Juvenile xanthogranuloma (JXG) is a rare histiocytic disorder predominantly affecting children, characterized by cutaneous lesions that typically regress spontaneously. Although systemic involvement is rare, it can lead to unfavorable outcomes. In particular, extracutaneous lesions involving various organs and the central nervous system (CNS) pose substantial challenges [1], with reports indicating high morbidity and mortality rates. Treatment modalities for CNS–JXG lack consensus, with surgical resection ranging from isolated CNS lesions to multifocal CNS lesions. Disseminated deep intracranial CNS–JXG is associated with high morbidity and mortality [2,3]. There is currently no consensus or guideline for treating CNS–JXG.
Here, we present a case of refractory extra-JXG with CNS involvement with multiple intracranial lesions successfully treated with vincristine and carboplatin. The Institutional Review Board of Asan Medical Center approved this case report (IRB approval no: 2024-1632).
A 2-year-old girl presented with red-to-yellow papulovesicular rashes on her face, trunk, back, genitalia, and extremities persisting for 6 months (Fig. 1). A punch biopsy of the back lesion confirmed juvenile xanthogranuloma through histopathological and immunohistologi-cal examination. Histologically, the biopsied skin demonstrated diffuse infiltration of histiocytes with numerous eosinophils in the dermis. Immunohistochemical staining showed positive results for CD68 and S100, while CD1, Langerin, and BRAF were negative. Brain MRI revealed multiple variable-sized, strongly enhancing nodules with perilesional edema, slightly hypointense on T2-weighted imaging. The largest nodule (1.3 cm) was located in the right dorsal globus pallidus, with no evidence of restricted diffusion, suggesting CNS involvement in JXG. Additionally, a well-defined small enhancing mass (1.1 cm) with perilesional edema was identified in the right basal ganglia (BG), along with multiple enhancing nodules, some with mild perilesional edema, in the right frontal lobe, both temporal, left subinsular area, and pons (Fig. 2). A spinal MRI did not reveal any evidence of leptomeningeal seed-ing. Ophthalmic examination showed no signs of intraocular involvement.
Due to parental refusal of a surgical biopsy of the intracranial lesions, chemotherapy was initiated as the primary treatment approach. First-line chemotherapy followed the LCH-III protocol, comprising prednisolone (40 mg/m2/day for 4 weeks, followed by a tapered dose for another 2 weeks) and vinblastine (6 mg/m2/week) for 6 weeks. However, after 6 weeks of chemotherapy, the patient presented with binocular Lt. lateral gaze limitation. Despite ongoing chemotherapy, there was no observed improvement in the cutaneous JXG lesion. Neurologic examination revealed no additional defects except binocular lateral gaze limitation. Subsequent brain MRI revealed an increase in the size and number of multiple variable-sized strongly enhancing nodules with perilesional edema. Consequently, chemotherapy was modified to cytarabine (100 mg/m2/dose for 4 days for 8 weeks) and vincristine (1.5 mg/m2/dose weekly for 8 weeks) 5 days after the neurological symptoms worsened. The patient’s extraocular movement limitation gradually improved and completely resolved 4 weeks later. Surgical resection was performed for the left temporal lobe lesion 4 weeks after the initiation of second-line chemothe-rapy, confirming the pathology of the brain lesion JXG with brain invasion. Next-generation sequencing analysis of brain lesions revealed the presence of BRAF rear-rangements. An additional 9 weeks of cytarabine (100 mg/m2/dose for 4 days) and vincristine (1.5 mg/m2/dose weekly) were administered, and a follow-up brain MRI showed a reduction in the size of multiple nodules. How-ever, 7 months post-treatment cessation, a follow-up brain MRI revealed new, strongly enhancing nodules in the supratentorial and infratentorial regions (Fig. 3). During treatment, the patient experienced high remittent fever, which was suspected to be induced by cytarabine administration, creating challenges in prolonging the chemotherapy regimen. Short-term follow-up brain MRI demonstrated a mixed response to intracranial lesions, with some showing progression while others remained stable or had decreased in size. The third-line chemotherapy regimen included weekly administration of vincristine (1.5 mg/m2 for 10 weeks) along with carboplatin (175 mg/m2 for 8 weeks) as induction (COG A9952), followed by main-tenance therapy comprising weekly administration of vincristine (1.5 mg/m2 for 3 weeks) and carboplatin (175 mg/m2 for 4 weeks) for 5 cycles. Serial MRI follow-up revealed a decrease in the size of multiple enhancing nodules in the brain, as well as a decrease in the extent and perilesional edema (Fig. 4).
The cutaneous JXG lesions have also been shown to simultaneously regress. We decided to discontinue chemotherapy and instead follow with the watch-and-wait approach, based on the improvement in all CNS–JXG lesions following the induction and subsequent five cycles of maintenance chemotherapy. Since the completion of the treatment 4 months ago, she has been in good health and her disease status is still stable. The girl is now 6 years old, and her growth and neurodevelopment are normal.
Juvenile xanthogranuloma is a prevalent form of non-LCH predominantly affecting children [4,5]. It manifests in two primary forms: cutaneous and systemic. Cutaneous JXG typically presents as asymptomatic single or multiple, waxy, yellow-red maculopapular lesions, often localized to the head, neck, and trunk. Previous reports indicate that cutaneous JXG lesions are benign, self-limiting, and uncomplicated.
Extracutaneous manifestations of JXG may involve various organs such as the kidneys, lungs, spleen, liver, eyes, CNS, and musculoskeletal system. Notably, intracranial systemic JXG poses substantial challenges in man-agement and is associated with elevated rates of morbidity and mortality [6]. Reports on the clinical characteristics, prognosis, and treatment guidelines of intracranial JXG are limited [1,7].
Treatment modalities for CNS–JXG encompass surgical resection, radiotherapy, systemic chemotherapy, immuno-suppressive therapy, or combinations thereof. Surgical resection of well-defined CNS lesions remains a standard first-line approach, supported by numerous case studies documented in the literature [8]. However, for patients with multifocal or deep intracranial lesions, surgical resection is not feasible. These patients are instead candidates for systemic therapy, radiation therapy, or a combination of the two. CNS irradiation is generally not considered for young children, and radiation therapy has not been commonly used in CNS–JXG due to the young age of most patients with JXG. Additionally, molecular targeting regimens may be considered in cases involving BRAFV600E and ALK mutations.
Chemotherapy regimens based on LCH, which include both vinca alkaloid and corticosteroid components, have shown favorable outcomes in systemic JXG cases [9-12]. Previous reviews suggest that LCH-based chemotherapy could be effective because both LCH and JXG are dendritic cell-related disorders [9]. Dolken reported a case of a 7-month-old girl with systemic JXG and multifocal CNS involvement successfully treated with a combination of systemic chemotherapy (prednisolone, vinblastine, and etoposide), intrathecal methotrexate, and prednisolone, along with surgical resection for the larger CNS lesion [10]. Orsey reported on 26 patients with CNS–JXG who were treated with surgical resection, various chemothe-rapy regimens, radiotherapy, immunosuppressive therapy, or combinations thereof. In one case, a patient with diffuse CNS–JXG treated with prednisolone, vinblastine, methotrexate, and etoposide did not respond to therapy and succumbed to disease progression to clonal histiocytic neoplasm [8]. Reports on relapsed or refractory CNS–JXG are rare, and there are no guidelines for treatment. Deci-sions regarding treatment for relapsed or refractory CNS–JXG should be tailored to the disease status of each patient.
Our patient did not respond to initial chemotherapy. Unfortunately, the tumor relapsed and showed refractoriness to second-line chemotherapy based on the LCH protocol, even when combined with surgical resection. We administered third-line therapy, which includes vincristine and carboplatin, typically used for low-grade astrocytoma (COG A9952) [13,14]. The combination of vincristine and carboplatin shows efficacy that is compara-ble or superior to other regimens in various chemotherapy protocols and is more tolerable and less toxic than other treatment options, except for potential allergic reactions to carboplatin. The intracranial JXG lesions of this patient were disseminated and deep but behaved indolently, similar to low-grade gliomas. We proceeded with vincristine and carboplatin given their high response and control rate, as well as their safety and durability, despite being a low-intensity chemotherapy regimen [13,14].
In conclusion, this review suggests that combined chemotherapy with carboplatin and vincristine is a feasible and well-tolerated treatment option for patients with CNS-JXG. Further research is needed to validate its efficacy and safety.
The authors have no conflict of interest to declare.