Table 5 Histiocytoses disorders

HLH

PRF1;

UNC13D;

STX11;

STXBP2.

AR

Fever, hepatosplenomegaly, lymphadenopathy, cytopenia, serositis, hepatic and CNS involvement

Increased levels of ferritin, triglycerides, d-dimer; Increased CRP, SAA, low ESR during disease flares; Cytopenia, low levels of fibrinogen, inactivity of natural killer cells, increased sIL2R; Presence of hemophagocytosis on myelogram or tissue biopsy

CS, IL-1i, Ig, etoposide, HSCT; Control of infectious agents

Langerhans cell histiocytosis¶

BRAF V600E;

MAPK.

Somatic mutation

Pruritic or ulcerative skin rashes, interstitial lung disease (cystic pattern), liver, spleen and/or bone marrow involvement

CD1a + Langerin + Langerhans cell Infiltration, CD1a + Langerin with + with BRAF V600E+ (50-60%) and eosinophils; Electron microscopy with Birbeck granules

Vinblastine + CS/ Cladribine + Cytarabine, Vemurafenib; Quit smoking

Erdheim-Chester disease

BRAF V600E;

MAPK.

Somatic mutation

Diaphyseal osteolytic lesions, coated aorta, renal lesion (hairy kidney), proptosis, cardiac and nervous system involvement

Touton cells on biopsy, histiocytes stained with CD68 + and CD1a- and S100- markers, BRAF V600E positive in tissue sample

Gamma interferon, Cyclophosphamide, Vemurafenib, Cladribine, Infliximab, Anakinra, Tocilizumab

Rosai-Dorfman disease

MAPK;

KRAS.

Somatic mutation

Localized or disseminated painful lymph node enlargement, retroorbital or skin involvement., autoimmune or neoplastic manifestations may be associated

Sinusoidal expansion in the lymph nodes; Emperipolesis or storiform fibrosis may be present in the tissue; Histiocytes CD68+, CD1a -, S100+; IgG4 + in some cases

Sporadic remission in 50% of cases;

Unifocal: Surgical excision; Multifocal: CS, Sirolimus, Chemotherapy, MAPK inhibitor

Kikuchi-Fujimoto disease

----*

----*

Fever, painful lymphadenopathy usually cervical, hepatosplenomegaly, arthralgia. may be associated with autoimmune diseases (SLE)

Increased IM during disease flares, leukopenia, atypical lymphocytes in peripheral blood. Clusters of small lymphocytes, histiocytes CD68+, immunoblasts and plasma cells in the absence of neutrophils with necrosis; Abundant karyorrhectic

Sporadic remission for self-limited disease, CS or surgical excision for severe clinical features

Multicentric reticulohistiocytosis

----*

----*

Skin papules and nodules on face, periungual nodules and papules (coral bead appearance), fever, xanthelasma, destructive arthritis (proximal interphalangeal DIP predominance); Autoimmune and neoplastic manifestations diseases may be associated

Increased IM during disease flares, hyperlipidemia and hypergammaglobulinemia; Positive RF, ANA, or CCP is rarely observed. Histiocytic multinucleated CD68+, CD1a-, S100-

CS, methotrexate, bisphosphonates, cyclophosphamide, TNF-inhibitors, Chemotherapy in cases with malignancy

Macrophage activation syndrome

----*

----*

Fever, hepatosplenomegaly, cytopenia, lymphadenopathy, hepatic and nervous system involvement

Increased levels of ferritin, triglycerides, d-dimer, cytopenia, low levels of fibrinogen, low/absent NK cell activity, increased sIL2R; Presence of hemophagocytosis on myelogram or tissue biopsy

CS, Ig, IL-1i, tocilizumab, cyclosporine, etoposide, control of infectious agents