Langerhans cell histiocytosis (LCH) is a disease in which Langerhans cells, which are antigen-presenting cells derived from bone marrow, infiltrate and proliferate monoclonally in various organs. Formerly collectively referred to as “histiocytosis X,” it includes the following three diseases:
In 1868, German physician Paul Langerhans first described Langerhans cells in the epidermis. It took over a century to elucidate their hematopoietic origin and antigen-presenting function as dendritic cells. In 2016, the International Histiocyte Society proposed a revised classification, categorizing LCH into group L (Langerhans group)4).
LCH is primarily a childhood disease, with a peak incidence between 1 and 10 years of age. The annual incidence is reported as 4.6–8.9 per million children under 15 years of age1)2)3). The median age at diagnosis is 3 years2), and the male-to-female ratio is 1.5:1, with a slight male predominance4). Children under 2 years of age tend to have a more aggressive course and poorer prognosis. LCH accounts for 1–3% of orbital tumors in children.
The annual incidence of LCH is approximately 5 to 9 per 1 million children under 15 years of age. It accounts for 1–3% of pediatric orbital tumors and, although rare, is an important differential diagnosis in children with orbital tumors.
The main symptoms of orbital LCH are as follows:
In children under 2 years of age, the disease progresses rapidly and often involves multiple organs.
LCH lesions prefer hematopoietic active bone marrow, so in the orbit they are most commonly found in the superotemporal orbit.
Eosinophilic Granuloma
Solitary bone lesion: Commonly occurs in individuals aged 20 years or younger, especially those under 10 years old.
Imaging findings: Tumor formation with bone destruction. Osteolytic defects (punch-out lesions).
Prognosis: Favorable, with spontaneous healing expected.
Hand-Schuller-Christian disease
Triad: Exophthalmos, osteolytic bone lesions (multiple skull defects), and diabetes insipidus.
Bone defects: Over 90% occur in the skull (including the orbital bones).
Others: Skin lesions (xanthomas), lung lesions, pituitary infiltration.
Letterer-Siwe disease
Onset: Most cases occur before 1 year of age.
Systemic: Hepatosplenomegaly, lymphadenopathy, skin eczema, fever, general weakness.
Prognosis: Extremely poor.
In a study of 24 consecutive cases at a tertiary medical institution, orbital involvement was observed in 9 cases (37.5%). The most commonly affected site was the frontal bone (n = 6), followed by the zygomatic bone (n = 3), sphenoid bone (n = 3), and maxilla (n = 2).
As systemic findings outside the orbit, bone lesions are the most frequent (approximately 80%), with the skull being the most common site 2)4). Skin lesions are observed in about one-third of patients, presenting as seborrheic dermatitis-like rashes, erythematous papules, and small vesicles 4).
The etiology of LCH is not fully understood. There was once a debate between neoplastic and reactive origins, but recent molecular genetic findings have advanced the understanding of LCH as a neoplastic disease.
One hypothesis is that transient immune dysfunction (e.g., viral infection) induces cytokine-mediated proliferation of susceptible Langerhans cells.
The BRAF V600E mutation is a genetic abnormality detected in 50–65% of LCH patients. It constitutively activates the MAPK pathway, promoting the proliferation of Langerhans cells. The presence of this mutation is associated with more severe multi-system disease.
Biopsy is essential for definitive diagnosis. The following immunostaining criteria are used for diagnosis 1)2)3).
Histologically, granulomatous lesions composed of Langerhans cells, macrophages, eosinophils, T lymphocytes, and plasma cells are observed. Infiltration of histiocyte-like cells with relatively abundant pale eosinophilic cytoplasm and kidney-shaped nuclei is characteristic. Electron microscopy reveals tennis racket-shaped Birbeck granules.
BRAF V600E mutation testing is useful for diagnostic assistance and treatment decision-making2)6).
The following diseases should be considered in the differential diagnosis of pediatric orbital lesions:
| Pathology | Representative Diseases |
|---|---|
| Inflammatory | Orbital cellulitis, orbital pseudotumor, sarcoidosis |
| Malignant tumors | Rhabdomyosarcoma, leukemia, metastatic neuroblastoma |
| Other tumors | Ewing sarcoma, orbital metastasis of Wilms tumor |
| Granulomatous | Granulomatosis with polyangiitis (GPA) |
Histopathological examination by biopsy is essential for definitive diagnosis. Immunostaining should confirm positivity for CD1a, S-100, and Langerin (CD207). Imaging (CT, MRI) is useful for evaluating the extent of the lesion.
Once a pathological diagnosis of eosinophilic granuloma is confirmed, follow-up observation with imaging is performed first. In cases where inflammatory symptoms or pain do not improve, or where there is a high risk of fracture, surgical curettage is performed to promote natural healing. Corticosteroids or low-dose radiation therapy may also be used.
In Hand-Schüller-Christian disease, corticosteroids are effective in controlling granulomatous inflammation. Immunosuppressants and low-dose radiation therapy are also used.
Steroid therapy and chemotherapy are effective, and hematopoietic stem cell transplantation is also performed in refractory cases.
In all patients with orbital LCH, biopsy is necessary to confirm the diagnosis and rule out other malignancies. Referral to a pediatric oncologist is recommended.
Single-system, single-site
Local treatment: Limited curettage plus intralesional steroid injection.
Observation: Spontaneous regression after biopsy can be expected.
Methylprednisolone: Single intralesional injection resulted in resolution of 31 out of 35 lesions (89%).
Recurrence rate: Approximately 15%.
Multicentric, Multiorgan Type
First-line: Systemic chemotherapy with vinblastine plus prednisone (12 months) 1)2).
LCH-III protocol: Initial Pred 40 mg/m2 for 4 weeks + VCR 6 mg/m2 IV weekly (W1-6). Maintenance Pred + VCR q3w + 6-MP 50 mg/m2/day (W7-52) 5).
CNS-risk lesions: Systemic therapy is mandatory.
For a single lesion without intracranial extension, limited curettage and intralesional steroid injection are the mainstays. For multisystem disease or CNS risk lesions, systemic chemotherapy with vinblastine and prednisone (for 12 months) is required.
Prognosis is good for children aged 2 years or older without multisystem disease. In a Mayo Clinic cohort study of 314 patients, 97% (114 of 114) of patients with isolated bone LCH achieved disease-free survival after treatment. Disease-free survival was 91% for single-system disease and 74% for multisystem disease, a significant difference (P < 0.003).
Orbital LCH often presents as an isolated single lesion, but regular follow-up is essential because multi-organ involvement may become apparent later even if initial workup is negative.
The core pathology of LCH is clonal proliferation of defective immature Langerhans cells. Pathological Langerhans cells express CD1a+/CD207 (Langerin)+ markers and form granulomatous lesions in various tissues 3).
BRAF V600E mutation is detected in approximately 50–65% of LCH cases 2). Additionally, MAP2K1 mutations are found in up to 33% of BRAF wild-type cases 1). Both mutations constitutively activate the RAS-RAF-MEK-ERK signaling pathway (MAPK pathway), driving clonal myeloid tumor cell proliferation 1).
It is suggested that BRAF V600E mutation occurring at the myeloid progenitor cell level is associated with more severe multi-organ disease, while mutation at the differentiated dendritic cell level is linked to more localized clinical presentation 2).
LCH lesions progress in stages3).
For refractory LCH with BRAF V600E mutation, vemurafenib has shown initial efficacy and safety in a phase II open-label trial (VE-BASKET study)1). However, further clinical trials are needed for clinical application.
The MEK inhibitor cobimetinib has been reported for the treatment of congenital LCH 2). Protein kinase inhibitors targeting the MAPK pathway may become important future treatment options for refractory cases.
SIRPa (signal regulatory protein alpha) is a transmembrane protein expressed on CD1a+ dendritic cells and has been proposed as a new therapeutic target for LCH 2). Additionally, germline mutations in the SMAD6 gene have been reported to increase susceptibility to LCH, advancing the understanding of genetic predisposition 2). Personalized treatment integrating molecular targeted therapy and immunotherapy is expected as a future prospect.
