MACROSCOPIC AND MICROSCOPIC APPEARANCES

Macroscopically, the brain usually appears normal, although there may be foci of softening and discoloration. Histology reveals occasional or numerous foci of hypercellularity (Fig. 13.1), within which many neurons and some astrocytes and oligodendrocytes contain eosinophilic inclusion bodies (Fig. 13.1). Most of these are intranuclear, largely filling the nucleus, apart from a few pyknotic clumps of marginated chromatin. Less well-defined eosinophilic inclusions may be visible in the cytoplasm. The lesions also contain reactive astrocytes and microglia, and occasional multinucleated cells. The lesions occur in any part of the brain. The inclusions are readily seen in hematoxylin–eosin preparations and can also be demonstrated immunohistochemically or by electron microscopy (Fig. 13.1).

MACROSCOPIC APPEARANCES

Often the brain is macroscopically normal. However, in cases of longer duration, there is usually moderate to marked brain atrophy and the white matter may have an abnormally firm texture and a mottled gray appearance that can simulate a leukodystrophy (Fig. 13.2).

MICROSCOPIC APPEARANCES

There is a chronic encephalitis, with leptomeningeal, perivascular, and parenchymal infiltration by lymphocytes (predominantly T cells) and microglia (Fig. 13.3).

The distribution and severity of lesions are variable, but the cerebral cortex, white matter, basal ganglia, and thalamus are usually involved. The affected gray matter shows inflammation, gliosis, loss of neurons, occasional neuronophagia, and sparse intranuclear inclusions, which are sharply defined eosinophilic bodies with a surrounding clear space (‘halo’) (Fig. 13.3). In most cases these sparse inclusion bodies can be detected immunohistochemically. Another finding, in some cases of several years’ duration, is the presence of Alzheimer-type neurofibrillary tangles (Fig. 13.3). These are most often found in the cerebral cortex and hippocampus, and may be numerous.

The affected white matter is severely gliotic and is characterized by a predominantly perivascular inflammation and a patchy, in some cases extensive, loss of myelinated fibers (Fig. 13.3).

MACROSCOPIC APPEARANCES

The cut surface of the fixed brain affected by PML appears asymmetrically pitted by small foci of gray discoloration mixed with larger confluent areas of abnormal parenchyma, which may be centrally necrotic (Fig. 13.5). The lesions tend to be most numerous in the cerebral white matter, but also involve the cerebral cortex and deep gray matter (Fig. 13.5). The cerebellum (Fig. 13.5), brain stem, and much less commonly the spinal cord, may also be involved.

MICROSCOPIC APPEARANCES

There are multiple foci of demyelination (Fig. 13.6). Some are small and rounded, others confluent, irregular, and occasionally with central necrosis. These lesions contain moderate numbers of foamy macrophages (Fig. 13.6), but only scanty perivascular lymphocytes. Lymphocytic infiltrates may be commoner in PML associated with AIDS and may confer a slightly better prognosis.

A striking feature, particularly in older lesions, is the presence of very large astrocytes with bizarre, pleomorphic, hyperchromatic nuclei (Fig. 13.6). These cells resemble the individual astrocytes that can be seen in glioblastomas. Typical reactive astrocytes are also present.

Mitoses are rare. Those that do occur may appear atypical. However, despite the nuclear pleomorphism, the lesions are easily distinguishable from a neoplasm by their relatively low cellularity and the presence of viral inclusions, which are seen towards the periphery of the foci of demyelination in the enlarged nuclei of oligodendrocytes. The homogeneous amphophilic inclusions (Fig. 13.6) largely fill the nuclei and consist of closely packed polyomavirus particles, which are readily identifiable on electron microscopy (Fig. 13.6). The virus can be demonstrated immunohistochemically (e.g. with SV40 antibody, which also labels JC virus), and viral nucleic acids can be detected and specifically identified by in situ hybridization.

Occasionally, in cases of PML involving the cerebellum, accumulations of cells with large vesicular nuclei and central nucleoli can be seen in the granule cell layer. These probably represent altered granule cells.

Very rarely, astrocytic neoplasms have been reported in PML.

MACROSCOPIC APPEARANCES

In longstanding cases of HAM, there may be meningeal thickening (Fig. 13.7) and atrophy of the spinal cord, particularly in the lower thoracic region. Lateral funicular degeneration may also be visible.

MICROSCOPIC APPEARANCES

An infiltrate of lymphocytes and macrophages is seen in the leptomeninges and parenchyma of the spinal cord (Fig. 13.7), and is most marked in the lower thoracic region. Hyaline thickening of small blood vessels is a prominent feature. Intramyelinic vacuolation and demyelination may be evident early in the course of disease, but soon progress to symmetric degeneration and gliosis involving the long tracts in the spinal cord (Fig. 13.7). The degeneration tends to be most severe in the lateral columns. The anterior and less commonly the posterior columns may also be involved. The neurons are relatively well preserved (Fig. 13.7). Sparse viral nucleic acids may be detectable within the spinal cord by in situ hybridization or by polymerase chain reaction. Adventitial fibrosis and scanty perivascular inflammation have been observed in the cerebral white matter and less commonly in the cerebellum and brain stem.

MACROSCOPIC APPEARANCES

The brain may appear normal or show diffuse atrophy with modest ventriculomegaly (Fig. 13.10) and ill-defined gray discoloration of the centrum semiovale.