The etiologies and patient characteristics associated with demyelinating lesions vary considerably. Most frequently encountered is the enigmatic autoimmune process of multiple sclerosis, in which multiple lesions occur over a discontinuous time course. Because solitary, monophasic lesions with identical histology also occur and have different clinical implications, multiple sclerosis as a diagnosis should generally be avoided by the pathologist in favor of a more generic and appropriate diagnosis of “demyelinating lesion.” Other autoimmune central nervous system (CNS) demyelination syndromes include acute disseminated encephalomyelitis (ADEM), acute hemorrhagic leukoencephalopathy (AHL), and neuromyelitis optica.

Most plaques of demyelination are recognized as such by the clinical team either by the history of the illness or by the characteristic radiographic features of demyelination. All ages are affected, and those in the third and fourth decades are the most common, with a female predominance.

On neuroimaging, demyelinating lesions are typically hyperintense on T2/FLAIR MR images and show areas of contrast enhancement, likely due to increased vascular permeability. Mass effect is generally absent but can be seen in cases of “tumefactive” demyelination. By definition, demyelinating lesions are limited to the white matter and should not overtly extend into gray matter structures. Solitary and progressive demyelinating lesions are sometimes biopsied with the expectation of a diagnosis of glioblastoma because a pattern of contrast enhancement forms peripherally around the lesion. However, unlike the unbroken ring enhancement in glioblastoma, demyelinating lesions usually have an “open ring” or telltale gap on one side, typically the more superficial side (1). This finding, although relatively specific to demyelination, is not a sensitive indicator and is occasionally present in other types of lesions (2). When multiple similar lesions are present on neuroimaging, the preoperative suspicion is usually metastatic disease.

Some patients with biopsy-proven demyelinating disease go on to develop high-grade lymphomas at the site of their plaque. Whether these two processes are pathogenetically linked, or are merely unfortunate coincidences, remains to be demonstrated. At least some cases represent lymphomas treated with steroids that altered the histology to appear as a demyelinating lesion (3). The initial insult is often referred to as a sentinel lesion and may be chronologically distant from the subsequent lymphoma (4).

Treatment of multiple sclerosis and other demyelinating diseases is based on immunosuppressive agents, with highly variable outcomes. Severity of disease ranges from a single monophasic demyelinating lesion that recedes without recurrence to debilitating widespread disease that culminates in death.

ADEM is a demyelinating illness that typically occurs in children and young adults, in most cases closely following a viral infection or immunization. A single monophasic course is typical, although relapsing–remitting cases may occur and are termed multiphasic diffuse encephalomyelitis. As the name indicates, ADEM is diffuse in the brain and spinal cord white matter. MRI of ADEM typically reveals diffusion restriction in the acute phase, with resolution over time, as well as decreasing N-acetyl aspartate/choline ratios on spectroscopy (5). Most cases are diagnosed based on clinical and imaging findings alone and are not biopsied, yet unusual cases may require tissue diagnosis. Acute hemorrhagic leukoencephalitis is a severe form of ADEM with vascular involvement, hemorrhage, and necrosis.

Demyelinating lesions display a set of consistent histologic features, although their overall appearance and the prominence of different components vary somewhat with the age of the lesion.

Macrophages are always a part of the cellular milieu and can be so dense as to give a strong impression of neoplasm, especially in new onset lesions in which macrophages have less abundant cytoplasm (Figure 2-1). Occasional mitotic macrophages add to the illusion of neoplasia. Lymphoplasmacytic infiltrates are also usually present in a perivascular pattern (Figure 2-2), suggesting inflammatory nature of the macrophage infiltrate rather than a reaction to necrosis, that is, infarct (Table 2-1). Immunohistochemical reactivity for CD68 or HAM56 can support the identity of macrophages, although caution is warranted because CD68, a lysosomal marker, is also expressed in granular cell astrocytomas, which are also rich in lysosomes. HAM56 is a marker for macrophages that should not be positive in granular cell astrocytoma, but this hypothesis has not been systematically tested. CD163 is probably the most specific marker for macrophages in this setting (6).

Reactive astrocytes are present in all but the most nascent lesions, extending prominent cytoplasmic processes from enlarged and eosinophilic cell bodies. The astrocytes take up evenly spaced positions within
the lesion and form a loose glial scar-like matrix in which the other cells are suspended (Figure 2-3). Occasional astrocytes display a starburst array of apparent chromosomes in place of the nucleus. These eye-catching granular mitotic figures (Figure 2-4) are often seen in reactive lesions, but cannot be considered by themselves as evidence of such because they also appear in neoplastic processes, including glioblastoma, albeit much less
frequently. The Creutzfeldt astrocyte is conceptually a granular mitotic figure in which the dense chromatin fragments have inflated to pale micronuclei (Figure 2-3). These generally occur in proximity with granular mitotic figures.

Demyelinating lesions are generally exclusive to the white matter and do not extend significantly into areas of gray matter, although special staining can reveal loss of sparse intracortical myelin in some cases. When examining macrophage-rich lesions, lack of overt gray matter involvement is one of the most helpful clues in distinguishing between demyelination and infarct. The presence of ischemic, “red” neurons indicates gray matter and strongly favors infarct.

When one is lucky enough to have it included in the biopsy, the transition from demyelinating plaque to adjacent brain is sharp and well delineated. This feature is accentuated and often visible to the naked eye following myelin staining with Luxol fast blue (Figure 2-5).

The resident axons of the white matter are left more or less intact in demyelinating lesions, the damage being most severe to the myelinating
oligodendrocytes. This is one of the cardinal features of demyelinating lesions, although it is difficult to appreciate on hematoxylin and eosin (H&E)-stained sections and usually requires application of immunostaining for neurofilament (Figure 2-6) or of Bielschowsky silver stain. Variable, but generally modest, degrees of axonal fragmentation and swelling can be
noted in florid lesions, whereas infarcts show widespread and marked disruption of axons.

ADEM is also typically a macrophage-rich demyelinating process, yet it has a perivenular distribution of smaller lesions that distinguishes it from multiple sclerosis-type lesions. AHL has a similar pattern to ADEM with the additional features of necrosis and hemorrhage.

Because the diagnosis of multiple sclerosis depends on identifying anatomically and temporally distinct lesions, it is fundamentally a clinical endeavor and cannot be issued on the basis of biopsy alone. Although many demyelinating lesions occur in the context of multiple sclerosis, the biopsy diagnosis should in most cases be limited to what is histologically demonstrable. The diagnosis “demyelinating lesion” fulfills this criterion and provides the clinician with sufficient information for proper management.

Increased sophistication and diagnostic accuracy of imaging techniques prevent all but a rare infarct from biopsy. When biopsy is performed, though, the infarct will often contain dense macrophage infiltrates comparable with those of demyelinating lesions. However, there are several key features that separate the two histologically. Unlike demyelinating lesions, infarcts affect the gray matter, destroy axons, and usually lack lymphocytes and plasma cells. Infarcts also induce endothelial hypertrophy in nearby vessels, and cause them to stand out against the parenchymal background.

Although technically a demyelinating disease itself, progressive multifocal leukoencephalopathy (PML) is pathophysiologically distinct, in that it results from unchecked replication of the JC virus in oligodendroglia due to severe immunosuppression. Most of the histologic features of PML are similar to those of other demyelinating diseases, with two exceptions. First, the presence of viral cytopathic effects, such as ground glass nuclear inclusions in oligodendrocytes and atypical nuclear features in astrocytes, is restricted to PML and not seen in autoimmune lesions. Also, perivascular lymphoplasmacytic inflammation is usually absent in PML. However, PML patients with immune reconstitution inflammatory syndrome (IRIS) may have brisk superimposed T and B cell infiltrates due to rapid recovery of immune function and response to the virus (7). Although macrophage infiltrates can be dense in PML, they are typically less than in multiple sclerosis.

The cellularity and nuclear uniformity of early demyelinating lesions can recreate the features of an oligodendroglioma or even diffuse astrocytoma. This misapprehension can be convincing in frozen sections that distort the cellular features, necessitating examination of smear preparations, which greatly facilitate the identification of macrophages (Figure 2-7). Perivascular lymphocytes and sharp circumscription are not features typically associated with infiltrating gliomas, yet are common in demyelinating disease.

Lymphomas that are treated with corticosteroids can have an appearance very similar to demyelinating lesions, but may show some necrosis and scattered apoptotic debris, both of which are unusual in the latter.

Granular cell astrocytomas are rare and aggressive infiltrating gliomas that have perivascular lymphocytic infiltrates and contain cells with ample cytoplasm and numerous lysosomes that react with antibodies to CD68, leading to a pathologic appearance that closely resembles demyelinating
disease. Comparison of the features of demyelinating lesions and granular cell astrocytoma is discussed in the section on anaplastic astrocytomas in Chapter 3.

This systemic inflammatory disease can affect any organ, but it has a proclivity for the lungs and hilar lymph nodes. CNS involvement occurs in approximately 5% to 20% of sarcoidosis patients and typically manifests as a cranial neuropathy, more often involving the optic nerves (8,9). Sarcoidosis maintains a worldwide distribution, including all races, although incidence is three to four times higher among people of African descent than among Caucasians (10).

The radiologic features of neurosarcoidosis are highly variable, famously mimicking several other disease processes, but can be distilled to several neuroimaging patterns that encompass most cases. The most common findings are of cranial nerve enlargement with contrast enhancement, correlating with cranial nerve deficits, or discontinuous dural thickening and enhancement that sometimes appears similar to a meningioma on MRI (9,11,12). The other major pattern is leptomeningeal enhancement, usually around the skull base and occasionally extending into the brain along perivascular spaces (12). Multiple enhancing and nonenhancing parenchymal lesions are less common but not unusual. Single intraparenchymal mass lesions are rare but may simulate neoplasia and require biopsy (13,14,15,16).

Noncaseating, epithelioid granulomas are the footprints of sarcoidosis, although several other processes may leave similar tracks. In general, the granulomas are small and formed of epithelioid histiocytes (Figure 2-8), although multinucleated giant cells are also seen. Asteroid bodies, cytoplasmic inclusions with a sea urchin shape, are occasionally seen in multinucleated giant cells but are not specific to sarcoidosis (17). A corona of lymphocytes rings many granulomas. Because other processes can also cause noncaseous granulomas, a diagnosis of “nonnecrotizing granulomatous inflammation” is generally appropriate because differentiating features are not histologically apparent.

Although necrosis is generally thought to exclude sarcoid granulomas, necrotizing granulomas have been demonstrated in the setting of sarcoid, although very rarely in the brain (18). The diagnosis of necrotizing sarcoid granulomatosis is difficult to establish with certainty and is essentially one of exclusion. Extensive necrosis is more often seen in infectious granulomas.

The differential diagnosis for sarcoid granulomas includes fungal or mycobacterial infection, germinoma, or another autoimmune illness. Application of stains for microorganisms decreases the likelihood of missing an infectious granuloma. In the case of granulomas from the pineal gland, posterior third ventricle, suprasellar region, or other midline locations, the thought of germinoma should be considered. Because germinoma can be greatly masked by inflammation, OCT4 or placenta-like alkaline phosphatase (PLAP) immunostaining can be useful to highlight tumor cells. The features of other autoimmune diseases are discussed later in this chapter.

Death of normal brain tissue is a late complication of radiation therapy and usually develops between 6 months and 2 years following exposure,
mostly at doses of 50 Gy and above (35). Infiltrating gliomas frequently undergo such radiotherapy, which, while an effective measure to slow down the advance of disease, creates a diagnostic dilemma for the treating clinician, who must then attempt to distinguish between changes due to tumor recurrence and those due to radionecrosis on subsequent surveillance imaging. If imaging studies are inconclusive or the patient is symptomatic, the lesion may be biopsied or resected.

The MRI appearance of radiation necrosis consists of a contrast-enhancing lesion that generally lacks mass effect, but generates an impressive corona of edema, imbuing a similarity to the appearance of high-grade glioma or lymphoma. Several radiologic techniques have been used to interrogate possible radionecrosis, including diffusion-weighted imaging (36), thallium uptake (37), positron-emission tomography (38), and spectroscopy (39), with mixed results.

Treatment for radiation necrosis may consist of surgical resection, corticosteroids or bevacizumab, an angiogenesis inhibitor (40).

Coagulative necrosis, with pale outlines of once-living structures, heterogeneously involves white matter and contains a sparse population of residual glial cells (Figure 2-11). Inflammatory cells are generally minimal, with only a sparse contingent of foamy macrophages, if any. The blood vessels react to the insult with fibrinoid necrosis, thickening and hyalinization of the media, and breakdown of the endothelial layer, which presumably causes the thrombi seen in many of the damaged vessels. Alternatively, some blood vessels may be proliferating, even floridly, under hypoxic conditions. The endothelial cells are generally atrophic but may be enlarged with radiation atypia. Deposits of hemosiderin, proteinaceous debris, and calcium occur as the lesion ages.

The differential diagnosis of radiation necrosis almost invariably includes recurrent tumor, and the course of the patient’s ongoing treatment often depends on which diagnoses are returned. If the interpretation is recurrent/progressive tumor, then the treatment regimen will most
likely be changed to another antineoplastic therapy, but a diagnosis of radiation necrosis will shift treatment focus to alleviate its effects. In the strictest sense, some residual tumor is always present in cases of infiltrating glioma, but the interpretation should reflect the overall theme of the biopsy tissue. Scant atypical cells do not justify a diagnosis of recurrence in the context of large amounts of radiation necrosis. Mentioning both recurrent tumor and radiation necrosis in the diagnosis, and including a comment estimating the relative amounts of each may be helpful to avoid confusion.

In an infiltrating astrocytoma, radiation-induced necrosis should not be taken as a sign of progression to glioblastoma, although proving whether necrosis is due to treatment or tumor biology is difficult. Progression to glioblastoma should be considered when increased cellularity and/or pseudopalisading necrosis develop(s). Microvascular proliferation can also be seen following radiation, and therefore should be used with caution as a criterion for glioblastoma following radiation.