In addition to lung cancers, tuberculosis infections have been associated with increased risk of non-pulmonary malignancies in case reports. Our population-based study employed standardized incidence ratios (SIRs) to systemically survey non-pulmonary cancer risks after tuberculosis infections.
Data of patients who had newly diagnosed tuberculosis, were aged 20 years or older, and had no prior cancer or tuberculosis were sampled from the Taiwan National Health Insurance database between 2000 and 2010. SIRs compared cancer incidence in patients with tuberculosis infections to the general population. SIRs of specific cancers were further analyzed with respect to gender and time after tuberculosis infections.
After a follow-up period of 28 866 person–years, 530 tuberculosis cases developed cancers compared with 256 cases in the general populations (2.07, 95% confidence interval (CI), 1.90–2.26). The SIR of non-pulmonary malignancies was also increased (1.71, 95% CI, 1.54–1.90). For males, SIRs were increased within 1 year after tuberculosis diagnosis for the following cancers: head and neck, esophageal, colorectal, liver, lung, melanomas, and Hodgkin’s disease. SIRs were increased for liver, biliary, lung, and bladder cancers beyond the first year after tuberculosis diagnosis. For females, SIRs were increased for leukemia, esophageal, and lung cancers within the first year, and only for leukemia beyond 1 year post diagnosis.
Having found increased risks of several cancers that differ with gender and time after tuberculosis diagnosis, physicians may consider these factors in patients following tuberculosis diagnosis.
Tuberculosis is an important public health issue with high mortality in low- and middle-income countries. In 2011, 8.7 million new cases were diagnosed and 1.4 million died of tuberculosis worldwide (WHO, 2012). In developed countries, mortality attributable to tuberculosis infections was rare (Sterling et al, 2006). However, caseous granulomas, tissue liquefaction, and cavity formation in lungs of infected patients often result in long-term deficits, such as impaired pulmonary function (Maguire et al, 2009). In addition, tuberculosis has been associated with subsequent risk of lung cancers (Pasipanodya et al, 2007; Engels et al, 2009). Although the etiological relationship between the two diseases is unknown, increased risk is consistently shown by population-based studies (Wu et al, 2011a; Yu et al, 2011), suggesting that physicians should be aware of lung cancers in patients with prior tuberculosis infections.
Chronic infections and inflammation are associated with carcinogenesis (Ohshima and Bartsch, 1994; Pisani et al, 1997). Tuberculosis is associated with subsequent malignancies other than lung cancer, such as pyothorax-associated lymphoma (Nakatsuka et al, 2002) and hematological malignancies (Vineis et al, 2000). Owing to the low incidence of malignancies following tuberculosis, the few previous investigations with small sample sizes did not provide comprehensive information regarding non-pulmonary cancers. Therefore, this nationwide, population-based study was to describe the risk of many types of cancers, especially non-pulmonary malignancies, 1 year following tuberculosis diagnosis.
Materials and methods
Background information of tuberculosis in Taiwan
In Taiwan, the total population is around 23 million. Tuberculosis is an endemic disease. The incidence of tuberculosis was 68 per 100 000 persons and mortality rate was 0.036 per person–year (Liao et al, 2012). Taiwan regulations stipulate mandatory registry and treatment of tuberculosis via the Directly Observed Treatment Short Course (DOTS) program, which is monitored by the Center for Disease Control (CDC, Taiwan). DOTS workers and public health nurses follow tuberculosis cases to monitor compliance and side effects, and they report directly to the local health authority. National Health Insurance (NHI) provides coverage for antituberculosis treatment and monitors the cost.
The NHI program is a mandatory health insurance program that covers up to 98% of medical care for all Taiwanese residents (Lin et al, 2009). Owing to its compulsive characteristics, management by government, and high coverage of whole population, the loss-of-follow-up rate is low. The NHI Research Database (NHIRD) catalogs all computerized claims data for inpatient and outpatient care including demographic data, examinations, drug prescriptions, and diagnosis by the international classification of disease, ninth revision (ICD-9-CM) (Deyo et al, 1992). The NHI sample files contain complete data of 1 000 000 randomly sampled beneficiaries from the original NHIRD, representing ∼5% of all enrollees in Taiwan. There were no significant differences in age or gender distribution in this sample of 1 000 000 beneficiaries and the original NHIRD.
The NHI Registry for Catastrophic Illness provided comprehensive utilization and enrollment information for all patients with severe diseases under the NHI program. All cancers were included in the category of catastrophic illness. Catastrophic illness certificate exempts the patients from copayment. Bureau of NHI performs strict validations of the cancer diagnoses; at least two independent specialists reviewed the medical records, laboratory, histological, and image studies of each patient who applied for catastrophic illness registration (Hwang et al, 2012). The data set used in our study consisted of de-identified secondary data released to the public for research purposes and, therefore, was exempt from full review by our institutional review boards.
From 1 January 2000 to 31 December 2010, data of adult patients (>20) with newly diagnosed tuberculosis were retrieved from NHI sample files according to ICD-9-CM code 010.x to 018.x. plus prescription of at least two antituberculosis drugs (for example, isoniazid, ethambutol, rifampin, and pyrazinamide) for 2 months. We also extracted their data between 1 March 1995 and 1 January 2000 to exclude patients with history of tuberculosis and/or cancers before their entry into the study.
The main outcome was the risk of cancers. The Registry for Catastrophic Illness was used to identify subjects who were diagnosed with cancer. We examined the risk of cancers among the tuberculosis cohort using the standardized incidence ratio (SIR), which is the ratio of observed cancer cases to the expected number of cancer cases. SIR has been used to systematically examine the association between a variety of inflammatory diseases and cancers (Chen et al, 2010a; Spanogle et al, 2010). The expected number of cancer cases was obtained from Taiwan National Cancer Registry by multiplying the national incidence rate of cancers according to gender, calendar year, and age in different intervals by the corresponding stratum-specific person–time accrued in the cohort. The 95% confidence intervals (CIs) for the SIRs were estimated under the assumption that the observed number of cancers followed a Poisson probability distribution. We determined the SIRs for subgroups according to gender and age, as well as each cancer type. Owing to a potential surveillance bias, subgroup analyses by the length of time since tuberculosis diagnosis were carried out. Extraction and computation of data were performed using the Perl programming language (version 5.12.2 http://www.perl.org/). Microsoft SQL Server 2005 (Microsoft Corp, Redmond, WA, USA) was used for data linkage, processing, and sampling. All statistical analyses were performed using SPSS statistical software version 17.0 for Windows (SPSS Inc, Chicago, IL, USA). Statistical significance was defined as a P-value of less than 0.05.
A total of 6699 patients with tuberculosis diagnosis with a median follow-up period of 3.8 years (interquartile range 1.3–6.9) were included (Table 1). The majority (69.1%) was male. The median age of tuberculosis diagnosis was 64 (range 47–76), but was older for males (66, range 50–77) than females (59, range 40–75). Females were distributed more equally in all ages than males.
Risk of all cancers
During a follow-up period of 28 866 person–years, 530 tuberculosis cases developed cancer compared with 256 cases in the general population. The overall risk of any cancer in all patients with newly diagnosed tuberculosis was higher than general population (2.07, 95% CI, 1.90–2.26), both for males (2.18, 95% CI, 1.98–2.40) and females (1.67, 95% CI, 1.34–2.05) (Table 2). For males, the elevated cancer risk was lessened with increasing age. SIRs for males in the age ranges of 20–39, 40–59, 60–79, and >80 were 6.32, 2.73, 2.16, and 1.83, respectively. For females, however, only patients aged between 40–59 or 60–79 years carried elevated risk. The period following tuberculosis diagnosis revealed further gender distinctions. For males, the SIR was increased within the first year (4.72, 95% CI, 4.08–5.43) and remained 1.52 thereafter. For females, increased risk of cancer was only elevated during the first year (SIR, 4.08, 95% CI, 2.97–5.48).
Risk of non-pulmonary cancers
Although the association between lung cancer and tuberculosis has been well documented, we sought to understand the relationship between tuberculosis and non-pulmonary cancers, and examine their impact on elevated SIRs. With cases of lung cancer excluded, 371 cases developed non-pulmonary cancers compared with 217 in controls (Table 3). The increased risk was both observed in males (1.81, 95% CI, 1.61–2.03) and females (1.36, 95% CI, 1.05–1.73). A trend of increasing risk of non-pulmonary cancers with younger age was observed in males. The risk of cancer was elevated for males during the first year following tuberculosis diagnosis and beyond. In contrast, females only had increased risk of non-pulmonary cancer during the first year after tuberculosis diagnosis.
Risk of specific cancers
To further identify increased risks of specific cancers after tuberculosis infection, the SIRs of several cancers were calculated (Table 4). In all patients with newly diagnosed tuberculosis, the SIRs of many cancers were significantly increased, including cancers of the head and neck, digestive tract, lung, skin, bladder, and hematological malignancies. Analysis by gender revealed that males had elevated risk for most of these cancers. Females, on the other hand, had elevated risks only for leukemia, esophageal, and lung cancers.
Risk of specific cancers in different follow-up periods
As the time after tuberculosis diagnosis had great impact on the SIR of lung cancers and non-pulmonary cancers (Tables 2 and 3), we further analyzed the SIRs of specific cancers with regard to the time between tuberculosis and cancer diagnoses (Table 5). For males, most of the cancers (except cancers of the biliary tract and bladder) developed within the first year of tuberculosis diagnosis. The risks of liver, biliary tract, and lung cancers were elevated during 1–5 years after tuberculosis diagnosis, but the risk of bladder cancer did not emerge until 5 years post-tuberculosis diagnosis. Females showed increased risk for esophageal cancer, lung cancer, and leukemia during the first year, but only a risk for leukemia persists beyond 5 years post diagnosis.
Several population-based and clinical studies have shown chronic infections and inflammations, such as hepatitis virus, Epstein–Barr virus, and autoimmune diseases, are correlated with cancers (Wei and Sham, 2005; Chen et al, 2010b; Wu et al, 2011a; Yu et al, 2011; Forner et al, 2012; Weng et al, 2012). Elevated risk for lung cancer has been repeatedly documented in patients with tuberculosis infections (Engels, 2008; Wu et al, 2011a; Yu et al, 2011). Although pilot studies implicated the association of tuberculosis with other cancers (Vineis et al, 2000; Falagas et al, 2010), systematic investigations have been sparse, given the relatively low incidence of cancers following tuberculosis infections. Our population-based study including 6699 tuberculosis patients with a follow-up of 28 866 person–years revealed elevated risk for several non-pulmonary malignancies after tuberculosis infections. Our study further characterized the incidence of specific cancer types and their correlation with gender and time after tuberculosis diagnosis. This study suggested that in addition to lung cancers, physicians should consider the increased risk of several solid and hematological malignancies, and how the risk varies by gender and time after tuberculosis diagnosis.
It is possible that the elevated SIRs observed within the first year were due to surveillance bias (Spanogle et al, 2010). In Taiwan, however, surveillance bias for cancer alone may not significantly skew the overall cancer incidence over a long study period because of the accessibility to medical service, high coverage of NHI (>98% of the population), and ongoing follow-up of the entire population by this database. Therefore, the surveillance bias for cancers may shorten the time of cancer diagnosis (increased SIRs within the first year), but may not be the main reason behind the observed increase of cancer incidence over the study period, especially beyond 1 year. As the compromised immunity in cancer patients may render cancer patients susceptible to new tuberculosis infections or reactivations (Wu et al, 2011b), another explanation is reverse causality; tuberculosis was diagnosed before cancers that actually predated the tuberculosis infections, leading to the increased SIRs within the first year.
The association of tuberculosis infections and cancers with higher SIRs 1 year after tuberculosis infections was less arguable. Previous population-based studies concluded that tuberculosis increased the risk of lung cancers because the incidence-rate ratio of lung cancers elevated 1 year after tuberculosis diagnosis (1.76, 95% CI 1.33–2.32 during 1–5 years after tuberculosis infections) (Wu et al, 2011a). The elevated SIRs of lung cancers 1 year after tuberculosis diagnosis in males in our study were consistent with this. Interestingly, our study also found other non-pulmonary malignancies with higher SIRs 1 year after tuberculosis diagnosis, namely, liver, biliary tract, and bladder cancers in males, and leukemia in females. However, whereas tuberculosis may contribute to increased risk of these cancers, the observed associations may also be due to shared risks. Tobacco smoking has been associated with malignancies (liver, biliary tract, and bladder cancers, and leukemia) as well as tuberculosis (Sasco et al, 2004; Yagyu et al, 2008; Lawn and Zumla, 2011). Impaired cellular immunity may contribute to both malignancies and tuberculosis infections (Wu et al, 2011b). The human susceptibility to tuberculosis has been also associated with the polymorphism of several innate immunity and inflammatory response genes (Azad et al, 2012) such as toll-like receptors, IL-1beta, and tumor necrosis factors, and inducible nitric oxide that have been associated with cancer susceptibility (Kamangar et al, 2006; Sawa et al, 2008; Kutikhin, 2011; Qidwai and Khan, 2011). Although the association of several non-pulmonary malignancies and tuberculosis infections was observed in our study, this relationship and mechanisms will require substantial and in-depth future studies.
The strengths of the current study include taking advantage of large longitudinal national databases and usage of well-documented methodology to compare the correlation of tuberculosis and cancers (Chen et al, 2011; Hwang et al, 2012; Wang et al, 2012). The limitations of this study include the difficulty to adjust confounding factors from smoking. However, the exact prevalence of smoking in patients with tuberculosis is not known in Taiwan and the effect of smoking on the development of each specific cancer differed. Avoidance of the confounding effect from smoking can only be accomplished by conducting a large prospective cohort study in patients with tuberculosis infections. Another limitation is the relatively small number of enrollees compared with >10 000 new tuberculosis cases per year in Taiwan. The NHI policy prohibits release of >10% of total data in the NHIRD. We were unable to access the data of all of the tuberculosis patients. However, the NHI sample files have been validated and applied for many population-based studies about risks of many cancers (Chen et al, 2010b, 2011). As for rare cancers, the cohort of this study may not be able to detect elevated risks.
In conclusion, our study revealed increased risk for several non-pulmonary malignancies after tuberculosis infections. The risk for specific cancers differed with gender and time after tuberculosis diagnosis. Physicians may consider the risk for these solid and hematological malignancies in relation to gender and time after tuberculosis diagnosis.
Azad AK, Sadee W, Schlesinger LS (2012) Innate immune gene polymorphisms in tuberculosis. Infect Immun 80: 3343–3359
Chen YJ, Chang YT, Wang CB, Wu CY (2010b) Malignancy in systemic lupus erythematosus: a nationwide cohort study in Taiwan. Am J Med 123 (1150): e1151–e1156
Chen YJ, Chang YT, Wang CB, Wu CY (2011) The risk of cancer in patients with rheumatoid arthritis: a nationwide cohort study in Taiwan. Arthritis Rheum 63: 352–358
Chen YJ, Wu CY, Huang YL, Wang CB, Shen JL, Chang YT (2010a) Cancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan. Arthritis Res Ther 12: R70
Deyo RA, Cherkin DC, Ciol MA (1992) Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 45: 613–619
Engels EA (2008) Inflammation in the development of lung cancer: epidemiological evidence. Expert Rev Anticancer Ther 8: 605–615
Engels EA, Shen M, Chapman RS, Pfeiffer RM, Yu YY, He X, Lan Q (2009) Tuberculosis and subsequent risk of lung cancer in Xuanwei, China. Int J Cancer 124: 1183–1187
Falagas ME, Kouranos VD, Athanassa Z, Kopterides P (2010) Tuberculosis and malignancy. QJM 103: 461–487
Forner A, Llovet JM, Bruix J (2012) Hepatocellular carcinoma. Lancet 379: 1245–1255
Hwang CY, Chen YJ, Lin MW, Chen TJ, Chu SY, Chen CC, Lee DD, Chang YT, Wang WJ, Liu HN (2012) Cancer risk in patients with allergic rhinitis, asthma and atopic dermatitis: a nationwide cohort study in Taiwan. Int J Cancer 130: 1160–1167
Kamangar F, Cheng C, Abnet CC, Rabkin CS (2006) Interleukin-1B polymorphisms and gastric cancer risk—a meta-analysis. Cancer Epidemiol Biomarkers Prev 15: 1920–1928
Kutikhin AG (2011) Association of polymorphisms in TLR genes and in genes of the Toll-like receptor signaling pathway with cancer risk. Hum Immunol 72: 1095–1116
Lawn SD, Zumla AI (2011) Tuberculosis. Lancet 378: 57–72
Liao CM, Hsieh NH, Huang TL, Cheng YH, Lin YJ, Chio CP, Chen SC, Ling MP (2012) Assessing trends and predictors of tuberculosis in Taiwan. BMC Public Health 12: 29
Lin HP, Deng CY, Chou P (2009) Diagnosis and treatment delay among pulmonary tuberculosis patients identified using the Taiwan reporting enquiry system, 2002-2006. BMC Public Health 9: 55
Maguire GP, Anstey NM, Ardian M, Waramori G, Tjitra E, Kenangalem E, Handojo T, Kelly PM (2009) Pulmonary tuberculosis, impaired lung function, disability and quality of life in a high-burden setting. Int J Tuberc Lung Dis 13: 1500–1506
Nakatsuka S, Yao M, Hoshida Y, Yamamoto S, Iuchi K, Aozasa K (2002) Pyothorax-associated lymphoma: a review of 106 cases. J Clin Oncol 20: 4255–4260
Ohshima H, Bartsch H (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat Res 305: 253–264
Pasipanodya JG, Miller TL, Vecino M, Munguia G, Garmon R, Bae S, Drewyer G, Weis SE (2007) Pulmonary impairment after tuberculosis. Chest 131: 1817–1824
Pisani P, Parkin DM, Munoz N, Ferlay J (1997) Cancer and infection: estimates of the attributable fraction in 1990. Cancer Epidemiol Biomarkers Prev 6: 387–400
Qidwai T, Khan F (2011) Tumour necrosis factor gene polymorphism and disease prevalence. Scand J Immunol 74: 522–547
Sasco AJ, Secretan MB, Straif K (2004) Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 45 (Suppl 2): S3–S9
Sawa T, Mounawar M, Tatemichi M, Gilibert I, Katoh T, Ohshima H (2008) Increased risk of gastric cancer in Japanese subjects is associated with microsatellite polymorphisms in the heme oxygenase-1 and the inducible nitric oxide synthase gene promoters. Cancer Lett 269: 78–84
Spanogle JP, Clarke CA, Aroner S, Swetter SM (2010) Risk of second primary malignancies following cutaneous melanoma diagnosis: a population-based study. J Am Acad Dermatol 62: 757–767
Sterling TR, Zhao Z, Khan A, Chaisson RE, Schluger N, Mangura B, Weiner M, Vernon A Tuberculosis Trials C (2006) Mortality in a large tuberculosis treatment trial: modifiable and non-modifiable risk factors. Int J Tuberc Lung Dis 10: 542–549
Vineis P, Crosignani P, Sacerdote C, Fontana A, Masala G, Miligi L, Nanni O, Ramazzotti V, Rodella S, Stagnaro E, Tumino R, Vigano C, Vindigni C, Costantini AS (2000) Haematopoietic cancer and medical history: a multicentre case control study. J Epidemiol Community Health 54: 431–436
Wang YP, Liu CJ, Hu YW, Chen TJ, Lin YT, Fung CP (2012) Risk of cancer among patients with herpes zoster infection: a population-based study. CMAJ 184: E804–E809
Wei WI, Sham JST (2005) Nasopharyngeal carcinoma. Lancet 365: 2041–2054
Weng MY, Huang YT, Liu MF, Lu TH (2012) Incidence of cancer in a nationwide population cohort of 7852 patients with primary Sjogren's syndrome in Taiwan. Ann Rheum Dis 71: 524–527
WHO (2012) Global Tuberculosis Report. World Health Organization
Wu CY, Hu HY, Pu CY, Huang N, Shen HC, Li CP, Chou YJ (2011a) Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study. Cancer 117: 618–624
Wu CY, Hu HY, Pu CY, Huang N, Shen HC, Li CP, Chou YJ (2011b) Aerodigestive tract, lung and haematological cancers are risk factors for tuberculosis: an 8-year population-based study. Int J Tuberc Lung Dis 15: 125–130
Yagyu K, Kikuchi S, Obata Y, Lin Y, Ishibashi T, Kurosawa M, Inaba Y, Tamakoshi A (2008) Cigarette smoking, alcohol drinking and the risk of gall bladder cancer death: a prospective cohort study in Japan. Int J Cancer 122: 924–929
Yu YH, Liao CC, Hsu WH, Chen HJ, Liao WC, Muo CH, Sung FC, Chen CY (2011) Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol 6: 32–37
We would like to thank the National Health Research Institute for making their database available. This work was supported by grants from the National Health Research Institute, Taipei Veterans General Hospital (V101E4-003 and V101A-017), and the National Science Council (98-2314-B-010-010-MY3).
The authors declare no conflict of interest.
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Kuo, SC., Hu, YW., Liu, CJ. et al. Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study. Br J Cancer 109, 229–234 (2013). https://doi.org/10.1038/bjc.2013.220
- tuberculosis infections
- standardized incidence ratios
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