# Langerhans Cell Histiocytosis and HLH > Birbeck granules, haemophagocytosis criteria and ferritin extremes in Langerhans cell histiocytosis and HLH, for NEET-PG Medicine exam preparation. - Canonical URL: https://prepelephant.com/topics/neet-pg/medicine/langerhans-cell-histiocytosis-and-hlh - Exam / course: NEET-PG · Subject: Medicine - Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team - First published: 2026-10-08 - Last updated: 2026-10-08 - Reference basis: Hoffbrand's Essential Haematology; Harrison's Principles of Internal Medicine; Histiocyte Society diagnostic criteria for HLH - How to cite: "Langerhans Cell Histiocytosis and HLH", PrepElephant, https://prepelephant.com/topics/neet-pg/medicine/langerhans-cell-histiocytosis-and-hlh ## Direct answer Langerhans cell histiocytosis is a neoplastic proliferation of CD1a-positive and langerin-positive dendritic cells that show Birbeck granules on electron microscopy. Haemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome of uncontrolled macrophage and T-cell activation. They share histiocytic biology but differ in cell origin and treatment. HLH is diagnosed by a molecular finding or by five of eight Histiocyte Society criteria, including raised ferritin and marrow haemophagocytosis. ## What you must remember - **Birbeck granules:** Tennis racket shaped organelles on electron microscopy, with CD1a and langerin (CD207) positivity on immunohistochemistry confirming Langerhans cell histiocytosis. - **Bone involvement:** The commonest site, often with punched-out lytic skull lesions; vertebra plana can occur in children. - **Diabetes insipidus:** Hypothalamic and pituitary stalk involvement, which signals more extensive disease. - **BRAF V600E:** Found in roughly half of Langerhans cell histiocytosis cases, and relevant to targeted therapy. - **HLH criteria:** A molecular diagnosis, or five of eight features: fever of 38.5 °C or more, splenomegaly, cytopenias in two lines or more, hypertriglyceridaemia or hypofibrinogenaemia, haemophagocytosis, low NK cell activity, ferritin of 500 ng/mL or more, and raised soluble CD25. - **Ferritin:** Extremely high values, often above 10,000 ng/mL, favour HLH or macrophage activation syndrome, but ferritin is also raised in sepsis, malignancy and adult-onset Still disease. - **Treatment:** Single-system Langerhans cell histiocytosis may need curettage or steroids; multisystem disease is commonly treated with vinblastine and prednisolone; HLH is treated with dexamethasone and etoposide, with ruxolitinib, anakinra or emapalumab for refractory disease. ## Worked scenario: a child with prolonged fever and pancytopenia A 4-year-old presents with ten days of fever, hepatosplenomegaly, a haemoglobin of 7.8 g/dL and a platelet count of 62,000/µL. Work through the workup in four steps, because the ferritin number alone cannot separate the two conditions. 1. **Send the cheap criteria:** Measure ferritin, triglycerides, fibrinogen and soluble CD25 alongside a full blood count, because these are the cheap criteria that carry the diagnosis. 2. **Read the pattern:** A ferritin in the thousands with raised triglycerides and low fibrinogen moves the team toward HLH, and a bone marrow aspirate is sent for haemophagocytosis. 3. **Biopsy if skin or bone is involved:** If a skull lesion or a rash of papules is also present, a biopsy with CD1a and langerin staining would test for Langerhans cell histiocytosis instead. The two can coexist, and both need histology. 4. **Track the response:** A ferritin value that falls quickly after treatment, alongside improving counts and triglycerides, supports the diagnosis and helps judge response. ## Where the examiner misdirects you Three traps recur on this topic. - **Trap:** reading a very high ferritin with fever as proof of HLH — **Correct:** adult-onset Still disease, septicaemia and malignancy raise ferritin too, so haemophagocytosis and cytopenias are needed as well. - **Trap:** treating the Birbeck granule as the practical test — **Correct:** granules are diagnostic on electron microscopy, but CD1a and langerin immunohistochemistry are the practical tests used today. - **Trap:** attributing the triad of skull lesions, diabetes insipidus and exophthalmos to HLH — **Correct:** this is the classic Hand-Schüller-Christian picture of Langerhans cell histiocytosis, not HLH. Candidates who recall the triad, the granules and the criteria together usually score well on this topic. ## Frequently asked questions ### What is the diagnostic marker of Langerhans cell histiocytosis? Birbeck granules on electron microscopy, together with CD1a and langerin positivity on immunohistochemistry, are the diagnostic markers of Langerhans cell histiocytosis. The tissue biopsy is the key investigation, since the cells are not identified on blood tests. Bone lesions are the commonest presentation. ### How many criteria are needed to diagnose HLH? HLH is diagnosed by a molecular finding consistent with the disease, or by five of the eight Histiocyte Society criteria. The criteria include fever, splenomegaly, cytopenias, hypertriglyceridaemia or hypofibrinogenaemia, haemophagocytosis, low NK cell activity, high ferritin and raised soluble CD25. Meeting the criteria guides urgent treatment. ### Why is ferritin not specific for HLH? Ferritin is not specific for HLH because it rises as an acute-phase reactant in sepsis, malignancy, liver disease and adult-onset Still disease. Its extreme levels, often above 10,000 ng/mL, raise suspicion of HLH but do not confirm it. Haemophagocytosis, cytopenias and low NK cell activity are needed for a secure diagnosis. ### What is first-line therapy for multisystem Langerhans cell histiocytosis? Vinblastine and prednisolone are commonly used first-line therapy for multisystem Langerhans cell histiocytosis, particularly in children with organ involvement. Targeted BRAF inhibition is an option in selected cases. Treatment intensity depends on the number of organ systems involved and the risk category. ### Which imaging finding is typical of skull involvement in Langerhans cell histiocytosis? Well-defined punched-out lytic lesions in the skull are the typical imaging finding of Langerhans cell histiocytosis. Biopsy of a lesion confirms the diagnosis when the imaging pattern is unclear. Diabetes insipidus may be coexistent when the pituitary stalk is involved.