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# Histiocytic disorders: HLH and Langerhans cell histiocytosis

- Lesion

Two very different disorders of histiocytes: a reactive cytokine storm that eats blood cells, and a clonal tumour of Langerhans-type cells.

Updated Nov 12, 2026

## Key points

- HLH: fever, hepatosplenomegaly, cytopenias, very high ferritin and soluble IL-2 receptor; triggers include EBV and T-cell lymphoma.
- Familial HLH: inherited defects in perforin or granule release by cytotoxic lymphocytes.
- LCH cells: CD1a, langerin (CD207) and S-100 positive, with Birbeck granules (tennis-racket shape) on electron microscopy.
- LCH forms: multisystem disease in young children (Letterer–Siwe), the triad of skull defects, diabetes insipidus and exophthalmos (Hand–Schüller–Christian), and the solitary bone lesion (eosinophilic granuloma).
- BRAF V600E is present in roughly half of LCH cases.

On this page

- The basics Key points
- What it is
- Structure
- Step by step
- HLH vs LCH
- Markers
- Memory aid
- Elsewhere in DurgiPedia

- Clinical Clinical notes

- Study Test yourself

- Connections Connections

## What it is

Haemophagocytic lymphohistiocytosis (HLH) is a reactive, life-threatening state in which macrophages and cytotoxic T cells are activated throughout the body; macrophages devour blood cells and a cytokine storm causes fever, cytopenias and organ failure. Langerhans cell histiocytosis (LCH) is a clonal neoplasm of immature dendritic cells, usually driven by MAPK pathway mutations such as BRAF V600E, that ranges from a single bone lesion to a fatal multisystem disease of infants.

## Structure

- HLH marrow, spleen and liver: macrophages with engulfed red cells, platelets and leukocytes (haemophagocytosis), which is supportive but not required for diagnosis.
- LCH: sheets of cells with abundant pale cytoplasm and grooved, folded, coffee-bean nuclei, mixed with many eosinophils.
- Electron microscopy of LCH: rod-like Birbeck granules with a dilated end.

## Step by step

- HLH: a trigger (EBV, other infection, lymphoma, autoimmune disease) meets cytotoxic cells that cannot kill infected cells efficiently.
- HLH: persistent T-cell and macrophage activation floods the body with interferon-γ, TNF, IL-6 and IL-12.
- HLH: macrophages eat blood cells; cytokines cause fever, liver injury, coagulopathy and shock.
- LCH: an acquired MAPK pathway mutation (often BRAF) arises in a myeloid dendritic precursor.
- LCH: the clone settles in bone, skin, pituitary, lung or liver and recruits eosinophils, causing lytic and destructive lesions.

## HLH vs LCH

| Feature | HLH | LCH |
| --- | --- | --- |
| Nature | Reactive (or inherited) immune hyperactivation | Clonal neoplasm of Langerhans-type dendritic cells |
| Key findings | Fever, cytopenias, hepatosplenomegaly, very high ferritin | Lytic bone lesions, skin rash, diabetes insipidus, lung cysts |

## Markers

- CD1a
- Langerin (CD207)
- S-100
- BRAF V600E
- Ferritin
- Soluble IL-2 receptor

## Clinical notes

- HLH should be suspected in any febrile patient with cytopenias and extreme ferritin; untreated it is often fatal.
- Smoking-related pulmonary LCH of adults causes nodules and cysts in the upper lobes.

## Memory aid

HLH: the macrophage that ate the blood. LCH: the cell with the coffee-bean nucleus and the tennis racket inside.

## Test yourself

Think of the answer, then tap the question to see it.

## Which laboratory value is typically extremely high in HLH?

Serum ferritin, together with soluble IL-2 receptor.

## Which ultrastructural finding identifies Langerhans cells?

Birbeck granules: pentalaminar rod-shaped structures with a dilated end, like a tennis racket.

## What triad defines Hand–Schüller–Christian disease?

Calvarial bone defects, diabetes insipidus and exophthalmos.

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## Elsewhere in DurgiPedia

- [Monocyte and macrophage](https://durgical.com/en/immunology/monocyte-and-macrophage/)
- [Dendritic cell (professional antigen-presenting cell)](https://durgical.com/en/immunology/dendritic-cell/)
- [CD8⁺ cytotoxic T cell](https://durgical.com/en/immunology/cd8-cytotoxic-t-cell/)

## Connections

## Related 4

- [Nodal T-cell lymphomas](https://durgical.com/en/general-pathology/nodal-t-cell-lymphomas/)
- [Hairy cell leukaemia: BRAF V600E, the dry tap and the red-pulp spleen](https://durgical.com/en/general-pathology/hairy-cell-leukaemia-braf-v600e-the-dry-tap-and-the-red-pulp-spleen/)
- [Smoking-related and rare diffuse lung diseases](https://durgical.com/en/general-pathology/smoking-related-and-rare-diffuse-lung-diseases/)
- [Systemic effects of inflammation: fever, acute-phase proteins, leukocytosis, sepsis](https://durgical.com/en/general-pathology/systemic-effects-of-inflammation-fever-acute-phase-proteins-leukocytosis-sepsis/)

## Related conditions 3

- [Langerhans cell histiocytosis](https://durgical.com/en/conditions/langerhans-cell-histiocytosis/)
- [Infectious mononucleosis](https://durgical.com/en/conditions/infectious-mononucleosis/)
- [Sepsis and septic shock](https://durgical.com/en/conditions/sepsis-and-septic-shock/)

## Microorganisms 1

- [Epstein–Barr virus](https://durgical.com/en/microbiology/epstein-barr-virus/)

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Educational content on the mechanisms of disease; not a diagnostic or treatment guide and no substitute for a health professional's advice. No doses are given.

Sources: [Langerhans Cell Histiocytosis Treatment (PDQ®)–Patient Version](https://www.cancer.gov/types/langerhans/patient/langerhans-treatment-pdq) (National Cancer Institute (NCI), 2026); [Familial hemophagocytic lymphohistiocytosis: MedlinePlus Genetics](https://medlineplus.gov/genetics/condition/familial-hemophagocytic-lymphohistiocytosis/) (MedlinePlus, US National Library of Medicine, 2026).

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Representative model, for educational purposes only.

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License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/general-pathology/histiocytic-disorders-hlh-and-langerhans-cell-histiocytosis/