Langerhans Cell Histiocytosis (Eosinophilic Granuloma)

Langerhans cell histiocytosis (LCH) is a clonal proliferation of CD1a+ and Langerin+ dendritic cells. The spectrum runs from the solitary eosinophilic granuloma of bone to disseminated multisystem disease (Letterer-Siwe), and treatment follows the extent: observation or curettage for unifocal bone disease, chemotherapy for multisystem involvement. The prognosis is excellent for unifocal disease and guarded when it is disseminated.

Who. Mostly children. The peak is at 5-10 years, 80% of cases occur under the age of 15, and the median age for skeletal LCH is 7. Boys outnumber girls 2:1 overall, 1.5:1 in unifocal disease and 3:1 in multisystem disease. Adults account for 20% of all LCH, usually as unifocal bone disease; neonatal LCH is rare and often multisystem.

How common. Four to nine cases per million children per year, with geographic variation and a higher incidence in Caucasian populations. The skeleton is involved in 80% of all LCH, and 20% of cases are multisystem disease.

Where. A solitary lesion in 60%, multiple lesions in 40%. The skull is the commonest site:

• Skull, 50% - calvarium, temporal bone (mastoid and petrous) and orbit
• Femur, 20% - diaphysis more than metaphysis
• Ribs, 10% - the posterior ribs are common
• Pelvis, 10% - ilium and acetabulum
• Vertebrae, 7% - vertebra plana, thoracic more than lumbar
• Mandible, 5%
• Other, 8% - humerus, scapula, clavicle

Cell of origin. LCH is a clonal proliferation of myeloid dendritic cells, which lie in an infiltrate of eosinophils, lymphocytes and macrophages. Their markers and Birbeck granules are set out under Histopathology.

The MAPK pathway. BRAF V600E, an activating mutation in the MAPK/ERK pathway, is present in 50-60% of cases and more often (60-70%) in multisystem disease. It is associated with an increased risk of recurrence and is the therapeutic target in refractory disease. MAP2K1 mutations are found in 20% of BRAF-negative cases; they activate the MAPK pathway by an alternative route and give a clinical phenotype similar to BRAF-mutated LCH.

RAS pathway mutations and chromosomal abnormalities are rare, and there is no specific chromosomal abnormality. Whether the BRAF mutation tracks disease stage is where the two BRAF evidence cards below part company: the 61-specimen Badalian-Very series found no association with site or stage, the 315-patient Héritier cohort found the mutation enriched in severe disease, and the cards explain the difference.

Classification. Lichtenstein's historical eponyms describe clinical syndromes; the last column of the table gives the modern term for each.

The Histiocyte Society classification in current use divides the disease by extent:

1. Single-system LCH - single-site (the solitary eosinophilic granuloma) or multiple-site (polyostotic, pulmonary)
2. Multisystem LCH - without or with involvement of the risk organs: liver, spleen and bone marrow

Symptoms. The presenting complaints, with their frequencies:

• Localised pain, 60-70% - worse at night and not relieved by rest
• Swelling, 50% - a soft-tissue mass over the bone lesion
• Functional limitation, 30% - a limp with lower-limb lesions
• Incidental finding on imaging, 20% - asymptomatic
• Pathological fracture, 10-15% - in long-bone lesions

Examination. Focal tenderness over the lesion, soft-tissue fullness or a mass, and limited movement when the lesion is vertebral or juxta-articular. A low-grade fever is present in 30% of cases; regional lymphadenopathy is uncommon.

Skull. A palpable defect, a "hole" in the calvarium, or scalp swelling from subperiosteal extension. Mastoid involvement presents as chronic otitis media or a polyp in the external auditory canal, and orbital involvement as proptosis or visual disturbance.

Spine. Back pain with activity, and a thoracic kyphosis when the body collapses to a vertebra plana; complete vertebral collapse is possible. A neurological deficit is rare, in fewer than 5%.

Long bones. Diaphyseal more often than metaphyseal. The periosteal reaction can simulate infection, and the bone may fracture with minor trauma.

Jaw. Loose teeth, gingival swelling, jaw pain and trismus, with the floating-tooth appearance on radiographs.

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Systemic Disease

The Hand-Schüller-Christian triad. The classic triad of multisystem disease:

1. Diabetes insipidus, in 25% of multisystem cases
2. Exophthalmos, from orbital involvement
3. Lytic skull lesions

Risk organs. Involvement of the liver, spleen or marrow is what separates high-risk multisystem disease:

• Liver - hepatomegaly, jaundice and dysfunction; a poor prognostic sign
• Spleen - splenomegaly and hypersplenism
• Bone marrow - cytopenias or pancytopenia

Lung. Cough, dyspnoea and pneumothorax, usually in older children and adults. The smoking-associated adult form has its own section below.

Skin and elsewhere. The skin is involved in 30-40% of multisystem cases, as a seborrhoeic dermatitis-like rash on the scalp and behind the ears or a papular eruption on the trunk and groin. Cervical and axillary lymphadenopathy, hepatosplenomegaly and, in disseminated disease, failure to thrive complete the picture.

Radiographs

Skull. A punched-out lytic lesion with well-defined margins. The bevelled edge, with the inner table destroyed more than the outer, is highly specific for LCH in children. A central fragment of bone within the lesion is the button sequestrum, and multiple coalescent lesions give the geographic skull.

Spine. Vertebra plana is complete collapse of an isolated vertebral body, the pancake vertebra, with the disc spaces preserved and no paraspinal soft-tissue mass. The preserved discs distinguish LCH from infection, where discitis destroys the disc, and from metastasis; the absent mass points away from tumour and infection.

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Long bones. A lytic lesion, diaphyseal or metaphyseal, with moth-eaten or permeative destruction. The periosteal reaction may be laminated, solid or onion-skin; a sequestrum can form, and the lesion may present as a pathological fracture.

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Advanced Imaging

MRI. MRI defines soft-tissue extension and spinal canal involvement, and for a spinal lesion it is essential to rule out epidural extension or instability. The lesion's signal:

• T1: low signal
• T2: high signal, with surrounding marrow oedema
• STIR: bright, with an extensive oedema pattern
• Contrast: marked enhancement (hypervascular)

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CT. Superior for cortical bone detail. It delineates skull-base and orbital lesions and vertebral body integrity, and 3D reconstruction helps plan surgery.

Nuclear medicine. A Tc-99m bone scan shows increased uptake at lesion sites. PET-CT is more sensitive than the skeletal survey for bone lesions and for multifocal disease, detects occult and extraskeletal involvement, and is useful for monitoring treatment response.

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Skeletal survey. Mandatory in every case of LCH, because finding multifocal disease changes prognosis and treatment:

• AP and lateral skull, spine and pelvis
• AP chest, including the ribs
• AP long bones, both sides

Laboratory Tests and Staging

Baseline studies. What each is for:

• Full blood count - cytopenias from marrow involvement
• ESR and CRP - often raised but non-specific
• Liver function tests - liver dysfunction; add PT and PTT if the liver is involved
• Renal function - a baseline before chemotherapy

Suspected diabetes insipidus. A water deprivation test showing a low urine osmolality, urinalysis for polyuria and a low specific gravity, and serum and urine osmolality to confirm it.

Staging. Skeletal survey or PET-CT, chest radiograph or CT for pulmonary involvement, and abdominal ultrasound or MRI for the liver and spleen. Consider a bone marrow biopsy if there are cytopenias.

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Histopathology

Macroscopic. Tan-grey, granular, friable soft tissue, without gross necrosis or haemorrhage.

Microscopic. Large Langerhans cells with abundant eosinophilic cytoplasm and eccentric, reniform coffee-bean nuclei with nuclear grooves and fine chromatin. Eosinophils are prominent and may form microabscesses, among T lymphocytes, scattered macrophages and occasional multinucleated giant cells. Necrosis may be present in active lesions.

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Immunohistochemistry. CD1a and Langerin make the diagnosis:

• CD1a - positive, membranous; the hallmark
• Langerin (CD207) - positive, cytoplasmic; more specific than CD1a
• S100 - positive, nuclear and cytoplasmic
• CD68 - variable
• Cytokeratin - negative, which helps exclude carcinoma

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Electron microscopy. Birbeck granules, rod-shaped cytoplasmic inclusions with a "tennis racket" or "zipper" appearance, are diagnostic but not required: CD1a and Langerin are sufficient.

Molecular testing. BRAF V600E mutation analysis, on paraffin-embedded tissue or blood, guides decisions about targeted therapy.

Infection. Blood cultures, bone biopsy and the clinical course separate it from LCH.

• Osteomyelitis - fever, raised white cell count and CRP, metaphyseal location
• Discitis - disc space narrowing, where LCH vertebra plana preserves the disc
• Tuberculous osteomyelitis - chronic course, epidemiology

Tumour. Biopsy and immunohistochemistry make the distinction.

• Ewing sarcoma - diaphyseal, onion-skin periosteal reaction, soft-tissue mass
• Osteosarcoma - metaphyseal, sunburst periosteal reaction, raised ALP
• Metastases - neuroblastoma in children, carcinoma in adults
• Lymphoma - older children and adults, systemic symptoms

Other histiocytic disorders. Separated by age, site or immunophenotype.

• Erdheim-Chester disease - adults, bilateral femoral and tibial diaphyseal sclerosis
• Rosai-Dorfman disease - massive lymphadenopathy, S100+ CD1a- cells
• Juvenile xanthogranuloma - skin lesions, CD68+ CD1a- cells

Metabolic and other. The remaining mimics.

• Fibrous dysplasia - ground-glass matrix, no Langerhans cells
• Hyperparathyroidism - brown tumours, raised PTH, multiple lesions
• Multiple myeloma - adults, monoclonal protein, plasma cells on biopsy

Stage first. The extent of disease and whether the risk organs are involved set the treatment.

Unifocal Bone DiseaseSystemic TherapySpine, Fracture and Surgery

Observation is a valid first line for the unifocal lesion: half resolve spontaneously within 1-2 years. The alternatives are chosen by symptoms, the bone involved and structural risk.

Observation. For the asymptomatic lesion in a non-weight-bearing bone with no structural risk. Monitor clinically and radiographically every 3-6 months until the lesion heals or stabilises.

Curettage with or without bone grafting. For pain, a weight-bearing bone or structural risk. Intralesional curettage with a local adjuvant (phenol or hydrogen peroxide) and autograft or allograft gives 90% local control and a recurrence rate under 10%; the bone fractures during healing in 5-10%. The approach depends on the site, the cavity is curetted thoroughly, and prophylactic fixation is added if there is structural concern.

Intralesional steroid injection. Methylprednisolone 80-120 mg, for vertebral lesions and inaccessible sites. It is minimally invasive, accelerates healing and is effective in 70-80%, though the injection may need repeating.

En bloc resection. For expendable bones (rib, fibula, clavicle). Local control is near 100%, and diagnosis and cure come in a single procedure.

Radiotherapy. Previously common and now avoided in children, because of the risk of secondary malignancy and growth-plate damage. Its role is very limited, to refractory cases, at 6-10 Gy if absolutely necessary.

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Multifocal bone and multisystem disease are treated with chemotherapy.

First line. The Histiocyte Society LCH-III backbone:

• Vinblastine 6 mg/m² IV weekly for 6 weeks, then every 3 weeks
• Prednisolone 40 mg/m² orally daily for 4 weeks, then tapered
• Duration 12 months for multifocal bone disease, 12-24 months for multisystem disease

Risk-organ involvement. Intensification adds mercaptopurine or methotrexate, doses more frequently and extends treatment to 24 months. Read the LCH-III card below alongside this: adding methotrexate to vinblastine and prednisone gave no additional benefit, and the randomised gain in that trial, lower reactivation in risk-organ-negative patients, came from treating for 12 months rather than 6.

Refractory disease. The second-line options:

• Cytarabine (Ara-C), in high-dose protocols
• Cladribine (2-CDA), 5 mg/m² IV daily for 5 days, in monthly cycles
• BRAF inhibitors (vemurafenib, dabrafenib) if the lesion is BRAF V600E-positive
• MEK inhibitors (trametinib, cobimetinib); as targeted therapy, these are the option for MAP2K1-mutated disease

Targeted therapy. BRAF V600E inhibitors are indicated for refractory multisystem disease with the BRAF mutation. Vemurafenib is given at 20 mg/kg/day in children (the dose used in the 54-child international series, PMID 31513482), commonly divided twice daily; adults in VE-BASKET received 960 mg twice daily. The toxicities are rash, photosensitivity and arthralgia.

Response rates of 60-70% are quoted in the salvage setting. The VE-BASKET card below shows why that figure needs care: only 4 of its 26 patients had LCH, no LCH-specific response rate was reported, and in the paediatric series 24 of 30 children who stopped vemurafenib reactivated.

Evidence

LCH-III Trial — Prolonging Therapy Cuts Reactivation

Level I (RCT)

Gadner H, Minkov M, Grois N, et al. • Blood (2013)

Key Findings:

• Risk-adjusted randomised trial: over 400 multisystem LCH patients stratified by risk-organ involvement
• Risk-organ-positive patients: 5-year survival 84%, reactivation 27% — superior to historical 6-month LCH-I/LCH-II regimens
• Adding methotrexate to vinblastine + prednisone gave no additional benefit
• Risk-organ-negative patients: 12-month treatment lowered 5-year reactivation to 37% vs 54% with 6-month treatment
• Establishes vinblastine + prednisone for 12 months as the standard first-line backbone

Clinical implication: Treatment duration matters: extending front-line therapy to 12 months reduces reactivation, while methotrexate intensification does not improve survival.

Limitation: THE RANDOMISED COMPARISON IN THE RISK-ORGAN-POSITIVE GROUP WAS NULL - adding methotrexate changed nothing, and the celebrated survival improvement to 84 percent is a HISTORICAL comparison against LCH-I (62 percent) and LCH-II (69 percent), separated by years of changing supportive care, imaging, referral and salvage practice. Sequential trials are not arms. The genuinely randomised result on this card is the other one: in risk-organ-NEGATIVE patients, 12 months of treatment gave a 5-year reactivation rate of 37 percent against 54 percent at 6 months, p = 0.03 - and note that this is reactivation, not survival, which was already near-universal in that group. Randomisation to duration occurred only after a response at 6 weeks, so the duration comparison applies to responders and says nothing about the early non-responder. Reactivation at 27 to 37 percent also means prolonging therapy reduces relapse without preventing it.

Verify on PubMed (PMID 23589673)

Evidence

VE-BASKET — Vemurafenib in BRAF V600 Histiocytosis

Level II (Phase 2)

Diamond EL, Subbiah V, Lockhart AC, et al. • JAMA Oncology (2018)

Key Findings:

• Histology-independent phase 2 basket study: 26 adults with BRAF V600-mutant histiocytosis (22 Erdheim-Chester disease, 4 LCH)
• Confirmed objective response rate 61.5% (95% CI 40.6-79.8); all evaluable patients achieved stable disease or better
• 2-year progression-free survival 86%, 2-year overall survival 96%
• All 15 patients assessed by FDG-PET achieved a metabolic response (80% complete metabolic response)
• Toxicity: arthralgia, maculopapular rash, fatigue, skin papilloma, QT prolongation

Clinical implication: BRAF inhibition is highly effective in BRAF V600-mutant refractory disease and is now a standard salvage option; however durable cure is uncommon and disease often rebounds on discontinuation.

Limitation: ONLY FOUR OF THE TWENTY-SIX PATIENTS HAD LCH - the cohort is 22 Erdheim-Chester disease and 4 LCH, so the headline 61.5 percent response rate is overwhelmingly an Erdheim-Chester result and no LCH-specific response rate is reported. Median age was 61 years with a range of 51 to 74, meaning not one participant was a child, while LCH is predominantly a disease of young children - for paediatric dosing and outcomes the relevant source is Donadieu's international observational study of 54 children (PMID 31513482), not this trial. The design is open-label, non-randomised and single-arm with no control, and the sponsor employed several of the authors. Most importantly for counselling, response is not cure: in the paediatric series, 24 of 30 children who stopped vemurafenib reactivated, and no maintenance strategy tested eradicated the mutant clone.

Verify on PubMed (PMID 29188284)

Vertebra plana. Observation relies on spontaneous reconstitution, which usually occurs (50-70%), gradually over 2-5 years and often incompletely. A brace is for kyphotic deformity or instability, and a steroid injection accelerates healing and reduces pain. Surgery is usually avoided, with steroid injection preferred, and is very rare, for neurological compromise only.

Instability or neurological signs. MRI assesses epidural extension, and a neurosurgeon is consulted. Decompression, with or without stabilisation, is for cord compromise, through a posterior approach for epidural extension; anterior corpectomy is rarely needed. Chemotherapy is the definitive treatment and surgery only an adjunct.

Pathological fracture. Managed conservatively in a cast, splint or brace, and the lesion usually heals along with the fracture; closed reduction and casting are usually sufficient. Surgery is rarely needed, for non-union or severe displacement, and an unstable pattern is fixed internally, with curettage of the lesion at the same time if it is accessible.

Indications for surgery. Surgery has five roles in LCH:

1. Diagnostic biopsy
2. Symptomatic relief of pain or mass effect
3. Structural instability, with a risk of pathological fracture
4. Neurological compromise from spinal cord compression
5. Failed conservative management

Diabetes insipidus. Develops in 18-25%, from involvement of the hypothalamic-pituitary axis; craniofacial bone lesions and multisystem disease are the risk factors. It presents with polyuria, polydipsia and hypernatraemia, is diagnosed as above, and is managed with lifelong desmopressin (DDAVP).

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Orthopaedic sequelae. The skeletal legacy of the disease:

• Vertebral collapse and kyphosis, 10-15%
• Limb length discrepancy after femoral lesions
• Malunion or nonunion of a pathological fracture, which is rare
• Joint stiffness after juxta-articular lesions
• Premature physeal closure after metaphyseal lesions

Neurocognitive dysfunction. Affects 10-20% and is associated with multisystem disease: cerebellar involvement (ataxia, dysarthria), behavioural and learning difficulties, and white-matter changes or cerebellar atrophy on MRI. Neurodegenerative LCH, the progressive late CNS syndrome, has its own section below.

Pulmonary. Spontaneous pneumothorax, respiratory failure with diffuse involvement, and progressive fibrosis in chronic disease.

Other. Hearing loss with temporal bone involvement, dental problems with mandibular lesions, sclerosing cholangitis with liver involvement, and growth retardation from pituitary dysfunction.

Prognosis

Favourable factors. Unifocal bone disease, single-system involvement, age over 2 years and a good response to initial therapy.

Unfavourable factors. These predict a worse course:

• Age under 2 years
• Risk-organ involvement: spleen involvement, marrow dysfunction with cytopenias, hepatomegaly or abnormal liver function tests
• Poor response to initial chemotherapy at 6 weeks
• Multisystem disease involving more than 3 organs
• Recurrent or reactivating disease (a 46-58% rate)
• Growth failure and systemic symptoms (fever, failure to thrive)

Age needs reading together with the risk organs. In LCH-II, children under 2 without risk-organ involvement had 100% survival, and risk-organ involvement, not age alone, was the dominant prognostic factor.

What it is. Neurodegenerative LCH (LCH-ND) is a progressive, non-mass CNS syndrome that can appear months to many years after the systemic disease has apparently resolved, and is a leading cause of long-term morbidity in survivors. It is distinct from a space-occupying CNS LCH lesion: there is no tumour to resect.

Who is at risk. The strongest associations are craniofacial or "CNS-risk" lesions (orbit, mastoid, temporal, sphenoid, maxilla/zygoma), diabetes insipidus, multisystem disease and BRAF V600E positivity. The lesions that predict diabetes insipidus also predict LCH-ND, and the two often coexist as part of the pituitary-hypothalamic/CNS-risk picture.

Presentation and MRI. Insidious cerebellar signs (ataxia, dysarthria, tremor, dysmetria), pyramidal signs, behavioural and learning decline and eventually cognitive impairment. MRI shows symmetrical T2/FLAIR high signal in the dentate nuclei/cerebellar white matter and basal ganglia, sometimes with cerebellar atrophy. These changes can precede symptoms, so at-risk children are surveilled with MRI.

Mechanism. It is thought to be driven by MAPK-activated myeloid cells seeding the CNS (BRAF V600E has been found in the marrow/blood of affected patients), a neuro-inflammatory/degenerative process rather than direct tumour.

Management. Difficult and not standardised. The options include chemotherapy (cytarabine) and, increasingly, MAPK-pathway (BRAF/MEK) inhibitors, with the hope, unproven, that early targeted therapy may prevent or halt progression. Established neurodegeneration is often irreversible, which is why recognition and surveillance matter.

A different disease in adults. Isolated pulmonary LCH (PLCH) is largely a disease of young-to-middle-aged adult smokers, typically 20-40 years, with a roughly equal sex incidence. Unlike multisystem childhood LCH, it is often a reactive, polyclonal response to cigarette smoke (though clonal BRAF V600E-positive forms also occur), which is why it behaves differently.

Presentation. Cough and dyspnoea, or an incidental finding. A classic acute presentation is spontaneous pneumothorax from cyst rupture, which can be recurrent. Constitutional symptoms and extrapulmonary disease are usually absent in the isolated pulmonary form.

Imaging. HRCT is characteristic: combined nodules and thin-walled cysts with an upper- and mid-zone predominance, sparing the costophrenic angles and lung bases. That is the reverse of the basal predominance of many other cystic and fibrotic lung diseases. The nodules cavitate into cysts over time.

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Management. Smoking cessation is first-line and the single most important intervention; it can stabilise or regress the disease. Systemic therapy (such as cladribine, or MAPK-directed therapy in clonal disease) is reserved for progressive disease, and lung transplantation for end-stage fibrosis, with a risk of recurrence, especially if smoking resumes. Recurrent pneumothorax may need pleurodesis.

Global Epidemiology

• Incidence approximately 4-9 per million children per year; rarer in adults (1-2 per million)
• Peak 1-3 years for multisystem disease; 5-10 years for single-system bone disease
• Slight male predominance (around 1.2-2:1); reported across all populations worldwide
• Bone is the most common organ involved overall (around 80% of paediatric cases)
• Pulmonary LCH in adults is strongly smoking-associated and follows a distinct natural history

Side-by-Side Guidance

Registry & Trial Networks

• Outcome data are driven by international cooperative trials (LCH-I, LCH-II, LCH-III, LCH-IV) rather than implant/arthroplasty registries
• The Histiocyte Society coordinates global protocol enrolment; regional groups (e.g. NACHO in North America, national paediatric oncology groups in Europe) feed shared datasets
• BRAF/MAPK genotyping is increasingly captured prospectively to stratify targeted-therapy use

High- vs Limited-Resource Practice

• High-resource: routine BRAF/MAP2K1 genotyping, PET-CT staging, access to BRAF/MEK inhibitors and cladribine/cytarabine salvage, long-term endocrine/neurocognitive surveillance
• Limited-resource: diagnosis may rest on morphology plus CD1a/S100 where Langerin and molecular testing are unavailable; skeletal survey substitutes for PET-CT; vinblastine + prednisone remains the affordable, effective backbone; targeted agents often inaccessible
• Universal principles: confirm tissue diagnosis, stage for risk organs, avoid radiotherapy in children, and screen lifelong for diabetes insipidus

• Reactive vs neoplastic: the discovery of clonal MAPK mutations (BRAF V600E, MAP2K1) reframed LCH as an inflammatory myeloid neoplasm, yet the prominent inflammatory infiltrate keeps the "neoplasia vs immune dysregulation" debate alive.
• Optimal duration of targeted therapy: BRAF/MEK inhibitors produce rapid responses but disease frequently rebounds on cessation, and the ideal duration, role of combination with chemotherapy, and long-term toxicity in children remain undefined.
• Vertebra plana management: the balance between observation, intralesional steroid and bracing is not standardised; most lesions reconstitute, but predicting the minority that deform is imprecise.
• Neurodegenerative LCH: progressive cerebellar/brainstem neurodegeneration can appear years after apparent cure; its pathogenesis, screening interval, and whether early MAPK-directed therapy prevents it are unresolved.
• Role of PET-CT vs skeletal survey: PET-CT is more sensitive for occult and extraskeletal disease, but cost, radiation and access limit universal use, so staging strategy varies by setting.