Erdheim-Chester Disease with a Posterior Fossa Tumour Mimicking Neurosarcoidosis: a Case Report

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis described in 1930 by Jakob Erdheim and William Chester; it presents as a multisystemic entity that forms xanthogranulomas, foamy histiocytes surrounded by fibrotic tissue. Lesions are commonly located in long bones, central nervous system (CNS), cardiovascular system, lungs, kidneys, and skin. The CNS is involved in approximately 50% of cases and can compromise both extra- or intra-axial structures and therefore can mimic schwannomas or meningiomas, among other mass lesions [7, 4]. Clinical presentation will differ from patient to patient; thus, diagnosis depends greatly on imaging, immunohistochemistry, and genetic findings within the pathology analysis [8]. The pathogenesis of this disease remains unknown. It is most commonly found in the middle-aged male population [1, 2]. Here, we present a case of a middle-aged woman with an extra-axial lesion that was initially considered to be neurosarcoidosis proving the diagnostic challenge this entity implies.

A 54-year-old female with a past medical history of systemic arterial hypertension, presented with hemicrania occipital oppressive headache, associated with numbness in both arms and legs, and progressive gait instability. A magnetic resonance image (MRI) reported a tumoral lesion within the posterior fossa in the pre-medullary region surrounding the right vertebral artery. Embolization of the right vertebral artery was performed, and the patient was referred to our outpatient clinic. She would reach our hospital 3 months later. Upon examination, she presented mild dysarthria, deviation of the tongue to the right, diminished strength in all four extremities, and truncal ataxia. A new brain MRI was performed (Fig. 1). Other nodular lesions were observed in both orbits, lacrimal glands, and in retro maxillary areas and pterygopalatine fossa. Neurosarcoidosis was the working diagnosis at this stage. All blood tests were normal but one slight elevation in the C-reactive protein (CRP). A chest X-ray was performed to rule out systemic sarcoidosis and was reported as normal.
The patient underwent a right retro mastoid craniotomy. We used an ultrasonic surgical aspirator for tumor debulking. No cranial nerves were visibly lesioned.
Following the surgery, in the intensive care unit, the asymmetric elevation of the soft palate was detected as well as peripheral facial palsy, House Brackman III. Later on, she was diagnosed with diabetes insipidus, rare given the mass location, but further studies by the endocrinology service proved it was secondary to this disease and is currently being treated with desmopressin. Postoperative computed tomography (CT) scan showed no evidence of hemorrhage or acute hydrocephalus.
Pathology reported a xanthogranulomatous lesion without evidence of malignancy. Immunohistochemistry showed focal This article is part of the Topical Collection on Medicine * Laura Parrado-Sanchez laura.parrado.s@gmail.com reactivity to S100, foamy histiocytic infiltrates positive for CD68 and negative for CD1a, and CD45, CD3, and CD20 lymphocytic infiltrates. Neurosarcoidosis was still being considered; also, the possibility of mycobacterial infection was contemplated given our regional epidemiology and IgG4 disease. The ratio of plasma cells IgG4/IgG was not greater than 40% not meeting diagnosis criteria. Chest CT showed a nodular pericardial thickening with periaortic inflammatory tissue indicative of periaortitis, pericardial and pleural effusion, interstitial pulmonary infiltrates, and sclerotic bone lesions. Erdheim-Chester disease was suggested at this point and later confirmed by bone scintigraphy and genetic screening where a mutation in the BRAF V600E/V600E2/V600D was detected and oriented treatment (Fig. 2). Treatment with Alpha 2A interferon was considered but due to unavailability in the country, Vemurafenib was started with appropriate tolerance reported by the patient; 2 years later, it was suspended due to uveitis that required a dexamethasone intravitreal implant. As far as the writing of this report, her dysphagia and facial palsy had improved, and the patient is currently in follow-up by the palliative care team.

Discussion
ECD is a rare non-Langerhans cell histiocytosis that causes a multisystemic disease that can compromise long bones with painful osteoclastic lesions and can also involve retroperitoneum, cardiovascular, pulmonary, or orbits and cause periaortitis, pericarditis, retroperitoneal fibrosis, pulmonary infiltrates, or xanthelasmas [1,2]. Its CNS involvement is relatively common, around 50%, and can mimic various intra and extra-axial lesions generating widespread neurological manifestations and/or complications such as diabetes insipidus and hydrocephalus [3,4]. Its diagnosis is achieved by pathological examination, imaging findings, and genetic studies.
On the other hand, neurosarcoidosis is an uncommon manifestation of sarcoidosis seen in about 5-35% of patients with sarcoidosis, occasionally presented in isolation without signs of systemic illness. Its CNS compromise includes meningeal, cranial nerves, hypothalamus, spinal cord, or peripheral nerve involvement showing granulomatous infiltrates in the pathology [5]. Its diagnosis requires all clinical histological, imaging, and laboratory test support, and given its broad clinical spectrum, it is considered one of the great imitators, masquerading itself as other diseases becoming a challenging diagnosis to come by, as well as a powerful confusing factor as seen in our case, initially considered to be a posterior fossa tumor.
The MRI showed that the posterior fossa lesion was isointense in those T1-and T2-weighted images with high contrast enhancement, and the orbit lesions were hypointense in the same sequences; this finding is nonspecific for neither of the conditions mentioned above. Both are present with a meningeal enhancement and hyperintense lesions on the FLAIR sequences. For neurosarcoidosis, the imaging findings can be classified according to Christoforidis et al., into six categories, being (1) dural thickening or mass, (2) leptomeningeal involvement, (3) enhancing brain parenchymal lesion, (4) non-enhancing brain parenchymal lesion, (5) cranial nerve involvement, and (6) spinal cord and root involvement [6]. In our case, the patient did not fit just one of the categories mentioned above given that her lesion had both dural thickening or mass and cranial nerve involvement.
No such classification exists for ECD but given the cases reported in literature it could be divided according to the location of the lesions: (1) meningeal involvement with thickening and/or mass, (2) hypothalamic-pituitary axis mass, (3) supratentorial brain parenchymal lesion excluding hypothalamic-pituitary axis, (4) infratentorial parenchymal mass lesions, and (5) cerebrovascular involvement with periarterial infiltration. Taking this into account, our patient showed meningeal involvement with a mass lesion, which is seen in 23% of ECD cases, and cerebrovascular involvement with orbital lesions. The concomitant presentation with intraconal orbital lesions that are seen hypointense in the T2-weighted sequences is indicative of ECD and should expedite diagnosis as does the coexistence of neurologic symptoms that are not attributed to the intracranial lesion such as diabetes insipidus or cerebellar symptoms [2].
Initial testing did not include CSF analysis given that the patient presented itself with a posterior fossa tumor and the risk of performing a lumbar puncture was high, therefore, omitted. Pathology studies of both diseases show inflammatory changes within the tissue with avid lymphocytic infiltration and granulomatous lesions formation. Differentiation between both of them can be challenging and not even immunohistochemistry can distinguish them. For ECD, granulomas present with positive CD68 and negative CD1a, 20% of cases can present positive S100 which correlates with what's seen in the patients' pathology, but it also presents lymphocytic infiltrates of CD3 T-lymphocytes and B-lymphocytes positive for CD20 that is present in neurosarcoidosis [7]. The lack of Birbeck granules in the electronic microscopy could have helped provide an early diagnosis of ECD, but it was not analyzed in our case due to the lack of this resource in our institution [4,8] At this stage, the diagnosis of ECD was obscured by the possibility of neurosarcoidosis given that both diseases can present similar clinical manifestations, imaging findings on MRI, and even undifferentiated histopathological infiltrates. Other differential diagnoses that could be taken into consideration are Langerhans cell histiocytosis, Rosai-Dorfman disease, juvenile xanthogranuloma, multiple sclerosis, and granulomatous infectious diseases like tuberculosis, toxoplasmosis, and fungal infections. Since tuberculosis was considered in our case, a chest CT was obtained giving the diagnostic possibility of ECD. It did not only show the presence of sclerotic lesions but also of periaortitis, pulmonary infiltrates, and pericardial and pleural effusion. The confirmation was made by bone scintigraphy in which bilateral symmetric metadiaphyseal medullary sclerosis without epiphyseal compromise and intense uptake of the radiotracer as seen in long bones [1]. Cranial vault involvement has been reported in up to 26% of cases [3].
First-line treatment is considered to be interferon alfa for disease stabilization but given that this medication is not available in Colombia we were forced to consider second-line treatments. Among those are anakinra, vemurafenib, imatinib and cladarbine. Our treatment was directed by genetic studies that revealed positive for BRAF V600E proto-oncogene that suggest clonal proliferation giving the possibility of treatment with vemurafinib and therefore inhibiting the activation of the RASextracellular-signal-regulated kinase limiting proliferation and lesion survival [1]. This mutation is present in 55-65% of ECD cases. So far, the patient responded adequately to the treatment and no salvage therapies like vincristine, vinblastine, cyclophosphamide, and methotrexate have been used. Nowadays, patients have a 1-year survival rate of 96% and a 5-year survival rate of 68% [4].

Conclusion
This case is relevant so that it showcases the diagnostic difficulty encountered and the fact that some diseases or great imitators such as neurosarcoidosis or tuberculosis can lead to a delay in diagnosis and treatment for a patient with ECD. The presentation of an intracranial lesion accompanied by intraconal orbital tumors and lacrimal gland infiltrates must be carefully studied and ECD should be considered a possibility from the start and chest scans and bone scintigraphy are recommended early on.