The treatment of systemic juvenile xanthogranulomas matures

By Warren R. Heymann, MD, FAAD
Jan. 8, 2025
Vol. 7, No. 1

Diagnosing juvenile xanthogranulomas (JXG) is simultaneously satisfying and slightly disconcerting. JXG’s clinical yellow appearance, the “setting sun” on dermoscopy, or the recognition of Touton giant cells histologically allows dermatologists to be reasonably confident of the diagnosis. It offers the ability to reassure patients (or parents) that this benign lesion(s) will usually resolve spontaneously. This commentary, however, will focus on advances in the realm of systemic JXG (SJXG), a disorder with profound implications and complications.

JXG is the most common form of non-Langerhans cell histiocytic disorder of childhood. Approximately 75% of cases appear during the first year of life, with >15-20% of patients having lesions at birth. (1) Congenital JXG may be giant (defined as > 2 cm), multiple, or ulcerated. (2,3) JXG is rare in adults, with a peak incidence in the late twenties to thirties and rarely arising in older adults. Most adult patients have solitary lesions. Typically, the clinical presentation consists of solitary or multiple yellow-orange-brown firm papules or nodules. (1) Unusual morphologies have been described as keratotic or plaque-like. (2) The most common locations are the face, neck, and upper torso. Oral lesions are rare. (1)

Although the association of JXG with neurofibromatosis type 1 (NF-1) and juvenile myelomonocytic leukemia (JMML) has long been recognized, the precise relationship has been debated. In their systematic review of 177 cases, Meyer et al., grouped patients by their association: NF1 + JXG (without leukemia), NF1 + leukemia (without JXG), and NF1 + JXG + leukemia. There were 55 patients with NF1 + JXG, 107 with NF1 + leukemia (54 with JMML), and 15 with NF1 + JXG + leukemia (13 with JMML). JMML was the most common leukemia subtype and, notably, more common in NF1 patients with JXG than those without (13/15, 86.7% vs. 54/98, 55.1%, respectively; p = 0.024). A family history of NF1 and male sex were more common in NF1 patients with JMML than those without, although this did not reach statistical significance. NF1 patients with JXG and JMML were younger at initial presentation (mean = 1.6 years for NF1 + JXG + JMML vs. 2.9 for NF1 + JMML vs. 2.5 for NF1 + JXG, p = 0.018), with a trend towards an earlier diagnosis of JXG (mean = 0.6 years for NF1 + JXG + JMML vs. 3.0 for NF1 + JXG, p = 0.099), and had larger JXG (mean = 8.5 mm for NF1 + JXG + JMML vs. 4.3 for NF1 + JXG, p = 0.011). The authors concluded: “NF1 patients have an increased risk of JMML. The triple association [NF1, JXG, JMML] remains very rare. Still, surveillance for JMML may be considered in children with NF1, mainly male patients with a family history of NF1 who have large or early-onset JXGs.” (4)

In their systematic review of 103 articles encompassing 159 patients with SJXG, Zou et al. reported a median onset age of 9 months, with a male predominance (61%). The distribution of major involved organs varied by age and younger onset age was associated with more organ involvement. The most commonly involved site was the central nervous system (CNS) (40.9%), followed by the liver (31.4%), lung (18.9%), and eye (18.2%). At the termination of follow-up, 93 patients (58.5%) were alive with no disease, 56 (35.2%) were alive with disease, and 10 (6.3%) had died from the disease. There was a significant difference in outcome between patients with and without spleen involvement (p = .0003), and patients with splenic involvement suffered a higher risk of death. Permanent sequelae mainly comprised CNS symptoms (mass effect, paraplegia, diabetes insipidus) and ocular manifestations (optic nerve atrophy, residual retinal pigment epithelium atrophy, squint). (5)

Other authors list ocular involvement as the most common extracutaneous feature of JXG. Risk factors for ocular involvement include multiple skin lesions, the micronodular form of JXG, newly diagnosed JXG, and age 2 years or younger. (6) Ocular JXG is characteristically unilateral and develops in less than 0.5% of patients. Hyphema and glaucoma are serious complications that can result in blindness. (1) So et al. recommend that for all patients with multiple JXGs, a comprehensive ophthalmologic examination should be performed regardless of age; however, in patients with a single JXG without ocular symptoms, a complete ophthalmologic examination is low yield. (7)

Although the etiology of JXGs is obscure, the past decade has witnessed a surge of genetic and immunohistochemical studies that suggest a neoplastic rather than reactive process. (8) Xu et al. retrospectively reviewed 456 pediatric patients with biopsy-proven JXG to investigate BRAF^V600E mutations and ALK translocations via digital drop polymerase chain reaction and in situ hybridization, respectively. Molecular alterations were present in 12 patients (52.2%) with SJXG, including 8 (34.8%) with ALK translocations and 4 (17.4%) with BRAF^V600E mutations. ALK translocations and BRAF^V600E mutations were mutually exclusive. (9)

As there is no well-defined treatment protocol for SJXG, standard therapy has been based on Langerhans cell histiocytosis regimens utilizing corticosteroids, vinblastine, methotrexate, cladribine, and cytarabine. (8) Molecular discoveries have resulted in novel advances. Zhang et al. presented a 2-year-old boy with SJXG and severe ophthalmologic involvement. Genetic testing demonstrated a BRAF^V600E mutation. A lack of response to oral prednisolone and intravenous vindesine prompted a trial of the BRAF inhibitor dabrafenib. The patient’s proptosis showed significant improvement after the first months of treatment. After 6 months of therapy, his ocular and systemic lesions regressed significantly. His lesions were stable at the follow-up visit 1 year after treatment. (10) Sugiyama et al. reported the case of a 2-week-old neonate with multiorgan SJXG and significant CNS disease. Analysis of a skin biopsy from a cutaneous JXG lesion identified a KIF5B-ALK fusion. Two months after treatment with the ALK-inhibitor alectinib, the subcutaneous lesions decreased in size. MRI revealed that the lesions of the medulla and cerebellum achieved complete regression. (11) Xu et al. reported a rapid response to alectinib in two neonatal girls with SJXG demonstrating ALK translocations. (12)

In conclusion, dermatologists should be mindful of the remote possibility of SJXG, especially if multiple cutaneous JXG are observed. Assessment is a multidisciplinary affair. We are on the cusp of precision medicine with targeted therapies for these patients that should alleviate severe complications.

Point to Remember: Advances in genetics and molecular biology have identified pathways confirming the usefulness of targeted therapies such as dabrafenib and alectinib in those patients with systemic juvenile xanthogranulomas harboring specific mutations in BRAF or ALK translocations, respectively.

Our expert’s viewpoint

Antonio Torrelo, MD
Head of the Department of Dermatology, Hospital Infantil Niño Jesús, Madrid, Spain

Juvenile xanthogranuloma is one of the most common skin tumors in children, and is usually considered a benign, self-resolving condition requiring no therapy. However, it’s been long acknowledged that JXG can involve other tissues, including the eye, central nervous system, lungs, liver, and bone marrow, among others. In extensive cases, the proliferating systemic JXG can be fatal due to compromise of vital organ functions. In its most common benign skin presentation, JXG appears as a solitary, brown papule or small nodule, whose color evolves to yellow or orange and eventually fades leaving mild atrophy or anetoderma. Nonetheless, atypical presentations of cutaneous JXG exist, including multiple, lichenoid, giant, agminated, and others. It is often considered that such ‘atypical’ forms of JXG, as well as early-onset JXG, are more likely associated with systemic forms than solitary lesions, but the frequency of involvement of extracutaneous organs is not precisely known for all forms of JXG. Hence, when clinicians are facing children with JXG, it is often difficult to decide when, where, and how deep to image or tissue them in search for a systemic association. Furthermore, children with JXG and any systemic complaint are often extensively studied, even though the symptoms and signs may be due to unrelated intercurrent conditions.

On the other hand, there is no hint on the histopathology of JXG that may help differentiating cutaneous from systemic JXG, and the diagnosis of JXG is still based on histopathology of skin and extracutaneous lesions. While the frequency of ALK translocations in systemic JXG is higher than BRAF^V600E mutations, such variants are not at all specific, but common to many other cutaneous and extracutaneous tumors. However, the discovery of such molecular alterations has opened a new way to the treatment of severe, potentially lethal, systemic JXG. When available, molecular testing is recommended for atypical cases of JXG or multiple JXG, especially if a targeted therapy is deemed necessary. The self-resolving nature of JXG has been well recognized both for cutaneous and systemic JXG, but the reasons for this are not well known. However, cases of systemic JXG may be progressive and lead to death; even though we assume that all cases will eventually experience regression, such a deadly potential is extremely challenging in clinical settings. It is hard to predict from clinical, histological, and even molecular grounds what cases of systemic JXG will eventually resolve or lead to fatality.

Even though systemic JXG may lead to death from massive spread, it is hard to consider JXG as a ‘malignant’ tumor. Biopsies of early lesions of JXG may be at times confused with hematologic neoplasms, but in time the lesions will experience maturation into a histologically benign histiocytic proliferation. This is the case in the skin lesions of both cutaneous and systemic JXG. The association between JXG, juvenile leukemia, and neurofibromatosis type 1 is intriguing, but again the JXG lesions in these cases do not show histologically malignant features.

We are still very early in the knowledge of non-Langerhans histiocytic diseases, and often we face difficulties derived from different denominations for similar conditions, including benign cephalic histiocytosis, progressive nodular histiocytosis, xanthoma disseminatum, or the recent ALK-positive histiocytosis. The lack of specificity of clinical, histological, and molecular features can be overcome with the use of a good correlation with all these, but we still need more potent tools to achieve a satisfactory classification with implications for outcome in these diseases.

1. Collie JS, Harper CD, Fillman EP. Juvenile Xanthogranuloma. 2023 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID: 30252359.

2. Carletti M, Nguyen DA, Susa JS, Weis SE. Congenital Giant Juvenile Xanthogranuloma, Let It Be. HCA Healthc J Med. 2022 Dec 30;3(6):329-333. doi: 10.36518/2689-0216.1333. PMID: 37427313; PMCID: PMC10327934.

3. Malana E, Kowalski P, Gallagher M. A Case of Multiple Self-Involuting, Mixed Presentation, Giant Congenital Juvenile Xanthogranuloma. Cureus. 2023 Apr 16;15(4):e37644. doi: 10.7759/cureus.37644. PMID: 37200655; PMCID: PMC10187945.

4. Meyer SN, Vaughn A, Li Y, Studer AC, Rauen KA, Kiuru M. The association between juvenile xanthogranulomas in neurofibromatosis type 1 patients and the development of leukaemia: A systematic review. J Eur Acad Dermatol Venereol. 2023 Dec;37(12):e1380-e1383. doi: 10.1111/jdv.19321. Epub 2023 Jul 20. PMID: 37422708.

5. Zou T, Wei A, Ma H, Lian H, Liu Y, Wang D, Zhao Y, Cui L, Li Z, Zhang R, Wang T. Systemic juvenile xanthogranuloma: A systematic review. Pediatr Blood Cancer. 2023 May;70(5):e30232. doi: 10.1002/pbc.30232. Epub 2023 Feb 13. PMID: 36779547.

6. Maalouf NS, Aouane A, Hamel P, Jean SÉ, Chababi-Atallah M, Fernandes CL. Disseminated juvenile xanthogranulomas with ocular involvement: A case report and literature review. SAGE Open Med Case Rep. 2022 Aug 11;10:2050313X221117693. doi: 10.1177/2050313X221117693. PMID: 35991957; PMCID: PMC9382061.

7. So N, Liu R, Hogeling M. Juvenile xanthogranulomas: Examining single, multiple, and extracutaneous presentations. Pediatr Dermatol. 2020 Jul;37(4):637-644. doi: 10.1111/pde.14174. Epub 2020 May 28. PMID: 32468628.

8. Xu J, Ma H, Yao X, Han X, Wen Y, Wang S, Xu Z, Ma L. Frequent detection of genetic aberrations reveals novel pathogenesis and treatment modalities in systemic juvenile xanthogranuloma. Pediatr Investig. 2023 Aug 28;7(3):212-215. doi: 10.1002/ped4.12398. PMID: 37736360; PMCID: PMC10509386.

9. Xu J, Huang X, Wen Y, Pan Z, Lian H, Zhao M, Li M, Duan Z, Zhang Y, Zhang G, Qi X, Tang J, Xu Z, Gao Z, Fu L, Ma L. Systemic juvenile xanthogranuloma has a higher frequency of ALK translocations than BRAFV600E mutations. J Am Acad Dermatol. 2023 Mar;88(3):656-659. doi: 10.1016/j.jaad.2020.08.053. Epub 2020 Aug 18. PMID: 32822792.

10. Zhang C, Feng ZX, Solarte CE, Li L. Ocular Juvenile Xanthogranuloma With BRAF V600E Mutation in a Child. J Pediatr Ophthalmol Strabismus. 2021 Jul-Aug;58(4):e19-e21. doi: 10.3928/01913913-20210416-01. Epub 2021 Jul 1. PMID: 34288768.

11. Sugiyama M, Hirabayashi S, Ishi Y, Kikuchi J, Ishikura A, Motegi H, Ueda Y, Sawai S, Hara K, Terashita Y, Cho Y, Takakuwa E, Honda S, Yamaguchi S, Kinoshita I, Manabe A. Notable therapeutic response in a patient with systemic juvenile xanthogranuloma with KIF5B-ALK fusion. Pediatr Blood Cancer. 2021 Nov;68(11):e29227. doi: 10.1002/pbc.29227. Epub 2021 Jul 10. PMID: 34245207.

12. Xu J, Yao X, Wen Y, Lian H, Han X, Xu Z. Alectinib In the Treatment of Systemic Juvenile Xanthogranuloma of Infancy With ALK Translocation. JAMA Dermatol. 2023 Dec 1;159(12):1399-1401. doi: 10.1001/jamadermatol.2023.4027. PMID: 37878279.

---