A 45‐YEAR OLD MALE WITH LEFT‐SIDED HEMIHYPESTHESIA

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 dysfunction, 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 abnormalities 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).

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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 (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 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%.

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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 interdisciplinary 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 stabilization 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 eccentric dark nuclei, along with infiltrating microglia and macrophages, including multinucleated forms (10, 11, 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.

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DIAGNOSIS

Tumefactive multiple sclerosis (MS).

DISCUSSION

Differential diagnosis based on clinical presentation and neuroimaging 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 concerning stereotactic needle biopsies, especially in the posterior fossa or brainstem (1). Histomorphology definitely excluded CNS lymphoma. The prominent astrocytosis with marked pleomorphism and even atypical mitotic figures argued in favor of a malignant variant of an astrocytoma. Abundant Rosenthal fibers, typically 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 demyelination, astrocytosis and inflammation with microglia cells and macrophages. 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). Histological 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 demyelination, extensive macrophage invasion, perivascular and parenchymal 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). Reactive astrocytes in MS lesions, that can display significant pleomorphism 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 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 infiltrates, different patterns of demyelination have been described, reflecting in part the broad heterogeneity within the clinical presentation of MS (3). Further histological subtyping and characterization of individual pathogenetic patterns may therefore even help in focusing treatment strategies (2). Finally, the insistence on a representative 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.

ABSTRACT

A 45‐year‐old man presented with progressive brainstem and cerebellar 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 diagnosis 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.