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What is the real risk of central nervous system involvement in mantle cell lymphoma?

It is well recognised that histologically highlyaggressive forms of non-Hodgkin lymphoma (NHL) such as lymphoblastic and Burkitt lymphoma have a very high risk of central nervous system (CNS) dissemination and CNS-directed prophylaxis is essential and highly beneficial [1]. Conversely, clinically indolent lymphomas, such as follicular or marginal zone, have a vanishingly low rate of CNS dissemination (as distinct from the rare cases of primary CNS marginal zone NHL) [2], and CNSdirected prophylaxis is not required. Between these extremes, in large series of unselected HIV-negative patients with systemic diffuse large B-cell lymphoma, the risk of CNS-dissemination is reported to be *5% [3], too low to justify universal routine CNS-directed prophylaxis. However, clinical, histologic and anatomic features have been established as identifying specific patient sub-groups with a 10–30% risk of CNS dissemination, justifying selective ‘‘riskadapted’’ CNS-directed prophylaxis in these specific sub-groups [3–5]. So where does mantle-cell lymphoma (MCL) fit within this spectrum of CNS risk, is cerebro-spinal fluid (CSF) cytology required at initial staging in all patients, and which (if any) patients with MCL warrant CNS-directed prophylactic therapy? MCL comprises approximately 6% of NHL [6] and patients typically present with advanced stage disease and a propensity for leukemic and gastrointestinal involvement. The subtype of blastoid MCL is thought to carry a poorer prognosis [7]. Involvement of the CNS in MCL has previously been reported to range from 4 to 26% [8–11] in series of 64–108 patients (Table I). Between 20% and 50% of cases had blastoid histology at diagnosis or blastoid transformation at relapse, and the majority of cases occur in the context of systemic relapse. The risk in the context of blastoid histology is difficult to accurately quantify, but our interpretation of the available data is that approximately 20– 25% of patients with blastoid histology will have CNS involvement [10,11]. The patients are almost uniformly symptomatic at the time of diagnosis of CNS disease (that is, few are diagnosed incidentally on routine CSF sampling, which may reflect the infrequent use of this modality in staging of MCL patients). This also reinforces the appropriateness of the current policy of not routinely performing CSF sampling as a part of initial staging, unless patients have specific CNS signs or symptoms which warrant investigation. The variable incidence of CNS involvement, as reported by the above quoted studies, may be explained by several factors. In the absence of uniform guidelines on CNS prophylaxis, incidental CNS disease at presentation would only be diagnosed by lumbar puncture for staging, a diagnostic modality not currently routinely performed by most units. The use of high-doses of systemic CNSpenetrating agents such as cytarabine or methotrexate, or specific CNS prophylaxis, which among the popular first-line regimens for MCL is utilised only in the hyper-CVAD program, may influence the incidence of clinically manifest CNS dissemination. However, the fact that in most reports, CNS involvement occurs late and in the setting of systemic