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Dermatology > PEDIATRIC DISEASES
Juvenile Xanthogranuloma (Nevoxanthoendothelioma)
Article Last Updated: Feb 29, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Caroline DS Piggott, MD, Resident, Department of Pediatrics, Thomas Jefferson University, A I DuPont Hospital for Children
Coauthor(s):
Michael L Smith, MD, Associate Professor of Medicine (Dermatology) and Pediatrics, Vanderbilt University School of Medicine; Consulting Staff, Vanderbilt University Hospital;
Hunter H Sams, MD, Consulting Staff, Denver Dermatology Consultants, PC
Editors: Jean Paul Ortonne, MD, Chair, Department of Dermatology, Professor, Hospital L'Archet, Nice University, France; Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University School of Medicine; Consulting Staff, Mountain View Dermatology, PA; Jeffrey Meffert, MD, Assistant Clinical Professor of Dermatology, University of Texas Health Science Center-San Antonio; Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania; William D James, MD, Paul R Gross Professor of Dermatology, University of Pennsylvania School of Medicine; Vice-Chair, Program Director, Department of Dermatology, University of Pennsylvania Health System
Author and Editor Disclosure
Synonyms and related keywords:
nevoxanthoendothelioma, xanthoma multiplex, juvenile xanthoma, multiple xanthoma in infancy, congenital xanthoma tuberosum, xanthoma naviforme, juvenile giant cell granuloma
Background
Juvenile xanthogranulomas (JXGs) are benign; usually asymptomatic; self-healing; red, yellow, or brown papules and nodules composed of histiocytic cells that predominantly occur in infancy and childhood. Papules or nodules occur in the skin, eyes, and viscera. JXG is the most common form of non–Langerhans cell histiocytosis. Adamson first reported JXG in the English literature in 1905. He presented a child who developed numerous yellow-white papules on the body in the first 2 weeks of life. He named the entity congenital xanthoma multiplex. In 1912, McDonagh presented the first case review and renamed the condition nevoxanthoendothelioma (although the condition is not associated with nevi or endothelial cells). In 1954, Helwig and Hackney again retermed it juvenile xanthogranuloma, reflecting its histopathologic appearance. Laurb and Lain first reported JXG with visceral involvement in 1937. Blank et al first described ocular involvement in 1949.
Pathophysiology
The etiology of JXG is not fully known. The papules and nodules of JXG represent collections of differentiated non–Langerhans cell histiocytes. The consensus is that the cells of origin are dermal dendrocytes. As postulated, JXG may be a granulomatous reaction of histiocytes to an unidentified stimulus, possibly of either physical or infectious etiology. Evidence from Kraus et al,1 however, suggests a possible CD4+ plasmacytoid monocyte origin. Inhibition of cellular apoptosis appears to play a minor role in the growth of xanthogranulomas.2 The appearance of giant cells and foamy lipid-laden histiocytes generally occurs late and apparently is a secondary event, possibly in response to cytokine production by histiocytes. Serum lipid levels are normal and remain normal.
Race
JXG occurs in whites approximately 10 times more frequently than in African Americans.
Sex
In childhood, JXG occurs predominately in males (1.4:1). Equal incidence occurs in adult males and females. Multiple cutaneous lesions occur predominantly in males (12:1).
Age
Approximately 35% of cases of JXG occur at birth, with as many as 71% of cases occurring in the first year. The mean age at presentation is 22 months. Most JXGs resolve by age 5 years. Despite the term juvenile in the disease name, 10% of cases manifest in adulthood.
History
- Patients usually present in infancy or early childhood with an asymptomatic; smooth; round; yellow, red, or brown papule or papules. Lesions are usually asymptomatic.
Physical
- The most frequent site of occurrence is on the head and neck, followed the trunk and upper extremities; however, JXG may occur anywhere on the skin.
- Up to 81% of cutaneous JXG cases manifest as a solitary lesion.
- Involvement is rare on mucous membranes, the tongue, palms, and soles.
- Both papular and nodular forms of JXG have been described.
- The papular form consists of multiple, 2- to 5-mm, smooth, firm papules that initially are red-brown, then quickly change to yellow.
- The rarer nodular form consists of round, 0.5- to 2-cm, translucent, red-to-yellow, rubbery nodules with telangiectasias (nodules change to yellow-brown with time).
- Giant JXG refers to nodules and masses greater than 2 cm (largest reported mass was 10 X 5 cm).
- Rarer variants include a mixed form characterized by both papular and nodular lesions, in which grouped papules coalesce, and a subcutaneous form (approximately 5%), with a single deep nodule or mass formation.
- Extracutaneous JXG is rare (3.9%) and most commonly involves the eye (<1%) and periorbital region. Ocular JXG most commonly manifests in the iris. Following in frequency are lung and liver manifestations of JXG.3
- Rarely, lesions occur in the adrenal gland, appendix, bones, bone marrow,3 central nervous system,4 gonads, kidney, larynx, myocardium, pericardium, retroperitoneum, small and large intestines, and spleen. Only 50% of systemic lesions are accompanied by cutaneous JXG, and these cutaneous lesions tend to appear as multiple, rather than solitary, papules or nodules. The size of a cutaneous lesion does not correlate with the presence or absence of systemic JXG.
- Café au lait macules occur in approximately 20% of patients with papular JXG.
Causes
- Coexistence of café au lait macules has been associated with epilepsy.
- Niemann-Pick disease has been associated with JXG.
- Urticaria pigmentosa has been associated with JXG.
- Neurofibromatosis type 1 (NF1) has been associated with JXG.5, 6, 7, 8 A retrospective study has estimated that as many as 1 in 5 children with NF1 before age 3 years will develop JXG.
- Juvenile chronic myelogenous leukemia, now primarily referred to as juvenile myelomonocytic leukemia (JMML), has been observed in association with multiple JXGs,9, 7, 8 and the prevalence is especially high in patients with coexistent neurofibromatosis. Statistics regarding this triple association are controversial; estimates indicate that patients with NF1 and JXG have a 20- to 32-times increased risk of developing JMML than patients with NF1 alone. Patients have also been diagnosed with JMML and JXG, but without NF1.
Dermatofibroma
Langerhans Cell Histiocytosis
Mastocytosis
Spitz Nevus
Xanthomas
Other Problems to be Considered
Non–Langerhans cell histiocytosis
Benign cephalic histiocytosis10
Generalized eruptive histiocytoma
Self-healing reticulohistiocytoma
Tuberous xanthoma
Papular xanthoma
Xanthoma disseminatum
Mastocytosis (Urticaria Pigmentosa)
Procedures
A skin biopsy may be performed, both for diagnosis and cosmesis. The specimen usually consists of a complete excision of the papule or nodule.
Histologic Findings
Histological examination of JXG demonstrates a variety of findings. A time-dependent progression exists in the development of the characteristic histological features of JXG, which correlates with the age of the lesion. Early biopsy specimens reveal a dense monomorphous histiocytic infiltrate in the dermis. Extension into subcutaneous tissue, fascia, and muscle occurs in approximately one third of cases.11 Older lesions contain foam cells, Touton giant cells, and foreign body giant cells. A mixed cellular infiltrate of neutrophils, lymphocytes, eosinophils, and (rarely) mast cells may be noted. Old lesions demonstrate fibrosis. No histological difference is reported between cutaneous and systemic JXG. Because of the difficulty in diagnosing JXG and because of the transient presence of Touton giant cells in JXG lesions, these classic elements may not be present in every case. The histiocytes contain pleomorphic nuclei, with few or absent mitotic figures, and irregular dense bodies. Clustered comma-shaped bodies occasionally are observed on electron microscopy but are not specific. Use of special stains is important to differentiate JXG from Langerhans and non–Langerhans cell histiocytoses. In JXG, histiocytes are positive to antibodies against Factor XIIIa, HAM56, HHF35, KP1 (CD68), Ki-M1P, and Vimentin, and are generally negative to CD1a and S-100. New reports have also demonstrated a CD4 positivity, which has been used as evidence that plasmacytic monocytes may be the normal cell type of the major constituent of JXG, instead of the dermal dendrocyte.
Medical Care
Anticipatory care, with patient reassurance, is appropriate because of the self-limiting benign nature of the lesions. Ocular and systemic lesions may respond to steroids or radiotherapy. Rare cases of severe systemic JXG have required single or multiagent chemotherapy regimens.
Surgical Care
Lesions may be excised for diagnostic and cosmetic reasons. Ocular and systemic lesion excision usually is curative. A 2008 case report describes a newborn with multiple cutaneous and hepatic JXGs requiring liver transplantation secondary to cholestasis and portal hypertension.12
Consultations
A reasonable cost-effective recommendation is to refer the patient to an ophthalmologist. Patients younger than 2 years with multiple skin lesions comprise 92% of associated cases of ocular involvement. Refer these patients to an ophthalmologist, and continue screening every 6 months through the second year of life. When presented with children diagnosed with both JXG and NF1, physicians should be on alert for possible JMML. Whether screening for JMML is necessary remains controversial, and little evidence supports performing hematological panels for detecting malignancy. Instead, physicians should look for clinical signs of JMML in patients with NF1 and JXG, particularly hepatosplenomegaly, lymphadenopathy, and pallor.
Systemic steroids may be used for problematic visceral lesions.13
Drug Category: Corticosteroids
Shrink visceral nodules. These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Meticorten, Orasone) |
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| Description | DOC for visceral lesions. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. |
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| Adult Dose | 40-60 mg PO qd; taper over 2 wk as symptoms resolve |
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| Pediatric Dose | 0.14 mg/kg PO divided bid/qid or 4-6 mg/m2/d PO in divided doses; taper over 2 wk as symptoms resolve |
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| Contraindications | Absolute: systemic fungal infection, herpes simplex keratitis, hypersensitivity (usually with corticotropin; occasionally with IV preparations)
Relative: hypertension, active tuberculosis, CHF, prior psychosis, positive intermediate purified protein derivative test, glaucoma, severe depression, diabetes mellitus, active peptic ulcer disease, cataracts, osteoporosis. recent bowel anastomosis, pregnancy |
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| Interactions | Ketoconazole, erythromycin, clarithromycin, estrogens, and birth control pills increase levels; aminoglutethimide, phenytoin, phenobarbital, rifampin, cholestyramine, and ephedrine decrease levels; levels of potassium-depleting diuretics (potentiates potassium loss and digitalis toxicity) and cyclosporine increase; levels of isoniazid, insulin (resistance is induced), and salicylates decrease; monitor anticoagulant therapy and theophylline levels |
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| Pregnancy | C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
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| Precautions | Abrupt discontinuation may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur
Use lower dose in hypothyroidism, liver disease, and obesity ( these conditions decrease cortisol-binding globulin and increase free fraction of steroid); pregnancy, hyperthyroidism and concurrent estrogen therapy may increase cortisol-binding globulin level |
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Further Outpatient Care
- Follow-up visits may be scheduled at regular intervals for reassurance and to monitor associated complications. For patients with JXG and NF1, physicians should watch for signs and symptoms of JMML.
- Patients with ocular involvement should be checked regularly by an ophthalmologist to prevent rare complications, such as glaucoma.14
Complications
- Complications are rare and are dependent on the site of involvement and associated conditions.
- Ocular involvement may progress to ocular hemorrhage, glaucoma, or retinal detachment. These complications are best prevented through early detection.
- CNS involvement is a very rare complication.
- Hepatic failure is a rare, but potentially fatal, complication of systemic JXG.
Prognosis
- In the absence of therapeutic intervention, skin lesions flatten with time. Both cutaneous and extracutaneous lesions involute spontaneously within 3-6 years.
- Hyperpigmentation, mild atrophy, or anetoderma may persist.
- Lesions can recur after resection. The relapse rate is approximately 7%.
- In the absence of neurofibromatosis, no systemic health implications are involved, with a few rare exceptions.
- Vigilantly screen male patients with neurofibromatosis and JXG for leukemia.
- Ocular, neurologic, and hepatic disease are rare but may have serious long-term consequences.
Patient Education
- Reassure patients and their families.
- Instruct patients concerning associations related to clinical situations (neurofibromatosis, ocular findings in diffuse JXG, JMML), and direct patient education toward these conditions.
Medical/Legal Pitfalls
- Failure to screen for associated conditions once a diagnosis has been made. Patients with JXG and café au lait macules have a 20% risk of seizure disorders. Patients with multiple JXGs have increased risk of JMML, which more likely occurs in patients with coexistent neurofibromatosis. Ocular hemorrhage, retinal detachment, and glaucoma are more likely to occur in patients younger than 2 years with multiple JXGs. Consider evaluating at-risk patients for JMML, epilepsy, and ocular findings.
| Media file 1:
Smooth, domed, yellow-brown, 5-mm papule on right arm of a 6-month-old boy. |
 |  View Full Size Image | |
Media type: Photo
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Juvenile Xanthogranuloma (Nevoxanthoendothelioma) excerpt Article Last Updated: Feb 29, 2008
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