Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots: A Case Report and Review of the Literature

Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots: A Case Report and Review of the Literature

Accepted Manuscript Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots. A Case Report and Review of the Literature Cody Wolf...

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Accepted Manuscript Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots. A Case Report and Review of the Literature Cody Wolfe, BS;, Tarek Y. El Ahmadieh, MD;, Salah G. Aoun, MD;, Awais Z. Vance, MD;, Kimmo J. Hatanpaa, MD, PhD;, Bryan Wohlfeld, MD PII:

S1878-8750(18)31753-4

DOI:

10.1016/j.wneu.2018.07.273

Reference:

WNEU 8838

To appear in:

World Neurosurgery

Received Date: 6 June 2018 Revised Date:

29 July 2018

Accepted Date: 30 July 2018

Please cite this article as: Wolfe C, El Ahmadieh TY, Aoun SG, Vance AZ, Hatanpaa KJ, Wohlfeld B, Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots. A Case Report and Review of the Literature, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.07.273. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT 1 1

Intradural Juvenile Xanthogranuloma with Involvement of Multiple Nerve Roots. A Case

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Report and Review of the Literature 1

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CODY WOLFE, B.S.; TAREK Y. EL AHMADIEH, M.D.;2 SALAH G. AOUN, M.D.;2 AWAIS Z. VANCE, M.D.; 2

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KIMMO J. HATANPAA, M.D., PHD;3 BRYAN WOHLFELD, M.D.2*

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School of medicine, Dallas, Texas, USA

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Dallas, Texas, USA

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Department of neurological surgery, The University of Texas Southwestern Medical Center,

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USA

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Department of neurological surgery, The University of Texas Southwestern Medical Center,

Department of pathology, The University of Texas Southwestern Medical Center, Dallas, Texas,

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*corresponding author.

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Correspondence to: [email protected].

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Department of Neurological Surgery, UT Southwestern Medical Center, 5323 Harry Hines Blvd.

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Dallas, TX 75390. Phone: 214-648-9317

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Conflict of interest: The authors have no disclosures related to the content of this manuscript.

Disclosure of funding: none

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Keywords: Juvenile Xanthogranuloma, thoracolumbar tumors, spinal lesions, inflammation,

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inflammatory spine disease

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ACCEPTED MANUSCRIPT 2 Abstract

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Background: Juvenile Xanthogranuloma is a rare, non-Langerhan’s cell histiocytic disorder that

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primarily presents as multiple cutaneous lesions in young males. Solitary lesions in the spinal

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column are a particularly rare presentation of this disease, and CNS involvement can portend a

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poor prognosis. This report highlights an unusual case of an adult woman with an unresectable

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JXG of the lumbar spine. A review of the published cases of thoracolumbar JXG and the current

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state of the literature in regard to diagnosis and treatment is presented.

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Case Description: A 28-year-old woman presented with back pain and worsening lower

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extremity pain, numbness and weakness. MRI demonstrated an enhancing lumbar mass, but at

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the time of surgery, no discrete mass was identified. Multiple roots were grossly enlarged, and

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electrical stimulation identified the L4 root as the most abnormal. Despite an attempt to debulk,

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the majority of the mass could not be safely removed. The patient had incomplete improvement

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of symptoms post-operatively but elected to forgo chemotherapy. Three-month follow-up

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imaging showed active lumbar spinal disease, and imaging and follow up at 27-months has

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revealed no changes. Her symptoms have been satisfactorily controlled with conservative

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therapy.

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Conclusions: Juvenile Xanthogranuloma of the spine is a rare disease who’s nonspecific clinical

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and radiographic findings can make difficult to diagnose and dictates the use of

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immunohistochemical staining. If possible, total surgical resection offers the greatest outcomes,

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but other modalities such as chemotherapy may be viable alternatives or adjuvants.

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Background: Juvenile Xanthogranuloma (JXG) is a rare, non-Langerhan’s cell histiocytic disorder

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caused by proliferation of cells derived from dermal dendrocytes.1 It is primarily a disease of

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early life, with most cases occurring at birth or during the first year of life.1-6 It is more

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commonly seen in males,1,3,4 who typically present with multiple cutaneous lesions. Early

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description of this disorder has been credited to Rudolf Virchow,7 and reports of these lesions in

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the literature date back to Adamson in 1905 8 and McDonagh in 19129 before the term JXA was

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introduced in 1954 by Helwig and Hackney,10 Initially noted to be a cutaneous disorder, the most

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common presentation of JXG is as benign nodules located on the head, neck and trunk.1 Less

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common presentations of JXG include multiple and systemic lesions that may be aggressive and

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lethal.1-3,11-13 Extracutaneous sites of JXG have been reported in the liver, spleen, lungs, kidneys,

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eyes, subcutaneous soft tissue, bones, and both peripheral (PNS) and central nervous systems

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(CNS).1,2,4,7,11,14,15

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JXG of the CNS typically follows an indolent course, although rare cases of clinically

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aggressive JXG have been reported.2 Treatment strategies vary and may depend on resectability

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of the tumor, as complete resection may be curative. Poorly accessible tumors, widespread or

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progressive disease may require aggressive systemic therapy which may include corticosteroids

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and vinca alkaloids and/or radiation.16 However, the efficacy of treatments has not clearly been

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established, and there is therefore no accepted protocol for treatment of JXG involving the CNS.

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Herein, we report on a patient who presented with a solitary lumbar mass in the absence

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of cutaneous disease that was histologically revealed to be JXG. The mass was not amenable to

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total resection and chemotherapy was declined. The surgical operation, histology, and follow-up

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treatment plan are reported. Reports of thoracolumbar JXG cases are reviewed and the relevant

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literature is discussed.

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Case Description:

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A 28-year-old woman presented with a one-year history of back and lower extremity

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pain, worsening numbness in legs and weakness in the left foot. Magnetic resonance imaging

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(MRI) of the lumbar spine demonstrated an enhancing mass from L3 to L5 that appeared to fill

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the foramen at L4/5 on the left (Figure 1A-D). The differential diagnoses included

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ependymoma, and peripheral nerve sheath tumors (schwannoma or neurofibroma). The decision was made to take the patient to surgery for a biopsy and potential total

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resection of the mass. Neuromonitoring was used. After laminectomies were performed, an

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ultrasound was used to define the mass which appeared solitary and confluent. After the dura

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was opened, no discrete mass was identified. Rather, multiple roots were grossly enlarged across

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this segment without obvious mass (Figure 2A&B). Electrical stimulation was used to identify a

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silent region of the L4 root which was the most abnormal. The pia was sharply incised and tumor

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forceps were used to remove specimen and debulk the root. Given the benign histology and

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intimate association of the JXA with eloquent nerve roots, the majority of the mass could not be

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safely removed. The process was not resectable, a decision was made to sew in an expansile

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duraplasty (Figure 2C).

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Postoperatively the patient had improvement in pain, sensation and strength. No

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cutaneous sites of disease were noted. She was counseled by hematology-oncology but elected to

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observe with imaging and not begin chemotherapy at this time. A 3-month follow-up MRI

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demonstrated postoperative changes with L3-5 laminectomy and partial debulking of intradural

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enhancing mass. A positron emission tomography (PET)–computed tomography (CT) scan was

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done that demonstrated active lumbar spinal disease and no other fluorodeoxyglucose (FDG)

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avid sites of disease.

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On the 27-month follow-up clinic visit, the patient was doing well. Her chronic lower

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back pain and left L4, L5 distribution paresthesia remain well controlled with medication. These

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symptoms have been present and stable since prior to surgery. She had full motor strength in

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both lower extremities as well as normal bowel and bladder control. Her MRI lumbar spine has

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also remained stable throughout this interval without evidence of enlargement or development of

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new enhancing lesions (Figure 3A-D). She has opted against adjuvant chemotherapy or radiation

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and continues conservative management with serial imaging and clinical follow up.

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Pathology:

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The lesion was classified as JXG. Chronic inflammatory infiltrates involving a peripheral

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nerve were seen. Touton giant cells were identified (Figure 4A&B). The infiltrates were

ACCEPTED MANUSCRIPT 5 primarily composed of CD68-positive histiocytes and CD3-positive T cells without atypia

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(Figure 4C). Approximately 10% of the histiocytes and giant cells were weakly positive for S-

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100, thought possibly to represent nonspecific staining from phagocytosis of peripheral nerve

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elements. Emperipolesis was seen in rare foamy histiocytes. No significant numbers of plasma

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cells or CD20-positive B cells were identified. There was diffuse IgG-immunopositivity but no

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immunopositivity for IgG4, which ruled out IgG4-related disease. There were no CD1a-positive

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Langerhans cells. Gram and fungal stains were negative as were stains for spirochetes and AFB.

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A GFAP immunostain showed no astrocytic or ependymal elements. The MIB-1 proliferation

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index was <0.1%. A molecular test for the BRAF V600E mutation was negative.

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According to a study done by Dehner1 in 2003, the most common presentation of JXG is

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a solitary skin lesion, and approximately 10% of JXG cases involve extracutaneous sites.

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Involvement of extracutaneous tissues and organs, and extensive proliferation or malignant

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transformation can increase morbidity and rarely, mortality rates. In their review of 36 patients,

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Freyer et al.2 characterized the frequency of extracutaneous sites where JXG manifested as a

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systemic disease and noted the CNS (8 of 36) and liver/spleen (8 of 36) to be the second most

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common sites involved after the subcutaneous soft tissue (12 of 36).

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CNS involvement of JXG4,17-19 is rare, but has been reported all along the neuroaxis. A

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2013 literature review by Diesch et at.17 noted 38 published reports of JXG in the nervous

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system, with 75% involving the CNS. The clinical characteristics between CNS and PNS cases

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differed significantly, but the reported outcomes were similar, with the exception that all three

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lethal cases involved the CNS. Diesch reported that CNS cases more commonly involved

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additional cutaneous or extra-nervous disease as compared to PNS cases,17 but Freyer et al.2

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reported that half of the CNS JXG cases lacked any cutaneous disease. In their 1997 case report

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and review of the literature, Schultz et al.18 described the clinical presentations of all CNS JXG

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cases in the literature. Their own case was the first report of a solitary intracranial JXG, and the

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patient presented with complex partial seizures.18 Later reports of intracranial cases of JXG have

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demonstrated seizures and focal cranial nerve deficits as common presenting signs.20 Others have

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ACCEPTED MANUSCRIPT 6 reported intracranial hypertension,20 elevated anterior fontanelle in an infant,21 incidental

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discovery,20 and recent onset headaches, blurry vision, cutaneous facial lesions in an adult with a

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history of diabetes insipidus.22 While less common than solitary lesions, reports of multiple23,24

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and extensive intracranial JXG lesions25 have been reported, and Tan et al.26 have even described

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JXG recurrence leading to “diffuse, miliary brain lesions”.26 Leptomeningeal involvement is

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rare. 2 but has been reported20,23,24,27 and can lead to further intracranial disease or spinal spread.

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Kitchen et al.28 described the first JXG lesion of spinal nerve root origin in 1995. Since

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then, extradural29,30 and intradural31 spinal JXG lesions have been reported. JXG lesions of spinal

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origin can present with single28 or multiple29 nerve compression and corresponding signs, or

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spinal cord compression leading to spastic paraparesis31 or acute paraplegia.30 Less commonly,

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JXG lesions have also been reported in the cauda equina.32,33 Table 1 lists the thoracolumbar

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JXG cases reported in the literature. In the current report, the patient had no obvious mass, but

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demonstrated gross enlargement of multiple lumbar nerve roots which lead to significant lower

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extremity pain and progressing numbness of the legs and weakness in the distal left lower

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extremity. Preoperative MRI revealed an enhancing mass from L3 to L5 that appeared to fill the

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foramen at L4/5 on the left, but diagnosis of JXG cannot be made by imaging alone.

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Radiographic findings for JXG are non-specific. Typically, the lesions are isointense on

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T1-weighted MRI and enhance with gadolinium, but this does not differentiate them from many

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other masses, including primary tumors or granulomatous disease. Several cases have

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demonstrated an increased choline signal on MRI, but further studies have identified this

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phenomenon in other infectious and inflammatory CNS lesions.34 However, Matsubara et al.35

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and Kwak et al.36 observed elevation of taurine, choline and glutamate, and reduction of N-

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acetylaspartate in JXG lesions. These findings have only been reported in neuroblastoma and

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may allow for a more specific differential diagnosis when observed.35

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Because imaging and clinical findings are nonspecific, diagnosis of JXG is dependent on

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biopsy and histologic findings. The differential diagnosis for histiocytic lesions includes

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Langerhans cell disease, non-Langerhans cell diseases, and other lesions of infectious, neoplastic

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or inflammatory origin. These can often be differentiated by immunohistochemical staining

ACCEPTED MANUSCRIPT 7 (IHC). IHC of JXG lesions stains positive for CD68, vimentin, S100 and factor XIIIa, and

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negative for CD1a, with the presence of classic “Touton giant cells” on histologic

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examination.1,3,37 As such, Langerhans cell disease can be ruled out by the absence of CD1a

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molecules that classically stain on their surface. Similar IHC staining and histologic analysis can

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distinguish between non-Langerhans cell histiocytoses such as Rosai-Dofman disease (RDD) and

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Erdheim Chester disease (ECD). RDD typically stains positively for S100 and demonstrates

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emperipolesis, which are both absent in JXG stains.3,17,37 ECD is usually characterized by the

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BRAF V600E mutation in the inflammatory infiltrates and presents in the sixth decade of life,

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both of which differentiate it from JXG. In the current report, the biopsy sample was negative for

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CD1a and BRAF, ruling out Langerhans cell histiocytosis and ECD. While there was some

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partial S100 staining, this was thought to represent nonspecific staining from phagocytosis of

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peripheral nerve elements. This, combined with the presence of Touton giant cells and the lack

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of emperipolesis served to rule out this disease.17 Other pertinent negatives found on analysis

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were the microbiologic stains, CD20, GFAP, and IgG4, ruling out infectious etiologies, B cell

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disorders, primary glial cell neoplasms, and IgG4 disease, respectively.

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JXG is typically a benign disease with many lesions resolving on their own. However,

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due to disease progression, inability for curative resection, or systemic involvement, multiple

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deaths have been reported in the literature.1,2,12 JXG disease of the CNS usually follows an

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indolent course, although rare cases of clinically aggressive JXG involving the CNS have been

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reported as well, including two deaths reported by Freyer et al.2 Many case reports have

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individually reported good outcomes with total resection38 and chemotherapy,20 but larger

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outcome studies are few, and one reported by Wang et al did not reveal any notable associations

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with good outcomes.19 Complications arising from CNS JXG include sterile brain abscess,36

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subdural effusion,39 and spread and recurrence of disease.26,27

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There are currently no established treatment protocols for JXG, though review of the

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literature supports surgical treatment as a definitive treatment option and possibly curative when

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a total resection is feasible.38 Although there is more literature about surgery for intracranial

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JXG, the same pattern seems to apply to spinal JXG as well.31 Of note, Nakasu et al.40 reported

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on successful implementation of stereotactic radiosurgery for the treatment of intracranial JXG.

ACCEPTED MANUSCRIPT 8 When total resection is not possible, those with systemic or progressive disease should be treated

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with adjuvant therapy. Reports of success with steroids, vincristine and cladribine have been

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published,20 and treatment with Langerhans cell multi-agent chemotherapy regimens,

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immunotherapy, and conventional radiation may also be considered.20 In the current report, the

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patient elected not to go for adjuvant therapy after subtotal resection and will be followed up

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with routine imaging.

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Conclusion

JXG are rare inflammatory lesions that often run an indolent course and may

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spontaneously involute. However, involvement of the CNS is a poor prognostic factor, and may

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lead to significant morbidity and even mortality when the disease is progressive, systemic or

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inaccessible to total surgical resection. Consistent with similar reports in the literature, the

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authors suggest surgical resection of these lesions with intent to cure. When total resection is

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infeasible, adjuvant therapy with steroids, chemotherapy, immunotherapy, radiation, and

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stereotactic radiosurgery should be considered. A patch duroplasty may also provide

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symptomatic relief of focal compression.

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Figure Legends

Table 1: Published cases of JXG afflicting the thoracolumbar spine.

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Figure 1: Preoperative axial T1 post contrast (A), sagittal T1 post contrast (B), sagittal T1 pre-

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contrast (C) and sagittal T2 MRI images show a large enhancing intra dural mass centered at

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L4/5 and extending out the left L4/5 neuroforamen. There is also diffuse thickening and

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enhancement of multiple lower thoracic and lumbar nerve roots.

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Figure 2: Multiple, grossly enlarged roots were noted without obvious mass (A), stimulation of

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abnormal roots demonstrated functional conduction to lower lumbar and sacral myotomes (B),

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expansile duraplasty was performed (C).

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ACCEPTED MANUSCRIPT 9 Figure 3: Axial T1 post contrast (A), sagittal T1 post contrast (B), sagittal T1 pre-contrast (C)

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and sagittal T2 MRI images obtained 27 months after surgery show overall stability of

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previously debulked intra dural enhancing mass centered at L4/5. Again, seen are numerous

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thickened and enhancing lower thoracic and lumbar nerve roots, which also have not

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significantly changed.

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Figure 4: Chronic inflammatory infiltrate with scattered Touton giant cells (arrows) (H&E) (A),

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A high-power view illustrating Touton giant cells (arrows). These are multinucleated histiocytes

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with eosinophilic cytoplasmic areas as well as peripheral foamy, pale-staining cytoplasmic areas

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(H&E) (B). The Touton giant cells (arrows) were positive for CD68, confirming that they are

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histiocytes. (Immunohistochemistry) (C).

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References

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1. Dehner LP. Juvenile xanthogranulomas in the first two decades of life: a clinicopathologic study of 174 cases with cutaneous and extracutaneous manifestations. Am J Surg Pathol 2003;27:579-93. 2. Freyer DR, Kennedy R, Bostrom BC, Kohut G, Dehner LP. Juvenile xanthogranuloma: forms of systemic disease and their clinical implications. J Pediatr 1996;129:227-37. 3. Janssen D, Harms D. Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kiel pediatric tumor registry. Am J Surg Pathol 2005;29:21-8. 4. Pagura L, de Prada I, Lopez-Pino MA, Huertas JG, Villarejo F. Isolated intracranial juvenile xanthogranuloma. A report of two cases and review of the literature. Childs Nerv Syst 2015;31:493-8. 5. White W, Garen P. Juvenile xanthogranuloma of the paravertebral soft tissue in infancy: a report of two cases. Pediatr Pathol 1991;11:105-13. 6. Shimosawa S, Tohyama K, Shibayama M, Takeuchi H, Hirota T. Spinal xanthogranuloma in a child: case report. Surg Neurol 1993;39:138-42. 7. Allen C MK. Juvenile Xanthogranuloma. 8. Adamson H. Society Intelligence: The dermatologic society of London. Br J Dermatol 1905;17:222. 9. McDonagh J. A Contribution to our Knowledge of the Nevoxanthoendotheliomata. . Br J Dermatol 1912;24:84-9. 10. Helwig EB HV. Juvenile Xanthogranuloma (nevoxanthoendothelioma). Am J Pathol 1954;30:625-6. 11. Azorin D, Torrelo A, Lassaletta A, et al. Systemic juvenile xanthogranuloma with fatal outcome. Pediatr Dermatol 2009;26:709-12.

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12. Hara T, Ohga S, Hattori S, et al. Prolonged severe pancytopenia preceding the cutaneous lesions of juvenile xanthogranuloma. Pediatr Blood Cancer 2006;47:103-6. 13. Hu WK, Gilliam AC, Wiersma SR, Dahms BB. Fatal congenital systemic juvenile xanthogranuloma with liver failure. Pediatr Dev Pathol 2004;7:71-6. 14. Agabegi SS, Iorio TE, Wilson JD, Fischgrund JS. Juvenile xanthogranuloma in an adult lumbar spine: a case report. Spine (Phila Pa 1976) 2011;36:E69-73. 15. Jain A, Mathur K, Khatri S, Kasana S, Jain SK. Rare presentation of juvenile xanthogranuloma in the thoracic spine of an adult patient: case report and literature review. Acta Neurochir (Wien) 2011;153:1813-8. 16. Stover DG, Alapati S, Regueira O, Turner C, Whitlock JA. Treatment of juvenile xanthogranuloma. Pediatr Blood Cancer 2008;51:130-3. 17. Deisch JK, Patel R, Koral K, Cope-Yokoyama SD. Juvenile xanthogranulomas of the nervous system: A report of two cases and review of the literature. Neuropathology 2013;33:39-46. 18. Schultz KD, Jr., Petronio J, Narad C, Hunter SB. Solitary intracerebral juvenile xanthogranuloma. Case report and review of the literature. Pediatr Neurosurg 1997;26:315-21. 19. Wang B, Jin H, Zhao Y, Ma J. The clinical diagnosis and management options for intracranial juvenile xanthogranuloma in children: based on four cases and another 39 patients in the literature. Acta Neurochir (Wien) 2016;158:1289-97. 20. Tamir I, Davir R, Fellig Y, Weintraub M, Constantini S, Spektor S. Solitary juvenile xanthogranuloma mimicking intracranial tumor in children. J Clin Neurosci 2013;20:183-8. 21. Sun LP, Jin HM, Yang B, Wu XR. Intracranial solitary juvenile xanthogranuloma in an infant. World J Pediatr 2009;5:71-3. 22. Stepan KO, Sharma A, Chicoine MR, Uppaluri R, Dahiya S. Juvenile xanthogranuloma of supra-sellar region: a rare presentation. Clin Neuropathol;34:368-70. 23. Bostrom J, Janssen G, Messing-Junger M, et al. Multiple intracranial juvenile xanthogranulomas. Case report. J Neurosurg 2000;93:335-41. 24. Chiba K, Aihara Y, Eguchi S, et al. Diagnostic and management difficulties in a case of multiple intracranial juvenile xanthogranuloma. Childs Nerv Syst 2013;29:1039-45. 25. Lalitha P, Reddy M, Reddy KJ. Extensive intracranial juvenile xanthogranulomas. AJNR Am J Neuroradiol 2011;32:E132-3. 26. Tan LA, Uy BR, Munoz LF. Recurrent juvenile xanthogranuloma manifesting as diffuse miliary brain lesions. Br J Neurosurg;28:817-8. 27. Ernemann U, Skalej M, Hermisson M, Platten M, Jaffe R, Voigt K. Primary cerebral nonLangerhans cell histiocytosis: MRI and differential diagnosis. Neuroradiology 2002;44:759-63. 28. Kitchen ND, Davies MS, Taylor W. Juvenile xanthogranuloma of nerve root origin. Br J Neurosurg 1995;9:233-7. 29. George DH, Scheithauer BW, Hilton DL, Fakhouri AJ, Kraus EW. Juvenile xanthogranuloma of peripheral nerve: a report of two cases. Am J Surg Pathol 2001;25:521-6. 30. Wille DA, Bozinov O, Scheer I, Grotzer MA, Boltshauser E. Isolated intraspinal juvenile xanthogranuloma in an infant presenting as acute paraplegia. Neuropediatrics 2013;44:171-3. 31. Kim DS, Kim TS, Choi JU. Intradural extramedullary xanthoma of the spine: a rare lesion arising from the dura mater of the spine: case report. Neurosurgery 1996;39:182-5.

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32. Castro-Gago M, Gomez-Lado C, Alvez F, Alonso A, Vieites B. Juvenile xanthogranuloma of the cauda equina. Pediatr Neurol 2009;40:123-5. 33. Iwasaki Y, Hida K, Nagashima K. Cauda equina xanthogranulomatosis. Br J Neurosurg 2001;15:72-3. 34. Venkatesh SK, Gupta RK, Pal L, Husain N, Husain M. Spectroscopic increase in choline signal is a nonspecific marker for differentiation of infective/inflammatory from neoplastic lesions of the brain. J Magn Reson Imaging 2001;14:8-15. 35. Matsubara K, Mori H, Hirai N, Yasukawa K, Honda T, Takanashi JI. Elevated taurine and glutamate in cerebral juvenile xanthogranuloma on MR spectroscopy. Brain Dev 2016;38:964-7. 36. Kwak ES, Marrero DE, Pfannl R, Erbay SH. Sterile brain abscess due to juvenile xanthogranuloma: DWI characteristics. J Neuroimaging 2013;23:437-40. 37. Dalia S, Sagatys E, Sokol L, Kubal T. Rosai-Dorfman disease: tumor biology, clinical features, pathology, and treatment. Cancer Control 2014;21:322-7. 38. Murphy JT, Soeken T, Megison S, Perez E. Juvenile xanthogranuloma: diverse presentations of noncutaneous disease. J Pediatr Hematol Oncol 2014;36:641-5. 39. Auvin S, Cuvellier JC, Vinchon M, et al. Subdural effusion in a CNS involvement of systemic juvenile xanthogranuloma: a case report treated with vinblastin. Brain Dev 2008;30:164-8. 40. Nakasu S, Tsuji A, Fuse I, Hirai H. Intracranial solitary juvenile xanthogranuloma successfully treated with stereotactic radiosurgery. J Neurooncol 2007;84:99-102.

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Age

Sex

Size

Location

Presenting Signs Imaging Treatment and Symptoms ACCEPTED MANUSCRIPT

Resection

Outcome

White et 5 al. (1991)

3 months

M

4 x 3 x 3 cm

T8; extraspinal, extrathoracic

Mass located on routine physical exam

CT: Non-calcified lesion in paraspinal musculature and subcutaneous tissue with attachment to spinous processes of T7 and T8

Resection and Laminectomy

n/a

No evidence of recurrent disease at 11 months

2 months

M

2 x 1.3 x 1 cm

T7-T8; extraspinal, extrathoracic

Mass located on routine physical exam

MRI: mass in subcutaneous tissue and paraspinal musculature with attachment to spinous processes of T7 and T8

Resection

Shimosawa 6 et al. (1993)

13 months

F

Unspecified

T6-T9 intradural, extramedullary

Mild lower extremity spastic paraparesis

MRI: T1 revealed low-intensity mass on dorsal spinal cord with compression; no enhancement with DPTA

Kitchen et al.28 (1995)

15 years

F

Unspecified

Right S1 nerve root

Chronic low back pain with new radiating right leg pain

No recurrence at 2 years

Laminoplastic laminectomy between T6-T9 with resection

Complete

Significant improvement at 6 months

L5 Laminectomy with resection of sacral hiatus and resection of mass

Complete

Complete resolution of symptoms postop

SC

n/a

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TE D

CT: expanded S1 nerve root with no enhancement; MRI: T1 mass had the same signal characteristics as nerve; T2 showed increased signal; proton density was same as bone marrow

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M

18 mm at largest diameter

T1-T2 intradural, extramedullary

Spastic paraparesis

MRI: T1 isointense intradural mass; T2 revealed homogenous enhancement with gadolinium

C7-T3 laminectomy and resection

Agabegi et 14 al. (2001)

47 years

F

Unspecified; “very large”

L2 vertebral body with diffuse extension

Bowel and bladder incontinence; perineal anesthesia; mild R hip flexor weakness

n/a

Pre-operative embolization, decompressive laminectomy T12-L3, spinal stabilization; postoperative radiotherapy

Dehner et 1 al. (2003)

14 years

F

Unspecified

L3

n/a

CastroGago et 32 al. (2009)

14 years

M

Unspecified

L2-L3

Back pain and collapsed vertebrae Lower extremity weakness with occasional pain and paresthesias

15

22 years

F

Unspecified

T7 with left paraspinal and anterolateral epidural soft tissue component

Complete

RI PT

16 months

Unspecified

n/a

Unspecified

Laminectomy at L2-L3

Partial

Decompressive laminectomy and mechanical fixation; complete removal

n/a

Treated with methylprednisolone and prednisone post-op. Initially improved with PT, but symptoms recurred at 12 months. Subsequently treated with prednisone and vinblastine and saw near complete clinical improvement. Resolution of presenting symptoms; 3-month follow up without recurrence

M AN U

SC

Resolution of presenting symptoms at 8 months

MRI: increased signal intensity of cauda equine roots with a string-ofbeads appearance and nodular lesions in posterior spinal canal.

EP AC C

Jain et al. (2010)

Pain in midthoracic region

Significant improvement by 3 months

partial

TE D

Kim et al. (1996)

n/a

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Highlights - Juvenile Xanthogranuloma are rare, non-Langerhan’s cell histiocytic lesions that primarily present as multiple cutaneous lesions in young males. - Solitary lesions in the spinal column are a particularly rare presentation of this disease.

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- Treatment strategies vary and may depend on resectability of the tumor, as complete resection may be curative. - Poorly accessible tumors, widespread or progressive disease may require aggressive systemic therapy which may include corticosteroids and vinca alkaloids and/or radiation.

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- The efficacy of treatments has not clearly been established yet.

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- A patch duroplasty may also provide symptomatic relief of focal compression.

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Abbreviations: AFB: Acid-Fast Bacillus CNS: central nervous system CT: computed tomography

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ECD: Erdheim Chester disease FDG: fluorodeoxyglucose GFAP: Glial fibrillary acidic protein IHC: immunohistochemical staining

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JXG: Juvenile Xanthogranuloma

PNS: peripheral nervous system PET: positron emission tomography

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RDD: Rosai-Dofman disease () and

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MRI: magnetic resonance imaging