This is a heterogeneous group of disorders with a wide range of histological, immunological, and cytogenetic subtypes. Non-Hodgkin lymphoma is the most frequent Tumours to complicate the primary immunodeficiency syndromes (see Table 1) and may also occur in families of patients with chronic lymphocytic leukemia.
The most frequent causes of non-Hodgkin lymphoma complicating primary immunodeficiency are ataxia telangiectasia, Wiskott–Aldrich syndrome, common variable immunodeficiency, and severe combined immunodeficiency, and it is the predominant malignancy in each of these disorders. Mean age at diagnosis is 7 years (from range less than 1–75 years), and the brain and gastrointestinal tract are frequent presenting sites. Compared to non-Hodgkin lymphoma in non-immunodeficient patients, lymph node involvement is less common.
Most non-Hodgkin lymphoma in primary immunodeficient children is of B cell origin, but the lymphomas in ataxia telangiectasia are very heterogeneous, with all the major histological sub-groups represented. There appears to be no relationship between the severity of immunodeficiency and the risk of malignancy (Kersey et al. 1988).
A tendency for familial aggregations of hematolymphoproliferative cancers is recognized. Pottern et al. (1991) found 4.5 % of patients with non- Hodgkin lymphoma had at least one sibling and 3.3 % had a parent with a hematoproliferative cancer, while only 1.7 % of controls had an affected sibling and 2.2 % had a parent with a hematoproliferative cancer. There is a fourfold excess of leukemia and lymphomas among first-degree relatives of patients with non-Hodgkin lymphoma. When familial aggregations of hematoproliferative cancers occur, there is often no particular pattern of Tumours type, so that although concordant cancers may occur, so may seemingly diverse cell types. A history of hemopoietic malignancy in any first-degree relative has been found to be associated with an increased risk of all non-Hodgkin’s lymphoma (OR = 1.8), more pronounced in siblings than in parent–child relationships (Chang et al. 2005). Familial clustering of lymphoma is uncommon, but Lynch et al. (1989) reported a single exceptional family with seven cases of malignant lymphoma (six non- Hodgkin lymphoma and one Hodgkin lymphoma) in three generations with autosomal dominant inheritance. However most family clusters are small. In familial clusters of non-Hodgkin lymphoma with vertical transmission, evidence for anticipation has been reported (Wiernik et al. 2000; Shugart et al. 2001).
Wiernik et al. (2000) analyzed 11 published reports of multigenerational familial non-Hodgkin lymphoma (NHL) and 18 previously unreported families with familial NHL for evidence of anticipation. The median age of onset in the child and parent generations of all families (48.5 and 78.3 years, respectively) and in the selected pairs (52.5 and 71.5 years, respectively) was significantly different. A significant difference was observed between the ages of onset between the child generation and that of the SEER population but not between the parent generation and the SEER population. They thus concluded that anticipation in familial NHL is a genuine phenomenon.
Using the Swedish Family-Cancer Database, Altieri et al. (2005) calculated standardized incidence ratios (SIRs) for histopathology-specific subtypes of NHL in 4,455 offspring with NHL whose parents or sibs were affected with different types of lymphoproliferative malignancies. SIRs for affected patients with a parental history of NHL were significantly increased for NHL (1.8) and diffuse large B cell lymphoma (2.3). SIRs for affected patients with a sib history of NHL were significantly increased for NHL (1.9), follicular lymphoma (2.3), and B cell lymphoma not otherwise specified (3.4). With a parental history of histopathology-specific concordant cancer, familial risks were significantly increased for diffuse large B cell lymphoma, follicular NHL, plasma cell myeloma, and chronic lymphocytic leukemia (SIRs of 11.8, 6.1, 2.5, and 5.9, respectively).
Clementi et al. (2005) reported 4 patients with non-Hodgkin lymphoma with features of hemophagocytic lymphohistiocytosis who had mutations in the perforin gene.
Diffuse large B cell lymphoma (DLBCL) is the most common form of non-Hodgkin lymphoma, accounting for 30–40 % of cases. Survival of the malignant cells is dependent on constitutive activation of the nuclear factor- κB (NF-κB) signaling pathway. In normal B cells, antigen receptor-induced NF-κB activation requires CARD11, a cytoplasmic scaffolding protein. Missense mutations in CARD11 have been demonstrated in about 10 % of LBCL biopsies, all within exons encoding the coiled-coil domain. Such experimental CARD11 mutants cause constitutive NF-κB activation and enhanced NF-κB activity upon antigen receptor stimulation (Lenz et al. 2008; Davis et al. 2010).
Follicular lymphoma susceptibility has been associated with a SNP on chromosome 6p21.33 (Skibola et al. 2009).