Immunomodulation and lymphoma in humans

Figures & data

Table 1. Lymphoma risk in individuals with primary immunodeficiencies.

Immunodeficiency class	Primary immunodeficiency	Cancer type	Relative risk or standardized incidence ratio (95% CI)^a	Citation
Predominantly antibody deficiencies	Common variable immune deficiency (CVID)	NHL/lymphoma	12.1 (6.03–21.6) 12.1 (3.3–31.0) 30 438 (females)	Vajdic et al. (2010) Mellemkjaer et al. (2002) Kinlen et al. (1985) Cunningham-Rundles  et al. (1987)
Combined T- and B-cell deficiencies	Severe combined immunodeficiency (SCID)	Lymphoma, leukemia	30	see Mueller & Pizzo (1995)
Other well-defined immunodeficiency syndromes	Ataxia-telangiectasia	NHL/lymphoma Leukemia	165 (4.19–922) 252–750 (whites–blacks) 244 (27–880) 71–500 (whites–blacks) 120 (36–241)	Vajdic et al. (2010) Morrell et al. (1986) Olsen et al. (2001) Morrell et al. (1986) Olsen et al. (2001)
	Wiskott-Aldrich Syndrome	Malignant neoplasms (predominantly lymphoma/ lymphoreticular tumors, leukemias)	100	Perry et al. (1980)
Diseases of immune dysregulation	X-linked lymphoproliferative disease	B-cell lymphomas	200	Nagy & Klein (2010)

^aSIR is a reasonable estimate for relative risk when population prevalence is low (Chaturvedi et al., 2008).

Table 2. Relative risk (as odds ratios with 95% confidence intervals) of non-Hodgkin’s lymphoma cancer (and sub-types) in individuals with autoimmunity compared to the general population.

Autoimmunity	Non–hodgkin’s lymphoma	Diffuse large b–cell	Chronic lymphocytic leukemia	Follicular	T–cell	Mantle cell	Marginal zone	Lympho–plasmacytic
Rheumatoid arthritis	1.2 (1.1–1.3)^a	1.4 (1.2–1.5)^a	1.4 (0.9–2.2)^b	1.0 (0.6–1.7)^b	1.5 (1.1–1.8)^a	1.2 (0.5–3.1)^b	1.2 (1.0–1.6)^a	2.5 (1.2–5.4)^b
	1.5 (1.1–1.9)^b	1.8 (1.2–2.6)^b			1.9 (0.9–3.9)^b		1.4 (0.5–3.5)^b
Sjögren syndrome	1.9 (1.5–2.3)^a	2.0 (1.5–2.8)^a			0.8 (0.2–2.4)^a		6.6 (4.6–9.5)^a
	6.1 (1.4–27)^b	11 (2.1–58)^b					28 (4.4–176)^b
	8.7 (4.3–15.5)^j	2.2 (1.5–3.1)^j
Systemic lupus erythematosus	1.5 (1.2–1.9)^a	1.4 (1.0–2.0)^a		2.9 (1.9–4.2)^c	2.4 (1.3–4.4)^a		2.8 (1.7–7.4)^a
	4.6 (1.0–22)^b	11 (2.1–58)^b
	2.7 (2.2–3.3)^c	3.3 (2.3–4.4)^c
	44 (12–111)^d
	7.0 (1.9–18)^e
	1.5 (0.02–8.6)^f
	11.6 (1.4–42)^g
	5.2 (2.2–10)^h
	3.6 (2.6–4.9)^i
Sarcoidosis	1.5 (1.0–2.2)^a	2.0 (1.2–3.3)^a	0.7 (0.2–3.2)^b	0.7 (0.2–3.2)^b	0.6 (0.1–4.6)^a		1.6 (0.5–5.0)^a	2.5 (0.3–20)^b
	0.5 (0.2–1.3)^b						2.2 (0.2–3.2)^b
Systemic sclerosis	1.4 (0.9–2.2)^a	2.0 (1.1–3.6)^a			0.8 (0.1–5.8)^a		1.8 (0.5–5.8)^a
Autoimmune hemolytic anemia	6.5 (4.4–9.4)^a	3.3 (1.7–6.3)^a			9.7 (4.3–22)^a		7.4 (3.1–18)^a
Aplastic anemia	1.8 (1.3–2.7)^a	1.9 (1.1–3.3)^a			2.8 (1.0–7.8)^a		1.3 (0.3–5.4)^a
Psoriasis	1.2 (1.0–1.3)^a	1.2 (1.0–1.4)^a	1.2 (0.8–1.7)^b	0.9 (0.6–1.3)^b	3.1 (2.5–4.0)^a	1.1 (0.5–2.4)^b	1.3 (1.0–1.9)^a	0.8 (0.3–2.1)^b
	1.2 (0.9–1.5)^b	1.3 (0.9–1.8)^b			1.4 (0.8–2.5)^b		0.9 (0.4–2.2)^b
Multiple sclerosis	0.6 (0.4–0.9)^a	0.4 (0.2–0.9)^a			0.4 (0.1–2.5)^a		0.3 (0.1–2.3)^a
Celiac disease	2.1 (1.0–4.8)^b	2.8 (1.8–8.0)^b	0.5 (0.1–4.0)^b	0.4 (0.1–3.6)^b	17 (6.3–46)^b	3.3 (0.4–28)^b		3.4 (0.4–28)^b
Crohn’s disease	1.4 (0.5–4.1)^b	2.7 (0.7–9.5)^b	1.3 (0.3–6.5)^b	0.6 (0.1–5.2)^b	3.0 (0.3–25)^b
Ulcerative colitis	1.1 (0.6–2.0)^b	1.2 (0.5–2.9)^b	0.9 (0.3–2.3)^b	0.5 (0.1–2.3)^b	1.8 (0.4–7.9)^b	1.6 (0.4–7.1)^b
Type 1 diabetes	1.5 (0.9–1.5)^b	1.3 (0.3–4.8)^b	3.6 (1.3–10)^b			5.0 (1.0–25)^b	2.8 (0.3–18)^b	3.9 (0.5–33)^b

Statistically significant results are in italic (p < 0.05).

Citations as follows: ^aAnderson et al. (2009); ^bSmedby et al. (2006), ^cParikh-Patel et al. (2008); ^dPettersson et al. (1992); ^eCibere et al. (2001); ^fRamsey-Goldman et al. (1998); ^gNived et al. (2001); ^hMellemkjaer et al. (1997); ⁱBernatsky et al. (2005); ^jKauppi et al. (1997).

Table 3. Relative risk (as standardized incidence ratios (95% confidence intervals)) of malignancies in patients with rheumatoid arthritis.

	Compared to general population, RR (95% CI), n			By treatment compared to general population (unless noted), RR (95% CI), n
Citation	Overall lymphoma	NHL	Other	Anti–TNF	Methotrexate
Abasolo et al. (2008)		5.4 (1.1–15.7), 3	Lung: 3.5 (1.4–7.1), 7 Leukemia: 8.8 (2.4–22.6), 4
Askling et al. (2005)	1.9 (1.7–2.1), 319			2.9 (1.3–5.5), 9 1.1 (0.6–2.1)^b
Askling et al. (2009)				2.7 (1.8–4.1), 26 1.4 (0.8–2.1)^a
Baecklund et al. (2006b)					0.7 (0.3–1.6)^a
Cibere et al. (1997)		0.55 (0.1–1.6), 3	Leukemia: 2.5 (1.1–4.7), 9
Ekstrom et al. (2003)	2.0 (1.8–2.2), 535	1.9 (1.7–2.1), 458	Hodgkin’s: 3.1 (2.4–3.8), 77
Engels et al. (2005)		1.3 (0.8–2.1), 48			2.3 (0.7–7.5), 10
Franklin et al. (2006)	2.94 (1.3–5.6), 9				3.3 (1.0–10.8)^a
Geborek et al. (2005)	1.3 (0.2–4.5), 2			11.5 (3.7–26.9), 5
Gridley et al. (1993)	2.0 (1.5–2.6), 48	1.9 (1.3–2.6), 36	Hodgkin’s: 2.3 (1.2–4.1), 12 Lung: 1.3 (1.0–1.7), 68
Hakulinen et al. (1985)		2.8 (2.0–3.9), 38^c
Kauppi et al. (1997)		2.2 (1.5–3.1), 34
Mariette et al. (2002)					1.07 (0.6–1.7), 18
Mellemkjaer et al. (1996)		2.4 (1.9–2.9), 85	Hodgkin’s: 3.4 (1.8–5.6), 14 Acute non-lymphocytic  leukemia: 1.9 (1.2–2.8), 25
Thomas et al. (2000)		M: 2.4 (1.6–3.4), 30 F: 2.0 (1.6–2.9), 71	Hodgkin’s: M: 5.5 (2.4–10.8), 8; F: 3.0 (1.4–5.8), 9 Lung: M: 1.3 (1.2–1.5), n = 208; F: 1.4 (1.3–1.6), n = 264
Setoguchi et al. (2006)		2.2 (1.71–2.87), 58	Multiple myeloma: 2.0 (1.3–3.1), 19 Melanoma: 2.3 (1.6–3.2), 29 Leukemia: 1.3 (0.9–2.0), 22 Lung: 1.8 (1.5–2.1), 169 Urinary/bladder: 2.0 (1.6–2.7), 54
Wolfe & Michaud (2004)	1.9 (1.3–2.7), 29			2.9 (1.7-4.9), 14	1.5 (0.8-2.7), 10
Wolfe & Michaud (2007)	1.8 (1.5–2.2), 95			1.8 (1.5-2.2) 1.0 (0.6–1.8)^a	1.3 (0.7–2.4)^a

^aResults presented as odds ratios or relative risks considering RA patients treated with the specified therapy vs those not receiving that therapy.

^bAs estimated by Wolfe & Michaud (2007) considering RA patients treated with anti-TNF therapy vs those not receiving that therapy.

^cAs reported by Zintzaras et al. (2005); n = number of patients with specified malignancy.

Table 4. EBV differentially contributes to lymphoma burden across patient populations.

Disease	% EBV^+ tumors	Citation
Lymphoma with no known immunosuppression	2–10%	Kamel et al. (1999); Hoshida et al. (2007)
Hodgkin’s lymphoma	40–50% 80%	Macsween & Crawford (2003); Swerdlow (2003); Young & Murray (2003); Young & Rickinson (2004); Thorley-Lawson & Gross (2004); Balandraud et al. (2005)
Burkitt’s lymphoma (developed world)	15–25%	Macsween & Crawford (2003); Young & Murray (2003); Young & Rickinson (2004)
NHL
Post-transplantation (<1 year)	>90%	Macsween & Crawford (2003)
Post-transplantation (>1 year)	50%	Young & Rickinson (2004)
HIV-associated lymphoma
NHL	28–66%	Rabkin (2001); Macsween & Crawford (2003); Balandraud et al. (2005)
Burkitt’s	25%	Macsween & Crawford (2003)
CNS Lymphoma	100%	Rabkin (2001); Macsween & Crawford (2003)
Primary Immunodeficiency
Lymphoma/BPLD	31%^a	Filipovich et al. (1994)
Lymphoma	0%	Gompels et al. (2003)
Lymphoma (mucosal-associated)	0%	Cunningham-Rundles et al. (2002)
RA-associated lymphoma	2%	Kamel et al. (1999)
	3%	Staal et al. (1989)
	15%	Mariette et al. (2002)
	27%	Hoshida et al. (2007)
	11%	Askling et al. (2005)
	26%	Dawson et al. (2001)
	17%	Baecklund et al. (2003)
	5--10%	Baecklund et al. (2006a)
	12%	Baecklund et al (2006b)

BPLD, B-cell lymphoproliferative disorder.

^aEB virus detected in 4/13 patients samples, including 3/5 tissues from patients with Wiskott-Aldrich Syndrome and 1/3 patients with Severe Combined Immunodeficiency.

Figure 1. Lymphomas arise at different stages of B-cell differentiation, most commonly after antigenic stimulation during the germinal center reaction. Antigen-stimulated B-cells form germinal centers in lymph nodes under the regulation of BCL6 and PAX5. DNA mutation and recombination occur in an effort to develop and expand a pool of B-cell clones that produce high affinity antibody (via somatic hypermutation) with the appropriate effector activity (via class-switch recombination) towards antigen. Errors arising from these hyper-mutable events give rise to malignant transformation at discrete stages in this process, and the specific DNA alterations contribute to the diversity of lymphomatous phenotypes. See text for details. (Figure adapted from Klein & Dalla-Favera (2008)).

Vajdic, C. M., Mao, L., van Leeuwen, M. T., et al. 2010. Are antibody deficiency disorders associated with a narrower range of cancers than other forms of immunodeficiency? Blood 116:1228–1234

 PubMed Web of Science ®Google Scholar

Mellemkjaer, L., Hammarstrom, L., Andersen, V., et al. 2002. Cancer risk among patients with IgA deficiency or common variable immunodeficiency and their relatives: A combined Danish and Swedish study. Clin. Exp. Immunol. 130:495–500

 PubMed Web of Science ®Google Scholar

Kinlen, L. J., Webster, A. D., Bird, A. G., et al. 1985. Prospective study of cancer in patients with hypogammaglobulinaemia. Lancet 1:263–266

 PubMed Web of Science ®Google Scholar

Cunningham-Rundles, C., Siegal, F. P., Cunningham-Rundles, S., and Lieberman, P. 1987. Incidence of cancer in 98 patients with common varied immunodeficiency. J. Clin. Immunol. 7:294–299

 PubMed Web of Science ®Google Scholar

Morrell, D., Cromartie, E., and Swift, M. 1986. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J. Natl. Cancer Inst. 77:89–92

 PubMedGoogle Scholar

Olsen, J. H., Hahnemann, J. M., Borresen-Dale, A. L., et al. 2001. Cancer in patients with ataxia-telangiectasia and in their relatives in the nordic countries. J. Natl. Cancer Inst. 93:121–127

 PubMedGoogle Scholar

Perry, G. S. 3rd, Spector, B. D., Schuman, L. M., et al. 1980. The Wiskott-Aldrich syndrome in the United States and Canada (1892–1979). J. Pediatr. 97:72–78

 PubMed Web of Science ®Google Scholar

Chaturvedi, A. K., Mbulaiteye, S. M., and Engels, E. A. 2008. Underestimation of relative risks by standardized incidence ratios for AIDS-related cancers. Ann. Epidemiol. 18:230–234

 PubMedGoogle Scholar

Anderson, L. A., Gadalla, S., Morton, L. M., et al. 2009. Population-based study of autoimmune conditions and the risk of specific lymphoid malignancies. Int. J. Cancer 125:398–405

 PubMed Web of Science ®Google Scholar

Smedby, K. E., Hjalgrim, H., Askling, J., et al. 2006. Auto-immune and chronic inflammatory disorders and risk of non-Hodgkin lymphoma by subtype. J. Natl. Cancer Inst. 98:51–60

 PubMed Web of Science ®Google Scholar

Parikh-Patel, A., White, R. H., Allen, M., and Cress, R. 2008. Cancer risk in a cohort of patients with systemic lupus erythematosus (SLE) in California. Cancer Causes Control 19:887–894

 PubMed Web of Science ®Google Scholar

Pettersson, T., Pukkala, E., Teppo, L., and Friman, C. 1992. Increased risk of cancer in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 51:437–439

 PubMed Web of Science ®Google Scholar

Cibere, J., Sibley, J., and Haga, M. 2001. Systemic lupus erythematosus and the risk of malignancy. Lupus 10:394–400

 PubMed Web of Science ®Google Scholar

Ramsey-Goldman, R., Mattai, S. A., Schilling, E., et al. 1998. Increased risk of malignancy in patients with systemic lupus erythematosus. J. Invest. Med. 46:217–222

 PubMed Web of Science ®Google Scholar

Nived, O., Bengtsson, A., Jonsen, A., et al. 2001. Malignancies during follow-up in an epidemiologically defined systemic lupus erythematosus inception cohort in southern Sweden. Lupus 10:500–504

 PubMed Web of Science ®Google Scholar

Mellemkjaer, L., Andersen, V., Linet, M. S., et al. 1997. Non-Hodgkin's lymphoma and other cancers among a cohort of patients with systemic lupus erythematosus. Arthritis Rheum. 40:761–768

 PubMed Web of Science ®Google Scholar

Bernatsky, S., Boivin, J. F., Joseph, L., et al. 2005. An international cohort study of cancer in systemic lupus erythematosus. Arthritis Rheum. 52:1481–1490

 PubMed Web of Science ®Google Scholar

Kauppi, M., Pukkala, E., and Isomaki, H. 1997. Elevated incidence of hematologic malignancies in patients with Sjogren's syndrome compared with patients with rheumatoid arthritis (Finland). Cancer Causes Control 8:201–204

 PubMed Web of Science ®Google Scholar

Abasolo, L., Judez, E., Descalzo, M. A., et al. 2008. Cancer in rheumatoid arthritis: occurrence, mortality, and associated factors in a South European population. Semin. Arthritis Rheum. 37:388–397

 PubMed Web of Science ®Google Scholar

Askling, J., Fored, C. M., Baecklund, E., et al. 2005. Hematopoietic malignancies in rheumatoid arthritis: Lymphoma risk and characteristics after exposure to TNF antagonists. Ann. Rheum. Dis. 64:1414–1420

 PubMed Web of Science ®Google Scholar

Askling, J., Baecklund, E., Granath, F., et al. 2009. Anti-TNF therapy in rheumatoid arthritis and risk of malignant lymphomas: Relative risks and time trends in the Swedish Biologics Register. Ann. Rheum. Dis. 68:648–653

 PubMed Web of Science ®Google Scholar

Cibere, J., Sibley, J., and Haga, M. 1997. Rheumatoid arthritis and the risk of malignancy. Arthritis Rheum. 40:1580–1586

 PubMed Web of Science ®Google Scholar

Ekstrom, K., Hjalgrim, H., Brandt, L., et al. 2003. Risk of malignant lymphomas in patients with rheumatoid arthritis and in their first-degree relatives. Arthritis Rheum. 48:963–970

 PubMed Web of Science ®Google Scholar

Engels, E. A., Cerhan, J. R., Linet, M. S., et al. 2005. Immune-related conditions and immune-modulating medications as risk factors for non-Hodgkin's lymphoma: A case-control study. Am. J. Epidemiol. 162:1153–1161

 PubMed Web of Science ®Google Scholar

Franklin, J., Lunt, M., Bunn, D., et al. 2006. Incidence of lymphoma in a large primary care derived cohort of cases of inflammatory polyarthritis. Ann. Rheum. Dis. 65:617–622

 PubMed Web of Science ®Google Scholar

Geborek, P., Bladstrom, A., Turesson, C., et al. 2005. TNF blockers do not increase overall tumor risk in patients with rheumatoid arthritis, but may be associated with increased risk of lymphomas. Ann. Rheum. Dis. 64:699–703

 PubMed Web of Science ®Google Scholar

Gridley, G., McLaughlin, J. K., Ekbom, A., et al. 1993. Incidence of cancer among patients with rheumatoid arthritis. J. Natl. Cancer Inst. 85:307–311

 PubMed Web of Science ®Google Scholar

Hakulinen, T., Isomaki, H., and Knekt, P. 1985. Rheumatoid arthritis and cancer studies based on linking nationwide registries in Finland. Am J Med 78:29–32

 PubMed Web of Science ®Google Scholar

Mariette, X., Cazals-Hatem, D., Warszawki, J., et al. 2002. Lymphomas in rheumatoid arthritis patients treated with methotrexate: A 3-year prospective study in France. Blood 99:3909–3915

 PubMed Web of Science ®Google Scholar

Mellemkjaer, L., Linet, M. S., Gridley, G., et al. 1996. Rheumatoid arthritis and cancer risk. Eur. J. Cancer 32A:1753–1757

 PubMed Web of Science ®Google Scholar

Thomas, E., Brewster, D. H., Black, R. J., and Macfarlane, G. J. 2000. Risk of malignancy among patients with rheumatic conditions. Int. J. Cancer 88:497–502

 PubMed Web of Science ®Google Scholar

Setoguchi, S., Solomon, D. H., Weinblatt, M. E., et al. 2006. TNFα antagonist use and cancer in patients with rheumatoid arthritis. Arthritis Rheum. 54:2757–2764

 PubMed Web of Science ®Google Scholar

Wolfe, F., and Michaud, K. 2007. The effect of methotrexate and anti-TNF therapy on the risk of lymphoma in rheumatoid arthritis in 19 562 patients during 89 710 person-years of observation. Arthritis Rheum. 56:1433–1439

 PubMed Web of Science ®Google Scholar

Zintzaras, E., Voulgarelis, M., and Moutsopoulos, H. M. 2005. The risk of lymphoma development in autoimmune diseases: A meta-analysis. Arch. Intern. Med. 165:2337–2344

 PubMed Web of Science ®Google Scholar

Kamel, O. W., Holly, E. A., van de Rijn, M., et al. 1999. A population based, case control study of non-Hodgkin's lymphoma in patients with rheumatoid arthritis. J. Rheumatol. 26:1676–1680

 PubMed Web of Science ®Google Scholar

Hoshida, Y., Xu, J. X., Fujita, S., et al. 2007. Lymphoproliferative disorders in rheumatoid arthritis: Clinicopathological analysis of 76 cases in relation to methotrexate medication. J. Rheumatol. 34:322–331

 PubMed Web of Science ®Google Scholar

Swerdlow, A. J. 2003. Epidemiology of Hodgkin's disease and non-Hodgkin's lymphoma. Eur. J. Nucl. Med. Mol. Imaging 30:S3–12

 Web of Science ®Google Scholar

Balandraud, N., Roudier, J., and Roudier, C. 2005. What are the links between Epstein-Barr virus, lymphoma, and TNF antagonism in rheumatoid arthritis? Semin. Arthritis Rheum. 34:31–33

 PubMedGoogle Scholar

Rabkin, C. S. 2001. AIDS and cancer in the era of highly active anti-retroviral therapy (HAART). Eur. J.Cancer 37:1316–1319

 PubMed Web of Science ®Google Scholar

Filipovich, A. H., Mathur, A., Kamat, D., et al. 1994. Lymphoproliferative disorders and other tumors complicating immunodeficiencies. Immunodeficiency 5:91–112

 PubMedGoogle Scholar

Gompels, M. M., Hodges, E., Lock, R. J., et al. 2003. Lymphoproliferative disease in antibody deficiency: A multi-centre study. Clin. Exp. Immunol. 134:314–320

 PubMed Web of Science ®Google Scholar

Cunningham-Rundles, C., Cooper, D. L., Duffy, T. P., and Strauchen, J. 2002. Lymphomas of mucosal-associated lymphoid tissue in common variable immunodeficiency. Am. J. Hematol. 69:171–178

 PubMed Web of Science ®Google Scholar

Staal, S. P., Ambinder, R., Beschorner, W. E., et al. 1989. A survey of Epstein-Barr virus DNA in lymphoid tissue. Frequent detection in Hodgkin's disease. Am. J. Clin. Pathol. 91:1–5

 PubMed Web of Science ®Google Scholar

Dawson, T. M., Starkebaum, G., Wood, B. L., et al. 2001. Epstein-Barr virus, methotrexate, and lymphoma in patients with rheumatoid arthritis and primary Sjogren's syndrome: Case series. J. Rheumatol. 28:47–53

 PubMed Web of Science ®Google Scholar

Baecklund, E., Sundstrom, C., Ekbom, A., et al. 2003. Lymphoma subtypes in patients with rheumatoid arthritis: Increased proportion of diffuse large B-cell lymphoma. Arthritis Rheum. 48:1543–1550

 PubMed Web of Science ®Google Scholar

Klein, U., and Dalla-Favera, R. 2008. Germinal centres: Role in B-cell physiology and malignancy. Nat. Rev. Immunol. 8:22–33

 PubMed Web of Science ®Google Scholar