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1110 Part VIII: Monocytes and Macrophages Chapter 71: Inflammatory and Malignant Histiocytosis 1111

elevation of IFN-α, IL-12, monocyte chemotactic protein-1 (MCP-1), fibrosis-like infiltrates (20 percent), can be seen on an abdominal CT
IL-4, and IL-7, but there was little difference in the levels of these before scan and MRI of the heart.
and after treatment with IFN-α.
Discovery of BRAF V600E mutations in LCH and ECD has opened DIFFERENTIAL DIAGNOSIS
important research initiatives as well as the possibility of targeted ther-
apy. Thirteen of 24 (54 percent) ECD patients and 38 percent of LCH Although histologically distinct, the clinical features may suggest
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patients had this mutation. An NRAS mutation has also been found LCH, RDD, JXG, or xanthoma disseminatum. Some clinical features
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in ECD, further documenting the importance of the MAPK pathway. overlap with sarcoidosis, amyloidosis, Paget disease, Ormond dis-
The frequent occurrence of lesions classified as LCH and ECD in the ease (idiopathic retroperitoneal fibrosis), and Whipple disease (intes-
same patient, along with common finding of BRAF V600E mutation, sug- tinal lipodystrophy). The histologic features can be confused with
gests a common cell of origin in some patients. 164 Gaucher disease, Niemann-Pick disease, mucopolysaccharidosis, or
malakoplakia. 172
CLINICAL FEATURES THERAPY
A consensus paper on the evaluation and treatment of ECD has been Subcutaneous IFN-α and pegylated IFN-α are considered the first-line
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published with helpful summaries of clinical, laboratory, and radiologic treatments for ECD. Survival has been improved using doses of 3 mil-
findings. Many patients have fever, weakness, and weight loss. The lion units, 3 times a week. 174–178 When the standard dose is ineffective,
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clinical findings include CNS symptoms (50 percent), bone pain (40 increasing the IFN-α dose to greater than 18 million units per week or
percent), xanthelasma (27 percent), exophthalmos (27 percent), and use of pegylated IFN-α to a dose greater than 180 mcg/wk is recom-
DI (22 percent). Some patients have cerebellar signs and focal neuro- mended. Treatments have been extended for as long as 3 years. Patients
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logic deficits. Fifty percent of patients have extraskeletal disease. It is treated with the high-dose regimens had a stabilization of CNS disease
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unusual for lymph nodes, liver, spleen, or axial skeleton to be affected, in 64 percent and of cardiac involvement in 79 percent.
whereas these areas are frequently affected in LCH and RDD. Retro- Earlier published treatment results include a review of 37 patients
peritoneal and renal involvement occurs in one-third of ECD patients treated with glucocorticoids, usually 1 mg/kg per day, orally, result-
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and causes abdominal pain, dysuria, and hydronephrosis. Pulmonary ing in decreased exophthalmos or general symptoms in 20 patients.
involvement may present in 20 percent of patients and results in dys- Among these patients, glucocorticoids were effective in six patients,
pnea. Skin manifestations of ECD include xanthomatous lesions that transiently effective in four, and ineffective in eight. Of eight patients
may begin as reddish-brown papules similar to xanthoma dissemina- treated with a variety of chemotherapy agents and glucocorticoids,
tum. Cardiac dysfunction occurs because of circumferential sheathing four had improvement. Radiation was ineffective for orbital
of the aorta, and aortic branches, including coronary arteries, but often masses, but transiently relieved bone pain. A series of six patients
is not symptomatic. There may also be endocardial, myocardial, or peri- treated with oral imatinib mesylate reported two had stable disease
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cardial involvement, leading to pericardial effusions with the risk of and one an initial response before worsening. Some patients
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tamponade. 168,169 have been treated effectively with intravenous cladribine. Anticy-
CNS involvement may occur in up to 50 percent of ECD patients. tokine treatments with anakinra, infliximab, and tocilizumab have had
Cerebellar and pyramidal symptoms are the most frequent, but head- varying degrees of success in a limited number of patients. Anakinra
aches, neuropsychiatric or cognitive difficulties, and cranial nerve pal- is given at 1 to 2 mg/kg per day, intravenously, and may work best for
sies are reported. Parenchymal CNS lesions causing disability are a patients with bone pain and other systemic symptoms. 181–183 However,
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poor prognostic indicator. ECD may infiltrate any CNS location it seems to be less effective than IFN-α. The same can be said for the
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within or outside the neuraxis, including the pachymeninges, and are anti–tumor necrosis factor α drugs, intravenous infliximab and intra-
similar to meningiomas, sarcoidosis, Wegener granulomatosis, RDD, venous etanercept.
or LCH. Orbital involvement causes proptosis and pituitary infiltration Clinical trials currently open to open to ECD patients include:
leads to DI in nearly 25 percent of patients. • NCTT01524978 Vemurafenib: anti-BRAF V600E
• NCT01727206 Tocilizumab: anti–IL-6 (phase II clinical trial)
• ACTRN12613001321730: Sirolimus and prednisone (prospective trial)
LABORATORY FEATURES
There are no specific laboratory findings, but elevated sedimentation COURSE AND PROGNOSIS
rate and alkaline phosphatase have been reported in approximately
one-fifth of cases. The consensus publication on ECD provides a list of Nearly 60 percent of ECD patients die of their disease; 36 percent die
baseline radiologic tests which include PET/CT, MRI brain with con- within 6 months. The mean survival duration is less than 3 years. Car-
trast and attention to the pituitary, cardiac MRI, and when indicated diac, pulmonary, and renal failure are the primary causes of death.
clinically, MRI of the orbits with contrast, renal artery ultrasound,
high-resolution CT of the chest, pulmonary function tests, testicular
ultrasound, and electromyography. Radiographs show bilateral patchy JUVENILE XANTHOGRANULOMA
osteosclerosis of the metaphysis and diaphysis of the femur, proximal
tibia, and fibula in nearly 100 percent of patients. Lytic lesions are found DEFINITION AND HISTORY
in approximately one-third of patients. Chest CT imaging findings JXG is a histiocytic disorder that affects the skin with multiple nodules
include diffuse interstitial infiltrates, and pleural and interlobular sep- in the head, neck, and trunk primarily in children, although adults can
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tal thickening. Perirenal infiltration, extending through the fat of the also be affected. The lesional cells are derived from dermal dendro-
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anterior or posterior pararenal spaces, leading to the classic “hairy kid- cytes. Systemic involvement occurs in a few cases. Rudolf Virchow may
ney” appearance (>60 percent of patients) and circumferential sheath- have been the first to describe a child with what he called “cutaneous
ing of the aorta (>60 percent of patients), as well as retroperitoneal xanthomas” in 1871.

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