MACROSCOPIC APPEARANCES

Hematogenous dissemination generally leads to multiple lesions, which vary from a few millimeters to several centimeters in diameter. These often occur in the anterior and middle cerebral artery distributions and involve the cerebral cortex (Fig. 17.1), white matter, and basal ganglia, but brain stem and cerebellar structures (Fig. 17.1) may also be affected.

Early lesions often resemble hemorrhagic infarcts (Fig. 17.1). These may form abscesses, although a thick fibrous capsule only rarely develops. In other lesions, there are foci of non-suppurative white or yellow necrotic material admixed with a variable amount of hemorrhagic tissue (Fig. 17.1). Much less frequently the fungus produces intraparenchymal granulomas or even meningitis. Aspergillus granulomas are usually a feature of chronic infection, but may be solitary lesions.

Aspergillus that enters the cranial cavity as a result of direct rather than hematogenous spread usually causes chronic, relatively localized infection with a tendency to fibrosis and granuloma formation.

MICROSCOPIC APPEARANCES

Prominent microscopic features are:

Hyphae are found in the lumen, the wall and adjacent tissue of blood vessels of varying caliber (Fig. 17.2) and may be visible as silhouette-like unstained structures in giant cells. Although they are faintly visible in hematoxylin and eosin preparations and stain with the PAS technique, the hyphae are most clearly demonstrated by methenamine silver impregnation. Because Aspergillus is morphologically similar to several other molds, a diagnosis of ‘invasive septate hyphae consistent with aspergillosis’ is the most accurate diagnosis that can be given on histopathology alone.

Neutrophils predominate in the early phase of disease and macrophages at later stages. In abscesses, frank pus can be seen in the center of the lesion and abundant neutrophil infiltration at the edges, in some cases accompanied by granulomas. Necrotizing non-suppurative lesions include zones of coagulative necrosis with scanty neutrophil reaction and hemorrhage. Both types of acute lesion are associated with vasculitis, vascular necrosis, and thrombosis (Fig. 17.3).

Granulomatous lesions consist of aggregates of lymphocytes, plasma cells, epithelioid macrophages, Langhans-type multinucleated giant cells, and variable amounts of collagen and necrotic tissue (Fig. 17.4). Chronic granulomas may become densely fibrotic.

Chronic abscesses may develop a dense collagenous connective tissue capsule (Fig. 17.5) without a granulomatous tissue reaction. The amount of inflammation varies from patient to patient and may be scanty in treated cases.

MACROSCOPIC APPEARANCES

In rhinocerebral mucormycosis, foci of hemorrhagic necrosis are most prominent in the orbital part of the frontal lobes (Fig. 17.6). Necrotic, hemorrhagic tissue is present in the nasopharynx, orbit, and adjacent skull base. There may be thrombosis in the cavernous sinus or carotid artery. When CNS involvement results from hematogenous dissemination, lesions tend to be concentrated in the basal ganglia.

MICROSCOPIC APPEARANCES

The diagnostic broad non-septate hyphae vary in caliber and branch at irregular intervals. They can be seen in and around the walls of blood vessels in the meninges and brain (Fig. 17.7). Admixed hyphae and thrombus occlude the lumina and are associated with extensive hemorrhagic infarction (Fig. 17.7). The hyphae, which may be relatively sparse, are best demonstrated by methenamine silver impregnation. A mixed or predominantly neutrophil inflammatory response may occur around the infiltrated blood vessels and where hyphae extend into adjacent brain tissue. Multinucleated giant cells are occasionally seen, but granulomas are not a typical feature.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

Disseminated infection can cause meningitis and brain abscesses, with an associated mononuclear inflammatory cell infiltrate. Microglial nodules may be widely scattered throughout the brain. The fungus tends to invade blood vessels, causing thrombosis and tissue necrosis. The septate, broad, branching hyphae are well visualized by silver impregnation (Fig. 17.8). Differentiation from other hyalohyphomycoses such as Aspergillus requires culture.

MACROSCOPIC AND MICROSCOPIC APPEARANCES

The hyphae invade blood vessels and, admixed with thrombus, occlude vascular lumina, causing hemorrhagic infarcts. These tend to evolve into cerebral abscesses, which are usually associated with chronic granulomatous inflammation in the surrounding brain parenchyma and leptomeninges.

MACROSCOPIC APPEARANCES

The frontal lobe is most often involved, but lesions can occur anywhere in the brain. Foci of infarction and necrosis occur, may cavitate and become encapsulated to form single or multiple abscesses (Fig. 17.9). These may extend into the subarachnoid space or ventricles, producing leptomeningitis or ventriculitis. The characteristic brown color of the mycelia can be recognized macroscopically.

MICROSCOPIC APPEARANCES

Histology reveals infarcts and parenchymal abscesses. There may be a chronic meningitis and ventriculitis. The abscesses contain necrotic debris and branching fungal hyphae with prominent round or elliptical conidia (Fig. 17.9). Both the conidia and the hyphae are pigmented, and can be seen in unstained sections. They are also well visualized with PAS, or methenamine silver impregnation. The parenchymal inflammatory reaction varies. In some cases the necrotic tissue and fungi are surrounded by neutrophils, lymphocytes, histiocytes and multinucleated giant cells, and there is prominent fibrosis and reactive gliosis. In other cases the reaction may be minimal.

MACROSCOPIC APPEARANCES

Macroscopic changes may be minimal. However, in most cases the meninges are moderately thickened and opacified (Fig. 17.10). In cases of particularly florid infection, the large number of organisms gives the surface of the specimen a slimy consistency. Rarely, small granulomas 2–3 mm in diameter and similar to those of tuberculous meningitis are seen (Fig. 17.10). In some patients with AIDS, there is a yellow–gray exudate in the ventricles and perivascular spaces as well as in the leptomeninges.

Subacute or chronic cryptococcal meningitis produces leptomeningeal fibrosis (Fig. 17.11) and is often associated with hydrocephalus (Fig. 17.12).

Approximately 50% of cases show, in addition to meningeal involvement, multiple intraparenchymal cysts that have been likened to soap bubbles (Fig. 17.12). These are related to the exuberant capsular material produced by proliferating cryptococci in perivascular spaces in the gray matter. Cryptococcal cysts are often prominent in the basal ganglia. The dura mater is occasionally involved, particularly in the spinal canal.

Cryptococcomas have a variable appearance. Some are solid gelatinous (Fig. 17.13) or granulomatous lesions, while others resemble bacterial abscesses. They can occur in the meninges, parenchyma, adjacent to ependymal surfaces, or in the choroid plexus.

MICROSCOPIC APPEARANCES

The organisms appear as singly budding yeast forms. They have a round body, 4–7 μm in diameter, and are surrounded by a capsule 3–5 μm thick, which stains strongly with Alcian blue or mucicarmine. The fungi can also be visualized by PAS staining or methenamine silver impregnation. Shrinkage of the capsule during paraffin embedding may leave a clear ‘halo’ around the stained organisms. The staining reactions are similar to those of corpora amylacea, with which cryptococci can be confused (Fig. 17.14).

Leptomeningeal inflammation is usually scant, but can be pronounced. When present, it comprises collections of lymphocytes, plasma cells, eosinophils, and multinucleated giant cells. The nuclei of the giant cells are generally located more centrally than in Langhans-type giant cells (Fig. 17.15). Cryptococci, with or without capsules, are often visible in the cytoplasm of the giant cells (Fig. 17.15).

Granulomas are found only rarely. They consist of fibroblasts, giant cells, massive aggregates of organisms, and areas of necrosis. Many of the organisms are found within multinucleated giant cells and show scant encapsulation.

The gelatinous parenchymal lesions consist of colonies of cryptococci, which fill and expand the perivascular spaces. There is usually little or no surrounding inflammation and gliosis (Fig. 17.14).

MACROSCOPIC APPEARANCES

In some cases, there are no macroscopic abnormalities. The meninges usually appear normal. Scattered hemorrhagic infarcts may involve any part of the CNS, but occur most often in the perfusion territories of the anterior and middle cerebral arteries. The infarcts evolve into small abscesses (Fig. 17.17) or granulomas.

MICROSCOPIC APPEARANCES

The budding yeasts and pseudohyphae are faintly basophilic in sections stained with hematoxylin and eosin (Fig. 17.18), stain intensely with PAS (Fig. 17.18), and are also well visualized with methenamine silver impregnation (Fig. 17.18). They are demonstrable in and around blood vessels and in and adjacent to foci of necrosis. There may be thrombosed blood vessels with adjacent hemorrhage and infarction.

There is usually only scanty lymphocytic infiltration of the meninges. The cellular response to the fungus in the brain parenchyma is variable. There may be:

MACROSCOPIC APPEARANCES

In most cases there is patchy thickening and opacity of the meninges due to a combination of purulent exudate and fibrosis, which may cause hydrocephalus. Small abscesses or granulomas are often present in the underlying brain parenchyma or in the subdural space. Solitary or multiple, larger abscesses or granulomas (blastomycomas) can occur in any part of the CNS.

MICROSCOPIC APPEARANCES

Although usually visible in hematoxylin and eosin-stained sections, the fungi are best demonstrated with PAS or methenamine silver impregnation (Fig. 17.20). B. dermatitidis elicits a mixed granulomatous and purulent reaction in varying combinations. Neutrophils, lymphocytes, plasma cells, and macrophages surround necrotic tissue containing variable numbers of yeasts. Older abscesses develop a thick collagenous capsule (Fig. 17.20). The lesions may resemble tuberculous granulomas with central caseous necrosis and Langhans-type multinucleated giant cells.

MACROSCOPIC APPEARANCES

An exudate is usually visible in the cerebral sulci or over the base of the brain. As the exudate organizes the leptomeninges thicken and opacify. Small granulomas may be discernible, particularly in the thickened basal meninges. Sectioning of the brain usually reveals scattered small granulomas or, less commonly, abscesses. There may be ischemic lesions, infarcts, or multifocal encephalomalacia due to the development of endarteritis.

MICROSCOPIC APPEARANCES

The spherules and enclosed endospores usually appear basophilic when stained with hematoxylin and eosin (Fig. 17.21), but are better demonstrated by methenamine silver impregnation. The spherules are surrounded by varying numbers of lymphocytes, plasma cells, epithelioid cells, multinucleated giant cells, and fibroblasts (Fig. 17.21). These may be aggregated to form small granulomas with central caseous necrosis. The inflammatory reaction resembles that of a tuberculous infection. On rupture of the spherules, however, the endospores tend to elicit a more acute inflammatory response with neutrophils and microabscess formation. Extension of the acute inflammation into the meninges may produce a florid but localized meningoencephalitis (Fig. 17.21).

MACROSCOPIC APPEARANCES

Lesions in the CNS consist of thickened leptomeninges, especially around the base of the brain, miliary granulomas, and small foci of necrosis. A yellowish gray exudate may accumulate within the cerebral sulci and basal meninges (Fig. 17.22). Basal inflammation and associated thrombosis of perforating vessels may cause infarction of the basal ganglia. The granulomas often involve the ependyma and choroid plexus.

MICROSCOPIC APPEARANCES

Diagnosis depends on identifying the organisms by staining or culture since the lesions closely resemble those of other granulomatous fungal infections and tuberculosis.

The 2–5 μm yeasts are best visualized with PAS or methenamine silver impregnation (Figs 17.22, 17.23). The fungi appear much smaller on hematoxylin and eosin staining, which reveals only the basophilic yeast cytoplasm and not the surrounding cell wall. The cytoplasm tends to shrink away from the cell wall during tissue processing to produce a halo, which on cursory examination resembles a capsule.

Lesions range from small nodular aggregates of macrophages to classical caseating or non-caseating granulomas containing epithelioid cells and Langhans giant cells. The yeasts are usually found aggregated within the cytoplasm of macrophages (Figs 17.22, 17.23), but may be sparse.

The meningeal infiltrate (Fig. 17.23) resembles that of tuberculous meningitis, with lymphocytes, macrophages, and plasma cells, and occasional granulomas. The inflammation can extend into the walls of blood vessels, causing focal vascular necrosis and thrombosis.

MACROSCOPIC APPEARANCES

The more frequent form of CNS paracoccidioidomycosis is the pseudotumorous form, which results from the formation of one or more paracoccidioidomycomas. These well-circumscribed necrotic nodules vary from a few millimeters to several centimeters in diameter (Fig. 17.24) and are usually situated in the cerebral cortex. Similar lesions can occur in the brain stem and spinal cord. Paracoccidioidomycomas in the dura mater may simulate meningiomas both clinically and macroscopically. The leptomeningitis is granulomatous, predominantly basal, and may cause obstructive hydrocephalus.

MICROSCOPIC APPEARANCES

The granulomas are formed from lymphocytes, macrophages, epithelioid cells, and Langhans- or foreign body-type giant cells (Fig. 17.25). The granulomas may have a necrotic center and resemble tubercles, but thick-walled budding yeasts are usually demonstrable in sections stained with hematoxylin and eosin, PAS, or methenamine silver impregnation (Fig. 17.25). There may be a chronic inflammatory infiltrate in the leptomeninges. The meningeal infiltrate tends to extend along the perivascular (Virchow–Robin) space into the underlying brain parenchyma, particularly in the hypothalamus and the lateral fissures.