J Neurosurg Pediatrics 12:187–191, 2013 ©AANS, 2013 Disseminated intracranial juvenile xanthogranulomatosis in a neonate without cutaneous lesions Case report Loyola V. Gressot, M.D.,1 Akash J. Patel, M.D.,1 Robert J. Bollo, M.D.,1 Carrie A. Mohila, M.D., Ph.D., 2 and Andrew Jea, M.D.1 Departments of 1Neurosurgery and 2Pathology, Texas Children’s Hospital, Houston, Texas Juvenile xanthogranuloma (JXG) is a rare disease that is part of a spectrum of histiocytic dendritic cell disorders. The authors report an unusual case of a 6-week-old male who presented with seizures. Neuroimaging revealed disseminated intracranial disease involving the optic apparatus, basal ganglia, lateral ventricles, and brainstem. The patient did not have any cutaneous lesions or evidence of extracranial disease. The patient underwent open biopsy of a large right midbrain lesion; pathology was consistent with JXG. He underwent postoperative chemotherapy and is doing well 7 months after surgery with regression of the intracranial lesions. To the best of the authors’ knowledge, this is the first report of a neonate with disseminated intracranial JXG without cutaneous stigmata. (http://thejns.org/doi/abs/10.3171/2013.5.PEDS1332) Key Words • juvenile xanthogranuloma Langerhans cell histiocytosis • oncology J uvenile xanthogranuloma is typically a benign, self- limited histiocytic disorder of infancy and early childhood manifesting as single or multiple cutaneous lesions.5,14 A small percentage of patients develop disseminated disease with visceral organ involvement in addition to the characteristic cutaneous findings. Involvement of the CNS is a frequent extracutaneous site of disseminated disease, but is very rare in patients without disseminated systemic disease.5,14 We report a case of a 6-week-old infant who presented with seizures and was found to have a multifocal infiltrating brain lesion involving the basal ganglia, optic apparatus, thalamus, and midbrain, as well as both lateral ventricles. Tissue diagnosis revealed the mass to be JXG with intracranial dissemination. To the best of our knowledge, this is the first report of diffusely disseminated intracranial JXG in a neonate without cutaneous lesions. We report this unusual case and review the literature (Table 1) on intracranial CNS manifestations of this rare disease. Abbreviation used in this paper: JXG = juvenile xanthogranuloma. J Neurosurg: Pediatrics / Volume 12 / August 2013 • histiocytic disorder • Case Report Presentation and Operative Course. This male infant born at 37 weeks’ gestation was noted to have macrocephaly, a full fontanelle, and splayed sutures. The patient did not have any cutaneous lesions or deformities, and a neurological examination was normal. Magnetic resonance imaging of the brain performed in the immediate postnatal period revealed triventricular ventriculomegaly and aqueductal stenosis, but no lesions. The patient underwent uncomplicated placement of a right frontal ventriculoperitoneal shunt for congenital hydrocephalus on the 5th day of life. He presented again to neurosurgical attention at 6 weeks of age with new-onset seizures. On examination he was fussy but awake, with reactive pupils and spontaneous movement of extremities. Repeat MRI revealed interval development of disseminated, contrastenhancing multifocal tumor, infiltrating the optic nerves, chiasm, and tracts, and the basal ganglia, right thalamus, lateral ventricular bodies, and midbrain (Fig. 1). Care­ful re-review of the MRI obtained at birth suggested scant abnormal enhancement of the dorsal midbrain. Sei­zures 187 L. V. Gressot et al. the histiocytes were immunoreactive for CD68, S100, and fascin, and a subpopulation were immunoreactive for factor XIIIa (Fig. 2C–F). Histiocytes were negative for CD1a and Langerin (CD207; not shown), and electron microscope examination did not reveal any Birbeck granules. Together, these histopathological and immunohistochemical features were consistent with JXG. Fig. 1. Axial (left) and coronal (right) T1-weighted MR images after contrast enhancement demonstrating an extensive infiltrating lesion involving the optic apparatus, basal ganglia, right thalamus, brainstem, and lateral ventricles. were controlled with antiepileptic medication. The patient underwent an occipital transtentorial approach to the dorsal midbrain for open biopsy and tissue diagnosis of the mass. Histopathological Analysis. Histopathological exam­ ination of the mass revealed an infiltrate of large plump histiocytes with abundant eosinophilic cytoplasm and reniform nuclei (Fig. 2A), including binucleated and multinucleated forms. An associated inflammatory infiltrate was composed of lymphocytes and prominent eosinophils (Fig. 2B). Immunohistochemical staining revealed Fig. 2. Photomicrographs of juvenile xanthogranuloma characterized by sheets of histiocytes (A) associated with a prominent inflammatory infiltrate rich in eosinophils (B). H & E, original magnification ×400. Histiocytes were diffusely immunoreactive for CD68 (C), S100 (D), and fascin (E), and a subset were positive for factor XIIIa (F). Original magnification ×400. 188 Postoperative Course. Postoperatively, the patient’s neurological examination was unchanged. Further workup did not reveal additional disease, which included a skeletal survey and a CT scan of the chest, abdomen, and pelvis, and bone marrow biopsy. A thorough physical examination failed to reveal any cutaneous lesions or deformities. Lumbar puncture did not reveal abnormal cells in the CSF. The patient underwent a course of adjuvant therapy with 6 cycles of monthly clofarabine followed by a maintenance clofarabine regimen. At 8 months of age, and 7 months after surgery, the patient was doing well with mild developmental delay, and was improving with physical and occupational therapy. Magnetic resonance imaging of the brain performed after 6 cycles of clofarabine showed a decrease in the size of several of the enhancing intracranial lesions, but persistence in thickening of the optic nerves, chiasm, and hypothalamus (Fig. 3). Discussion Juvenile xanthogranuloma is the most common histiocytic disorder, with the exception of Langerhans cell histiocytosis.1,11,13 This proliferative disorder is typically noted in the first 2 decades of life and is primarily characterized by lesions in the skin or soft tissue in the majority of patients.5 Males are more commonly affected than females, and most cases are diagnosed in infancy or early childhood, although the solitary cutaneous form may be observed in late childhood.5,11,14 Cutaneous lesions may be single or multiple and are waxy, yellow-red papules with a predilection for the head, neck, and trunk.5 Approximately 5% of patients present with a single extracutaneous tumor without skin involvement; another 5% of patients present with disseminated disease with involvement of 2 Fig. 3. Axial (left) and coronal (right) T1-weighted MR images after contrast enhancement obtained 7 months after treatment showing marked improvement but with residual nodules in the dorsolateral brainstem, optic apparatus, hypothalamus, and basal ganglia. J Neurosurg: Pediatrics / Volume 12 / August 2013 Intracranial juvenile xanthogranulomatosis TABLE 1: Previously reported patients with intracranial JXG* Authors & Year Flach & Winkelmann, 1986 Age, Sex Intracranial Manifestations Cutaneous & Extracutaneous Lesions Treatment 10 yrs, M multiple bilat cerebral, cerebellar, & brainstem lesions 12 yrs, M sellar & lat ventricular masses 7 yrs, M Meckel cave cutaneous chemo stable disease cutaneous none death stable disease Botella-Estrada et al., 1993 Okubo et al., 1995 10 yrs, M temporal lobe 3rd ventricle, cerebellum cutaneous chemo & cranial XRT resection, recurrence, re-resection, XRT none 8 mos, M lt temporal lobe cutaneous solitary tumor surgical excision Freyer et al., 1996 Schultz et al., 1997 5 mos, M lt parietal & 2 rt frontal lesions 13 yrs, M lt parietal cutaneous & lung none chemo, antiepileptics resection Boström et al., 2000 Ernemann et al., 2002 Nakatani et al., 2004 4 yrs, M lateral ventricles, lt sphenoid ridge, ten- none torium cerebelli 18 yrs, F rt ventricular subependymal nodule, none leptomeningeal dissemination 0 days, F lt cerebellopontine angle cutaneous, liver, bone Ashley et al., 2005 7 yrs, M Janssen & Harms, 2005 Dölken et al., 2006 2 yrs, F 7 mos, F Fulkerson et al., 2008 8 yrs, M Auvin et al., 2008 7 mos, M Stover et al., 2008 16 yrs, M 10 mos, F Sun et al., 2009 5 mos, M Rajendra et al., 2009 2 mos, M Rajaram et al., 2010 3 yrs, M Meshkini et al., 2012 6 yrs, M Deisch et al., 2012 14 yrs, F Tamir et al., 2013 3 yrs, M Paulus et al., 1992 3 yrs, F present case Outcome 6 wks, M resection stable disease no evidence of disease stable disease no evidence of disease stable residual chemo, steroids, XRT death in 1 yr w/ progression chemo regression of lesions rt frontal none resection no evidence of disease vermis & lt cerebellar cutaneous, liver, bone mar- chemo, partial resection stable disease row, gastrointestinal of brain lesions rt frontal, others liver, skin, kidney, intestine, resection, steroids, stable disease bone chemo lt frontal none resection no evidence of disease periventricular lesion, subdural effusion cutaneous, lung, testis, chemo & steroids stable disease ocular, bone, liver pituitary cutaneous steroids, chemo stable disease multiple parenchymal bone, cutaneous, lung, kid- steroids, chemo stable disease ney rt parietal none resection no evidence of disease rt parietal cutaneous, liver, lung, renal chemo, steroids resolution of lesions lt frontal none resection no evidence of disease multiple supratentorial & infratentorial cutaneous chemo, steroids resolution of lesions lesions lt Meckel cave & trigeminal nerve none subtotal resection, ste- stable residual roids rt parietooccipital none resection no evidence of disease lt Meckel cave extending to posterior none subtotal resection, ste- stable disease fossa roids, chemo multiple midbrain, thalamic, basal gan- none partial resection, chemo stable disease glia lesions & diffuse infiltration along optic nerves, tracts, lat ventricles * chemo = chemotherapy; XRT = radiation therapy. J Neurosurg: Pediatrics / Volume 12 / August 2013 189 L. V. Gressot et al. or more visceral organs, in addition to skin manifestations.5,11,14 Although extracutaneous manifestations are rare, common sites of involvement include the CNS, liver, spleen, and lungs.11 The clinical course of JXG is benign in the majority of cases with spontaneous involution of cutaneous lesions.9 Disseminated disease remains very rare but may have a more malignant course; significant complications and death from acute hepatic failure and thrombocytopenia have been reported.11 Intracranial involvement is a common site of extracutaneous and extraosseous involvement in the systemic form of the disease; however, the incidence of intracranial JXG without cutaneous or other systemic manifestations is very rare. Our review of the literature revealed only 11 other reported cases of intracranial JXG without extracranial manifestations, and 24 total cases of intracranial JXG (Table 1). Our literature search was limited to English literature reporting intracranial mass lesions; papers without sufficient clinical information, as well as those reporting purely osseous lesions, were excluded. Ten of the 11 patients with intracranial manifestations without systemic disease were single, isolated intracranial lesions. Only 1 other case (Boström et al.) was previously reported with multiple intracranial lesions without extracranial manifestations.3 We also report the youngest case of isolated intracranial JXG and document the rapid development of extensive lesions over a period of 6 weeks, as this patient underwent MRI that did not show lesions at birth. Although subtle, the abnormal midbrain enhancement observed in the midbrain at birth may be evidence of active disease at birth without systemic manifestations. There are reports of newborns diagnosed with JXG, but they have all presented with cutaneous manifestations or coagulopathy, and liver failure due to liver lesions.5,16 Nakatani et al.16 have reported a case of a newborn with JXG found to have multiple cutaneous lesions, pancytopenia, coagulopathy, and obstructive liver failure. Upon further imaging, this patient was also found to have a large, right hip tumor, temporal subcutaneous lesion, and solitary left cerebellopontine angle brain lesion. We present the youngest reported case of isolated, multifocal intracranial JXG. The case we report is also unusual because there was clinical and radiographic evidence of CSF dissemination with hydrocephalus and diffuse infiltration of the optic nerves, chiasm, and tracts. This behavior has rarely been reported. Ernemann et al.8 reported the case of an 18-year-old female who presented with evidence of extensive dissemination of JXG in CSF without any cutaneous findings, with intracranial hypertension, enhancement of multiple cranial nerve roots, and a subependymal nodule in the right lateral ventricle. This patient experienced rapid progression of JXG despite medical treatment, extensive spread throughout her spine, and succumbed to death. Orsey et al. reported the case of an 11-year-old boy with papilledema and elevated pressure on lumbar puncture, initially diagnosed with pseudotumor cerebri, who was found to have diffuse leptomeningeal infiltration but no mass lesion.18 Juvenile xanthogranulomatosis was diagnosed in this patient after a meningeal biopsy. Despite treatment, the patient succumbed to this disease and was 190 found at autopsy to have diffuse infiltration of the leptomeninges, brain, spine, abdominal and pelvic serosal surfaces, and bone marrow by a histiocytic sarcoma. Because this is a relatively rare disease process, little evidence exists to guide the management of intracranial JXG. The majority opinion is that symptomatic, isolated, surgically accessible lesions should be resected. Patients with inaccessible or multiple lesions can be treated with corticosteroids, chemotherapy, radiation, or a combination of these treatments.3,21 More data are needed to determine the efficacy of these treatments for intracranial JXG. Conclusions Juvenile xanthogranulomatosis is a histiocytic proliferative disorder that can affect a multitude of organ systems. We report the unusual case of a 6-week-old male with disseminated intracranial JXG with multiple tumor foci and evidence of CSF spread. This case is also noteworthy because the lesions appeared over a period of 6 weeks and the patient was without any cutaneous or systemic manifestations. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Jea. Acquisition of data: Jea, Gressot, Mohila. Analysis and interpretation of data: Jea, Gressot, Mohila. Drafting the article: Jea, Gressot, Mohila. Crit­ic­ ally revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the man­ uscript on behalf of all authors: Jea. Statistical analysis: Jea, Mo­­ hi­la. Administrative/technical/material support: Jea, Mohila. Study supervision: Jea. References 1. Ashley WW Jr, Narayan P, Park TS, Tu PH, Perry A, Leonard JR: Incidental pediatric intraparenchymal xanthogranuloma. Case report and review of the literature. J Neurosurg 102 (3 Suppl):307–310, 2005 2. 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