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NI FEATURE: PATHOLOGY PANORAMA - COMMENTARY
Year : 2016  |  Volume : 64  |  Issue : 4  |  Page : 737-741

Glioblastoma multiforme masquerading as a tumefactive demyelinating lesion: Lessons learned at autopsy


1 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
2 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
3 Department of Radiodiagnosis, Postgraduate Institute of Medical Education and Research, Chandigarh, India
4 Department of Neurosurgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
5 Department of Internal Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Date of Web Publication5-Jul-2016

Correspondence Address:
Dr. Kirti Gupta
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.185351

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 » Abstract 

Tumefactive demyelinating (TD) lesions are extremely challenging lesions to diagnose during their histopathological examination and are often misdiagnosed as tumors. On the contrary, a glioblastoma multiforme is rarely misdiagnosed as a TD unless the two coexist. We present a case of a 60-year old man who was diagnosed as having tumefactive demyelination on a stereotactic biopsy. At autopsy, however, the lesion revealed a grade IV glioblastoma. The myelin loss along the periphery of the lesion was erroneously interpreted as TD during the histopathological examination. We have described the imaging, the biopsy, and the autopsy findings of this instructive case. It is pertinent to recognize its histology to prevent a misdiagnosis.


Keywords: Glioblastoma multiforme; pitfalls; tumefactive demyelination


How to cite this article:
Gupta K, Mehta S, Ahuja CK, Salunke P, Sharma N. Glioblastoma multiforme masquerading as a tumefactive demyelinating lesion: Lessons learned at autopsy. Neurol India 2016;64:737-41

How to cite this URL:
Gupta K, Mehta S, Ahuja CK, Salunke P, Sharma N. Glioblastoma multiforme masquerading as a tumefactive demyelinating lesion: Lessons learned at autopsy. Neurol India [serial online] 2016 [cited 2019 Nov 18];64:737-41. Available from: http://www.neurologyindia.com/text.asp?2016/64/4/737/185351



 » Clinical Findings Top


A 60-year-old man presented with a one month history of holocranial headache, which at times was severe enough to disturb his sleep. It was not associated with vomiting or transient visual obscuration. He developed difficulty in appreciating objects on the left side and would occasionally bump into them. He also had difficulty in dressing. This gradually progressed to development of weakness of left side of the body over the following month. There was no associated speech disturbance, diplopia, facial deviation, history of altered sensorium, or any other cranial nerve involvement. On neurological examination, he was conscious, oriented to time, place, and person. His mini-mental status examination score was 29/30, the missing point being due to his inability to perform construction of images. The detailed higher mental function confirmed the presence of constructional apraxia with the presence of left hemineglect. All cranial nerves were normal except for the presence of bilateral papilledema. Motor system examination revealed left hemiparesis, and the deep tendon reflexes were brisk on the left side with left plantar reflex showing an extensor response. Examination of the ocular fundus disclosed papilledema. A review of the other systems did not reveal any abnormality.

Investigations revealed a normal hemogram. Renal and liver function tests were within normal limits. The cerebrospinal fluid analysis showed mildly elevated proteins (65 mg%) and a normal sugar (79 mg%) value. No malignant cells were detected on the cytological examination.

A contrast-enhanced magnetic resonance imaging (CEMRI) of the brain performed at this time revealed a focal lesion in the right temporoparietal region showing a thick peripheral contrast enhancement with central necrosis and moderate perilesional edema resulting in adjoining mass effect [Figure 1]a and [Figure 1]b. On magnetic resonance spectroscopy, a reduced N-acetyl aspartate with mildly elevated choline and a tall lipid-lactate peak were evident [Figure 1]c. With a radiological possibility of a neoplastic (high-grade glioma/lymphoma) lesion and a differential of tumefactive demyelination, a contrast-enhanced computed tomography (CECT) of the chest and abdomen were done which were normal. The positron emission tomography scan revealed fluorodeoxyglucose non-avid hypodense lesion in the right parietotemporal region. A stereotactic biopsy from the lesion was performed, which revealed few linear cores of cortical tissue admixed with hemorrhage, and a cellular fragment chiefly composed of macrophages (highlighted by immunohistochemistry with CD68 antibody) and reactive astrocytes (highlighted with glial fibrillary acidic protein [GFAP]) in a fine neurofibrillary background [Figure 2]a,[Figure 2]b,[Figure 2]c,[Figure 2]d,[Figure 2]e. Few mitotic figures were identified as well. These macrophages were filled with breakdown products of myelin, as demonstrated with Luxol fast blue/periodic acid-Schiff's (LFB-PAS) stain [Figure 2]f. The biopsy was interpreted as tumefactive demyelination.
Figure 1: Axial T2 (a) and contrast-enhanced T1-weighted (b) magnetic resonance images show the presence of a peripherally enhancing right temporoparietal lesion having moderate perilesional edema. (c) Magnetic resonance spectroscopy from the center of the lesion reveals mildly elevated choline (arrow) with a tall lipid-lactate peak (arrowhead)

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Figure 2: (a) Scattered macrophages present within the stereotactic biopsy (H and E, ×400). (b) Clusters of astrocytes admixed with the macrophages (H and E, ×200); (c) High magnification depicting the astrocytes that were interpreted as being reactive in nature (H and E, ×1000); (d) Macrophages highlighted by CD68 stain (anti-CD68, ×200); (e) Astrocytes highlighted by glial fibrillary acidic protein immunoreactivity (anti-glial fibrillary acidic protein, ×400); (f) Luxol fast blue/periodic acid-Schiff's stain demonstrates myelin breakdown products filling up the cytoplasm of the macrophages, as seen in inset (arrow), (Luxol fast blue/periodic acid-Schiff's, ×400)

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With a diagnosis of tumefactive demyelination, he was started on intravenous methylprednisolone therapy followed by oral steroids. Over the next few days, there was a dramatic improvement in his condition, and he started walking without support and the hemineglect disappeared. He was discharged on oral steroids, which were tapered over the next 2 months. A repeat CEMRI imaging performed 1 month later revealed a significant decrease in mass effect, perilesional edema, and size of the lesion [Figure 3]a and [Figure 3]b.
Figure 3: Axial T2 (a) and contrast-enhanced T1 (b) weighted images following steroid therapy show the central lesion necrosis with marked reduction in the perilesional edema and mass effect

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Two months later, he presented with fever and cough of 2 week duration that was followed by generalized tonic-clonic seizures and altered consciousness. Over the next 2 days, his clinical condition deteriorated rapidly with the development of acute respiratory failure and shock. A chest CECT scan showed bilateral ground-glass opacities with left upper zone consolidation with evidence of pulmonary embolism. Keeping in view his steroid-induced immunocompromised status, he was started on parenteral piperacillin-tazobactam, vancomycin, amphotericin-B, and heparin was added to prevent the development of pulmonary embolism. Multi-organ failure soon set in and he succumbed to his illness.


 » Pathology Findings Top


A complete autopsy was performed. At autopsy, the brain weighed 1370 g. There were no exudates or hemorrhage within the subarachnoid space. The right cerebral hemisphere was slightly swollen; however, there was no significant uncal or cerebellar tonsillar herniation. On coronal slicing, a large lesion was identified affecting the central white matter (WM) of right temporo-parietal and occipital lobes [Figure 4]a and [Figure 4]b. The overlying cortex was spared. The lesion measured 10 cm antero-posteriorly. Medially, it was extending to the lateral ventricle at the trigonal level and involved the splenium of the corpus callosum [Figure 4]a. In major portions, it showed areas of necrosis with a soft consistency and yellowish discoloration [Figure 4]b. At the periphery, the site of biopsy was seen, well-walled off with brownish to yellowish discoloration [Figure 4]c. On microscopy, the tumor demonstrated features of a high-grade astrocytic tumor with moderate to marked pleomorphism [Figure 4]d and [Figure 4]e. Many tumor giant cells were seen. Mitotic figures were readily identified. Areas of necrosis were noted as well. The tumor was infiltrating the adjacent subcortical region, which at places showed pallor. The gray matter was spared in almost all the sections. GFAP was strongly positive within the tumor cells [Figure 4]f. Collection of numerous hemosiderin pigment-laden macrophages and necrosis were seen at the site of biopsy [Figure 4]g. The periphery of the lesion predominantly demonstrated pallor of the subcortical WM with edema and focal myelin loss [Figure 5]a, [Figure 5]b, [Figure 5]c. The tumor was classified as a glioblastoma; grade IV (WHO classification 2007).
Figure 4: (a and b) Large grayish-white necrotic lesion identified in the right parietal and occipital lobes with sparing of the overlying cortex. Medially, the lesion is extending to the splenium of the corpus callosum (arrow). (c) Site of the biopsy identified at the periphery of the lesion as a walled-off area of brownish discoloration. (d) Neoplastic cells dispersed in the fine fibrillary background with moderate to marked nuclear atypia (H and E, ×100). (e) High magnification demonstrating tumor giant cells. Mitotic figures are also seen (H and E, ×400). (f) Glial fibrillary acidic protein positivity within the tumor cells (anti-glial fibrillary acidic protein, ×400). (g) Abundant hemosiderin-laden macrophages present at the biopsy site (H and E, ×200)

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Figure 5: (a) Low magnification image of the section depicting pallor in the subcortical region adjacent to the tumor (Luxol fast blue/periodic acid-Schiff's stain, ×40). (b and c) Pallor due to edema in the subcortical region highlighted with Luxol fast blue/periodic acid-Schiff's stain (Luxol fast blue/periodic acid-Schiff's ×100, ×200). (d) Abscess cavities in the lungs invaded by the Aspergillus hyphae (H and E, ×100). (e) Slender, septate Aspergillus hyphae highlighted by periodic acid-Schiff's stain (periodic acid-Schiff's, ×400)

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Both lungs revealed multiple abscess cavities ranging from 6 cm × 5 cm × 4 cm to small 0.5 cm, randomly distributed in both lobes. On histology, there was extensive, organizing bronchopneumonia with abscess cavities colonized and invaded by fungal hyphae belonging to the Aspergillus group [Figure 5]d and [Figure 5]e. At the periphery of these abscess cavities, many vessels showed thrombi and infection-associated vasculitis with infarction of the adjacent tissue.


 » Discussion Top


Demyelinating disorders including variants of multiple sclerosis (Balo's concentric type and Marburg's type) or acute disseminated encephalomyelitis may sometimes present as large tumefactive lesions and simulate brain tumors on imaging.[1] Termed as tumefactive demyelinating (TD) lesions, they are usually solitary lesions, greater than 2 cm, and have distinctive features on imaging.[2],[3],[4] They are also referred to as demyelinating pseudotumors.[2] These lesions are frequently mistaken for tumors both at radiology and histology.[5],[6],[7] An analysis of 168 cases of TD in a two-center study, reported a 31% rate of misdiagnosis by the pathologists.[8] While a low-grade astrocytoma is the most common entity misdiagnosed as TD amounting to 39% in this study, other lesions included a nondiagnostic biopsy (18%), a high-grade astrocytoma (15%), an oligodendroglioma, or an area of infarction or infection, and rarely a lymphoma. On histology, TD is characterized by a sharp demarcation of the demyelinating lesion from the surrounding intact WM. This demarcation is well-highlighted on the (Luxol fast blue-Periodic acid Schiff) LFB-PAS stain. Numerous macrophages, many of which filled with myelin breakdown products, populate the lesion. There are interspersed reactive multipolar astrocytes with variable nuclear atypia that are termed as Creutzfeldt astrocytes.[6],[9] They may have micronucleoli. Occasional mitotic figures, and in some instances, focal necrosis, may be seen. Perivascular lymphocytic cuffing is also an important histological finding; however, this should not be mistaken for cuffing as seen in a primary central nervous system lymphoma.[5],[6] Neurofilament protein shows the axons to be largely intact. The LFB-PAS stain highlights the myelin breakdown products within the foamy macrophages, which are visualized as blue granules. Immunostains helpful in characterizing the lesion are GFAP and CD68, highlighting the reactive astrocytes and macrophages, respectively. The distinction of low-grade astrocytomas from TD is mainly aided by their infiltrative nature with perineuronal and perivascular satellitosis, the presence of nuclear atypia, and lack of macrophages and lymphocytes.[6],[10] Nuclear atypia, mitoses, secondary structures of Sherer, glomerular endothelial proliferation, and palisading necrosis are features helpful in differentiating a high-grade astrocytoma from TD. Neoplastic cells in oligodendrogliomas have clear rather than vacuolated cytoplasm and again the infiltrative nature with secondary structures and cortical involvement are features that favor a neoplasm. Differentiation is critical as the management of TD lesions is largely different from the commonly encountered neoplastic lesions and radiotherapy exacerbates the TD disease.[10]

On the contrary, a high-grade glioma is rarely misdiagnosed as a TD lesion unless the two lesions coexist.[11] In our patient, the initial favorable response to steroids further strengthened the clinico-radiological possibility of a TD. However, on review, the imaging findings of a thick peripheral enhancement, central necrosis, markedly elevated lipids in the center of the lesion, and moderate perilesional edema [12] strongly favored a neoplastic lesion. Importantly, the amount of tissue on a stereotactic biopsy is always a limiting factor for a precise diagnosis. Correlation of the clinical presentation, as well as the imaging and morphological features cannot be understated. The nuclear atypia and the presence of mitotic figures should always be interpreted in the light of imageological findings. Unfortunately, the biopsy picked up the tissue from the periphery of the lesion wherein the edema in the subcortical region adjoining the tumor was misinterpreted as a TD lesion. The site of biopsy is of paramount importance in the accurate diagnosis of any entity, but more particularly for TD lesions. The imaging, especially CEMRI plays an important role here, as apart from giving a probable diagnosis of the lesion, it helps in choosing the most appropriate site for planning a biopsy. The ideal biopsy would consist of cores from multiple sites, especially the enhancing solid component of the lesion. In a suspicious malignant lesion, a biopsy from both the centre and the periphery of the lesion is critical for an accurate diagnosis and minimizes the chances of misdiagnosis. Furthermore, correlation of the clinical features with the imaging findings helps to minimize misinterpretation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
 » References Top

1.
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. 1
    
2.
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. 2
    
3.
McAdam LC, Blaser SI, Banwell BL. Pediatric tumefactive demyelination: Case series and review of the literature. Pediatr Neurol 2002;26:18-25.  Back to cited text no. 3
    
4.
Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology 1996;38:560-5.  Back to cited text no. 4
    
5.
Salunke P, Aggarwal A, Gupta K, Agrawal P, Ahuja CK, Vasishta RK. Large demyelinating lesions: A neurosurgical perspective. Br J Neurosurg 2012;26:490-8.  Back to cited text no. 5
    
6.
Zagzag D, Miller DC, Kleinman GM, Abati A, Donnenfeld H, Budzilovich GN. Demyelinating disease versus tumour in surgical neuropathology. Clues to a correct pathological diagnosis. Am J Surg Pathol 1993;17:537-45.  Back to cited text no. 6
    
7.
Gavra M, Boviatsis E, Stavrinou LC, Sakas D. Pitfalls in the diagnosis of a tumefactive demyelinating lesion: A case report. J Med Case Rep 2011;5:217.  Back to cited text no. 7
    
8.
Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S, et al. Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain 2008;131(Pt 7):1759-75.  Back to cited text no. 8
    
9.
Erana-Rojas IE, Barboza-Quintana A, Ayala AG, Fuller GN. Demyelinating pseudotumour. Ann Diagn Pathol2002;6:265-71.  Back to cited text no. 9
    
10.
Donev K, Scheithauer BW. Pseudoneoplasms of the nervous system. Arch Pathol Lab Med 2010;134:404-16.  Back to cited text no. 10
    
11.
Roemer SF, Scheithauer BW, Varnavas GG, Lucchinetti CF. Tumefactive demyelination and glioblastoma: A rare collision lesion. Clin Neuropathol 2011;30:186-91.  Back to cited text no. 11
    
12.
Colonnese C, Romanelli P. Advanced neuroimaging techniques in the management of glioblastoma multiforme. Curr Radiopharm 2012;5:300-7.  Back to cited text no. 12
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]



 

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