Conditions

Dendritic cell (antigen presenting cell)-related:

•Langerhans cell histiocytosis (LCH)

•Localized form mainly as eosinophilic granuloma of the bone

•Disseminated form with bone lesions, diabetes insipidus, exophthalmos, and retro-orbital granulomas (formerly Hand–Schüller–Christian syndrome)

•Disseminated form with involvement of various organs (formerly Abt–Letterer–Siwe syndrome of infants and small children

Macrophage-related:

•Hemophagocytic lymphohistiocytosis (HLH) and Infection-associated hemophagocytic syndrome (IAHS)

•Familial erythrophagocytic lymphohistiocytosis (FEL)

•Malignant histiocytosis

•Acute monocytic leukemia

•Malignant histiocytoma (MH), mostly as anaplastic large-cell lymphoma of the child

(ALCL; see Chap. 6)

•Histiocytic sarcoma

Adapted from WHO committee Classification Working Group of Histiocytic Society

8.2Langerhans Cell Histiocytosis

•Disorder with clonal proliferation of abnormal Langerhans cells

•Variable clinical presentation and course ranging from a solid lesion of the bone to the disseminated form with or without organ dysfunction

•Spontaneous regression occurs on occasion, usually in bone lesions and cutaneous involvement

8.2.1Incidence

•Three percent of neoplasias in children

•Four to eight in one million children less than 16 years of age are diagnosed each year; occurs in adults at approximately the same incidence as in children

•Ratio of males to females is 1:1

•Peak age, 1–4 years, slightly male preponderance;

•In children below the age of 2 years, acute, life-threatening form, with multiorgan involvement and organ dysfunction in about 20% of children

8.2.2Etiology and Pathogenesis

•The etiology remains unknown; lesions express significant amounts of selective cytokines and chemokines; the lesional LC have been shown to be clonal, pos- sess shortened telomeres, and have BRAF mutations in approximately 50% of samples thus far tested

8.2.4.1 Bone

•Painful swelling of the involved bone

•Localization: mostly in the skull and pelvic bones; often in several different locations

•In patients presenting with a single lesion, often additional lesions occur within the next 6 months unless treatment is given

•Radiologically, bones show lytic lesions with a punched-out appearance, with or without marginal sclerosis and periosteal reactions. PET is a sensitive technique for identifying active lesions from inactive lesions, although it is not specific for LCH

•Infiltration of the orbit leads to proptosis, exophthalmos, and asymmetry of the eyes

•Infiltration of the jaw with loose, painful teeth, tender swelling of the mandible and/or maxilla

•Infiltration of the mastoid leads to chronic otitis or mastoiditis

•Vertebral lesions may cause collapse of vertebral bone (vertebra plana) followed by scoliosis

•With treatment, bone lesions respond slowly and may remain sclerotic for many years; vertebra planae will usually remodel to achieve their original height over time

•Treatment usually reduces pain and may decrease the development of LCH at other sides

•Curettage: for histology; may sometimes be followed by spontaneous resolution of a unilocal lesion

•Excisional surgical resections are usually not indicated if they will result in

8.2.4.2 Skin

•Seborrheic, maculopapular exanthema, sometimes with crusting; usually reddish-brown or purple

•Petechial lesions occur mainly in advanced forms of the disease in infants and small children

•Xanthomatous skin lesions occasionally present

•Ulcerative changes of the oral cavity and in the genital and perianal region are common

•Appearance of the skin and mucosal changes resemble extensive seborrheic dermatitis (differential diagnosis)

•Skin biopsy confirms the diagnosis

8.2.4.3 Lungs

•Involvement may be asymptomatic but usually predominates in the upper lobes

•Occasionally cough, dyspnea, cyanosis, pneumothorax, and/or pleural effusion can occur

•Pulmonary dysfunction occurs mainly in children below the age of 2 years, but may also be the first manifestation in adolescents and young adults; pulmonary

LCH may be activated by cigarette or other types of smoking

•Interstitial fibrosis with hypoxemia and cor pulmonale occurs in progressive disease

•Radiologically: reticulonodular pattern of interstitial infiltration expanding from central to peripheral lung tissue; cystic features also are a key characteris- tic and can lead to spontaneous pneumothoraces; upper lobes most commonly involved

•Pulmonary function tests and bronchoalveolar lavage (>5% CD1a-positive cells are positive for LHC)are useful to make a diagnosis and in following patients; lung biopsy may be necessary to exclude opportunistic lung infection

8.2.4.4Lymph Nodes

•Often generalized adenopathy, especially with cervical, axillary and inguinal involvement

•Occasionally localized enlargement of a lymph node or cluster of nodes is observed

8.2.4.5Liver

•Hepatomegaly with or without increased serum liver enzymes in about 30% of patients with multiorgan involvement; hepatic dysfunction is considered an adverse prognostic factor

•Abnormal coagulation parameters (serum fibrinogen decreased, prothrombin time prolonged) indicate liver dysfunction

•Jaundice in patients with infiltration of intraand extrahepatic bile system

8.2.4.6Spleen

•In one-third of children with LCH, spleen involvement is noted

•In marked splenomegaly, sequestration of erythrocytes, leukocytes, and platelets results in pancytopenia and indicates an unfavorable prognosis

8.2.4.7Endocrine Organs

•Diabetes insipidus:

– In about 5–30% of patients

– Polydipsia and polyuria

– May occur before a definitive diagnosis, at the time of diagnosis, whether in treatment or post-treatment

– Serum antidiuretic hormone (ADH) level is low

– Diagnostic tests using serum or urine osmolarity before and after a waterdeprivation test along with a test dose of DDAVP if indicated by electrolytes, serum, and urine osmolality; an MRI with and without contrast should also be done

•Growth retardation: often in combination with diabetes insipidus (see also “Long-Term Sequelae”)

– Galactorrhea on females with hypothalamic/pituitary involvement can occur

– Profound weight gain secondary to hypothalamic syndrome can occur

– Absence of progressing through puberty

– Development of early menopause

– Precocious or delayed puberty

•Thyroid involvement in LCH can occur, but thyroid dysfunction is usually associated with hypothalamic/pituitary disease