Supplementary appendix

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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 2012; published online May 9. DOI: /S (12)

2 The global burden of cancers attributable to infections in the year 2008: a review and synthetic analysis Web appendix section Catherine De Martel MD, Jacques Ferlay ME, Silvia Franceschi MD, Jérôme Vignat M.Sc., Freddie Bray PhD, David Forman PhD, and Martyn Plummer PhD International Agency for Research on Cancer, Lyon, France CHOICE OF BIOLOGICAL AGENTS AND CANCER SITES Our decision to follow the recommendations of the working group for the volume 100B of the IARC Monographs series 1 requires some explanation and further clarification. The IARC Monographs programme classifies agents according to a 5-point scale summarized in the table below. 1 Carcinogenic to humans 2A Probably carcinogenic to humans 2B Possibly carcinogenic to humans 3 Not classifiable 4 Evidence suggesting lack of carcinogenicity For a given agent, the evidence for an association with a particular cancer site is classified as sufficient, limited or inadequate. We have chosen only agents classified as group 1 and only those cancer sites with sufficient evidence. In doing so, we based our estimates on a comprehensive, systematic, and expert-led review of the evidence. REVIEW OF INFECTIOUS AGENTS Helicobacter pylori (H. pylori) Non cardia gastric adenocarcinoma A causal association between chronic gastric infection with H. pylori and development of gastric adenocarcinoma is well established. 2 The risk is restricted to the non-cardia part of the stomach; adenocarcinoma of the gastric cardia shares risk factors with esophageal cancer and is not associated with H. pylori. 1,3 While environmental factors such as diet, or genetic factors in both host and bacteria may modulate the strength of the causal relation between the bacterium and the cancer, no other strong independent risk factor has been recognized for non-cardia gastric adenocarcinoma. A well-known difficulty in estimating the prevalence of H. pylori infection is the gradual decline in the burden of H. pylori infection with increasing gastric atrophy, a precursor lesion of gastric adenocarcinoma, and the consequent lack of sensitivity of serological markers at the time of cancer diagnosis. 4,5 Studies in which H. pylori antibodies were measured well before the onset of cancer are considered the most reliable for the calculation of the true prevalence in cases and controls and therefore for the estimate of the relative risk (RR). A review of such studies in 2001 reported that the average prevalence of H. pylori infection in cases is 90%, a figure that was quite homogeneous across studies in various continents despite a highly variable background rate in population-based controls. 3 A pooled analysis of 11 of these studies yielded a common RR of 5.9 (95% confidence interval, CI: ) for patients who developed cancer more than 10 years after blood draw. 3 This yields a PAF of 75% for H. pylori in non-cardia gastric adenocarcinoma. 1

3 Gastric lymphoma Non Hodgkin lymphomas (NHL) of the stomach are classified into two main histological types: the mucosa-associated lymphoid tissue (MALT) and the diffuse large B-cell (DLBCL) lymphomas whose relative proportion seems to vary according to geographic location. 6 The two types are not distinguished in most cancer registries. However, in the few registries with data allowing cross tabulation between topography and histology codes, NHL of gastric location represents approximately 5% of all NHL and less than 2% of all gastric cancers. Nearly all MALT and an unknown proportion of DLBC in the stomach are related to H. pylori infection. The only nested case-control study published to date included both MALT and DLBC lymphoma patients from two large cohort studies in the USA and Norway. Overall, 85% of the 33 cases were infected with H. pylori compared to 55% of the matched controls, and the resulting RR was of 6.3 (CI: ). 7 Another populationbased case-control study conducted in Spain showed H. pylori in 4/4 cases compared to 430/604 controls (71%). 8 Based on these limited data, the pooled prevalence of H. pylori in gastric lymphoma is 86% and the pooled RR estimate was 7.2, giving a PAF of 74%. Hepatitis B and C viruses (HBV and HCV) Hepatocellular carcinoma (HCC) Chronic infection with HBV and/or HCV is the most common risk factor for hepatocellular carcinoma (HCC) worldwide, but other strong risk factors exist, such as alcohol-induced liver cirrhosis in more developed countries, or exposure to aflatoxin, especially in China, other parts of Eastern Asia and Sub-Saharan Africa. The contribution of each risk factor, alone or in association, varies greatly in different geographic areas. For hepatitis viruses, HBV infection is found in the general population substantially more often than HCV infection in most Asian and African countries, while the reverse is true in Europe and in the United States, but also in Japan, Pakistan and Mongolia. 9 In HBV endemic areas, HBV is typically acquired in early life, and the prevalence of chronic HBV carriage is stable at older ages. Conversely, HCV infection can be acquired at any age through contaminated needles and blood, and HCV prevalence increases steadily with age due to the accumulating risk of exposure. 10 Prevalence estimates in HCC cases were derived from a 2007 review, 9 which was updated using more recent papers. 1 There are few data on HBV and HCV prevalence in large parts of Eastern Europe and Central Asia. Furthermore, HCV infection does not show geographical clustering. High-prevalence countries may thus be neighbours with low-prevalence countries. For these reasons, regional prevalence estimates were derived by risk-based aggregation. For RR assessment, many sero-epidemiological studies, prospective and retrospective, have been conducted all over the world. 1 In most of these studies, chronic infection with HBV was assessed by the presence of HB surface antigen (HBsAg) in serum, while infection with HCV was best assessed using second or third generation HCV antibody status or HCV RNA. A meta-analysis of 32 such case-control studies published between 1992 and 1997 yielded a summary RR of 22.5 ( ) for HBV alone, and 17.3 ( ) for HCV alone (Table 2). The dual impact of HBV and HCV infection on risk is however less well quantified. 11 Recent prospective and retrospective studies are consistent with previous studies in that they yield RRs of a similar magnitude. 1 The estimated prevalence of HBV or HCV in cases varied from 42% in North America to 87% in Japan, with a global average of 80%. Non- Hodgkin lymphoma (NHL) HCV infection is a well-established cause of essential mixed cryoglobulinemia, a lymphoproliferative disease that can evolve into B-cell NHL. Several studies found a high prevalence of HCV seropositivity in patients with B-cell lymphoproliferative disorders, particularly B-cell NHL, including cases where essential mixed cryoglobulinemia was absent. A meta-analysis of studies of NHL and HCV seropositivity showed a pooled RR for NHL of 2.5 (95% CI: ) based on 15 case-control studies and 2.0 (95% CI: ) in three cohort investigations. 12 RRs were increased for all major B-NHL subtypes, but the association seemed weaker for follicular than for MALT and diffuse large-cell NHL. Some heterogeneity by study location was found, depending mainly on the frequency of HCV infection in different populations. The number of new cases of NHL attributable to HCV varies therefore by country but could reach 10% in Italy, Japan and Egypt where HCV 2

4 prevalence is high. Based on a summary RR of 2.5 and prevalence of HCV in cases as described in Table 2, the PAF for HCV in NHL is 8%. An association between HBV and NHL of a similar magnitude to the association between HCV and NHL has been recently reported in cohort studies from Europe 13 and Korea. 14 It is, however, not considered in the present report as HBV has not been judged to cause NHL by the IARC Monograph programme. Gastric carcinoma Although EBV DNA has been found in 5-10% of gastric carcinomas, the IARC Monograph 100B working group concluded that there is insufficient epidemiological evidence for the involvement of EBV. Therefore we have not calculated the PAF for EBV and gastric cancer. Human papillomavirus (HPV) Cervical cancer HPV is a necessary cause of cervical cancer; its genome can be found in nearly all invasive carcinomas using the most sensitive methods of detection. 15 Persistent infection with high-risk (HR) HPVs in the squamous columnar junction in the cervix uteri is accompanied by expression of early viral genes E6 and E7, leading to a cascade of carcinogenic events. Cohort studies to assess risk estimates for cervical cancer are nearly impossible to undertake because of the interference of screening, and treatment of precancerous lesions. However, the abundance of mechanistic and retrospective epidemiological data have firmly established the chain of causality, with RR >100 in many case-control studies. 1 It is difficult to classify the rarer HPV types with respect to their carcinogenicity, but it is generally acknowledged that 100% cervical cancers are attributable to 13 HR HPV types classified as carcinogenic or probably carcinogenic (i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68). 16 HPV16 and 18 are the most virulent types and account together for approximately 70% of cervical cancer. 17 Other anogenital cancers: anus, vulva, vagina, and penis In contrast to the universal presence of HPVs in cervical cancers, other anogenital cancer sites show a varying prevalence of HPV infection, depending upon the cancer sub-type, the age distribution and the geographical area of the population studied. 18 Compared to cervical carcinoma, a stronger predominance of HPV type 16 is constantly reported, with a relative importance that increases with the severity of the precancerous lesion. No strong risk factors are known to exist for anogenital cancers other than those associated with HPVs transmission (i.e. number of sexual partners and anal intercourse). HPV infections are however frequently found everywhere in the anogenital tract of both sexes and may not always be the cause of a cancer. It has been shown for instance for vulvar cancers and penile cancers that there are different oncogenic pathways, with or without active involvement of HPV infection However, based on the extrapolation of cervical findings to other sites, and awaiting more mechanistic and virological data (i.e. studies using the presence of E6/E7 mrna or p16 overexpression in microdissected lesions), the presence of HR HPV DNA in cancer biopsy is generally considered sufficient to attribute at least a necessary step of the carcinogenic process to HPV. Thus, RRs are not used in the calculation of the attributable fraction at these sites, and the proportion of cases infected with HR HPV types is considered a good approximation of the attributable fraction. The prevalence of HPV in anogenital cancer cases was estimated from case series where HPV diagnosis in tumour samples was ascertained using validated PCR methodology. HR HPVs were found in approximately 88% of anal cancers; 70% of vagina cancers; 50% of penile cancers and 43% of vulvar cancers; (see Table 2; prevalence data from references De Vuyst et al (2009) 18 and Backes et al (2009). 22 Head and neck cancers Head and neck cancers represent a large and heterogeneous group of malignancies, for which cigarette smoking and alcohol consumption are strong risk factors. Over the last decade, HPV DNA has been reported to be present in a variable fraction of head and neck cancers (0 to 60%). Among HPV-positive cancers, HPV type 16 predominates (90% of HPV-positive carcinomas). HPV prevalence is notably high in carcinomas of the 3

5 oropharynx, 23 in which HPV16 is present in high copy number, localized to cell nuclei, frequently integrated in the cell genome and actively transcribing viral oncoproteins E6 and E7. 24,25 Survival differences by HPV DNA presence have also been consistently reported exclusively for oropharyngeal cancers. 26 These features suggest a role of persistent HPV infection in the onset and maintenance of some carcinomas in the oropharynx, whose incidence is currently increasing in some of the more developed countries. 27 We consider in this work only cancers of the oropharynx including tonsils and base of tongue (ICD-10 code C01, and C09-C10). Case-control studies using serology or PCR in exfoliated cells as a means of HPV detection report RR estimates that are constantly greater than No cohort studies have yet been published. The prevalence of HPV was estimated from case series where HPV diagnosis in tumour samples was ascertained using validated PCR methodology (studies extracted and updated from Kreimer et al (2005). 31 HR HPVs were found in approximately half of oropharyngeal cancers in more developed countries, but this weighted average prevalence varied in different areas, being generally higher in North America and Northern Europe than in Southern Europe, and being consistently higher when studies restricted their cases to tonsillar cancers instead of all oropharynx cancers. In the few less developed countries with available data, HR HPVs were found in 0 to 30%. Percentages used for the calculation of PAF are found in Table 2. The RRs of cancers of the oropharynx associated with the presence of both HPV and consumption of tobacco and alcohol are ill-defined but they are unlikely to correspond to the multiplication of RR for HPV and tobacco/alcohol. HPV and tobacco smoking act, at least in part, through the same mechanisms (e.g., knock-down of onco-suppressor genes TP53 and TPRb). It is, therefore, probable that the PAF of HPV in the oropharynx is larger among non-smokers than among current or former smokers. Epstein-Barr virus (EBV) Hodgkin lymphoma (HL) The proportion of EBV-positive HL varies with age, geographical area, and histological subtype. The classical HL type, which accounts for more than 95% of all HLs, has been classified into four different subtypes, according to the histological structure of the reactive infiltrate surrounding the pathognomonic Reed-Sternberg cells. 32 Worldwide, EBV is more commonly associated with nodular sclerosis and mixed cellular subtypes. The bimodal age distribution has a different shape in more developed versus less developed countries. 32 In less developed countries, where EBV infection occurs at a very young age, the first peak of incidence is seen well before the age of 15, and virtually all pediatric HL are EBV-related. In more developed countries however, the first peak of HL is seen between the ages of 15 and 35. In both areas, a second peak is often seen in older adults. Finally, in the HIV positive population, the vast majority of HL is EBV related and mainly consists of mixed cellular subtypes. The proportion of EBV-related lymphomas in adults in more developed countries is approximately 40%. In less developed countries, it is closer to 90% in children, and around 60% in adults (Table 2). 1,33 Burkitt lymphoma (BL) The association between the endemic form of Burkitt lymphoma (BL) and EBV has long been established. In endemic areas of Sub-Saharan Africa, the presence of clonal EBV episomes has been detected in virtually all endemic BL tumors, suggesting that the tumor develops from a single infected cell, and that EBV has a role in the initiation of the neoplasic transformation. Similar to Hodgkin lymphoma, the detection of specific EBV transcriptional gene products in tumor cells allows the lymphoma to be attributed to EBV, even in areas of lower BL incidence. 34 In endemic areas, over 95% of BL are attributable to EBV. Outside the endemic areas, EBV transcriptional gene products are detected much less frequently in BL. Sporadic forms have been described in Europe and North America, of which only around 20% are associated with EBV. 1 In the rest of the world, a few published data suggest that the rate of detection varies greatly (e.g. in Brazil alone), with a conservative estimate around 30%. 35,36 Nasopharyngeal carcinoma (NPC) NPC is a rare cancer worldwide but shows exceptionally high incidence (10 to 30 per 100,000 personyears in men) in Southern China, Singapore and Malaysia. Intermediate incidence rates are found in the Arctic, 4

6 Middle East, South-Eastern Asia and North Africa. 37 The WHO classifies NPC into three histologic types: keratinising squamous cell carcinoma (SCC) (type I); and nonkeratinising carcinoma characterized as differentiated (type II) or undifferentiated (type III). Type III comprises over 95% of NPC in high and intermediate incidence areas, and most of the remaining 5% is type II. For the nonkeratinising subtypes, EBV genome or gene products have been detected in virtually all cases, irrespective of the geographic origin, and thus EBV appears to be a necessary step in the malignant process. 1 Incidence data from GLOBOCAN 2008 show that high and intermediate incidence areas comprise about half the cases of NPC worldwide. The remaining half of the NPC cases occur in low incidence areas, where type I seems to be more frequent, and may have an etiology distinct from that of the other two histologic types. In these areas, it appears that only 1/3 of SCC is associated with EBV. 38,39 A precise calculation would depend on two estimates that are very sparse in the literature. First, the proportion of type I (keratinising) NPC in low incidence areas, and second, the proportion of EBV positive tumor among type I NPC in low incidence areas. In summary, the fraction of NPC attributable to EBV in areas of high or intermediate incidence is nearly 100%. It is probably less (possibly around 80%) in areas of low incidence, although the lack of published data does not allow a precise estimate. The worldwide estimate used for the calculation of the PAF was 85%. Other Non-Hodgkin lymphoma (NHL) Due to the heterogeneity of this group of tumors, even a crude estimation of the PAF is not possible from the published data. Data suggest that most NHL arising in HIV positive individuals are causally related to EBV. 40 Human herpes virus 8 (HHV-8) Kaposi sarcoma (KS) HHV-8 is a causal factor for the development of KS, and a few rare lymphoproliferative disorders, including primary effusion lymphoma and multicentric Castleman s disease. 1 Although virtually all cases of KS are attributable to HHV-8, various forms of the disease have been described and suggest that other factors, notably immunosuppression associated with HIV or organ-transplantation, have important contributory role in cancer development. In some regions of Europe and North America, after years of dramatically increasing incidence, a rapid decline of KS has followed the introduction of highly active antiretroviral therapy (HAART). 41 Conversely, with the rapid spread of the HIV/AIDS epidemic in Sub-Saharan Africa and the limited access to treatment, the estimated incidence of KS is around 40 per 100,000 person-years in Zimbabwe, making KS the most common cancer in men in that country. 42 Human T-cell leukemia virus type I (HTLV-1) Adult T-cell Leukemia HTLV-1, the first identified human retrovirus, was first isolated in 1980 from American and Japanese patients suffering from adult T-cell leukemia (ATL). 43,44 Since then, a causal association between the virus and the malignancy has been firmly established. ATL develops only in HTLV-1 infected persons and all ATL cells contain monoclonal integrated HTLV-1 provirus. Thus 100% of ATL are attributable to HTLV-1. Restriction of the duration of breast-feeding has diminished the circulation of HTLV-1 and the corresponding cancer burden in Japan. 45 Helminth infections Cholangiocarcinoma Chronic infections with the liver flukes Opisthorchis viverrini (O. viverrini) and Clonorchis sinensis (C. sinensis) have long been associated with cholangiocarcinoma. Endemic areas are found in China, Korea, Thailand, Laos, Vietnam and Cambodia, where it is estimated that a total of 24.4 million people are infected. 1 5

7 The complex life cycle of the parasites requires freshwater fish and human hosts. Humans are infected by ingestion of raw or partially cooked fish containing infective cysts. The mature flukes reside in the intrahepatic bile ducts. Retrospective calculation of the PAF was not possible due to limited data on the prevalence of infection in cholangiocarcinoma. Attributable risk calculations were therefore based on the methodology of Parkin. 46 Pooled RRs from the available case control studies were estimated to be 7.8 for O. viverrini and 7.7 for C. sinensis. Baseline incidence rates for cholangiocarcinoma in non-endemic areas were estimated from Japanese cancer registry data. These baseline rates were multiplied by 7.7 to yield an estimate of the incidence rates in infected individuals. These rates were then applied to the estimated number of infected persons in Eastern Asia summarized above. This yields an estimate of 2,000 cases of cholangiocarcinoma attributable to liver flukes. Bladder carcinoma The causal link between the parasite Schistosoma haematobium (S. haematobium) and bladder cancer is strong and consistent. 16 In highly endemic areas (including Egypt), bladder cancer is the leading cause of cancer incidence and death in men. 42 S. haematobium has a complex life cycle requiring both human and water-dwelling snail hosts. Endemic areas are found in Sub-Saharan Africa, Sudan, Egypt and Yemen, where the snail is present. A single country may contain both high and low prevalence areas and the geographical pattern of infection has been wellcharacterized by population prevalence surveys. 47 The number of people infected in Sub-Saharan Africa is estimated to be 112 million. 48 The eggs of S. haematobium provoke granulomatous inflammation, ulceration, and pseudopolyposis of the bladder and urethral walls. Chronic lesions can evolve into fibrosis, and squamous cell carcinoma (SCC) of the bladder. In contrast, bladder cancer in non-endemic areas is usually transitional cell carcinoma, which is associated with tobacco or occupational factors. 49 In the absence of data on the prevalence of infection in bladder cancer cases, we attributed all SCC occurring in endemic areas to S. haematobium. Prevalence of SCC in bladder cancer was estimated to be 41% in Sub-Saharan Africa and 42% in Northern Africa and Western Asia, using microscopically verified cases from cancer registries in endemic areas. 50,51 These prevalence estimates were then applied to the estimated number of bladder cancers in countries with endemic areas, yielding an estimate of 6,000 bladder cancers attributable to S. haematobium. 6

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