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A Very Rare Case of Right Insular Lobe Langerhans Cell Histiocytosis (CD1a+) Mimicking Glioblastoma Multiforme in a Young Adult
Accepted Manuscript A very rare case of a right insular lobe Langerhans cell histiocytosis (CD1a +) mimicking glioblastoma multiforme in a young adult Patrick Bärtschi, MD, Enrique Luna, MD, Pablo González-López, MD-PhD, Javier Abarca, MD, Joaquín Herrero, MD, Estela Costa, MD, Artemio Paya, MD, Juan Sales, MD, Pedro Moreno, MD PII:
S1878-8750(18)32139-9
DOI:
10.1016/j.wneu.2018.09.093
Reference:
WNEU 10298
To appear in:
World Neurosurgery
Received Date: 21 May 2018 Revised Date:
11 September 2018
Accepted Date: 12 September 2018
Please cite this article as: Bärtschi P, Luna E, González-López P, Abarca J, Herrero J, Costa E, Paya A, Sales J, Moreno P, A very rare case of a right insular lobe Langerhans cell histiocytosis (CD1a +) mimicking glioblastoma multiforme in a young adult, World Neurosurgery (2018), doi: https:// doi.org/10.1016/j.wneu.2018.09.093. 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.
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ACCEPTED MANUSCRIPT TITLE PAGE. Case report A very rare case of a right insular lobe Langerhans cell histiocytosis (CD1a +) mimicking glioblastoma multiforme in a young adult Patrick Bärtschi, MD1, Enrique Luna, MD1, Pablo González-López, MD-PhD1, Javier Abarca, MD1, Joaquín Herrero, MD2, Estela Costa, MD3, Artemio Paya, MD3, Juan Sales MD1, Pedro
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Moreno, MD1
Neurosurgery Department, University General Hospital of Alicante, Foundation for the
Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Avda. 2
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Pintor Baeza sn. CP. 03010. Alicante, Spain
Oncology Department, University General Hospital of Alicante, Foundation for the Promotion
CP. 03010. Alicante, Spain 3
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of Health and Biomedical Research in the Valencian Region (FISABIO), Avda. Pintor Baeza sn.
Pathology Department, University General Hospital of Alicante, Foundation for the Promotion
of Health and Biomedical Research in the Valencian Region (FISABIO), Avda. Pintor Baeza sn. CP. 03010. Alicante, Spain
Corresponding author
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Pablo González-López MD, PhD Email: [email protected]
Cell Phone: (+34) 646076100 Fax: 965245971
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Postal address: Servicio de Neurocirugía. Hospital General Universitario de Alicante. Planta 6. Avda. Pintor Baeza sn. CP. 03010. Alicante, Spain
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Key words
Langerhans cell, histiocytosis, insula, Birbeck granules, 5-ALA
Abbreviations list
LCH. - Langerhans cell histiocytosis SS-LCH – Single system Langerhans cell histiocytosis MS-LCH RO+ - Multisystemic Langerhans cell histiocytosis wit risk organ CNS. - Central nervous system 5-ALA. - 5-Aminolevulinic acid DI. - Diabetes insipidus GBM. - Glioblastoma multiforme
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ACCEPTED MANUSCRIPT MCA. - Middle cerebral artery
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MFM. - Mycophenolate Mofetil
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ACCEPTED MANUSCRIPT ABSTRACT
Background. Langerhans cell histiocytosis (LCH) is a multi-systemic dendritic cell proliferation relatively uncommon in adults. Central nervous system (CNS) LHC outside the pituitary is even more uncommon. Case description. We report a case of a 42-years-old male complaining of a right side
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hemicranial pain and left arm minor paresis due to a right insular lobe heterogeneous enhancing lesion associated with extensive vasogenic edema. The first diagnostic impression suggested a glioblastoma multiforme or a localized metastasis. The thoracic-abdominal-pelvic CT only detected small upper lungs inactive nodules suggesting a silent focal LHC. A very hard
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consistency lesion was almost completely removed through a pterional craniotomy approach, with no fluorescence after aminolevulinic acid (5-ALA) infusion. The intraoperative biopsy ruled out a glioma but could not confirm a lymphoma. Definitive cerebral biopsy reported
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lymphocytes and histiocytes (CD1a+, S1001+). This gave rise to the diagnosis of an intracerebral parenchymal LCH. The treatment with fractioned radiotherapy maintained a clinical and radiological remission.
Conclusions. This case is so rare that it cannot be used as a guide and we probably will never see again a single intraparenchymal supratentorial CNS LHC in a neurosurgery ward, but we
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hope that it might help colleagues in the future with the thought process.
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ACCEPTED MANUSCRIPT INTRODUCTION
Langerhans cell Histiocytosis (LHC) is a rare heterogeneous disease, affecting mainly the pediatric population in about 1:200000, becoming even more rare in a population over 15-yearold (1:560000).1,2 LHC is characterized by an accumulation of dendritic cells with features similar to epidermal Langerhans cell in various organs.3 The most common involved organs are
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the skeleton (80% of cases), skin (33%), pituitary gland (25%) and the lymph nodes (5-10%). The prognosis depends on the organ involved and it is particularly worse if there is “high-risk” organs involvement such as the bone marrow, the liver and the spleen.4
The definitive diagnosis is made based on a biopsy where Langherhans cells (LC) and
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eosinophils are associated with at least one of the following immunohistochemical stain should be present: Langerin (CD207) positivity, (CD1a+) positivity or the presence of Birbeck granules on electronic microscopy.5
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Langherhans cell Histiocytosis is the official term used by the Histiocyte Society for over 2 decades, LHC is classified as single organ or system (SS-LCH) and can be unifocal o multifocal like in bone lesions, and as multisystem disease (MS-LHC) when two or more organ are affected. Then we classified the “risk organs” (RO+) of mortality when the liver, the bone marrow, or the spleen are involved. The “special site organs” are the CNS and the skull. Historical terms such as “Hand Schüller Christian” disease describing a child with
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exophthalmos, skin lesion, lytic bone lesion and diabetes insipidus DI and “Letterer Siwe” disease describing infants with disseminated inflammatory lesions including liver, spleen, and bone marrow are no longer in use. Nowadays both of these diseases would be classified as (MSLHC RO+).6
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The central nervous system (CNS) involvement excluding the pituitary is less than 4% of the cases and the main presentations are bilateral cerebellar or basal ganglia degenerative lesions and extra axial involving the meninges, the pineal gland and the choroid plexus.7
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A cerebral unilateral lobar intraparenchymal without diabetes insipidus (DI) presentation is such a rarity that it is worth reporting.
CASE REPORT
A healthy 42 years-old male complained of a mild bothersome headache mainly on the right side of the cranium for several months without complete relief with common pain killers. He developed a subtle left upper extremity paresis and paresthesia worth to be investigated by his family practice physician with a head CT. His past medical history is only remarkable for an active heavy smoking (15 pack-year) and a spontaneous pneumothorax at the age of 18 yearsold, which resolved after a thoracic drain. His family medical history is remarkable for a grand4
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ACCEPTED MANUSCRIPT mother on his mother side who died from colon cancer and a grand-father who died from leukemia. The neurological examination at the time of referral to the neurosurgery department was unremarkable due to a short course of corticosteroids and the patient referred himself as asymptomatic. There were no laboratory abnormality finding. The cerebral CT scan with contrast showed an enhancing irregular right insular lobe lesion with
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significant fronto-temporal vasogenic edema (Figure 1). The brain MRI described a right operculo-insular enhancing neoplastic lesion with significant vasogenic edema producing a midline shift to the left and an incipient right side uncal herniation (Figures 2 & 3). A primary brain neoplasia should be suspected, mainly a glioblastoma multiforme as the first differential
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diagnosis followed by a localized unique metastasis.
A work up looking for a primary neoplasia was completed. Tumor marker cells were negative and the total body CT scan was only remarkable for small multiple nodules and cysts in apices
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of both lungs (Figure 4). In association with smoking and a previous history of a spontaneous pneumothorax, a focal Langerhans cell histiocytosis (former Histiocytosis X) should be considered. However, the case was brought to the neuro-oncology tumor board and a surgical resection guided with 5-ALA fluorescence was decided.
The insular tumor was approached through a traditional right side pterional craniotomy. There was no 5-ALA fluorescence under a 405-nm wavelength blue light. A very hard consistency
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tumor has been almost completely removed. A small nodule remnant and strongly adherent to the M3 segment of the middle cerebral artery (MCA) has been left intact to avoid vascular damage. The intraoperative biopsy ruled out immediately a glioma but couldn’t confirm if the lymphocytic perivascular infiltration was a lymphoma. For that reason, the tumor resection
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continued (Figure 5).
The definitive biopsy described a brain parenchyma with perivascular T-Lymphocytes infiltration, with a cluster of histiocytes (LC) and eosinophils, thus ruling out any type of
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lyphoma.8,9
Because of the suspected lung focal LHC, immunohistochemical stain for CD1a and S-100 were carried out and came back positive for both. This gave the definite diagnosis of an intraparenchymal brain LHC. There was no mutation V600E on the BRAF oncogene (Figure 6).
The patient recovered well from the surgery, with no neurological deficit and a small nodule as a residual tumor on the post-operative MRI (Figure 7). The decision of the neuro-oncology tumor board was to treat with radiotherapy for a total of 37.8 Gy, fractioned in 180 cGy/day and a mandatory smoking prohibition. After 3 months of radiotherapy completion, the patient remained asymptomatic, neurologically intact and the residual nodule disappeared on the last cerebral MRI (Figure 8). Pulmonary
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ACCEPTED MANUSCRIPT function tests were normal. A total body PET-CT showed no active hyper metabolism and the lung nodules without activity. He had a hard time to stop smoking, needing a prescription of Varenicline (Champix- delete the commercial name).
DISCUSSION
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Central nervous system LCH excluding pituitary involvement is extremely rare in adults and in childhood accounting for less of 4 % of all LHC. Most of these cases are mainly pontine and cerebellar lesions.4 Furthermore, these cases were seldom reported in the literature. Malpas and Norton had described 1 case in a series of 47 CNS LHC,4 24 more cases reported by Hunt et al.
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between 1980 and 1999. In 2003, 1 case of 5 multisystemic LHC treated with 2chlorodeoxyadenosin (CDA) at Mayo Clinic.10,11 So far none of those cases were
multiforme on neuroimaging.
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intraparenchymal supratentorial and even less were they mistaken with a glioblastoma
We found in the entire literature only one case report similar to ours despite major differences ( see Table 1).12 In 2010 F. Perren from University Hospital of Geneva in Switzerland, reported a case of a 55 year-old-women with a left side hemiataxia, hemiparesis, hemisensory loss and a short-lasting episode of an alien left hand due to lesion of the right internal capsule and thalamus with extension to the mesencephalon associated with extensive edema.12 The
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neuroimaging suggested a GBM, but inoperable due to its extension and depth. The brain biopsy came as inflammatory brain tissue suggestive of a ‘pseudotumoral’ multiple sclerosis and treated with steroids with reversal of the clinical signs. An extensive endocrine and rheumatologic work up gave no finding. The patient had respiratory symptoms with a chest wall
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pain and the lung CT showed a diffuse reticulonodular infiltration. The lung and rib biopsy gave a characteristic nodular infiltration of LHC, the immunohistochemical staining CD1a was positive so confirming the diagnosis of LHC. However, the CD1a stain on the brain remained
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negative. Thus, the patient has been treated as a multisystemic LHC with Mycophenolate Mofetil (MMF) and got a good clinical response in a 10 year follow up. This case had been considered a multisystemic LHC, and the brain lesion had been considered a neurodegenerative inflammation without CD1a. In 2005 Grois et al. classified CNS LHC into three different types of lesions and concluded that CNS LHC lack features that are diagnostic at other organs, therefore they are usually CDa1 negative. CDa1 is mainly positive in pituitary CNS LHC.10 CNS LHS is accounting for 25% off all LCH and DI being the classic presentation but can also manifest itself as other endocrine deficiency. Pituitary LCH can be primary or “acquired“ as recent knowledge suggests that prolonged involvement of skull bones (excluding those in the vault) predisposes patients to the development of DI (5). In this study, patients with MS-LCH
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ACCEPTED MANUSCRIPT and "craniofacial involvement" – particularly those with involvement of the ‘‘ear,’’ ‘‘eye,’’ and the "oral" sites at diagnosis – carried a significantly increased risk to develop DI during their course.14. What makes our case almost exceptional is that it was unilateral, parenchymal, with no pituitary involvement and most of all the CD1a positivity meant that the true active LHC was primarily (and only) in the brain. Because of mimicking a GBM we think that it is the first and only CNS
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LHC operated and removed so far. After retrospection, we can fairly ask the question if surgical removal was a good option. The accessible lesion and the suspicion of a GBM in a young adult gave us little room for other alternatives and allowed us to reach a surprising diagnosis. This diagnosis was suspected by the clinical silent nodules in both lung apices discovered
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incidentally, and to which we wrongly paid no attention. This is the other particularity of our case. The patient had two organs, lung and brain, with LHC but only the CNS LHC was active. Therefore, we had to decide during the neuro-oncology tumor board that the patient had ‘two’
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single focal organ with LHC, one inactive and one active, so we had to assume that they were independent one from the other and we took the decision to treat the CNS LHC has a single organ involvement. We do not think there was any other case of LHC reported with that presentation.
The next challenge we faced was how to treat our patient. For the silent incidental lung nodules, suggestive of focal lung LHC (former Histiocytosis X) the only treatment was straight forward
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consisting of stop smoking.15 The difficulty was for the unusual CNS LHC presentation. Because our patient had no extraaxial (skull or meninges) involvement he would not benefit from bone curettage, or local steroids instillation or dura removal.16 Intralesional instillation of steroids in limited bone lesions is safe and effective.17
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Therapeutic approaches to CNS LHC are poorly standardized, because of the historical uncertainty defining LCH as inflammatory versus neoplastic and incomplete understanding of mechanisms of pathogenesis.18 Our patient had a lack of Vm600E on the BRAF oncogene, so
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Vemurafenib (anti RAS) was not an option and we had not look up for mutation MP2K1.19 Because there was no hypothalamus pituitary region (HPR) involvement we did not wanted to start with the recommended first line Vinblastine/Prednisone for 6 weeks.20nor the salvage 2CDA21 or antimetabolites such as Cytosine(Ara-C), Cladribine or Cytarabine.22 Because the CNS LHC in our patient was not neurodegenerative nor multi systemic we renounced to start a heavy treatment combination with intravenous immunoglobulin, antimetabolite and transretinoic acid.23 Because the active CNS LHC had been almost completely removed and the fact that the patient was an adult one, we decided to use a small dose radiotherapy for a total radiation dose of 37.8 Gy, fractioned into 180 cGy/session. As there are evidences of pituitary LHC mass reduction with radiosurgery,24 we opted for radiotherapy because of the good results
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ACCEPTED MANUSCRIPT in small number of patients but with cranial extraaxial lesion (former Eosinophilic granuloma).25 The outcome after 3 months of fractioned sessions of radiotherapy was a radiological remission of the residual nodule on the last MRI, the patient remained asymptomatic without neurological deficit since the postoperative period. The more difficult aspect of the follow up came from the
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patient himself having a hard time to stop smoking.
CONCLUSION
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The clinical interest of our case came from the exceptional presentation of an already uncommon disease, a surgery performed because of the high suspicion of a high-grade glioma, and that the surprising diagnosis started with an incidental finding on a lung CT.
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The CDa1+ positivity on a brain tissue outside the pituitary has not been reported as far as we are aware. This could be the first CNS LHC removed surgically. The empirical treatment with low dose radiotherapy resulted effective. This case is so rare that it cannot be used as a guide and we probably will never see again a single intraparenchymal supratentorial CNS LHC in a neurosurgery ward, but we hope that it might help colleagues in the future with the thought
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process.
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ACCEPTED MANUSCRIPT REFERENCES
1. Yagci B, Varane A, Caglar M, et al. Langerhans cell histiocytosis: retrospective analysis of 217 cases in a single center. Pediatr Hematol Oncol 2008;25:399-408 2. Nicholson HS, Egler MR, Nesbit ME. The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998:12:379-84.
assessment of 43 biopsies. Pediatr Pathol Lab Med 1997:17:769-87
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3. Favara BE, Steele A. Langerhans cell histiocytosis of lymph nodes: a morphological
4. Malpas JS, Norton AJ. Langerhans cell histiocytosis in adults. Med Pediatr Oncol 1996:26:540-6 5. Cheng-Wei Li, Man-Hui Li et al. Pulmonary Langerhans cell histiocytosis: analysis of 14
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patients and literature review. J Thorac Dis. 2016: 8: 1283-1289
6. Lampert F. et al. Langherhans Cell histiocytosis, Historical perspectives. Heamtol OncolClin NorthAm.1998;12(2):213-219 ]
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7. Haupt R, Minkov M. Langherhans Cell Histiocytosis (LHC): Guidelines for diagnosis. Clinical Work up and Treatment for Patients till the Age of 18 years. Pediatr Blood Cancer.2013 Feb; 60(2):175-84 8. Hoover KB, Rosenthal DI, Mankin H. Langerhans cell histiocytosis. Skeletal Radiol. 2007;36:95–104.doi: 10.1007/s00256-006-0193-2. PubMed PMID: 17028900 9.Safei et al. Langerhans cell histiocytosis followed by Hodgkin Lymphoma Iran J Med Sci. 2015 May; 40(3): 282–286
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10. Hund E, Steiner H Jansen O, et al. Treatment of cerebral Langerhans cell histiocytosis. J Neurol Sci 1999:171:145-52
11. Pardanani A, Phyliky RI, Li CY, Tefferi A. 2-Chlorodeoxyadenosisne therapy for disseminated Langerhans cell histiocytosis, Mayo ClinProc 2003:78:301-6
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12. F.Perren , L.Fankhauser, B.Thiévent, J-C Pache e al.Late adult onset of Langherhans cell histiocytosis mimicking glioblastoma multiforme. J Neurol Sci 2011:301:96-99
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13. Grois NG, Prayer D, Prosh H, Lassman H et al. LCH CNS Cooperative Group. Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 2005:128(Pt 4) :829-38 14.Grois N, Potschger U, Prosch H, Minkov M, Arico M, Braier J, et al. Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 2006;46(2):228-33. 15. Abdellatif Tazi, Constance de Margerie, Jean Marc Naccache, et al. The natural history of adult pulmonary Langerhans cell histiocytosis: a prospective multicenter study. Orphanet Journal of rare diseases 2015:10:30: 2-10 16. Woo Kl et al. Eosinophilic granuloma of the orbit-understanding the paradox of aggressive responsive to minimal intervention. Opthal Plast Reconstr Surg 2003;19:429-39 17. Egeler et al. Intralesional infiltration of corticosteroids in localized Langherhans cell histiocytosis-J Pediatr Orthop 1992;12:811-4
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ACCEPTED MANUSCRIPT 18. Carl E. Allen et al. How I treat Langherhans cell histiocytosis Blood 2015:125:26-34 19. Abla O , Weitzman S. Treatment of Langherhans cell histiocytosis: role of BRAF / MAPK inhibition Hematol Am Soc Educ Program 2015:2015:565-570 20.Grois N,Portscher U et al. Risks factor for diabetes insipidus I Langerhans cell histiocytosis. Pediatr Blood Cancer 2006;46:228-33
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21. Dall G, Finlay JL et al. Analysis of outcome for patient with mass lesions of the central nervous system due to Langherhans cell histiocytosis treated with 2-chlorodeoxyadenosine Pediatr Blood Cancer 2008:50:72-9 22. Simko et al. Clofarabine salvage therapy in refractory multi focal histiocytic disorders. Pediat Blood Cancer 2014:61:479-487
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23. Ibdaih A, et al. retinoic acid therapy in “degenerative like” neuro-Langherhans cell histiocytosis , a prospective pilot study Pediatr Blood Cancer 2004:43:55-8 24. Kotecha R, Venkatramani R, Jubran RF, et al. Clinical outcomes of radiation in the Langherhans cell histiocytosis Am J Clin Oncol 2014:37:592-596
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25. Kriz et al. Radiotherapy in Langherhans cell histiocytosis –a rare indication in a rare disease. Radiation Oncology 2013, 8:233-239
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ACCEPTED MANUSCRIPT FIGURES Figure 1. Head CT-Scan. A) No contrast head Ct shows right fronto-temporal edema with collapse of the ventricular temporal horn. B) With contrast, there is an intense enhancement of an irregular lesion in contact with M3 branches and left side mid line shift. Figure 2. Cerebral MRI with contrast: right insular lobe neoplastic lesion with significant
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vasogenic perilesional edema causing right side uncal herniation. The lesion suggests a primary neoplasia such as a glioblastoma multiforme or a unique localized metastasis.
Figure 3. Cerebral MRI-FLAIR and T2 sequences on A) axial, and B) coronal views. Note the
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significant vasogenic edema from the insula spreading to the frontal and temporal lobes.
Figure 4. Total body CT scan. The thoracic CT shows multiple nodules (blue arrows) on both
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apices. Compatible with granulomas of LHC.
Figure 5. A) Right side pterional craniotomy. B) Transcortical Insular opening after a distal to proximal Sylvian fissure dissection. C) No 5-ALA fluorescence seen under exposure to a 405 nm-wavelength blue light. D) Hard consistency tumor difficult to remove with an ultrasonic surgical aspirator firmly adherent to M3 branches.
Figure 6. Post-operative cerebral MRI. A) Axial view shows a right side nodular residual tumor
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adherent to M3 branch of MCA (blue arrows). B) The same nodule on a sagittal, and C) coronal
Figure 7. Definitive pathology of the brain tumor lesion. A) Cerebral parenchyma with
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abundant lymphocytic inflammation process. B) Perivascular lymphocytic infiltration. C)Cluster of histiocytes and eosinophils D) Immunohistochemical stain reveals positivity for CD1a giving
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the ultimate and definite diagnosis of histiocytosis of Langerhans. No mV600E on oncogene BRAF.
Figure 8. Cerebral MRI post 3 months of radiotherapy showing complete remission of the residual tumor. A) Coronal T1-Gadolinium. B) Axial T1-Gadolinium. C) Coronal T2 weighted image. D) Axial T2 weighted image.
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ACCEPTED MANUSCRIPT Table 1. Characterization and comparison between 2 similar case reports
Late adult onset of LHC mimicking glioblastoma multiforme. (1)
A very rare case of right insular lobe LHC (CD1a+) mimicking glioblastoma in a young adult. (2)
Variables
Late adult onset of LHC mimicking glioblastoma multiforme. (1)
A very rare case of right insular lobe LHC (CD1a+) mimicking glioblastoma in a young adult. (2)
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Sex
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Left side mild weakness, dysmetria and central facial paresis
LCH stratification
CNS LCH localization
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MS-LHC RO-(3)
And paresthesia.
SS-LHC RO-(4)
Right insular lobe
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Right thalamus
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Headache, left side upper extremity paresis
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Clinical presentation
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Age
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Variables
First diagnosis
“pseudotumoral” multiple sclerosis
Intraparenchymal CNS LCH
CD1a and S-100 negative
CD1a and S-100 positive
Bilateral active upper lung lesions new osteolytic ribs lesions
Asymptomatic upper lungs nodules
CNS lesion Immunostaining
Other organs involved
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Surgical procedure
Medical treatment
Steroids Mofetil Micophenolate MMF
Craniotomy and tumor removal
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Stereotactic biopsy
Fractioned radiotherapy for a total of 37Gy
Outcome
remnant disappearance
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Symptoms free for over ten years
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Asymptomatic and radiological
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(1) F.Perren , L.Fankhauser, B.Thiévent, J-C Pache e al.Late adult onset of Langherhans cell histiocytosis mimicking glioblastoma multiforme. J Neurol Sci 2011:301:96-99 (2) Current paper Bärtschi et al. (3) Multisystemic Langerhans cell Histiocytosis without risk organ (4) Single system Langherhans cell Histiocytosis without risk organ
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HIGHLIGHTS
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Langerhans cell Histiocytosis (LCH) is a rare heterogeneous disease characterized by an accumulation of dendritic cells in various organs The central nervous system (CNS) involvement excluding the pituitary is extremely uncommon
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A rare intraparenchymal radiological presentation may be misinterpreted as a high-grade glioma
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A multispecialty approach should be mandatory when suspecting a CNS LGH
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Abbreviations list LCH. - Langerhans cell histiocytosis CNS. - Central nervous system 5-ALA. - 5-Aminolevulinic acid
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DI. - Diabetes insipidus GBM. - Glioblastoma multiforme MCA. - Middle cerebral artery
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MFM. - Mycophenolate Mofetil
S1878-8750(18)32139-9
DOI:
10.1016/j.wneu.2018.09.093
Reference:
WNEU 10298
To appear in:
World Neurosurgery
Received Date: 21 May 2018 Revised Date:
11 September 2018
Accepted Date: 12 September 2018
Please cite this article as: Bärtschi P, Luna E, González-López P, Abarca J, Herrero J, Costa E, Paya A, Sales J, Moreno P, A very rare case of a right insular lobe Langerhans cell histiocytosis (CD1a +) mimicking glioblastoma multiforme in a young adult, World Neurosurgery (2018), doi: https:// doi.org/10.1016/j.wneu.2018.09.093. 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.
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ACCEPTED MANUSCRIPT TITLE PAGE. Case report A very rare case of a right insular lobe Langerhans cell histiocytosis (CD1a +) mimicking glioblastoma multiforme in a young adult Patrick Bärtschi, MD1, Enrique Luna, MD1, Pablo González-López, MD-PhD1, Javier Abarca, MD1, Joaquín Herrero, MD2, Estela Costa, MD3, Artemio Paya, MD3, Juan Sales MD1, Pedro
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Moreno, MD1
Neurosurgery Department, University General Hospital of Alicante, Foundation for the
Promotion of Health and Biomedical Research in the Valencian Region (FISABIO), Avda. 2
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Pintor Baeza sn. CP. 03010. Alicante, Spain
Oncology Department, University General Hospital of Alicante, Foundation for the Promotion
CP. 03010. Alicante, Spain 3
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of Health and Biomedical Research in the Valencian Region (FISABIO), Avda. Pintor Baeza sn.
Pathology Department, University General Hospital of Alicante, Foundation for the Promotion
of Health and Biomedical Research in the Valencian Region (FISABIO), Avda. Pintor Baeza sn. CP. 03010. Alicante, Spain
Corresponding author
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Pablo González-López MD, PhD Email: [email protected]
Cell Phone: (+34) 646076100 Fax: 965245971
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Postal address: Servicio de Neurocirugía. Hospital General Universitario de Alicante. Planta 6. Avda. Pintor Baeza sn. CP. 03010. Alicante, Spain
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Key words
Langerhans cell, histiocytosis, insula, Birbeck granules, 5-ALA
Abbreviations list
LCH. - Langerhans cell histiocytosis SS-LCH – Single system Langerhans cell histiocytosis MS-LCH RO+ - Multisystemic Langerhans cell histiocytosis wit risk organ CNS. - Central nervous system 5-ALA. - 5-Aminolevulinic acid DI. - Diabetes insipidus GBM. - Glioblastoma multiforme
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ACCEPTED MANUSCRIPT MCA. - Middle cerebral artery
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MFM. - Mycophenolate Mofetil
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ACCEPTED MANUSCRIPT ABSTRACT
Background. Langerhans cell histiocytosis (LCH) is a multi-systemic dendritic cell proliferation relatively uncommon in adults. Central nervous system (CNS) LHC outside the pituitary is even more uncommon. Case description. We report a case of a 42-years-old male complaining of a right side
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hemicranial pain and left arm minor paresis due to a right insular lobe heterogeneous enhancing lesion associated with extensive vasogenic edema. The first diagnostic impression suggested a glioblastoma multiforme or a localized metastasis. The thoracic-abdominal-pelvic CT only detected small upper lungs inactive nodules suggesting a silent focal LHC. A very hard
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consistency lesion was almost completely removed through a pterional craniotomy approach, with no fluorescence after aminolevulinic acid (5-ALA) infusion. The intraoperative biopsy ruled out a glioma but could not confirm a lymphoma. Definitive cerebral biopsy reported
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lymphocytes and histiocytes (CD1a+, S1001+). This gave rise to the diagnosis of an intracerebral parenchymal LCH. The treatment with fractioned radiotherapy maintained a clinical and radiological remission.
Conclusions. This case is so rare that it cannot be used as a guide and we probably will never see again a single intraparenchymal supratentorial CNS LHC in a neurosurgery ward, but we
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hope that it might help colleagues in the future with the thought process.
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ACCEPTED MANUSCRIPT INTRODUCTION
Langerhans cell Histiocytosis (LHC) is a rare heterogeneous disease, affecting mainly the pediatric population in about 1:200000, becoming even more rare in a population over 15-yearold (1:560000).1,2 LHC is characterized by an accumulation of dendritic cells with features similar to epidermal Langerhans cell in various organs.3 The most common involved organs are
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the skeleton (80% of cases), skin (33%), pituitary gland (25%) and the lymph nodes (5-10%). The prognosis depends on the organ involved and it is particularly worse if there is “high-risk” organs involvement such as the bone marrow, the liver and the spleen.4
The definitive diagnosis is made based on a biopsy where Langherhans cells (LC) and
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eosinophils are associated with at least one of the following immunohistochemical stain should be present: Langerin (CD207) positivity, (CD1a+) positivity or the presence of Birbeck granules on electronic microscopy.5
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Langherhans cell Histiocytosis is the official term used by the Histiocyte Society for over 2 decades, LHC is classified as single organ or system (SS-LCH) and can be unifocal o multifocal like in bone lesions, and as multisystem disease (MS-LHC) when two or more organ are affected. Then we classified the “risk organs” (RO+) of mortality when the liver, the bone marrow, or the spleen are involved. The “special site organs” are the CNS and the skull. Historical terms such as “Hand Schüller Christian” disease describing a child with
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exophthalmos, skin lesion, lytic bone lesion and diabetes insipidus DI and “Letterer Siwe” disease describing infants with disseminated inflammatory lesions including liver, spleen, and bone marrow are no longer in use. Nowadays both of these diseases would be classified as (MSLHC RO+).6
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The central nervous system (CNS) involvement excluding the pituitary is less than 4% of the cases and the main presentations are bilateral cerebellar or basal ganglia degenerative lesions and extra axial involving the meninges, the pineal gland and the choroid plexus.7
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A cerebral unilateral lobar intraparenchymal without diabetes insipidus (DI) presentation is such a rarity that it is worth reporting.
CASE REPORT
A healthy 42 years-old male complained of a mild bothersome headache mainly on the right side of the cranium for several months without complete relief with common pain killers. He developed a subtle left upper extremity paresis and paresthesia worth to be investigated by his family practice physician with a head CT. His past medical history is only remarkable for an active heavy smoking (15 pack-year) and a spontaneous pneumothorax at the age of 18 yearsold, which resolved after a thoracic drain. His family medical history is remarkable for a grand4
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ACCEPTED MANUSCRIPT mother on his mother side who died from colon cancer and a grand-father who died from leukemia. The neurological examination at the time of referral to the neurosurgery department was unremarkable due to a short course of corticosteroids and the patient referred himself as asymptomatic. There were no laboratory abnormality finding. The cerebral CT scan with contrast showed an enhancing irregular right insular lobe lesion with
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significant fronto-temporal vasogenic edema (Figure 1). The brain MRI described a right operculo-insular enhancing neoplastic lesion with significant vasogenic edema producing a midline shift to the left and an incipient right side uncal herniation (Figures 2 & 3). A primary brain neoplasia should be suspected, mainly a glioblastoma multiforme as the first differential
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diagnosis followed by a localized unique metastasis.
A work up looking for a primary neoplasia was completed. Tumor marker cells were negative and the total body CT scan was only remarkable for small multiple nodules and cysts in apices
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of both lungs (Figure 4). In association with smoking and a previous history of a spontaneous pneumothorax, a focal Langerhans cell histiocytosis (former Histiocytosis X) should be considered. However, the case was brought to the neuro-oncology tumor board and a surgical resection guided with 5-ALA fluorescence was decided.
The insular tumor was approached through a traditional right side pterional craniotomy. There was no 5-ALA fluorescence under a 405-nm wavelength blue light. A very hard consistency
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tumor has been almost completely removed. A small nodule remnant and strongly adherent to the M3 segment of the middle cerebral artery (MCA) has been left intact to avoid vascular damage. The intraoperative biopsy ruled out immediately a glioma but couldn’t confirm if the lymphocytic perivascular infiltration was a lymphoma. For that reason, the tumor resection
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continued (Figure 5).
The definitive biopsy described a brain parenchyma with perivascular T-Lymphocytes infiltration, with a cluster of histiocytes (LC) and eosinophils, thus ruling out any type of
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lyphoma.8,9
Because of the suspected lung focal LHC, immunohistochemical stain for CD1a and S-100 were carried out and came back positive for both. This gave the definite diagnosis of an intraparenchymal brain LHC. There was no mutation V600E on the BRAF oncogene (Figure 6).
The patient recovered well from the surgery, with no neurological deficit and a small nodule as a residual tumor on the post-operative MRI (Figure 7). The decision of the neuro-oncology tumor board was to treat with radiotherapy for a total of 37.8 Gy, fractioned in 180 cGy/day and a mandatory smoking prohibition. After 3 months of radiotherapy completion, the patient remained asymptomatic, neurologically intact and the residual nodule disappeared on the last cerebral MRI (Figure 8). Pulmonary
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ACCEPTED MANUSCRIPT function tests were normal. A total body PET-CT showed no active hyper metabolism and the lung nodules without activity. He had a hard time to stop smoking, needing a prescription of Varenicline (Champix- delete the commercial name).
DISCUSSION
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Central nervous system LCH excluding pituitary involvement is extremely rare in adults and in childhood accounting for less of 4 % of all LHC. Most of these cases are mainly pontine and cerebellar lesions.4 Furthermore, these cases were seldom reported in the literature. Malpas and Norton had described 1 case in a series of 47 CNS LHC,4 24 more cases reported by Hunt et al.
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between 1980 and 1999. In 2003, 1 case of 5 multisystemic LHC treated with 2chlorodeoxyadenosin (CDA) at Mayo Clinic.10,11 So far none of those cases were
multiforme on neuroimaging.
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intraparenchymal supratentorial and even less were they mistaken with a glioblastoma
We found in the entire literature only one case report similar to ours despite major differences ( see Table 1).12 In 2010 F. Perren from University Hospital of Geneva in Switzerland, reported a case of a 55 year-old-women with a left side hemiataxia, hemiparesis, hemisensory loss and a short-lasting episode of an alien left hand due to lesion of the right internal capsule and thalamus with extension to the mesencephalon associated with extensive edema.12 The
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neuroimaging suggested a GBM, but inoperable due to its extension and depth. The brain biopsy came as inflammatory brain tissue suggestive of a ‘pseudotumoral’ multiple sclerosis and treated with steroids with reversal of the clinical signs. An extensive endocrine and rheumatologic work up gave no finding. The patient had respiratory symptoms with a chest wall
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pain and the lung CT showed a diffuse reticulonodular infiltration. The lung and rib biopsy gave a characteristic nodular infiltration of LHC, the immunohistochemical staining CD1a was positive so confirming the diagnosis of LHC. However, the CD1a stain on the brain remained
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negative. Thus, the patient has been treated as a multisystemic LHC with Mycophenolate Mofetil (MMF) and got a good clinical response in a 10 year follow up. This case had been considered a multisystemic LHC, and the brain lesion had been considered a neurodegenerative inflammation without CD1a. In 2005 Grois et al. classified CNS LHC into three different types of lesions and concluded that CNS LHC lack features that are diagnostic at other organs, therefore they are usually CDa1 negative. CDa1 is mainly positive in pituitary CNS LHC.10 CNS LHS is accounting for 25% off all LCH and DI being the classic presentation but can also manifest itself as other endocrine deficiency. Pituitary LCH can be primary or “acquired“ as recent knowledge suggests that prolonged involvement of skull bones (excluding those in the vault) predisposes patients to the development of DI (5). In this study, patients with MS-LCH
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ACCEPTED MANUSCRIPT and "craniofacial involvement" – particularly those with involvement of the ‘‘ear,’’ ‘‘eye,’’ and the "oral" sites at diagnosis – carried a significantly increased risk to develop DI during their course.14. What makes our case almost exceptional is that it was unilateral, parenchymal, with no pituitary involvement and most of all the CD1a positivity meant that the true active LHC was primarily (and only) in the brain. Because of mimicking a GBM we think that it is the first and only CNS
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LHC operated and removed so far. After retrospection, we can fairly ask the question if surgical removal was a good option. The accessible lesion and the suspicion of a GBM in a young adult gave us little room for other alternatives and allowed us to reach a surprising diagnosis. This diagnosis was suspected by the clinical silent nodules in both lung apices discovered
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incidentally, and to which we wrongly paid no attention. This is the other particularity of our case. The patient had two organs, lung and brain, with LHC but only the CNS LHC was active. Therefore, we had to decide during the neuro-oncology tumor board that the patient had ‘two’
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single focal organ with LHC, one inactive and one active, so we had to assume that they were independent one from the other and we took the decision to treat the CNS LHC has a single organ involvement. We do not think there was any other case of LHC reported with that presentation.
The next challenge we faced was how to treat our patient. For the silent incidental lung nodules, suggestive of focal lung LHC (former Histiocytosis X) the only treatment was straight forward
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consisting of stop smoking.15 The difficulty was for the unusual CNS LHC presentation. Because our patient had no extraaxial (skull or meninges) involvement he would not benefit from bone curettage, or local steroids instillation or dura removal.16 Intralesional instillation of steroids in limited bone lesions is safe and effective.17
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Therapeutic approaches to CNS LHC are poorly standardized, because of the historical uncertainty defining LCH as inflammatory versus neoplastic and incomplete understanding of mechanisms of pathogenesis.18 Our patient had a lack of Vm600E on the BRAF oncogene, so
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Vemurafenib (anti RAS) was not an option and we had not look up for mutation MP2K1.19 Because there was no hypothalamus pituitary region (HPR) involvement we did not wanted to start with the recommended first line Vinblastine/Prednisone for 6 weeks.20nor the salvage 2CDA21 or antimetabolites such as Cytosine(Ara-C), Cladribine or Cytarabine.22 Because the CNS LHC in our patient was not neurodegenerative nor multi systemic we renounced to start a heavy treatment combination with intravenous immunoglobulin, antimetabolite and transretinoic acid.23 Because the active CNS LHC had been almost completely removed and the fact that the patient was an adult one, we decided to use a small dose radiotherapy for a total radiation dose of 37.8 Gy, fractioned into 180 cGy/session. As there are evidences of pituitary LHC mass reduction with radiosurgery,24 we opted for radiotherapy because of the good results
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ACCEPTED MANUSCRIPT in small number of patients but with cranial extraaxial lesion (former Eosinophilic granuloma).25 The outcome after 3 months of fractioned sessions of radiotherapy was a radiological remission of the residual nodule on the last MRI, the patient remained asymptomatic without neurological deficit since the postoperative period. The more difficult aspect of the follow up came from the
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patient himself having a hard time to stop smoking.
CONCLUSION
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The clinical interest of our case came from the exceptional presentation of an already uncommon disease, a surgery performed because of the high suspicion of a high-grade glioma, and that the surprising diagnosis started with an incidental finding on a lung CT.
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The CDa1+ positivity on a brain tissue outside the pituitary has not been reported as far as we are aware. This could be the first CNS LHC removed surgically. The empirical treatment with low dose radiotherapy resulted effective. This case is so rare that it cannot be used as a guide and we probably will never see again a single intraparenchymal supratentorial CNS LHC in a neurosurgery ward, but we hope that it might help colleagues in the future with the thought
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process.
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ACCEPTED MANUSCRIPT REFERENCES
1. Yagci B, Varane A, Caglar M, et al. Langerhans cell histiocytosis: retrospective analysis of 217 cases in a single center. Pediatr Hematol Oncol 2008;25:399-408 2. Nicholson HS, Egler MR, Nesbit ME. The epidemiology of Langerhans cell histiocytosis. Hematol Oncol Clin North Am 1998:12:379-84.
assessment of 43 biopsies. Pediatr Pathol Lab Med 1997:17:769-87
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3. Favara BE, Steele A. Langerhans cell histiocytosis of lymph nodes: a morphological
4. Malpas JS, Norton AJ. Langerhans cell histiocytosis in adults. Med Pediatr Oncol 1996:26:540-6 5. Cheng-Wei Li, Man-Hui Li et al. Pulmonary Langerhans cell histiocytosis: analysis of 14
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patients and literature review. J Thorac Dis. 2016: 8: 1283-1289
6. Lampert F. et al. Langherhans Cell histiocytosis, Historical perspectives. Heamtol OncolClin NorthAm.1998;12(2):213-219 ]
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7. Haupt R, Minkov M. Langherhans Cell Histiocytosis (LHC): Guidelines for diagnosis. Clinical Work up and Treatment for Patients till the Age of 18 years. Pediatr Blood Cancer.2013 Feb; 60(2):175-84 8. Hoover KB, Rosenthal DI, Mankin H. Langerhans cell histiocytosis. Skeletal Radiol. 2007;36:95–104.doi: 10.1007/s00256-006-0193-2. PubMed PMID: 17028900 9.Safei et al. Langerhans cell histiocytosis followed by Hodgkin Lymphoma Iran J Med Sci. 2015 May; 40(3): 282–286
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10. Hund E, Steiner H Jansen O, et al. Treatment of cerebral Langerhans cell histiocytosis. J Neurol Sci 1999:171:145-52
11. Pardanani A, Phyliky RI, Li CY, Tefferi A. 2-Chlorodeoxyadenosisne therapy for disseminated Langerhans cell histiocytosis, Mayo ClinProc 2003:78:301-6
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12. F.Perren , L.Fankhauser, B.Thiévent, J-C Pache e al.Late adult onset of Langherhans cell histiocytosis mimicking glioblastoma multiforme. J Neurol Sci 2011:301:96-99
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13. Grois NG, Prayer D, Prosh H, Lassman H et al. LCH CNS Cooperative Group. Neuropathology of CNS disease in Langerhans cell histiocytosis. Brain 2005:128(Pt 4) :829-38 14.Grois N, Potschger U, Prosch H, Minkov M, Arico M, Braier J, et al. Risk factors for diabetes insipidus in langerhans cell histiocytosis. Pediatr Blood Cancer 2006;46(2):228-33. 15. Abdellatif Tazi, Constance de Margerie, Jean Marc Naccache, et al. The natural history of adult pulmonary Langerhans cell histiocytosis: a prospective multicenter study. Orphanet Journal of rare diseases 2015:10:30: 2-10 16. Woo Kl et al. Eosinophilic granuloma of the orbit-understanding the paradox of aggressive responsive to minimal intervention. Opthal Plast Reconstr Surg 2003;19:429-39 17. Egeler et al. Intralesional infiltration of corticosteroids in localized Langherhans cell histiocytosis-J Pediatr Orthop 1992;12:811-4
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ACCEPTED MANUSCRIPT 18. Carl E. Allen et al. How I treat Langherhans cell histiocytosis Blood 2015:125:26-34 19. Abla O , Weitzman S. Treatment of Langherhans cell histiocytosis: role of BRAF / MAPK inhibition Hematol Am Soc Educ Program 2015:2015:565-570 20.Grois N,Portscher U et al. Risks factor for diabetes insipidus I Langerhans cell histiocytosis. Pediatr Blood Cancer 2006;46:228-33
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21. Dall G, Finlay JL et al. Analysis of outcome for patient with mass lesions of the central nervous system due to Langherhans cell histiocytosis treated with 2-chlorodeoxyadenosine Pediatr Blood Cancer 2008:50:72-9 22. Simko et al. Clofarabine salvage therapy in refractory multi focal histiocytic disorders. Pediat Blood Cancer 2014:61:479-487
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23. Ibdaih A, et al. retinoic acid therapy in “degenerative like” neuro-Langherhans cell histiocytosis , a prospective pilot study Pediatr Blood Cancer 2004:43:55-8 24. Kotecha R, Venkatramani R, Jubran RF, et al. Clinical outcomes of radiation in the Langherhans cell histiocytosis Am J Clin Oncol 2014:37:592-596
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25. Kriz et al. Radiotherapy in Langherhans cell histiocytosis –a rare indication in a rare disease. Radiation Oncology 2013, 8:233-239
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ACCEPTED MANUSCRIPT FIGURES Figure 1. Head CT-Scan. A) No contrast head Ct shows right fronto-temporal edema with collapse of the ventricular temporal horn. B) With contrast, there is an intense enhancement of an irregular lesion in contact with M3 branches and left side mid line shift. Figure 2. Cerebral MRI with contrast: right insular lobe neoplastic lesion with significant
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vasogenic perilesional edema causing right side uncal herniation. The lesion suggests a primary neoplasia such as a glioblastoma multiforme or a unique localized metastasis.
Figure 3. Cerebral MRI-FLAIR and T2 sequences on A) axial, and B) coronal views. Note the
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significant vasogenic edema from the insula spreading to the frontal and temporal lobes.
Figure 4. Total body CT scan. The thoracic CT shows multiple nodules (blue arrows) on both
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apices. Compatible with granulomas of LHC.
Figure 5. A) Right side pterional craniotomy. B) Transcortical Insular opening after a distal to proximal Sylvian fissure dissection. C) No 5-ALA fluorescence seen under exposure to a 405 nm-wavelength blue light. D) Hard consistency tumor difficult to remove with an ultrasonic surgical aspirator firmly adherent to M3 branches.
Figure 6. Post-operative cerebral MRI. A) Axial view shows a right side nodular residual tumor
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adherent to M3 branch of MCA (blue arrows). B) The same nodule on a sagittal, and C) coronal
Figure 7. Definitive pathology of the brain tumor lesion. A) Cerebral parenchyma with
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abundant lymphocytic inflammation process. B) Perivascular lymphocytic infiltration. C)Cluster of histiocytes and eosinophils D) Immunohistochemical stain reveals positivity for CD1a giving
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the ultimate and definite diagnosis of histiocytosis of Langerhans. No mV600E on oncogene BRAF.
Figure 8. Cerebral MRI post 3 months of radiotherapy showing complete remission of the residual tumor. A) Coronal T1-Gadolinium. B) Axial T1-Gadolinium. C) Coronal T2 weighted image. D) Axial T2 weighted image.
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ACCEPTED MANUSCRIPT Table 1. Characterization and comparison between 2 similar case reports
Late adult onset of LHC mimicking glioblastoma multiforme. (1)
A very rare case of right insular lobe LHC (CD1a+) mimicking glioblastoma in a young adult. (2)
Variables
Late adult onset of LHC mimicking glioblastoma multiforme. (1)
A very rare case of right insular lobe LHC (CD1a+) mimicking glioblastoma in a young adult. (2)
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Sex
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Left side mild weakness, dysmetria and central facial paresis
LCH stratification
CNS LCH localization
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MS-LHC RO-(3)
And paresthesia.
SS-LHC RO-(4)
Right insular lobe
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Right thalamus
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Headache, left side upper extremity paresis
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Clinical presentation
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Age
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Variables
First diagnosis
“pseudotumoral” multiple sclerosis
Intraparenchymal CNS LCH
CD1a and S-100 negative
CD1a and S-100 positive
Bilateral active upper lung lesions new osteolytic ribs lesions
Asymptomatic upper lungs nodules
CNS lesion Immunostaining
Other organs involved
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Surgical procedure
Medical treatment
Steroids Mofetil Micophenolate MMF
Craniotomy and tumor removal
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Stereotactic biopsy
Fractioned radiotherapy for a total of 37Gy
Outcome
remnant disappearance
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Symptoms free for over ten years
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Asymptomatic and radiological
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(1) F.Perren , L.Fankhauser, B.Thiévent, J-C Pache e al.Late adult onset of Langherhans cell histiocytosis mimicking glioblastoma multiforme. J Neurol Sci 2011:301:96-99 (2) Current paper Bärtschi et al. (3) Multisystemic Langerhans cell Histiocytosis without risk organ (4) Single system Langherhans cell Histiocytosis without risk organ
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HIGHLIGHTS
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Langerhans cell Histiocytosis (LCH) is a rare heterogeneous disease characterized by an accumulation of dendritic cells in various organs The central nervous system (CNS) involvement excluding the pituitary is extremely uncommon
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A rare intraparenchymal radiological presentation may be misinterpreted as a high-grade glioma
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A multispecialty approach should be mandatory when suspecting a CNS LGH
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Abbreviations list LCH. - Langerhans cell histiocytosis CNS. - Central nervous system 5-ALA. - 5-Aminolevulinic acid
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DI. - Diabetes insipidus GBM. - Glioblastoma multiforme MCA. - Middle cerebral artery
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MFM. - Mycophenolate Mofetil