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 2
Figure 3
Figure 4
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 7
Figure 8
Figure 9
Figure 10
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 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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