What is Langerhans Cell Histiocytosis?
Langerhans cell histiocytosis (LCH) is a clonal neoplastic disorder—not an inflammatory condition—driven by MAPK/ERK pathway mutations (particularly BRAF V600E in >90% of cases) characterized by the proliferation and infiltration of specific histiocytic cells (Langerhans cells) into various organ systems. 1, 2
Disease Classification and Pathogenesis
LCH is now classified as an inflammatory myeloid neoplasm according to the revised 2016 Histiocyte Society classification, representing a fundamental shift from viewing it as a reactive inflammatory process. 3
The BRAF V600E mutation is the primary oncogenic driver, present in over 90% of cases, with 100% of LCH cases showing ERK phosphorylation, confirming its neoplastic nature. 1, 2, 3
The disease represents clonal proliferation of pathologic Langerhans cells that morphologically resemble skin Langerhans cells but actually originate from myeloid dendritic cells. 3, 4
Clinical Spectrum and Organ Involvement
The clinical presentation ranges from isolated single-organ disease to life-threatening multisystem involvement:
Most Common Sites of Involvement
Bone lesions (60% of patients): Aggressive cortically-based osteolytic "punched-out" lesions, particularly affecting the skull, femur, mandible, pelvis, and spine. 1, 5, 6
Pulmonary involvement (50-60% with respiratory disease): Upper lobe-predominant nodular cystic lung lesions, strongly associated with tobacco smoking, presenting with dry cough, dyspnea, and spontaneous pneumothorax in 25% of cases. 7, 1
Endocrine manifestations (40-70%): Central diabetes insipidus is the hallmark endocrine complication, occurring in 50-70% of LCH patients and accounting for 5-10% of apparently idiopathic diabetes insipidus cases. 1, 2
Skin, lymphoid organs, central nervous system, liver, and intestinal tract can also be affected, though hepatic and gastrointestinal involvement is less frequent. 8, 9
Characteristic Clinical Presentations
Asymptomatic radiographic findings occur in approximately 15% of patients. 7
Bone-related symptoms (pain, swelling, pathologic fractures) are the most common presenting complaints. 6
Vertebra plana (complete vertebral body collapse) is a distinctive spinal manifestation. 5
Recurrent pneumothorax may be the initial presentation in pulmonary disease. 7, 9
Diagnostic Requirements
Histopathologic Confirmation (Mandatory)
Definitive diagnosis requires tissue biopsy demonstrating:
Positive immunohistochemistry for CD1a, S100, and Langerin (CD207)—this triad is pathognomonic for LCH. 1, 2
Characteristic Langerhans cells with nuclear grooves (slightly enlarged nuclei with delicate longitudinal indentations). 1
Intermixed eosinophils are commonly numerous within lesions. 1
A comprehensive immunohistochemistry panel (including CD163 or CD68, Factor XIIIa, IgG/IgG4, and CD20) should be performed to exclude mimicking entities. 1
Molecular Testing
BRAF V600E mutation testing should be performed on all tissue samples using immunohistochemistry, PCR, or next-generation sequencing. 1
Negative BRAF V600E immunohistochemistry should be confirmed with molecular testing due to potential insufficient sensitivity of immunohistochemistry alone. 1
Radiographic Features
Imaging characteristics that raise suspicion for LCH:
Skeletal radiographs: Well-defined osteolytic "punched-out" lesions with beveled edges in skull lesions, sharply demarcated margins (unlike the permeative destruction of Ewing sarcoma or diffuse periosteal reaction of osteomyelitis). 5
Chest CT: Characteristic peribronchiolar nodular infiltrates combined with irregularly shaped cystic spaces, with upper and middle lobe predominance and costophrenic angle sparing. 7
The combination of nodules and thin-walled cysts on CT is virtually diagnostic of pulmonary LCH. 7
Required Staging Evaluation (Once Diagnosis Confirmed)
Complete staging workup includes:
Full-body FDG PET-CT (preferred over technetium-99m bone scans for simultaneous bone and soft-tissue assessment). 1
Brain MRI with gadolinium contrast. 1
High-resolution chest CT. 1
Complete blood count with differential (to identify concurrent myeloid neoplasm, present in ~10% of cases). 1
Comprehensive metabolic panel, C-reactive protein, and LDH. 1
Comprehensive endocrine assessment is mandatory (imaging alone is insufficiently sensitive): morning urine and serum osmolality, FSH/LH with testosterone or estradiol, corticotropin with morning cortisol, thyrotropin and free T4, prolactin and IGF-1. 1, 2
Critical Diagnostic Pitfalls
Aggressive bone lesions can mimic Ewing sarcoma or osteomyelitis, requiring careful clinicopathologic correlation—LCH shows sharply demarcated margins rather than permeative destruction or diffuse periosteal reaction. 5
Diabetes insipidus may develop 20-30% of the time in multisystem LCH and can occur years after initial diagnosis, necessitating long-term endocrine surveillance. 1, 2
Ambiguous histopathologic cases require re-evaluation at centers with histiocytosis expertise, particularly when atypical histiocytic infiltrates are present. 1
Approximately 10% of adult LCH patients have a concomitant myeloid neoplasm, which may adversely affect prognosis. 1
Treatment Principles
Smoking Cessation
- Discontinuation of tobacco smoking is critical in pulmonary LCH and can result in clinical improvement in 33% of patients, with potential resolution of cough. 7, 2
Systemic Therapy
Treatments have included systemic corticosteroids, chemotherapeutic drugs (vinblastine with or without prednisolone is most commonly used), and lung transplantation for advanced pulmonary disease. 7, 6
Vemurafenib, a BRAF V600E-specific inhibitor, is FDA-approved for BRAF V600E-mutant histiocytic neoplasms and is effective in refractory or recurrent LCH. 1
Prognosis
The clinical course is variable and unpredictable, ranging from asymptomatic radiographic presentation to progressive respiratory failure and death in approximately 10% of pulmonary cases. 7
Overall survival at 8 years is approximately 84%, with event-free survival of 51.5%. 6
Prognosis is significantly worse in patients younger than 2 years and those with organ dysfunction, particularly pulmonary, hepatic, or hematological involvement. 6
Spontaneous remissions do not occur in established disease. 7