STEPTRACKERHEMATOLOGY + ONCOLOGY | PATHOLOGY | HIGH-YIELD REVIEW

Histiocytic & Mast Cell Disorders

Langerhans cell histiocytosis, HLH, systemic mastocytosis and the less common histiocytoses.

FOCUS ON
LCH: CD1a⁺, S-100⁺, langerin⁺, Birbeck "tennis racket" granules, often BRAF V600E. Know its three age-based forms (solitary bone lesion, skull + diabetes insipidus, infant multisystem). Mastocytosis: KIT D816V, Darier sign, ↑ tryptase. HLH: fever, cytopenias, and an enormous ferritin.
DISORDER
CELL · MECHANISM
FEATURES
CLUE · TREATMENT
Langerhans cell histiocytosis
overview
Clonal Langerhans (dendritic) cells: CD1a⁺, S-100⁺, langerin (CD207)⁺; BRAF V600E often.
Birbeck granules on EM; lesions full of eosinophils
Immature cells that can't activate T cells
Unifocal (eosinophilic granuloma)
Single bone lesion.
Adolescents/young adults: painful lytic lesion (skull, femur), pathologic fracture
Good prognosis; may heal spontaneously
Multifocal (Hand-Schüller-Christian)
Several bone and soft-tissue sites.
Children: lytic skull lesions, diabetes insipidus, exophthalmos, rash
Posterior pituitary involvement
Multisystem (Letterer-Siwe)
Widespread organ infiltration.
Infants < 2: scaly seborrheic-like rash, hepatosplenomegaly, nodes, lytic bones, pancytopenia, lung
Poor prognosis
Pulmonary LCH
Lung-only disease linked to smoking.
Young adult smokers: upper-lobe nodules and cysts
Spontaneous pneumothorax · smoking cessation
HLH
cytokine storm
Uncontrolled T-cell and macrophage activation; familial (perforin defects) or secondary (EBV, lymphoma, autoimmune "macrophage activation syndrome").
Fever, splenomegaly, cytopenias, liver dysfunction
Ferritin very high, ↑ triglycerides, ↓ fibrinogen, ↑ soluble IL-2R, hemophagocytosis in marrow
Systemic mastocytosis
KIT D816V → clonal mast cells in marrow, skin, GI, liver.
Flushing, itching, urticaria pigmentosa (Darier sign), hypotension/anaphylaxis, peptic ulcers, diarrhea (histamine → acid)
↑ serum tryptase · H1 + H2 blockers, cromolyn; KIT inhibitors (midostaurin, avapritinib)
Other histiocytoses
Rosai-Dorfman: macrophages engulf intact lymphocytes (emperipolesis). Erdheim-Chester: BRAF⁺ foamy histiocytes.
Massive painless neck nodes · symmetric long-bone sclerosis, retroperitoneal fibrosis
Storage-disease macrophages: Gaucher ("crumpled tissue paper")

Mechanism — two clonal cell types

Langerhans cellSkin dendritic APC
→
BRAF/MAPK mutationClonal expansion
→
Eosinophil-rich lesionsBone, skin, pituitary, lung
Mast cell
→
KIT D816VGrowth signal on
→
MediatorsHistamine, tryptase, PGD₂
→
Flushing, ulcers, shock

LCH by age

FORM
AGE
KEY FEATURES
Unifocal
Adolescent / young adult
One lytic bone lesion
Multifocal
Child
Skull lesions, diabetes insipidus, exophthalmos
Multisystem
Infant < 2
Rash, organomegaly, cytopenias
Pulmonary
Adult smoker
Upper-lobe cysts, pneumothorax
LCH markers
CD1a · S-100 · langerin (CD207) · Birbeck granules
Mastocytosis markers
CD117 (KIT) · CD25 on mast cells · ↑ tryptase

How it's tested

COMMON CONFUSIONS-100 marks Langerhans cells, melanoma and schwannoma. CD1a and langerin are what make it LCH.
THE TRAPA child with polyuria and polydipsia plus lytic skull lesions has LCH infiltrating the posterior pituitary, causing central diabetes insipidus.
YOUR APPROACHLytic bone lesion + eosinophils → stain CD1a/langerin. Flushing + ulcers + skin wheals → tryptase and KIT. Fever + cytopenias + huge ferritin → HLH criteria.

If you see… think…

Child with lytic skull lesions + diabetes insipidus + exophthalmos → multifocal LCH
Infant with scaly rash, big liver and spleen, lytic bones, pancytopenia → multisystem LCH
Teen with one painful lytic lesion full of eosinophils, CD1a⁺ → eosinophilic granuloma
Tennis-racket granules on EM → Birbeck granules (LCH)
Young smoker with upper-lobe cysts and pneumothorax → pulmonary LCH
Rubbing a brown skin spot raises a wheal → Darier sign — mastocytosis
Flushing, diarrhea, peptic ulcers, ↑ tryptase → systemic mastocytosis (KIT D816V)
Fever, big spleen, cytopenias, ferritin > 10,000 → HLH
Massive painless neck nodes with emperipolesis → Rosai-Dorfman disease