Lymphoproliferative Disorders and Malignancies Related to Immunodeficiencies

Robert J. Hayashi

Birte Wistinghausen

Bruce Shiramizu

INTRODUCTION

In 1959, Thomas conceptualized that the immune system played a role in oncogenesis. He hypothesized that immune surveillance was an active process that controlled the emergence of malignant clones from somatic cells in an immunocompetent individual. This hypothesis was derived from the observation of increased malignancies in patients with immunodeficiencies, both primary and secondary, compared with the general population.¹ Primary immunodeficiencies result from genetic defects, while secondary immunodeficiencies are acquired from infections from pathogens such as human immunodeficiency virus (HIV) type 1 or immunosuppression administration following solid organ transplantation (SOT) or hematopoietic blood or marrow transplantation (BMT). Although it is possible an ineffective “immune surveillance” accounts for these clinical observations, recent work characterizing the malignancies in this population indicate that there are several variables accounting for the observed increase in the incidence of cancer.

Children and adolescents with primary and secondary immunodeficiencies are at risk for developing unique types of cancers. In the majority of primary and secondary immunodeficiency conditions, reactivated or chronic infections play a pivotal role in the development of malignancy. Patients with primary or secondary immunodeficiencies affecting T-cell functions are at increased risk for developing lymphomas, often associated with Epstein-Barr Virus (EBV). Prolonged immune-suppressed states, as a result of HIV infection or iatrogenic immunosuppression used in transplantation, also increases the risk of solid tumors that are linked to infection with other viruses such as human herpesvirus-8 (HHV-8)-associated Kaposi Sarcoma (KS) or human papillomavirus (HPV)-associated squamous cell carcinoma (skin, cervical, and anal cancers).²^,³^,⁴ Alternatively, individuals with inherited defects of DNA repair and genomic instability, for example, Bloom syndrome and ataxia telangiectasia (AT), have a propensity to develop tumors of hematopoietic and epithelial origin as alterations in the genome result in transforming events.⁵ Thus, the clinical spectrum of malignancies seen in in these patients rely in part on the nature of their defect accounting for their immunodeficient state, leading to the inability to properly control infections, the inability to prevent transforming alterations in the genome, or the inability to identify and/or eliminate abnormal cells with defects in proliferation, function, and/or apoptosis.

Regardless of the etiology of the immune defect, immunodeficient patients with cancer have increased morbidity and mortality compared with the general population with histologically similar malignancies. However, the malignancies associated with immunodeficiencies are not necessarily more resistant to conventional therapies. Unfortunately the nature of this patient population places them at increased risk for infectious complications, in part accounting for their compromised condition. This chapter will focus on advances made in understanding the pathogenesis and in the treatment of malignancies and lymphoproliferative disorders (LPDs) related to immunodeficient states in children. We will review the current state of knowledge of viral pathogens associated with malignancies in immunocompromised patients, review the scope of immunodeficient states, and how they differ in their presentation, and finally review specifically the LPDs commonly encountered in this population and the current approach to treatment.

VIRAL PATHOGENS AND THE DEVELOPMENT OF MALIGNANCIES

Many viral pathogens have been associated with malignancies including Hepatitis B and C, EBV, HHV8, and HIV, while other viruses (HHV6) have been associated with cancer, but a true link has been difficult to establish rather than just an association. In the immunodeficient host, viral pathogens develop a variety of strategies to maintain themselves, often in states of latency, which can lead to malignant transformation. There are two types of latency, episomal, in which the viral DNA is established as distinct objects in the cytoplasm or nucleus, or proviral latency, in which the viral DNA gets incorporated into the host DNA. Examples of episomal latency include EBV and other herpes viruses, in contrast to retroviruses such as HIV or HTLV-1 that establish proviral latency.⁶ Ongoing investigations are defining the critical steps from latency to malignant transformation, with EBV the most extensively studied model system. We will review what is currently known about EBV and cancer development, and also discuss other viral pathogens with similar links to cancer development in the immunocompromised patient.

EPSTEIN-BARR VIRUS AND MALIGNANCIES

Extensive work has implicated EBV in the development of several types of malignancies ranging from lymphoproliferative disorders to solid tumors. Lymphoproliferative disease associated with EBV (EBV-LPD) is the most common “malignancy” seen in patients with T-cell defects, either inherited or acquired. EBV-LPD represents a spectrum of clinically and morphologically heterogeneous lymphoid proliferative processes. Primarily due to the growing number of SOT and BMT, it is estimated that more than 150 cases of EBV-LPD are diagnosed in children in the United States each year.⁷^,⁸ This compares with the approximately 750 cases of childhood and adolescent non-Hodgkin lymphoma (NHL) diagnosed per year in the United States consisting of 300 Burkitt lymphoma (BL), 200 lymphoblastic lymphoma, 100 anaplastic large cell lymphoma, 100 diffuse large B-cell lymphoma (DLBCL), and 50 cases of other NHL.⁷ Many other forms of cancer have also been associated with EBV. Understanding the gene expression of EBV in the infected host cell gives us insight into the
nature of the cancers that arise and how a compromised immune system influences their development.

Pathophysiology of Epstein-Barr Virus Infection and Malignancy Generation

EBV is a gamma herpesvirus and one of eight known Human Herpes Viruses (HHV). Human beings are the only host for the virus, and B lymphocytes and the epithelium of the oronasopharynx express CD21/CR2, which is the EBV receptor and provides the entry port into the cell for infection, although other means of entry may also exist. EBV initially infects B lymphocytes in the lymphoid tissue of Waldeyer ring, where B cells may persist in a latent state. The latently infected B lymphocytes circulate as resting memory B cells to secondary lymphatic organs, that is, lymph nodes, spleen, and bone marrow, and become the reservoir for the virus.⁹ During viral reactivation and replication, cell lysis occurs with viral shedding into the saliva.

Recent work has improved our understanding of the role that specific genes play in the malignant diseases associated with this virus. Specific types of cancer have been associated with various states of latency. Latency is a means by which the virus maintains its genome within the host. Although latency has been studied in several settings, among the gammaherpesvirus family, only EBV and HHV-8 have clearly demonstrated transforming capability. EBV has four distinct latency phases, each defined by the viral genes expressed. Each latency phase is associated with a different scope of malignancies giving potential insight into the role the virus plays in each specific transformation event (Table 24.1). Gene products expressed during latency include nuclear proteins EBNA-1, EBNA-2, EBNA-3A, EBNA-3B, EBNA-3C, latent membrane proteins (LMP-1), LMP-2A, and LMP-2B), small noncoding RNAs (EBER-1, 2A, and 2B), and BamH1-A rightward transcripts (BARTs).¹⁰ Expression of these genes varies among the spectrum of EBV-associated diseases and often differs from in vitro immortalized lymphoblastoid B-cell lines (LCLs) or normal human resting B cells infected by EBV. For example, EBV-positive Burkitt lymphoma cells commonly express only EBNA-1, EBER-1, and EBER-2 that define type I latency. Type I latency is also observed in a portion of EBV-positive gastric carcinoma. Type II latency, as defined by EBNA-1, LMP-1, LMP-2, EBER1, and EBER2 expression, is found in EBV-positive nasopharyngeal carcinoma, T-cell NHL, and the Reed-Sternberg cells of some Hodgkin lymphoma. The EBV-LPD-infected cells observed in immunodeficient patients resemble in vitro immortalized LCL and generally express all nine of EBV-related latent proteins (type III latency). It has been shown that peripheral resting CD23+ B cells are the source of EBV latency in seropositive healthy individuals. These EBV-infected resting B cells express only LMP-2, EBER1, and EBER2 together with BART (type IV latency).

TABLE 24.1 Viral Proteins Linked to Malignant Transformation

Virus	Proteins Expressed Linked to Malignant Transformation	Proteins Expressed Disrupting Antiviral Responses	Impact on Immunity	Associated Malignancies
EBV
Latency 1 Latency 2 Latency 3	EBNA 1, EBNA 1, LMP 1,2 EBNA1, 2, 3A, 3B, 3C, LP, LMP 1,2	BNLF2a, BILF1, BGLF5 BCRF-1	Downregulation of MHC Class I and II IL-10 homolog	Burkitt lymphoma, Gastric CA Hodgkin Disease, NPC CA PTLD
HHV8	G-protein homologs, cyclin D, interleukin 6, bcl-2, latent nuclear antigen-1, viral cyclin, a LANA, vcyc, vFLIP, and kaposin	vIL-6	Impedes interferon signaling	Kaposi Sarcoma Primary Effusion Lymphoma
HIV	P17, Tat			Kaposi Sarcoma, NHL

Regulation of gene expression in EBV is mediated by the control of four distinct promoters: Wp, Cp, Qp, and Fp. Activation of different promoters occurs with different latency states and defines the gene products specific for the state.¹¹ Extensive work expressing these proteins in vitro and the examination of effects of mutations and altered expression patterns of both viral and host proteins have improved our understanding of the complex influence this virus has on human cells.¹² EBV expressed genes can alter susceptibility to apoptosis, cell cycle regulation, proliferation, host gene expression, and perform direct transforming events that are still being defined. Beyond the effects EBV has on facilitating malignant transformation, it also actively evades the immune system by modulating MHC class I and II expression to reduce viral detection, and generating homologs to cytokines such as IL-10 by BCRF-1 to reduce the immune system’s efficiency in viral elimination.¹³ The demonstration that infusion of cytotoxic T-lymphocytes (CTLs) specific for EBV can combat established tumors is an illustration of the relationship between immune competency and the control of EBV-mediated malignancies.

HHV-8 AND MALIGNANCIES IN IMMUNODEFICIENT PATIENTS

Kaposi Sarcoma (KS) was, and still is, an extremely rare condition in immunocompetent individuals, but its association in the setting of HIV infection and in acquired immunosuppressed states is well documented.¹⁴^,¹⁵ HHV-8/KSHV was subsequently reported as a highly associated pathogenic agent responsible for KS.¹⁶ It was postulated that the inability of a patient with AIDS to control HHV-8/KSHV infection leads to the development of KS, suggesting that KS is an opportunistic malignancy.

HHV-8/KSHV incorporates several eukaryotic cellular protein genes that may contribute to tumor formation, including G-protein homologs, cyclin D, interleukin 6, bcl-2, latent nuclear antigen-1, viral cyclin, and interferon regulatory factor.¹⁶^,¹⁷ The tumor microenvironment has been shown to be an essential aspect of KS progression.¹⁷ The cross talk of cytokines and chemokines between host T cells and cancer cells can lead to further proliferation and survival of circulating malignant cells.¹⁸ The association of KS development and the severity of the immunosuppressed state, and the reports of spontaneous resolution of KS with improved immunity in the host reinforce the notion of the intimate relationship of T-cell immunity and cancer development. Current research efforts studying classic KS has identified kindred with gene defects that involve T-cell function such as STIM-1 and Ox-40 supporting the notion that KS is an “opportunistic cancer” of immunosuppression.¹⁹

Primary Effusion Lymphoma (PEL) is an entity observed in both HIV and immunosuppressed patients, and HHV-8 has been
implicated as the primary viral pathogen associated with this condition. Latent proteins such as LANA, vcyc, vFLIP, and kaposin have been expressed in these tumors, although their role in transformation is unclear.²⁰

Like EBV, HHV-8 generates homologs to cytokines to evade the immune system. In the instance of HHV-8, a homolog to IL-6, (vIL-6) is produced by the virus. Studies have demonstrated that this viral expressed protein can enhance survival and promote growth in PEL cell lines, and, furthermore, vIL-6 reduces the effects of α interferon signaling, thus impeding viral clearance by the immune system.¹⁸ Thus, like EBV, a compromised immune system will result in the growth and spread of HHV-8, allowing the pathogen to persist and induce malignant disease.

HIV and Malignancies

Since the initial description of HIV and AIDS, it has been appreciated that the condition was associated with an increased risk of malignancy.¹⁷ The profound effects of HIV on the immune system inherently lead to unregulated state of viral pathogens such as EBV, HHV-8, and Human Papilloma Virus (HPV) that can lead to transforming events.²¹ In some cases, viral gene products from HIV have been shown to enhance the spread and activation of HHV-8 and EBV, which in turn may further transactivate HIV via its long terminal repeat (LTR). HIV proteins such as Tat, have shown to increase the activation of HHV-8 and increase the rate of malignant transformation in the cells they have infected.²² This appears to be mediated by enhancing the effects of vIL-6 on tumor genesis, but also mediating PI3 kinase and AKT pathways. Thus, the synergy between these viral pathogens could enhance each other’s replication and spread, increasing the likelihood of malignant transformation.

In other instances, it is clear that HIV is associated with malignancies not mediated by other pathogens as the incidence of certain types of lymphoma such as Burkitt Lymphoma have increased in incidence in HIV patients receiving antiviral therapy and reconstitution of the immune system.²³ It is known that HIV can mediate B-cell hyperactivation, and such states can lead to transforming events from errors in class switch recombination and somatic hypermutation, normally activities of developing B cells. HIV gene products like p17 have been shown to be taken up by B cells, leading to activation via a PI3Kinase dependent pathway.²⁴ Thus, HIV may be able to induce malignancies independent of the presence of other viral pathogens.

MALIGNANCIES IN PRIMARY IMMUNODEFICIENCIES

It has long been recognized that defects in the immune system lead to an increased risk of malignancy. Following observations by Drs. Good and Gatti in the early 1970s, the International Immunodeficiency Cancer Registry (ICR) was established and maintained at the University of Minnesota. This voluntary registry was pivotal in the description of tumors observed in primary immunodeficiencies (PID) and showed that patients with primary immunodeficiency are at a significantly increased risk for lymphomas but also have an increased risk of other neoplasms such as adenocarcinomas. Of all patients with PID and cancer reported to the Immunodeficiency Cancer Registry, 30% had AT as underlying immunodeficiency, followed by 24% of patients with Common Variable Immunodeficiency (CVID), 16% with Wiskott-Aldrich Syndrome (WAS), 8% with Severe Combined Immunodeficiency (SCID), 8% IgA deficiency, 4% X-linked Agammaglobulinemia (XLA), and 3% hyper-IgM syndrome.²⁵ More recently, data from the Australasian Society of Clinical Immunology and Allergy Primary Immunodeficiency Registry between 1990 and 2008 were published and showed a modest overall 1.6-fold excess relative risk of cancer, but an 8.82-fold excess relative risk of NHL and 5.36-fold excess relative risk of leukemia for all reported PID combined.²⁶ In addition, neoplasms of the stomach (adenocarcinoma), thymus (thymoma in males), and breast (in females) were reported at a higher incidence than in the general population. Individuals with specific molecular alternation causing distinct immunodeficiencies are also at risk for cancer, as noted in sections below. A nationwide survey in Japan of 2,500 patients with PID showed 2.5% of patients developed a malignancy.²⁷ Lymphoma, especially EBV-related, and leukemia were the most prevalent malignancies. The overall incidence of neoplasms and specific types of neoplasms vary between different primary immunodeficiencies and has been reported to be as high as 53% in Nijmegen Breakage Syndrome (NBS)²⁸ (Table 24.2). Neoplastic disorders, particularly lymphoproliferative complications, remain the second most common cause of premature mortality behind infectious etiologies in primary immunodeficiency.

Immunodeficiency and Cancer in Genetic Disorders of DNA Repair

Several rare genetic disorders of DNA repair with immunodeficiency and intrinsic susceptibility to carcinomas have been identified and include Nijmegen Syndrome, AT, Bloom and Werner Syndrome and other rare cases with immunodeficiency and cancers whose molecular defect has yet to be identified.

Ataxia telangiectasia (AT) is an autosomal disorder with cancer predisposition that has variable and profound immunologic and other systemic manifestations, principally cerebellar degeneration, affecting 1/40,000 to 100,000.²⁹^,³⁰ For some time, it has been recognized that AT cells fail to normally activate cell cycle checkpoints after exposure to γ-irradiation or radiomimetic agents.³⁰ The gene involved in AT (ATM) is a member of the phosphatidyl inositol kinase family of molecules involved in signal transduction, which is implicated in meiotic recombination. Thus, in response to oxidative stress, damage repair pathways are activated, including cell cycle checkpoint control, p53 activation, and DNA repair.²⁹^,³⁰ In the context of normal lymphopoiesis, ATM is involved in the control of productive gene rearrangements of the B- and T-cell immune receptor molecules, since AT lymphocytes demonstrate a 25-fold increase in nonrandom rearrangements of immunoglobulin and TCR genes compared with lymphocytes from normal individuals.²⁹^,³⁰ Although lymphoid tumors (both lymphomas and leukemias) are the main types of malignancies observed in patients with AT, high rates of epithelial cancers involving the skin, gastrointestinal tract, genitourinary tract, CNS, and breast cancer are known.³⁰^,³¹ The extent of response of tumors in AT patients to conventional chemotherapy remains controversial; however, the frequent development of chronic lung disease in AT and the inability to maintain chemotherapy intensity may contribute to poorer outcomes.

Nijmegen breakage syndrome is a rare autosomal recessive syndrome, affecting less than 1 in 200,000, that is associated with both humoral and T-cell defects, clinical radiosensitivity, chromosomal instability and predisposition to lymphoid, epithelial cancers, and sarcomas.³² Other characteristics of patients with NBS are growth retardation, microcephaly, and “birdlike” facies. The protein defective in NBS—NBS1, nibrin, or p95—appears to function together with ATM to “sense” DNA double-strand breaks and activate a diversity of corrective actions. As in AT, frequent chromosomal aberrations at the sites of TCR and IgH rearrangement are observed in lymphocytes of patients with NBS. Standard chemotherapy regimen for HD has successfully been used in one case.³²

Bloom syndrome is inherited in an autosomal recessive pattern involving mutations in the BLM gene with patients predisposed to cancer affecting 1 in 48,000, especially of Ashkenazi Jewish descent. Patients with Bloom syndrome experience growth retardation, progeria, impaired fertility, sun-sensitive erythema of the face, and chronic lung disease (similar to patients with AT). The defective protein is a member of the RecQ helicase family and
appears to function during DNA replication or in the postreplication process to resolve aberrancies incurred during replication. The BLM protein colocalizes with a gene, hMLH1, that is linked to DNA mismatch repair. A propensity for colonic adenomas, epidermal carcinomas, and acute myeloid leukemia has been reported in these patients.³³^,³⁴

TABLE 24.2 Primary Immunodeficiencies Associated with Lymphoma and Other Malignancies

Primary Immunodeficiency	Genetic Defect (Inheritance)	Immune Defect	Frequency of Lymphoma	Types of Lymphoma	Frequency of Other Malignancies	Other Malignancies
DNA repair defects
Nijemegen breakage syndrome	NBN (AR)	Progressive decrease of T cells, variably reduced B cells, decreased Ig subclasses	48.5%	Mostly B- cell, T-cell, rarely HD	4.7%
Ataxia telangiectasia	ATM (AR)	Progressive decrease of T cells, decreased Ig subclasses	15%-19%	Predominantly T-cell, B-cell, Hodgkin Disease	6.4%	Brain tumors, breast cancers, thyroid carcinoma, AML, HCC, pancreatic cancer
Immune dysregulation
X-linked lymphoproliferative disease	SH2D1A (XL)	Variably reduced B cells and Ig	24%-30%	Majority EBV + B-cell, followed by EBV- B-cell
Autoimmune lymphoproliferative disease	TNFRSF6 (AD, rarely AR)	Increased doublenegative T cells, increased IgG	7.7%	B-cell, HD	1%	Glioma
Combined immunodeficiency
Wiskott-Aldrich syndrome	WAS (XL)	Progressive loss of T cells, decreased IgM	11%-13.2%	Predominantly EBV-related B-cell	1.8%-8.8%	Myelodysplasia, testicular cancer, acoustic neuroma, glioma
SCID	Several	Markedly decreased T- and B cells, variable NK cells depending on subtype	1%	Mostly B-cell, Hodgkin Disease	0.5%	Leukemia, adenocarcinoma
Antibody deficiency
CVID	Several + unknown	Low immunoglobulins	3%-9.1%	Mostly B-cell, few Hodgkin Disease	3%-8.2%	Mostly breast, followed by gastric carcinoma and melanoma, other epithelial cancers

Werner syndrome is an autosomal recessive disorder with features of progeria, and multiple endocrine neoplasias result from loss of function mutations in the WRN gene that encodes a helicase/exonuclease affecting 1 in 20,000.³⁵ Genomic instability in these patients is typified by elevated illegitimate recombination events and accelerated loss of telomerase sequences. Cancer susceptibility appears increased with aging and noted with thyroid carcinomas, melanomas, meningiomas, soft tissue sarcomas, leukemias, lymphomas, and osteosarcomas.³⁵

Immunodeficiency and Cancer in Diseases with Immune Dysregulation

X-Linked Lymphoproliferative Syndrome is a condition in which affected males are characterized by the clinical triad of increased susceptibility to primary EBV infection, dysgammaglobulinemia, and lymphoma.³⁶ The incidence is estimated to be 1-3/1,000,000 males, and most cases are the result of germline mutation of the SH2D1A gene that encodes for SAP (signaling lymphocytic activation molecule (SLAM)-associated protein) with other mutations in the XIAP gene encoding for XIAP (X-linked inhibitor of apoptosis protein) described.³⁷ Although the function of SAP is still being delineated, it has been shown to bind to regulatory molecules known to alter T and NK cell functions by both activation and suppression, and it is thought to be involved in T-B-cell interactions through cytokine regulation.³⁸^,³⁹ Clinical features of XLP include an excessive immune reaction to EBV associated with hemophagocytosis and liver failure that is clinically indistinguishable from other forms of hemophagocytic syndromes and has been called fulminant infectious mononucleosis (FIM) or EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH).⁴⁰^,⁴¹ XLP patients may also present with lymphoproliferative disease, hypogammaglobulinemia, or hematologic cytopenias.⁴² An atypical lymphocytosis is usually present at early stages of the disease, but patients subsequently develop severe, persistent pancytopenia, hepatic dysfunction resulting in fulminant hepatitis, meningoencephalitis, and varying degrees of myocarditis.⁴² The development of hepatic dysfunction, often with coagulation abnormalities secondary to
liver failure or disseminated intravascular coagulation, and pancytopenia are ominous signs, as are other signs and symptoms of hemophagocytic syndromes, such as hypofibrinogenemia and elevated triglycerides.⁴¹ About 30% of patients with XLP present with lymphoma and are of B-cell phenotype that responds to standard chemotherapy.³⁶ Rare cases of non-B-cell phenotype occur as well and other non-B-cell lymphoproliferative diseases.⁴³^,⁴⁴ Treatment options are relatively limited, but allogeneic hematopoietic stem cell transplantations have had some success in patients achieving remission.⁴⁵

Autoimmune lymphoproliferative syndrome presents clinically with nonmalignant lymphadenopathy, pancytopenia, and splenomegaly.⁴⁶ The syndrome was initially described as a single disorder caused by defects in genes of the FAS pathway of apoptosis (FAS, FASLG, and CASP10), but other syndromes with similar clinical presentations are now included in the group, including RAS-associated autoimmune leukoproliferative disorder (somatic mutations in NRAS or KRAS); CASPASE-Eight Deficiency Syndrome; FAS-associated protein with death domain deficiency; and protein kinase C delta deficiency.⁴⁶ Characteristic clinical features present in early childhood or even at birth. These include chronic multifocal lymphadenopathy, splenomegaly, and autoimmune hemolytic anemia (and often other immune cytopenias), with increased proportions of circulating senescent T cells (CD3⁺, CD4^–, CD8^–), so-called double-negative T cells. The majority of patients experience symptomatic improvement with steroid therapy, and, generally, the autoimmune complications lessen in severity with age. However, the relative risk of developing lymphoma in patients is estimated up to 40 to 50 times higher than in the general population.⁴⁷^,⁴⁸ Many patients with chronic cytopenias improve with age, sometimes requiring short-term immunosuppressive treatment; however, severe cases including those who develop lymphoma or refractory cytopenias might benefit with allogeneic hematopoietic stem cell transplantation.⁴⁹ Patients who develop NHL or HD may respond to chemotherapy including rituximab and sulfadoxine/pyrimethamine, agents that induce apoptosis in the senescent lymphocytes bypassing the FAS/FAS ligand signal.⁵⁰ Mutations in GATA transcription factors, which control hematopoietic cellular differentiation, have been associated with hematologic malignancies.

Cancer in Combined Immunodeficiencies

Wiskott-Aldrich Syndrome (WAS) is an X-linked disorder of variable immunodeficiency and characterized by microthrombocytopenia, resulting from mutations in the Wiskott-Aldrich syndrome protein (WASP) gene with an estimated incidence of 1 to 10 per 1 million individuals.⁵¹ The WASP gene encodes a large intracellular protein with several functional domains involved with cytoskeletal integrity and signal transduction that is expressed in hematopoietic cells and in the thymus. Advances in understanding the role of the WASP gene and proteins provide evidence as a regulator of actin polymerization in hematopoietic cells with functional domains involved in cell signaling and cell locomotion, immune synapse formation, and apoptosis.⁵² Mutations in the WASP protein impair its interaction with the WIPF1 protein, thus placing patients diagnosed with WAS at risk for leukemia and lymphoma.⁵¹ Patients with WAS-associated malignancies are typically related to EBV; however, there are rare reports of EBV-negative B-cell lymphomas, although it is unclear what the mechanism is for dysregulation in the absence of EBV.⁵¹ Treatment approaches for WAS-associated lymphomas usually involves allogeneic hematopoietic stem cell transplantation.

Severe combined immunodeficiencies (SCIDs), with an incidence of 1/66,000 newborns, are genetic syndromes characterized by T- and B-cell impairment in which affected individuals are prone to life-threatening infections.⁵³^,⁵⁴ In general, patients with SCIDs who retain the ability to make B cells are at risk for developing NHL including patients with (a) X-linked SCIDs in which loss of function through mutations in the X-linked common gamma chain gene of multiple interleukin receptors blocks T-cell development, but maintain adequate B-cell numbers; (b) purine nucleoside phosphorylase deficiency in which T-cell expansion and function are impaired by accumulation of toxic intracellular metabolites, with lesser effects on B cells⁵⁵; and (c) Omenn syndrome, caused by mutations in RAG1 genes predominantly that severely restricts both B- and T-cell repertoire development, and results in marked skewing toward a type 2 cytokine production that is suppressive of T-cell cytotoxic functions, but enhance T-cell help for B-cell proliferation.⁵⁴ Although most patients with adenosine deaminase-deficient SCIDs lack B cells, cases of NHL have been reported.⁵⁶ Therapy with allogeneic hematopoietic stem cell transplantation is often instituted for NHL.

Cancer and Antibody Deficiencies

Common variable immunodeficiency in children, with an estimated prevalence of 1/50,000, presents with comparable symptoms and disorders as in adults, which are characterized by B-cell differentiation impairment and immunoglobulin impairment.⁵⁷^,⁵⁸^,⁵⁹ Increased incidence of lymphoma and gastric carcinoma is observed in patients with common variable immunodeficiency with Helicobacter pylori infection, a common cofactor for gastric carcinoma and is associated with mucosa-associated lymphoid tissue (MALT) lymphomas.⁶⁰ MALT lymphomas are generally monoclonal and can take on the appearance of aggressive large B-cell lymphomas that are seen in adults with primary immunodeficiency, though rarely seen in children. Children less than 16 years of age who develop common variable immunodeficiency have an estimated incidence of cancer of 2.5% compared with older children with an increased incidence of 8.5%.⁶¹ Fortunately, effective eradication of H. pylori with antibiotics, antacid therapy, and occasionally surgical excision is highly curative for both gastric carcinomas and MALT lymphomas.⁶²

Patients with X-linked agammaglobulinemia, with an incidence of 1 in 100,000 to 200,000 males, clinically present between 6 and 18 months of age with recurrent sinopulmonary and gastrointestinal infections characterized by panhypogammaglobulinemia and absent B cells with a high rate of adenocarcinomas reported.⁶³ The disease is caused by mutations in the X chromosome Bruton tyrosine kinase (BTK) gene that encodes the enzyme involved in intracellular signaling and B-cell development with more than 1,200 mutations identified.⁶⁴

IgA deficiency is the most common inherited immunodeficiency, with incidence ranging from 1 in 300 to 1 in 1200, defined as decreased serum IgA in the presence of normal levels of IgG and IgM in a patient older than 4 years.⁶⁵ The age threshold is to avoid premature diagnosis of IgA deficiency, which may be transient in younger children with delayed ontogeny of the IgA system after birth. Epithelial tumors such as gastric cancers as well as lymphomas occur in patients with selective IgA deficiency.⁶¹ While viruses are not typically detected in lymphomas, suppression or lack of secretory IgA has been hypothesized to compromise defense against infection with Helicobacter pylori.

X-linked hyper-IgM syndrome, also known as X-linked CD40 ligand deficiency with an estimated incidence of 1/1,030,000 live births, results in a failure of immunoglobulin switching by B cells that 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.⁶⁶ Patients with X-linked hyper-IgM syndrome have an increased risk of lymphomas, including HD associated with EBV infection, as well as adenocarcinoma of the gastrointestinal tract.⁶⁷ For hematopoietic malignancies, bone marrow transplantation is an option, while for those with adenocarcinoma, liver transplants and/or chemotherapy have been attempted with poor prognosis.⁶⁶

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