From brain to testis: immune escape and clonal selection in a B cell lymphoma with selective out-growth in two immune sanctuariesy

Abstract

We describe a patient with a primary diffuse large B-cell lymphoma of the central nervous system who developed a localized testicular relapse after 8 years. Both tumours lacked HLA-DR expression, the relapse additionally lost HLA class I expression. Immunoglobulin heavy chain gene rearrangements were identical in both lymphomas with extensive and ongoing somatic hypermutations resulting in extensive idiotype modulation. We hypothesize that these immune sanctuaries initially provided a safe haven for the tumour cells. When the environment becomes more permissive for an anti-tumour response, the continuous idiotype modulation and progressive loss of HLA expression on the tumour cells facilitates further immune escape.

Primary central nervous system lymphoma (PCNSL) and lymphoma of the testis are rare forms of diffuse large B cell lymphoma (DLBCL). Both lymphoma types are immune-privileged site-associated DLBCL (IP-DLBCL), are EBV negative (except for immune-compromised patients), and almost exclusively have an activated B cell-like (ABC) phenotype.1,2 Lymphomas are considered to develop and progress in a multistep manner due to accumulation of genetic aberrations. Where a lymphoma is subject to selective pressure of the immune system, such aberrations may give rise to an immune escape phenotype.3 A common aberration leading to immune escape of PCNSL and testicular DLBCL is loss of HLA expression.4,5,6 Another common feature of both lymphoma types is a high level of (often ongoing) somatic hypermutation (SHM) in the immunoglobulin heavy chain (IgH) genes.1,7,8

Although usually presenting with stage IE disease, patients with PCNSL or testicular DLBCL have a poor prognosis that has only recently improved upon introduction of novel chemotherapy strategies.9,10 Primary testicular DLBCL frequently relapse in the CNS up to 10 years after initial presentation.10,11 Relapse of PCNSL is almost always (90–95%) confined to the CNS. One patient has been reported with a relapse of PCNSL in the testis, accompanied by extensive systemic involvement,12 but no patients have been described with a relapse solely in the testis. We describe a unique patient having a CNS lymphoma with a relapse confined to the testis 8 years after diagnosis. The ongoing modulation of the idiotype, in addition to progressive loss of HLA class II and I proteins, might have provided an efficient tumour escape mechanism in these lymphomas.