Severe Combined Immunodeficiencies

SCID is a collection of more than a dozen genetically distinct disorders with severe impairment of both cellular and humoral immune function, leading to early mortality from opportunistic infections, usually during infancy.²² EBV-associated lymphomas are almost exclusively seen in patients with SCID. However, the only SCID phenotypes at risk are those in which both B cells (targets for EBV transformation) and severe quantitative or qualitative defects in T cells are present. Examples of such types of SCID include mutations in the following: X-linked common γ-chain gene of multiple interleukin (IL) receptors (IL-2RG), JAK3, IL-7 alpha-chain, CD3 delta and/or epsilon chains, and CD45.²² EBV-associated lymphomas are seen to a lesser extent in patients with purine nucleoside phosphorylase and adenosine deaminase deficiency. In these two diseases, T-cell expansion and function are impaired by accumulation of toxic intracellular metabolites; although B cells are affected to a lesser extent, absence of B cells is common. EBV-associated lymphomas are seen to a lesser extent in persons with Omenn syndrome, caused by mutations in RAG1 genes predominantly, resulting in severe restrictions on both B- and T-cell repertoire development.²²

Wiskott-Aldrich Syndrome

WAS, an X-linked disorder of variable immunodeficiency and microthrombocytopenia, results from mutations in the WAS gene.²³ The WAS gene encodes a large intracellular protein with several functional domains involved with cytoskeletal integrity and signal transduction. Several molecules reported to be associated with WAS are involved in normal progression through the cell cycle. WAS is expressed in cells of hematopoietic origin and in the thymus. Experimental evidence suggests that B cells in patients with WAS are resistant to apoptosis, and reports of EBV-negative B-cell lymphomas do exist, especially among men with clinically milder forms of WAS, which are sometimes termed “X-linked thrombocytopenia.”

X-Linked Lymphoproliferative Syndrome

X-linked lymphoproliferative (XLP) syndrome, a condition associated with severe or fatal complications of EBV infection and a high risk of lymphoma, results from mutations in the SH2D1A or SAP gene on the X chromosome.24,25 Clinical features of XLP syndrome include an intense immune reaction to EBV associated with hemophagocytosis and liver failure, lymphomas, aplastic anemia, and/or acquired hypogammaglobulinemia.²⁶ Slam-associated protein, an adaptor protein linked to at least four known regulatory molecules, can alter T and natural-killer cell functions in both activating and downregulating directions and is thought to be involved in T-cell/B-cell interactions through cytokine regulation.²⁴ Contrary to early reports, it is now known that many of the lymphomas occurring in patients with XLP syndrome are EBV negative.²⁶

A syndrome caused by a deficiency in the XIAP gene has recently been described.²⁷ Patients have defects in their antiapoptic functions, and the disorder has been named “deficiency of X-linked inhibitor of apoptosis” (XIAP). Because patients with deficiency of XIAP frequently have problems with EBV infections, XIAP has also been called XLP2. However, patients with deficiency of XIAP do not have an increased incidence of lymphoma.²⁸

X-Linked CD40 Ligand Deficiency

X-linked CD40 ligand deficiency, also known as hyper-immunoglobulin M syndrome, results in failure of immunoglobulin switching by B cells (which requires signaling through CD40) and decreased development and maintenance of type 1 cell–mediated responses (including natural killer cell function) because of impaired responsiveness of CD40-expressing monocyte-derived antigen-presenting cells.²⁹ Interestingly, patients with CD40 ligand deficiency seem to have an increased risk of EBV-associated Hodgkin lymphoma, but not NHL. Patients with CD40 ligand deficiency are also at increased risk for biliary carcinomas, because a high rate of sclerosing cholangitis occurs in patients with a history of chronic cryptosporidiosis.³⁰

Autoimmune Lymphoproliferative Syndrome

Autoimmune lymphoproliferative syndrome (ALPS) represents a constellation of genetic apoptosis defects associated with mutations in FAS, Fas ligand, and caspase 8 genes.³¹ Patients with ALPS usually have an increase of circulating CD3⁺, αβ T-cell receptor⁻, CD4⁻CD8⁻ T cells (so-called double-negative T cells). Characteristic clinical features of ALPS include chronic multifocal lymphadenopathy, splenomegaly, and/or autoimmune cytopenias.³¹ Most patients experience symptomatic improvement with immunosuppressive therapy, and autoimmune complications generally lessen in severity with advancing age. The incidence of lymphoma, B-cell, T-cell, or Hodgkin lymphoma in patients with ALPS is as high as 30%, and in some patients, more than one lymphoid tumor have developed over time.³²

Cancer in Immunodeficiency-Associated Genetic Disorders of DNA Repair

Several rare genetic disorders of DNA repair may result in an immune deficiency and an associated increased risk of cancer. The following sections provide a brief description of known molecular defect and cancer pathogenesis.

Treatment of Cancer in Primary Immunodeficiencies

Regardless of the etiology of the immune defect, immunodeficient children with cancer have a worse prognosis than does the general population.40–42 One potential exception is the more indolent low-grade lymphomas (e.g., MALT lymphomas).^43,44 Patients with primary immunodeficiencies usually tolerate cytotoxic therapy poorly, with increased morbidity and mortality due to increased infectious complications and often increased end-organ toxicities.^40–42 In the current era, improved antiviral and antifungal therapies allow most patients with primary immunodeficiencies who have cancer to be treated more aggressively. Treatment strategies differ somewhat depending on the immune defect and cancer type. For patients with primary defects in T-cell development or function (e.g., SCID, WAS, and XLP) in whom lymphoma develops, the goal is to achieve remission with the least aggressive therapy required followed by immune reconstitution with allogeneic hematopoietic stem cell transplant (HSCT), if a suitable donor is available.⁴⁵ Patients with DNA repair defects (e.g., AT and NBS) are particularly difficult to treat.^41,42 Although sensitivities to genotoxic agents (e.g., radiation and alkylating agents) may differ depending on the underlying mutation, the use of these agents can produce excessive toxicity in these patients and may increase the risk of secondary malignancies. Furthermore, the treatment of cancer in these patients often exacerbates other manifestations of the disease, such as neurological degeneration and/or chronic pulmonary disease. Therefore survival for more than 5 years after the diagnosis of cancer is rare.⁴²

Cancer Associated with HIV Infection

The use of combination antiretroviral therapy has been correlated with a significant decline in cancer in HIV-infected patients.⁴⁶ Although a low CD4 cell count has consistently been identified as a risk factor for the development of cancer in HIV-infected patients, the specific immunologic mechanisms associated with HIV infection that increase the risk of cancer remain ill defined. It is clear that HIV leads to a lack of immunosurveillance to control viral infections, resulting in cancers associated with EBV (B-cell lymphoma, Hodgkin lymphoma, and leiomyosarcoma), HHV8 (Kaposi sarcoma, pleural effusion lymphoma, and Castleman disease), and HPV (cervical and anal neoplasm and skin cancer). See Chapter 65 for more details about HIV-associated malignancies.

Cancer in Patients with Autoimmune disease

The risk of lymphoma is increased in patients with autoimmune disease, although the overall incidence remains quite low.6,47 In patients who receive chronic immunosuppressive therapy, the pathogenesis of lymphoma is likely the same as other immune-deficient states. However, the abnormal immune response and lymphocyte proliferation to chronic antigenic stimulation may also play a role.

Persons with Sjögren syndrome have a sixfold to thirteenfold increased risk of NHL, which is the highest risk among autoimmune disorders.6,48,49 This risk has been associated with both primary and secondary disease. Of note, neither age nor use of immunosuppressive therapy appears associated with this risk.^6,48 Persons with systemic lupus erythematosus appear to have a threefold to sevenfold increased risk of NHL. The risk appears to be highest in older patients.^{6, 49} The risk of NHL in patients with rheumatoid arthritis is increased with the use of immunosuppressive therapy, and use of anti-TNF monoclonal antibody therapy may additionally increase the risk.^6,48,49 Inflammatory bowel disease is not associated with increased risk of NHL.⁶ However, persons with celiac disease have an increased incidence of T-cell NHL and enteropathy-type T-cell lymphoma, and persons with Crohn disease have an increased incidence of hepatosplenic T-cell lymphoma.^6,50 There appears to be no increased incidence of NHL in persons with type 1 diabetes, pernicious anemia, scleroderma, myasthenia gravis, sarcoidosis, multiple sclerosis, or polymyositis/dermatomysositis.⁶

As opposed to NHL observed in other immune-deficient hosts, it appears that upon adjustment for co-morbidities, patients with autoimmune disease do as well as immunocompetent patients when treated with standard chemotherapy regimens,⁵¹ although the prognosis for enteropathy-type and hepatosplenic T-cell lymphomas is dismal.^50,51

Cancer After Hematopoietic Stem Cell Transplantation

De novo cancers that appear after HSCT can be divided by the time of occurrence after HSCT. Early after HSCT, usually within the first 3 to 6 months, EBV-associated lymphoproliferative disease is almost exclusively seen. This disease occurs because of the delayed T-cell immune reconstitution or T-cell dysfunction associated with aggressive immunosuppression for the treatment of graft-versus-host disease.⁷ HSCT recipients are also at risk for malignancies that occur late, that is, years after HSCT, but these malignancies are usually a consequence of genotoxic therapies used in HSCT preparative regimens and/or pre-HSCT therapy.⁷ One large retrospective study identified four high-risk factors: ≥50 years of age of the recipient, ex vivo T-cell depletion, use of antithymocyte globulin (in vivo T-cell depletion), and human leukocyte antigen mismatched donor. The incidence of posttransplant lymphoproliferative disease (PTLD) was <1% with no risk factor and up to 8% for three or more risk factors.⁵² PTLD has been reported after autologous HSCT, usually in the setting of CD34 selection performed for tumor cell purging.^53,54

A common strategy is to monitor the EBV level in peripheral blood by polymerase chain reaction in high-risk patients and initiate anti-CD20 (rituximab) as preemptive therapy to “buy time” for EBV cytotoxic T-lymphocyte reconstitution.⁵⁵ Adoptive T-cell therapy with EBV-specific cytotoxic T lymphocytes is effective at preventing and treating PTLD after HSCT, but this therapy is limited to only a few centers.⁵⁶ The outcome of patients who fail to respond to rituximab and/or adoptive cellular therapy is very poor.⁵⁷

Posttransplant Lymphoma after Solid-Organ Transplantation

Three scenarios exist in which immune suppression in persons who undergo SOT may increase the risk of cancer. The first scenario is the development of de novo cancer in the SOT recipient. The second scenario is the increased risk of recurrence in SOT recipients with a history of cancer. The third scenario is the risk of cancer transmission from the donor.