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Clinico-Pathological Conference
Case Study




Answer to CPC #6 (Wednesday, March 19, 2003)

This patient presents with chronically decreased memory, verbal unresponsiveness and focal neurologic deficits including a sluggish right pupil and flaccidity of the left arm. The patient has both pulmonary and brain nodules on imaging studies.

 

The differential diagnosis centers upon infectious, neoplastic, and inflammatory disorders. Infectious causes include endocarditis with resulting septic emboli caused by typical bacteria such as Staphylococcus, but also atypical bacteria such as Mycobacterium tuberculosis, Mycobacterium avium-intracellulare, Nocardia, and Rhodococcus. Possible viral pathogens include Cytomegalovirus, which could induce a cerebritis and pneumonitis, or less likely, Epstein-Barr virus. Fungal pathogens to consider include Aspergillus species and Cryptococcus. Parasitic pathogens include Toxoplasmosis gondii and Pneumocystis carinii. The patient received therapy for many of these organisms, including trimethamine for Toxoplasmosis, trimethoprim for Pneumocystis, fluconazole for fungal infection, and cephtriaxone for bacterial infection. The patient's illness progressed despite these therapies.

Malignant lymphoma tops the list of neoplastic possibilities. Specifically, in the setting of AIDS, an Epstein-Barr virus driven B-cell lymphoma is a strong possibility. Solid tumors, such as Kaposi's sarcoma or metastatic adenocarcinoma, are less likely. A multicentric glioma could account for the central nervous system findings but would unlikely to yield the pulmonary nodules. Among the inflammatory disorders, sarcoidosis and vasculitis should be considered.

Given the wide range of diagnostic possibilities, in a patient with a better chance of survival, a brain biopsy could have been crucial to guide the proper course of therapy. Given this patient's extremely poor prognosis, a biopsy was not performed and the patient expired.

A complete autopsy was requested and performed with consent. Internal examination revealed the most significant findings in the lung and brain. Examination of the lungs revealed significant pulmonary edema and five peripherally-based, grossly calcified lesions within the lung parenchyma bilaterally. Microscopically, the lesions appeared to be granulomatous with areas of central necrosis (Figure 1, 2). Special stains for microorganisms, including fungi and acid-fast organisms were negative. However, occasional cells demonstrated intranuclear inclusions consistent with cytomegalovirus (CMV) infection, and these were confirmed using immunohistochemistry (IHC) (Figure 3, 4). Disseminated CMV infection was seen in the lungs, kidney (Figure 5), adrenal gland, pancreas, ovary and spleen. Also, several peripheral areas of parenchymal hemorrhage were seen in the lungs, consistent with infarcts from pulmonary emboli.

Figure 1
Figure 1

Figure 2
Figure 2

Figure 3
Figure 3

Figure 4
Figure 4

Figure 5
Figure 5

Examination of the brain revealed 5 poorly defined lesions in the right frontal lobe, bilateral caudate, left insula and left cerebellum (Figure 6). Microscopically, these lesions were necrotic with large numbers of atypical large lymphocytes in a perivascular distribution with extension into the brain parenchyma (Figure 7, 8). Immunohistochemical stains for CD20 (Figure 9) and CD3 (Figure 10) demonstrated that these were predominantly CD20-positive B-cells, and these cells focally expressed the Epstein-Barr virus latent membrane protein antigen (EBV-LMP) (Figure 11). This is consistent with an HIV- related primary CNS B-cell lymphoma. Microscopically, the lymphoma involved all regions of the brain except the occipital lobe, thus accounting for the patient's neurologic symptoms immediately preceding her demise.

Figure 6
Figure 6

Figure 7
Figure 7

Figure 8
Figure 8

Figure 9
Figure 9

Figure 10
Figure 10

Figure 11
Figure 11

Lymphomas arising in the setting of HIV are a topic of great importance (Figure 12, 13). The incidence of non-Hodgkins lymphoma has increased 200 fold in the setting of HIV. The pathogenesis is thought to be multifactorial, involving specific genetic abnormalities in oncogenes such as MYC and BCL-6, chronic antigen simulation, cytokine disregulation, and herpes viruses such as EBV and HHV8. Specific aggressive subtypes of lymphoma seen in HIV include Burkitt's lymphoma, diffuse large B-cell lymphoma, primary effusion lymphoma and plasmablastic lymphoma of the oral cavity. The latter two are almost exclusively seen in immunosuppressed hosts. These have specific pathogenic association with viruses. Thirty percent of diffuse large B-cell lymphomas will be associated with EBV infection, while 100 percent of primary effusion lymphomas are associated with HHV8 infection. Lymphomas in the setting of HIV have a propensity to involve extra-nodal sites such as the gastrointestinal tract, central nervous system, liver, and bone marrow; lymph nodes are involved in only one third of cases at presentation. Patients typically present at advanced clinical stage with extranodal disease, elevated serum LDH levels, and variable CD4 counts. The clinical outcome correlates with the degree of immunodeficiency. Given that this patient had an extremely low CD4 count, her chances of surviving this tumor were extremely poor.

Figure 12
Figure 12

Figure 13
Figure 13

Hence, this patient expired from a combination of neoplasm (large B-cell lymphoma of the brain, associated with Epstein-Barr virus infection) and infection, (disseminated Cytomegalovirus infection). The patient was predisposed to both of these disorders by having AIDS. In retrospect, the diagnostic dilemma with the case was that most of the disorders that cause pulmonary nodules and hypoxia (e.g. CMV, pulmonary emboli, etc.) do not generally cause mass lesions in the brain (e.g. toxoplasmosis, primary CNS lymphoma, etc.), and vice versa. One of the general principles of medicine is the principle of parsimony (a.k.a. "Ockham's razor," after the 14th century philosopher who articulated it), which postulates that, given multiple clinical abnormalities, a single unifying process that can account for all abnormalities is more likely than multiple separate processes. In this case, this principle led the discussant to focus on unusual fungal and mycobacterial infections that might produce both the brain and lung findings. While the parsimony principle generally holds, it is less likely to hold in the setting of immunocompromise, where patients not infrequently have multiple processes occurring simultaneously. The present case exemplifies how this rule is may be violated in the setting of AIDS.


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