doi:10.1111/j.1750-3639.2009.00364.
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COM DECEMBER 2009 CASE 1 bpa_364
A 45-YEAR OLD MALE WITH LEFT-SIDED HEMIHYPESTHESIA
Contributed by:
Rainer Ehling, MD*1, William Sterlacci, MD*2, Hans Maier, MD2, Thomas Berger, MD1
Departments of 1 Neurology and 2 Neuropathology, Medical University Innsbruck, Austria
* Both authors contributed equally to this work.
CLINICAL HISTORY
A 45-year-old man presented with left-sided hemihypesthesia,
which remitted spontaneously within two months. 18 months later
the same symptoms appeared again but were now aggravated by
hemiparesis, dysarthria, ataxia and neurogenic bladder dysfunc-
tion, which finally led to pyelonephritis and acute renal failure.
The patient’s past medical, surgical and family history were all
non-contributory. Cerebrospinal fluid (CSF) showed normal cell
counts, glucose, protein, IgG index and no oligoclonal bands.
Cytology was negative for malignant cells.
NEURO-RADIOLOGY
At disease onset, brain MRI demonstrated white matter abnormali-
ties in the mesencephalon, pons and cerebellar peduncles, while
other white matter areas were spared. Follow-up MRI 18 months
later exhibited progression in the brainstem with mild mass effect.
The lesions were hyperintense on proton density scans (Figure 1)
and on T2-weighted images but with inhomogeneous contrast-
enhancement on T1-weighted images (Figure 2). An additional
lesion was suspected in the cerebellar cortex. MR spectroscopy
showed a decrease in N-acetylaspartate and a peak in choline.
Positron emission tomography (PET) with 18-fluorodeoxyglucose
(FDG) revealed intense lesion hypermetabolism (Figure 3).
STEREOTACTIC BIOPSY
H&E stained sections of the of the brainstem biopsy revealed white
matter with abundant Rosenthal fibers and interjacent spindle-
shaped and gemistocytic astrocytes, some with hyperchromatic and
irregularly shaped nuclei (Fig. 4, 5). Some fragments contained
large cells with similar nuclei displaced to the periphery. The glial
origin of the conspicuous cells was identified by positive glial
fibrillary acidic protein expression. Immunocytochemistry using
an antibody against myelin basic protein (MBP) detected focal loss
of myelin (Fig. 6), while axons were relatively preserved as shown
Figure 1.
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by SMI-31 staining (Fig. 7). Infiltrating microglial cells and CD8-
positive T cells (Fig. 8) were sparse. Ki-67 proliferation index was
lower than 2%.
The lesion was interpreted as an astrocytic tumor and because of
the bizarre pleomorphic cells, a high-grade tumor was considered.
Because of the intense infiltration of glial cells amidst Rosenthal
fibers a second opinion by J. Hainfellner and H. Budka (Institute of
Neurology, Medical University of Vienna, Austria) argued, that the
sections are likely to be from the margin of a demyelinating lesion.
However, an astrocytic tumor could finally not be ruled out.
CLINICAL HISTORY, CONTINUED
Lacking a definite histopathological diagnosis, the local interdisci-
plinary tumor board recommended treatment for the worst case
scenario. Extended tumor field and total brain radiotherapy with a
dosage of 54 Gray and concomitant temozolomide therapy was
performed and led to a transient clinical and radiological stabiliza-
tion of the disease until the patient suffered from acute renal
failure. Shortly after having recovered from hemofiltration, the
patient had respiratory and renal failure again and finally died of
sepsis-associated multi-organ failure, three and a half years after
disease onset.
POST MORTEM PATHOLOGY
White matter of the cerebellum and the brainstem contained lesions
consisting of central amorphic necrosis without significant
amounts of remaining myelin, as evidenced by MBP-staining
(Fig. 9), or oligodendroglial cells. The lesions were surrounded by
reactive astroglial cells with sometimes bizarre shapes and eccen-
tric dark nuclei, along with infiltrating microglia and macrophages,
including multinucleated forms (Fig. 10–12). Peripheral blood
vessels displayed only rare CD4- and CD8-positive lymphocyte
cuffs (Fig. 13). Apart from the brainstem, a small focus of densely
packed foamy macrophages was found near the posterior horn of
the left ventricle.
Figure 2. Figure 3.
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Figure 5.

Figure 4.

Figure 7.

Figure 6.

Figure 8.

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Figure 9. Figure 10.

Figure 11. Figure 12.

Figure 13.

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DIAGNOSIS
Tumefactive multiple sclerosis (MS).
DISCUSSION
Differential diagnosis based on clinical presentation and neuroim-
aging included a demyelinating disease, a diffuse intrinsic brain
tumor as well as a lymphoma, the latter being rather unlikely due
to several normal CSF evaluations (no malignant cells, normal
protein). Apart from the fulminant clinical deterioration, atypical
features for a demyelinating disease in our patient included the
absence of intrathecal immunoglobulin production, the absence
of periventricular lesions as well as the mass effect seen on MRI.
Reduction of N-acetylaspartate and increase of choline suggesting
glial proliferation along with hypermetabolism of the lesions seen
on 18-FDG PET left the differential diagnosis of a brain tumor
open and urged the histopathological confirmation.
Stereotactic biopsy was challenging in our patient. Notably, the
described histopathology resulted from the third sampling after two
biopsy attempts in vain, reflecting the technical difficulties con-
cerning stereotactic needle biopsies, especially in the posterior
fossa or brainstem (1). Histomorphology definitely excluded CNS
lymphoma. The prominent astrocytosis with marked pleomor-
phism and even atypical mitotic figures argued in favor of a malig-
nant variant of an astrocytoma. Abundant Rosenthal fibers, typi-
cally found in pilocytic astrocytomas and Alexander’s disease,
have been described in both brain neoplasms and in chronic MS
lesions of patients with long-standing disease and did not aid in the
differential diagnosis (8). The lymphocytic infiltrate found in the
stereotactic specimen, which by its nature represented only a small
part of the lesion, was too mild for a prototypic early MS lesion. In
summary, histopathological investigations could by no means rule
out a malignant astrocytoma, which led to the therapeutic scenario
mentioned above.
Post mortem pathology finally confirmed a chronic destructive
demyelinating disease, compatible with MS. Multifocal lesions
were found within the white matter of the brainstem, the cerebellar
peduncles and the posterior horn of the left ventricle with central
amorphic necrosis surrounded by areas of significant demyelina-
tion, astrocytosis and inflammation with microglia cells and mac-
rophages. The necrosis was interpreted as the resulting from the
radiation treatment. In cases of atypical clinical symptoms, normal
CSF evaluation and uncommon MRI findings biopsies are required
to establish the diagnosis of a demyelinating disease (4). Histologi-
cal characteristics of chronic MS lesions are well known, however,
diagnosing an acute, inflammatory demyelinating process in small
biopsy specimens (especially stereotactic needle biopsies) can be
challenging. The key features of early MS lesions are still demyeli-
nation, extensive macrophage invasion, perivascular and parenchy-
mal T cell infiltrates as well as relative axonal preservation. Since
early MS lesions are characterized by hypercellularity as well as
extensive and prominent astrocytosis they can be confused with
astrocytic tumors, especially in small biopsy specimens (2). Reac-
tive astrocytes in MS lesions, that can display significant pleomor-
phism and even atypical mitotic figures (so-called Creutzfeldt-
Peters cells) can be misleading (5). Additionally, the rare
coincidence of MS and glial tumors can add to the difficulties of
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arriving at the correct diagnosis (6). Sending ambiguous biopsy
specimens to specialized centers can help in lesion classification
(7). Based on the extent of myelin protein loss, oligodendrocyte
preservation as well as the composition of the inflammatory infil-
trates, different patterns of demyelination have been described,
reflecting in part the broad heterogeneity within the clinical presen-
tation of MS (3). Further histological subtyping and characteriza-
tion of individual pathogenetic patterns may therefore even help in
focusing treatment strategies (2). Finally, the insistence on a repre-
sentative stereotactic specimen is the conditio sine qua non for a
clear histological diagnosis, but the presence of abnormal tissue
does not necessarily mean the specimen will be diagnostic.
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ABSTRACT
A 45-year-old man presented with progressive brainstem and cer-
ebellar dysfunction. Extensive immunological and radiological
investigations were not able to differentiate between an intrinsic
brain tumor and a demyelinating disease. Stereotactic biopsies of
the brainstem were performed; the findings of abundant Rosenthal
fibers, interjacent spindle-shaped and gemistocytic cells partially
with dark and irregularly formed nuclei favored primarily the diag-
nosis of a malignant astrocytoma, although a demyelinating disease
could not be definitely excluded. Facing the fulminant clinical
course radio- and chemotherapy was initiated; however, the patient
died of sepsis-associated multi-organ failure three and a half years
after disease onset. Post mortem pathology finally revealed lesions
with central amorphic necrosis surrounded by areas of significant
demyelination, astrocytosis, microglia cells and macrophages
typical for MS. Although criteria for establishing MS are well
known, a correct diagnosis can be extremely challenging in small
stereotactic specimens, where so-called pathological hallmarks are
spared and unusual pathological findings are predominant.
Brain Pathology 20 (2010) 515–518