INTRODUCTION
Langerhans cell histiocytosis (LCH) is an exceptionally rare malignancy characterized by inflammatory lesions featuring pathological clonal infiltration of cells belonging to the mononuclear phagocyte system, which exhibit phenotypical traits resembling Langerhans cells, notably expressing CD1a and CD207 (1). It is an exceptionally rare disease, with reported incidence rates ranging from 2.6 to 8.9 cases per million among children under 15 years of age, peaking at an average age of approximately three years (2). Notably, the disease presents a diverse clinical course, ranging from self-limited forms to aggressively progressive multisystemic variants, often entailing an unfavorable prognosis (3).
To address this diversity, the therapeutic approach to LCH is intricately tailored based on the extent of organ involvement. In cases of localized, single-organ disease, a watch-and-wait strategy may suffice. Alternatively, when isolated bone involvement occurs, surgical interventions may be considered. Notably, localized disease often carries a favorable prognosis (4).
Conversely, multisystemic disease is characterized by the presence of affected risk organs such as the bone marrow, spleen, and liver, significantly worsening the prognosis (5). One persistent challenge in LCH treatment is the notable rate of disease reactivation, particularly in instances where risk organs are implicated (6). Patients with refractory histiocytosis typically exhibit characteristics such as age under 2 years, risk organ involvement, elevated inflammatory markers, resistance to standard treatment, and often harbor the BRAF V600E mutation (7).
Recent advancements have illuminated the pathophysiology of LCH, unveiling the pivotal role of the ”Ras/Raf/MEK/ERK” signaling pathway in myeloid differentiation. Within the spectrum of mutations, the BRAF mutation stands out as the most prevalent, accounting for over 50% of LCH cases. It is closely associated with severe clinical presentations, heightened resistance to conventional chemotherapy, and an increased risk of relapse (8). The BRAF gene regulates the synthesis of the BRAF protein, a crucial component of the RAS/MAPK signaling pathway that governs fundamental cellular processes such as proliferation, differentiation, migration, and apoptosis (9). In the presence of BRAF mutations, the aberrant BRAF protein perpetuates unregulated signaling to the cell nucleus, fueling unrestrained growth and differentiation of Langerhans cells (10). Other genetic mutations, including those within the MAP2K and ARAF genes, have also been identified (11).
With these recent molecular insights into the central role of the BRAF mutation in LCH pathogenesis, Vemurafenib has emerged as a therapeutic option for children grappling with high-risk multisystemic disease that proves refractory to conventional treatments or experiences recurrent relapses. Vemurafenib (VMF), initially approved for metastatic melanoma in adults, has demonstrated the capacity to target and inhibit the BRAF V600E mutation (12). While the off-label use of VMF in refractory multisystemic LCH among children persists in Brazil, the European Medicines Agency has sanctioned its utilization. Observational studies in Europe have already attested to the safety and efficacy of VMF in children afflicted with refractory LCH carrying the BRAF V600E mutation (13). However, it is crucial to underscore that this therapeutic approach has yet to definitively eradicate the neoplastic clone, and long-term toxicities remain a subject of ongoing investigation (14).
In this paper, we will delineate the cases of two Brazilian children suffering from refractory LCH, which remained unresponsive to both standard and second-line treatments but exhibited a positive response to Vemurafenib therapy. Furthermore, we will provide an extensive review of the current literature on this subject.