Systemic Relapses In Primary CNS Lymphoma (PCNSL) - Unexpected Clonal Diversity

PCNSL is a rare form of extranodal diffuse large B-cell lymphoma (DLBCL). Relapses after initial therapy are usually within the CNS. Systemic relapses (SR) have been reported only occasionally. We conducted a systemic analysis of immunocompetent patients with PCNSL und SR using both clinical data and tumor samples at first diagnosis and SR to determine clonal relatedness.

Records of patients included in a multicenter therapy trial (n=411) and all PCNSL patients treated at our institution outside the trial after 1993 (n=39) were reviewed for SR. PCR analysis of the rearranged Ig heavy-chain (IgH) and light-chain (IgL) genes was performed according to the BIOMED-2 protocol.

All patients had received high-dose methotrexate based chemotherapy with our without adjuvant whole brain irradiation as first line therapy. Of 450 patients 26 (5.8%) were identified with SR. Median time from PCNSL diagnosis to SR was 14.5 months (range 2–61). SR was extranodal in 22 (85%) patients: testicular n=3, gastric n=3, mamma n=3, liver n=2, bone/bone marrow n=3, intestinal n=1, [sub-]cutaneous/muscular n=5, pancreatic n=1, pulmonary n=1. Four patients had concomitant CNS relapse. Median overall survival from diagnosis was 38 months, from SR 9.8 months. Causes of death were SR in 13, CNS relapse in 3, toxicity of chemotherapy in 3 and unknown in 1 patients; 6 patients were alive at last follow up. All 26 patients initially had DLBCL. SR was biopsied in 20 patients: 19 had DLBCL, 1 a Burkitt-like DLBCL. DNA of 7 patients was sufficient for PCR analysis. The same clone was found in the CNS and SR in 4 patients, in 3 patients the clones were different. Clonally related SR occurred after 4, 8, 14 and 25 months; the unrelated SR after 30, 35 and 36 moths.PCR products in 2 of 4 clonally related samples were suitable for sequencing. One case exhibited 6 identical somatic mutations in both biopsies. The second case harbored 35 mutations in the CNS sample and 45 in the SR sample. Here 26 mutations were identical in both samples, 3 involved different nucleosides, 16 were only present in SR, and 6 mutations exclusively present in the CNS sample.

SR is a rare and frequently fatal complication in PCNSL. The localization of SR is predominantly extranodal. A proportion of SR is not clonally related to the primary tumor and then most likely represent a secondary lymphoma. In clonally related SR the presence of somatic mutations unique to the CNS tumor and the SR might be explained by a common ancestor, whose localization however remains unknown.

No relevant conflicts of interest to declare.