Lymphoproliferative disease in antibody deficiency: a multi-centre study

Abstract

SUMMARYWe have undertaken a retrospective study of antibody deficient patients, with and without lymphoma, and assessed the ability of specific polymerase chain reaction (PCR) primers to determine if the detection of clonal lymphocyte populations correlates with clinical and immunohistochemical diagnosis of lymphoma. We identified 158 cases with antibody deficiency presenting during the past 20 years. Paraffin-embedded biopsy specimens or slides were available for analysis in a cohort of 34 patients. Of these patients, 29 had common variable immunodeficiency, one X-linked agammaglobulinaemia, one Xlinked immunoglobulin deficiency of uncertain cause and three isolated IgG subclass deficiency. We have confirmed that lymphoma in antibody deficiency is predominantly B cell in origin. Clonal lymphocyte populations were demonstrated in biopsies irrespective of histology (16/19 with lymphoma and 11/15 without). Isolated evidence of clonality in biopsy material is therefore an insufficient diagnostic criterion to determine malignancy. Furthermore, our data suggest that clonal expansions are rarely the result of Epstein-Barr virus-driven disease.

Common variable immunodeficiency –

“…There are also additional diseases, including infections or inflammatory diseases of the gastrointestinal tract, lymphadenopathy, splenomegaly and autoimmune diseases [5]. Due to the diversity of the clinical picture and a low incidence of CVID, the diagnosis is often delayed -in children about 2.5 years, in adults -even up to 5.5 years [8]. This situation poses a real threat to both the short-term and longterm prognosis.…”

“…Their origin is connected with EBV infection resulting in polyclonal B-cell proliferation, which together with concomitant immunological defects leads to uncontrolled proliferation of B cells and the development of lymphoma [35,40]. The genetic material of the virus is not always detected, so that its role in carcinogenesis in the primary hypogammaglobulinemia seems to be of minor importance [8]. In addition to malignant lymphatic hyperplasia in CVID, mild hyperplasia, characterized by lymphadenopathy and splenomegaly is often seen [25,28,47].…”

Immunomodulation and lymphoma in humans

“…However, EBV is associated with only $50% of lymphomas arising after 1 year post-transplantation (Young & Rickinson, 2004), and 28-66% of non-CNS lymphomas among HIV patients (Balandraud et al, 2005;Rabkin, 2001;Macsween & Crawford, 2003). Among patients with primary immunodeficiencies, EBV RNA was present in biopsy samples (detected using in situ hybridization) in some patients with Wiskott-Aldrich Syndrome (3 of 5) and SCID (1 of 3), but not in patients with other primary immunodeficiencies (n ¼ 5; Filipovich et al, 1994), patients with antibody deficiencies (n ¼ 10; Gompels et al, 2003), or patients with common variable immunodeficiency (CVID) presenting with mucosal-associated lymphomas (Cunningham-Rundles et al, 2002). As discussed above, patients with X-linked lymphoproliferative disorder appear to have a unique sensitivity to EBV based on a genetic defect in functional SAP protein, which normally regulates activation-induced lymphocyte apoptosis (Nagy & Klein, 2010).…”

Common Variable Immunodeficiency

“…Most of these are B-cell non-Hodgkin lymphoma, although Hodgkin lymphoma is sometimes seen. EBV is found very infrequently (8). A European registry of CVID has collected 334 patients with a cumulative 9461 patient-years of observation (1).…”