HISTIOCYTOSIS

Histiocytosis is a diverse group of rare disorders with excessive proliferation of the cells of monocyte-macro­phage system, with infiltration and accumulation of histiocytes within different tissues.

Histiocytosis is classified into 3 major types (Table 20.15), the commonest in children being Langerhans cell histiocytosis (LCH).

Langerhans cell histiocytosis (LCH), is characterized by clonal proliferation of the cells of monocyte lineage, resembling Langerhans cells-a normal antigen presenting cell of the skin. Hallmark feature of these cells is presence of CD1a positive Birbeck granules (tennis-racket shaped granules in cytoplasm), on electron microscopy.

Clinical presentation depends on the age and extent of disease, as follows:

• Letterer-Siwe disease, common in infants with pre­dominantly soft-tissue involvement (multi-systemic disease)

• Hand-Schtiller-Christian disease, common in toddlers and preschool children, with soft-tissue as well as skeletal involvement, and

• Eosinophilic granuloma, common in older children gt;5 years, with predominantly skeletal involvement.

Clinical features of LCH usually include:

• Skeletal involvement (80%) as painless or painful bony swellings, mainly over skull or flat-bones, which appear as osteolytic lesions with sharp punched-out areas on X-rays (Fig. 20.4). Later, these cases may develop pathological fractures, spinal compression or teeth loss due to mandibular involvement.

TABLE 20.15: IHS classification of histiocytic disorders

Dendritic cell disorders

• Langerhans cell histiocytosis

• Secondary dendritic cell processes

• Juvenile xanthogranuloma

• Solitary histiocytoma with dendritic phenotype

Macrophage-related disorders

• Hemophagocytosis syndromes (primary/secondary)

• Rosai-Dorfman syndrome

• Solitary histiocytoma with macrophage phenotype

Malignant histiocyte disorders

• Monocyte related leukemia

• Extramedullary monocytic tumors

• Dendritic cell/ macrophage related histiocytic sarcoma

IHS: International Histiocyte Society

Fig.

• Skin involvement (50%) as seborrheic dermatitis (Fig.

20.4) or petechial exanthems with/without mucosal involvement, e.g. gingival hypertrophy.

• Lymphoreticular involvement with generalized lympha­denopathy and/or hepatosplenomegaly (30%). Signs of chronic hepatic failure may be present.

• Endocrinal involvement with growth failure, diabetes insipidus, etc.

• Bone marrow involvement with anemia, thrombo­cytopenia, etc.

• Uncommon manifestations, e.g., chronic lung disease or progressive neurological disease (ataxia, dysarthria), etc. Otitis media is common.

Diagnosis depends on tissue biopsy from suspected skin or bone lesions, to demonstrate CD1a-positive Langerhans cells with Birbeck granules. Detailed evaluation is necessary to determine the extent of disease and includes complete hemogram, liver function test, chest and skeletal X-rays for bony lesions, and PET-scan for staging and assessment of response to therapy.

Treatment depends on site and extent of lesions.

Single-system disease (limited to bones, lymph nodes or skin) is generally benign with high chance of spon­taneous regression. Treatment in these cases aims to prevent progression of lesion and secondary damage to neighbouring organs, with local curettage, intralesional steroids or low-dose radiotherapy. Skin disease may respond to topical/systemic steroids, topical 20% nitrogen mustard or PUVA therapy.

Multi-system disease (specially involving risk-organs,

e. g. liver, spleen, marrow and lungs) needs multi-drug chemotherapy including vinblastine, 6 mercaptopurine and prednisolone, with/without other agents.

Experimental therapies with immunosuppressive agents, e.g. cyclosporine, interferon, or bone marrow transplant is indicated only in unresponsive cases.

Outcome depends on the extent of disease and res­ponse to therapy. Late complications include patho­logical fractures and bony deformities, neurological dysfunctions, chronic pulmonary or liver disease (with exacerbations) and secondary malignancy.

Hemophagocytic Iymphohistiocytoses (HLH) are characterized by clonal proliferation of the morpho­logically normal antigen-processing cells, i.e. macro­phages and CD8 lymphocytes in involved tissues. HLH is attributed to defective functions of natural killer (NK) cells and cytotoxic cells leading to uncontrolled activation of pro-inflammatory cytokines. Many genetic mutations are known for this dysfunction. Two major type of HLH include:

a. Familial HLH, an autosomal recessive disorders contributing 25% cases, and

b. Infection-associated hemophagocytic syndrome, secondary to viral infections (CMV, EBV, HHV-6), fungi, protozoa and bacteria, often in presence of immunodeficiency. Rare non-infectious causes of secondary HLH include

drugs, e.g. phenytoin, transplant, autoimmune diseases and immunodeficiency states.

Clinically, all forms of HLH present similarly with a generalized disease process - fever, rash (10-60%) and weight loss. Familial HLH usually presents at a younger age (lt;4 years) than secondary disease. Hepato- splenomegaly, lymphadenopathy and jaundice are common. Neurological involvement usually mimics acute disseminated encephalomyelitis.

Diagnosis rests on the basis of a molecular genetic defect or presence of any 5 of the 8 clinico-pathological criteria (Table 20.16). No absolute distinction can be made between familial and secondary HLH, except on the basis of genetic markers (mutations in performing or Munc13-4 proteins) or positive family history. Acute onset with a documented infection suggests secondary HLH.

Management depends on the probable aetiology.

• Familial HLH without documented infection, needs multi-drug chemotherapy including Etoposide, Dexamethasone, with/without intrathecal metho­trexate. Some recommend antithymocyte globulin and cyclosporine for maintenance phase. Despite initial response, FHLH without transplant is ultimately fatal, due to relapses. Stem-cell transplant is effective in curing ~60% cases.

TABLE 20.16: Diagnostic criteria for hemophagocytic Iymphohistiocytoses

• Molecular diagnosis consistent with HLH or

• Any five of the following 8 features

- Fever (IL-2R#945; chain; #8805;2,400 U/mL)

- Splenomegaly (IL-2R#945; chain; #8805;2,400 U/mL)

- Pancytopenia Or Bicytopenia (Hb lt; 9 g/dl or ANC

lt; 1000#8725;#956;L or PLC lt; 100000#8725;#956;L)

- Hypertriglyceridemia (#8805;265 mg/dL) or hypofibrinogene­mia (#8804;150 mg/dL)

- Hemophagocytosis in marrow, spleen or lymph nodes without evidence of malignancy

- Low/Absent natural killer cell cytotoxicity

- Hyperferritinemia (#8805;500 ng/mL)

- Elevated soluble CD25 (IL-2R#945; chain; #8805;2,400 U/mL)

• Secondary HLH needs treatment of underlying infection or other identifiable cause, along with supportive care.

BIBLIOGRAPHY

1. Agrawal S. National comprehensive cancer metwork guidelines for pediatric acute lymphoblastic leukemia. Indian Pediatr. 2020;57.

2. Sachdeva A et al. Hemophagocytic lymphohistiocytosis. standard treatment guidelines. Indian Academy of Pediatrics. 2022.