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Chapter 64: Histiocytoses – Comprehensive Study Notes

OVERVIEW

• Histiocytoses = heterogeneous group of rare haematologic/immune disorders characterised by pathological accumulation of cells of macrophage & dendritic‐cell (DC) lineage.
• Two dominant clinical entities in children:
– Langerhans Cell Histiocytosis (LCH) → clonal proliferation of LC-like DCs.
– Hemophagocytic Lymphohistiocytosis (HLH) → hyper-inflammatory syndrome driven by uncontrolled macrophage / cytotoxic T/NK activation.
• Additional non-LCH entities (juvenile xanthogranuloma, Rosai-Dorfman disease, Erdheim-Chester, etc.) exist but are far rarer.

DENDRITIC CELLS – TYPES & FUNCTIONS

• Professional Antigen-Presenting Cells (APCs) able to fully activate naïve T cells (provide Major Histocompatibility Complex + co-stimulation).
• Two broad functional classes:
– Conventional DCs (steady-state antigen sampling – tolerance vs activation).
– Inflammatory DCs (arise de-novo during infection / inflammation, secrete cytokines e.g. TNF\,\alpha, iNOS).
• Subdivision by anatomic location (Box 64-1):
– Migratory DCs → Langerhans cells (LCs), dermal & interstitial DCs; shuttle peripheral antigen to nodes; CCR6 → CCR7 switch (ligands CCL20 \rightarrow CCL19/21).
– Lymphoid Tissue–resident DCs → thymic, splenic, nodal; immature at baseline (high uptake, low presentation).
– Mucosal DCs, Predendritic cells (plasmacytoid DCs, monocytes).
• Key LC identifiers: surface CD1a, Langerin/CD207 (internalises to Birbeck granules), Birbeck granules (‘tennis racket’).

ORIGINS OF DENDRITIC CELLS

• Ontogeny is flexible; committed myeloid or lymphoid precursors (FLT3 +) can yield all DC subsets.
• Steady-state turnover:
– Splenic DCs replaced every ≈3 days (local division + marrow input).
– LCs long-lived; replenished by skin precursors + circulating monocytes (CCR2-dependent).
• Immature DCs derive from non-inflammatory CCR2− monocytes; plasmacytoid DCs branch early.

LANGERHANS CELL HISTIOCYTOSIS (LCH)

Pathogenesis

• Accumulation of CD1a+ / Langerin+ LC-like cells in tissues.
• Gene expression resembles myeloid DC precursors > mature LCs.
• Evidence for neoplasia > reactive:
– Clonality proven by non-random X-inactivation.
– ~60\% harbour BRAF^{V600E}; MAPK-ERK pathway activated in nearly 100\% (alternate BRAF variants or other MAPK lesions).
– TP53 over-expression common; further cooperating events likely.
• Adult pulmonary LCH – >40\% BRAF^{V600E}, strong smoking association; spontaneous remission on cessation.

Epidemiology

• Incidence children

Clinical Spectrum

• Single-system (SS-LCH) ≈ \tfrac23:
– Bone (75 %), skin (⅓), less often lymph node, lung, CNS.
• Multisystem (MS-LCH) ≈ \tfrac13; half have ‘risk organs’: liver, spleen, bone marrow/hematopoietic.
• Historic terms: eosinophilic granuloma (solitary bone), Hand-Schüller-Christian triad (bone+exophthalmos+polyuria), Letterer-Siwe (fulminant infantile).

Pathology

• Lesional LCs: large cells, abundant eosinophilic cytoplasm, grooved ‘coffee-bean’ nuclei.
• Mixed infiltrate: T cells, eosinophils, macrophages, plasma cells; site-specific architecture (bone – osteoclast-rich; skin – epidermotropism).
• IHC: CD1a+, Langerin+, S100+, Fascin+.

Work-Up

• History + PE ➔ skeletal survey, consider CT/MRI for soft tissue, FDG-PET (most sensitive, detects extra-osseous).
• Labs: CBC, LFTs, ESR, early-morning urine specific gravity (DI screen).
• MRI brain if cranial lesions or DI suspected.
• Chest X-ray ± high-resolution CT, abdominal US if hepatosplenomegaly.
• Biopsy mandatory; complete excision unnecessary.

Organ-Specific Details

• Bone: pain worse at night, “punched-out” lytic lesions; vertebra plana; unifocal vs polyostotic; treatments – observation, curettage, intralesional steroids (\uparrow healing), rarely low-dose RT (secondary malignancy risk).
• Skin: seborrheic, papulonodular or vesicular rash in flexures/scalp/perineum; in infants may be self-healing (Hashimoto-Pritzker). Topical steroids, nitrogen mustard, PUVA, IFN-α as needed.
• CNS:
– DI from pituitary stalk infiltration; MRI loss of posterior ‘bright spot’ or thick stalk.
– Anterior pituitary failure possible.
– Parenchymal granulomas (mass lesions) → chemotherapy / surgery / RT.
– Late neurodegeneration (brain-stem/cerebellar signal, gliosis); limited treatment (retinoic acid, low-dose chemo, IVIg).
• Lung: nodules/cysts ± pneumothorax; in children occurs with MS-LCH; in isolation usually adult smoker. Not an independent risk organ.
• Gastrointestinal/Lymph node involvement uncommon but possible.

Risk Organs & Prognosis

• Hematopoietic cytopenia, liver dysfunction (hepatomegaly, \gamma-GT↑, bilirubin↑, hypoalbumin), and/or spleen enlargement define high-risk.
• Mortality confined almost exclusively to risk-organ + cases (29/29 deaths in one cohort).
• Early response to therapy at 6 wk strongest predictor (survival 88 % vs 17 % if no response).

Therapy

• Localised SS-LCH → biopsy ± local therapy; observation frequent.
• Indications for systemic Rx:
– CNS-risk skull lesions; multifocal bone; symptomatic skin; MS-LCH.
• Standard frontline (per Histiocyte Society LCH-III):
– Vinblastine 6\,mg/m^2 weekly + Prednisone 40\,mg/m^2/day taper; duration 12 mo low-risk, 12 mo + 6-MP for high-risk.
• Intensification (etoposide, methotrexate) did NOT improve outcome.
• Refractory: 2-CdA ± cytarabine, clofarabine, targeted BRAF inhibitors (BRAF^{V600E} Erdheim-Chester & some LCH).
• Allogeneic Hematopoietic Cell Transplantation (HCT) for highly refractory cases; reduced-intensity conditioning preferred.

Reactivation & Sequelae

• Reactivation in \approx40\% multifocal vs 10\% unifocal; mostly within \le2 yrs.
• Manage locally or re-induce systemic Rx; NSAIDs, bisphosphonates, thalidomide considered.
• Late effects in ~50\% survivors: DI (22 %), orthopedic deformities, dental loss, hearing loss, hepatic cirrhosis, pulmonary fibrosis, neurodegeneration.

NON-LANGERHANS CELL HISTIOCYTOSES

• Juvenile Xanthogranuloma (JXG): CD1a−/Langerin−/CD68+/CD163+; cutaneous yellow-brown nodules in infants (median 5 mo); usually regress; systemic (5 %) – eye, CNS, liver – may need LCH-like chemo. Association with NF1, Noonan, JMML.
• Sinus Histiocytosis with Massive Lymphadenopathy (Rosai-Dorfman): CD1a−/Langerin−/S100+/CD68+ histiocytes with emperipolesis; massive painless cervical nodes ± extranodal (skin, bone, orbit, meninges). Often self-limited; steroids, debulking, RT, chemo in organ-threatening disease.
• Erdheim-Chester, Langerhans cell sarcoma, histiocytic sarcoma – rare, aggressive (adult).

MONOCYTES & MACROPHAGES

• Tissue-resident macrophage subsets:
– Host defence: alveolar, gut, Kupffer.
– Homeostasis: osteoclasts, microglia.
– Lymphoid organ heterogeneity (red-pulp vs marginal zone vs nodal sinus).
• Activation states (in vitro):
– M1 (classical/innate) – IFN-γ, LPS → microbicidal, MHC\,II↑.
– M2 (alternative/deactivation) – IL-4/IL-13 or IL-10/TGF-β → tissue repair / anti-inflammation.
• Circulating monocytes:
– Inflammatory (CD14^{hi}CD16− / Ly6C+) CCR2^{hi} CX3CR1^{lo}.
– Resident (CD14^{+}CD16^{+} / Ly6C−) CCR2− CX3CR1^{hi}.
• Under inflammation Ly6C+ migrate to tissue → macrophage/DC; osteoclast differentiation requires M-CSF + RANK-L.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH)

Definition & Pathophysiology

• Hyperinflammatory syndrome from uncontrolled activation of macrophages & cytotoxic lymphocytes, leading to cytokine storm, tissue damage, hemophagocytosis.
• Two broad categories:
– Familial/primary HLH (FHL) – autosomal recessive defects in cytotoxic granule pathway.
– Secondary HLH (sHLH) – triggered by infection (esp. EBV), malignancy, rheumatologic MAS, drugs (CAR-T).

Diagnostic Criteria (HLH-2004)

• Molecular confirmation OR ≥5 of 8:

  1. Fever
  2. Splenomegaly
  3. Cytopenias (≥2 lines: Hb <9\,g/dL, Plt <100\times10^9/L, Neut <1\times10^9/L)
  4. Hypertriglyceridemia (≥\text{3 SD}) and/or hypofibrinogenemia (\le3\,SD)
  5. Hemophagocytosis (BM/spleen/LN)
  6. Ferritin >500\,μg/L (often >10,000)
  7. Low/absent NK activity
  8. sCD25 (soluble IL-2R) ≥2400\,U/mL.

Genetics of FHL & Related Syndromes

• FHL1 – unknown gene (9q21).
• FHL2 – PRF1 (perforin).
• FHL3 – UNC13D\,(MUNC13\text{-}4).
• FHL4 – STX11 (syntaxin-11).
• FHL5 – STXBP2\,(MUNC18\text{-}2).
• Syndromic overlap:
– Chédiak-Higashi (LYST), Griscelli 2 (RAB27A), XLP1 (SH2D1A/SAP), XLP2 (XIAP), Lysinuric Protein Intolerance (SLC7A7).
• All disrupt granule trafficking, docking or perforin function → defective cytolytic killing → prolonged immune activation.

Epidemiology

• FHL incidence ≈1/50,000 births; onset median 1–6 mo (range birth–adult).
• sHLH more common; exact incidence unknown; EBV triggers ≈55 % reported infection cases; Asian predominance noted.

Clinical Features

• Persistent high fever, hepatosplenomegaly, irritability, cytopenias (esp. thrombocytopenia), liver dysfunction (↑AST, hyperbilirubinemia), coagulopathy, hypertriglyceridemia, DIC risk.
• Hyperferritinemia (often >10,000\,μg/L) highly sensitive/specific.
• CNS involvement (irritability, seizures, focal signs); CSF pleocytosis/protein↑; MRI brainstem/cerebellar lesions.
• Bone marrow – hemophagocytosis (75 % at dx).
• Functional tests: NK cytotoxicity ↓; CD107a degranulation abnormal in most FHL (except PRF1).

Management Principles

• Rapid initiation of therapy critical even before full work-up complete.

First-Line Chemo-immunotherapy

• HLH-94 / HLH-04 regimen:
– Etoposide 150\,mg/m^2 twice weekly ×2 then weekly,
– Dexamethasone (8 wk taper),
– Cyclosporine A (added upfront in HLH-04),
– Intrathecal methotrexate for progressive CNS.
• Response ~86\%; 5-yr OS ~54\% overall; mandatory bridge to HCT in familial/refractory.

Alternative / Adjuncts

• ATG + steroids + CSA (rabbit) – response 73 %.
• Alemtuzumab (anti-CD52) salvage bridging to HCT.
• Rituximab for EBV-HLH (reduces viral load).
• Tocilizumab / steroids for CAR-T cytokine-release HLH-like syndrome.

Supportive Care

• Broad-spectrum antibiotics, antifungal & Pneumocystis prophylaxis.
• Blood products; manage coagulopathy; treat triggers (e.g., amphotericin for leishmania).

Hematopoietic Cell Transplantation

• Only curative option for FHL.
• Disease control pre-HCT improves survival (Remission > active).
• Myeloablative busulfan/cyclophosphamide/etoposide/ATG historically high TRM (~33 %).
• Reduced-intensity conditioning (e.g., fludarabine/melphalan/ alemtuzumab) → higher survival (≈70 %), need for donor chimerism monitoring + DLI.

Secondary HLH Specifics

• EBV-HLH: early etoposide crucial; mortality 14× higher if delayed >4 wk.
• Malignancy-associated HLH: treat underlying tumour; if during chemo consider HLH chemo; HCT for refractory.
• MAS (rheumatologic): high-dose IV steroids, CSA; anti-TNF (etanercept/infliximab) for refractory.

COMPARATIVE SNAPSHOT: LCH vs HLH

• LCH = clonal DC tumour; HLH = immune dysregulation/storm.
• LCH pathology: CD1a+, Langerin+, Birbeck; HLH: CD68+ macrophage hemophagocytosis.
• LCH incidence \approx 3–9/million; HLH rarer but acute fatal if untreated.
• LCH therapy: vinblastine/prednisone ± 6-MP; targeted BRAF inhibition; transplant rare.
• HLH therapy: etoposide/dexamethasone/CSA ➔ HCT (familial).

ETHICAL / PRACTICAL POINTS

• Genetic counselling crucial for FHL families; prenatal diagnosis possible.
• Long-term survivors of LCH need endocrine, neuro-cognitive, orthopedic, audiologic follow-up; counsel against smoking.
• Risk–benefit of cytotoxic agents (etoposide) vs fatality; informed consent and fertility preservation.
• Equity of access to specialist diagnostics (NK assays, genetics) & transplant.

REAL-WORLD / EXAM HIGHLIGHTS

• BRAF^{V600E} positivity does NOT predict LCH prognosis but opens targeted therapy.
• DI in child with skull lesion = think LCH; polyuria work-up critical.
• Ferritin >10,000 μg/L strongly suggests HLH in febrile child with cytopenias.
• Early response (week-6) to vinblastine/prednisone predicts LCH survival.
• Etoposide within 4 weeks crucial in EBV-HLH.
• Reduced-intensity HCT conditioning improves FHL outcomes; myeloablative high TRM.