Category Archives: Primary CNS lymphoma

Primary CNS lymphoma

– 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.

Diagnosis

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.

Treatment

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.

References

Aboulafia DM. Interleukin-2, ganciclovir, and high-dose zidovudine for the treatment of AIDS-associated primary central nervous system lymphoma. Clin Infect Dis 2002, 34: 1660-2.

Aboulafia DM, Puswella AL. Highly active antiretroviral therapy as the sole treatment for AIDS-related primary central nervous system lymphoma: a case report with implications for treatment. AIDS Patient Care STDS 2007;21:900-7.

Camilleri-Broet S, Davi F, Feuillard J, et al. AIDS-related primary brain lymphomas: histopathologic and immunohistochemical study of 51 cases. Hum Pathol 1997, 28:367-74.

Carrabba MG, Reni M, Foppoli M, et al. Treatment approaches for primary CNS lymphomas. Expert Opin Pharmacother 2010, 11:1263-76.

Corales R, Taege A, Rehm S, Schmitt S. Regression of AIDS-related CNS Lymphoma with HAART. XIII International AIDS-Conference, Durban, South Africa, 2000, Abstract MoPpB1086.

Corcoran C, Rebe K, van der Plas H, Myer L, Hardie DR. The predictive value of cerebrospinal fluid Epstein-Barr viral load as a marker of primary central nervous system lymphoma in HIV-infected persons. J Clin Virol 2008, 42:433-6.

DeAngelis LM. Primary central nervous system lymphomas. Curr Treat Options Oncol. 2001, 2:309-18.

Fine HA, Mayer RJ. Primary central nervous lymphoma. Ann Intern Med 1993, 119:1093-1104.

Hoffmann C, Tabrizian S, Wolf E et al. Survival of AIDS patients with primary central nervous system lymphoma is dramatically improved by HAART-induced immune recovery. AIDS 2001, 15:2119-2127.

Jacomet C, Girard PM, Lebrette MG, Farese VL, Monfort L, Rozenbaum W. Intravenous methotrexate for primary central nervous system non-Hodgkin’s lymphoma in AIDS. AIDS 1997, 11:1725-30.

Levine AM. AIDS-related lymphoma: clinical aspects. Semin Oncol 2000, 27:442-53.

McGowan JP, Shah S. Long-term remission of AIDS-related PCNSL associated with HAART. AIDS 1998, 952-954.

Newell ME, Hoy JF, Cooper SG, et al. Human immunodeficiency virus-related primary central nervous system lymphoma: factors influencing survival in 111 patients. Cancer 2004, 100:2627-36.

Patsalides AD, Atac G, Hedge U, et al. Lymphomatoid granulomatosis: abnormalities of the brain at MR imaging. Radiology 2005, 237:265-73.

Polesel J, Clifford GM, Rickenbach M, et al. Non-Hodgkin lymphoma incidence in the Swiss HIV Cohort Study before and after highly active antiretroviral therapy. AIDS 2008;22:301-6.

Raez L, Cabral L, Cai JP, et al. Treatment of AIDS-related primary central nervous system lymphoma with zidovudine, ganciclovir, and interleukin 2. AIDS Res Hum Retroviruses 1999, 15:713-9.

Rigolet A, Bossi P, Caumes E, et al. Epidemiological features and incidence trends of primary cerebral lymphomas observed in 80 HIV-infected patients from 1983 to 1999. Pathol Biol (Paris) 2001, 49:572-5.

Skiest DJ, Crosby C. Survival is prolonged by highly active antiretroviral therapy in AIDS atients with primary central nervous system lymphoma. AIDS 2003, 17:1787-93.

Slobod KS, Taylor GH, Sandlund JT, Furth P, Helton KJ, Sixbey JW. Epstein-Barr virus-targeted therapy for AIDS-related primary lymphoma of the central nervous system. Lancet 2000, 356:1493-94.

Wyen C, Stenzel W, Hoffmann C, Lehmann C, Deckert M, Fatkenheuer G. Fatal cerebral lymphomatoid granulomatosis in an HIV-1-infected patient. J Infect. 2006 Dec 11.

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Filed under 13. Malignant Lymphomas, Part 3 - AIDS, Primary CNS lymphoma