1. Principles of Lymphoma Epidemiology
Paolo Boffetta
Mount Sinai School of Medicine, New York, NY

2. Worldwide Incidence of NHL in 2008 - Men

3. Worldwide Incidence of NHL in 2008 - Women

4. NHL Incidence Rate in Los Angeles, by ethnic
group, 1998-2002
20
Age stand. rate/100,000
15
10
5
0
Black Chinese Japanese Filipino Korean Hispanic Non-
White Hispanic
White
Men Women

5. The increasing incidence of NHL during
the second half of the 20th century
10
Men
8 Women
6
4
2
Denmark
0
45
50
55
60
65
70
75
80
85
90
95
00
19
19
19
19
19
19
19
19
19
19
19
20

6. Trends of age-adjusted incidence rates of NHL in females
65+ years, SEER 9 Regions, 1973-2003
50
DLBCL
40 Marginal
Zone
AAIR/100,000
30 Follicular
20 CLL/SLL
Mantle cell
10
Burkitt's
0
5 9 3 7 1 5 9 3 Lymphoplas
97 97 98 98 99 99 99 00
-1 -1 -1 -1 -1 -1 -1 -2 macytic
73 76 80 84 88 92 96 00
19 19 19 19 19 19 19 20 T cell/NK
Morton, et al., 2006

7. Established causes of NHL
• EBV infection (Burkitt)
• Severe immunodeficiency (acquired or
inherited)
• Severe immunostimulation
• Chemotherapy

8. NHL risk in organ transplant recipients
Study Country Org N Obs RR
Hoover 1992 US K 6297 54 18
Kinlen 1979 UK K 3823 34 60
Opeiz 1993 US, Eur K 45141 155 16
Adami 2003 Sweden K 5004 27 4
Whiterspoon 1989 US BM 2264 16 350
Opeiz 1993 US, Eur H 7643 162 67
Adami 2003 Sweden non-K 927 18 37

9. NHL risk in RA patients
Study Country N Obs RR
Silman 1988 UK 404 6 7.3
Gridley 1993 Sweden 11683 36 1.9
Gridley 1994* USA 906 19 13
Mellemkjaer 1996 Denmark 20699 85 2.4
* Felty syndrome patients

10. NHL risk after chemotherapy for HD
Study N O RR
Kaldor 1987 28462 24 3.0
Tucker 1988 1507 9 18
Henry-Amar 1992 12411 106 32
van Leeuwen 1994 1939 NA 21
Swerdlow 1997 1039 3 4.6
Excess mainly in first 5 years
Risk also in HD patients without chemotherapy

11. Suspected causes of NHL
• Genetic factors
– candidate genes
– GWAS
• Infections
– HCV
• Sunlight
• Hair dyes
• Agricultural-related factors
– pesticides, animal viruses
• Occupational exposures
– school teachers, meat workers
• Diet, obesity

12. Pooled analysis of 14 polymorphisms
in 10 immunological genes
Rothman et al., 2006

13. GWAS of NHL
• Stage 1 3-stage
GWAS
FL SNP at 6p21.32 (MHC region)
Conde et al., 2010

14. Risk of NHL associated to HCV
Table 2. Risk estimates for Non-Hodgkin lymphoma associated withConsortium
Results from InterLymph HCV by study
Prevalence
†
Control Case Control Case OR (95% CI)
n n n % n %
Connecticut 534 463 5 0.94 8 1.73 2.08 (0.65-6.64)
‡
Italy 504 225 45 8.93 44 19.56 2.67 (1.66-4.31)
‡
NCI 684 813 14 2.05 32 3.94 1.89 (0.99-3.61)
‡
NSW 518 587 2 0.39 3 0.51 1.15 (0.19-7.00)
UCSF 1,544 554 57 3.69 23 4.15 1.24 (0.75-2.05)
‡
Epilymph Europe 1,788 1,346 41 2.29 43 3.19 1.44 (0.93-2.24)
Canada 697 796 5 0.72 19 2.39 3.28 (1.20-8.98)
§
Pooled data 6,269 4,785 169 2.7 172 3.59 1.74 (1.39-2.19)
†
OR and 95% CI were estimated using unconditional logistic regression models, adjusted for age, sex and race
‡
Adjusted for study center or geographic region of data collection
§
Joint fixed-effects logistic regression model; also adjusted for study cente
Resultados preliminares
de Sanjose et al., 2008
Courtesy of Silvia de Sanjose, Institut Català d' Oncologia, IDIBELL

15. Other infections suspected to cause NHL
• H. pylori gastric MALT and DLBCL
• B. burgdorferi cutaneous MALT
• C. jejuni small intestine MALT
• HHV-8 PEL
• SV40 DLBCL

16. UV radiation and NHL risk
•Ecological analyses showing a positive association between UV
exposure/skin cancer and NHL
OR (95% CI)
•InterLymph-based pooled analysis
• 8 case-control studies
• 8200 cases, 9700 controls
• RR for high vs. low quartile of UV
exposure distribution 0.87 (95% CI
0.71, 1.05)
0.1 1.0 10.0
OR
Kricker et al., 2008

17. Tobacco smoking and NHL risk
InterLymph pooled analysis
Morton et al., 2005

18. Risk of NHL among farmers
• Meta-analysis of 43 studies
– overall RR 1.06 (95% CI 1.02-1.11)
– higher for men, US studies and case-
control studies
– heterogeneity of risk estimates

19. Risk of NHL among teachers
• Meta-analysis of 17 studies
– overall RR 1.18 (95% CI 1.13-1.29)
– dominated by a record linkage study from
US
– limited heterogeneity of risk estimates

20. Risk of NHL attributable to selected factors
Risk factor RR Exp % PAR %
MHC SNP (FL only) 1.95 12 10
TNF SNP 1.19 26 5
Chemotherapy - HD 10 0.1 0.1
Chemotherapy - testis/ovary 2.0 0.5 0.3
Farmers 1.05 5 0.3
Dry cleaners 1.4 1 0.4
Meat workers 1.3 0.5 0.1
Teachers 1.2 5 1
Hair dyes 1.07 37 3
Smoking 1.07 30 2
HCV infection 1.7 5 3

22. Epidemiology of NHL
Challenges
• Complex geographic and temporal
patterns
– epidemiology of NHL subtypes
• Limited understanding of causes
– small proportion of cases explained
• Need to integrate biological, clinical and
epidemiological research

23. Epidemiology of NHL
Opportunities
• Insights into mechanisms of
carcinogenesis
– role of immunocompetence in human cancer
– development of new therapies
• Fostering international collaboration
– access to well-annotated series

24. Acknowledgments
• InterLymph
– Anne Kricker, Wendy Cozen, Nat
Rothman, Christine Skibola, Lindsay
Morton, Trisha Hartge
• Epilymph
– Silvia de Sanjose, Gigi Cocco, Alexandra
Nieters, Marc Maynadie
• Other groups
– Hans-Olov Adami, Anders Ekbom