BRAF V600E Mutation-Assisted Risk Stratification of Solitary Intrathyroidal Papillary Thyroid Cancer for Precision Treatment

Abstract Background Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0 cm and 4.0 cm or less is undefined. Methods A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow–up time of 64 months at 11 medical centers in six countries. The chi-square test or, for analyses with small numbers, Fisher’s exact test was performed to compare recurrence rates. Recurrence-free probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results Recurrence of SI-PTC larger than 1.0 cm and 4.0 cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI = 1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0 cm and 4.0 cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR = 5.44, 95% CI = 1.93 to 15.34; and adjusted HR = 5.58, 95% CI = 1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0 cm and 4 cm or less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR = 18.40, 95% CI = 2.21 to 152.98; and adjusted HR = 14.73, 95% CI = 1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0 cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0 cm and 4.0 cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI = 96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI = 96.3% to 99.3%) for conventional SI-PTC. Conclusions BRAF V600E identifies a subgroup of SI-PTC larger than 1.0 cm and 4.0 cm or less, particularly tumors larger than 2.0 cm and 4.0 cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

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Association Between BRAF V600E Mutation and Recurrence of Papillary Thyroid Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.56.8253 ◽

2015 ◽

Vol 33 (1) ◽

pp. 42-50 ◽

Cited By ~ 238

Author(s):

Mingzhao Xing ◽

Ali S. Alzahrani ◽

Kathryn A. Carson ◽

Young Kee Shong ◽

Tae Yong Kim ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Multicenter Study ◽

Braf Mutation ◽

Prognostic Value ◽

Braf V600e Mutation ◽

Braf V600e ◽

Disease Stage ◽

Papillary Thyroid ◽

Recurrence Rates

Purpose To investigate the prognostic value of BRAF V600E mutation for the recurrence of papillary thyroid cancer (PTC). Patients and Methods This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months). Results The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAF V600E mutation–positive and 11.6% (125 of 1,082) of BRAF V600E mutation–negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation–positive versus –negative patients (P < .001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage I or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation–positive versus –negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P < .001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. Conclusion This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

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BRAF Mutation Predicts a Poorer Clinical Prognosis for Papillary Thyroid Cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2005-0987 ◽

2005 ◽

Vol 90 (12) ◽

pp. 6373-6379 ◽

Cited By ~ 627

Author(s):

Mingzhao Xing ◽

William H. Westra ◽

Ralph P. Tufano ◽

Yoram Cohen ◽

Eli Rosenbaum ◽

...

Keyword(s):

Multivariate Analysis ◽

Thyroid Cancer ◽

Risk Stratification ◽

Papillary Thyroid Cancer ◽

Braf Mutation ◽

Advanced Tumor Stage ◽

Papillary Thyroid ◽

Clinical Prognosis ◽

Mutation Status ◽

Predictors Of Recurrence

Context: Use of BRAF mutation in papillary thyroid cancer (PTC) has the potential to improve risk stratification of this cancer. Objective: The objective of the study was to investigate the prognostic value of BRAF mutation in patients with PTC. Design, Setting, and Subjects: In a multicenter study of 219 PTC patients, data on their clinicopathological characteristics and clinical courses between 1990 and 2004 were retrospectively collected, and their tumor BRAF mutation status was determined. Associations of BRAF mutation with initial tumor characteristics and subsequent recurrence were analyzed. Main Outcome Measure: Relationships between the BRAF mutation status and clinicopathological outcomes, including recurrence, were measured. Results: We found a significant association between BRAF mutation and extrathyroidal invasion (P < 0.001), lymph node metastasis (P < 0.001), and advanced tumor stage III/IV (P = 0.007) at initial surgery. This association remained significant on multivariate analysis, adjusting for conventional clinicopathological predictors of recurrence excluding the histological PTC subtype, but was lost when the tumor subtype was included in the model. BRAF mutation was also significantly associated with tumor recurrence, 25 vs. 9% with and without mutation, respectively (P = 0.004), during a median of 15 (interquartile range, 3–29) months of follow-up. This association remained significant on multivariate analysis adjusting for conventional clinicopathological predictors of recurrence, even including the PTC subtype (odds ratio, 4.0; 95% confidence interval, 1.1–14.1; P = 0.03). BRAF mutation was even an independent predictor of recurrence in patients with stage I/II disease, 22 vs. 5% with and without BRAF mutation, respectively (P = 0.002). BRAF mutation was also more frequently associated with absence of tumor I-131 avidity and treatment failure of recurrent disease. Conclusions: In patients with PTC, BRAF mutation is associated with poorer clinicopathological outcomes and independently predicts recurrence. Therefore, BRAF mutation may be a useful molecular marker to assist in risk stratification for patients with PTC.

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BRAF V600E and TERT Promoter Mutations Cooperatively Identify the Most Aggressive Papillary Thyroid Cancer With Highest Recurrence

Journal of Clinical Oncology ◽

10.1200/jco.2014.55.5094 ◽

2014 ◽

Vol 32 (25) ◽

pp. 2718-2726 ◽

Cited By ~ 332

Author(s):

Mingzhao Xing ◽

Rengyun Liu ◽

Xiaoli Liu ◽

Avaniyapuram Kannan Murugan ◽

Guangwu Zhu ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Braf V600e ◽

Papillary Thyroid ◽

Recurrence Rates ◽

Clinicopathologic Characteristics ◽

Therapeutic Implications ◽

Tert Promoter ◽

Promoter Mutations ◽

Relationship Of

Purpose To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC). Patients and Methods We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months). Results Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation–positive versus –negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI, 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000 person-years; 95% CI, 22.96 to 39.74) in TERT mutation–positive versus –negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI, 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000 person-years; 95% CI, 14.59 to 31.97) in patients harboring both mutations versus patients harboring neither mutation (HR, 8.51; 95% CI, 4.84 to 14.97), which remained significant after clinicopathologic cofactor adjustments. Disease-free patient survival curves displayed a moderate decline with BRAF V600E or TERT C228T alone but a sharp decline with two coexisting mutations. Conclusion Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications.

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Preoperative Factors Associated with Extrathyroidal Extension in Papillary Thyroid Cancer

European Thyroid Journal ◽

10.1159/000506474 ◽

2020 ◽

Vol 9 (5) ◽

pp. 256-262 ◽

Cited By ~ 1

Author(s):

Chi-Yu Kuo ◽

Po-Sheng Yang ◽

Ming-Nan Chien ◽

Shih-Ping Cheng

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Tumor Size ◽

Braf Mutation ◽

Extrathyroidal Extension ◽

Additive Models ◽

Braf V600e ◽

Papillary Thyroid ◽

Factors Associated ◽

Preoperative Factors

Objective: Extrathyroidal extension may not be accurately recognized during thyroidectomy and can increase the risk of positive margins and even recurrence. This study aimed to investigate the preoperative factors associated with extrathyroidal extension. Methods: We analyzed 887 patients with papillary thyroid cancer (PTC) who underwent surgery in the period of 2005–2017. Binary logistic regression analyses and generalized additive models were used to identify associations. Results: Minimal extrathyroidal extension was present in 233 (26%) patients and advanced extrathyroidal extension was found in 60 (7%) patients. Age, BMI, and tumor size were independent predictors of all or advanced extrathyroidal extension. Among the 493 patients whose BRAF mutation status was available, age (OR = 1.025), BMI (OR = 1.091), tumor size (OR = 1.544), and BRAF V600E mutation (OR = 2.311) were independently associated with extrathyroidal extension. Conclusions: Older age, a greater BMI, a larger tumor size, and presence of the BRAF mutation were predictive of extrathyroidal extension. These factors should be taken into consideration in decision-making before surgery is performed.

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BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer

Hormone and Metabolic Research ◽

10.1055/a-0765-9078 ◽

2018 ◽

Vol 51 (01) ◽

pp. 69-75 ◽

Cited By ~ 2

Author(s):

Jan Groener ◽

Debora Gelen ◽

Carolin Mogler ◽

Esther Herpel ◽

Csaba Toth ◽

...

Keyword(s):

Thyroid Cancer ◽

Retinoic Acid ◽

Papillary Thyroid Cancer ◽

Initial Response ◽

University Hospital ◽

Braf V600e ◽

Papillary Thyroid ◽

Wild Type ◽

Mutational Status ◽

Before And After

AbstractRadioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome.

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Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer

JAMA Oncology ◽

10.1001/jamaoncol.2016.3288 ◽

2017 ◽

Vol 3 (2) ◽

pp. 202 ◽

Cited By ~ 81

Author(s):

Rengyun Liu ◽

Justin Bishop ◽

Guangwu Zhu ◽

Tao Zhang ◽

Paul W. Ladenson ◽

...

Keyword(s):

Thyroid Cancer ◽

Risk Stratification ◽

Papillary Thyroid Cancer ◽

Mortality Risk ◽

Braf V600e ◽

Papillary Thyroid ◽

Tert Promoter ◽

Tert Promoter Mutations ◽

Promoter Mutations

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THE BRAF MUTATION V600E IN PAPILLARY THYROID CANCER, CLINICAL-MORPHOLOGICALPARALLELES AND PROGNOSIS

Russian Journal of Oncology ◽

10.18821/1028-9984-2017-22-1-15-20 ◽

2017 ◽

Vol 22 (1) ◽

pp. 15-20

Author(s):

A. A Ivanov ◽

A. M Avdalyan ◽

V. J Gerval’d ◽

E. L Lushnikova ◽

Yu. N Zorkina ◽

...

Keyword(s):

Thyroid Cancer ◽

Lymph Nodes ◽

Papillary Thyroid Cancer ◽

Braf Mutation ◽

Negative Impact ◽

Morphological Characteristics ◽

Braf V600e ◽

Papillary Thyroid ◽

Ki 67 ◽

Regional Lymph Nodes

On the material of the 67 cases of papillary thyroid cancer (PTC) authors executed the study of the interrelationship between the BRAF mutation V600E and the forecast, biomolecular and morphological characteristics of the disease. There was implemented the analysis of samples for the presence of 7 KRAS gene mutations, 4 mutations of the PIK3CA gene, mutation BRAF V600E with the revealing of the interrelationship between such biomolecular markers for proliferation and apoptosis as Ki-67, p53, Bcl2. Also there was performed chromogenic hybridization (CISH method) in situ to study the status of the HER2 gene. There was determined the interrelationship between BRAF mutation V600E and clinical indices of prognosis: tumor sizes, capsule invasion, presence of metastases in regional lymph nodes. In addition, there was evaluated the interrelationship between BRAF mutation V600E and 10-years survival rate. No mutation were identified in KRAS, PI3K genes. BRAF mutation V600E was identified in 50 cases (75%). The frequency of V600E in women accounted of 75 ± 6.4%, in men - 67 ± 27.1%. In patients with the presence of V600E the size of a node was slightly less than in the absence of mutations and in 76% of cases did not reach the average value of 1.8 cm. Invasion into the capsule was identified in 35 ± 12.7% cases with a positive BRAF mutation V600E status and in 56 ± 8.4% - in cases with a negative status. Metastases in regional lymph nodes occurred in 36 ± 11.6% in patients with V600E and in 47 ± 18.9% of cases without this mutation. There was obtained the interrelationship between V600E and Ki-67: the average level of the proliferative activity in the presence of the given mutation was 4.4 ± 0.6%, in the absence - 9.4 ± 3.9%. No interrelationship was obtained between V600E and other biomolecular parameters or this interrelationship was tendentious in character. In terms of 10-years survival the groups with or without V600E statistically did not differ. Based on the data, it was possible to say about the absence of the negative impact of V600E on the prognosis in PTC patients

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BRAF V600E Confers Male Sex Disease-Specific Mortality Risk in Patients With Papillary Thyroid Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2018.78.5097 ◽

2018 ◽

Vol 36 (27) ◽

pp. 2787-2795 ◽

Cited By ~ 17

Author(s):

Fei Wang ◽

Shihua Zhao ◽

Xiaopei Shen ◽

Guangwu Zhu ◽

Rengyun Liu ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Mortality Rates ◽

Interquartile Range ◽

Braf V600e ◽

Papillary Thyroid ◽

Wild Type ◽

Specific Mortality ◽

Male Sex ◽

Multivariable Adjustment

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women ( P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women ( P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women ( P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.

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BRAF V600E Maintains Proliferation, Transformation, and Tumorigenicity of BRAF-Mutant Papillary Thyroid Cancer Cells

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2006-1613 ◽

2007 ◽

Vol 92 (6) ◽

pp. 2264-2271 ◽

Cited By ~ 74

Author(s):

Dingxie Liu ◽

Zhi Liu ◽

Stephen Condouris ◽

Mingzhao Xing

Keyword(s):

Cell Proliferation ◽

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Nude Mice ◽

Braf Mutation ◽

Soft Agar ◽

Braf V600e ◽

Papillary Thyroid ◽

Small Interference Rna

Abstract Context: Although the BRAF V600E mutant can initiate the formation of papillary thyroid cancer (PTC), it is unclear whether it is required to maintain cell proliferation, transformation, and tumor growth of BRAF mutation-harboring PTC. Objective: The aim of the study was to investigate whether BRAF V600E is required for the proliferation, transformation, and tumorigenicity of BRAF mutation-harboring PTC cells. Design: We addressed this issue using BRAF small interference RNA (siRNA) to transfect stably several BRAF mutation-harboring PTC cell lines, isolated clones with stable suppression of BRAF, and assessed their ability to proliferate, transform, and grow xenograft tumors in nude mice. Results: PTC cell proliferation and transformation were suppressed in specific BRAF siRNA clones, but not in control scrambled siRNA clones. Specifically, taking the advantage of stable BRAF knockdown, we were able to show continued suppression of PTC cell proliferation and transformation, or anchorage-independent colony formation in soft agar, after long-term culture. Moreover, we also demonstrated that in vivo tumorigenicity and growth of tumors from the specific BRAF siRNA cell clones in nude mice were suppressed compared with control clones. Conclusions: BRAF V600E is not only an initiator of PTC as demonstrated previously but is also a maintainer of proliferation, transformation, and tumorigenicity of PTC cells harboring BRAF mutation, and growth of tumors derived from such cells continues to depend on BRAF V600E. These results provide further support for potentially effective therapy targeted at BRAF for BRAF mutation-harboring PTC.

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Concomitant BRAF Mutation in Hairy Cell Leukemia and Papillary Thyroid Cancer

Blood ◽

10.1182/blood-2018-99-116084 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5140-5140

Author(s):

Shehab Mohamed ◽

Mohamed A Yassin ◽

Abdulqadir Jeprel Nashwan ◽

Halima El Omri ◽

Firyal Ibrahim ◽

...

Keyword(s):

Bone Marrow ◽

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Hairy Cell Leukemia ◽

Braf Mutation ◽

Braf V600e ◽

Hairy Cell ◽

Papillary Thyroid ◽

Cell Leukemia ◽

Cell Neoplasm

Abstract Hairy cell leukemia (HCL) is an uncommon but distinct form of mature B-cell neoplasm that originates from activated late B-cells. It represents only 2% of all adult lymphoid leukemia; patients are predominantly middle-aged to elderly males with a median age of 50 years and is characterized by pancytopenia, monocytopenia and usually associated with massive splenomegaly. HCL associated with BRAF mutation 100% of cases, it's associated with hematological and oncological malignancies such as melanoma and papillary thyroid cancer with positive BRAF in 40 % of cases. Although the association of both cancers (HCL & papillary thyroid cancer) with BRAF mutation is well established in the literature, up to our knowledge, this specific combination has not been previously reported in one patient. Here we report a case of 48-year old Lebanese male, who presented to with bilateral hip pain and found to have lytic bone lesions on both x-ray and MRI. HIS CBC were normal and abdominal US didn't show any splenomegaly. Work-up for myeloma were negative. Bone marrow examination and flow cytometry results confirmed the diagnosis of hairy cell leukemia. The patient treated with cladrabine. Patient responded but have continues fever, PUO included Piston tomography showed abnormal uptake in thyroid. Ultrasound and final needle aspiration diagnose him as case of papillary thyroid cancer. He was treated with total thyroidectomy and followed up with RAI 30 micori. We sent BRAF from both bone marrow biopsy and thyroid tissue which turn out positive in both. The mutation results in substitution of adenine for thymine at position 1799 in exon 15 of the BRAF that replaces Valine (V) by glutamate (E) at amino acid 600(BRAF V600E). Although the BRAF V600E mutation is frequently present in different neoplasms, such as melanoma, papillary thyroid cancer, non-small cell lung cancer, colorectal cancer and Langerhans cell histiocytosis (X), within the lymphoid neoplasms, the BRAFV600E mutation is found to be highly specific for HCL and testing for this mutation is particularly useful in differentiating classic HCL from other B- cell neoplasm with overlapping features, such as HCL variant Mutation in BRAF (particularly V600E) in HCL remarkably increase the BRAF kinase activity renders the protein constitutively active, phosphorylating then ERK as a monomers independent from upstream regulatory signals or in a RAS-independent manner leading to constitutive activation of RAF-MEK-ERK signaling pathway and enhanced survival of leukemic hairy cells, similar to what occurs in other BRAF-mutated tumors as papillary thyroid carcinomas Other BRAF mutations outside exon 15 were rarely reported as exon 11 F468C and D449E mutations. We emphasize on the link of BRAF mutation in HCL and papillary thyroid cancer. The biology has been established but never in real clinical case. We recommend having high clinical suspicion and sending BRAF mutation in those types of cancers and link it with other possible abnormal findings, as might detect more cases of similar association. Disclosures No relevant conflicts of interest to declare.

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