Neuroimaging in Pediatric Patients with Juvenile Xanthogranuloma of the CNS

DISCUSSION

In this cohort of pediatric patients with biopsy-proven CNS JXG (from the CNS site and/or from other locations), most JXG lesions were typified by small-to-medium masses with isointense signal on T1WI, iso- or hyperintense signal on T2WI, restricted diffusion and perilesional edema. Almost all xanthogranulomas showed marked contrast enhancement. Cases were categorized into 3 primary neuroradiologic patterns: unifocal, multifocal, and multifocal leptomeningeal.

The category of histiocytosis includes Langerhans cell histiocytosis (LCH), Erdheim-Chester disease (ECD), JXG, Rosai-Dorfman disease (RDD), hemophagocytic lymphohistiocytosis (HLH), and malignant histiocytosis. These entities are characterized by pathogenic myeloid cells that share histologic features with macrophages or dendritic cells.^5,8 The lesional cells may originate from the embryonic yolk sac, fetal liver, or postnatal bone marrow.⁵ The term “histiocytic disorders” for LCH, ECD, JXG, RDD, and HLH has been proposed to differentiate them from hyperproliferative cancer-typical lesions such as Langerhans cell sarcoma and malignant histiocytosis.⁵ While LCH, ECD, JXG, and RDD have somatic mutations in MAPK pathway genes and show an accumulation of clonal, mononuclear phagocytes, HLH is a syndrome of immune dysregulation.^5,8

The Working Group of the Histiocyte Society published the first classification system of histiocytic diseases in 1987, which consisted of 3 categories, namely, Langerhans cell histiocytosis, histiocytosis of mononuclear phagocytes other than Langerhans cells, and malignant histiocytic disorders.¹⁷ In the past decades with the incorporation of molecular features, there have been several revisions, with the most recent revision in 2016.^8,18 This updated contemporary classification consists of 5 groups (the Langerhans-related; cutaneous and mucocutaneous histiocytoses; malignant histiocytoses; RDD; and HLH and macrophage activation syndrome) and is based on histology, phenotype, molecular alterations, and clinical characteristics.⁸ The proposed Langerhans group includes LCH, ECD, and extracutaneous JXG.⁸

Depending on the histiocytic entity, these diseases may be seen in both the pediatric and adult populations in various proportions and may show a broad variety of clinical presentations and outcomes.^1,5,8,18 The intense inflammatory infiltrates in histiocytic disorders play a key role in the origination and maintenance of organ-specific lesions and contribute to the clinical symptoms.⁵ To date, very little is known concerning the underlying pathogenetic mechanisms of JXG.⁵ JXG cells share some common features with dermal macrophages, including expression of fascin, factor-XIIIa, CD163, and CD68 (Online Supplemental Data).⁵

JXG is a rare entity; a frequency of approximately 1 per million children and a male/female ratio of 1.4:1 have been described in the Kiel Pediatric Tumor Registry.⁹ In our cohort, there was a 1.33:1 female predominance. With systemic JXG, a predominance of females of up to 3:1 has been reported in the literature.¹⁹ Most often, JXG presents in children (< 4 years) as a solitary red-brown or yellow skin papule or nodule of 0.5–1 cm in diameter and may undergo spontaneous regression.^2,3,5,8 Most skin lesions involve the head, neck, or upper trunk.^3,4 Some patients have isolated or very few cutaneous lesions, while others may develop hundreds of lesions.⁵ A small subset present with systemic JXG.² Besides the CNS (7%), extracutaneous JXG may involve the liver (22%), lungs (16%), soft tissue (16%), spleen (11%), eyes (9%), oral cavity (7%), adrenal glands (7%), gastrointestinal tract (7%), lymph nodes (7%), bone marrow (7%), and heart (4%).^5⇓-7 In this study, 7 of 14 patients (50%) had isolated CNS involvement. Seven patients (50%) had involvement of ≥2 organ systems, with involvement of the skin and/or bones being most common (Online Supplemental Data).

The clinical presentation depends on the involved organ systems.^5,10 For CNS JXG, clinical presentation is nonspecific and includes headache, seizures, ataxia, increased intracranial pressure, macrocrania, developmental delay, weakness, numbness, cranial nerve abnormalities, and diabetes insipidus.^1,2,5,10 These findings are in line with the initial presentation of the patients in our study, which included headache, seizure, ataxia, strabismus, hearing loss, facial paresis, and diabetes insipidus, among others (Online Supplemental Data).

In general, JXG is a self-limiting disease.⁴ However, systemic JXG, especially with CNS involvement, may be associated with long-term problems such as structural damage by brain lesions or liver failure by large hepatic tumors or may even be fatal.^2,5,9,20 Available treatment options for JXG include “wait and see/follow-up,” chemotherapy (eg, clofarabine), targeted therapies such as ALK inhibition (for ALK fusion events) and MAPK pathway blockade with BRAF V600E or MAP2K inhibitors, surgery, or a combination of these modalities.^5,9,11,12,14 Most skin-limited JXG lesions show spontaneous involution, but surgical excision may be considered if lesions are cosmetically unacceptable or endanger or impair functions such as vision or swallowing.⁵ In patients with systemic JXG including CNS lesions, there is evidence of successful treatment using chemotherapy (eg, clofarabine) or targeted therapies such as MAPK pathway blockade, or ALK inhibition (for ALK fusion events).^5,11,12

Recurrent activating somatic mutations in MAPK genes have been identified in JXG.^5,8 In our cohort, there were 1 patient with coexisting LCH and JXG and 1 patient with coexisting JXG and RDD. There is evidence of the coexistence of JXG and LCH²¹ and JXG and RDD,²² supporting a potential common cell of origin.⁵ Additionally, JXG has been reported in patients with neurofibromatosis 1 and other “RASopathies”.^23,24 JXG can be found in up to 29% of patients with neurofibromatosis 1,²⁴ consistent with the known role of MAPK pathway activation in the pathogenesis of both diseases.²⁵ The literature concerning a triple association between JXG, neurofibromatosis 1, and juvenile myelomonocytic leukemia is contradictory, with some studies suggesting an association²⁶ and others reporting no increased incidence.²⁴ In addition, there is a rare subtype of histiocytic disorder, the ALK-positive histiocytosis, which is mainly associated with KIF5B-ALK fusions and shows frequent neurologic involvement and may have a successful outcome with ALK inhibition treatment.¹² A subgroup of ALK-positive histiocytosis demonstrates histopathologic features of classic JXG.¹² Additionally, recurrent mutations in CSF1R have recently been described in JXG.²⁷

To date, data describing imaging features of CNS JXG are largely limited to case studies^1,6,13⇓-15 and reviews, including clinical and pathological aspects as well as a summary description of the imaging features.² This article aims to present a large case series focusing on neuroimaging features of CNS JXG in children. Intracranial xanthogranulomas have been described variously as T1-/T2-hypo-, iso-, or hyperintense lesions on MR imaging.^{1,2,6,13⇓-15,20} In our cohort, on T1WI, xanthogranulomas were mainly isointense compared with cortical GM (7/12; Online Supplemental Data), several lesions were hyperintense (4/12; Fig 2), and 1 lesion was hypo- to isointense (1/12). On T2WI, xanthogranulomas were mainly isointense (5/13; Fig 1 and Online Supplemental Data) or hyperintense (4/13), followed by an iso- to hyperintense (3/13; Fig 2) or hypo- to isointense (1/13) appearance.

Ginat et al²⁸ characterized the imaging features of head and neck xanthogranulomas of 10 patients, with 6 patients undergoing MR imaging.²⁸ They reported that on T1WI, lesions were characterized by an iso- or hyperintensity, and on T2WI, by an iso- or hypointensity.²⁸ Within our cohort, several lesions showed a high signal on T1WI and T2WI. This could be due to lipid components within these lesions because lipidized or xanthomatous cells may be found within xanthogranulomas.²⁹ In general, CNS JXGs^1,2 and head and neck JXGs²⁸ are described as showing homogeneous contrast enhancement on T1+CE-weighted images. Marked contrast enhancement seems to be a reliable imaging feature of JXG because almost all xanthogranulomas showed avid contrast enhancement (Fig 1–3 and Online Supplemental Data), and only 1 patient (1/14) who had multifocal xanthogranulomas showed lesions with marked contrast enhancement as well as lesions without contrast enhancement on T1+CE-weighted images. Most lesions (7/10) demonstrated restricted diffusion (Figs 1 and Online Supplemental Data). This finding is in agreement with the literature describing decreased diffusion in such lesions.^1,28 Ginat et al described decreased diffusivity as likely attributed to hypercellularity and/or a collagenous matrix.

Because there are heterogeneous, nonpathognomonic imaging appearances of CNS JXG with neuroradiologic patterns ranging from unifocal to multifocal leptomeningeal involvement, neuroradiology alone is not able to provide an accurate diagnosis. Accordingly, a wide array of differential diagnoses must be considered, including primary brain neoplasms, lymphoma and leukemia, other histiocytic disorders such as LCH or ECD, and infections. If multifocal lesions with leptomeningeal involvement are evident, metastatic and granulomatous diseases such as sarcoidosis and tuberculosis should be included in the differential diagnosis.

The range of intracranial CNS findings in LCH is better known and comprises a neurodegenerative pattern including infratentorial WM abnormalities more pronounced in the peridentate regions, abnormalities of the dentate nuclei and basal ganglia, and bilateral symmetric leukoencephalopathy-like abnormalities in the supratentorial white matter.^30⇓-32 In addition, CNS LCH may show mass lesions in the hypothalamic-pituitary region, seen as thickening and enhancement of the pituitary stalk with possibly loss of the posterior bright spot, and it is clinically frequently accompanied by diabetes insipidus.^31,32 Rare neuroimaging manifestations include enlargement of the pineal gland, thickening and enhancement of the choroid plexus, and intraparenchymal masses.^31,32 Hence, in contrast to CNS JXG, in CNS LCH, intra-axial parenchymal mass lesions are rather uncommon. However, involvement of the hypothalamic-pituitary region appears to be a common feature of both CNS JXG and LCH. In our cohort, infundibular involvement was seen in 6 patients, and pituitary gland or hypothalamic involvement was noted in 3 patients each. In addition, the posterior pituitary gland T1-hyperintense signal or bright spot was absent in 3 patients. In general, a loss of the posterior bright spot is thought to be a result of a lack of vasopressin-containing granules.³¹ We assume a similar mechanism as seen in LCH, in which an absent pituitary bright spot and involvement of the infundibulum are frequent but do not necessarily occur in all patients. In our cohort, we did not find changes suggestive of posterior fossa neurodegeneration. In addition to CNS LCH, neurodegeneration has also been described in the context of ECD.³³ CNS JXG may not be prone to neurodegeneration, or neurodegeneration could potentially develop later in the course of the disease because neuroimaging in our cohort was performed for the initial diagnostic work-up of new symptoms.

We are aware of several limitations in our study. The imaging findings are based on a retrospective study design with a quite limited number of pediatric patients and MR imaging was performed as a diagnostic work-up of newly emerged symptoms on various scanners with somewhat different protocols. Subsequent studies with larger cohorts and standardized imaging protocols are needed to confirm the proposed imaging patterns presented in our study. In addition, future prospective studies should correlate histologic features to neuroimaging characteristics, and longitudinal follow-up studies may shed more light on the rate of progression, the response to therapy, and the possible changes in imaging characteristics.