Malignancy in inborn errors of immunity

INTRODUCTION — Patients with inborn errors of immunity (IEI), formerly called primary immunodeficiencies (PIDs), are at an increased risk of malignancy compared with the normal population [1-3]. After infections, malignancy is the second most common cause of death in these patients.

The epidemiology and etiology of common IEI-associated cancers, the most common types of cancer seen in patients with different forms of IEI, monitoring of patients with IEI for malignancies, and issues surrounding cancer treatment will be reviewed here. An overview of the medical management of immunodeficiency and a discussion of the pulmonary complications of IEI are found separately. (See "Inborn errors of immunity (primary immunodeficiencies): Overview of management" and "Pulmonary complications of primary immunodeficiencies" and "Gastrointestinal manifestations in primary immunodeficiency".)

EPIDEMIOLOGY AND PREVALENCE OF CANCER IN IEI — The overall risk for developing cancer in patients with IEI is increased less than two-fold above that of the general population, and has been estimated to range from 4 to 25 percent [4,5]. Advances in the therapeutic management of IEI, most notably immune globulin replacement therapy, have resulted in a longer life expectancy and duration of disease [1]. As patients with IEI live longer, malignancies are diagnosed more commonly. A few studies have examined the increased risk of malignancy in patients with IEI:

●The largest study included 3658 IEI patients enrolled in the United States Immune Deficiency Network (USIDNET) Registry between 2003 and 2015, among which approximately 5 percent of patients reported cancers. There was a 1.42-fold excess relative risk compared with the age-adjusted population surveyed in the Surveillance, Epidemiology, and End Results (SEER), which is a population-based registry for cancer in the United States [5]. Male patients with IEI had a 1.91-fold excess relative risk of cancer compared with the age-adjusted male SEER population. In contrast, female IEI patients had similar cancer rates compared with their age-adjusted counterparts in the population. There was also a 10-fold increase for lymphoma in male IEI patients and an 8.34-fold increase for female IEI patients. There was no significant difference in the rates of common malignancies (ie, lung, colon, breast, and prostate) in patients with IEI compared with the control population.

●An earlier study by the Australasian Society of Clinical Immunology and Allergy (ASCIA) calculated the standardized incidence ratio (SIR) of malignancy in 1132 IEI patients [6]. SIRs were significantly elevated for all cancers (combined SIR 1.60), cancer of the thymus gland (SIR 67.3), non-Hodgkin lymphoma (NHL) (SIR 8.82), stomach cancer (SIR 6.10), and leukemia (SIR 5.36). "All cancer" and site-specific SIRs were not different for men and women, except for thymoma, which was only identified in men [6].

●In a study of 745 patients with IEI reported in the Netherlands between 2009 and 2012, almost 10 percent of the patients suffered from a malignancy. Compared with the general Dutch population, the relative risk of developing any malignancy was two- to threefold higher, with a >10-fold increase for some solid (eg, thyroid, thymus) and hematologic tumors (eg, leukemia, lymphoma) [7].

●In a study of 1318 patients with IEI studied in the UK National Institute for Health Research and BioResource–Rare Diseases programme, 8 percent had malignancy with a predominant clinical diagnosis of antibody deficiencies [8]. Patients with combined immunodeficiency (13 percent), phagocyte disorders (13 percent), and severe autoimmunity (12 percent) showed a higher risk of malignancy relative to others.

●A 2019 systematic review of 456 patients with IEI and malignancy reported unspecified NHL (37 percent), diffuse large B cell lymphoma (DLBCL, 15 percent), and Hodgkin lymphoma (HL, 13 percent), with similar rates in males and females [9]. Antibody deficiency and DNA repair disorders (mainly NBS and AT deficiencies) were the most frequently reported disorders. T cell lymphomas were reported in 74 patients, mostly males.

Most common types of cancer — According to the Immunodeficiency Cancer Registry database on immunodeficiency-associated cancer at the University of Minnesota, the most common types of malignancies among IEI patients are NHL and Hodgkin lymphoma, which account for 48.6 and 10 percent of cancers seen in IEI patients, respectively [10]. In the USIDNET study, lymphomas were again the most common and accounted for 48 percent of all cancers observed in IEI patients (mainly in patients with common variable immunodeficiency [CVID]), followed by skin cancer (15 percent), and gastrointestinal and genitourinary cancers (each 8 percent) [5]. NHL represented 28 percent of all identified cancers in the ASCIA study [6]. The most common type of NHL in IEI patients is diffuse large B cell lymphoma [11]. A table summarizing the cancers most commonly seen in patients with different types of IEI is provided (table 1).

Both NHL and Hodgkin lymphoma are diagnosed at younger ages in patients with IEI, and NHL is more common in males with IEI [12-14]. In a study of 1413 patients with NHL, of whom 19 had IEI, the median age of the patients at the time of diagnosis was significantly lower among IEI patients compared with immunocompetent individuals (7.8 years versus 9.3 years) [12]. Similarly, in a case-control study of 120 pediatric Hodgkin lymphoma patients consisting of 20 IEI and 100 immunocompetent individuals, the mean age of the patients at the time of diagnosis was 7.8 years and 11.5 years, respectively [15]. Surprisingly, tumors that are known to use mechanisms to escape immune detection, such as melanoma and renal cell carcinoma, do not appear to be prevalent in IEI [16].

Disorders with higher cancer incidence — The majority of IEI-related cancers are associated with two specific IEI disorders: ataxia-telangiectasia and CVID, which account for 30 and 24 percent of malignancy among IEI patients, respectively [13]. Another one-third of cases are reported in association with Wiskott-Aldrich syndrome, severe combined immunodeficiency, and selective immunoglobulin (Ig)A deficiency.

MECHANISMS OF INCREASED SUSCEPTIBILITY TO MALIGNANCY — The exact pathophysiology of cancer is not fully determined in many IEI cases, although several mechanisms have been suggested to contribute to the high susceptibility of distinct groups of patients to specific types of malignancies [17]. These include intrinsic factors associated mainly with hematologic cancers (eg, impaired genetic stability, genetic predisposition, and impaired immune function) and extrinsic factors associated mainly with carcinomas (eg, impaired clearance of oncogenic viruses, chronic tissue inflammation, and iatrogenic causes) [16]. These oncogenic factors might synergize with or even depend upon each other. The fourth column of the table lists mechanisms of malignant transformation in various IEI disorders (table 1).

Impaired genetic stability — One of the better-understood mechanisms is impaired genetic stability caused by defective DNA repair [1]. Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are the best known examples of IEI involving defective DNA repair [18]. This mechanism may also contribute to the development of malignant cells in patients with Wiskott-Aldrich syndrome (WAS) and epidermodysplasia verruciformis (EV). Defects of chromosome stability and DNA repair predispose selected patients with severe combined immunodeficiency (with mutations in nonhomologous end-joining), ICF syndrome (or immunodeficiency, centromere instability and facial anomalies syndrome), dyskeratosis congenital, Bloom syndrome, and class-switching recombination defects to a higher risk of lymphoma, leukemia, and carcinoma [16].

Ataxia-telangiectasia — Ataxia-telangiectasia (AT) is an autosomal recessive disorder caused by a defect in the AT mutated (ATM) gene resulting in impaired DNA repair [19]. AT is clinically characterized by recurrent infections due to defective cellular and humoral immune response, neurologic complications in the form of ataxia, and high susceptibility to malignancy, as well as increased radiosensitivity [20]. In a study of the French national registry of IEI, among 279 patients with AT, 69 (24.5 percent) were diagnosed with cancer, with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, and T cell acute lymphoblastic leukemia being the most common [21]. (See "Ataxia-telangiectasia".)

The ATM protein plays an essential role in regulation of the cell cycle checkpoints and phosphorylation of p53 protein, a product of the TP53 tumor suppressor gene, which promotes cell cycle arrest and apoptosis in cells with damaged DNA [22-25]. Functional products of the ATM gene are also essential in the phosphorylation of the breast cancer susceptibility gene 1 tumor suppressor protein [25]. Accordingly, patients with biallelic mutations and individuals with heterozygous mutant ATM genes are reported to be at increased risk of breast cancer [26-28]. There has also been some evidence in support of a possible increase in the risk of gastrointestinal malignancies in individuals with heterozygous mutations in ATM. However, the relationship does not seem to be as strong as that with breast cancer [29]. (See "Factors that modify breast cancer risk in women", section on 'Personal and family history of breast cancer'.)

Nijmegen breakage syndrome — Nijmegen breakage syndrome (NBS) is a rare, autosomal recessive disorder caused by a defective NBS gene, also known as NBN, NBS1, and P95 gene, resulting in an impaired DNA repair, similar to AT [1]. NBS is clinically characterized by recurrent infections due to a defective cellular and humoral immune response, neurologic complications in the form of microcephaly, and high susceptibility to malignancy, including lymphoma and acute leukemia [30]. (See "Nijmegen breakage syndrome".)

The NBS gene product is considered a component of the same pathway as the ATM protein. The NBS gene directs the production of nibrin protein [31]. Nibrin phosphorylation is promoted by ATM [32,33]. Phosphorylated nibrin is considered a catalyst for phosphorylation of other molecules involved in the cell cycle, including checkpoint kinase 2, checkpoint kinase 1, and structural maintenance of chromosome 1 [34,35]. Moreover, nibrin itself forms a complex with products of MRE11 and RAD50 genes, known as MRN complex (Mre11-Rad50-Nbs1 complex), which is an essential component of ATM-mediated response to DNA damage [36]. Hence, the NBS gene has roles in both upstream and downstream of DNA damage response regulated by the ATM gene [31].

Wiskott-Aldrich syndrome — Wiskott-Aldrich syndrome (WAS) is a combined immunodeficiency with an X-linked pattern of inheritance caused by mutations in gene-encoding WAS protein (WASP), which acts as a key regulator of cell signaling and reorganization of cytoskeleton in hematopoietic cells [37]. WAS is clinically characterized by thrombocytopenia, eczema, immunodeficiency, autoimmune manifestations, and increased susceptibility to malignancy [38]. Although some authors have suggested that WASP may play a direct role in genomic stability, genetic instability is not considered to be the main reason for the development of malignancies in WAS patients [39,40]. (See "Wiskott-Aldrich syndrome".)

The incidence of malignancy in WAS patients ranges between 13 and 22 percent, with a 9 percent incidence of lymphoma [39,41]. Leukemia and lymphoma are most commonly observed in adolescents and young adults. Epstein-Barr virus (EBV)-related B cell lymphoma is the most common malignancy [42,43]. Other malignancies, including cerebellar astrocytoma, Kaposi sarcoma, or rarely, smooth muscle tumors, have also been reported [44-46].

Epidermodysplasia verruciformis — Epidermodysplasia verruciformis (EV) is a rare disorder that is clinically characterized by a high susceptibility to specific genotypes of cutaneous human papillomavirus (HPV) and squamous cell carcinoma [38]. Manifestations of EV begin during infancy or childhood and include tinea versicolor-like macules and flat wart-like papules. These cutaneous lesions may undergo malignant transformation to in situ or invasive squamous cell carcinoma, especially in sun-exposed areas [47]. In the majority of the cases, the disease is inherited as an autosomal recessive trait, due to mutations of the EVER1 or EVER2 genes [48].

Genetic instability due to a defective DNA repair is observed in EV patients [17,49]. E6 oncoprotein produced by EV-associated HPVs (EV-HPVs) inhibits the proapoptotic role of B cell lymphoma 2 (Bcl-2) protein in ultraviolet light-induced apoptosis [50]. In addition, the E6 protein produced by HPV-8 may directly cause genetic instability by binding to x-ray repair cross-complementing protein 1 (XRCC1), a crucial protein needed in DNA repair [51]. This EV-HPV-induced genetic instability is known to be responsible in the early stages of malignant formation of cutaneous cells in EV patients [52,53]. Impaired function of the immune system is also believed to contribute to malignancy in this disorder. (See 'Epidermodysplasia verruciformis' below.)

Genetic predisposition — A genetic predisposition to specific types of malignancies is a probable etiology of cancer in a number of IEI patients, although not usually as a result of oncogenic genes. Instead, other mechanisms appear to be important, such as the presence of certain mutations in genes associated with leukocyte development or defective tumor suppression genes.

Leukocyte development defects — Multipotential self-renewing hematopoietic cells (<0.1 percent of the bone marrow cells) develop continuously to both myeloid and lymphoid lineages. As stem cell differentiation progresses, there is an advanced commitment to a given lineage due to regulation of a specific group of genes, which defects in those can manifest as severe congenital neutropenia (SCN) and other bone marrow failure syndromes.

Severe congenital neutropenia — Severe congenital neutropenia (SCN) is a IEI caused by impaired myelopoiesis, resulting in neutropenia. SCN is clinically characterized by a tendency to recurrent and severe infections and a high prevalence of leukemia [54]. Autosomal dominant, autosomal recessive, and X-linked patterns of inheritance are reported [54]. (See "Congenital neutropenia".)

In a long-term survey on the incidence of leukemia among SCN patients, mutations in the gene for granulocyte colony-stimulating factor (G-CSF) receptor (CSF3R) were observed in 78 percent of patients with a diagnosed malignancy [55]. Although these mutations are not essential in the formation of leukemia in SCN patients, mutations in CSF3R are considered a predisposing factor for malignant transformation. Moreover, high-dose treatment and overstimulation with G-CSF may increase the risk of malignancy in SCN patients [56]. (See "Congenital neutropenia", section on 'Treatment'.)

Bone marrow failure syndromes — Shwachman-Diamond syndrome, cartilage-hair hypoplasia, and other immuno-osseous dysplasias may present with short stature, myelodysplasia, bone marrow failure, susceptibility to lymphoma, and leukemia [57]. (See "Shwachman-Diamond syndrome" and "Cartilage-hair hypoplasia".)

Defective tumor suppression genes — Tumor suppressor genes encode for proteins that are involved in inhibiting the proliferation of immune cells and controlling the inflammatory process, which is crucial to normal cell development and differentiation of both innate and adaptive immunities. Patients with mutations in these genes, including dedicator of cytokinesis 8 (DOCK) deficiency, common variable immunodeficiency (CVID), autoimmune lymphoproliferative syndrome (ALPS), and other chronic inflammatory disorders, are at a higher predisposition to malignancy.

DOCK8 deficiency — Dedicator of cytokinesis 8 (DOCK8) deficiency is a combined immunodeficiency with an autosomal recessive pattern of inheritance [58]. DOCK8 deficiency is characterized by recurrent respiratory tract infections, widespread cutaneous viral infections, atopy, and malignancy (vulvar, facial, and anal squamous cell dysplasia and carcinomas, and T cell lymphoma-leukemia) [59]. It was categorized previously as a subgroup of hyperimmunoglobulin E syndrome, due to similar clinical features [60]. (See "Autosomal dominant hyperimmunoglobulin E syndrome", section on 'Dedicator of cytokinesis 8 and tyrosine kinase 2 deficiencies' and "Combined immunodeficiencies: Specific defects", section on 'DOCK8 deficiency'.)

Although the exact etiology of malignant transformation in DOCK8-deficient patients is not clearly understood, it is suggested that DOCK8 protein may play a direct tumor suppressor role, which is lost in these individuals [61]. This theory is supported by the observation of decreased expression of the DOCK8 protein in cell lines of patients with lung cancer and soft tissue sarcomas [62,63].

Common variable immunodeficiency — Common variable immunodeficiency (CVID) is a heterogeneous group of disorders caused by impairments in B cell differentiation, resulting in defective immunoglobulin production. CVID is clinically characterized by recurrent infections, especially of the upper and lower respiratory tract, autoimmune manifestations, gastrointestinal complications, and increased susceptibility to malignancies. Although several genetic mutations have been reported in CVID patients, the molecular basis of this disorder is not known in most cases, and knowledge about the process of malignant formation in these individuals is limited [64,65]. However, impaired immunity to herpes viruses, chronic inflammation, and DNA repair defects are known predisposing factors in this group of patients [66]. (See "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults" and "Pathogenesis of common variable immunodeficiency" and "Treatment and prognosis of common variable immunodeficiency" and "Common variable immunodeficiency in children".)

The incidence of malignancy among CVID patients has been estimated to be around 10 percent, ranging from 1.5 to 20.7 percent in different studies [67]. This incidence was reported to be about three to four times higher when CVID is diagnosed in adulthood, compared with when the onset of symptoms is before the age of 16 years [2]. In the Australasian Society of Clinical Immunology and Allergy study, a 7-fold increase in the risk of stomach cancer, a 12-fold increase in NHL risk, and a 146-fold increase in thymus cancer were identified [6]. Lymphoma decreased the survival rate of CVID patients compared with age- and sex-matched controls [68]. The mechanisms of increased susceptibility to NHL and thymus cancer have not been elucidated. Although hematopoietic cell transplantation (HCT) is not usually indicated in CVID patients due to poor outcome, the survival rate for patients undergoing transplantation with reduced-intensity conditioning regimens for lymphoma was 83 percent, and these patients tended to have a more favorable comorbidity score [69].

Altered function of P53 protein produced by the TP53 tumor suppressor gene is considered to be associated with gastric malignancies in patients with CVID [70]. However, several other factors, including chronic Helicobacter pylori infection, pernicious anemia, achlorhydria, and decreased gastric IgA secretion may also predispose these patients to the development of gastric malignancies [6]. Of note, long-term follow-up of IgA-deficient individuals, a milder form of antibody deficiency compared with CVID, showed a moderately increased risk of gastrointestinal cancer [71].

Autoimmune lymphoproliferative syndrome — Autoimmune lymphoproliferative syndrome (ALPS) is characterized by dysregulation of the immune system due to an inability to regulate lymphocyte homeostasis through the process of lymphocyte apoptosis (a form of programmed cell death). Impaired lymphocyte differentiation and senescence results and patients with ALPS have a higher risk of lymphoma [72]. (See "Autoimmune lymphoproliferative syndrome (ALPS): Epidemiology and pathogenesis".)

Other IEI disorders with chronic tissue inflammation — Chronic mucocutaneous candidiasis is often accompanied by extensive inflammatory disorders, predisposing patients mainly to carcinoma. Careful oral hygiene is important for these patients, and aggressive treatment of oral and oesophageal candidiasis, as well as routine endoscopic screening for esophageal cancer, are recommended [73]. (See "Chronic mucocutaneous candidiasis", section on 'Treatment'.)

Another example of a IEI disorder involving chronic tissue inflammation is immune dysregulation with colitis due to mutations in interleukin (IL)-10 receptor genes (IL10RA and IL10RB), which may carry an increased risk of lymphoma [74]. (See "Lower gastrointestinal bleeding in children: Causes and diagnostic approach", section on 'Infantile and very early-onset inflammatory bowel disease'.)

Impaired function of immune system — The immune system plays a critical role in the surveillance of oncogenic pathogens, as well as premalignant and malignant cells. Impaired immune response results in decreased viral clearance, chronic antigen stimulation, chronic inflammatory response, and survival and proliferation of premalignant and malignant cells, all of which can predispose these patients to oncogenic mutations and malignant transformation [75-77].

X-linked lymphoproliferative disease — X-linked lymphoproliferative disease (XLP), also known as Duncan disease, is caused by mutations in the signaling lymphocytic activation molecule (SLAM)-associated protein (SAP) gene [78,79]. XLP is clinically characterized by excessive susceptibility to EBV infection, resulting in fulminant infectious mononucleosis, dysgammaglobulinemia, and lymphoma [80]. There is another form of the disorder (XLP2) that is not known to be associated with increased susceptibility to malignancy. (See "X-linked lymphoproliferative disease".)

SAP expression has been observed in thymocytes, T cells, natural killer (NK) cells, invariant natural killer T (iNKT) cells, and possibly in a subgroup of B cells [81,82]. SAP is known to facilitate the interaction between T cells and antigen-presenting cells, as well as between NK cells and target cells [83]. Additionally, absence of iNKT cells has been reported among SAP-deficient patients [17,84]. Loss of cytotoxic function of T and NK cells may result in the survival of EBV-transformed B cells in these patients [85,86]. SAP is also known to promote an apoptotic response to DNA damage among malignant T and B lymphocyte-derived cell lines, which may explain the dysregulated activation and expansion of T cells, as well as the persistence of premalignant B cells, even in the absence of EBV infection [87].

ITK deficiency — IL-2-inducible T cell kinase (ITK) deficiency is a rare form of EBV-associated lymphoproliferative disease caused by mutations in the ITK gene, also known as IL-2-inducible T cell kinase and tyrosine-protein kinase (ITK/TSK) gene, with a similar clinical presentation to XLP. ITK deficiency is clinically characterized by EBV-induced immune dysregulation and susceptibility to Hodgkin lymphoma [88,89].

ITK expression has been observed in thymocytes, mature T cells, NK cells, iNKT cells, and mast cells [89,90]. ITK is believed to play a modulatory role in the signaling cascade of T cell receptors, which results in the cytotoxic function of T cells [89,91]. In addition, a significant decrease in the number of iNKT cells has been reported in ITK-deficient patients [88]. Hence, an impaired cytotoxic response may predispose these patients to infections by oncogenic viruses, such as EBV. On the other hand, a reported impaired NK cell-mediated cytotoxicity due to ITK deficiency may be responsible for the survival of premalignant or malignant cells [92].

Epidermodysplasia verruciformis — Impaired function of the immune system may also be involved in the high prevalence of cutaneous malignancies among epidermodysplasia verruciformis (EV) patients. Mutations in EVER1 and EVER2 genes have been reported in up to 75 percent of EV patients [93]. The expression of EVER proteins has been observed in T, B, NK, and dendritic cells, indicating their probable role in the impaired immune response against HPV, as well as survival of premalignant cells in EV patients [94].

Wiskott-Aldrich syndrome — Impaired function of the immune system may also be partially responsible for tumor development in Wiskott-Aldrich syndrome (WAS) patients. There is some evidence that defects in the function of NK cells, as well as other components of the human immune system, may result in malignant formation due to defective tumor surveillance [1,43]. (See "Wiskott-Aldrich syndrome".)

CD40 ligand deficiency — CD40 ligand (CD40L) is a molecule expressed by CD4+ T cells upon activation and interacts with CD40, expressed by multiple cell types, including B cells, dendritic cells, monocytes, and some endothelial and epithelial cells. Mutations in the CD40L gene cause X-linked immunodeficiency with hyperimmunoglobulin M. These patients are highly prone to biliary tract infections sustained by Cryptosporidium and by cytomegalovirus and are at increased risk of cholangiocarcinoma and peripheral neuroectodermal tumors of the gastrointestinal tract [95]. Other genetic causes of hyperimmunoglobulin M, including mutations in the gene for the postmeiotic segregation increased 2 protein (PMS2), can be associated with lymphoma due to impaired function of the immune system and genetic instability [96].  

Natural killer cell deficiency — Natural killer (NK) cells have diverse functions for contact and antibody-dependent killing of cancerous cells and serve as the main member of innate immune defense against malignancies. Therefore, patients with genetically defined congenital immunodeficiency in low-affinity immunoglobulin Fc-gamma-receptor IIIA (FCGR3A) and minichromosome maintenance complex component 4 (MCM4) genes mutation are more susceptible to carcinoma [97,98]. (See "NK cell deficiency syndromes: Clinical manifestations and diagnosis".)

Decreased viral clearance — Oncogenic viruses may play a role in the malignant transformation in about 10 to 15 percent of malignancies in the general population [75]. Since immune dysregulation is the main feature of IEI disorders, it is not surprising that decreased viral clearance is one of the main etiologies for an increased prevalence of malignancies among these patients. In IEI patients, infection with these viruses can lead to a persistent inflammatory response, ongoing cell proliferation, and abnormal cell survival, all of which may increase the chance that an oncogenic mutation arises [76].

Epstein-Barr virus — Epstein-Barr virus (EBV) is the best-studied virus responsible for malignant transformation in IEI disorders [17]. EBV is transmitted via person-to-person oral or sexual contact, blood transfusion, or tissue transplantation [99]. (See "Infectious mononucleosis", section on 'Transmission'.)

EBV infection involves lymphocytes, especially B cells, which act as a reservoir for the virus. As a result, lymphomas of B cell origin are the most common malignancy linked to EBV infections [99]. EBV infection triggers an initial immune response consisting of B cell proliferation and secretion of both specific and nonspecific antibodies against EBV. In a person with an intact immune system, cellular immunity as provided by T cell cytotoxicity and other components of the immune system follows this process, limiting the primary infection. The inability to suppress the EBV and keep the infection in a latent state is believed responsible for several B cell lymphoproliferative disorders (BLPDs), including Hodgkin lymphoma, Burkitt lymphoma, and post-transplant lymphoproliferative disorders (PTLDs) in patients with IEI [17].

EBV infection is associated with BLPDs in:

●Severe combined immunodeficiencies (eg, adenosine deaminase [ADA] deficiency [96], coronin 1A [CORO1A] deficiency [100]) (see "Severe combined immunodeficiency (SCID): Specific defects", section on 'Adenosine deaminase deficiency' and "Severe combined immunodeficiency (SCID): Specific defects", section on 'Actin-regulating protein coronin 1A deficiency')

●Combined immunodeficiencies (eg, interleukin 2-inducible T cell kinase [ITK] deficiency [101]) (see 'ITK deficiency' above)

●Syndromic combined immunodeficiencies (eg, Wiskott-Aldrich syndrome [WAS])

●Diseases of immune dysregulation (eg, X-linked lymphoproliferative syndrome [XLP], cytidine 5' triphosphate synthase 1 [CTPS1] deficiency [102], and X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia [XMEN]) (See "X-linked lymphoproliferative disease" and 'XMEN disease' below and 'CTP synthase 1 deficiency' below.)

XMEN disease — X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) is a IEI disorder caused by a loss-of-function mutation of the gene encoding magnesium transporter 1 (MAGT-1) [103-105]. It is characterized by chronic EBV infection, splenomegaly, elevated EBV-infected B cells, reversed CD4:CD8 ratio, and unusual susceptibility to EBV-associated lymphomas. The small number of patients reported have also suffered from frequent sinopulmonary infections, epiglottitis, and diarrhea. They have been developmentally normal.

CTP synthase 1 deficiency — Synthesis of cytidine 5' triphosphate (CTP), which is required for the metabolism of DNA, RNA, and phospholipid, involves two enzymes, CTP synthase 1 and 2 (CTPS1 and CTPS2). CTPS1 is required for proliferation, but not differentiation, of T cells in response to TCR-CD3 activation by antigens. Proliferation of B cells is also dependent upon CPTS1.

Several patients have been identified with a homozygous mutation in CTPS1 that ablates protein expression [102]. Symptoms begin in infancy to early childhood. All patients reported have had severe chronic viral infections and recurrent encapsulated bacterial infections. Two patients had non-Hodgkin lymphoma associated with EBV infection. Three of the eight patients reported in this series had died, and six had undergone HCT. No patients had extra-hematopoietic manifestations.

Most patients had lymphopenia of varying degrees that worsened during infections [102]. The CD4:CD8 T cell ratio was inversed. Proliferation to antigens and mitogens was impaired. Immunoglobulin levels were normal to increased (particularly IgG), although antibody titers to Streptococcus pneumoniae were low.

Other inborn errors of immunity — Susceptibility to EBV, lymphoproliferative conditions, and lymphoma are the main presenting features of other IEI, including those due to defects in the following [16,106,107]:

●T cell-B cell costimulatory signaling (CD27 and CD70 deficiencies, OX40 deficiency, CD137 deficiency)

●Regulatory T cells controlling pathways (lipopolysaccharide [LPS]-responsive vesicle trafficking, beach- and anchor-containing [LRBA] and cytotoxic T lymphocyte antigen 4 [CTLA4] deficiencies)

●Antigen-receptor downstream signaling (gain-of-function in phosphatidylinositol 3-kinase [PI3K], signal transducer and activator of transcription 3 [STAT3], and loss-of-function of nuclear factor [NF]-kappa-B1 [NFKB], and caspase recruitment domain-containing protein 11 [CARD11] over-activities)

●Lymphocyte epigenetic regulators (TET2 deficiency)

Human herpesvirus-8 (HHV8) — Besides EBV and HPV, five other viruses are well recognized to be oncogenic in humans [108]. Among them, only human herpesvirus-8 (HHV8) or Kaposi sarcoma-associated herpesvirus (KSHV) had been occasionally reported in malignant primary immunodeficient patients with interferon-gamma receptor 1 (IFNGR1), stromal interaction molecule 1 (STIM1), and OX40 deficiencies.

Human papillomavirus — Human papillomavirus (HPV) is also responsible for malignant transformation in some IEI disorders. Recurrent, severe recalcitrant HPV infections are associated with many forms of IEI, including EV, WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), MonoMAC syndrome (GATA2 deficiency), and DOCK8 deficiency [109]. Patients with these disorders may develop malignancies (eg, cervical cancers) in the setting of severe or refractory mucosal warts. (See "Virology of human papillomavirus infections and the link to cancer".)

As an example, HPV infection is considered the main predisposing factor for skin cancers in patients with EV. Overexpression of HPV viral genes, especially E6 and E7 oncogenetic genes, contributes to the impaired zinc homeostasis due to mutations in either of the EVER1 or EVER2 genes. The expression of EVER proteins has been observed in T and B cells, NK cells, bone marrow myeloid cells, and dendritic cells, and it is suggested that EVER genes modulate the immune response against HPV [94,110,111].

WHIM syndrome — Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare IEI disorder, with an autosomal dominant pattern of inheritance caused by mutations in the gene responsible for the encoding of chemokine receptor CXCR4 [112]. Susceptibility to HPV infection in WHIM patients is known to be associated with CXCR4 gain-of-function. Patients are particularly prone to HPV infection, resulting in numerous warts, condylomata acuminate, and subsequent severe papillomatosis and malignant transformation of the lesions [113]. Impairments in the number and function of dendritic cells have been reported, which may also contribute to increased susceptibility to HPV and several other viral infections, such as EBV, herpes zoster, and herpes simplex viruses [1,113]. (See "Epidermodysplasia verruciformis", section on 'WHIM syndrome'.)

Iatrogenic — Iatrogenic interventions are probably an uncommon cause of malignancy in IEI patients. However, diagnostic or therapeutic procedures may trigger malignant formation in IEI patients with predisposing conditions.

Radiation — Patients with AT and NBS are prone to genetic instability and malignant formation after exposure to radiation or radiomimetic agents. Radiosensitivity in these patients is explained by defects in DNA repair, which acts as the primary response to ionizing radiation in healthy individuals [32,33].

In patients with CVID, a dose-dependent radiosensitivity was demonstrated by in vitro irradiation of lymphocytes [64]. This finding seemed to be more prominent among patients with consanguineous parents, suggesting that genetic defects with an autosomal recessive of inheritance are responsible in this subgroup of CVID patients. However, since the underlying genetic defect is not identified in most CVID cases, the exact etiology of increased radiosensitivity in these patients remains unknown.

Post-transplant lymphoproliferative disorders — Post-transplant lymphoproliferative disorders (PTLDs) are lymphoid and/or plasmacytic proliferations that mostly develop during the first six months after allogeneic HCT. They are usually caused by EBV-driven increased cell survival of germinal center B cells due to iatrogenic suppression of cellular immunity. Although uncommon, PTLDs are a potentially fatal complication of transplantation, with a mortality rate of approximately 50 percent. In both IEI and non-IEI patients, receiving T cell-depleted bone marrow transplantation is strongly associated with a higher incidence of PTLD. (See "Epidemiology, clinical manifestations, and diagnosis of post-transplant lymphoproliferative disorders" and "Treatment and prevention of post-transplant lymphoproliferative disorders".)

HCT is the only available curative therapy for severe forms of IEI, such as severe combined immunodeficiency, and without transplantation, patients usually do not survive beyond the first two years of life. In a large survey of IEI patients undergoing HCT, PTLD was the most prevalent post-transplantation malignancy, observed in 52 out of 2266 cases (2.3 percent), with a median onset of three months post-HCT [114]. Of these 52 cases, 40 died, mainly due to post-transplantation malignancy. Thus, PTLD carries a poor prognosis, although even for patients with IEI, the overall risk is relatively low [114,115].

HALLMARKS OF CANCERS IN IEI — A system of categorizing hallmarks of cancer was proposed to help dissect the complexity of the neoplastic disease. Patients with antibody deficiency, combined immunodeficiency, and immune dysregulation have the most diverse array of hallmarks , including avoiding immune destruction, genome instability, mutation, enabling replicative immortality, tumor-promoting inflammation, resisting cell death, sustaining proliferative signaling, evading growth suppressors, deregulating cellular energetics, inducing angiogenesis, and activating invasion and metastasis [116].

FEATURES OF MALIGNANCIES IN PID — Cancer in patients with IEI is generally more likely to disseminate or be widespread at the time of diagnosis and therefore have a poorer prognosis [1]. Malignancy in patients with IEI has some characteristic features compared with malignancies in immunocompetent individuals, based largely on observations in non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma [117].

Non-Hodgkin lymphoma — Patients with IEI are more likely to have non-Hodgkin lymphoma (NHL) with B cell origin, high histologic grades, and extranodal involvement, especially in the gastrointestinal tract or central nervous system [11,14]. In addition, NHL is more commonly detected in association with Epstein-Barr virus (EBV) infection in about 30 to 60 percent of cases, especially in B cell types [12,14]. As mentioned previously, patients with NHL and IEI are diagnosed at younger ages, and males are disproportionally affected. (See 'Epidemiology and prevalence of cancer in IEI' above.)

Hodgkin lymphoma — The prognosis for patients with IEI and Hodgkin lymphoma is not as good as that for immunocompetent patients. In a case-control study of 120 pediatric Hodgkin lymphoma patients consisting of 20 IEI cases with Hodgkin lymphoma and 100 immunocompetent individuals, the chance of achieving remission and five-year survival was lower in patients with IEI [15].

MONITORING FOR MALIGNANCY — Patients with IEI should undergo all age-appropriate cancer screening procedures periodically, as it is indicated for immunocompetent individuals. Evaluation of IEI patients with suspected lymphoma is the same as those with normal immune systems. Diagnostic tests useful for cancer screening include measurement of uric acid, lactic dehydrogenase, and erythrocyte sedimentation rate [118,119]. Patients with ataxia-telangiectasia (AT) and their female family members with heterozygous mutant ATM should be advised to start the screening for breast cancer at an earlier age. This age can be determined by considering the type of mutation in the ATM gene [29].

Reviews of screening for cancer in adults and children and discussions of the clinical presentations of lymphomas are found separately:

●(See "Overview of common presenting signs and symptoms of childhood cancer".)

●(See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Clinical presentation'.)

●(See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

●(See "Overview of non-Hodgkin lymphoma in children and adolescents", section on 'Clinical presentation'.)

●(See "Overview of Hodgkin lymphoma in children and adolescents", section on 'Clinical presentation'.)

●(See "Clinical presentation and diagnosis of primary gastrointestinal lymphomas".)

PATIENT EDUCATION

Warning signs of cancer — Warning signs of malignancies should be carefully explained to patients. Special attention should be given to signs of lymphoma, as the most prevalent malignancy among IEI patients, as well as other types of cancers that are more prevalent among specific IEI disorders. Patients should be advised to report all signs to their clinicians, even though some of these, such as weight loss, recurrent fever, soaking night sweats, easy bruising or bleeding, and prolonged tiredness, may be explained by their underlying IEI disorder. (See "Patient education: Lymphoma (The Basics)".)

What to avoid — General recommendations for cancer prevention (eg, avoidance of sexually transmitted diseases, excessive alcohol, obesity, etc) should be discussed with patients. (See "Overview of cancer prevention".)

Patients with specific disorders, including ataxia-telangiectasia, Nijmegen breakage syndrome, and common variable immunodeficiency, should be informed regarding their radiosensitivity, which may increase the risk of developing malignancy. These patients should consult their immunologist before agreeing to any diagnostic or therapeutic intervention involving radiation that is suggested by other clinicians. Clinicians should consider the risks and benefits of the intervention in the context of the underlying disorder, the necessity of the procedure, replacement with radiation-free technique alternative (eg, sonography and magnetic resonance imaging) and, when possible, in vitro analysis of the patient's radiosensitivity [64].

Patients with epidermodysplasia verruciformis should be informed regarding the necessity of stringent sun protection and avoidance of sun exposure. Regular physical examinations by a dermatologist are recommended for such patients. (See 'Epidermodysplasia verruciformis' above.)

Consanguinity — A number of IEI disorders are inherited in an autosomal recessive pattern. It should be explained to individuals with autosomal recessive disorders and to their families that marriages between relatives increase the likelihood of other children being affected. This is especially important in countries where this practice is prevalent. (See "Overview of cancer prevention".)

TREATMENT CONSIDERATIONS — Due to the rare and heterogeneous nature of IEI disorders, only a few studies evaluated specific protocols in the treatment of various types of malignancies in these patients.

Malignant cells in patients with IEI do not show an increased resistance to the standard therapeutic protocols [1]. However, management of cancer can be challenging in these individuals compared with immunocompetent patients, since they are more likely to develop widespread cancer requiring more aggressive cytotoxic therapies, which in turn, are more likely to cause life-threatening infections and end-organ damage in patients with IEI [1]. Thus, whenever possible, clinicians should attempt to customize the therapeutic management of cancers in IEI patients based on the condition of their immune system and complications of the underlying disorder [120].

Chemotherapy — Patients with IEI can receive the same chemotherapy protocols used in immunocompetent individuals with a similar malignancy. However, short chemotherapy protocols are preferable to longer regimens, with special attention to infection control and prophylaxis against Pneumocystis jirovecii pneumonia [1,2]. When possible, the chemotherapy regimen should be modified according to risk factors and tolerance of each individual. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults" and "Treatment and prevention of Pneumocystis pneumonia in patients without HIV".)

Examples of response to treatment and tolerance to chemotherapy in specific IEI disorders include the following:

●X-linked lymphoproliferative disease (XLP) – Although XLP patients with lymphomas may achieve remission after receiving standard chemotherapy without increased complications compared with immunocompetent individuals, relapse and development of another distinct lymphoma are also common [121]. XLP patients with lymphoma are usually treated using the standard chemotherapy regimen, which should be followed by allogeneic hematopoietic cell transplantation (HCT) as quickly as possible [122]. (See "X-linked lymphoproliferative disease", section on 'Management'.)

●Ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS) – Management of malignancies in AT and NBS patients is challenging due to poor tolerance of radiotherapy [123]. However, the exclusive use of chemotherapy without radiation seems to be efficient and well-tolerated in these patients. In a study on the outcome of polychemotherapy without radiotherapy in five AT and four NBS patients with non-Hodgkin lymphoma (NHL), only one patient died due to toxic complications. Two patients died as a result of relapse, one died of a second malignancy, and five patients remained at complete clinical remission after a median follow-up of five years [124]. Another group also reported good tolerance and response to treatment among AT patients with NHL, Hodgkin lymphoma, and acute lymphoblastic leukemia who received standard chemotherapy regimen as the sole treatment [123,125,126].

Radiotherapy — In patients with AT and NBS, radiotherapy should be limited to situations in which there is an absolute need for this treatment, and it should be administered at the lowest possible doses.

Radiotherapy and radiation-based diagnostic tests should be used very cautiously in patients with common variable immunodeficiency (CVID) due to reports of dose-dependent radiosensitivity of lymphocytes in vitro [64,127,128]. However, clinical trials evaluating the safety and efficacy of radiotherapy in patients with CVID and malignancies are unfortunately lacking.

Antiviral agents — Antiviral agents could theoretically decrease the risk of malignant transformation by reducing viral load, chronic inflammatory response, and persistent antigenic stimulation, although clinical studies have not been performed. Acyclovir, as the standard antiviral agent in the management of Epstein-Barr virus (EBV) infection, inhibits EBV DNA polymerase, which results in limiting the permissive (lytic) EBV infection. However, evidence regarding the role of the permissive phase of infection as a predisposing factor to malignancy is needed. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)

Helicobacter pylori infection eradication — Helicobacter pylori is implicated in the development of chronic gastritis and gastric atrophy, promoting carcinogenesis through intestinal metaplasia and dysplasia to carcinoma. Rates of gastric cancer may be decreasing in CVID patients with the more prevalent use of antibiotics that eliminate H. pylori [68].

Rituximab — Rituximab is an anti-CD20 monoclonal antibody that eliminates B cells and is used in the treatment of B cell lymphoma. EBV-induced malignant transformation among IEI patients is considered to be the result of uncontrolled expansion of EBV-infected B cells and a probable subsequent proliferation and activation of T cells. Thus, it is possible that rituximab may reduce the risk of EBV-induced lymphoma by eliminating EBV-infected B cells.

Rituximab has been used with apparent success in controlling acute EBV infection in a small number of patients with X-linked lymphoproliferative (XLP) disease [129]. In these patients, the number of B cells dropped to about 1 percent or less of the total number of circulating lymphocytes, and leukocyte-associated EBV DNA in patients' peripheral blood declined to the limits below the detection limit. The use of rituximab in XLP is described separately. (See "X-linked lymphoproliferative disease", section on 'Treatment of acute EBV infection'.)

Other targeted therapies

The selective phosphatidylinositol 3-kinase (PI3K) inhibitors, which can be used in cases with activated PI3K mutations, have shown impressive efficacy and tolerability in patients with certain B cell cancers and are in phase III clinical trials [130]. Treatment with sirolimus (rapamycin), an mTOR inhibitor, can also partially restore NK cell cytotoxicity which is important in immune surveillance of these patients as well as ALPS cases [131,132] .

Monoclonal antibodies may replace traditional chemotherapy and its sometimes life-threatening side effects, or at least allow for reduced chemotherapy dose intensity, in patients with DNA repair defects characterized by a progressive decrease in T cell numbers [133]. However, monoclonal antibodies have their own adverse effects. Some are the consequence of off-target effects, such as the neurotoxicity reported after administration of blinatumomab (bi-specific T cell engager antibodies) [96]. (See "Neurologic complications of cancer treatment with molecularly targeted and biologic agents", section on 'Bispecific T cell engagers'.)

Stem cell transplantation — HCT is the only curative therapy available for a number of IEI disorders associated with higher malignancy rates, including severe combined immunodeficiency, XLP, Wiskott-Aldrich syndrome, X-linked hyperimmunoglobulin M syndrome, and dedicator of cytokinesis 8 (DOCK) deficiency [134-136]. However, even after HCT, some patients may remain at increased risk for malignancies. As an example, patients with DOCK8 deficiency remain predisposed to cancers because DOCK8 may play a tumor suppression role in nonhematopoietic tissues [17]. (See "Hematopoietic cell transplantation for non-SCID inborn errors of immunity" and "Hematopoietic cell transplantation for severe combined immunodeficiencies".)

Viral-specific T cell therapies — Viral-specific T lymphocyte therapies (VSTs) involve infusions of cytotoxic T lymphocytes that have been engineered in vitro to target specific viruses. VST can be used to prevent or treat specific viral infections, or to treat virally-driven malignancies [133]. A review collated data from 18 studies in which 63 patients with IEI received VSTs to either prevent or treat viral infections, usually following HCT, with an overall response rate of 79 percent [137]. The most common diagnoses were SCID and hemophagocytic lymphohistiocytosis. The main virus targets were tumorigenic ones (CMV, EBV), although VSTs were also useful against adenovirus, BK virus, and human herpesvirus 6 (HHV6) with a low rate of side effects, including graft-versus-host disease and cytokine release syndrome. Production of VSTs currently requires a clean-room or good manufacturing practice facility and the regulatory infrastructure to support the quality of process, which is the main current challenge for this modality.

SUMMARY AND RECOMMENDATIONS

●Risk of malignant disease in patients with IEI – The overall risk for developing cancer in patients with inborn errors of immunity (IEI), formerly called primary immunodeficiencies (PIDs), is estimated to range from 4 to 25 percent, which is less than twofold above that of the general population. As advances in the treatment of IEI have resulted in longer life expectancies, there has been a corresponding increase in diagnosed malignancies. The most common types of cancer in patients with IEI are non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma, which together account for approximately 60 percent of malignancy cases. Patients with IEI develop lymphomas at somewhat younger ages compared with immunocompetent populations. The IEIs with the highest incidences of cancers are ataxia-telangiectasia and common variable immunodeficiency. (See 'Epidemiology and prevalence of cancer in IEI' above.)

●Potential mechanisms – Several mechanisms have been suggested to contribute to the high susceptibility of distinct groups of IEI patients to specific types of malignancies. These include impaired genetic stability, genetic predisposition, immune dysregulation, impaired clearance of oncogenic viruses, and iatrogenic interventions (table 1). (See 'Mechanisms of increased susceptibility to malignancy' above.)

●Features of malignancies in IEI – Cancers of all types in patients with IEI are more likely to disseminate or be widespread at the time of diagnosis. NHL in patients with IEI tends to be of B cell origin, have high histologic grades, be associated with Epstein-Barr virus infection, and involve extranodal tissues, especially the gastrointestinal tract and central nervous system. (See 'Features of malignancies in PID' above.)

●Monitoring – Patients with IEI should undergo all age-appropriate cancer screening procedures periodically, as indicated for immunocompetent individuals. In addition to general measures to avoid developing cancer (eg, avoidance of sexually-transmitted diseases, excessive alcohol, obesity, etc), patients should be educated about the signs and symptoms of the specific types of cancer associated with their IEI, especially lymphoma. In cultures in which consanguinity is widespread, families with a member with IEI should be counseled to avoid marriages between relatives. (See 'Monitoring for malignancy' above and 'Patient education' above.)

●Treatment principles – Malignant cells in IEI patients do not show an increased resistance to the standard therapeutic protocols. However, patients with IEI are more likely to develop widespread cancer requiring more aggressive therapy, and the adverse effects of these treatments, such as infections and end-organ damage, are often poorly tolerated. Therefore, treatments should be chosen with the patient's underlying susceptibilities in mind and less toxic therapies preferred whenever possible. Monoclonal antibodies and virus-specific T cell therapies are expanding treatment options for this vulnerable population. (See 'Treatment considerations' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Asghar Aghamohammadi, MD, PhD and Babak Mirminachi, MD, MPH, who contributed as authors to earlier versions of this topic review.

The UpToDate editorial staff also acknowledges E Richard Stiehm, MD, who contributed as a Section Editor to earlier versions of this topic review.