Emerging Evidence of BRAFV600E in LCH: The Iranian Experience

Abstract

Introduction: Langerhans cell histiocytosis (LCH) is an inflammatory neoplasm of myeloid origin. The pathologic CD1a+/CD207+ cells are characterized when mutations in the mitogen-activated protein kinase (MAPK) pathway (particularly in BRAFV600E) are activated and involvement of pulmonary, skeletal, pituitary, and cutaneous is seen. we aimed to evaluate a cohort of pediatric LCH patients regarding BRAFV600E mutations. Methods: Three referral centers between 2009-2020 collected definite LCH patients. The patients classified by the detection of BRAFV600E mutations by real-time polymerase chain reaction (RT-PCR) assay, and comparison was done in demographic and clinical manifestations, response to therapy, and outcome. Results: Among 50 LCH patients, 17 (34%) female and 33 (66%) male, somatic mutations in the BRAFV600E gene were detected in 30 (60%) patients and wild-type genotype was seen in 20 (40%) patients. There was remarkable higher frequency of mutation in young children (less than 8 years old particularly < 2 years, p= 0.024). In this study, 21 patients (42%) had multi-system involvement, with no significant difference between the BRAFV600E positive group (14 out of 21, 66.7%) and the BRAFV600E negative group (7 out of 21, 33.3%, p = 0.380). Among patients with risk organ involvement, the BRAFV600E mutation was present in most cases (7 out of 8), and all four patients with central nervous system involvement had this mutation. Patients with the BRAFV600E mutation showed a lower response to treatment, while those without the mutation responded significantly better to first-line therapies. Notably, 6 out of 7 patients who died had the BRAFV600E mutation. Conclusions: In LCH patients, BRAFV600E mutation may influence the onset age, sort and intensity of clinical symptoms, level of the response to therapy, and prognosis.