Joumal of the

American Academy of
AAI) 1938
O6",~ ~,1.A ~ OX'O
DERMATOLOGY
V O L U M E 36 NUMBER 3 PART 1 M A R C H 1997

CONTINUING MEDICAL EDUCATION

Juvenile xanthogranuloma
Angela Hernandez-Martin, MD,* Eulalia Baselga, MD, Beth A. Drolet, MD,
and Nancy B. Esterly, M D Milwaukee, Wisconsin

Juvenile xanthogranuloma (JXG) is a benign, self-healing disorder characterized by solitary

or multiple yellow-red nodules on the skin and, occasionally, in other organs. It is predom-
inantly a disease of infancy or early childhood, although adults may also be affected. His-
tologically, JXG represents an accumulation of histiocytes lacking Birbeck granules
(non-Langerhans cells), which can be differentiated from Langerhans cells by specific stain-
ing techniques. Affected persons have normal lipid metabolism. JXG is therefore classified
as a normolipemic non-Langerhans cell histiocytosis. The patient's general health is not im-
paired and, in the absence of associated conditions, the prognosis is excellent. Diagnosis is
readily made in typical cases, but may be more difficult in unusual variants. (J Am Acad
Dermatol 1997;36:355-67.)

Learning objective: At the completion of this learning activity, participants should have a
good understanding of the clinical presentations, histologic features, immunochemistry,
prognosis, and management of the patient with juvenile xanthogranuloma.

The first case of juvenile xanthogranuloma (JXG)
was reported by Adamson I in 1905, who termed the
entity congenital xanthoma multiplex. Mc Donagh
described an additional case in 19092 and a series of
five cases in 1912. 3 He considered the disorder to be
of endothelial origin and coined the term nevoxan-
thoendothelioma. In 1936, Senear and Caro 4 cor-
rectly recognized the xanthomatous nature of the le-
sion and offered their preferred term juvenile xan-
thoma, which supported a suggestion of Artz 5 in
1919. Helwig and Hackney 6 demonstrated that these
lesions had no relation to nevi or endothelial cells and
ORtriO The CME articles are made possible through an educational
grant from the Dermatological Division, O ~ o Pharma-
ceutical Corporation.
From the Medical College of Wisconsin.
Supported in part by grant T32ARO7577 from the National Institutes
of Health, Bethesda, Md. (to Dr. Drolet).
Reprint requests: Nancy B. Esterly, MD, Pediatric Dermatology, 9200
W. Wisconsin Ave., Milwaukee, WI 53226.
*Affiliated with the Hospital Universitario de Salamanca (Spain). At
the time of this work, Dr. Hemandez-Martin was performing a
6-month rotation at the Medical College of Wisconsin (Milwaukee).
Copyright © 1997 by the American Academy of Dermatology, Inc.
0190-9622/97/$5.00 + 0 16/2/79119
proposed the term juvenile xanthogranuloma on the
basis of the histologic findings of lipid-laden histio-
cytes and giant cells. In 1937, Lamb and L a i n 7
reported the first case of JXG with pulmonary
involvement, although no biopsies were performed
on the lesions. Since then, there have been several
reports of biopsy-proven JXGs at extmcutaneous
sites. Ocular involvement was first observed by
Blank, Egfick, and Beerman 8 in 1949. Crocker 9 de-
s c r i m a child with " a small yellow papule" on the
hard palate in 1951, but the first documented
intraoral JXG was not reported until 1974. l°
Although the disease occurs mainly in children,
affected adults have also been observed since
Gartmann and Tritsch's report 11 in 1963.
To our knowledge, nine large case series of JXG
have been published since the initial report, 6' 12-20
including one of the adult form exclusively 14 and
two focused on intraocular manifestations) 2, 13
EPIDEMIOLOGY
JXG is the most common form of non-Langer-
hans cell histiocytosis (Table I). The real incidence
of JXG is tmknown, but it may be higher than is
355

356 Hernandez-Martin et al.
Fig. 1. Micronodular form of JXG. Multiple papular
lesions on the face of a Mack patient.
generally appreciated because JXGs occur early in
life, often as solitary lesions, regress within several
years, and are often mistaken for innocent "moles"
(Table 1/). A male predominance has been noted in
childhood, 15-19 estimated as 1.5:1 from a recent
analysis of the world literature21; however, in adults
there is no sex predilection. 14-16,22 JXG may affect
all races, but few black patients with JXG have been
reported in the English-language literature 6, 22 (Fig.
1). In one series JXG was found to occur 10 times
more often in white than in black persons. 12 Most
tumors appear earlyin life. From 5% to 17% of JXGs
are present at birth, 6, 15, 16 and 40% to 70% appear
during the first year of life. 15-17However, despite the
term juvenile xanthogranuloma, onset during adult-
hood is possible, 14, 17, 23-25 with a peak incidence in
the late twenties to early thirties. 17 So far, the oldest
reported patient was 80 years of age. 14 To our
knowledge, familial cases have not been observed.
CLINICAL FINDINGS
JXG is a well-demarcated, firm, robbery, round
to oval papule or nodule usually varying from 0.5 to
Journal of the American Academy of Dermatology
March 1997
T a b l e I. Classification of the histiocytoses
Langerhans-cell histiocytosis (histiocytosis X)
Letterer-Siwe disease
Hand-Schuller-Christian disease
Eosinophilic granuloma
Serf-healing reticulohistiocytosis
(Hashimoto-Pritzker disease)
Non-Langerhans-cell histiocytosis (histiocytosis
non-X)
Juvenile xanthogranuloma
Papular xanthoma
Necrobiotic xanthogranuloma
Benign cephalic histiocytosis
Xanthoma disseminatum
Multicentric reticulohistiocytosis
Progressive nodular histiocytoma
Generalized eruptive histiocytoma
2.0 cm in diameter. In early stages it is pink to
red with a yellow tinge (Fig. 2), but with time it ac-
quires a yellow-brown hue and may develop occa-
sional telangiectases on the surface (Fig. 3). The on-
set is abrupt, but new lesions can continue to appear
for years. 16,24 JXG is usually asymptomatic. How-
ever, a child with severe pruritus and pain resulting
in poor feeding and restlessness has been
described. 26
Ulceration and bleeding are unusual but may oc-
cur occasionally26-3° (Fig. 4). Gianotti 31 distin-
guished two clinical variants of JXG, depending on
the size and number of lesions: the small nodular and
the large nodular forms. The former is characterized
by numerous, dome-shaped papules of 2 to 5 mm in
diameter (Fig. 1), and the latter by one or a few larger
nodules ranging from 10 to 20 mm in diameter. Fre-
quently, both types of lesions coexist. Solitary
lesions are found in 60% to 82% of patients. 15-17,22
In both the infancy-childhood and adult forms, the
most common location is the head and neck, fol-
lowed by the upper torso, the upper extremities, and
the lower extremities.
Involvement of oral mucous membranes is ex-
ceptional.lO, 16,32-37 Oral JXG presents as a well-
defined, yellow, rubbery, solitary nodule, 2 to 15 mm
in diameter, that may ulcerate and bleed. 33'38 The
lateral aspects of the tongue and the midline of the
hard palate are the most common sites. 33, 37 Oral
JXG usually develops after 3 years of age. 35 There
is a single case report of multiple oral lesions, in
which cutaneous papules coexisted (Fig. 5). 32 Con-
genital oral JXG has been documented once. 35
Journal of the American Academy of Dermatology
Volume 36, Number 3, Part 1 Hernandez-Martin et al. 357

T a b l e II. Incidence of juvenile xanthogranuloma

Author(s) Institution Period No. of cases

Sanders 12 Armed Forces Institute of Pathology 1948-1960" 4

(Washington, D.C.)
Z i m m e r m a n 13 Armed Forces Institute of Pathology 1940-1962t 11
(Washington, D.C.)
Rodriguez & Ackerman 14 Skin and Cancer Unit 1973-19745 9~
(New York University)
Sonoda, Hashimoto, Enjoji15 Kyushu University (Japan) 1965-1983 57§
Cohen & Hood16 Johns Hopkins Hospital (Baltimore) 1940-1984 6411
Tahan et al. 17 Massachusetts General Hospital ND 34
(Boston)
Torok & Daroczy 18 Heim Pal Children's Hospital ND 45
Semmelweis University
(Budapest, Hungary)
Marrogi et al.19 Barnes Hospital (Washington 1973-1990 30
University, St. Louis, Mo.)
Zelger, Orchard, St. John's Hospital University of ND 26
Wilson-Jones2° Innsbruck (Austria)
Caputo et al.40 Institute of Dermatological Sciences 20yr 109][
University of Milan, Italy
Esterly Children's Hospital of Wisconsin 1990-1996 20
(Milwaukee)**
ND, Nonspecified dates.
*Skin and eye survey between 1928 and 1960.
1-Skin and eye survey between 1928 and 1964; includes the cases reported by Sanders. TM
~:Fifteen-month period; only adult cases included.
§Sixty lesions biopsied from 57 patients; 10 adults included.
IITen adults included.
q[Authors mentioned data; nonpubfished series.
**Authors' observation; unpublished data,

UNUSUAL CLINICAL ASPECTS OF JXG

The shape, location, distribution, and size can vary
widely, resulting in unusual clinical forms of JXG.
Patients with hyperkeratotic nodules 39 (Fig. 6) and
pedunculated lesions 18,40 have been described. As
already mentioned, the head, neck, and upper trunk
are the areas most commonly involved, but JXG can
appear at any site of the body surface, including un-
der a toenail, 41 on the penis, 32,42, 43 on the skin ad-
jacent to the clitoris, 44 the eyelid, 13'45 the scro-
tum, 46-48the tips, 18the palms and soles49 (Fig. 7), the
great toe, 5° and the fingers. 15,51 In the giant or ma-
cronodular form of JXG, the tumors are larger than
2 cm. The largest nodule reported measured 10 x 5
cm and was located in the groin. 5° The giant variant
has also been observed on the scapula 52 (Fig. 8),
shoulder, 3° trunk, 27, 29 antecubital f o s s a , 26 scalp, 27' 29
thigh, 27 eyelid,42 nose (mimicking the hemangiom-
atous Cyrano nose),40 and hand. 53 Congeni-
tal26, 28, 40, 45,50 and multiple giant JXGs have been
described.27, 29, 40
Other exceptional clinical features reported in-
clude presentation as a generalized lichenoid emp-
tion, 49 a reticulated, maculopapular eruption, 51 a so-
called "clustered" form of JXG, 41 and as flat,
plaque-like lesions (Fig. 9). Recently, adult-onset
xanthogranulomas appearing symmetrically on the
ear lobes have been observed. 54
The frequency of occurrence of JXG in the deep
soft tissue has been estimated to be 5%. 15 The clin-
ical features consist of a nontender, well-demar-
cated, soft mass not attached to the skin and, in most
cases, without skin changes. 55-57 Subcutaneous JXG
has been reported on the hand, the neck, 15 the
paravertebral tissue, 55' 56 the back, 55 the scalp, and
the forehead. 57 The lesions are asymptomatic, unless
the space occupied by the tumors produces func-
tional impairement.
EXTRACUTANEOUS INVOLVEMENT
The eye is the extracutaneous site most frequently
affected. In a recent study, the incidence of eye in-

358 Hernandez-Martin et al.
Fig. 2. Early JXG. Red, shiny, firm nodule on infant's
neck.
volvement in patients with cutaneous JXG was es-
timated to be 0.3% to 0.5%. In contrast, at least 41%
of patients with ocular involvement had cutaneous
lesions that were always multiple. 58 In up to 45% of
patients with coexistent cutaneous JXGs, skin le-
sions developed after those in the e y e , 13'58-60 b u t
m a y also precede 59 or appear simultaneously58,6°
with those in the eye. Ocular involvement occurs
more often during the first 2 years of life, 13'58 but
adult onset is also possible. 22' 61-64 To our knowl-
edge, the oldest reported patient with intraocular in-
volvement was 38 years old. 62 Most ocular JXGs
occur on the iris. Sanders ~2 described a series of 20
patients with ocular involvement, all of w h o m had
iris lesions. Z i m m e r m a n ] 3 after reviewing 52 pa-
tients with eye involvement, stated that only 63%
had uveal findings. Uveal JXG usually presents with
one or more of the following: (1) an asymptomatic
localized or diffuse iris tumor, (2) tmilateral glau-
coma, (3) spontaneous hyphema (Fig. 10), (4)
erythema with signs of uveitis, and (5) congenital or
acquired heterochromia iridis. 13 The eyelid is the
Journal of the American Academy of Dermatology
March 1997
Fig. 3. Mature JXG. Well-demarcated, dome-shaped,
yellow nodule on the temporal hair line.
second most commonly affected site, whereas the
posterior pole is only rarely involved. 65, 66 Orbital
involvement is also unusual13' 61, 67-70 and appears to
occur mainly during the perinatal period. 13"65, 67-70
Therefore JXG must be considered when evaluating
a unilateral exophthalrnos in an infant. Bilateral oc-
ular JXG is exceptional. 13' 60, 71
Other extracutaneous manifestations are summa-
rized in Table III. Previous reports of patients with
extracutaneous JXGs identify the lung as the next
most frequent location after the eye, 6' 7, 43, 72-78 fol-
lowed by the liver. 43' 74, 77-79 Radiographs of pulmo-
nary JXGs demostrate multiple, round, nodnlar
intrapulmonary homogeneous opacities mimicking
metastases. 75'79 Hepatomegaly is characteristic
when the liver is affected], 72.75, 43 Additional rare
sites of extracutaneous JXG are the pericardium, 74
the myocardium, 39 the spleen, 43 the retroperitone-
u r n , 77 the kidney, 58' 78, 79 the central nervous sys-
tern, 29 ' 43 ' 78 ' 80 the ~,onads,
o 78 ' 81 the adrenalgland, the
Journal of the American Academy of Dermatology
Volume 36, Number 3, Part 1 Hernandez-Martin et al. 359

Fig. 5. lntraoral JXG. Characteristic lesion on the ton-

silar pillar. (From Ossof RH, Levin DL, Esterly NB, et al.
Ann Otol Rhinol Laryngol 1980;89:268.)

Fig. 4. Ulcerated JXG in the perineal area.

bones,58,67. 78 and the larynx. 81 All reviewed pa-

tients with visceral involvement except tWO77"81
had skin involvement that was noted before or con-
current with the systemic abnormalities. In all
patients the cutaneous lesions were multiple and no
patient had ocular involvement. 6, 7, 29, 72-79,82, 83
Symptoms of visceral tumors are those derived
from a mass effect, such as dyspnea, 7' 39,74,75, 81
seizures43, 8O or peripheral nerve paralysis. 78 Be-
cause most patients with visceral involvement have
cutaneous lesions, the diagnosis of the systemic tu-
mors is usually readily made, However, it m a y be
difficult in those instances without coexistent cuta-
Fig. 6. Keratotic, atypical variant of JXG on the nostril.
neous nodules.

ASSOCIATED CONDITIONS
Unlike other xanthomatous disorders, JXG has no
associated metabolic abnormalities, hyperfipemia, or
diabetes insipidus. 6, 14, 74
The association between JXG and pigmentary
abnormalities was fn-st suggested in 1960 by Marten
and Sarkany, 84 although there were previous reports
describing the coexistence of cafd-au-lait spots and
JXG.46, 85 Since then, several patients with JXG,
caf6-au-lait spots, and a family history of neurofibro-
matosis type 1 (NF1) have been reportedJ s"47, 86, 87
In addition, some authors found a high prevalence of

360 Hernandez-Martin et al.
Fig. 7. Multiple JXGs on the soles.
Fig. 8. Giant form of JXG on the scapula of a 5-month-
old infant,
epilepsy in patients with JGXs and caf6-au-lait
spots. 18
Another well-documented association is that of
JXG and childhood leukemia ("xantholeukemia"),
most cormnonly juvenile chronic myelogenous leu-
kemia (JCML). 9, 88-96In the majority of patients, the
JXG antedates or is noted at the same time that the
leukemiais diagnosed.48• 86, 89 JXGs in children with
JCML are usually multiple,89 although occasionally
Journal of the American Academy of Dermatology
March 1997
Fig. 9. Hyperpigmented, plaquelike form of JXG on the
face.
Fig. 10. Spontaneous hyphema secondary to uveal
JXG. This patient had bilateral lesions.
they can be solitary. 71 Ocular involvement in pa-
tients with NF1 or JCML, or both, has been report-
ed,97, 98 but to our knowledge visceral lesions have
not been described in these patients.
The association between JXG and leukemia is of
Journal of the American Academy of Dermatology
Volume 36, Number 3, Part 1 Hernandez-Martin et al. 361

Table I l L Extracutaneous juvenile xanthogranuloma

Age
?
I Noncutaneo~ sites
Lung, testis
I Reference
No.
6
Skin lesions
Multiple
Clinicalfeatures
?
3 mo Lung, liver 7 Multiple Dyspnea
2.5 mo Lung, liver, testis 70 Multiple ?
5 mo Lung 73 Multiple None
3 mo Lung, pericardium 74 Multiple Respiratory distress
At birth Lung, liver, subcutaneous tissue 75 Multiple Respiratory distress
1.5 yr Lung 76 Multiple None
10 days Lung, spleen, retroperitoneum 77 Multiple None
3 mo Lung, liver, kidney, gonads, orbits 78 Multiple None
3 days Orbits, CNS, bone, adrenal 78 None Facial and cord paralysis
At birth Liver, subcutaneous tissue 79 Multiple None
5 rno Kidney, liver 82 Multiple None
7 rno Testis 83 Multiple None
8 mo CNS 80 Subcutaneous Seizures
10 yr CNS 29 Multiple Memory loss
4 mo Larynx 83 None Respiratory distress
1 mo Lung, CNS 43 Multiple Seizures
1 wk Liver, spleen 43 Multiple Jaundice, organomegaly

interest in view of the known relation between NF1
and childhood leukemia, especially JCML. 91, 99-102
In fact, there are several reported cases of the triple
association of NF1, JCML, and JXG. 21' 48 In the
most recent review of the literature, 21 the observed
frequency of the triple association was 30- to 40-fold
higher than expected, and children with NF1 and
JXG were estimated to have a 20- to 32-fold higher
risk for JCML than patients with NF1 and no JXG.
These findings indicate that JXG in children with
NF1 should alert the physician to the possible
development of JCML. In this study, the prevalence
of a family history of NF 1 was higher in patients with
JCML, suggesting that this may be a risk factor for
the development of JCML. A strong male predilec-
tion was found in children with NF1, JCML, and
JXG, which may reflect the predominance of this sex
in both JXG 15-19 and JCML. 48, 92, 99 Definitive diag-
nosis of NF1 in patients with associated JCML is
often difficult because of the early onset of JCML
and death at an age when caft-au-lait macules are the
only clinical manifestation of the disease. However,
reports of children with JXGs, neurofibromas, and
even extracutaneous manifestations of NF1 have
been published. 99, 103
Acute lymphoblastic leukemia with m2, 104or with-
out 96 NF1, monocytic leukemia, 1°5 histiomonocytic
reticulosis, 1°6 and juvenile myelomonocytic leuke-
mia90, 99 have also been reported in association with
JXG. Single reports of other conditions observed
coexisting with JXG are urticaria pigmentosa, 44 Ni-
emann-Pick disease, 1°7 cytomegalovirus infec-
tion, 1°8 and ingestion of oral contraceptives. 1°9 The
existence of a real association with JXG is unknown.
HISTOPATHOLOGIC FEATURES
JXGs are characterized histologically by a dense,
sheetlike, nonencapsulated, well-demarcated, histi-
ocytic infiltrate within the papillary dermis only or
the papillary and reticular dermis. Extension into
subcutaneous tissue, fascia, and peripheral muscle
occurs in up to 38% of cases. 17'50'57'110'111 The
epidermis and adnexal skin structures are spared, but
the proliferating tumor can thin or flatten the epider-
mis and eventually ulcerate it. 28,38'51 Expansion
within the dermis with displacement of adnexal
components occurs in some cases. 17 The cellular in-
filtrate includes, in different proportions, histiocytes,
giant cells, Touton cells, lymphocytes, eosinophils,
and neutrophils. Some authors have also found a
significant number of mast cells) °' 1~0The morphol-
ogy of the infiltrate varies with the clinical evolution
of the lesion) s'51,52" ~11,112 In early stages, many
histiocytes with a small degree of lipidization are in-
termingled with a scanty inflammatory infiltrate.
The histiocytic cells have a homogeneous ampho-
philic or eosinophilic cytoplasm that reacts with fat
stains.15, 1ll, 112 In older lesions, the histiocytes have
a vacuolated, foamy, xanthomatous cytoplasm, and
there are more of inflammatory cells, giant cells, and
 Journal of the American Academy of Dermatology
362 Hernandez-Martin et al. March 1997

Table IV. Antibodies used for immunochemistry in juvenile xanthogranuloma

Marker I Type of antibody Main specifidty

CDI(OKT6) M LCs, cortical thymocytes

Mac-387 M Monocyte-derived macrophages
HAM56 M Monocyte-derived macrophages
KP1 M Reactive monocytes and macrophages
KiM1P M Reactive monocytes and macrophages
HHF35 M Smooth muscle cells, myofibroblasts
Vimentin M Mesenchymal cells
S-100 protein P Nerves, melanocytes, LCs, myoepithelial cells
Lysozyme P Monocyte-derived macrophages
oq-Antitrypsin P Monocyte-derived macrophages
oq-Antichymotrypsin P Monocyte-derived macrophages
Factor XIIIa P Dermal dendrocytes
Peanut agglutinin I_gctin Epithelial cells, sebaceous glands, endothelial cells
LC, Langerhans cell; M, monoclonal; P, polyclonal.

Touton cells. The presence of Touton cells showing
the typical "wreath" of nuclei surrounded by foamy
cytoplasm is characteristic, although not specific,
and may be absent./5,H3 In regressing lesions,
fibroblast proliferation and fibrosis are observed)12
Ultrastructurally, the histiocytes of early lesions
have an irregular nuclus, and are rich in pseudopods,
lysosomal structures and dense bodies, l°,46,51,11°
Clusters of comma-shaped bodies can occasionally
be observed,TM but Birbeck granules are ab-
sent.W, 110,112,114 In older lesions non-membrane-
limited lipid droplets within the cytoplasm are iden-
tified. TM No true features of atypia and only rare mi-
toses are found. 17,5L 110,112 The mature Touton cell
has relatively few lipid vacuoles, and the nuclei are
interconnected by thin bridges of nuclear material. 1°
Unlike certain types of eruptive xanthomas, there are
no lipid droplets within the endothelial cells, al-
though they may be occasionally present in pericytes
and smooth-muscle cells of arteries and arrectores
pilorum)7, Ho However, the vascular endothelium
can be remarkably swollen, sometimes to the point
of luminal occlusion) °, 110
The immunohistochemical findings are important
because the distinctive marker profile may help to
establish a diagnosis in atypical variants of JXG and
to separate JXG from other Langerhans-cell and
non-Langerhans-cell histiocytoses and fibro-
cytic lesions (Table IV). Proliferating histiocytes
of JXG are negative for S-100 protein and Mac-
38715,18, 19, 50, 115 and positive for HAM56, HHF35,
KP1, KiM1P, and vimentin) 9 Factor XIIIa is also
positive.W, 116 Other cell markers such as lysozyme,
oq-antitrypsin, eq-antichymotrypsin, and peanut ag-
glutinin show no consistent results. The OKT6
(CD1) marker has long been considered a specific
marker for Langerhans cells, but a case of JXG with
positive labeling for this antibody has been
reported. 117
When histologic features are compared, no sig-
nificant differences between the juvenile and adult
forms have been found./s, 19
PATHOGENESIS
Most authors believe that JXG is a reactive gran-
ulomatous response of histiocytes to an unknown
stimulus,17,50,51,110 although this postulate has not
been substantiated. Physical53 and infectious 1°8 fac-
tors have been considered.
DIFFERENTIAL DIAGNOSIS
In the differential diagnosis of JXG, several dis-
orders with similar clinical or histologic features (or
both) have to be considered. The nodular lesions of
Langerhans cell histiocytosis can display similar
clinical features but can be ruled out by histologic,
inmunohistochemical, and ultrastructural findings.
Cleaved nuclei and epidermotropism seen on light
microscopy as well as Birbeck granules on electron
microscopy (EM) are characteristic of the disease.
The histiocytic infiltrate stains for S- 100 protein and
CDI(OKT6). H2 In serf-healing reticulo-histiocyto-
sis (Hashimoto-Pritzker disease), which is consid-
ered part of the spectrum of Langerhans-cell histio-
cytosis, the lesions often ulcerate and regress rapidly
in approximately 2 to 3 months (but not in years as
JXG does). In addition, 10% to 20% of the cells are
positive for S-IO0 protein and show Birbeck gran-
Journal of the American Academy of Dermatology
Volume 36, Number 3, Part 1
ules on EM.114 Benign cephalic histiocytosis may be
impossible to differentiate histologically from early
nonlipidized JXG, and some authors believe that
benign cephalic histiocytosis is part of the spectrum
of JXG. 3°,118 Comma-shaped bodies and coated
vesicles seen on EM, initially thought to be charac-
teristic of benign cephalic histiocytosis, have been
observed in several histiocytic disorders, including
JXG.117, 118 Cutaneous lesions may be similar to the
micronodular form of JXG. However, in benign
cephalic histiocytosis, the lesions are flatter, (resem-
bling plane warts), are mainly on the head and neck,
affect mostly young children, and do not involve
mucous membranes. Generalized eruptive histiocy-
toma affects mainly adults. Histologically, it is not
granulomatous and does not show cellular lipidiza-
tion; wormlike bodies are occasionally found on
EM. Papular xanthoma is a normolipemic, cutane-
ous, papular xanthomatosis distinguishable from
JXG only on the basis of histologic findings because
a primitive histiocytic phase is lacking. H4, 119 Ultra-
structural findings and clinical evolution may be
identical to those of mature J X G . TM Xanthoma dis-
seminatum affects mainly adults, is associated with
diabetes insipidus in many patients, and mucous
membrane involvement is characteristic. The lesions
tend to merge into plaques, and visceral lesions are
not a feaRu'e. 114'119 Tuberous xanthoma appears
only in hyperlipidemic states and localizes to the el-
bows, knees, and buttocks. Histologic examination
shows a more uniform proliferation of cells with a
large foamy cytoplasm. TM
In solitary mastocytoma, the lesions became urti-
carial after rubbing and contain abtmdant mast cells
within the dermis. Spitz nevus may be clinically
identical to early stages of JXG, but the presence in
the former of spindle and epithelioid cells in the his-
tologic study is distinctive. 112 Histopathologic dif-
ferentiation of JXG from dermatofibroma with lip-
idization can be difficult. However, the latter only
rarely contain wreath-shaped Touton cells, may have
areas of hemosidefin deposits, and often display a
hyperplastic epidermis. 112
Atypical clinical forms are usually diagnosed af-
ter histopathologic analysis. Clinical features mim-
icking dermatofibroma, dermal nevus, calcinosis
curls, keloid, adnexal tumor, 19 pyogenic granuloma,
xanthoma,17, 19 cyst,17-19 or keratoacanthoma (Fig.
11) have been described. Diagnosis in these in-
stances relies on the results of histopathologic
examination.
Hernandez-Martin et al. 363
Fig. 11. Atypical JXG on the forehead, mimicking a
keratoacanthoma.
JXG located in the deep tissues may be mistaken
for malignant tumors such as rhabdomyosarcoma,
fibrosarcoma, or malignant fibrohistiocytoma.111
The lack of nuclear atypia, numerous mitoses, and
pleomorphism of the tumor cells excludes malig-
nancies.
The clinical diagnosis of an ocular mass is often
difficult and is usually based on statistical analysis,
considering the tumors more frequently encountered
in childhood in a given location. Histopathologic
study is always necessary to confirm the nature of the
neoplastic process.22, 45
Visceral JXGs may mimic any type of malignant
or benign mass. However, because most patients
with visceral involvement also have cutaneous le-
sions, the diagnosis should not be a problem.
PROGNOSIS
JXG is a benign condition that appears in other-
wise healthy persons. It usually regresses spontane-
ously within 3 to 6 years. 16, 120In up to 48%, an area
of hyperpigrnentation, slight atrophy, or anetoderma
remains15, 26,49 (Fig. 12). Recurrence after partial or
complete excision of cutaneous lesions has been
documented.27, 28, 33 In adults, there is no spontane-
ous resolution as a rule, la' 16,22 although such cases
have been observed. 23, 24 Spontaneous involution of
oral lesions is also rare. 34
When there is intraocular involvement, the risk of
complications is high. 12'13'22'59'71 The main con-
cem is of uveal lesions, which may invade the angle
and produce hyphema or uncontrolled glaucoma.
Although posterior involvement is rare, when ex-
tensive, it may produce obliteration of the central

364 Hernandez-Martin et al.
Fig. 12. Slightly atrophic, anetoderma-like scars at the
sites of regressed JXGs on the ann and back of a patient
with multiple, widespread lesions.
retinal vein and/or artery and detachment of the ret-
ina, leading to blindness. 61, 62
Extracutaneous lesions also undergo spontaneous
remission, similar to the skin. 7'73-75'77'78'81 I m p l i -
c a t i o n s for the patient's health depend on the sever-
ity of visceral dysfunction from the histologically
benign masses, v, 74,75, 78, 81 There is a case of fatal
evolution in a child with multiple cutaneous xan-
thogranulomas and nervous system involvement,
but no pathologic confirmation of the brain lesions
was available. 121
TREATMENT
No treatment is required because of the self-lim-
iting nature of the skin lesions. Despite this, many
patients have the tumors excised for diagnostic or
cosmetic reasons. 10, 16. 29
. . . 35
. 37 50 53.117 However, as
already mentioned, recurrences after complete or
incomplete excision of the lesion have been report-
ed.27, 28, 33
Early treatment of uveal lesions is necessary be-
Journal of the American Academy of Dermatology
March 1997
fore the complications of secondary glaucoma and
anterior chamber hemorrhage develop.13, 59, 71 Top-
ical, intralesional, and systemic steroids 59, 61, 64, 71,122
have been used successfully for intraocular and or-
bital JXGs. In addition, low-dose, noncataractogenic
radiotherapy may be considered when steroids can-
not be administered or do not improve the condi-
tion.12, 59, 63, 64 Surgical treatment may be required if
complicated by hyphema or glaucoma. 123
Systemic lesions do not need to be treated unless
their location interferes with vital functions. 74, 78, 81
Chemotherapy,43, 78, 121 radiotherapy,40, 73,121 high-
dose corticosteroids, and 121 cyclosporine43 have
been used occasionally. Response to these treat-
ments is difficult to assess because of the possibility
of spontaneous involution. Because of the benign
nature of the disease, the aggressive excisional ther-
apies performed in the past 12'13'60'80'81 are no
longer justified, and conservative management is
recommended.
APPROACH TO THE PATIENT WITH JXG
In general terms, given the uncomplicated course
of cutaneous JXG, further observation of the lesions
is unnecessary. However, several issues must be
considered: Is there a need for histologic confirma-
tion? Do all patients have to be referred to an oph-
thalmologist, and, if so, how often should they be
examined? Does the presence of visceral lesions
need to be determined? Is it necessary to rule out an
associated leukemia? Does a patient with JXGs need
to be observed until complete healing of the lesions?
The answers to these questions are not always
straightforward and may depend on the clinical set-
ting in which the case is being evaluated.
The clinical diagnosis of a solitary cutaneous JXG
is easily made in most cases and often does not re-
quire histologic confirmation. In contrast, biopsies of
multiple skin lesions may be required to exclude
other disorders. A complete review of systems and
physical examination is recommended to detect ex-
tracutaneous involvement. Because of the associa-
tion of JXG and NF1 a complete skin examination
of the patient should be performed and a family his-
tory of NF1 should be sought.
The need to perform routine ocular screening is
controversial, Because of the low incidence of ocu-
lar involvement in patients with cutaneous JXG
(0.3 % to 0.4 % ), routine screening does not appear to
be indicated. On the other hand, in approximately
Journal of the American Academy of Dermatology
Volume 36, Number 3, Part 1
half the patients, cutaneous lesions appear before
those in the e y e and can lead to early detection o f
ocular lesions, which, if undiagnosed, could h a v e
serious consequences, including blindness. G i v e n
that patients with cutaneous and ocular J X G s a l w a y s
have multiple skin lesions and are usually y o u n g e r
than 2 years o f age (92%), 5s it w o u l d be reasonable
and cost-effective to refer only this s u b g r o u p o f
higher risk patients to an ophthalmologist. I f the first
examination does not detect ocular J X G , screening
every 6 m o n t h s up to the s e c o n d y e a r o f life is ad-
visable.
R o u t i n e h e m a t o l o g i c and metabolic screening is
not indicated. Searching for visceral lesions is not
necessary because these c o m m o n l y r e m a i n a s y m p -
tomatic and require no treatment. In those patients
with caf6-au-lait spots and J X G , it m i g h t be advis-
able to alert the p r i m a r y physician about the in-
creased risk o f leukemia, especially if the patient is
m a l e and has a family history o f NF1.
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