Abeloff's Clinical Oncology, 4th Edition

Part I – Science of Clinical Oncology

Section B – Genesis of Cancer

Chapter 15 – Immunodeficiency and Cancer

Alexandra H. Filipovich,Thomas G. Gross

SUMMARY OF KEY POINTS

  

   

Neoplasms are the second most common cause of mortality (after infections) among patients with primary and acquired immunodeficiencies.

  

   

Infections, whether de novo, reactivated, or chronic, play a pivotal role in promoting development of both lymphomas and carcinomas. Examples include the following:

  

   

Epstein-Barr virus (EBV) associated with lymphoproliferative disorders

  

   

Helicobacter pylori associated with gastric carcinomas and mucosa-associated lymphoid tissue (MALT) lymphomas

  

   

Human papillomavirus associated with skin and cervical carcinomas

  

   

Categories of genetic immunodeficiencies with increased risk of developing tumors include the following:

  

   

Combined defects with T-cell dysfunction (e.g., Wiskott-Aldrich syndrome)

  

   

Defects that inhibit lymphoid apoptosis (e.g., autoimmune lymphoproliferative syndrome [ALPS])

  

   

Defects of genomic instability (e.g., ataxia telangiectasia)

  

   

Categories of acquired immunodeficiencies with increased risk of developing tumors include the following:

  

   

Recipients of solid-organ allografts

  

   

Recipients of T-cell-depleted mismatched allogeneic hematopoietic stem cells

  

   

HIV/AIDS patients

  

   

The risk of lymphoproliferative disorders in immunodeficient hosts can be reduced by the following:

  

   

Correction of primary immunodeficiencies with bone marrow transplant

  

   

Reduction of immune suppression in allograft recipients

  

   

Aggressive treatment for HIV

INTRODUCTION

Retrospective surveys of patients with primary and acquired immune deficiencies have revealed several patterns of increased risk for specific cancer types. In the majority of immunodeficiency conditions—whether de novo, reactivated, or chronic—infections play a pivotal role in promoting the development of both lymphomas and carcinomas. Specifically, patients with primary (genetically determined) or acquired immune deficiencies that affect primarily T-cell function are at increased risk of developing cancer. This risk group includes patients who are immune suppressed following solid-organ allografting, hematopoietic stem cell transplantation (HSCT), or secondary to human immunodeficiency virus (HIV) infection. Chronic immune suppression also increases the risk for carcinomas that are linked to infection with viruses, such as human herpesvirus 8 or Kaposi's sarcoma–associated herpesvirus associated with Kaposi's sarcoma or human papillomavirus associated with squamous cell carcinoma of the skin and cervix. People with congenital humoral immune defects (especially IgA deficiency) who are persistently colonized with Helicobacter pylori experience a higher rate of gastric carcinomas and gastric mucosa–associated lymphoid tissue (MALT) lymphoma. A minor, but biologically instructive, category of individuals at increased risk of tumors of both hematopoietic and epithelial origin are those with inherited defects of genomic instability, which may lead to both immunodeficiency and propensity to tumor development. Examples of such disorders include ataxia telangiectasia and Bloom's syndrome.

Although tumors in immune-deficient persons remain a major cause of morbid and fatal complications, progress has been made in reducing the risk of malignant transformation in many patients through better understanding of the etiopathogenesis. The risk of life-threatening “lymphomas” can be reduced substantially by correcting the underlying primary immune defect via HSCT, by minimizing immune suppression in transplant recipients, and by aggressive anti-HIV therapy in HIV/AIDS patients. More recently, the availability of sensitive methods for monitoring reactivation of EBV in immune-compromised populations using quantitative polymerase chain reaction (PCR) techniques, combined with the preemptive or therapeutic use of anti-CD20 antibodies to thwart EBV-associated lymphoproliferation, have led to successful control of posttransplant “lymphomas.” Highly active antiretroviral therapies (HAART) and other approaches that maintain and strengthen cell-mediated immunity in HIV-infected individuals have reduced their risk of “opportunistic” cancers. Rapid and reliable diagnosis of H. pylori infection and appropriate antibiotic treatment for susceptible hosts diminishes the risks of both carcinomas and lymphomas of the stomach.

HISTORY

In 1959, Lewis Thomas[1] proposed the concept that immune surveillance was an active process controlling the emergence of malignant clones from somatic cells that undergo precancerous mutations during the lifetime of a normal, immune-competent individual. This hypothesis predicted that immune-deficient subjects should experience much higher rates of all types of cancers as compared with the general population. Indeed, surveys of patients with primary and acquired immune deficiencies have demonstrated increased incidence of cancer but not substantiated an increased risk of all cancer types.[2]Retrospective clinical investigations have revealed several patterns of association between certain malignancies and underlying disease types. In many cases, de novo, reactivated, or chronic infections play a substantial role in tumor development. Specifically, patients with primary (genetically determined) or acquired immune deficiencies that affect primarily T-cell function are at increased risk of developing lymphomas, often associated with EBV. [3] [4] Chronic immune suppression also increases a patient's risk of developing carcinomas that are linked to infection with viruses. For example, HIV-infected subjects and solid-organ allograft recipients run an increased risk of Kaposi's sarcoma, which is associated with human herpesvirus-8 or also known as Kaposi's sarcoma–associated herpesvirus. Solid-organ allograft recipients are also at greater risk of developing squamous cell carcinoma of the skin and cervix associated with HPV. Persons with congenital humoral immune defects (especially IgA deficiency) who are persistently colonized with H. pylori experience higher rates of gastric carcinomas and gastric MALT lymphomas. The third category of patients at increased risk of tumors of hematopoietic and epithelial origin is individuals with inherited defects of genomic instability, which lead to both immune deficiency and propensity to tumor development.[5]

Even among classic primary immunodeficiencies, the array of tumors observed varies among the specific immunodeficiency diagnoses. The recent delineation of precise genetic causes for many of the primary immune deficiencies has made possible initial molecular dissection of affected pathways of cellular proliferation and programmed cell death in distinct disorders and has helped to reconcile the differences in tumors seen among patients with those disorders.

Although tumors in immune-deficient persons remain a major cause of morbid and fatal complications, progress has been made in reducing the risk of malignant transformation in many patients through better understanding of the etiopathogenesis. The risk of life-threatening “lymphomas” can be reduced substantially or even eliminated in some patients by correcting the underlying primary immune defect via HSCT, by minimizing immune suppression in recipients of transplantation, or by aggressive anti-HIV therapies in HIV/AIDS patients. [6] [7] [8] More recently, the availability of sensitive methods for monitoring reactivation of EBV in immune-compromised populations using quantitative PCR techniques, combined with the preemptive or therapeutic use of anti-CD20 antibodies to thwart EBV infection, have led to successful control of posttransplant “lymphomas.” [9] [10] [11] Newer antiretroviral therapies and other approaches that maintain and strengthen cell-mediated immunity in HIV-infected individuals have reduced their risk of “opportunistic” lymphomas. Rapid and reliable diagnosis of H. pylori infection and appropriate antibiotic treatment for susceptible hosts diminishes the risks of both carcinomas and lymphomas of the stomach. [12] [13] [14]

At the same time, new medical advances could create new populations of patients at risk for lymphoid tumors in particular. Use of ever more intensive therapies to eradicate cancer in adults, such as nonmyeloablative but highly immunosuppressive HSCTs, and use of immune-ablative chemotherapy in the setting of autologous transplants for underlying autoimmune diseases place subjects at risk for reactivation of EBV for many months or years after these procedures. [15] [16] [17] In all of these settings there is a significant probability of prolonged erasure of the immune repertoire “memory,” with a limited capacity to restore thymopoiesis. Finally, genetic manipulation of the immune system that bypasses normal regulatory mechanisms has the potential to create rather than reduce lymphoproliferative consequences, as is seen in murine and human trials of gene therapy for primary immunodeficiencies.

LYMPHOMAS AND IMMUNODEFICIENCY

Contributors to Increased Risk of Lymphoproliferative Disorders in Primary and Secondary Immunodeficiencies

Three general biologic circumstances, often occurring in concert, predispose individuals with primary or acquired immunodeficiencies to the development of lymphoproliferative disorders:

  

1.   

The endemic incidence of EBV infection

  

2.   

The predominance of type 2 cytokine production in susceptible hosts and in the case of primary immune defects

  

3.   

Disruption of normal pathways that regulate lymphocyte cell cycling and survival by genetic mutations

EBV is a major cofactor in many lymphomas (lymphoproliferative tumors) in the setting of immune compromise, as a result of the unique properties of EBV as a transforming agent of B cells and its expression of genes that inhibit human cell-mediated immunity. Because of the ubiquitous presence of EBV, most people become infected during their lifetime, leading to a state of lifelong viral latency. The latent state of EBV is maintained by host-specific, cell-mediated immune responses (conferred by T and natural killer [NK] cells). In cases in which cell-mediated control of EBV latency is inadequate (because of genetic immunodeficiency) or fails (after immune suppression or destruction), EBV-immortalized B cells are able to proliferate unchecked, which can result in sequential loss of heterozygosity mutations and/or frank cytogenetic rearrangements. The emergence and persistence of EBV-transformed B cells and resultant lymphoproliferative disorders is further favored by a type 2–skewed cytokine milieu, inhibiting the type 1 cellular immunity that is essential for the control of EBV-bearing B cells.[18] Type 2 cytokine skewing has been observed in patients with several different primary immune defects characterized by compromised quantity, maturity, diversity, and/or responsiveness of T cells. Disorders such as Omenn's syndrome (a form of severe combined immunodeficiency [SCID]) and Wiskott-Aldrich syndrome (WAS) are examples of such primary immunodeficiencies. Patients recovering from HSCT and solid-organ allograft recipients immunosuppressed with calcineurin inhibitors (FK506 or cyclosporine A) also develop type 2 skewing, as do HIV-infected patients, who demonstrate progressive loss of CD4 cells. Identification of many of the specific molecular defects responsible for primary immunodeficiencies reveal additional mechanisms that could contribute to lymphomagenesis in some of the diseases.

Clinical Characteristics of Lymphomas in Primary Immune Deficiencies

Advances in prevention and treatment of opportunistic infections now allow patients with primary immunodeficiencies to enjoy longer lives than ever before; however, neoplastic disorders—particularly lymphoproliferative complications—remain the second most common cause of premature mortality (still preceded by infections).[19] The incidence of tumors in patients with certain immunodeficiency diseases, such as WAS, ataxia telangiectasia, and common variable immunodeficiency, is estimated at between 15% and 25%, with a substantially increased risk of developing lymphoma that increases with advancing age. [20] [21]

An important early contribution to the relationship between primary immunodeficiency and cancer was provided by the international Immunodeficiency Cancer Registry (ICR), which evolved in the 1970s as an outgrowth of the observations of Good and Gatti[22] regarding cancers diagnosed in immunodeficient children. This voluntary registry was pivotal in the description of the distribution of tumor types in patients with primary immunodeficiencies, pointing to the remarkable predominance of lymphomas across virtually all diagnoses. Table 15-1 is a reproduction of earlier publications of the ICR data listing tumor types reported for various immunodeficiency diseases. In recent times, with the advantage of retrospective review of clinical and pathologic materials from the early cases, we recognize imperfections in the original cataloging. For example, it is likely that a significant proportion of the boys listed as having hypogammaglobulinemia, because they had normal numbers of lymphocytes, who developed lymphomas were actually affected with X-linked severe combined immunodeficiency (XSCID). Similarly, review of slides from cases of “leukemia” in patients with SCID, hypogammaglobulinemia, and WAS suggest that these were actually disseminated lymphoproliferative disorders of mature B cells. Nonetheless, the general outline of tumor types and their proportional distribution among patients with various immunodeficiencies that was provided by the ICR has withstood the test of time.


Table 15-1   -- Immunodeficiency Cancer Registry Cases: Distribution of Tumors and Immunodeficiencies

Immunodeficiency

Adenocarcinoma

Lymphoma

Hodgkin's Disease

Leukemia

Other Tumors

Total

Severe combined immunodeficiency

1 (2.4%)

3 (73.8%)

4 (9.5%)

5 (11.9%)

1 (2.4%)

42 (8.4%)

X-linked agammaglobulinemia

3 (14.3%)

7 (33.3%)

3 (14.3%)

7 (33.3%)

1 (4.8%)

21 (4.2%)

Common variable immunodeficiency

20 (16.7%)

55 (45.8%)

8 (6.7%)

8 (6.7%)

29 (24.2%)

120 (24.0%)

IgA deficiency

8 (21.1%)

6 (15.8%)

3 (7.9%)

0 (0%)

21 (55.3%)

38 (7.6%)

Hyper-IgM syndrome

0 (0%)

9 (56.3%)

4 (25.0%)

0 (0%)

3 (18.8%)

16 (3.2%)

Wiskott-Aldrich syndrome

0

59 (75.6%)

3 (3.8%)

7 (9.0%)

9 (11.5%)

78 (15.6%)

Ataxia telangiectasia

13

69 (46.0%)

16 (10.7%)

32 (21.3%)

20 (13.3%)

150 (30.0%)

Other immunodeficiencies

1 (4.0%)

12 (48.0%)

1 (4.0%)

4 (16.0%)

7 (28.0%)

25 (5.0%)

Total immunodeficiency categories

46 (9.2%)

252 (50.4%)

43 (8.6%)

63 (12.6%)

96 (19.2%)

500 (100%)

 

 

The descriptive information provided by the ICR has made possible a comparison of clinical characteristics and response to chemotherapy for non-Hodgkin's lymphomas (NHL) and Hodgkin's disease between patients with primary immunodeficiencies and the general population, guiding clinicians with these unique cases. Table 15-2 , also a reproduction of previously published ICR data, summarizes clinical characteristics of reported cases of NHL. The data highlight several features, including the following:

  

   

Male predominance, even in patients with autosomal recessive disorders such as ataxia telangiectasia

  

   

Young median age at diagnosis

  

   

High frequency of extranodal presentation involving predominantly gastrointestinal, central nervous system (CNS), or disseminated sites


Table 15-2   -- Characteristics of Non-Hodgkin's Lymphomas in the Immunodeficiency Cancer Registry[*]

 

 

 

 

PRIMARY TUMOR SITES (%)[‡]

Immunodeficiency

N

Gender[†] (M : F)

Median Age at Diagnosis (Yr)

CNS

GI Tract

Lymph Node

Multiple

Severe combined immunodeficiency

31

23 : 7

1.6

6.5

3.2

9.7

48.4

X-linked agammaglobulinemia

7

7 : 0

1.2

0

14.3

14.3

14.3

Common variable immunodeficiency

55

30 : 23

23.0

1.8

12.7

12.7

25.5

IgA deficiency

6

4 : 1

9.4

16.7

0

0

0

Hyper-IgM syndrome

9

7 : 2

7.8

11.1

22.2

22.2

0

Wiskott-Aldrich syndrome

59

59 : 0

6.2

23.7

6.8

8.5

20.3

Ataxia telangiectasia

69

40 : 24

8.5

0

8.7

10.1

14.5

Other immunodeficiencies

4

4 : 0

4.0

0

0

0

0

Total immunodeficiency categories

240

174 : 57

7.1

7.9

8.8

10.4

21.7

GI, gastrointestinal tract.

 

*

This table excludes cases of non-Hodgkin's lymphoma in immunodeficiency categories with fewer than two cases reported.

Sex reported where known.

For 51.3% of ICR cases, primary tumor site is other or unknown.

 

EBV has been identified as a common cofactor in the predominant β-cell phenotypes but also in cases of T-cell NHL and Hodgkin's disease. In contrast to tumors in patients with other types of immunodeficiency, lymphomas in patients with ataxia telangiectasia are usually EBV-. This finding is consistent with the hypothesis that genetic predisposition to tumorigenesis in patients with ataxia telangiectasia occurs as a result of mutations arising from the chromosomal repair defect.

Lymphoproliferative disorders or “lymphomas” in both primary and secondary immunodeficient states span the spectrum from reactive hyperplasias through frank malignancy. Not all lymphomas in immunodeficient hosts, despite clonal origin or malignant histologic appearance, require intensive chemotherapy to achieve remission. Resolution has occurred with antibiotic therapy in MALT lymphomas and with steroids, interferon-a, low-dose chemotherapy, or rituximab in EBV+ tumors.

Historically, treatment of NHL with conventional doses of chemotherapy and radiation met with inferior results in immunodeficient patients. [23] [24] Tumor responses were reported as inferior to those observed in the general population for reasons that remain quite obscure, although the major reported causes of early mortality in the 1950s to 1980s were opportunistic infections. In the current era, improved antiviral and antifungal therapies allow most patients with immunodeficiencies who have cancer to be treated more aggressively. Ideally, achievement of remission should be followed by reconstituting HSCT if a suitable donor is available.

Based on ICR reporting, Hodgkin's disease accounts for approximately 10% of tumors arising in patients with immunodeficiencies and occurs at an early median age—less than 10 years of age.[25] A case-control study performed by the ICR in the late 1980s compared the immunodeficiency cases with other pediatric cases from a multi-institutional international cooperative study group. Immunodeficient patients with Hodgkin's disease presented earlier in life (mean age, 7.8 years vs. 11.5 years in the general population) and were significantly less likely to achieve initial remission. Hodgkin's disease in immunodeficient patients far more commonly presented with histologies of mixed cellularity and lymphocyte depletion (now recognized as representing feeble immune response to the true malignant population) when compared with presumed nonimmunodefcient subjects.[25] For immunodeficient patients who achieved remission of Hodgkin's disease, the probability of survival is also inferior as compared with patients in the general population. Patients with primary immunodeficiency who achieve remission of Hodgkin's disease should be considered for allogeneic bone marrow transplantation.

Primary Immunodeficiencies Associated with Lymphomas

Table 15-3 lists some of the primary immunodeficiencies associated with lymphomas and epithelial cancers, identifying the underlying molecular defects and other biologic characteristics associated with predisposition to lymphoma development.


Table 15-3   -- Primary Immunodeficiencies: Predominant Reported Tumors

Disorders

Inheritance

Gene Defect

Susceptibility to EBV

Type 2 Cytokine Skewing

Disruption of Normal Apoptosis

Tumors

Severe combined immunodeficiency

 

 

 

 

 

 

 X-SCID

X

Common γ-chain[†]

+

 

 

Lymphoma

 Omenn's

AR

RAG 1/2[‡]

+

+

 

Lymphoma

 PNP deficiency

AR

PNP[§]

+

+

 

Lymphoma

Wiskott-Aldrich syndrome

X

WASP

+

+

+

Lymphoma[*]

CD40-L deficiency

X

CD40 L

+

 

+

HD, biliary tract tumors

X-linked lymphoproliferative syndrome

X

SH2D1

+

 

 

Lymphoma[*]

Chédiak-Higashi syndrome

AR

LYST[16]

+

 

 

Lymphoma[*]

ALPS

AD, AR

FAS[21]

 

 

+

Lymphoma

Hyper-IgE syndrome

AD

?

 

+

 

Lymphoma

IgA deficiency/CVID

AD, S

?

 

 

 

Lymphoma[*], GI carcinoma

AD, autosomal dominant; ALPS, autoimmune lymphoproliferative syndrome; AR, autosomal recessive; CVID, common variable immunodeficiency; EBV, Epstein-Barr virus; GI, gastrointestinal; HD, Hodgkin's disease; PNP, purine nucleoside phosphorylase; S, sporadic; SCID, severe combined immunodeficiency; X, X-linked.

 

*

Frequently associated with EBV.

From Noguchi M, Yi H, Rosenblatt HM, et al: Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 1993;73:147–157.

From Villa A, Sobacchi C, Notarangelo LD, et al: V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood 2001;97:81–88.

§

From Markert ML: Purine nucleoside phosphorylase deficiency. Immunodefic Rev 1991;3:45–81.

 

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 during infancy in the absence of aggressive medical intervention.[26] SCID patients who have developed lymphomas share the characteristics of presence of B cells (targets for EBV transformation) and severe quantitative or qualitative defects in T cells. Examples of such conditions include the following:

  

   

XSCID, in which loss of function mutations in the X-linked common γ-chain gene of multiple interleukin receptors block T-cell development, but β-cell numbers are generally plentiful

  

   

Purine nucleoside phosphorylase deficiency, in which T-cell expansion and function are impaired by accumulation of toxic intracellular metabolites, with lesser effects on B cells

  

   

Omenn's syndrome, caused by mutations in RAG1 genes predominantly, resulting in severe restrictions on both β- and T-cell repertoire development leading to marked skewing toward a type 2 cytokine production

Wiskott-Aldrich Syndrome

Wiskott-Aldrich syndrome (WAS), an X-linked disorder of broad-ranging and variable immunodeficiency and microthrombocytopenia, results from mutations in the WASP gene.[27] The WASP gene encodes a large intracellular protein with several functional domains involved with cytoskeletal integrity and signal transduction. Several molecules reported to be associated with WASP are involved in normal progression through the cell cycle. WASP is expressed in cells of hematopoietic origin and in the thymus. Experimental evidence suggests that WAS B cells are relatively resistant to apoptosis, and rare reports of EBV- β-cell lymphomas have surfaced, especially among adult males with clinically milder forms of WAS that are sometimes termed X-linked thrombocytopenia.

X-Linked Lymphoproliferative Syndrome

X-linked lymphoproliferative syndrome (XLP), long recognized as a condition associated with severe or fatal complications of EBV infection and a high risk of lymphoma, results from mutations in theSH2D1A or SAP (slam-associated protein) gene on the X chromosome. [28] [29] Clinical features of XLP include an excessively intense immune reaction to EBV associated with hemophagocytosis and liver failure, lymphomas, aplastic anemia, and/or acquired hypogammaglobulinemia. SAP, an adaptor protein linked to at least four known regulatory molecules, can alter T and NK cell functions in both activating and downregulating directions and is thought to be involved in T-cell/B-cell interactions through cytokine regulation.[28] Analyses from the XLP (Purtilo) registry indicate that many of the lymphomas occurring in patients with XLP are EBV-, contrary to early predictions.[30] More recently, cases of boys who have developed separate, clonally distinct tumors years apart have been found to be due to XLP.[31]

Chédiak-Higashi Syndrome

Chédiak-Higashi syndrome (CHS) is an autosomal recessive disorder characterized by recurrent bacterial infections, oculocutaneous albinism, abnormal platelets, varied neurologic dysfunction, and a 90% probability of developing a lethal hemophagocytic complication associated with EBV infection (referred to as the accelerated phase) before age 20.[32] As part of the “accelerated phase,” some patients develop disseminated lymphoproliferative disorder. CHS is caused by mutations in the LYST gene (lysosomal trafficking regulator), and giant lysosomes are characteristic findings in leukocytes on blood smear. Because lysosomes are the key storage compartments for cytolytic proteins (including perforin and granzyme B), the cytotoxic effector function of NK and T cells is typically impaired in CHS, presenting a vulnerability to control of EBV infection.[33] A transport defect inhibiting peptide loading and antigen presentation by human lymphocyte antigen class II molecules on EBV-transformed CHS B lymphocytes has also been proposed as an additional mechanism contributing to escape of transformed B cells from immunologic control.

X-Linked Hyper-IgM Syndrome (X-Linked CD40 Ligand Deficiency)

X-linked hyper-IgM (XHIM) results in failure of immunoglobulin switching by B cells (which requires signaling through CD40) and in decreased development and maintenance of type 1 cell–mediated responses (including NK cell function) due to impaired responsiveness of CD40-expressing monocyte-derived antigen-presenting cells.[34] Patients with XHIM seem to have an increased risk of lymphomas, but especially of Hodgkin's disease associated with EBV infection. Presumably, depressed cell-mediated function required for control of EBV is responsible for this occurrence. Patients with XHIM are also at increased risk for biliary carcinomas, because there is a high rate of sclerosing cholangitis in patients with a history of chronic cryptosporidiosis.[35] In parts of the world where cryptosporidial infection is less prevalent, this complication of XHIM is rarely observed.

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.[36] Most of the cases described have had heterozygous, dominant-negative mutations involving FAS. Characteristic clinical features of the syndrome present in early childhood or even at birth. These include chronic multifocal lymphadenopathy, splenomegaly, autoimmune hemolytic anemia (and often other immune cytopenias), with increased proportions of circulating senescent T cells (CD3+, αβ T-cell receptor [TCR]-, CD4-CD8-), so-called double-negative T cells. The majority of patients experience symptomatic improvement with steroid therapy, and generally, autoimmune complications lessen in severity with advancing age. The estimated risk of lymphoma, β-cell, T-cell or Hodgkin's disease, in such patients ranges around 30%, however, and some patients have developed more than one lymphoid tumor over time.[37]Patients who have the most severe forms of ALPS should be considered for correction with HSCT. Recently, use of rituximab and rapamycin, agents that induce apoptosis in the senescent lymphocytes bypassing the FAS/FAS ligand signal, have been shown to reduce lymphadenopathy and autoimmune symptoms in patients with ALPS.[38] Whether such strategies will ultimately reduce the risk of lymphomas remains to be determined.

Clinical Characteristics of Lymphoproliferative Disorders in Acquired Immunodeficiencies

Patients recovering from HSCT or solid-organ allografting and patients with HIV infection all demonstrate rates of lymphoproliferative complications substantially exceeding those seen in the general population.

Epstein-Barr Virus Posttransplant Lymphoma after Hematopoietic Stem Cell Transplantation

After HSCT, the incidence of posttransplant lymphoma (PTLD) ranges from approximately 1% or less after unmanipulated matched-sibling donor transplants or autologous transplants to greater than 30% after T-depleted haploidentical (mismatched) transplants in patients with certain underlying immunodeficiencies (e.g., WAS).[39] Virtually all cases of PTLD are associated with EBV and generally present during the first 6 months after transplantation—the period when T-cell immune reconstitution is still very poor. The majority of cases of PTLD occur in donor-derived EBV-transformed B cells, although occasionally EBV reactivation in host cells is demonstrated. Several risk factors for development of PTLD—both host- and transplant-related—have been identified. These include the following:

  

   

T-cell depletion of the stem cell product (a procedure aimed at decreasing the risk of graft-vs.-host disease after allogeneic transplantation); T-cell specific depletion increases risk more than pan–lymphocyte depletion methods

  

   

HLA mismatching

  

   

Older age of the transplant recipient

  

   

Use of anti-T-cell antibody therapy, which is commonly used in newer, reduced-intensity protocols

PTLD after HSCT has several symptomatic presentations. Failure to diagnose and treat patients early and effectively can lead to dissemination with β-cell infiltration of the marrow, lungs, reticuloendothelial system, and CNS, which once developed is usually fatal. It is likely that many cases of PTLD still go unrecognized premortem, and given the low rate of autopsy in posttransplant deaths, the actual incidence has probably been underestimated. Sustained remission of PTLD has been shown to coincide with the development of donor-type EBV-specific cytotoxic T lymphocytes. A common strategy is to monitor the EBV level in peripheral blood by PCR in high-risk patients and initiate anti-CD20 (rituximab) as preemptive therapy to “buy time” for EBV cytotoxic T lymphocyte reconstitution.[11] [40] Adoptive T-cell therapy with EBV-specific cytotoxic T lymphocytes has been demonstrated to be effective at preventing and treating PTLD following HSCT, but this therapy is limited to few centers.[41]

Posttransplant Lymphoma after Solid-Organ Grafting

The use of immunosuppression after allografting heightens the risk of PTLD in previously immunocompetent subjects. Use of more intensive and prolonged immunosuppression—especially use of anti-T-cell monoclonal antibody for treatment of graft rejection—has been associated with an increased PTLD risk in patients with all types of organ transplants.[42] Rates of PTLD range from 1% to 5% after kidney transplantation (increased 30- to 50-fold over age- and sex-matched general population) to as high as 25% after visceral organ transplants (liver and small bowel), especially in EBV- pediatric recipients of EBV+ organs, who have a higher rate of PTLD than adult transplant recipients.[43] As opposed to HSCT, PTLD after solid-organ transplantation is associated with EBV in only 70% to 80% of cases, with late-occurring PTLD (more than 1 year posttransplant) more likely not to be EBV-associated.[44] Presentation of PTLD varies considerably, ranging from a systemic mononucleosis-like disease, to solid lymphoid lesions (often in extranodal sites that include the CNS), or even with disseminated lymphoma. Histologies range from β-cell hyperplasia to frank lymphoma and may be polyclonal, oligoclonal, or monoclonal.[43] Although the incidence of PTLD as a complication of immune suppression after organ transplantation has declined, the mortality rate from this cause remains at approximately 50% in affected patients and has changed little over time. [24] [42] [45] The critical role of intact cell-mediated immunity in control of EBV-associated PTLD is demonstrated in cases in which regression occurs after reduction in immune suppression, at the risk of organ rejection. Surgical excision and/or radiation of limited disease are associated with a high rate of durable remissions.[43] In more aggressive or persistent tumors, rituximab and other anti-B-cell therapies have been used successfully. [46] [47] Chemotherapy is usually reserved for the most resistant disease because of high treatment-related mortality. [24] [46] A low-dose chemotherapy approach has been shown to be effective in PTLD observed in children.[48] It is still unclear whether use of rituximab alone or in combination with chemotherapy is optimal.

Lymphomas Associated with HIV Infection

The incidence of lymphomas among HIV-infected adults during the early years of the worldwide epidemic was reported to exceed 20%.[49] Incidence of cancer has decreased since the introduction of HAART.[8] However, the incidence of Hodgkin's disease seems to be increasing in the HIV population,[50] and causes of death in a U.S.-based population that had received HAART shows increasing proportions of death from non-AIDS-defining malignancies and chronic disorders of adulthood.[51] Although the reported association of lymphomas with EBV in HIV-infected persons ranges between 30% and 60%, extranodal and CNS sites are more frequently seen in HIV-infected patients than in age- and gender-matched controls in the general population.[52] In the current era of supportive care, it is recommended that HIV patients with cancer be treated with standard therapies used for nonimmunocompromised patients; however, infectious complications are increased and outcomes usually inferior to the general population.

CARCINOMAS ASSOCIATED WITH IMMUNE DEFICIENCIES

Gastric Carcinomas and Mucosa-Associated Lymphoid Tissue Lymphoma

A relationship between gastric atrophy, long-standing dyspepsia and gastric ulcer disease, and the development of gastric carcinomas in adults with common variable immunodeficiency was observed decades before the discovery of a causal link to chronic H. pylori infestation.[53] A retrospective study of banked sera from a group of presumed nonimmunodeficient adult patients diagnosed with gastric carcinoma revealed an increased incidence of IgA deficiency in cancer-bearing subjects (1 in 20) as compared with the general blood donor pool (1 in 400), further implicating defective humoral immunity as contributory to this unusual type of tumor.[54]

It is now recognized that H. pylori infection is the most common cofactor for gastric carcinoma and is associated with MALT lymphomas in nonimmunodeficient whites.[54] Chronic inflammation from H. pylori incites local cytokine production, which alters adhesive properties of local epithelial surfaces and promotes ectopic lymphoid proliferation. Mucosa-associated lymphoid tissue is not present in healthy gastric mucosa, but it can develop in sites of long-persisting inflammation.[55] MALT lymphomas are generally monoclonal and can take on the appearance of aggressive, large β-cell lymphomas. These tumors are reported not only in adults with primary immunodeficiency but also in immunosuppressed organ transplant recipients, to the extent that diagnostic endoscopy is now recommended as part of the posttransplant follow-up for symptomatic individuals.[14] Fortunately, effective eradication of H. pylori with antibiotics, antacid therapy, and (occasionally) surgical excision is highly curative for many of these gastric carcinomas and MALT lymphomas.[14] Presumably, surveillance for H. pylori infection and antibiotic suppression can prevent these tumors in immune-deficient populations in the future.

Carcinomas after Allografting

The risk of posttransplant carcinomas after bone marrow transplantation is influenced by several factors, the strongest of which is probably the patient's inherent susceptibility to carcinogenesis. For example, patients who have an underlying systemic defect in DNA repair (e.g., Fanconi anemia) might be “cured” of their marrow failure or acute leukemia by replacement of genetically normal hematopoietic stem cells but remain at high risk for epithelial cancers, especially in areas of transplant-related radiation such as the head and neck.[56] Even among patients without obvious susceptibility to DNA damage, differences in response to the radiation commonly used in transplant treatment of patients with hematologic malignancies could account for future risk of skin, bone, and CNS tumors ( Box 15-1 ).

Box 15-1 

FOSTERING AWARENESS ABOUT CARCINOMAS IN ORGAN TRANSPLANT RECIPIENTS

The cumulative risk of cancer in solid organ transplant recipients exceeds 50% 20 years after grafting. Compared with the general adult population, the risk of developing cancer after organ transplantation increases three- to fivefold. Patient education about specific cancer risks and preventive lifestyle, coupled with regular medical examinations screening for early malignancy, might reduce cancer mortality in organ recipients. The skin and lips are the most common sites of cancer in allograft recipients; development of squamous cell carcinomas is markedly accelerated by sun exposure in this population. In addition to squamous cell carcinoma, unusual skin cancers such as Merkel cell cancer and Kaposi's sarcoma occur with markedly increased incidence after organ transplantation. Cervical cancer accounts for 10% of cases of posttransplant cancers in women; although the rate of breast cancer does not seem to increase, mortality from more advanced-stage disease is increased. De novo lung cancer in immune-suppressed individuals carries a particularly poor prognosis regardless of histologic type. Thus, recommendations regarding avoidance to sun exposure, regular dermatologic and gynecologic screening, and intervention to achieve sustained smoking cessation should be included as part of routine long-term transplant follow-up.

The incidence of cancer in solid-organ transplant recipients increases greater than 1% per year after transplant such that about 20% of patients will experience a cancer within 10 years following transplantation. [42] [57] Many of these cancers involve the skin and are enhanced by increased sun exposure (i.e., time to development of skin cancer decreases with increasing latitude). Compared with thegeneral population, the risk of developing cancer after organ transplantation is increased three- to fivefold. Table 15-4 tallies the relative increased risks of certain carcinomas in organ transplant recipients as collected through the Israel Penn Tumor Transplant Registry in Cincinnati, Ohio.[42]


Table 15-4   -- Incidence of Carcinomas following Solid-Organ Transplantation

Incidence

Incidence vs. General Population

Factor Increasing Risk

Skin cancer

 

 

 Squamous cell carcinoma

40- to 50-fold

Sun exposure, latitude

 Basal cell carcinoma

10-fold

 

 Melanoma

5-fold

 

Cervical cancer[*]

14-fold

Human papillomavirus infection

Endometrial cancer

2-fold

 

Bladder cancer

4-fold

 

Kidney cancer

8-fold

Usually developing in native kidney

Ureteral cancer

1000-fold

 

Kaposi's sarcoma

1000-fold

Kidney transplant, Mediterranean descent

Data provided by the Israel Penn Transplant Tumor Registry, Cincinnati, Ohio.

 

*

Majority in situ.

 

Skin and lip cancers account for nearly 40% of all posttransplant cancers, showing a male predominance of 2:1. With close surveillance, deaths are infrequent. An unusual “skin” cancer diagnosed in transplant recipients is Merkel cell cancer, a highly aggressive neuroendocrine tumor arising principally in the head and neck region. No clear association with an inciting pathogen is known for this unusual tumor, which is usually seen in elderly whites; organ transplant recipients account for nearly 8% of the fewer than 1000 cases of Merkel cell cancer reported worldwide.[42]

Kaposi's sarcoma has long been identified as one of the “opportunistic tumors” in organ transplant recipients, with a nearly 1000-fold increase over the general population, although it is not reported after HSCT or in primary immunodeficiencies. Kaposi's sarcoma is more commonly reported after renal transplantation and in individuals of “Mediterranean” descent, such as Greeks, Italians, Turks, and Arabs. In this setting it is usually not associated with HIV infection. Other de novo sarcomas also account for some of the posttransplant risk of malignancy and seem to have a particularly aggressive biologic activity.[42]

Cervical cancer accounts for about 10% of posttransplant cancers in women. Fortunately, 75% of the lesions are in situ. It is hoped that future vaccine interventions against human papillomavrus can lower the rate of this complication for women in general. The number of breast cancer cases after allografting is comparable to that expected among women of like age; however, a higher mortality has been observed among stage III and IV patients when compared with nonimmunosuppressed women.[58] Thus, more frequent screening, if it identifies earlier, lower grade malignancies, could be indicated for female organ transplant recipients.

Immunodeficiency and Cancer in Genetic Disorders of DNA Repair

Table 15-5 lists several rare genetic disorders of DNA repair in which resultant immune deficiency and intrinsic susceptibility to carcinomas have been identified. DNA is constantly exposed to potentially damaging insults, both external (e.g., environmental radiation) and intrinsic (e.g., byproducts of cellular metabolism). Several molecular strategies have evolved to maintain genomic stability. Mechanisms used in eukaryotes include those involved in the following processes:

  

   

Recognition and direct repair of DNA damage

  

   

Cell-cycle checkpoints that pause cell-cycle progression in the presence of damage, allowing the time needed for repair

  

   

Mechanisms for removal of irreversibly damaged cells, such as the triggering of apoptosis (discussed previously in the section on ALPS)


Table 15-5   -- Genetic Disorders Associated with Chromosomal Instability That Result in Immunodeficiency and Predisposition to Cancer

Disorder

Gene Defect

Immune Defects

Cancers Reported

Ataxia telangiectasia

ATM[60]

IgA deficiency, ↓T cells

Lymphoma, leukemia, hepatocarcinoma, genitourinary carcinoma, skin cancer

Nijmegen breakage syndrome

NBS1[64]

Hypogammaglobulinemia, lymphopenia

Myeloid leukemia, lymphoma

Bloom's syndrome

BLM[65]

Hypogammaglobulinemia, natural killer cell deficiency

Lymphoma, epithelial cancer

Werner's syndrome

WRN[66]

Antibody deficiency?

Lymphoma

 

 

DNA double-strand breaks represent the most potentially serious damage to the genome. Two major pathways exist to repair such damage: homologous recombination repair and nonhomologous end joining. Defects in either of these pathways can result in chromosomal rearrangements, loss of heterozygosity, and gene mutations leading to cancers.

On the other hand, generation of immunologic diversity among both B and T cells requires a well-orchestrated “creation” of DNA breaks followed by rearrangement of immunoglobulin and T-cell receptor gene sequences and repair to stabilize the final genetic product. In this process of gene rearrangement, sequence changes such as mutations and additions, which contribute to the desired diversity of new coding regions, occur frequently. Mechanisms creating this immunologic diversity probably include helicases, polymerases, and DNA ligases. Several of the known genetic defects associated with immunodeficiency and predisposition to cancers are described in the following sections. Many other rare cases with immunodeficiency and cancers have been identified, but the specific molecular defects are still unknown.

Ataxia Telangiectasia

Ataxia telangiectasia is an autosomal recessive disorder with cancer predisposition that has variable and profound immunologic and other systemic manifestations, principally cerebellar degeneration.[59]For some time, it has been recognized that ataxia telangioectasia cells fail to activate cell-cycle checkpoints normally after exposure to γ-irradiation or radiomimetic agents. The mutant gene in ataxia telangiectasia (ATM) is a member of the phosphotidylinositol kinase family of molecules involved in signal transduction and has also been implicated in meiotic recombination.[60] ATM seems to act as a sensor of double-stranded DNA breakage (e.g., in response to oxidative stress), activating numerous damage repair pathways, including cell-cycle checkpoint control, p53 activation, and DNA repair. Mutations in ATM lead to accelerated telomere loss and premature aging.[61] In the context of normal lymphopoiesis, ATM is clearly involved in control of productive gene rearrangements of the β- and T-cell immune receptor molecules, in that lymphocytes from persons with ataxia telangiectasia demonstrate a 25-fold increase in nonrandom rearrangements of immunoglobulin and TCR genes as compared with lymphocytes from normal individuals.[62] Thymic output in ataxia telangiectasia is very reduced. The consequent restricted T-cell repertoire emerges from oligoclonal post-thymic expansion.[63] Some of the nonrandom rearrangements involve translocation of immunoglobulin chains with c-Myc, reflecting, in magnified proportion, commonly seen cytogenetic rearrangements in general lymphomagenesis. In addition to the predominant lymphoid tumors (both lymphomas and leukemias), individuals with ataxia telangiectasia experience high rates of epithelial cancers involving the skin, gastrointestinal tract, genitourinary tract, and CNS. Multiple tumors can be present simultaneously or can develop sequentially. Early reports from the ICR discussed concordance of histologies in tumors affecting ataxia telangiectasia siblings from the same family—an intriguing but still mysterious observation. The extent of response of tumors in ataxia telangiectasia patients to conventional chemotherapy remains controversial; however, the frequent development of chronic lung disease in ataxia telangiectasia and the tendency by treating physicians to reduce chemotherapy intensity could contribute to poorer outcomes.

Nijmegen Breakage Syndrome

Nijmegen breakage syndrome (NBS) is another rare autosomal recessive syndrome, which, like ataxia telangiectasia, is associated with both humoral and T-cell defects, clinical radiosensitivity, chromosomal instability, and predisposition to lymphoid and epithelial cancers.[64] Other characteristics of patients with NBS are growth retardation, microcephaly, and “birdlike” facies. The protein defective in NBS (NBS1, nibrin, or p95) seems to function together with ATM to “sense” DNA double-strand breaks and activate a diversity of corrective actions. As in ataxia telangiectasia, lymphocytes of patients with NBS display frequent chromosomal aberrations at the sites of TCR and IgH rearrangement.

Bloom's Syndrome

Bloom's syndrome has autosomal recessive inheritance involving mutations in the BLM gene.[65] In addition to immunodeficiency—especially humoral defects and predisposition to cancer—patients with Bloom's syndrome experience growth retardation, progeria, impaired fertility, sun-sensitive erythema of the face, and chronic lung disease (similar to patients with ataxia telangiectasia). The protein defective in Bloom's syndrome is a member of the RecQ helicase family and seems to function during DNA replication or in the postreplication process to resolve aberrancies incurred during replication. The BLM protein colocalizes with a gene, hMLH1, which is linked to mismatch repair. A propensity to colonic adenomas, epidermal carcinomas, and acute myeloid leukemia has been reported in patients with Bloom's syndrome.

Werner's Syndrome

Werner's syndrome, an autosomal recessive disorder with features of progeria and multiple endocrine neoplasias, results from loss-of-function mutations in the WRN gene, which encodes a helicase/exonuclease.[66] Reports of immunodeficiency are not well substantiated, but predilection to sinopulmonary infections is noted. Genomic instability in Werner's syndrome is typified by elevated illegitimate recombination events and accelerated loss of telomerase sequences.

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