# CIM Case: Langerhans Cell Histiocytosis - Eosinophilic Granuloma ## Clinical Scenario **Patient:** 7-year-old boy **Presentation:** Localised skull pain and tender swelling over the right parietal region for 3 weeks, worse at night, mild irritability **Relevant history:** Previously well, no weight loss, no polyuria/polydipsia, normal development, no family history of malignancy **Examination findings:** - 3cm tender, non-mobile swelling over right parietal bone - No overlying skin changes - No lymphadenopathy - No hepatosplenomegaly - No skin rash or petechiae - No exophthalmos - Neurologically intact - No other bony tenderness --- ## Investigations Provided ### Laboratory Results | Test | Result | Normal Range | Interpretation | |------|--------|--------------|----------------| | Haemoglobin | 125 g/L | 115-145 | Normal | | WCC | 8.2 x 10⁹/L | 5-13 | Normal | | Platelets | 280 x 10⁹/L | 150-400 | Normal | | ESR | 25 mm/hr | 0-10 | Mildly elevated | | CRP | 8 mg/L | <5 | Mildly elevated | | LDH | 180 U/L | 120-300 | Normal | | ALP | 220 U/L | 150-400 | Normal (child) | | Albumin | 42 g/L | 35-50 | Normal | | LFTs | Normal | - | No liver involvement | | Urine osmolality | 650 mOsm/kg | 500-800 | Normal (no DI) | ### Imaging **Image 1: Skull X-ray (AP and Lateral)** **Radiological features:** - Well-defined, punched-out lytic lesion in right parietal bone - Size approximately 3 x 2.5 cm - Geographic bone destruction - No sclerotic rim - "Bevelled edge" appearance (outer table more affected than inner) - No periosteal reaction - No soft tissue calcification - No other skull lesions visible **Image 2: CT Head with Bone Windows** **CT findings:** - Sharply marginated lytic lesion - Destruction of both inner and outer tables - Bevelled margins confirming asymmetric involvement - Soft tissue component extending into subgaleal space - No intracranial extension - No dural involvement **Image 3: Skeletal Survey** **Findings:** - No other bony lesions identified - Normal spine (no vertebra plana) - Normal pelvis and long bones - Unifocal disease confirmed ## Questions & Model Answers **Diagnosis: Langerhans Cell Histiocytosis (LCH) - Unifocal Eosinophilic Granuloma** **Radiological Features Supporting Diagnosis:** | Feature | This Case | Significance | |---------|-----------|--------------| | **Punched-out lesion** | Yes | Classic LCH appearance | | **No sclerotic rim** | Yes | Unlike healing lesion or NOF | | **Bevelled edges** | Yes | Asymmetric table destruction = LCH | | **Age 5-15 years** | Yes (7 years) | Peak age for LCH | | **Skull location** | Yes | Most common site for LCH | **Spectrum of Langerhans Cell Histiocytosis:** | Category | Clinical Features | Prognosis | |----------|-------------------|-----------| | **Unifocal (Eosinophilic Granuloma)** | Single bone lesion, most common (70%), skull, femur, ribs, vertebrae | Excellent (>95% cure) | | **Multifocal Unisystem** | Multiple bone lesions, no organ involvement | Good (85-90% cure) | | **Hand-Schüller-Christian** | Classic triad: skull lesions, diabetes insipidus, exophthalmos | Intermediate | | **Letterer-Siwe (Multisystem)** | Skin, liver, spleen, marrow, lungs, often infants | Poor (50-60% survival) | **Common Bone Sites:** | Site | Frequency | Notes | |------|-----------|-------| | Skull | 40-50% | Parietal > frontal > temporal | | Femur | 15-20% | Diaphysis or metaphysis | | Ribs | 10% | Often discovered incidentally | | Vertebrae | 10% | May cause vertebra plana | | Pelvis | 10% | Ilium most common | | Mandible | 5-10% | "Floating teeth" appearance | > **Consultant Tip:** The "punched-out" appearance without sclerotic rim in a child's skull is classic for eosinophilic granuloma. The bevelled edge sign is pathognomonic. **Staging Workup for LCH:** **1. Laboratory Investigations:** | Test | Purpose | |------|---------| | **FBC** | Bone marrow involvement (cytopenia) | | **ESR, CRP** | Disease activity marker | | **LFTs, coagulation** | Liver involvement | | **Urine osmolality/SG** | Diabetes insipidus screening | | **Morning urine sample** | Overnight concentration ability | **2. Imaging:** | Modality | Indication | Notes | |----------|------------|-------| | **Skeletal survey** | PREFERRED for staging | LCH may be "cold" on bone scan | | **Bone scan** | Adjunct, not primary | 30% false-negative rate | | **CT of lesion** | Soft tissue extent, surgical planning | | | **MRI spine** | If vertebral involvement suspected | | | **Chest X-ray** | Pulmonary involvement | | | **Abdominal US** | Hepatosplenomegaly | | **Why Skeletal Survey Over Bone Scan?** | Factor | Skeletal Survey | Bone Scan | |--------|-----------------|-----------| | **Sensitivity for LCH** | 90-95% | 60-70% | | **Reason** | Detects lytic lesions directly | LCH often lacks reactive bone formation | | **Skull lesions** | Excellent | Often missed | | **Recommendation** | ALWAYS perform | Adjunct only | **3. Biopsy:** | Approach | Indication | |----------|------------| | **Excisional** | Small accessible lesions | | **Core needle** | Deep lesions, spine | | **Incisional** | Large lesions, adequate sampling | **This Patient's Staging:** - Skeletal survey: unifocal disease ✓ - Normal bloods: no marrow/liver involvement ✓ - Normal urine osmolality: no diabetes insipidus ✓ - **Classification: Unifocal LCH - excellent prognosis** > **Consultant Tip:** ALWAYS get a skeletal survey - bone scan misses 30% of LCH lesions because they don't show osteoblastic activity. **Histopathology of Langerhans Cell Histiocytosis:** **1. Light Microscopy:** | Finding | Description | |---------|-------------| | **Langerhans cells** | Large cells with kidney-bean/coffee-bean nuclei | | **Nuclear grooves** | Characteristic folded nuclei | | **Eosinophilic cytoplasm** | Abundant pale cytoplasm | | **Eosinophil infiltrate** | Mixed with Langerhans cells (hence "eosinophilic granuloma") | | **Multinucleated giant cells** | May be present | | **Necrosis** | Variable | **2. Immunohistochemistry (Essential for Diagnosis):** | Marker | Result | Significance | |--------|--------|--------------| | **CD1a** | POSITIVE | Specific for Langerhans cells | | **S100** | POSITIVE | Neural crest marker | | **Langerin (CD207)** | POSITIVE | Most specific marker | | **CD68** | Variable | Histiocyte marker | | **CD45 (LCA)** | Positive | Confirms haematopoietic origin | **3. Electron Microscopy (Gold Standard but Rarely Needed):** | Finding | Description | |---------|-------------| | **Birbeck granules** | Pathognomonic "tennis racquet" or "zipper-like" structures | | **Intracytoplasmic** | Pentalaminar rod-shaped organelles | | **Size** | 200-400nm long | **Diagnostic Criteria:** | Level | Requirements | |-------|--------------| | **Presumptive** | Light microscopy consistent with LCH | | **Designated** | Light microscopy + CD1a OR S100 positive | | **Definitive** | Birbeck granules on EM OR Langerin (CD207) positive | **Differential Diagnosis on Histology:** | Condition | Distinguishing Features | |-----------|------------------------| | **Osteomyelitis** | Neutrophils, bacteria, no CD1a | | **Ewing sarcoma** | Small round blue cells, CD99+, t(11;22) | | **Lymphoma** | CD20+ (B-cell) or CD3+ (T-cell) | | **Metastatic neuroblastoma** | NSE+, synaptophysin+, <5 years old | > **Consultant Tip:** CD1a and S100 positivity is sufficient for diagnosis. Electron microscopy for Birbeck granules is rarely needed in modern practice. **Management of Unifocal LCH (Eosinophilic Granuloma):** **Key Principle:** Many lesions self-resolve, especially after biopsy trauma. **Treatment Options:** | Option | Indication | Notes | |--------|------------|-------| | **Observation** | Asymptomatic, post-biopsy | 50% resolve spontaneously | | **Intralesional steroid** | Accelerate healing | Methylprednisolone 40-80mg | | **Curettage ± bone graft** | Large lesions, fracture risk | Healing rate >90% | | **Low-dose radiation** | Inaccessible lesions, spinal cord compression | 6-10 Gy | **Algorithm for This Patient:** ``` Skull lesion confirmed as LCH ↓ Biopsy performed (diagnostic + therapeutic) ↓ Observe for 6-8 weeks ↓ If persistent/symptomatic → Intralesional steroid ↓ If still no response → Curettage ``` **Intralesional Steroid Technique:** | Step | Detail | |------|--------| | **Agent** | Methylprednisolone 40-80mg OR Triamcinolone 20-40mg | | **Frequency** | Single injection, may repeat at 6 weeks | | **Response rate** | 70-90% resolution | | **Mechanism** | Induces apoptosis of Langerhans cells | **Surgical Indications:** | Indication | Rationale | |------------|-----------| | **Impending fracture** | Weight-bearing bone with >50% cortical destruction | | **Pathological fracture** | Stabilisation required | | **Spinal cord compression** | Rare, usually responds to steroids | | **Failed conservative treatment** | Persistent after 3-6 months | **Follow-up Protocol:** | Time | Assessment | |------|------------| | 6 weeks | Clinical + X-ray | | 3 months | X-ray (expect healing) | | 6 months | X-ray | | Annually | Clinical until 2 years | **Expected Outcome for This Patient:** - Unifocal skull LCH: >95% cure rate - High likelihood of spontaneous resolution - No long-term sequelae expected > **Consultant Tip:** Don't rush to treat - many skull lesions resolve after biopsy alone. Intralesional steroid is first-line if intervention needed. **LCH and Vertebra Plana:** **Definition:** Complete vertebral body collapse (loss of >50% height) - also called "coin-on-edge" or "wafer" vertebra. **Key Features:** | Feature | Description | |---------|-------------| | **Classic appearance** | Flattened vertebral body, preserved disc spaces | | **Most common levels** | Thoracic > lumbar > cervical | | **Age** | Peak 5-10 years | | **Symptom** | Back pain, usually no neurological deficit | **Calve's Disease:** - Historical term for vertebra plana - Now known to be LCH in majority of cases - Other causes: Ewing sarcoma, osteomyelitis, leukaemia **Investigation for Vertebra Plana:** | Test | Purpose | |------|---------| | **MRI spine** | Soft tissue extension, cord compression, multiple levels | | **Biopsy** | Confirm LCH (CT-guided or open) | | **Staging workup** | As above - skeletal survey essential | **Management of Vertebra Plana:** | Scenario | Management | |----------|------------| | **Stable, no neurology** | Observation ± bracing | | **Pain only** | Bracing, NSAIDs, consider steroid injection | | **Cord compression** | High-dose corticosteroids, rarely surgery | | **Instability** | Bracing; surgery only if progressive | **Spinal Cord Compression (Rare):** | Treatment | Response | |-----------|----------| | **High-dose steroids** | 80-90% respond | | **Radiation** | If steroids fail, 6-10 Gy | | **Decompression surgery** | Rarely needed | **Natural History of Vertebra Plana:** | Time | Outcome | |------|---------| | Initial | Complete collapse | | 6-12 months | Beginning reconstitution | | 2-5 years | 50-70% height recovery | | Long-term | Mild residual deformity, usually asymptomatic | **Reconstitution Factors:** | Factor | Effect on Recovery | |--------|-------------------| | **Age** | Younger = better reconstitution | | **Preserved disc** | Essential for reconstitution | | **Single level** | Better than multiple | | **No surgery** | Surgery may impair reconstitution | > **Consultant Tip:** Vertebra plana from LCH usually reconstitutes spontaneously. Avoid surgery unless there's progressive neurological deficit - it impairs reconstitution potential. **Features of Multisystem LCH:** **Risk Organ Involvement (Poor Prognosis):** | Organ | Clinical Features | Investigation | |-------|-------------------|---------------| | **Liver** | Hepatomegaly, jaundice, coagulopathy | LFTs, coagulation, US | | **Spleen** | Splenomegaly | Physical exam, US | | **Bone marrow** | Cytopenias, fever | FBC, bone marrow biopsy | | **Lungs** | Dyspnoea, cough, pneumothorax | CXR, HRCT | **Non-Risk Organ Involvement:** | Organ | Clinical Features | |-------|-------------------| | **Skin** | Seborrheic-like rash, petechiae | | **Lymph nodes** | Cervical lymphadenopathy | | **CNS** | Diabetes insipidus (pituitary), cerebellar syndrome | | **GI tract** | Diarrhoea, failure to thrive | **Hand-Schüller-Christian Triad:** 1. Multiple skull lesions 2. Diabetes insipidus (30% of multisystem) 3. Exophthalmos (orbital involvement) **Diabetes Insipidus in LCH:** | Feature | Detail | |---------|--------| | **Incidence** | 15-25% of multisystem LCH | | **Mechanism** | Pituitary stalk/posterior pituitary infiltration | | **Presentation** | Polyuria, polydipsia, low urine SG | | **Investigation** | Urine osmolality, MRI pituitary (loss of bright spot) | | **Prognosis** | Usually permanent, requires DDAVP | **Management of Multisystem LCH:** | Disease Extent | Treatment | |----------------|-----------| | **Multifocal bone only** | Systemic chemotherapy (vinblastine + prednisolone) | | **Low-risk multisystem** | Vinblastine + prednisolone x 12 months | | **High-risk (risk organ +)** | Intensive chemotherapy, may need cytarabine, cladribine | | **CNS involvement** | Cladribine-based regimens | **LCH Chemotherapy Protocol (Histiocyte Society):** | Phase | Duration | Agents | |-------|----------|--------| | **Induction** | 6 weeks | Vinblastine weekly + prednisolone daily | | **Continuation** | 12 months | Vinblastine + prednisolone pulses q3 weeks | **Prognosis by Disease Extent:** | Category | 5-Year Survival | |----------|-----------------| | Unifocal bone | >99% | | Multifocal bone | 90-95% | | Multisystem (no risk organs) | 85-90% | | Multisystem (risk organs +) | 60-70% | **This Patient:** - Unifocal disease confirmed - No systemic symptoms - Normal investigations - Excellent prognosis - systemic treatment NOT required > **Consultant Tip:** Screen all LCH patients for diabetes insipidus - it can present years after initial diagnosis and is usually permanent. --- ## Key Teaching Points ### Pattern Recognition **This pattern suggests Eosinophilic Granuloma (Unifocal LCH):** - Child aged 5-15 years - Punched-out lytic lesion without sclerotic margin - Bevelled edge on skull (pathognomonic) - No periosteal reaction - Single lesion on skeletal survey - No systemic symptoms **Distinguish from Other Lesions:** | Feature | LCH | Osteomyelitis | Ewing Sarcoma | |---------|-----|---------------|---------------| | Age | 5-15 years | Any | 10-20 years | | Margin | Punched-out | Ill-defined | Permeative | | Periosteal reaction | Minimal | Aggressive | Onion-skin | | Soft tissue mass | Small | Abscess | Large | | Systemic symptoms | Rare | Fever, malaise | B symptoms | ### Critical Management Points 1. **Skeletal survey is ESSENTIAL** - bone scan misses 30% of lesions 2. **Screen for diabetes insipidus** - urine osmolality in all patients 3. **Unifocal lesions often self-resolve** - especially after biopsy 4. **Intralesional steroids are first-line** - for persistent lesions 5. **Vertebra plana reconstitutes** - avoid surgery when possible 6. **CD1a + S100 positive** - confirms diagnosis --- ## Common Examiner Follow-ups **Q: "Why does bone scan miss LCH lesions?"** LCH lesions are often "cold" on bone scan because: - Rapid bone destruction outpaces osteoblastic response - Bone scan relies on osteoblastic activity for uptake - Skull lesions particularly prone to false negatives - Up to 30% of lesions missed on bone scan Therefore, skeletal survey (plain X-rays) is the preferred staging modality. --- **Q: "What is the role of chemotherapy in LCH?"** | Indication | Agents | |------------|--------| | **Not indicated** | Unifocal bone lesion | | **Indicated** | Multifocal bone disease | | **Indicated** | Any multisystem involvement | | **First-line** | Vinblastine + prednisolone x 12 months | | **Salvage** | Cladribine, cytarabine | --- **Q: "What are the late effects of LCH?"** | Late Effect | Incidence | Management | |-------------|-----------|------------| | Diabetes insipidus | 15-25% | DDAVP lifelong | | Growth hormone deficiency | 10% | GH replacement | | Orthopaedic sequelae | 20% | Usually mild | | Hearing loss | 10-15% | If temporal bone involved | | Neurodegenerative disease | 1-4% | Cerebellar, rare | --- **Q: "Can LCH recur?"** | Disease Type | Recurrence Rate | Notes | |--------------|-----------------|-------| | Unifocal | 10-15% | Usually another bone lesion | | Multifocal | 30-40% | May need prolonged therapy | | Multisystem | 50-60% | May need salvage chemotherapy | Recurrence is most common within 2 years of diagnosis. Follow-up should continue for at least 5 years. --- ## Related Topics - Bone Tumours in Children - Paediatric Spine Tumours - Vertebra Plana Differential - Skeletal Survey Indications - Ewing Sarcoma - Osteomyelitis