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.