Cerebral Aspergillosis: Radiologic and Pathologic Findings
An 18-year-old man presented initially with a large left-sided neck mass and left-sided pleural effusion, and a diagnosis of T-cell lymphoblastic lymphoma was made. The patient was treated with standard chemotherapy, which led to complete remission. Several months later, at the end of the delayed intensification phase of therapy, the patient experienced local recurrence. He subsequently received high-dose mediastinal and left whole lung–field radiation. Posttreatment imaging showed extensive retroperitoneal disease with involvement of the left kidney and testis. The patient underwent additional chemotherapy and radiation therapy, and several months later he received a matched unrelated donor bone marrow transplant. The patient’s posttransplantation course was complicated by graft-versus-host disease, hemorrhagic cystitis, and renal failure.
Eighteen months after the original diagnosis, and 1 month following bone marrow transplantation, the patient was readmitted to the hospital after 3 days of nausea, vomiting, and diarrhea. There was no evidence of lymphoma at physical examination or blood testing. After several days in the hospital, the patient developed increasing lethargy and speech difficulties, and magnetic resonance (MR) imaging of the brain was performed.
MR imaging revealed a 3-cm heterogeneous lesion in the right frontal lobe. Un-enhanced T1-weighted imaging showed the lesion with a thin rim of increased signal intensity (,Fig 1a,,,). At T1-weighted imaging performed after the intravenous injection of gadopentetate dimeglumine, only slight peripheral enhancement was seen (,,Fig 1b,,). Gradient-echo imaging showed low signal intensity with susceptibility artifact within the lesion, findings that were consistent with blood products (,,,Fig 1c,). T2-weighted imaging demonstrated a heterogeneous mass with irregular margins, a hyperintense center, and a hypointense rim, as well as a large amount of surrounding vasogenic edema (,,,,Fig 1d). The patient was treated with antifungal therapy, but 2 weeks later his symptoms of lethargy had worsened. The patient underwent a second MR imaging examination, which showed interval growth of the frontal lesion as well as a second right occipital lesion. Three days later, the patient became comatose, and two days later he died. Autopsy revealed the cause of death to be acute respiratory distress syndrome with underlying disseminated aspergillosis. The mediastinal T-cell lymphoma was completely necrotic.
Gross pathologic evaluation of the brain at autopsy revealed bulging of the right frontotemporal region, with flattening and widening of the gyri. Axial sections showed a 5 × 4 × 3-cm necrotic lesion in the right frontal lobe (,Fig 2). The lesion was surrounded by a hemorrhagic rim, which was in turn surrounded by an area of yellow-green discoloration with loss of distinction of the overlying gray matter–white matter junction. A similar but smaller lesion was seen in the right occipital lobe. Petechial hemorrhages surrounded both lesions.
Microscopic evaluation of the brain lesions showed foci of coagulative necrosis of brain tissue containing intravascular and invasive septate fungal hyphae with acute angle branching (,Fig 3). A neutrophilic infiltrate surrounded the necrosis and was in turn rimmed by acute hemorrhage and edematous but viable brain tissue (,Fig 4). Aspergillus fumigatus was isolated from a fungal culture of brain tissue.
Opportunistic infections, particularly fungal infections, are a common complication in bone marrow transplant recipients. Candida and Aspergillus are among the most common fungal pathogens and are responsible for the majority of brain abscesses in immunocompromised patients (,1,,2). Cryptococcosis is another common mycotic infection of the central nervous system (CNS), manifesting primarily as meningitis (,3).
Aspergillus spores are commonly airborne and inhaled by the host, causing infection of the respiratory system. Aspergillus may then gain access to the CNS via hematogenous spread or direct spread from the paranasal sinuses (,4). Cerebral aspergillosis has a poor prognosis in immunocompromised patients, with the mortality rate approaching 100% (,2). Pulmonary aspergillosis can be treated with amphotericin B; therefore, it is crucial that the diagnosis of pulmonary aspergillosis be made and treatment instituted before spread to the brain occurs (,5).
The clinical diagnosis is difficult to make because the presenting signs and symptoms are non-specific. Multiple studies have described a variety of presenting symptoms such as headache, hemi-paresis, dysarthria, lethargy, and seizures with or without fever (,5–,7).
Aspergillosis has a predilection for invasion of the walls of both small and large blood vessels, resulting in thrombosis and subsequent infarction and hemorrhage (,8). The organism can then spread beyond the vessel walls and form abscesses in the altered brain tissue. Another common occurrence in the CNS is mycotic aneurysm (,4).
The most distinct imaging characteristics at computed tomography or MR imaging are multiple lesions with infarction or hemorrhage in a random distribution due to the angioinvasive nature of the infection (,9). Hemorrhage occurs in approximately 25% of lesions, and contrast material enhancement is usually vague or absent (,10). Low signal intensity is often seen in the periphery of the lesions on T2-weighted MR images. This finding corresponds at least partially to areas of hemorrhage. A study of fungal sinus infections by Zinreich et al (,11) attributed the zones of low T2 signal intensity to the presence of iron, manganese, and magnesium in the fungal concretions. Aspergillus abscesses have been shown to contain a dense population of hyphal elements peripherally with a relative paucity of fungal elements centrally, features that likely contribute to the distinct peripheral T2 hypointensity (,1).
In the present case, the lesions had a central core that was isointense relative to gray matter. Histologic analysis showed this finding to represent coagulative necrosis from vascular occlusion by fungi. The areas of low T2 signal intensity within the core and in a ring around the lesion corresponded histologically to areas of hemorrhage.
The differential diagnosis of multiple brain lesions in an immunocompromised patient includes lymphoma, metastatic disease, septic emboli, and multiple infarcts. Lack of enhancement may suggest the diagnosis of aspergillosis, since most brain tumors enhance. It is important to understand that regardless of whether the diagnosis of cerebral aspergillosis has been established, a prospective diagnosis should be suggested in the setting of early infarction and hemorrhage in the brain of an immunocompromised patient, so that antifungal therapy may be instituted (,9).
Editor’s Note.—Everyone who has taken the course in radiologic pathology at the Armed Forces Institute of Pathology (AFIP) remembers bringing beautifully illustrated cases for accession to the Institute. In recent years, the staff of the Department of Radiologic Pathology has judged the “best cases” by organ system, and recognition is given to the winners on the last day of the class. With each issue of RadioGraphics, one or more of these cases are published, written by the winning resident. Radiologic-pathologic correlation is emphasized, and the causes of the imaging signs of various diseases are illustrated.
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