– Christian Hoffman –
Primary CNS lymphomas (PCNSL) are a late complication of HIV infection and used to occur in up to 10% of AIDS patients. Large autopsy series in the 1990s showed even higher prevalence rates. The incidence of PCNSL seems to have decreased significantly in the last years in comparison to systemic lymphomas (Polesel 2008). PCNSL are EBV-associated in almost 100% of cases (Camilleri-Broet 1997). Histologically, findings are almost always consistent with diffuse large-cell non-Hodgkin’s lymphomas. In these patients, the CD4 T cells are almost always below 50/μl at the time of diagnosis. In the pre-HAART era, PCNSL had the poorest prognosis of all the AIDS-defining illnesses, with a median survival of less than three months (Fine 1993). In the last years, this bleak picture, often characterized by therapeutic nihilism, has changed significantly. In the HAART-era, survival may be several years and even complete remission has become possible (Hoffmann 2001).
Signs and symptoms
Different neurological deficits occur depending on the localization. Epileptic seizures may be the first manifestation of disease. Personality changes, changes in vigilance, headache and focal deficits such as paresis are also frequent. Fever is usually absent. As patients are almost always severely immunocompromised, constitutional symptoms may mask the actual problem.
Cranial CT or (better) MRT scan should be performed rapidly. The most important differential diagnosis is cerebral toxoplasmosis. A solitary mass is usually more indicative of PCNSL. However, 2-4 lesions may be present, which are usually fairly large (more than 2 cm in diameter). More than four lesions of a PCNSL are rarely found.
In addition to an updated toxoplasmosis serology, which – if negative – makes toxoplasmosis very unlikely, a recent CD4 T cell count should be available. The better the immune status, the less likely the diagnosis of PCNSL. In our own cohort, less than 20% of patients had more than 50 CD4 T cells/μl at the time of diagnosis. At over 100 CD4 T cells/µl, however, cerebral toxoplasmosis is also less likely.
In addition to the physical examination, a minimal diagnostic program (chest radiography, abdominal ultrasound) should clarify whether the CNS involvement is secondary to systemic lymphoma. This should always include fundoscopy to exclude ocular involvement (up to 20%).
Besides cerebral toxoplasmosis, differential diagnoses include abscesses, glioblastoma and cerebral metastasis of solid tumors. In the absence of increased intracranial pressure, lumbar puncture is advised. If steroids have already been administered, however, the probability of finding malignant cells is diminished. EBV DNA is commonly detected in CSF of HIV-infected patients. Quantitative EBV PCR in the CSF improves the diagnostic specificity, however, the predictive value remains too low for it to be used as an isolated marker for PCNSL (Corcoran 2008).
In most cases, a treatment attempt for toxoplasmosis can be made initially. If this is unsuccessful, PCNSL is more likely. In such cases, stereotactic brain biopsy is essential to secure the diagnosis.
For many years, cranial radiation therapy has been the only option for patients with PCNSL, independent of the HIV status. In HIV-negative patients, using the combination of radiation therapy and steroids, a remission of 12-18 months duration is usually achieved. In HIV patients in the pre-HAART era, radiation only improved survival from 0.9 to 3.0 months (Fine 1993). Survival of more than one year was rare.
The prognosis for HIV-negative patients has improved in the last years due to the introduction of methotrexate-based (MTX) chemotherapies (Carraba 2010). Whether these results will be applicable in HIV patients is not clear. In addition, the incidence of PCNSL is now diminishing to such an extent that convincing data on therapy efficacy can hardly be expected in the near future. A clear recommendation for treatment can therefore not be made at this time.
Some clinicians still favor cranial radiation therapy alone in HIV-infected patients (fractionated, 40 Gy total dose). In our experience, before radiation a treatment attempt with intravenous MTX is justified (3 g/m2 every 14 days with leucovorin rescue) – also in order to avoid possible neurological damage from radiation. A small study in HIV patients has shown that this approach is practical (Jacomet 1997).
However, the decisive factor in all cases – independent of the specific therapy chosen – is the best possible immune reconstitution. Under ART, survival of several years has become realistic. Complete remissions have even been described after treatment with ART alone (McGowan 1998, Aboufila 2007). In our own cohort of 29 patients with histologically diagnosed PCNSL, all four patients who experienced an increase in CD4 T cells survived longer than 18 months. Three out of four patients reached complete remission. One patient has now lived for over six years without evidence of relapse (Hoffmann 2001). In a multivariate analysis, combination ART was shown to be the only factor associated with a prolonged survival in addition to cranial radiation therapy. Two of these patients, however, died after about three years of a progressive neurological syndrome, which was probably a long-term sequela of radiation therapy in both cases. In view of the better prognosis for patients today, radiation toxicity should therefore be considered more than in the past. Three further studies from France, the USA and Australia have since shown a survival of several years due to ART (Rigolet 2001, Skiest 2003, Newell 2004).
All patients with PCNSL should therefore be treated intensively with antiretroviral therapy, to achieve the best possible immune reconstitution. If only a moderate immune reconstitution is possible, additional immunomodulatory or antiviral therapies should be evaluated. The partially very positive reports about ganciclovir and interleukin-2 (Raez 1999, Aboulafia 2002) or hydroxyurea (Slobod 2000) should, however, be interpreted with caution. “Between the lines” of these publications, in which either individual or hardly more than 2-4 patients were described, combination ART was almost always a factor.
In all cases with signs of raised intracranial pressure, rapid administration of steroids (e.g. dexamethasone 8 mg tid, decreasing the dose rapidly after resolution of edema) is indicated, even if diagnostic testing is more difficult as a result.
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