Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Malignancy in primary immunodeficiency

Asghar Aghamohammadi, MD, PhD
Payam Mohammadinejad, MD
Section Editor
Luigi D Notarangelo, MD
Deputy Editor
Anna M Feldweg, MD


Patients with primary immunodeficiency (PID) are at an increased risk of malignancy compared with the normal population [1-4]. After infections, malignancy is the second most common cause of death in these patients [1].

The epidemiology and etiology of common PID-associated cancers, the most common types of cancer seen in patients with different forms of PID, monitoring of patients with PID 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 PID are found elsewhere. (See "Medical management of immunodeficiency" and "Pulmonary complications of primary immunodeficiencies".)


The overall risk for developing cancer in patients with primary immunodeficiency (PID) is estimated to range from 4 to 25 percent [5]. Advances in the therapeutic management of PID, most notably immunoglobulin replacement therapy, have resulted in a longer life expectancy and duration of disease [2]. As patients with PID live longer, malignancies are diagnosed more commonly. However, the cancer risk associated with PID is not well characterized in most studies due to various limitations, including small sample size (because of the rarity of PID), limited follow-up, lack of matched comparison groups, and the scarcity of population-based studies.

The Australasian Society of Clinical Immunology and Allergy (ASCIA) study was the first large study to calculate the standardized incidence ratio (SIR) of malignancy in PID patients, and it remains one of the largest studies performed to date [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, with the exception of thymoma, which was only identified in men [6]. In a study of 745 patients with PID 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].

Most common types of cancer — According to the Immunodeficiency Cancer Registry (ICR) database on immunodeficiency-associated cancer at the University of Minnesota, the most common types of malignancies among PID patients are NHL and Hodgkin lymphoma, which account for 48.6 and 10 percent of cancers seen in PID patients, respectively [8]. NHL represented 28 percent of all identified cancers in the ASCIA study [6]. The most common type of NHL in PID patients is diffuse large B cell lymphoma [9]. A table summarizing the cancers most commonly seen in patients with different types of PID is provided (table 1).


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Mar 15, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Mueller BU, Pizzo PA. Cancer in children with primary or secondary immunodeficiencies. J Pediatr 1995; 126:1.
  2. Shapiro RS. Malignancies in the setting of primary immunodeficiency: Implications for hematologists/oncologists. Am J Hematol 2011; 86:48.
  3. Kinlen LJ, Webster AD, Bird AG, et al. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet 1985; 1:263.
  4. Salavoura K, Kolialexi A, Tsangaris G, Mavrou A. Development of cancer in patients with primary immunodeficiencies. Anticancer Res 2008; 28:1263.
  5. Filipovich AH, Mathur A, Kamat D, Shapiro RS. Primary immunodeficiencies: genetic risk factors for lymphoma. Cancer Res 1992; 52:5465s.
  6. Vajdic CM, Mao L, van Leeuwen MT, et al. Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood 2010; 116:1228.
  7. Jonkman-Berk BM, van den Berg JM, Ten Berge IJ, et al. Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy. Clin Immunol 2015; 156:154.
  8. Kersey JH, Shapiro RS, Filipovich AH. Relationship of immunodeficiency to lymphoid malignancy. Pediatr Infect Dis J 1988; 7:S10.
  9. Cohen JM, Sebire NJ, Harvey J, et al. Successful treatment of lymphoproliferative disease complicating primary immunodeficiency/immunodysregulatory disorders with reduced-intensity allogeneic stem-cell transplantation. Blood 2007; 110:2209.
  10. Seidemann K, Tiemann M, Henze G, et al. Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials. Med Pediatr Oncol 1999; 33:536.
  11. Gross TSB. Lymphoproliferative disorders and malignancies related to immunodeficiencies. In: Principles and Practice of Pediatric Oncology, 6th ed, Pizzo PA, Poplack DG (Eds), Lippincott Williams & Wilkins, Philadelphia, PA 2006. p.748.
  12. Filipovich AH, Mathur A, Kamat D, et al. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 1994; 5:91.
  13. Robison LL, Stoker V, Frizzera G, et al. Hodgkin's disease in pediatric patients with naturally occurring immunodeficiency. Am J Pediatr Hematol Oncol 1987; 9:189.
  14. Rezaei N, Hedayat M, Aghamohammadi A, Nichols KE. Primary immunodeficiency diseases associated with increased susceptibility to viral infections and malignancies. J Allergy Clin Immunol 2011; 127:1329.
  15. Taylor AM, Metcalfe JA, Thick J, Mak YF. Leukemia and lymphoma in ataxia telangiectasia. Blood 1996; 87:423.
  16. McGrath-Morrow SA, Gower WA, Rothblum-Oviatt C, et al. Evaluation and management of pulmonary disease in ataxia-telangiectasia. Pediatr Pulmonol 2010; 45:847.
  17. Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, et al. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 2004; 144:505.
  18. Suarez F, Mahlaoui N, Canioni D, et al. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol 2015; 33:202.
  19. Canman CE, Lim DS. The role of ATM in DNA damage responses and cancer. Oncogene 1998; 17:3301.
  20. Rotman G, Shiloh Y. ATM: from gene to function. Hum Mol Genet 1998; 7:1555.
  21. Khanna KK, Keating KE, Kozlov S, et al. ATM associates with and phosphorylates p53: mapping the region of interaction. Nat Genet 1998; 20:398.
  22. Cortez D, Wang Y, Qin J, Elledge SJ. Requirement of ATM-dependent phosphorylation of brca1 in the DNA damage response to double-strand breaks. Science 1999; 286:1162.
  23. Chen J. Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage. Cancer Res 2000; 60:5037.
  24. Swift M, Reitnauer PJ, Morrell D, Chase CL. Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 1987; 316:1289.
  25. Athma P, Rappaport R, Swift M. Molecular genotyping shows that ataxia-telangiectasia heterozygotes are predisposed to breast cancer. Cancer Genet Cytogenet 1996; 92:130.
  26. Chrzanowska KH, Gregorek H, Dembowska-Bagińska B, et al. Nijmegen breakage syndrome (NBS). Orphanet J Rare Dis 2012; 7:13.
  27. Demuth I, Frappart PO, Hildebrand G, et al. An inducible null mutant murine model of Nijmegen breakage syndrome proves the essential function of NBS1 in chromosomal stability and cell viability. Hum Mol Genet 2004; 13:2385.
  28. Gatei M, Young D, Cerosaletti KM, et al. ATM-dependent phosphorylation of nibrin in response to radiation exposure. Nat Genet 2000; 25:115.
  29. Wu X, Ranganathan V, Weisman DS, et al. ATM phosphorylation of Nijmegen breakage syndrome protein is required in a DNA damage response. Nature 2000; 405:477.
  30. Buscemi G, Savio C, Zannini L, et al. Chk2 activation dependence on Nbs1 after DNA damage. Mol Cell Biol 2001; 21:5214.
  31. Falck J, Petrini JH, Williams BR, et al. The DNA damage-dependent intra-S phase checkpoint is regulated by parallel pathways. Nat Genet 2002; 30:290.
  32. Uziel T, Lerenthal Y, Moyal L, et al. Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 2003; 22:5612.
  33. Thrasher AJ, Burns SO. WASP: a key immunological multitasker. Nat Rev Immunol 2010; 10:182.
  34. Lutzner MA. Epidermodysplasia verruciformis. An autosomal recessive disease characterized by viral warts and skin cancer. A model for viral oncogenesis. Bull Cancer 1978; 65:169.
  35. Sullivan KE, Mullen CA, Blaese RM, Winkelstein JA. A multiinstitutional survey of the Wiskott-Aldrich syndrome. J Pediatr 1994; 125:876.
  36. Cotelingam JD, Witebsky FG, Hsu SM, et al. Malignant lymphoma in patients with the Wiskott-Aldrich syndrome. Cancer Invest 1985; 3:515.
  37. Imai K, Morio T, Zhu Y, et al. Clinical course of patients with WASP gene mutations. Blood 2004; 103:456.
  38. Thrasher AJ. New insights into the biology of Wiskott-Aldrich syndrome (WAS). Hematology Am Soc Hematol Educ Program 2009; 132.
  39. Bosticardo M, Marangoni F, Aiuti A, et al. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Blood 2009; 113:6288.
  40. Ochs HD, Thrasher AJ. The Wiskott-Aldrich syndrome. J Allergy Clin Immunol 2006; 117:725.
  41. Picard C, Mellouli F, Duprez R, et al. Kaposi's sarcoma in a child with Wiskott-Aldrich syndrome. Eur J Pediatr 2006; 165:453.
  42. Meropol NJ, Hicks D, Brooks JJ, et al. Coincident Kaposi sarcoma and T-cell lymphoma in a patient with the Wiskott-Aldrich syndrome. Am J Hematol 1992; 40:126.
  43. de Oliveira WR, Festa Neto C, Rady PL, Tyring SK. Clinical aspects of epidermodysplasia verruciformis. J Eur Acad Dermatol Venereol 2003; 17:394.
  44. Ramoz N, Rueda LA, Bouadjar B, et al. Mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. Nat Genet 2002; 32:579.
  45. Vohra S, Sharma NL, Shanker V, et al. Autosomal dominant epidermodysplasia verruciformis: a clinicotherapeutic experience in two cases. Indian J Dermatol Venereol Leprol 2010; 76:557.
  46. Jackson S, Harwood C, Thomas M, et al. Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 2000; 14:3065.
  47. Iftner T, Elbel M, Schopp B, et al. Interference of papillomavirus E6 protein with single-strand break repair by interaction with XRCC1. EMBO J 2002; 21:4741.
  48. Forslund O, Lindelöf B, Hradil E, et al. High prevalence of cutaneous human papillomavirus DNA on the top of skin tumors but not in "Stripped" biopsies from the same tumors. J Invest Dermatol 2004; 123:388.
  49. Orth G. Human papillomaviruses associated with epidermodysplasia verruciformis in non-melanoma skin cancers: guilty or innocent? J Invest Dermatol 2005; 125:xii.
  50. Welte K, Zeidler C, Dale DC. Severe congenital neutropenia. Semin Hematol 2006; 43:189.
  51. Germeshausen M, Ballmaier M, Welte K. Incidence of CSF3R mutations in severe congenital neutropenia and relevance for leukemogenesis: Results of a long-term survey. Blood 2007; 109:93.
  52. Zhang Q, Davis JC, Lamborn IT, et al. Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 2009; 361:2046.
  53. Su HC. Dedicator of cytokinesis 8 (DOCK8) deficiency. Curr Opin Allergy Clin Immunol 2010; 10:515.
  54. Engelhardt KR, McGhee S, Winkler S, et al. Large deletions and point mutations involving the dedicator of cytokinesis 8 (DOCK8) in the autosomal-recessive form of hyper-IgE syndrome. J Allergy Clin Immunol 2009; 124:1289.
  55. Saelee P, Wongkham S, Puapairoj A, et al. Novel PNLIPRP3 and DOCK8 gene expression and prognostic implications of DNA loss on chromosome 10q25.3 in hepatocellular carcinoma. Asian Pac J Cancer Prev 2009; 10:501.
  56. Takahashi K, Kohno T, Ajima R, et al. Homozygous deletion and reduced expression of the DOCK8 gene in human lung cancer. Int J Oncol 2006; 28:321.
  57. Nagayama K, Kohno T, Sato M, et al. Homozygous deletion scanning of the lung cancer genome at a 100-kb resolution. Genes Chromosomes Cancer 2007; 46:1000.
  58. Aghamohammadi A, Moin M, Kouhi A, et al. Chromosomal radiosensitivity in patients with common variable immunodeficiency. Immunobiology 2008; 213:447.
  59. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol 1999; 92:34.
  60. Zullo A, Romiti A, Rinaldi V, et al. Gastric pathology in patients with common variable immunodeficiency. Gut 1999; 45:77.
  61. Martin D, Gutkind JS. Human tumor-associated viruses and new insights into the molecular mechanisms of cancer. Oncogene 2008; 27 Suppl 2:S31.
  62. Philip M, Rowley DA, Schreiber H. Inflammation as a tumor promoter in cancer induction. Semin Cancer Biol 2004; 14:433.
  63. Bartkova J, Horejsí Z, Koed K, et al. DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis. Nature 2005; 434:864.
  64. Sayos J, Wu C, Morra M, et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 1998; 395:462.
  65. Shinozaki K, Kanegane H, Matsukura H, et al. Activation-dependent T cell expression of the X-linked lymphoproliferative disease gene product SLAM-associated protein and its assessment for patient detection. Int Immunol 2002; 14:1215.
  66. Parolini S, Bottino C, Falco M, et al. X-linked lymphoproliferative disease. 2B4 molecules displaying inhibitory rather than activating function are responsible for the inability of natural killer cells to kill Epstein-Barr virus-infected cells. J Exp Med 2000; 192:337.
  67. Sumegi J, Huang D, Lanyi A, et al. Correlation of mutations of the SH2D1A gene and epstein-barr virus infection with clinical phenotype and outcome in X-linked lymphoproliferative disease. Blood 2000; 96:3118.
  68. Morra M, Howie D, Grande MS, et al. X-linked lymphoproliferative disease: a progressive immunodeficiency. Annu Rev Immunol 2001; 19:657.
  69. Schwartzberg PL, Mueller KL, Qi H, Cannons JL. SLAM receptors and SAP influence lymphocyte interactions, development and function. Nat Rev Immunol 2009; 9:39.
  70. Pasquier B, Yin L, Fondanèche MC, et al. Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. J Exp Med 2005; 201:695.
  71. Nagy N, Matskova L, Kis LL, et al. The proapoptotic function of SAP provides a clue to the clinical picture of X-linked lymphoproliferative disease. Proc Natl Acad Sci U S A 2009; 106:11966.
  72. Renukaradhya GJ, Khan MA, Vieira M, et al. Type I NKT cells protect (and type II NKT cells suppress) the host's innate antitumor immune response to a B-cell lymphoma. Blood 2008; 111:5637.
  73. Bassiri H, Janice Yeo WC, Rothman J, et al. X-linked lymphoproliferative disease (XLP): a model of impaired anti-viral, anti-tumor and humoral immune responses. Immunol Res 2008; 42:145.
  74. Felices M, Berg LJ. The Tec kinases Itk and Rlk regulate NKT cell maturation, cytokine production, and survival. J Immunol 2008; 180:3007.
  75. Huck K, Feyen O, Niehues T, et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J Clin Invest 2009; 119:1350.
  76. Miller AT, Berg LJ. Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase. J Immunol 2002; 168:2163.
  77. Linka RM, Huck K, Krux F, et al. Germline mutations within the IL2-inducible T cell kinase impede T cell differentiation or survival, cause protein destabilisation, loss of membrane recruitment and lead to severe EBV lymphoproliferation. American Society of Hematology Meeting. Orlando, FL 2010.
  78. Khurana D, Arneson LN, Schoon RA, et al. Differential regulation of human NK cell-mediated cytotoxicity by the tyrosine kinase Itk. J Immunol 2007; 178:3575.
  79. Orth G. Genetics of epidermodysplasia verruciformis: Insights into host defense against papillomaviruses. Semin Immunol 2006; 18:362.
  80. Su AI, Wiltshire T, Batalov S, et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci U S A 2004; 101:6062.
  81. Hayward AR, Levy J, Facchetti F, et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J Immunol 1997; 158:977.
  82. Revy P, Buck D, le Deist F, de Villartay JP. The repair of DNA damages/modifications during the maturation of the immune system: lessons from human primary immunodeficiency disorders and animal models. Adv Immunol 2005; 87:237.
  83. Stepensky P, Weintraub M, Yanir A, et al. IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach. Haematologica 2011; 96:472.
  84. Martin E, Palmic N, Sanquer S, et al. CTP synthase 1 deficiency in humans reveals its central role in lymphocyte proliferation. Nature 2014; 510:288.
  85. Moshous D, Martin E, Carpentier W, et al. Whole-exome sequencing identifies Coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J Allergy Clin Immunol 2013; 131:1594.
  86. Li FY, Chaigne-Delalande B, Su H, et al. XMEN disease: a new primary immunodeficiency affecting Mg2+ regulation of immunity against Epstein-Barr virus. Blood 2014; 123:2148.
  87. Li FY, Chaigne-Delalande B, Kanellopoulou C, et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 2011; 475:471.
  88. Chaigne-Delalande B, Li FY, O'Connor GM, et al. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 2013; 341:186.
  89. Leiding JW, Holland SM. Warts and all: human papillomavirus in primary immunodeficiencies. J Allergy Clin Immunol 2012; 130:1030.
  90. Lazarczyk M, Cassonnet P, Pons C, et al. The EVER proteins as a natural barrier against papillomaviruses: a new insight into the pathogenesis of human papillomavirus infections. Microbiol Mol Biol Rev 2009; 73:348.
  91. Lazarczyk M, Pons C, Mendoza JA, et al. Regulation of cellular zinc balance as a potential mechanism of EVER-mediated protection against pathogenesis by cutaneous oncogenic human papillomaviruses. J Exp Med 2008; 205:35.
  92. Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol 2009; 16:20.
  93. Pablos JL, Amara A, Bouloc A, et al. Stromal-cell derived factor is expressed by dendritic cells and endothelium in human skin. Am J Pathol 1999; 155:1577.
  94. Kamani NR, Kumar S, Hassebroek A, et al. Malignancies after hematopoietic cell transplantation for primary immune deficiencies: a report from the Center for International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant 2011; 17:1783.
  95. Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study. Blood 1999; 94:2208.
  96. Levine AM. Lymphoma complicating immunodeficiency disorders. Ann Oncol 1994; 5 Suppl 2:29.
  97. Woolf SH, Harris R. The harms of screening: new attention to an old concern. JAMA 2012; 307:565.
  98. Welch HG, Black WC. Overdiagnosis in cancer. J Natl Cancer Inst 2010; 102:605.
  99. Tran H, Nourse J, Hall S, et al. Immunodeficiency-associated lymphomas. Blood Rev 2008; 22:261.
  100. Booth C, Gilmour KC, Veys P, et al. X-linked lymphoproliferative disease due to SAP/SH2D1A deficiency: a multicenter study on the manifestations, management and outcome of the disease. Blood 2011; 117:53.
  101. Sumegi J, Johnson J, Filipovich A, et al. Lymphoproliferative disease, X-linked. In: GeneReviews, Pagon RA, Adam MP, Bird TD, et al. (Eds), University of Washington, Seattle 2009.
  102. Sandoval C, Swift M. Treatment of lymphoid malignancies in patients with ataxia-telangiectasia. Med Pediatr Oncol 1998; 31:491.
  103. Seidemann K, Henze G, Beck JD, et al. Non-Hodgkin's lymphoma in pediatric patients with chromosomal breakage syndromes (AT and NBS): experience from the BFM trials. Ann Oncol 2000; 11 Suppl 1:141.
  104. Sandoval C, Swift M. Hodgkin disease in ataxia-telangiectasia patients with poor outcomes. Med Pediatr Oncol 2003; 40:162.
  105. Dembowska-Baginska B, Perek D, Brozyna A, et al. Non-Hodgkin lymphoma (NHL) in children with Nijmegen Breakage syndrome (NBS). Pediatr Blood Cancer 2009; 52:186.
  106. Vorechovský I, Scott D, Haeney MR, Webster DA. Chromosomal radiosensitivity in common variable immune deficiency. Mutat Res 1993; 290:255.
  107. Serra G, Milito C, Mitrevski M, et al. Lung MRI as a possible alternative to CT scan for patients with primary immune deficiencies and increased radiosensitivity. Chest 2011; 140:1581.
  108. Milone MC, Tsai DE, Hodinka RL, et al. Treatment of primary Epstein-Barr virus infection in patients with X-linked lymphoproliferative disease using B-cell-directed therapy. Blood 2005; 105:994.
  109. Griffith LM, Cowan MJ, Notarangelo LD, et al. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J Allergy Clin Immunol 2009; 124:1152.