A lymphoproliferative disease arising in the setting of a primary immune deficiency (PID) or a primary immunoregulatory disorder (1).

Congenital immunodeficiency syndromes, also commonly referred to in the literature as PIDs, are a large and heterogeneous group of disorders that were initially named and classified in 1971 by a special committee of the World Health Organization (WHO) (2). Since that initial classification, as our understanding of immunology and molecular biology has grown, so too has the number of PIDs. There are now approximately 100 PIDs described and, in a number of these syndromes, the specific genetic defects involved also have been described (3,4).

In the United States, it is estimated that one child in 500 is born with a defect (minor or major) in at least one component of their immune system (3). Many of these children have mild abnormalities and do not develop clinical evidence of marked immunodeficiency. However, the prevalence of PIDs is increasing as a result of improved identification at the clinical level, recognition of specific gene mutations in relatively asymptomatic patients, identification of new genetic abnormalities, and reduced mortality as a result of early recognition and better therapy. Therefore, the current incidence of clinically evident PIDs is 1 in 10,000 (3). In the United States, this incidence translates into approximately 400 newly diagnosed cases of PID per year. The incidence also varies widely for each specific type of PID. For example, IgA deficiency is relatively common, at 1 in 600 (5). In contrast, the incidence of X-linked agammaglobulinemia (also known as Bruton agammaglobulinemia) is 1 in 250,000 males, and the incidence of X-linked lymphoproliferative syndrome (also known as Duncan syndrome) is 1 in 1,000,000 males (5). Most PIDs become manifest in early childhood, often during the first year of life, and are initially suspected because of the presence of recurrent infections. Some patients, for example, those with common variable immunodeficiency, are first diagnosed with PID as teenagers or young adults. Overall, PIDs affect males more often than females. This is true, in part, because a number of these syndromes are inherited in an X-linked fashion. However, a male predominance is also the case for patients with ataxia-telangiectasia, a disease inherited in an autosomal recessive fashion.

In the 1970s, an association between primary immunodeficiencies and subsequent malignancy was recognized (6,7). This was an important impetus for Robert Good and colleagues at the University of Minnesota, with support for the National Cancer Institute, to create the Immune Deficiency Cancer Registry (7,8). As of 1992, over 500 cases had been included in the registry (9). Accumulated data have shown that childhood cancer-related mortality is 0.8% per year, 80-fold higher than it is in normal children (0.01% per year). Non-Hodgkin lymphomas are the most frequent tumors to arise in PID patients, representing approximately 50% of all neoplasms overall (9,10). Leukemias and Hodgkin lymphomas are the second and third most common tumors that occur in this patient population (9). The overall risk of developing lymphoma is 10- to 200-fold greater than expected, but the degree of risk and the relative frequency of these neoplasms varies according to the specific type of PID (1,9). Solid tumors also occur with increased frequency in patients with PID, with the highest relative frequency in patients with common variable immunodeficiency syndrome (9,10).

Although the diagnosis of many types of PID is most often established in the first year of life, the median age of lymphoma onset in the Immune Deficiency Cancer Registry is 7.1 years (9). Therefore, it appears that a latency period is required before neoplasms arise. Age of onset of PID and the apparent latency interval also are dependent on the specific type of PID. Longer patient survival, achieved by early recognition of disease and efficient treatment of infections, also correlates with increased risk of lymphoma (11). As stated in the WHO classification (1), the PIDs most commonly associated with lymphoproliferative disorders are ataxia telangiectasia, Wiskott-Aldrich syndrome, common variable immunodeficiency, severe combined immunodeficiency, X-linked lymphoproliferative syndrome, Nijmegen breakage syndrome, hyper-IgM syndrome, and autoimmune lymphoproliferative syndrome (Table 79.1).

As suggested by the report of The International Union of Immunological Societies and the WHO (3,12), primary immunodeficiencies can be divided into five major categories: (a) defects in nonspecific host defense (e.g., natural killer cells, phagocytes, the complement cascade), (b) defects of specific humoral immunity (e.g., B cells and antibodies), (c) combined defects of the cellular (T-cell mediated) and humoral immune systems, (d) immune defects associated with other major defects, and (e) immunodeficiency associated with or secondary to other diseases.

Each of the five components of this operational classification includes a heterogeneous group of diseases, each of which has one or more molecular defects. Furthermore, the immunologic and molecular abnormalities that are responsible for these diseases are actively being worked out, resulting in both improved understanding and an increased number of primary immunodeficiencies being described. A discussion of the molecular pathogenesis of PIDs is beyond the scope of this chapter, but was recently summarized in detail by Lim and Elenitoba-Johnson (13).

The reasons for the increased risk of hematologic neoplasms in PID patients are incompletely understood. However, patients with PID who are cured by bone marrow transplantation also have a reduced the risk of subsequent lymphoma, thereby empirically implicating PID as being at least partly responsible. It seems clear that impaired host immunosurveillance is involved in Epstein-Barr virus (EBV)-associated lymphoproliferative disorders in which a defective host cytotoxic T-cell response allows EBV to drive atypical immunoblastic proliferations and lymphomas, usually of B-cell lineage (1,9). Other factors involved in the pathogenesis of hematologic neoplasms in PID patients include polyclonal activation of lymphoid cells, host dysregulation of the lymphoid system (most likely associated with cytokine imbalance), and genetic defects that increase the likelihood of chromosomal abnormalities arising, for example, from mistakes in antigen receptor gene rearrangement leading to chromosomal translocations (9). Most likely, a combination of these factors is involved in the increased risk of lymphoma.

A detailed discussion of the clinical features of all of the known PIDs is beyond the scope of this chapter. Clinical aspects of some of the best characterized PIDs, including those with the highest risk for developing lymphomas (as mentioned earlier), are summarized in Table 79.1.