REVIEW ARTICLE

JIACM 2012; 13(2): 142-4

Cancer and tuberculosis

J Harikrishna*, V Sukaveni**, D Prabath Kumar***, Alladi Mohan****

Abstract
Lung cancer and pulmonary tuberculosis (TB) are two major public health problems. The association of cancer and TB is intriguing and diverse. Clinicians often encounter patients with co-existent lung cancer and pulmonary TB. These patients may be lung cancer developing active pulmonary TB; or occurrence of cancer in patients treated for pulmonary TB. Chronic inflammation due to TB is thought to be responsible for the genesis of cancer. Co-existence of cancer and TB often causes a delay in the diagnosis. Patients with cancer are vulnerable to develop active TB because of immunosuppression due to malnutrition, or due to the use of intensive treatment modalities, such as aggressive chemotherapy. A high index of clinical suspicion and a focused diagnostic approach is essential to establish the diagnosis early. Key words: Tuberculosis, cancer.

Introduction
Lung cancer and pulmonary tuberculosis (TB) are two major public health problems associated with significant morbidity and mortality. Cancer is a global health problem causing more than 7 million deaths accounting to nearly 13% of all deaths worldwide. The burden of cancer is increasing globally, with an expected 20 million new cases per year in 2020, half of which will be in the low-and middle-income countries1. TB is one of the major causes of death amongst infectious diseases and it is estimated that one-third of the human population is infected with Mycobacterium tuberculosis . In 2010, there were an estimated 8.8 million incident cases of TB (range 8.5 - 9.2 millions) and 1.1 million deaths (range 0.9 - 1.2 millions) among human immunodeficiency virus (HIV)-negative cases of TB and an additional 0.35 million deaths (range, 0.32 - 0.39 million) among people who were HIV-positive (20/100,000 population). India alone accounted for an estimated one-quarter (26%) of all TB cases worldwide2. The co-existence of TB and cancer has attracted attention for several years and has remained controversial3. The association of TB and cancer is intriguing and diverse. Simultaneous occurrence of both TB and cancer in the same organ causes a diagnostic dilemma. Inflammation and scarring due to chronic TB results in metaplasia, dysplasia, and cancer. On the other hand reactivation of latent TB in patients with cancer can occur because of immunosuppression due to malnutrition, aggressive chemotherapy, and immunomodulatory therapy.

Historical account
Co-existence of carcinoma and TB was described by many pathologists. Berroya 4 cites an early description of cancerous pthisis by Bayle (1815). Meyer4 quoted Penard documenting co-existence of bronchogenic carcinoma and pulmonary TB with definitive histological evidence. Pearl 6 based on autopsy findings at Johns Hopkins Hospital, USA, suggested that carcinoma lung was less common in patients who died of pulmonary TB than in those who died of other causes, and went on to even suggest that this formed sufficient evidence to support the treatment of cancer patients with tuberculin . Berroya 4 stated that Rokitansky (1854) considered pulmonary TB and carcinoma of lung were thought to be mutually antagonistic. Lubarsch (1888)7 cited by Berroya4 also endorsed Pearls view6. Randall and Spalding8 state that Carlson and Bell (1929) opposed Pearls conclusions6 and opined that the less frequent occurrence of lung cancer in patients with pulmonary TB could be because of the fact that TB killed the patients before lung cancer could develop in them. Carry and Greer9 studied 140 cases of bronchogenic carcinoma complicated by pulmonary TB and felt that there was no relationship between TB and bronchogenic carcinoma. As per Miller10, Pilliet and Piattot were the first to describe the coexistence of TB and cancer. Since then many reports have been published in the literature refuting and supporting the causal relationship between TB and cancer.

* Assistant Professor, *** Professor, *** Associate Professor, **** Professor and Head, Department of Medicine, Sri Venkateswara Institute of Medical Sciences (SVIMS), Tirupati - 517 507, Andhra Pradesh.

Pathogenesis
The association between TB and cancer can occur in several ways (Table I)7. Even though the relationship between chronic inflammation and cancer is well established, causal relationship between TB and cancer is not well understood. Pulmonary TB in immunocompetent individuals is a chronic infectious process characterised by the formation of granuloma . In the natural course of evolution of the granuloma, imbalance between tissue damaging agents that can result in deoxyribonucleic acid (DNA) damage and tissue repair mechanisms is thought to generate a microenvironment that predisposes to malignant transformation11, 12. Table I: Possible associations between cancer and TB. A chance coincidence without any apparent relation Metastatic carcinoma developing in an old TB lesion Secondary infection of cancer with TB Chronic progressive tubercle in which a carcinoma develops Simultaneous development of both TB and cancer
TB = tuberculosis; Source: reference 7.

A hypothetical pathway has been postulated based on in vitro and in vivo experiments to explain inflammation as a cause of scar-cancer of lung. Production of ROS, prostaglandins, leukotrienes (LT), cytokines due to cell mediated response by macrophages infected with Mycobacterium tuberculosis leads to damage to DNA, enhanced rate of cell division by inhibiting synthesis of p21, inhibition of apoptosis of cells with damaged DNA by enhancing synthesis of B-cell lymphoma 2 family of apoptosis regulator proteins. These result in mutagenesis of progeny cells, enhanced angiogenesis stimulated by cyclooxygense-2 products and extensive fibrosis associated with recurrent infection eventually causing tumourigenesis14.

Tuberculosis as a cause of lung cancer

The causal relationship between TB and carcinoma was studied by case reports, case-control studies, and cohort studies. In a population-based cohort study15 in 5,657 TB patients and 23,485 age- and gender-matched controls that were followed-up for 12 years it was observed that the incidence of lung cancer was significantly higher in patients with pulmonary TB compared with controls with incident risk ratio (IRR) of 1.76. Cox proportional hazards model revealed pulmonary TB infection (hazard ratio [HR], 1.64; 95% confidence intervals [CI], 1.24 - 2.15; p < 0.001) and chronic obstructive pulmonary disease (COPD) (HR, 1.09; 95% CI, 1.03 - 1.14; p = 0.002) to be independent risk factors for lung cancer and concluded that pulmonary TB was associated with an increased risk of lung cancer15. In a cohort analysis of data from prostate, lung, colorectal, and ovarian cancer screening trials16, 66,863 cancer-free trial participants aged 55 to 74 years who had undergone a baseline chest radiographic examination and were followed-up subsequently for up to 12 years were studied. Scarring was evident on the baseline chest radiograph in 5,041 (7.5%) subjects. Scarring was associated with elevated lung cancer risk (809 lung cancer cases; HR, 1.5; 95% CI, 1.2 - 1.8); specifically for occurrence of cancer in the lung ipsilateral to the scar (HR, 1.8; 95% CI, 1.4 - 2.4). Ipsilateral lung cancer risk remained elevated throughout the follow-up duration. The authors hypothesised that localised inflammatory processes associated with scarring promote the subsequent development of lung cancer. In another cohort study17 conducted in 716,812 subjects

Experimental work in mice13 intended to prove the causal relationship between TB and cancer has shown that chronic TB infection can result in a multistep transformation of cells resulting in dysplasia and malignant squamous cell carcinoma by accumulation of genome alterations and effect of growth factors. Mycobacterium tuberculosis infected macrophages express high levels of inducible nitric oxide synthase, resulting in the production of reactive nitrogen and oxygen species (ROS) leading to DNA damage. Activation of transcription factor, nuclear factor E2 related factor by oxidative stress, directly induced squamous cell metaplasia. Proliferation of cells with damaged DNA would normally be blocked through G2/M check point or these cells would be eliminated through p53 mediated pro-apoptotic pathway. This is antagonised by activation of nuclear factor-KappaB mediated pro-inflammatory pathway leading to pro-liferation of cells with damaged DNA. Thus, factors that are essential for protective immunity also participate in initiation and promotion of lung tumourigenesis. Mycobacterium tuberculosis infected macrophages produce a potent epithelial growth factor epiregulin, which acts as a potent growth factor for premalignant epithelial cells.

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including 4,480 patients with newly diagnosed TB who were followed-up for 7 years, the incidence of lung cancer was found to be 11- fold higher in patients with TB with a HR of 4.37 for TB cohort. After further adjustment for COPD, the HR increased to 6.22 with the combined effect of TB with COPD. The authors17 concluded that the there was an increased risk of lung carcinoma in patients with pulmonary TB. In a meta-analysis18 of 37 case-control and 4 cohort studies published during the period from 1966 2009, a statistically significant 1.8-fold increased risk of lung cancer was found among pulmonary TB patients.

References
1. Sharma V, Kerr SH, Kawar Z, Kerr DJ.Challenges of cancer control in developing countries: current status and future perspective. Future Oncol 2011; 7: 1213-22. World Health Organization. Global tuberculosis control 2011. Geneva: World Health Organization; 2011. Pandey M. Tuberculosis and cancer. In: Sharma SK, Mohan A, editors. Tuberculosis. New Delhi: Jaypee Brothers Medical Publishers; 2001; p. 396-403. Berroya RB, Polk JW, Raju P, Bailey AH. Concurrent pulmonary tuberculosis and primary carcinoma. Thorax 1971; 26: 384-7. Meyer EC, Scatliff JH, Lindskog GE. The relation of antecedent tuberculosis to bronchogenic carcinoma. A study of the tuberculin test, radiologic and pathologic evidences. J Thorac Cardiovasc Surg 1959; 38: 384-97. Pearl R. Cancer and tuberculosis. Am J Hyg 1929; 9: 97-159. Lubarsch O. Ueber den primaren Krebs des ileum, nebst bemerhunge uber das gleichzeitge vorkommen von krebs und tuberculose. Virchows Arch 1888; 111: 280-317. Randall KJ, Spalding JE. Simultaneous carcinoma and tuberculosis of the colon; report of a case and review of the literature. Br J Surg 1946; 34: 372-5. Carey JM, Greer AE. Bronchogenic carcinoma complicating pulmonary tuberculosis: a report of eight cases and a review of 140 cases since 1932. Ann Intern Med 1958; 49: 161-80.

2. 3.

4. 5.

Co-existent pulmonary tuberculosis and lung cancer

Clinical diagnosis of co-existing TB and cancer is often challenging. This often causes a delay in diagnosis and institution of appropriate treatment and is associated with poor prognosis. Wofford et al19 reported 34 cases of coexisting carcinoma lung and pulmonary TB and reported the average delay in making the diagnosis when TB and cancer co-exist to be 13 months. Atypical course of TB, presence of pain, radiological evidence of rib erosion and ipsilateral hilar lymphadenopathy casts doubt on the possibility of coexistence of a malignancy.

6. 7.

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10. Miller RE, Salomon PF, West JP. The co-existence of carcinoma and tuberculosis of the breast and axillary lymph nodes. Am J Surg 1971; 121: 338-40. 11. Russell DG. Who puts the tubercle in tuberculosis? Nat Rev Microbiol 2007; 5: 39-47. 12. Saunders BM, Britton WJ. Life and death in the granuloma: immunopathology of tuberculosis. Immunol Cell Biol 2007; 85: 103-11. 13. Nalbandian A, Yan BS, Pichugin A et al. Lung carcinogenesis induced by chronic tuberculosis infection: the experimental model and genetic control. Oncogene 2009; 28: 1928-38. 14. Ardies CM. Inflammation as cause for scar cancers of the lung. Integr Cancer Ther 2003; 2: 238-46. 15. Wu CY, Hu HY, Pu CY et al. Pulmonary tuberculosis increases the risk of lung cancer: a population-based cohort study. Cancer 2011; 117: 618-24. 16. Yu YY, Pinsky PF, Caporaso NE et al. Lung cancer risk following detection of pulmonary scarring by chest radiography in the prostate, lung, colorectal, and ovarian cancer screening trial. Arch Intern Med 2008; 168: 2326-32. 17. Yu YH, Liao CC, Hsu WH et al. Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol 2011; 6: 32-7. 18. Liang HY, Li XL, Yu XS et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer 2009; 125: 2936-44. 19. Wofford JL, Webb WR, Stauss HK. Tuberculous scaring and primary lung cancer. Clinical and aetiologic considerations. Arch Surg 1962; 85: 928-35. 20. Kaplan MH, Armstrong D, Rosen P. Tuberculosis complicating neoplastic disease. A review of 201 cases. Cancer 1974; 33: 850-8. 21. Wu CY, Hu HY, Pu CY et al . Aerodigestive tract, lung and haematological cancers are risk factors for tuberculosis: an 8-year population-based study. Int J Tuberc Lung Dis 2011; 15: 125-30.

Tuberculosis complicating cancer

TB has been known to complicate the course of cancer. Kaplan20 studied 201 patients with cancer who developed TB during the period 1945 - 1971. High TB prevalence was seen in patients with Hodgkins disease and lung cancer compared to carcinoma bladder, carcinoma colon. The TB rate for patients with lung cancer varied widely (52 - 320 cases per 100,000 persons). Wu and colleagues21 in Taiwan studied 16,487 patients with cancer and 65, 948 controls. In conclusion, chronic inflammation and scarring due to TB can lead to the development of cancer. Co-existence of TB and cancer causes diagnostic dilemma due to similarities in presentation leading to delay in the diagnosis and institution of appropriate therapy. Patients with lung cancer are also vulnerable to develop active pulmonary TB due to immunosuppression and malnutrition resulting from the use of intensive treatment modalities such as aggressive chemotherapy. A high index of clinical suspicion and a focussed diagnostic approach is essential to establish the diagnosis early.

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Vol. 13, No. 2

April-June, 2012