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1104 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1105

the lesions often disappear during the first year of life with no therapy. Liver and Spleen Patients with liver and spleen involvement have
However, these patients should be evaluated for other sites of disease a significantly increased risk of death from LCH. Hence, these are con-
which may coexist with skin lesions as multisystem LCH. Some reports sidered “high-risk organs.” Hepatic infiltration by LCH lesions can be
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describe multisystem LCH arising after presenting with lesions limited accompanied by dysfunction, leading to hypoalbuminemia with ascites,
to the skin, 32,33 although infants with skin lesions were not observed to hyperbilirubinemia, and clotting factor deficiencies. Sonographic
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develop disseminated disease in a relatively large institutional series. imaging, computed tomography (CT), or magnetic resonance imaging
In a report of 61 neonatal LCH cases, nearly 60 percent had multisys- (MRI) of the liver may show hypoechoic or low-signal intensity along
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tem disease and 72 percent had high-risk organ involvement. The the portal veins or biliary tracts when the liver is involved. One of the
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overall survival was poorer in neonates with high-risk organ involve- most serious complications of hepatic LCH is cholestasis and progres-
ment compared to infants and children with the same extent of disease. sive sclerosing cholangitis. The median age of children with hepatic
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Response to therapy at 12 weeks was more important than patient age LCH is 23 months. Patients generally present with hepatomegaly with
in determining outcome. A review of 71 children with skin involvement or without splenomegaly, elevated alkaline phosphatase, liver transam-
revealed that those without other organ systems involved had nearly a inases, and γ-glutamyl transpeptidase. Biopsies may or may not show
90 percent progression-free survival after initial therapy or observation. CD207+ DCs. A classic histologic feature is the collection of lympho-
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Often dermatologists or general practitioners who see a patient with cytes around bile ducts. Seventy-five percent of children with sclerosing
skin LCH do not perform a complete evaluation searching for LCH in cholangitis do not respond to chemotherapy and ultimately require liver
other sites. Thus, we found that 40% of patients referred for apparent transplantation. 41
“skin only” LCH did have other sites of disease when a complete evalu- Massive splenomegaly may lead to consumptive cytopenias and
ation was done. 34 respiratory compromise. Splenectomy may ameliorate severe throm-
Isolated skin involvement is rarely observed in children older than bocytopenia, but the effect is generally not sustained with progressive
18 months of age. Children and adults may develop red papular lesions hepatomegaly and inflammation in the setting of uncontrolled dissem-
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in the scalp, skin of the groin, abdomen, back, or chest that resemble the inated LCH.
diffuse rash of Candida infection. Seborrhea-like involvement of the scalp Lung The lungs were once considered a high-risk organ; however,
may be mistaken for a severe case of dandruff in older individuals. Ulcer- review of a large series of patients shows that the treatment outcome
ative lesions behind the ears, involving the scalp, skin of the genitalia, or for patients with lung and bone involvement is not statistically different
perianal region are often misdiagnosed as bacterial or fungal infections. from those with only bone LCH. The lungs are less frequently involved
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Oral Mucosa Presenting symptoms include gingival hypertro- in children (13 percent) than in adults (60 percent), in whom smok-
phy, ulcers of the soft or hard palate, buccal mucosa, or on the tongue ing is a key etiologic factor. In young children with diffuse disease,
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and lips. Lesions of the oral mucosa may precede evidence of LCH therapy can halt tissue destruction and normal repair mechanisms may
elsewhere. 36 restore some lung parenchyma and function. “Spontaneous” pneumot-
Bone The most frequent site of LCH in children is a lytic lesion of horax can be the first sign of LCH in the lung. Patients also present
the skull which may be asymptomatic or painful. LCH can occur in with cough, tachypnea, or dyspnea. Ultimately, widespread fibrosis
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any bone. The most frequently involved sites are skull, femur, ribs, ver- and destruction of lung tissue leads to severe pulmonary insufficiency.
tebrae, and humerus. Spine lesions are most often located in the cervical Declining diffusion capacity may also herald the onset of pulmonary
vertebrae and are frequently associated with other bone lesions. Prop- hypertension. Chest radiographs may show a nonspecific interstitial
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tosis from a LCH mass in the orbit mimics rhabdomyosarcoma, neu- infiltrate. A high-resolution CT image of the chest is needed to visualize
roblastoma, and benign fatty tumors of the eye. Some skull lesions are the cystic and nodular pattern of LCH that leads to the destruction of
not only lytic but may have an accompanying mass that impinges on the lung tissue.
dura. Whether or not this affects risk of progression or not is unknown. Marrow Involvement of the marrow is considered an indicator of
Lesions of the facial bones (orbit, mastoid), or anterior or middle cranial high risk. Most patients with marrow involvement are young children
fossae (e.g., temporal, sphenoid, ethmoid, or zygomatic bone) comprise who also have diffuse disease in the liver, spleen, lymph nodes, and skin
the “CNS-risk” sites. These patients have a threefold increased risk for with significant thrombocytopenia or neutropenia, though some may
developing diabetes insipidus (DI) and an increased risk of other CNS also have scattered marrow involvement with more mild cytopenias. 46,47
disease (see “Central Nervous System and Endocrine System” below). An institutional study found patients with high-risk LCH with the
Lymph Nodes and Thymus Cervical nodes are the ones most BRAF V600E mutation to have 0.2 to 2.1 percent of cells from the marrow
frequently involved and may be soft or hard-matted masses with aspirate carry the mutation, with only four of seven cases being reported
accompanying lymphedema. An enlarged thymus or mediastinal node as having abnormal histology. LCH patients sometimes present with
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involvement can mimic lymphoma or an infectious process and may hemophagocytosis in the marrow. The presence of CD1a+/CD207+
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cause asthma-like symptoms. Biopsy of the node or mass with histo- in the marrow or at other sites identifies hemophagocytic syndrome
logic examination and microbial cultures is helpful even in patients with as secondary to LCH rather than from primary HLH (discussed in the
known LCH as lymphadenopathy may represent LCH, coexisting neo- section “Hemophagocytic Lymphohistiocytosis” below).
plastic disease, or infection. 38 Endocrine System DI is the most frequent endocrine manifesta-
Pituitary Gland The posterior pituitary gland can be affected in tion of LCH. Patients may present with an apparent “idiopathic” DI and
LCH patients causing central DI (see “Endocrine System” below). Ante- sometimes with an enlarged pituitary gland or stalk before other LCH
rior pituitary involvement may result in impaired growth and sexual lesions are identified. Approximately half of these patients will have
maturation. other lesions diagnostic of LCH within a year of identifying the DI. A
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review of patients with DI and enlarged pituitary glands found the three
Multisystem Disease most likely diagnoses were germinoma, LCH, and lymphoma. DI
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In multisystem LCH, the disease presents in multiple organs or body followed the initial LCH diagnosis at other sites by a mean of 1 year
systems, including liver and spleen, marrow (high-risk sites) or bones, and growth hormone deficiency occurred on the average 5 years later.
lungs, skin, lymph nodes endocrine system, gastrointestinal system Historically, the 10-year risk of pituitary involvement has been reported
(low-risk sites), and CNS (intermediate-risk site depending on extent). as 24 percent. In one series, this incidence of DI did not decrease
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