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Year : 2012  |  Volume : 55  |  Issue : 4  |  Page : 496-500
Tumefactive demyelinating lesions: A Clinicopathological correlative study


1 Department of Pathology, Sree Chitra Tirunal Institute of Medical sciences and Technology, Trivandrum, Kerala, India
2 Department of Neurosurgery, Sree Chitra Tirunal Institute of Medical sciences and Technology, Trivandrum, Kerala, India
3 Department of Neurology, Sree Chitra Tirunal Institute of Medical sciences and Technology, Trivandrum, Kerala, India
4 Department of Imaging sciences and Interventional Radiology, Sree Chitra Tirunal Institute of Medical sciences and Technology, Trivandrum, Kerala, India

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Date of Web Publication4-Mar-2013
 

   Abstract 

Tumefactive demyelinating (TDL) lesions are focal zones of demyelination in the central nervous system and they often mimic the neuroimaging features of an intraxial neoplasm. In this report we describe the clinical, neuroimaging and neuropathological features of six cases of TDL. Only in two patients the neuroimaging features in MRI (magnetic resonance imaging) scans were suggestive of TDL while in the other four cases a diagnosis of glioma was suggested. In order to establish a confirmatory diagnosis neuronavigation/stereotactic biopsy was undertaken and the diagnosis of TDL was established in all six cases at histopathology. Two out of six patients did not respond to the conventional corticosteroid therapy and they were treated with plasma exchange. It is being concluded that neuronavigation biopsy, though provide only a small amount of tissue, and is extremely useful in making the diagnosis of TDL.

Keywords: Glioma, neuronavigation biopsy, tumefactive demyelination

How to cite this article:
Neelima R, Krishnakumar K, Nair M D, Kesavadas C, Hingwala DR, Radhakrishnan V V, Nair SS. Tumefactive demyelinating lesions: A Clinicopathological correlative study. Indian J Pathol Microbiol 2012;55:496-500

How to cite this URL:
Neelima R, Krishnakumar K, Nair M D, Kesavadas C, Hingwala DR, Radhakrishnan V V, Nair SS. Tumefactive demyelinating lesions: A Clinicopathological correlative study. Indian J Pathol Microbiol [serial online] 2012 [cited 2019 Jul 18];55:496-500. Available from: http://www.ijpmonline.org/text.asp?2012/55/4/496/107788



   Introduction Top


Primary demyelinating diseases of central nervous system (CNS) encompass several entities such as multiple sclerosis, myelinoclastic diffuse sclerosis and acute demyelinating encephalomyelitis (ADEM). [1] These lesions are synonymously termed as 'tumefactive demyelination (TDL), 'demyelinating pseudotumor', tumefactive multiple sclerosis, Tumor like demyelinating lesions, giant plaques in the literature. [1] At times a demyelinating disease can manifest as a solitary enhancing lesion in MRI scan resembling an intraaxial glial neoplasm and pose a diagnostic challenge to the clinician as well as the radiologist. A precise diagnosis of TDL is absolutely essential as the management modalities vary in TDL and gliomas. [1] In this study the salient microscopic features and potential histopathological pitfalls when diagnosing a case of TDL has been highlighted.


   Materials and Methods Top


In this retrospective study [January 2005 till Dec 2011], six patients with a histopathological diagnosis of TDL were selected. The clinical, neuroimaging and management modalities in these six cases are summarized in [Table 1]. A provisional diagnosis of an intra-axial neoplasm or abscess was given in each case. In order to arrive at a diagnosis neuronavigation/stereotactic biopsy was done in all the cases. Total decompression was done for recurrence of the lesion in one patient. The paraffin blocks of all these cases were retrieved from the archives of Pathology Department of our Institute. The formalin fixed paraffin sections were stained with hematoxylin and eosin, special stains such as Luxol fast blue, Bodian stain, periodic acid Schiff, modified Grocott and PTAH (phosphotungstic acid hematoxylin). For immunohistochemistry the slides were incubated for primary antibodies after antigen retrieval with heat: GFAP (1:100) and neurofilament protein (1:100) (Novocastra, Newcastle upon Tyne, UK).
Table 1: Clinical and imaging profiles in patients with TDL

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   Results Top


Clinical Features

Four out of the six patients were males in our study. The median age of onset of disease was 45 years with the youngest being a child of 12 years. Out of the six, four patients had presented with acute onset weakness. One patient had presented with diplopia and another patient with left sided hemianopia. There was no predisposing illness prior to the onset of symptoms except one case who had fever. Vasculitis workup done was negative in all these cases. As the clinical diagnosis was not certain in any of these patients, they were subjected to MRI imaging.

Neuroimaging Features

In all the six cases, lesions were confined to the supratentorial region. Two patients had presented with lesions at multiple sites. The lesions were hypointense on T1W [Figure 1]a and e images, hyperintense on T2W images, hypointense on FLAIR (Fluid attenuated inversion recovery) images [Figure 1]b and f and showed perifocal edema and mass effect. The lesions showed ring enhancement on contrast [Figure 1]c and g and hypoperfusion on rCBV (relative cerebral blood volume) studies [Figure 1]h. Two cases had cystic component on imaging. An imaging diagnosis of TDL was offered in two cases only whereas in other cases a possibility of TDL was considered and could not be differentiated from a glial neoplasm.Almost all the cases showed partial/complete improvement after treatment in spite of recurrence in three cases. This was clearly demonstrated by repeat imaging studies [Figure 1]d.
Figure 1: (a) shows hypointense lesions in left fronto-parietal and right parietal lobes on T1W image. (b) On FLAIR axial image centre shows suppression of signal. Perilesional vasogenic edema seen. (c) Characteristic 'broken ring' of contrast enhancement seen. (d) Follow-up FLAIR image after treatment with steroids shows decrease in size of the lesionsSecond case (e) T1W and (f) FLAIR axial images showing a hypointense lesion in the right peritrigonal white matter with surrounding vasogenic edema, (g) Peripheral contrast enhancement and (h) Hypoperfusion on Dynamic T2* perfusion rCBV map

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Cytological and Histopathological Findings

Four out of the six cases were diagnosed as glioma during intraoperative squash-cytological examination. These cases showed of perivascular lymphocytic infiltrate [Figure 2]a and abundant foamy macrophages [Figure 2]b in sheets in smears without necrosis. Few reactive astrocytes with nuclear atypia were seen which were mistaken for tumour cells. Only in two cases a differential diagnosis of TDL was offered where the astrocytes did show any nuclear pleomorphism.
Figure 2: (a) squash smear cytology showing perivascular lymphocytic infiltrate and (b) collection of foamy macrophages. Photomicrograph showing perivascular (c and d-left) as well as diffuse parenchymal lymphocytic infiltrate (c) and sheets of macrophages (d-right). The macrophages showed ingested myelin breakdown products (e and inset) (Toluidine blue: a, bx400) (Hematoxylin and eosin: c×200: dx400) (Luxol Fast Blue-Hematoxylin eosin: ex400 and inset)

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Hematoxylin and eosin stained paraffin sections in all six cases showed dense infiltration by foamy macrophages, intense perivascular lymphocytic infiltration [Figure 2]c and d and reactive gliosis. The cytoplasm of macrophages contained ingested myelin breakdown products, which were well illustrated in Luxol fast blue stain [Figure 2]e. Preserved axonal fibres were demonstrated by Bodian stain [[Figure 3]b-left] as well as positive immunostaining for neurofilament protein [[Figure 3]b-right] ruling out the possibility of an infarct. Evenly spaced, preserved reactive gemistocytes and well preserved fibrillary processes amongst the macrophages were demonstrated by immunostaining for GFAP [Figure 3]a. Fungal stains were negative and PTAH stain did not show any fibrinoid vessel wall destruction supporting evidence of vasculitis. A diagnosis of TDL was made based on the above histomorphological findings. The histopathological and other relevant laboratory findings are given in [Table 2].
Figure 3: (a) Photomicrograph showing reactive astrocytes and preserved gliofibrillary processes positive for GFAP and preserved neuronal fibres by Bodian stain (b-left) and Neurofilament immunohistochemistry (b-right) [Bodian: bx400; Avidin-Biotin Complex: a, bx400]

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Table 2: Laboratory and Pathological findings in patients of TDL

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   Discussion Top


The term Tumefactive demyelinating lesion (TDL) was first introduced by Kepes et al. in 1993. [2] The incidence of TDL has been reported to be 0.3 cases per 100,000 per year. [3] Approximately 15 cases have been documented from the Indian subcontinent. [4],[5],[6],[7] They occur more frequently in females especially during the second or third decade of life. [8] The clinical features in most of the patients with TDL are non-specific. However the most common presentation is the acute onset of weakness with periods of exacerbation and remission.

TDL are more often misdiagnosed. [1],[15] 4 out of 6 cases in our study were diagnosed to have intracranial glial neoplasm clinically. In MRI scan, TDL appears as a lesion with ill-defined margins, variable degree of perilesional edema, mass effect, central zones of necrosis and cystic degeneration. These neuroimaging features mimic closely with that of glial neoplasm or even a chronic abscess. [1] This misdiagnosis can lead to inadvertent surgery or radiotherapy. [7],[15] However there are some neuroimaging features which could distinguish TDL from gliomas. These include incomplete ring enhancement, location in the subcortical hemispheric white matter, relative lack of mass effect, perifocal edema, [9] perfusion studies showing decreased cRBV, increased diffusion coefficients and MR spectroscopic metabolic information can also be helpful. [10],[11],[12] Distinct elevation of glutamic glutamate can be to the diagnosis of TDL because elevation of glutamic glutamate is seldom seen in gliomas. [13] Evoked potentials and elevated CSF gamma globulin levels with oligoclonal bands can only be used as supplementary diagnostic tools as seen in our study. [14]

In most of the cases of TDL, either neuronavigation or stereotactic biopsy are undertaken to arrive at a tissue diagnosis. The target of biopsy should always be the wall of the lesion, unlike in tumours where the central core of the lesion is more important. A small hypointense region in the wall of the ring region, which is the margin between remyelination and demyelination, is the ideal site for biopsy in these cases according to our experience. Hence even a slight variation in the site of biopsy within the same lesion can cause an erroneous diagnosis in histopathology.

Intraoperative squash preparations from TDL may be helpful in the identification of cell type. [15] Foamy macrophage clusters with lymphocytic infiltrate if abundantly seen in the squash smears and should always arouse a suspicion of TDL. But they can be deceptive and extremely difficult to interpret as seen in our study. Similar findings can be seen in inflammatory lesions, high-grade gliomas or metastasis if samples are collected from the cystic or necrotic regions. The macrophages in smears can be mistaken for oligodendroglial or carcinomatous cells. Hence histopathological examination is definitely essential for the confirmation of TDL. The characteristic histopathological feature is the presence of foamy macrophages, reactive gliosis and perivascular lymphocytic infiltrate. [1] Many lesions in biopsy can resemble the features of TDL. Hypercellularity, reactive creutzfeldt astrocytes, occasional mitotic Figures and focal necrosis seen in TDL, can be easily mistaken for a glioma. Extensive perivascular lymphocytic infiltrates in TDL may mimic a primary CNS lymphoma. Similarly a cerebral infarct can also show perivascular inflammatory infiltrate, necrosis and foamy macrophage collections. Another lesion that closely resembles TDL is progressive multifocal leukoencephalopathy (PML)characterized by demyelinating lesions of different sizes, with necrotic areas at the centre of the lesion both affecting predominantly the white matter. [15] Rarely infections and vasculitis with infarcts can also mimic TDL as both can have perivascular inflammatory infiltrate.

These diagnostic difficulties can be overcome by close histological examination and the judicious application of special stains. The sharp demarcation of TDL from the surrounding intact white matter can be well demonstrated with myelin stains (Luxol fast blue). The myelin breakdown products are seen within foamy macrophages and appear as blue granules. However this can be seen occasionally in cases of infarct which can be misleading. Silver stains and immunostaining for neurofilament protein demarcate the intact axonal processes amongst the macrophages in TDL. In infarct axons as well as glial fibres will be absent in the necrotic zones and foci with macrophage collections. Necrosis is extremely rare in TDL. Bizarre giant astrocytes and oligodendrocytes showing enlarged hyperchromatic nuclei and Cowdry's inclusion bodies help in distinguishing PML from TDL. Characteristic hyperchromatic nuclear morphology, the uneven pattern of distribution of neoplastic astrocytes, atypical mitotic figures, necrosis and endothelial proliferation can distinguish gliomas from TDL. [15] PTAH stain can demonstrate vessel walls with fibrinoid necrosis which is specific for vasculitis whereas in TDL the vessel walls will be intact. Similarly Grams stain, special stains for fungi can rule out any infectious etiology. However a biopsy study alone can be misleading. All the histological findings should be correlated with clinical, imaging, microbiology culture and relevant laboratory studies to arrive at a diagnosis of TDL.

Most patients with TDLs do respond to steroid therapy. [2] However response to steroids is suboptimal if there is association of TDL with multiple sclerosis. [1] Steroid nonresponsive patients can be treated with intravenous immunoglobulin, plasma exchange or immunosuppressive therapy. [16] In spite of all these very rarely TDL do manifest a progressively deteriorating course as seen in our study.The optimal therapeutic approach to TDLs seems yet to be standardized.


   Conclusion Top


An accurate diagnosis of TDL is extremely challenging. Early treatment of these patients would promote a dramatic complete clinical recovery. The neurologist, neurosurgeon and neuropathologist should be familiar with of this non-neoplastic entity and must consider this entity in the differential diagnosis of a solitary space-occupying lesion. Stereotaactic biopsy, though provide only a small amount of tissue, is adequate in diagnosing TDL. Imaging features, laboratory findings, and prompt response to steroid as well as immunosupressive therapy in conjunction with the histology gives a clue to diagnosis in a particular patient.


   Acknowledgments Top


We express our sincere gratitude to the Director of our institute for giving us permission to publish this article. We are also grateful to all our laboratory staff for their expert technical support.

 
   References Top

1.Xia L, Lin S, Wang ZC, Li SW, Xu L, Wu J, et al. Tumefactive demyelinating lesions: Nine cases and a review of the literature. Neurosurg Rev 2009;32:171-9.  Back to cited text no. 1
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2.Kepes JJ. Large focal tumor-like demyelinating lesions of the brain: Intermediate entity between multiple sclerosis and acute disseminated encephalomyelitis? A study of 31 patients. Ann Neurol 1993;33:18-27.  Back to cited text no. 2
    
3.Ragel BT, Fassett DR, Baringer JR, Browd SR, Dailey AT. Decompressive hemicraniectomy for tumefactive demyelination with transtentorial herniation: Observation. Surg Neurol 2006;65:582-3.  Back to cited text no. 3
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4.Puri V, Chaudhry N, Gulati P, Tatke M, Singh D. Recurrent tumefactive demyelination in a child. J Clin Neurosci 2005;12:495-500.  Back to cited text no. 4
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5.Jain D, Rajesh LS, Vasishta RK, Radotra BD, Banerjee AK. Demyelinating disease simulating brain tumours: A histopathologic assessment of seven cases. Indian J Med Sci 2006;60:47-52.  Back to cited text no. 5
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6.Malhotra HS, Jain KK, Agarwal A, Singh MK, Yadav SK, Husain M, et al. Characterization of tumefactive demyelinating lesions using MR imaging and in- vivo proton MR spectroscopy. Mult Scler 2009;15:193-203.  Back to cited text no. 6
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7.Sinha MK, Garg RK, Bhatt M, Chandra A. Tumefactive demyelinating lesion: Experience with two unusual patients J Postgrad Med 2010;56:146-9.  Back to cited text no. 7
    
8.Comi G. Multiple sclerosis: Pseudotumoral forms. Neurol Sci 2004;25:374-9.  Back to cited text no. 8
    
9.Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology 1996;38:560-5.  Back to cited text no. 9
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10.Cha S, Pierce S, Knopp EA, Johnson G, Yang C, Ton A, et al. Dynamic contrast-enhanced T2*-weighted MR imaging of tumefactive demyelinating lesions. Am J Neuroradiol 2001;22:1109-16.  Back to cited text no. 10
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11.Ernst T, Chang L, Walot I, Huff K. Physiologic MRI of a tumefactive multiple sclerosis lesion. Neurology 1998;51:1486-88.  Back to cited text no. 11
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12.Given CA, Stevens BS, Lee C. The MRI appearance of tumefactive demyelinating lesions. Am J Roentgenol 2004;182:195-99.  Back to cited text no. 12
    
13.Cianfoni A, Niku S, Imbesi SG. Metabolite findings in tumefactive demyelinating lesions utilizing short echo time proton magnetic resonance spectroscopy. Am J Neuroradiol 2007;28:272-7.  Back to cited text no. 13
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14.Miller A. Diagnosis of multiple sclerosis. Semin Neurol 1998;18:309-16.  Back to cited text no. 14
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15.Donev K, Schiethauer B W. Pseudoneoplasms of the nervous system.Arch Pathol Lab Med 2010;134:404-16.  Back to cited text no. 15
    
16.Mao-draayer Y, Braff S, Pendlebury W, Panitch H. Treatment of steroid unresponsive tumefactive demyelinating disease with plasma exchange. Neurology 2002;59:1074-7.  Back to cited text no. 16
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Correspondence Address:
V V Radhakrishnan
Department of Pathology, Sree Chitra Tirunal Institute of Medical sciences and Technology, Medical college P O, Trivandrum, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0377-4929.107788

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