Report

Juvenile xanthogranuloma: retrospective analysis of 44

pediatric cases (single tertiary care center experience)
ß akır2, MD
Selcen Kundak1, MD and Yasemin C

1
Department of Dermatology, Dr. Behcet Abstract
Uz Children’s Research and Training Background/Objective Juvenile xanthogranuloma (JXG) is a rarely encountered skin
Hospital, Izmir, and 2Department of
disorder, which is characterized by the proliferation of non-Langerhans cell histiocytes. As
Pathology, Dr. Behcet Uz Children’s
Research and Training Hospital, Izmir,
JXG primarily affects infants and young children, this study aims to describe the
Turkey epidemiologic, clinical, and histopathologic characteristics of 44 children diagnosed with
JXG at a tertiary health care center.
Correspondence Methods Fourty-four children with a histopathologic diagnosis of JXG between January
Selcen Kundak, MD
2003 and January 2017 were retrospectively reviewed. Data related to epidemiologic,
Department of Dermatology
Izmir Dr. Behcet Uz Children’s Research
clinical, and histopathologic features were extracted from hospital records.
and Training Hospital Results The mean age of the affected patients was 4.6 years old (range: 0–17 years old)
Alsancak - Konak, 35210 at the time of diagnosis. Twenty-five patients (56.8%) were male, and 19 patients were
Izmir female (43.2%). Thirty-six children (81.8%) had solitary JXG, one of which was a giant
Turkey
congenital JXG; eight children (18.2%) had eruptive JXG. The heterozygote mutation
E-mail: drselcen@yahoo.com
associated with neurofibromatosis 1 gene was detected in one patient who had both
eruptive JXG and numerous cafe  -au-lait spots. Another patient with eruptive JXG was
Conflict of interest: None.
identified to have hypercholesterolemia. None of the children with eruptive JXG developed
Funding source: None. symptoms or signs of extracutaneous involvement during their clinical follow-up.
Conclusion Since JXG is rarely encountered, there may be a tendency toward over-
treatment, given concerns for extracutaneous involvement. However, our review revealed
doi: 10.1111/ijd.15223 no instances of extracutaneous involvement.

characteristics of 44 children diagnosed with JXG at a tertiary

Introduction
Juvenile xanthogranuloma (JXG), initially termed xanthoma mul-
tiplex, juvenile xanthoma, and/or xanthoma tuberosum, is the
most common type of non-Langerhans cell histiocytosis.1 JXG
most often occurs during infancy or soon after. It is generally
considered a benign skin disorder presenting as a solitary,
asymptomatic, red-yellow papule or nodule. Multiple cutaneous
lesions are observed in approximately 7% of patients.2 On
histopathology, these papules and nodules are characterized by
the accumulation of the histiocytes with a progressively increas-
ing degree of lipidation within the dermis. The most common
locations of these lesions are the head and neck, followed by
the upper and lower extremities.1-3 Extracutaneous involvement
is rare but may occur in the eyes, bones, lungs, and liver.3,4
This skin disorder has also been associated with neurofibro-
matosis type 1 (NF1).5-8 Importantly, it has been suggested that
the risk of developing juvenile myelomonocytic leukemia is 20–
30 times higher in patients who are diagnosed with both NF1
gene mutation and multiple JXG.5-8
This study aims to contribute to the understanding of JXG by
describing the demographic, clinical, and histopathologic
health care center.
Materials and methods
This study was approved by the Institutional Review Board and
Ethical Committee of Dr. Behcet Uz Pediatric and Pediatric
Surgery Hospital. This center provides medical services
primarily to Caucasian individuals but also receives referrals
from all parts of Turkey. Forty-four children with a
histopathologic diagnosis of JXG between January 2003 and
January 2017 were retrospectively reviewed.
JXG indicates great variability in clinical presentation. In our
clinic, biopsy is performed for diagnostic purposes.
The histopathological diagnosis of JXG was confirmed by the
examination of skin biopsies with a dense dermal infiltrate
consisting of histiocytes with finely vacuolated foamy
cytoplasms and a variable number of multinucleated Touton
giant cells, Langhans type giant cells and foreign body type
giant cells. Data related to epidemiologic, clinical, and
histopathologic features were obtained from hospital records.
Collected data were analyzed with Statistical Package for Social 1

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Kundak and C

Table 1 Histopathological and clinical characteristics of juvenile xanthogranuloma patients

Eruptive (n = 8) Solitary (n = 36) Total

Gender Male 4 (50.0%) 21 (58.3%) 25

Female 4 (50.0%) 15 (41.7%) 29
Age groups 0–1 years 5 (62.5%) 14 (38.9%) 19
2–3 years 1 (12.5%) 6 (16.6%) 7
4–5 years 0 (0.0%) 4 (11.1%) 4
6–7 years 1 (12.5%) 5 (13.9%) 6
8–9 years 0 (0.0%) 0 (0.0%) 0
10–11 years 0 (0.0%) 3 (8.3%) 3
12–13 years 0 (0.0%) 1 (2.8%) 1
14–15 years 0 (0.0%) 1 (2.8%) 1
16–17 years 1 (12.5%) 2 (5.6%) 3
Number of lesions 1 0 (0.0%) 36 (100.0%) 36
2–5 0 (0.0%) 0 (0.0%) 0
≥6 8 (100.0%) 0 (0.0%) 8
Location of lesions Head and neck 0 (0.0%) 14 (38.9%) 14
Lower extremities 0 (0.0%) 4 (11.1%) 4
Trunk 2 (25.0%) 7 (19.5%) 9
Upper extremities 0 (0.0%) 4 (11.1%) 4
Groin and buttocks 0 (0.0%) 4 (11.1%) 4
Multifocal (including head and neck) 5 (62.5%) 0 (0.0%) 5
Multifocal (without head and neck) 1 (12.5%) 0 (0.0%) 1
Armpit 0 (0.0%) 3 (8.3%) 3
Size of lesions ≤5 mm 6 (75.0%) 14 (38.9%) 20
6–10 mm 1 (12.5%) 12 (33.3%) 13
>10 mm 1 (12.5%) 10 (27.8%) 11
Histopathological localization Superficial dermis 8 (100.0%) 8 (22.2%) 16
Deep dermis 0 (0.0%) 0 (0.0%) 0
Superficial and deep dermis 0 (0.0%) 28 (77.8%) 28
Giant cells No giant cells 3 (37.5%) 6 (16.6%) 9
Touton type giant cells 3 (37.5%) 27 (75.0%) 30
Langhans type giant cells 1 (12.5%) 8 (22.2%) 9
Foreign body type giant cells 1 (12.5%) 11 (30.6%) 12
Immunohistochemical examinationa Not performed 2 (25.0%) 19 (52.8%) 21
Performed 6 (75.0%) 17 (47.2%) 23
CD68 Negative 1 (16.7%) 0 (0.0%) 1
Positive 5 (83.3%) 17 (100%) 22
S100 Negative 5 (100%) 4 (57.1%) 9
Positive 0 (0.0%) 3 (42.9%) 3
CD1a Negative 6 (100%) 9 (100%) 15
Positive 0 (0.0%) 0 (0.0%) 0

a
Immunohistochemical analysis and percentages were evaluated according to the number of samples examined by immunohistochemistry.

Sciences version 18.0 (SPPS IBM, Armonk, NY, USA).
Continuous variables were expressed as mean  SD (range:
minimum-maximum), and categorical variables were denoted as
numbers or percentages.
Results
At the time of diagnosis, the mean age of the JXG patients was
4.6 years (range: 0–17 years). Twenty-five patients (56.8%)
were male, and 19 patients (43.2%) were female.
Thirty-six children (81.8%) had solitary JXG. These solitary
lesions were located on the head and neck in 14 patients
(38.8%) and on the trunk in seven patients (19.4%). The solitary
lesions were larger than 10 mm in ten patients (27.8%). None
of the patients with solitary JXG had ocular involvement. Giant
cells on histopathology were observed in 30 children with soli-
tary JXG lesions (83.3%). Immunohistochemical staining with
CD68 was performed in 17 patients with solitary JXG (47.2%)
and positive in all cases (100%) (Table 1).
One patient with solitary JXG had a congenital, ulcerated,
4 cm wide area of involvement lesion that was identified as
giant congenital JXG. This underwent spontaneous regression
and healed in 2 years (Fig. 1).
A total of eight children (18.2%) had eruptive JXG (Fig. 2).
Table 1 shows the clinical and histopathological characteristics
of the patients with eruptive JXG. These occurred within the first

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 ß akir
Kundak and C
Figure 1 A 4 cm wide giant congenital JXG
lesion was detected in a 1-year-old female
patient
2 years of life in six patients (75.0%). A heterozygote mutation
associated with NF1 was detected in one patient who had both
eruptive JXG and numerous cafe -au-lait spots (Fig. 3). Another
patient with eruptive JXG was identified as having hypercholes-
terolemia. None of the children with eruptive JXG developed
extracutaneous involvement during the period of clinical follow-
up.
Giant cells were observed on histopathology in five children
with eruptive JXG (62.5%). Immunohistochemical staining with
CD68 was performed in six patients with eruptive JXG (75.0%),
and it was positive in five cases (83.3 %).
Discussion
JXG is a rarely encountered skin disorder which primarily pre-
sents during the first two decades of life.2 Generally, JXG
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Juvenile xanthogranuloma Report 3
appears as a solitary cutaneous lesion that resolves sponta-
neously without treatment. However, multiple lesions may erupt,
and there is the possibility of systemic involvement.9-13
The incidence of extracutaneous/systemic involvement has
not been well-established. A study by Samulev et al.3 reported
no incidence of ocular involvement. In this report, review of pre-
viously published series of JXG revealed a 0.75% incidence of
systemic involvement (22/2949 patients) and 0.24% incidence
of ocular involvement (7/2949). This report concluded that rou-
tine eye examination is probably not warranted in JXG patients
without any ocular concerns. In our series, there were no
patients, with either solitary or eruptive JXG, with ocular or sys-
temic diseases.
-au-lait spots has been
Concurrent eruptive JXG with cafe
reported, which may be associated with NF1 mutations and
NF1 as a clinical diagnosis.7,14-17 Although an increased risk of
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Kundak and C

Figure 2 Eruptive JXG lesions in an 8-month-old female patient

juvenile myelocytic leukemia in patients with JXGs and NF1 Congenital JXG is the rarest type of JXG lesions. A meta-
mutations has been reported,6-8,15 none of the patients in our analysis conducted by Oza et al.18 reports that the behavior of
study with eruptive JXG developed signs or symptoms of hema- congenital JXG resembles the typical JXG lesions, although
tologic disorders during the period of clinical follow-up. authors mentioned that it should be emphasized that infants

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 ß akir
Kundak and C
-au-lait spots were detected in a 15-month-old female patient
Figure 3 Eruptive JXG lesions and numerous cafe
with multiple congenital JXG lesions should be evaluated in
terms of hepatic involvement.
Cutaneous lesions demonstrate poorly demarcated nodular
lesions characterized by varying proportions of nonatypical histi-
ocytes, Touton-type giant cells, and eosinophils located in the
dermis and sometimes in the upper subcutaneous tissue. In
early stage, lesions consist of monomorphous small histiocytes
with vacuolated cytoplasm and scattered inflammatory infiltrate.
Rarely Touton-type giant cells accompany histiocytes. Mature
lesions consist of xanthomatous histiocytes, Touton-type giant
cells (observed in 85% of JXG), mononuclear cells (may show
a spindled or elongated appearance), and interstitial fibrosis. In
longer standing lesions, fibrosis and spindle cells become
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Juvenile xanthogranuloma Report 5
dominant, making it difficult to distinguish the lesion from fibrous
histiocytomas.19
The lesions formed because of skin involvement of Langer-
hans cell histiocytosis (LCH) constitute the main differential
diagnosis of JXG. In addition, benign fibrous histiocytoma, mel-
anocytic tumors, xanthoma, reticulohistiocytoma, granular cell
tumor, and storage diseases should be considered in the differ-
ential diagnosis. Unlike juvenile xanthogranuloma, cells in LCH
are more spindle-shaped, have a coffee bean-like nucleus, and
are positive for S-100 protein and CD1a. Touton-type giant cells
are not a feature of LCH. In JXG, histiocytes are positive for
CD68, negative for CD1a, and usually negative for S-100
protein.19
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6 Report Juvenile xanthogranuloma
Giant cell type and protein expression patterns of lesions
detected in our histopathological examinations are shown in
Table 1. Touton-type giant cell was the most commonly
observed type (30/44).
Immunohistochemical evaluation revealed 22 cases of JXG
were immunoreactive for CD68. Dehner et al.2 reported similar
results in 28 cases of JXG, although these cases were nonreac-
tive for CD1a. In our study, all 17 solitary cases and 5 of 6 erup-
tive cases performed by immunohistochemical examination were
immunoreactive for CD68. All cases examined by immunohisto-
chemistry were nonreactive for CD1a (6/6 eruptive and 9/9 soli-
tary JXG) (Table 1). These results suggest that there is
immunoreactivity for CD68 and no reactivity for CD1a in JXG.
Given that JXG is rarely encountered, there is an absence of
established standardized management, leading to a tendency
toward unnecessary evaluation and potential for overtreatment,
even though the risk of extracutaneous involvement is low. This
study aims to contribute to our understanding of JXG by
describing the experience with JXG at one tertiary care health
center. Further research is needed to clarify the management
and prognosis of JXG lesions in pediatric patients.
Statement of ethical stament
The study protocol was approved by the Izmir Dr. Behcet Uz
Children Research and Training Hospital local ethics committee
(2019/327).
Statement of informed consent
Written informed consent was obtained from the parents of
every patient for performing biopsy and photograph. The infor-
mation in the informed consent for biopsy noted that histopatho-
logical and epidemiological data of the patient and photography
can be used in the studies when necessary.
References
1 Ladha MA, Haber RM. Giant juvenile xanthogranuloma: case
report, literature review, and algorithm for classification. J Cutan
Med Surg 2018; 22: 488–494.
2 Dehner LP. Juvenile xanthogranulomas in the first two decades
of life: a clinicopathologic study of 174 cases with cutaneous
and extracutaneous manifestations. Am J Surg Pathol 2003; 27:
579–593.
3 Samuelov L, Kinori M, Chamlin SL, et al. Risk of intraocular and
other extracutaneous involvement in patients with cutaneous
juvenile xanthogranuloma. Pediatr Dermatol 2018; 35: 329–335.
International Journal of Dermatology 2020
ß akir
Kundak and C
4 Chang MW, Frieden IJ, Good W. The risk intraocular juvenile
xanthogranuloma: survey of current practices and assessment
of risk. J Am Acad Dermatol 1996; 34: 445–449.
5 Burgdorf WH, Zelger B. JXG, NF1, and JMML: alphabet soup or
a clinical issue? Pediatr Dermatol 2004; 21: 174–176.
6 Cambiaghi S, Restano L, Caputo R. Juvenile xanthogranuloma
associated with neurofibromatosis 1: 14 patients without
evidence of hematologic malignancies. Pediatr Dermatol 2004;
21: 97–101.
7 Jans SR, Schomerus E, Bygum A. Neurofibromatosis type 1
diagnosed in a child based on multiple juvenile
xanthogranulomas and juvenile myelomonocytic leukemia.
Pediatr Dermatol 2015; 32: e29–e32.
8 Liy-Wong C, Mohammed J, Carleton A, et al. The relationship
between neurofibromatosis type 1, juvenile xanthogranuloma,
and malignancy: a retrospective case-control study. J Am Acad
Dermatol 2017; 76: 1084–1087.
9 Paxton CN, O’Malley DP, Bellizzi AM, et al. Genetic
evaluation of juvenile xanthogranuloma: genomic
abnormalities are uncommon in solitary lesions, advanced
cases may show more complexity. Mod Pathol 2017; 30:
1234–1240.
10 Kolde G, Bonsmann G. Generalized lichenoid juvenile
xanthogranuloma. Br J Dermatol 1992; 126: 66–70.
11 Lee TK, Jung T-Y, Baek H-J, et al. Disseminated juvenile
xanthogranuloma occurring after treatment of Langerhans cell
histiocytosis: a case report. Childs Nerv Syst 2018; 34:
765–770.
12 Meyer M, Grimes A, Becker E, et al. Systemic juvenile
xanthogranuloma: a case report and brief review. Clin Exp
Dermatol 2018; 43: 642–644.
13 Mori H, Nakamichi Y, Takahashi K. Multiple juvenile
xanthogranuloma of the eyelids. Ocul Oncol Pathol 2018; 4: 73–
78.
14 Hsiao PF, Liu HC, Wu YH. An infant with juvenile
xanthogranuloma, multiple cafe-au-lait macules, acute myeloid
leukaemia: an incomplete, rare form of triple association? J Eur
Acad Dermatol Venereol 2008; 22: 1378–1379.
15 Paulus S, Koronowska S, Folster-Holst R. Association between
juvenile myelomonocytic leukemia, juvenile xanthogranulomas
and neurofibromatosis type 1: case report and review of the
literature. Pediatr Dermatol 2017; 34: 114–118.
16 Syrbe S, Eberle K, Strenge S, et al. Neurofibromatosis type 1
and associated clinical abnormalities in 27 children. Klin Padiatr
2007; 219: 326–332.
17 Thami GP, Kaur S, Kanwar AJ. Association of juvenile
xanthogranuloma with cafe-au-lait macules. Int J Dermatol
2001; 40: 283–285.
18 Oza VS, Stringer T, Campbell C, et al. Congenital-type juvenile
xanthogranuloma: a case series and literature review. Pediatr
Dermatol 2018; 35: 582–587.
19 Collie JS, Fillman EP. Juvenile Xanthogranuloma
(Nevoxanthoendothelioma, JXG). StatPearls Publishing LLC.,
SAUSHEC, Campbell University, San Antonio Military Medical
Center, 2020.
ª 2020 the International Society of Dermatology