNT) is a benign glioneuronal neoplasm that most commonly occurs in children and young adults and may present with medically intractable, chronic seizures. Radiologically, this tumor is characterized by a cortical topography and lack of mass effect or perilesional edema. Partial complex seizures are the most common presentation. Three histologic subtypes of DNTs have been described. Histologically, the recognition of a unique, specific glioneuronal element in brain tumor samples from patients with medically intractable, chronic epilepsy serves as a diagnostic feature for complex or simple DNT types. However, nonspecific DNT has diagnostic difficulty because its histology is indistinguishable from conventional gliomas and because a specific glioneuronal element and/or multinodularity are absent. This review will focus on the clinical, radiographic, histopathological, and immunohistochemical features as well as the molecular genetics of all three variants of DNTs. The histological and cytological differential diagnoses for this lesion, especially the nonspecific variant, will be discussed.

The Frequency and Clinical Implications of the BRAF(V600E) Mutation in Papillary Thyroid Cancer Patients in Korea Over the Past Two Decades

BACKGROUND: Over the past several decades, there has been a rapid worldwide increase in the prevalence of papillary thyroid cancer (PTC) as well as a number of changes in the clinicopathological characteristics of this disease. BRAF(V600E), which is a mutation of the proto-oncogene BRAF, has become the most frequent genetic mutation associated with PTC, particularly in Korea. Thus, the present study investigated whether the prevalence of the BRAF(V600E) mutation has increased over the past two decades in the Korean population and whether various PTC-related clinicopathological characteristics have changed. METHODS: The present study included 2,624 patients who underwent a thyroidectomy for PTC during two preselected periods; 1995 to 2003 and 2009 to 2012. The BRAF(V600E) mutation status of each patient was confirmed using the polymerase chain reaction-restriction fragment length polymorphism method or by the direct sequencing of DNA. RESULTS: The prevalence of the BRAF(V600E) mutation in Korean PTC patients increased from 62.2% to 73.7% (P=0.001) over the last two decades. Additionally, there was a greater degree of extrathyroidal extension (ETE) and lymph node metastasis in 2009 to 2012 patients with the BRAF(V600E) mutation and a higher frequency of thyroiditis and follicular variant-PTC in 2009 to 2012 patients with wild-type BRAF. However, only the frequency of ETE was significantly higher in 1995 to 2003 patients with the BRAF(V600E) mutation (P=0.047). Long-term recurrence rates during a 10-year median follow-up did not differ based on BRAF(V600E) mutation status. CONCLUSION: The BRAF(V600E) mutation rate in Korean PTC patients has been persistently high (approximately 70%) over the past two decades and continues to increase. The present findings demonstrate that BRAF(V600E)-positive PTC was associated with more aggressive clinicopathological features, especially in patients who were recently diagnosed, suggesting that BRAF(V600E) mutation status may be a useful prognostic factor for PTC in patients recently diagnosed with this disease.

Analysis of the BRAF(V600E) Mutation in Thyroid Nodules: the Preoperative Diagnostic Role of Fine-needle Aspiration Biopsy for Patients with Papillary Thyroid Cancer and Its Impact on Patient Care

PURPOSE: We wanted to evaluate the frequency of BRAF(V600E) mutations on the preoperative fine-needle aspiration biopsies (FNAB) of thyroid nodules and the effect of this on the accuracy of diagnosing papillary thyroid cancer (PTC). We also wanted to evaluate the influence of BRAF(V600E) analysis on patient care. MATERIALS AND METHODS: The results of cytology and BRAF(V600E) mutation analysis of 190 thyroid nodules were retrospectively reviewed. The results of the cytology and BRAF(V600E) analysis were compared with the histopathological diagnosis for the surgically confirmed cases, and we calculated the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and the diagnostic accuracy of FNAB and combining the modalities of FNAB and BRAF(V600E) mutation. The frequency of BRAF(V600E) mutation according to age and the influence of BRAF(V600E) analysis on patient care were studied. The nodule size was compared between the malignant and other categories of BRAF(V600E) positive nodules. RESULTS: Seventy four percent of the PTC were BRAF(V600E) positive. BRAF(V600E) analysis increased the sensitivity, NPP and diagnostic accuracy of FNAB. Fifty percent of the BRAF(V600E) positive nodules with other than malignant cytology received surgery and these were confirmed to be PTC. The frequency of BRAF(V600E) mutation increased with age, which was statistically significant. There was a statistically significant difference in the nodule size between the cytologically malignant nodules and the other nodules. CONCLUSION: BRAF(V600E) analysis increased the diagnostic accuracy of FNAB and it should be considered as being complementary to cytological analysis. The frequency of the BRAF(V600E) mutation increased with age. The size of the malignant nodules was larger than that of the benign nodules.