- Email: [email protected]
Astrocytoma-like multiple sclerosis
Clinical Neurology and Neurosurgery 107 (2005) 152–157
Case report
Astrocytoma-like multiple sclerosis E.E. Pakosa,∗ , P.G. Tsekerisa , K. Chatzidimoub , A.C. Goussiac , S. Markoulab , M.I. Argyropouloud , E.G. Pitoulia , S. Konitsiotisb a
Department of Radiation Therapy, School of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina 45500, Greece b Department of Neurology, School of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina 45500, Greece c Department of Pathology, School of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina 45500, Greece d Department of Radiology, University Hospital of Ioannina, University of Ioannina, School of Medicine, Ioannina 45500, Greece Received 11 November 2003; received in revised form 26 April 2004; accepted 2 June 2004
Abstract Multiple sclerosis (MS) may sometimes mimic clinically and radiologically a brain tumor. The initial recognition of such cases is essential as it might avoid a surgical intervention and supplementary treatment. However, even in patients who underwent surgery, the appropriate preparation of the specimen is of crucial importance for the correct pathological diagnosis since tumors and non-neoplastic demyelinating lesions share some common histopathological features. We present such a case of multiple sclerosis presenting with features of an astrocytoma and was treated with surgery and additional radiotherapy. © 2002 Elsevier B.V. All rights reserved. Keywords: Astrocytoma; Multiple sclerosis; Tumor; Radiotherapy
1. Introduction Multiple sclerosis (MS) is one of the most common diseases of the central nervous system showing a variety in its clinical and radiological presentations. The diagnosis is mainly based on the clinical course and supported by CSF protein electrophoresis, IgG banding and magnetic resonance imaging (MRI) findings. However, no specific diagnostic laboratory test is yet found. Several cases have been reported of demyelinating processes mimicking a mass lesion indistinguishable from a tumor of the central nervous system [1–4]. A biopsy of the tumor-like demyelinating area and histological examination of the specimen seems necessary to differentiate multiple sclerosis from a brain tumor, although sometimes even biopsy material may be misinterpreted [5–7].
∗ Corresponding author. Tel.: +30 2 6510 44589; Mobile: 306972772961; fax: +30 26510 97853. E-mail address: [email protected] (E.E. Pakos).
0303-8467/$ – see front matter © 2002 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2004.06.003
The initial recognition of these demyelinating tumor-like lesions is essential, to spare an unnecessary brain biopsy or even a neurosurgical intervention and/or supplementary therapy (radiotherapy or chemotherapy). We report a case of multiple sclerosis mimicking an astrocytoma. 2. Case report A 51-year old right-handed female was admitted to the Neurological Department of the University Hospital of Ioannina in the summer of 1996 with aphasia and behavior problems. These symptoms were present in a mild form for at least one year prior to the clear onset of her problems. There was no history of virus infection or vaccination. CT scan of the brain revealed a mass in the left frontal lobe. A subsequent brain MRI (Fig. 1) demonstrated a frontal lesion measuring 2 cm × 3 cm × 5.5 cm without mass effect. The lesion presented with a high signal on T2 and flair weighted images and with low signal on plain T1 weighted images. An incomplete peripheral ring enhancement was observed after intravenous
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
153
Fig. 1. Brain MRI on July 1996 showing an enhancing lesion at the left frontal lobe.
(iv) gadolinium Gd-DTPA. No other lesions were noted on that scan. The patient was operated in July 1996 and the lesion was partially removed. Histological evaluation showed a neoplastic lesion consisting of astrocytes with minimal degree of anaplasia. The final diagnosis was low-grade astrocytoma (WHO grade II [8]). On August 1996 she started postoperative external beam radiation therapy with two parallelopposed fields (anterior and posterior). The tumor bed with a 3 cm margin was treated in each field. Radiotherapy was given in thirty fractions with a linear accelerator (6 MV). The daily dose was 2.0 Gy and the total dose was 60 Gy. The fields were reduced after 40 Gy (Shrinkage technique). She tolerated radiotherapy well, without interruption of her treatment due to side effects.
She was doing relatively well until November 1996 when her speech deteriorated again. A repeat MRI of the brain revealed a second non-enhancing lesion in the white matter of her right frontal lobe. She was treated with high doses of dexamethasone and her condition gradually improved. In January 1997, she developed expressive aphasia progressively and a new MRI demonstrated the old bilateral frontal lesions and some smaller T2 abnormalities in the white matter throughout the hemispheres. In view of these imaging findings the histopathologic material was re-evaluated in February 1997. Sections showed increased cellularity composed of reactive astrocytes, some gemistocytic and uniform cells with round nuclei and vacuolated cytoplasm that dominated the cellular infiltrate (Fig. 2). Immunohistochemistry performed with the CD68 antibody revealed that the latter
154
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
Fig. 2. Multiple sclerosis. Hypercellularity is produced by macrophages with discrete cell borders, vacuolated cytoplasm and round nuclei as well as by reactive gemistocytic astrocytes (H/E X200).
cells were macrophages. Additional immunostains showed a relative axonal persistence (neurofilament, silver technique) and foci of myelin loss (myelin basic protein). The conclusion was that the lesion was not an astrocytoma, but inflammatory demyelinating disease. A new brain MRI (June 1997) did not show any new lesions or the presence of enhancement, and sustained the presence of postoperative changes in the left frontal lobe, and a few punctuate high signal foci in T2 in periventricular white matter and centrum semiovale bilaterally. An MRI of the cervical spinal cord revealed a high signal lesion in T2 images, without enhancement. Up to that time and from the beginning of her illness she was receiving corticosteroids (before and after the operation and radiation therapy she received high doses of corticosteroids which were gradually tapered). Steroids were discontinued and after an induction phase where she received a full course of IVIg. Her neurological condition was stable, without any new signs or symptoms. There was a mild residual aphasia but otherwise she was in a good condition and since July 1998 she returned to work. On December 2000 she stopped treatment with IVIg. Several MRIs were done till that time, but none of them demonstrated any significant increase in the number and size of lesions or the presence of enhancement. In September 2002, the patient presented with a 2-week history of progressive worsening of her speech disorder (global aphasia), sleepiness and urgency in urination. Neurological examination did not reveal paralysis, or any other signs from the long tracks. Her gait was slightly unsteady, but
she still could walk unassisted. EEG did not show anything of significance. An MRI of the brain was performed that showed a new lesion on the right parietal lobe with incomplete ring enhancement (Fig. 3). She received intravenous methylprednisolone 1 g/day for 3 days and then 500 mg/day for another 2 days. In the following weeks her speech and gait showed some improvement and she gained a better control of her bladder. At the time of this writing the patient has mild residual motor aphasia, urgency in urination and mild spasticity in legs. She is functional and she is back to work.
3. Discussion Multiple sclerosis is one of the most important neurological conditions due to its frequency, its chronic nature and its tendency to attack and eventually render disabled young adults. The diagnosis depends mainly on a history of exacerbations and remissions as well as on evidence of at least two topographically separate lesions within the central nervous system. Although no specific test exists, elevated cerebrospinal fluid IgG levels, the presence of oligoclonal bands in the CSF and delayed visual or somatosensory evoked potentials can support the diagnosis. The magnetic resonance imaging (MRI) is the most reliable examination for confirming the diagnosis as well as for assessing the progress of the disease [9,10]. MRI shows abnormalities typically in the form of T2 intense, asymmetrical, well-demarcated lesions oriented perpendicularly to the ventricular surface as well
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
155
Fig. 3. Brain MRI in September 2002 showing a new enhancing lesion at the right parietal lobe.
as in the brainstem and the spinal cord. Contrast enhancement can be observed in some of these lesions representing an ongoing inflammatory process [6]. These radiologic changes are not specific for MS and can be seen in many other processes including normal aging, migraine, cerebrovascular disease and vasculitis. Large solitary acute lesions that produce a mass effect on MRI and show ring-like contrast enhancement are only rarely observed and represent a diagnostic challenge since they are difficult to differentiate from other space-occupying lesions such as neoplasms and infarcts
[6] or other demyelinating diseases such as progressive multifocal encephalopathy and adrenoleukodystrophy [2,3,11]. In particular in our patient there was a challenging dilemma about whether it was a case of multiple sclerosis or a case of multifocal disseminated encephalomyelitis (DEM), since both pathological modalities share similar clinical, radiological and histological presentations [1,12,13]. However, the absence of history of virus infection or vaccination, the absence of precursor signs and symptoms along with the lack of clinical polysymptomatic presentation—typical
156
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
of disseminated encephalomyelitis—were in favor of MS. Moreover, the diagnosis of MS was supported by the elevated cerebrospinal fluid IgG levels, the elevated IgG index (1.18), the presence of oligoclonal bands in the CSF and the delayed visual evoked potentials (VEPs). Finally the spinal cord lesion at MRI extended over less than 2 vertebral segments, a finding against DEM where the lesions are usually large and extend over a long segment of the spinal cord at MRI. Rarely the clinical and radiological features of multiple sclerosis are suggestive of a brain tumor and then a biopsy is required to establish a definite diagnosis. However, sometimes it is equally difficult for neuropathologists to arrive to a conclusion, since malignant tumors such as gliomas and non-neoplastic demyelinating lesions share some common histopathological features [14]. Stained by the hematoxylin and eosin method, the acute multiple sclerosis plaque is hypercellular because of the presence of multiple foci of foamy macrophages, chronic inflammatory cells and, to a lesser extent, reactive astrocytes. The cellularity of the process may result in the mistaken diagnosis of glioma, particularly at the time of frozen section. However, the recognition of the distinctive histologic appearance of the process and the application of special stains for myelin and axons as well as the determination of the immunophenotype of the constituent cells usually results in the correct diagnosis. At low magnification, the monotonous population of macrophages can suggest an oligodendroglioma, but at high magnification their bland, spherical nuclei, vacuolation and distinct cell borders are telling features. Recognition of foamy macrophages is facilitated by the use of smear preparations or imprints wherein the uniformity of nuclei and the granulation or vacuolation of cytoplasm are especially apparent. Even so, immunohistochemical stains for macrophage markers such as HAM-56 or KP1 (CD68) should be used to confirm their presence. The often prominent reactive astrocytosis in the lesion can raise the diagnosis of a gemistocytic astrocytoma. The astrocytes may be atypical with nuclear enlargement with bizarre hyperchromatic and multi-nucleated forms. Occasional cells with dispersed chromatin even suggest mitotic figures. However, the astrocytes are not significant in number to consider seriously a diagnosis of an astrocytoma.On the the other hand, attention must be given to the presence of Creutzfeldt astrocytes which are multinucleated reactive astrocytes seen in a variety of conditions but particularly characteristic of demyelinating diseases [5]. The increased cellularity and the occasionally observed non-distinct sharp border of the lesion with the adjacent normal white matter, due to a fibrillary gliosis of the latter, are histologic fetaures that may lead to an erroneous diagnosis of a glioma. The identification of myelin debris and macrophages containing Luxol fast blue-positive debris at the edge of the lesion are in favor of multiple sclerosis. Demyelination defined by loss of myelin with relative sparing of axons is a finding commonly apparent when comparing sections stained for myelin with corresponding sec-
tions stained for axons (myelin basic protein, silver impregnation or neurofilament protein immunostains). Finally, a lymphocytic infiltration within the parenchyma or in the perivascular region should alert one to the possibility of a demyelinating disease. Although mononuclear infiltration may also be present in astrocytomas, mainly in those of gemistocytic type, its presence in brain tissue especially in a young adult may raise the issue of demyelinating disorder. The firm pathological diagnosis of multiple sclerosis in tumor-presenting cases where a surgical intervention was unavoidable is essential since it might preclude further treatment such as radiotherapy. The role irradiation played in the progression of multiple sclerosis in our patient is a matter of investigation. The effect of irradiation in normal tissues has been extensively described [15–17]. The most common radiation induced injuries in the central nervous system are necrosis, white matter changes, mineralizing microangiopathy, cerebral atrophy, vasculopathy and others. Most of these sequels can be usually revealed with the MRI. However, although several studies have extensively dealt with radiation injury to normal tissues, only few have been reported regarding the role of radiotherapy in the progression of demyelinating diseases. Peterson et al. [18] reported five patients with demyelinating lesions mimicking brain tumors. The four patients who received radiation in full tumoricidal doses had unexpectedly poor clinical outcome, suggesting that irradiation is injurious to patients with demyelinating disease. Recently, Murphy et al. [19] described a 30-year-old woman with multiple sclerosis who developed an attack of demyelination 2 months after radiotherapy for a parotid malignancy and indicated that radiation treatment likely triggered an exacerbation of multiple sclerosis. In our case it is unknown whether the clinical course of our patient would be the same if she had not been irradiated, although we have no indications that she had an unexpected disease progression and a poor outcome. Multiple sclerosis should be considered in all patients presenting with sudden onset of neurological symptoms and single mass lesions on MRI. Additional tests such as lumbar puncture, CSF examination and evoked potentials can confirm the diagnosis and therefore a biopsy can be avoided. Even in the cases where a biopsy is necessary, preparation of the specimen with specific stains is vital, so that the demyelinating nature of the process can be revealed. References [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. [2] Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology 1996;38:560–5. [3] Hunter SB, Ballinger Jr WE, Rubin JJ. Multiple sclerosis mimicking primary brain tumor. Arch Pathol Lab Med 1987;111:464–8. [4] Censori B, Agostinis C, Partziguian T, Gazzaniga G, Biroli F, Mamoli A. Large demyelinating brain lesion mimicking a herniating tumor. Neurol Sci 2001;22:325–9.
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157 [5] Zagzag D, Miller DC, Kleinman GM, Abati A, Donnenfeld H, Budzilovich GN. Demyelinating disease versus tumor in surgical neuropathology. Clues to a correct pathological diagnosis. Am J Surg Pathol 1993;17:537–45. [6] Friedman DI. Multiple sclerosis simulating a mass lesion. J Neuroophthalmol 2000;20:147–53. [7] Mujic A, Liddell J, Hunn A, McArdle J, Beasley A. Non-neoplastic demyelinating process mimicking a disseminated malignant brain tumor. J Clin Neurosci 2002;9:313–7. [8] Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol 1993;3:255–68. [9] Kurihara N, Takahashi S, Furuta A, Higano S, Matsumoto K, Tobita M, Konno H, Sakamoto K. MR imaging of multiple sclerosis simulating brain tumor. Clin Imag 1996;20:171–7. [10] Ernst T, Chang L, Walot I, Huff K. Physiologic MRI of a tumefactive multiple sclerosis lesion. Neurology 1998;5:1486–8. [11] Krenn M, Bonelli RM, Niederwieser G, Reisecker F, Koltringer P. Adrenoleukodystrophy mimicking multiple sclerosis. Nervenarzt 2001;72:794–7. [12] Tsai ML, Hung KL. Multiphasic disseminated encephalomyelitis mimicking multiple sclerosis. Brain Dev 1996;18:412–4.
157
[13] Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 2000;123:2407–22. [14] Sugita Y, Terasaki M, Shigemori M, Sakata K, Morimatsu M. Acute focal demyelinating disease simulating brain tumors: histopathologic guidelines for an accurate diagnosis. Neuropathology 2001;21:25– 31. [15] New P. Radiation injury to the nervous system. Curr Opin Neurol 2001;14:725–34. [16] Valk PE, Dillon WP. Radiation injury of the brain. AJNR Am J Neuroradiol 1991;12:45–62. [17] Fike JR, Cann CE, Turowski K, Higgins RJ, Chan AS, Phillips TL, Davis RL. Radiation dose response of normal brain. Int J Radiat Oncol Biol Phys 1988;14:63–70. [18] Peterson K, Rosenblum MK, Powers JM, Alvord E, Walker RW, Posner JB. Effect of brain irradiation on demyelinating lesions. Neurology 1993;43:2105–12. [19] Murphy CB, Hashimoto SA, Graeb D, Thiessen BA. Clinical exacerbation of multiple sclerosis following radiotherapy. Arch Neurol 2003;60:273–5.
Case report
Astrocytoma-like multiple sclerosis E.E. Pakosa,∗ , P.G. Tsekerisa , K. Chatzidimoub , A.C. Goussiac , S. Markoulab , M.I. Argyropouloud , E.G. Pitoulia , S. Konitsiotisb a
Department of Radiation Therapy, School of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina 45500, Greece b Department of Neurology, School of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina 45500, Greece c Department of Pathology, School of Medicine, University Hospital of Ioannina, University of Ioannina, Ioannina 45500, Greece d Department of Radiology, University Hospital of Ioannina, University of Ioannina, School of Medicine, Ioannina 45500, Greece Received 11 November 2003; received in revised form 26 April 2004; accepted 2 June 2004
Abstract Multiple sclerosis (MS) may sometimes mimic clinically and radiologically a brain tumor. The initial recognition of such cases is essential as it might avoid a surgical intervention and supplementary treatment. However, even in patients who underwent surgery, the appropriate preparation of the specimen is of crucial importance for the correct pathological diagnosis since tumors and non-neoplastic demyelinating lesions share some common histopathological features. We present such a case of multiple sclerosis presenting with features of an astrocytoma and was treated with surgery and additional radiotherapy. © 2002 Elsevier B.V. All rights reserved. Keywords: Astrocytoma; Multiple sclerosis; Tumor; Radiotherapy
1. Introduction Multiple sclerosis (MS) is one of the most common diseases of the central nervous system showing a variety in its clinical and radiological presentations. The diagnosis is mainly based on the clinical course and supported by CSF protein electrophoresis, IgG banding and magnetic resonance imaging (MRI) findings. However, no specific diagnostic laboratory test is yet found. Several cases have been reported of demyelinating processes mimicking a mass lesion indistinguishable from a tumor of the central nervous system [1–4]. A biopsy of the tumor-like demyelinating area and histological examination of the specimen seems necessary to differentiate multiple sclerosis from a brain tumor, although sometimes even biopsy material may be misinterpreted [5–7].
∗ Corresponding author. Tel.: +30 2 6510 44589; Mobile: 306972772961; fax: +30 26510 97853. E-mail address: [email protected] (E.E. Pakos).
0303-8467/$ – see front matter © 2002 Elsevier B.V. All rights reserved. doi:10.1016/j.clineuro.2004.06.003
The initial recognition of these demyelinating tumor-like lesions is essential, to spare an unnecessary brain biopsy or even a neurosurgical intervention and/or supplementary therapy (radiotherapy or chemotherapy). We report a case of multiple sclerosis mimicking an astrocytoma. 2. Case report A 51-year old right-handed female was admitted to the Neurological Department of the University Hospital of Ioannina in the summer of 1996 with aphasia and behavior problems. These symptoms were present in a mild form for at least one year prior to the clear onset of her problems. There was no history of virus infection or vaccination. CT scan of the brain revealed a mass in the left frontal lobe. A subsequent brain MRI (Fig. 1) demonstrated a frontal lesion measuring 2 cm × 3 cm × 5.5 cm without mass effect. The lesion presented with a high signal on T2 and flair weighted images and with low signal on plain T1 weighted images. An incomplete peripheral ring enhancement was observed after intravenous
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
153
Fig. 1. Brain MRI on July 1996 showing an enhancing lesion at the left frontal lobe.
(iv) gadolinium Gd-DTPA. No other lesions were noted on that scan. The patient was operated in July 1996 and the lesion was partially removed. Histological evaluation showed a neoplastic lesion consisting of astrocytes with minimal degree of anaplasia. The final diagnosis was low-grade astrocytoma (WHO grade II [8]). On August 1996 she started postoperative external beam radiation therapy with two parallelopposed fields (anterior and posterior). The tumor bed with a 3 cm margin was treated in each field. Radiotherapy was given in thirty fractions with a linear accelerator (6 MV). The daily dose was 2.0 Gy and the total dose was 60 Gy. The fields were reduced after 40 Gy (Shrinkage technique). She tolerated radiotherapy well, without interruption of her treatment due to side effects.
She was doing relatively well until November 1996 when her speech deteriorated again. A repeat MRI of the brain revealed a second non-enhancing lesion in the white matter of her right frontal lobe. She was treated with high doses of dexamethasone and her condition gradually improved. In January 1997, she developed expressive aphasia progressively and a new MRI demonstrated the old bilateral frontal lesions and some smaller T2 abnormalities in the white matter throughout the hemispheres. In view of these imaging findings the histopathologic material was re-evaluated in February 1997. Sections showed increased cellularity composed of reactive astrocytes, some gemistocytic and uniform cells with round nuclei and vacuolated cytoplasm that dominated the cellular infiltrate (Fig. 2). Immunohistochemistry performed with the CD68 antibody revealed that the latter
154
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
Fig. 2. Multiple sclerosis. Hypercellularity is produced by macrophages with discrete cell borders, vacuolated cytoplasm and round nuclei as well as by reactive gemistocytic astrocytes (H/E X200).
cells were macrophages. Additional immunostains showed a relative axonal persistence (neurofilament, silver technique) and foci of myelin loss (myelin basic protein). The conclusion was that the lesion was not an astrocytoma, but inflammatory demyelinating disease. A new brain MRI (June 1997) did not show any new lesions or the presence of enhancement, and sustained the presence of postoperative changes in the left frontal lobe, and a few punctuate high signal foci in T2 in periventricular white matter and centrum semiovale bilaterally. An MRI of the cervical spinal cord revealed a high signal lesion in T2 images, without enhancement. Up to that time and from the beginning of her illness she was receiving corticosteroids (before and after the operation and radiation therapy she received high doses of corticosteroids which were gradually tapered). Steroids were discontinued and after an induction phase where she received a full course of IVIg. Her neurological condition was stable, without any new signs or symptoms. There was a mild residual aphasia but otherwise she was in a good condition and since July 1998 she returned to work. On December 2000 she stopped treatment with IVIg. Several MRIs were done till that time, but none of them demonstrated any significant increase in the number and size of lesions or the presence of enhancement. In September 2002, the patient presented with a 2-week history of progressive worsening of her speech disorder (global aphasia), sleepiness and urgency in urination. Neurological examination did not reveal paralysis, or any other signs from the long tracks. Her gait was slightly unsteady, but
she still could walk unassisted. EEG did not show anything of significance. An MRI of the brain was performed that showed a new lesion on the right parietal lobe with incomplete ring enhancement (Fig. 3). She received intravenous methylprednisolone 1 g/day for 3 days and then 500 mg/day for another 2 days. In the following weeks her speech and gait showed some improvement and she gained a better control of her bladder. At the time of this writing the patient has mild residual motor aphasia, urgency in urination and mild spasticity in legs. She is functional and she is back to work.
3. Discussion Multiple sclerosis is one of the most important neurological conditions due to its frequency, its chronic nature and its tendency to attack and eventually render disabled young adults. The diagnosis depends mainly on a history of exacerbations and remissions as well as on evidence of at least two topographically separate lesions within the central nervous system. Although no specific test exists, elevated cerebrospinal fluid IgG levels, the presence of oligoclonal bands in the CSF and delayed visual or somatosensory evoked potentials can support the diagnosis. The magnetic resonance imaging (MRI) is the most reliable examination for confirming the diagnosis as well as for assessing the progress of the disease [9,10]. MRI shows abnormalities typically in the form of T2 intense, asymmetrical, well-demarcated lesions oriented perpendicularly to the ventricular surface as well
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
155
Fig. 3. Brain MRI in September 2002 showing a new enhancing lesion at the right parietal lobe.
as in the brainstem and the spinal cord. Contrast enhancement can be observed in some of these lesions representing an ongoing inflammatory process [6]. These radiologic changes are not specific for MS and can be seen in many other processes including normal aging, migraine, cerebrovascular disease and vasculitis. Large solitary acute lesions that produce a mass effect on MRI and show ring-like contrast enhancement are only rarely observed and represent a diagnostic challenge since they are difficult to differentiate from other space-occupying lesions such as neoplasms and infarcts
[6] or other demyelinating diseases such as progressive multifocal encephalopathy and adrenoleukodystrophy [2,3,11]. In particular in our patient there was a challenging dilemma about whether it was a case of multiple sclerosis or a case of multifocal disseminated encephalomyelitis (DEM), since both pathological modalities share similar clinical, radiological and histological presentations [1,12,13]. However, the absence of history of virus infection or vaccination, the absence of precursor signs and symptoms along with the lack of clinical polysymptomatic presentation—typical
156
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157
of disseminated encephalomyelitis—were in favor of MS. Moreover, the diagnosis of MS was supported by the elevated cerebrospinal fluid IgG levels, the elevated IgG index (1.18), the presence of oligoclonal bands in the CSF and the delayed visual evoked potentials (VEPs). Finally the spinal cord lesion at MRI extended over less than 2 vertebral segments, a finding against DEM where the lesions are usually large and extend over a long segment of the spinal cord at MRI. Rarely the clinical and radiological features of multiple sclerosis are suggestive of a brain tumor and then a biopsy is required to establish a definite diagnosis. However, sometimes it is equally difficult for neuropathologists to arrive to a conclusion, since malignant tumors such as gliomas and non-neoplastic demyelinating lesions share some common histopathological features [14]. Stained by the hematoxylin and eosin method, the acute multiple sclerosis plaque is hypercellular because of the presence of multiple foci of foamy macrophages, chronic inflammatory cells and, to a lesser extent, reactive astrocytes. The cellularity of the process may result in the mistaken diagnosis of glioma, particularly at the time of frozen section. However, the recognition of the distinctive histologic appearance of the process and the application of special stains for myelin and axons as well as the determination of the immunophenotype of the constituent cells usually results in the correct diagnosis. At low magnification, the monotonous population of macrophages can suggest an oligodendroglioma, but at high magnification their bland, spherical nuclei, vacuolation and distinct cell borders are telling features. Recognition of foamy macrophages is facilitated by the use of smear preparations or imprints wherein the uniformity of nuclei and the granulation or vacuolation of cytoplasm are especially apparent. Even so, immunohistochemical stains for macrophage markers such as HAM-56 or KP1 (CD68) should be used to confirm their presence. The often prominent reactive astrocytosis in the lesion can raise the diagnosis of a gemistocytic astrocytoma. The astrocytes may be atypical with nuclear enlargement with bizarre hyperchromatic and multi-nucleated forms. Occasional cells with dispersed chromatin even suggest mitotic figures. However, the astrocytes are not significant in number to consider seriously a diagnosis of an astrocytoma.On the the other hand, attention must be given to the presence of Creutzfeldt astrocytes which are multinucleated reactive astrocytes seen in a variety of conditions but particularly characteristic of demyelinating diseases [5]. The increased cellularity and the occasionally observed non-distinct sharp border of the lesion with the adjacent normal white matter, due to a fibrillary gliosis of the latter, are histologic fetaures that may lead to an erroneous diagnosis of a glioma. The identification of myelin debris and macrophages containing Luxol fast blue-positive debris at the edge of the lesion are in favor of multiple sclerosis. Demyelination defined by loss of myelin with relative sparing of axons is a finding commonly apparent when comparing sections stained for myelin with corresponding sec-
tions stained for axons (myelin basic protein, silver impregnation or neurofilament protein immunostains). Finally, a lymphocytic infiltration within the parenchyma or in the perivascular region should alert one to the possibility of a demyelinating disease. Although mononuclear infiltration may also be present in astrocytomas, mainly in those of gemistocytic type, its presence in brain tissue especially in a young adult may raise the issue of demyelinating disorder. The firm pathological diagnosis of multiple sclerosis in tumor-presenting cases where a surgical intervention was unavoidable is essential since it might preclude further treatment such as radiotherapy. The role irradiation played in the progression of multiple sclerosis in our patient is a matter of investigation. The effect of irradiation in normal tissues has been extensively described [15–17]. The most common radiation induced injuries in the central nervous system are necrosis, white matter changes, mineralizing microangiopathy, cerebral atrophy, vasculopathy and others. Most of these sequels can be usually revealed with the MRI. However, although several studies have extensively dealt with radiation injury to normal tissues, only few have been reported regarding the role of radiotherapy in the progression of demyelinating diseases. Peterson et al. [18] reported five patients with demyelinating lesions mimicking brain tumors. The four patients who received radiation in full tumoricidal doses had unexpectedly poor clinical outcome, suggesting that irradiation is injurious to patients with demyelinating disease. Recently, Murphy et al. [19] described a 30-year-old woman with multiple sclerosis who developed an attack of demyelination 2 months after radiotherapy for a parotid malignancy and indicated that radiation treatment likely triggered an exacerbation of multiple sclerosis. In our case it is unknown whether the clinical course of our patient would be the same if she had not been irradiated, although we have no indications that she had an unexpected disease progression and a poor outcome. Multiple sclerosis should be considered in all patients presenting with sudden onset of neurological symptoms and single mass lesions on MRI. Additional tests such as lumbar puncture, CSF examination and evoked potentials can confirm the diagnosis and therefore a biopsy can be avoided. Even in the cases where a biopsy is necessary, preparation of the specimen with specific stains is vital, so that the demyelinating nature of the process can be revealed. References [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. [2] Dagher AP, Smirniotopoulos J. Tumefactive demyelinating lesions. Neuroradiology 1996;38:560–5. [3] Hunter SB, Ballinger Jr WE, Rubin JJ. Multiple sclerosis mimicking primary brain tumor. Arch Pathol Lab Med 1987;111:464–8. [4] Censori B, Agostinis C, Partziguian T, Gazzaniga G, Biroli F, Mamoli A. Large demyelinating brain lesion mimicking a herniating tumor. Neurol Sci 2001;22:325–9.
E.E. Pakos et al. / Clinical Neurology and Neurosurgery 107 (2005) 152–157 [5] Zagzag D, Miller DC, Kleinman GM, Abati A, Donnenfeld H, Budzilovich GN. Demyelinating disease versus tumor in surgical neuropathology. Clues to a correct pathological diagnosis. Am J Surg Pathol 1993;17:537–45. [6] Friedman DI. Multiple sclerosis simulating a mass lesion. J Neuroophthalmol 2000;20:147–53. [7] Mujic A, Liddell J, Hunn A, McArdle J, Beasley A. Non-neoplastic demyelinating process mimicking a disseminated malignant brain tumor. J Clin Neurosci 2002;9:313–7. [8] Kleihues P, Burger PC, Scheithauer BW. The new WHO classification of brain tumours. Brain Pathol 1993;3:255–68. [9] Kurihara N, Takahashi S, Furuta A, Higano S, Matsumoto K, Tobita M, Konno H, Sakamoto K. MR imaging of multiple sclerosis simulating brain tumor. Clin Imag 1996;20:171–7. [10] Ernst T, Chang L, Walot I, Huff K. Physiologic MRI of a tumefactive multiple sclerosis lesion. Neurology 1998;5:1486–8. [11] Krenn M, Bonelli RM, Niederwieser G, Reisecker F, Koltringer P. Adrenoleukodystrophy mimicking multiple sclerosis. Nervenarzt 2001;72:794–7. [12] Tsai ML, Hung KL. Multiphasic disseminated encephalomyelitis mimicking multiple sclerosis. Brain Dev 1996;18:412–4.
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