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A 45-year-old man develops pancytopenia and brain lesions
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A 45-year-old black man with no significant medical history presented with newly onset grand mal seizures.
He had experienced some headaches and weight loss, which he attributed to his recent flu-like illness. He had no history of trauma or seizures. His medical history was significant for asthma and Lyme disease.
His medications included a multivitamin and albuterol on an as-needed basis.
He was a nonsmoker and did not use alcohol. Family history was noncontributory.
MRI shows lesions
Ramya Varadarajan
A head CT showed no abnormalities. MRI showed two faintly enhancing lesions — a 6-mm x 8-mm left frontal mass and a 14-mm right parietal mass. Complete blood count showed pancytopenia with an especially low white count of 2.9. A lumbar puncture, performed for infectious etiology, showed no white blood cells, as well as normal protein and glucose levels. There were insufficient cells for flow cytometry. An HIV enzyme-linked immunosorbent assay (ELISA) was ordered and was positive, and it was confirmed by Western blot technique. His CD4 count was less than 10. His toxoplasma antigen and cryptococcal antigen were negative.
The patient’s symptoms worsened during the next week with increasing nausea, vomiting and lethargy. A second MRI showed interval increase in the original lesions, as well as new lesions in the cerebellum. Stereotactic biopsy of the brain showed abundant numbers of large malignant-appearing lymphoid cells clustered in a concentric fashion around blood vessels, with infiltration into the cerebral cortex.
Flow cytometry results demonstrated a population of B cells, which were CD45-, CD19- and CD20-positive with lambda light chain restriction. Immunoperoxidase studies on the formalin fixed paraffin-embedded tissue demonstrated strong positive staining with CD20 and negative staining with CD3. A reticulin stain highlighted concentric staining around the blood vessels with an onionskin pattern. These were all consistent with primary central nervous system lymphoma.
The patient was started on highly active antiretroviral therapy (HAART) for HIV and high-dose methotrexate chemotherapy for central nervous system lymphoma. Initially, he had a long hospitalization with severe diarrhea of noninfectious etiology, resulting in hypokalemia. He also had episodes of confusion and agitation. He eventually improved clinically and was discharged. After three cycles of methotrexate, a repeat MRI was performed and showed reduction in the size of lesions. He has completed five doses of high-dose methotrexate and, so far, is clinically doing well.
Overview of PCNSL
Primary central nervous system lymphoma (PCNSL) is currently under one of the four AIDS-defining malignancies. Systemic non-Hodgkin’s lymphoma accounts for the great majority of AIDS-related lymphomas, whereas PCNSL accounts for about 15% and primary effusion lymphoma accounts for less than 1%.
Among patients with HIV, the incidence of PCNSL is 2% to 6%, but it has been as high as 10% in an autopsy series in the pre-HAART era. This incidence is at least 1,000 times higher than that of the general population. PCNSL accounts for up to 15% of NHLs in HIV-infected patients compared with 1% of NHLs in the general population.
Figure 1. A diagnostic MRI shows an 8 mm x 6 mm frontal mass.
Source: Images courtesy of R. Varadarajan, MD.
PCNSL requires a more severe degree of immunosuppression than most other AIDS-related complications, as the CD4 counts in affected patients are generally less than 50/mL. The effect of CD4 count was observed regardless of HAART use. A high HIV viral load also is a risk factor for NHLs.
The overall incidence of NHL has declined with the widespread use of HAART. Nevertheless, the incidence of NHL in HIV-seropositive patients remains above that of the non-HIV–infected population.
Although the incidence of AIDS-defining cancers decreased in the HAART era, the incidence of certain types of non-AIDS–defining cancers — such as anal, lung, liver and prostate cancers, as well as Hodgkin’s lymphoma — has increased, likely reflecting increased survival of HIV-infected individuals.
The incidence of PCNSL increases with prolonged survival from HIV-1 infection and is rarely an initial AIDS-defining illness.
The pathogenesis of NHL in the setting of HIV infection is thought to be due to immune deregulation leading to loss of control of viruses, such as Epstein-Barr virus (EBV). AIDS-related PCNSL are most commonly derived from B cells. There is an unregulated expansion of cells that are arrested in development and are unable to undergo terminal differentiation. Genetic alterations may be involved, in the pathogenesis and in determining the histology of the resulting clonal proliferations.
The clinical presentation is variable and may present as confusion, lethargy, memory loss, hemiparesis, aphasia or seizures. Systemic B symptoms can occur in more than 80% of patients.
Differential diagnosis
Diagnosis is initially made by imaging modalities such as CT scan or MRI of the brain. Differential diagnosis of a HIV-positive patient presenting with brain lesions are PCNSL, toxoplasmosis and progressive multifocal leukoencephalopathy. The distinction is made using a combination of cerebrospinal fluid (CSF) cytology, toxoplasmosis serologic testing, an empiric trial of antibiotics (less commonly used in these days), measurement of EBV DNA in a CSF sample, and brain biopsy.
PCNSL shows a high degree of enhancement on both CT and MRI with contrast, which is unusual in the HIV-seronegative population. This difference is thought to be from the rapid growth rate of lymphomas resulting in high degree of central necrosis. PCNSL and toxoplasmosis are more likely to produce a mass effect on imaging compared with progressive multifocal leukoencephalopathy.
Figure 2. A follow-up MRI 10 days later shows the increase in size of the frontal mass with surrounding edema.
PCNSLs are very sensitive to steroids. Corticosteroids can cause significant shrinkage of the tumor within a few days and can convert enhancing lesions into nonenhancing lesions. Biopsy in these situations may yield necrotic or nondiagnostic tissue. Thus, in the absence of severe manifestations, steroids are avoided prior biopsy. Combining imaging with measurement of EBV DNA in CSF had 100% sensitivity and almost 100% negative predictive value.
Lumbar puncture is another relatively noninvasive and may provide a diagnosis of PCNSL if it was positive by cytology. If CSF cytology does not establish the diagnosis, toxoplasma serologies should be obtained. If the toxoplasma serology is negative, early brain biopsy is recommended. Stereotactic brain biopsy is an effective diagnostic procedure in HIV-infected patients with focal brain lesions.
Staging is generally not indicated in patients with PCNSL, as it almost always remains confined to the CNS but can spread within the CNS, such as to the leptomeninges, spinal cord and eye.
Optimal therapy
Figure 3. A follow-up MRI after three cycles of high-dose methotrexate shows the decrease in size and edema of the frontal mass.
The optimal therapy for PCNSL is not clear. High-dose methotrexate therapy (eg, 3 g/m2 for four to eight cycles) with leucovorin rescue administered concurrently with steroids and potent antiretroviral therapy, offers palliation for up to 12 to 18 months. High-dose methotrexate plus temozolomide (Temodar, Schering-Plough) and rituximab (Rituxan, Genentech/Idec Pharmaceuticals), used for non-HIV–related PCNSL, may be an approach in certain patients.
A small pilot study evaluated the efficacy of high-dose methotrexate given intravenously without radiation therapy in 15 patients with PCNSL and a mean CD4 cell count of 30/mL. Forty-seven percent of patients had a complete response, and the median survival was 19 months. This occurred without the neurologic impairment that can occur with radiation therapy.
PCNSL is extremely sensitive to radiation therapy, but its use in the initial treatment is controversial. Radiation alone had been the initial therapy of choice before introduction of high-dose systemic methotrexate. It still remains an option for the palliative treatment of patients who are not candidates for high-dose systemic chemotherapy, but it is associated with long-term neurotoxicity.
For younger patients who fail to achieve a complete response with high-dose methotrexate, the addition of a second chemotherapy agent or the addition of whole-brain radiation therapy after completion of chemotherapy rather than waiting until the development of progressive disease can be considered.
References:
Coté TR. Int J Cancer. 1997;73:645.
Jacomet C. AIDS. 1997;11:1725-1730.
For more information:
Ramya Varadarajan, MD, is a consultant at Regional Hematology and Oncology, PA, at Helen Graham Cancer Center in Newark, Del. She also is a member of the HemOnc Today Editorial Board. She can be reached at Regional Hematology & Oncology, 4701 Ogletown Stanton Road, Suite 2400, Newark, DE 19713.
Disclosure: Varadarajan reports no relevant financial disclosures.