INT J TUBERC LUNG DIS 18(10):1211–1219 Q 2014 The Union http://dx.doi.org/10.5588/ijtld.14.0161

Tuberculosis and risk of cancer: a Danish nationwide cohort study D. F. Simonsen,* D. K. Farkas,* M. Søgaard,* C. R. Horsburgh,† H. T. Sørensen,* R. W. Thomsen* *Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; † Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA SUMMARY O B J E C T I V E S : To investigate the short- and long-term risk of cancer in patients with active tuberculosis (TB). D E S I G N : Using Danish nationwide databases, we quantified cancer risk in TB patients during 1978– 2011 compared with the general population. R E S U LT S : We observed 1747 cancers in 15 024 TB patients (median follow-up 8.5 years), reflecting a standardised incidence ratio (SIR) of 1.52 (95%CI 1.45–1.59). All-time SIR for extra-pulmonary cancer was 1.29 (95%CI 1.22–1.36) and for lung cancer it was 3.40 (95%CI 3.09–3.74). Absolute cancer risk 3 months after TB was 1.83% (SIR 11.09, 95%CI 9.82–12.48), with highly increased SIRs for malignant pleural mesothelioma (368.4), lung cancer (40.9), Hodgkin’s lymphoma (30.6), ovarian cancer (26.4) and nonHodgkin’s malignant lymphoma (23.8). Between the 3-

month and 5-year follow-up, the SIR for any cancer was 1.59 (95%CI 1.46–1.72), including 19- and 3-fold increases for malignant pleural mesothelioma and lung cancer. Beyond 5 years, the SIR of cancer was 1.17 (95%CI 1.10–1.25). Elevated long-term risks persisted for haematological (SIR 1.34, 95%CI 1.01–1.74) and tobacco-related cancers (SIR 1.78, 95%CI 1.60–1.97). C O N C L U S I O N : TB is a marker of occult lung cancer and several extra-pulmonary cancers. TB also predicts increased long-term risk of cancer, possibly related to chronic inflammation and shared risk factors, including immunosuppression and smoking. K E Y W O R D S : epidemiological study; chronic inflammation; immunosuppression; tobacco smoking; lung cancer

SECOND ONLY to human immunodeficiency virus/ acquired immune deficiency syndrome (HIV/AIDS), tuberculosis (TB) is the greatest killer worldwide due to a single infectious agent.1 Several studies have suggested an association between tuberculosis and lung cancer,2–5 whereas data on extra-pulmonary cancer risk are scarce. With 8.7 million new cases of active TB worldwide in 2012, any association between TB and cancer is of great clinical importance.1 TB and malignancy may be related in three ways: first, prevalent occult cancer may lead to locally reduced infection barriers and/or generalised immunosuppression, rendering a cancer patient susceptible to tuberculous infection or TB reactivation.6 TB may thus be a marker for occult cancer. Second, TB may increase the risk of cancer locally and systemically through chronic inflammation and production of carcinogenic molecules.6 Third, shared risk factors for TB and some cancers, such as smoking, alcoholism, chronic obstructive pulmonary disease (COPD) and immunosuppression, including HIV, may lead to

both TB and cancer, affecting both prevalent and subsequent cancer risk.7–9 Previous epidemiological data have suggested increased short- and long-term risks of lung cancer following TB.2–5 A Taiwanese population-based cohort study of 6699 TB patients (median follow-up 3.8 years) recently found an increased standardised incidence ratio (SIR) of 1.71 for any extra-pulmonary cancer (95% confidence interval [CI] 1.54–1.90).10 The magnitude and period of increased risk for rarer site-specific cancers and the role of shared risk factors were not examined. Such data may increase our understanding of the clinical course of TB patients and have implications for their clinical follow-up, including monitoring for specific cancers. We therefore examined short- and long-term cancer risk by site after first hospital contact with TB using nationwide population-based data.

STUDY POPULATION AND METHODS The Danish health care system provides tax-support-

Correspondence to: Dennis F Simonsen, Department of Clinical Epidemiology, Aarhus University Hospital, Olof Palmes All´e 43–45, 8200 Aarhus N, Denmark. Tel: (þ45) 871 68236. Fax: (þ45) 871 67215. e-mail: [email protected] Article submitted 24 February 2014. Final version accepted 23 May 2014.

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ed health care services for all residents, guaranteeing free access to hospitals and primary medical care. The civil registration number, a unique identifier assigned to every Danish citizen, allows for accurate linkage among the databases used in this study.11 Identification of tuberculosis patients We used the Danish National Registry of Patients (DNRP), which covers all hospitalisations in Danish hospitals since 1977 and all hospital out-patient clinic and emergency department visits since 1995,12 to identify all patients with a first-time hospital contact with a primary diagnosis of active TB disease (see Appendix Table A.1 for International Classification of Diseases 8th and 10th Revision codes)* from 1978 to 2011. A previous Danish validation study based on a detailed review of hospital records found that 80% of patients with a first-time primary TB diagnosis in the DNRP were correctly diagnosed according to the European Union TB case classification criteria, corresponding to a positive predictive value (PPV) of 80% (95%CI 69–89).13 In the study, 58% of TB cases were culture-confirmed. Identification of cancer We obtained information on all cancer diagnoses from the Danish Cancer Registry (DCR), which contains nationwide data on cancer incidence in Denmark and is 95–98% complete and valid.14 We excluded patients with a cancer diagnosis preceding the first hospital contact with TB. Data on comorbidity We computed Charlson Comorbidity Index (CCI) scores based on each patient’s complete hospitalisation record in the DNRP preceding the date of TB diagnosis.15 Three comorbidity levels were defined: low (score of 0), medium (score of 1–2), and high (score of 73). We further identified medical history of alcoholism and substance use-related conditions, which are not included in the CCI (see Appendix Table A.1). Statistical analysis We followed TB patients for occurrence of cancer from the date of first hospital contact with TB until the date of death, emigration or 31 December 2011, whichever came first. The SIRs of cancer were computed as the observed number of cancers divided by the expected number of cancers.16 Expected numbers were based on national cancer incidence rates by sex, age (5-year groups) and year of diagnosis (5-year intervals). 95%CIs were computed using Byar’s approximation to the Poisson distribution. * The Appendix is available in the online version of this article, at http://www.ingentaconnect.com/content/iuatld/ijtld/2014/ 00000018/00000010/art00013.

We computed cancer SIRs for short-term follow-up (0–3 months, likely prevalent occult cancer), intermediate follow-up (3 months–5 years) and long-term follow-up (.5 years).17 We also computed SIRs for each year following TB diagnosis to show cancer risk during follow-up. We performed stratified analyses according to sex, age group, comorbidity, TB patient’s country of origin (Denmark, non-Denmark, Somalia, Asia, Other) and respiratory vs. non-respiratory TB. SIRs were computed for any, site-specific, extra-pulmonary, localised, metastatic and tobacco-related,18 and alcohol-related cancers,19 cancers associated with immunosuppression,17 haematological cancers, and HIV/AIDS-related cancers. HIV/AIDS-related cancers included AIDS-defining cancers (Kaposi’s sarcoma, non-Hodgkin’s malignant lymphoma and cervix of the uterus) and non-AIDS-defining but HIVassociated cancers (liver, anal, lung, colon, rectum and Hodgkin’s malignant lymphoma).20 Statistical analyses were performed using SAS 9.2 software (Statistical Analysis Software Institute, Cary, NC, USA). Ethics statement The study was approved by the Danish Data Protection Agency (number 1-16-02-1-08).

RESULTS Patient characteristics We identified 15 024 patients (6596 [44%] women and 8428 [56%] men; median age 43.4 years, interquartile range [IQR] 28.3–62.2) with a first hospital contact with active TB disease during 1978– 2011 (Table 1). Follow-up time was 150 400 personyears, with a median follow-up of 8.5 years (IQR 3.1– 14.9); 4396 died during the study period and 967 were lost to follow-up; 22% of the patients had recorded comorbidity (CCI score . 0); 7% had a diagnosis of COPD, 8% alcoholism, 10% substance use and 1% HIV/AIDS. More than one third (37%) were immigrants. All-time cancer risk We observed 1747 cancers (expected 1149), yielding an increased all-time SIR for any cancer of 1.52 (95%CI 1.45–1.59) (Figure 1). The relative risk (RR) was higher for men (SIR 1.65, 95%CI 1.55–1.75) than for women (SIR 1.36, 95%CI 1.26–1.47). The all-time RR of any extra-pulmonary cancer was 1.29 (95%CI 1.22–1.36). The all-time RR of any cancer was higher for TB patients with alcoholism, substance use or of Danish origin than for TB patients without these factors, but not for patients with both TB and COPD. TB patients from Somalia and Asia had a lower age- and sex-adjusted all-time RR of any cancer than the background population. All-time any

TB and cancer risk

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Figure 1 SIRs for any cancer calculated for each year after diagnosis. SIR ¼ standardised incidence ratio.

cancer SIR in patients with a CCI score of 0 was 1.50 (95%CI 1.42–1.58). Three-month standardised incidence ratios for cancer TB patients had a substantially increased risk of cancer shortly after diagnosis compared with individuals in the general population. During the first 3 months of follow-up, 275 cancers were diagnosed in patients with TB vs. only 25 expected cancers (SIR 11.09, 95%CI 9.82–12.48). For 168 of these 275 cancers, the diagnosis was made during the index admission with TB. The 3-month SIR for extrapulmonary cancer was 7.09 (95%CI 6.02–8.29) and for lung cancer, it was 40.9 (95%CI 34.0–49.0). The RR of metastatic cancer disease was substantially higher than for localised malignancy (20-fold vs. 4fold). Table 2 shows highly increased 3-month SIRs for malignant pleural mesothelioma (MPM) (368.4), Hodgkin’s lymphoma (30.6), ovary (26.4) and nonHodgkin’s malignant lymphoma (23.8). SIRs were 710 times higher for kidney, liver, and gallbladder cancer, lymphoid leukaemia and pancreatic cancer. Three-month to 5-year standardised incidence ratios for cancer SIRs decreased substantially for most cancers after more than 3 months (Tables 1 and 2). The any-cancer SIR remained 1.6-fold higher between 3 months and 5 years. It should be noted that the risk of MPM remained more than 19-fold higher, while that of lung cancer remained 3.5-fold higher. The RR of extrapulmonary cancer was 1.34 (95%CI 1.22–1.47). SIRs of .1.5 were seen for oral cancer, Kaposi’s sarcoma, pharynx cancer, non-Hodgkin’s malignant lymphoma, liver and kidney cancer, myeloid leukaemia and

cancers of other parts of the larynx. High 3-months– 5-year cancer SIRs were found especially among TB patients with alcoholism. The 0-1-year SIR for lung cancer was 16.87 (95%CI 14.50–19.51) and for extra-pulmonary cancer, 3.31 (95%CI 2.93–3.74) (Figures 2 and 3). Standardised incidence ratios for cancer beyond 5 years Beyond 5 years of follow-up, the SIR for any cancer remained modestly increased, at 1.17 (95%CI 1.10– 1.25). This stemmed mainly from a 2.24-fold (95%CI 1.88–2.64) increased risk beyond 5 years for lung cancer following respiratory TB (Table 1). In contrast, non-respiratory TB was not associated with any substantially increased long-term cancer risk, either for lung or extra-pulmonary cancer. The long-term cancer risk following TB was clearly increased in men vs. women, and in Danes vs. immigrants (Table 1). Patients with alcoholism had an RR of 1.82 (95%CI 1.39–2.35), and elevated RRs were also seen for persons with substance use. SIRs beyond 5 years remained substantially increased for Kaposi’s sarcoma, oral cancer, myeloid leukaemia and liver cancer. A slight decrease in any-cancer SIR was observed in the most recent calendar periods. Beyond 20 years of follow-up, the risk of lung cancer was still considerably increased, at 1.85 (95%CI 1.20–2.74). Standardised incidence ratios for cancers grouped according to aetiology The high relative risk of haematological (SIR 19.6, 95%CI 13.1–28.1) and tobacco-related (SIR 19.2, 95%CI 16.3–22.5) cancers within the first 3 months and the more than 2-fold increased all-time risk for

4 080 (27.2) 6 165 (41.0) 4 779 (31.8)

Calendar period 1978–1988 1989–2000 2001–2011

(0.80–2.70) (0.88–1.41) (1.37–1.73) (1.49–1.77) (1.34–1.58) (1.39–1.81)

1343/895.6 349/222.5 55/31.3

Comorbidity CCI score: 0 CCI score: 1–2 CCI score: 73

1620/1092.6 127/56.8

13 815 (92.0) 1 209 (8.1)

13 548 (90.2) 1 476 (9.8)

14 904 (99.2) 120 (0.8)

Substance abuse No Yes

HIV/AIDS No Yes

1741/1146.8 6/2.6

1603/1082.8 144/66.6

1625/1069.9 122/79.5

14 022 (93.3) 1 002 (6.7)

COPD No Yes Alcoholism No Yes

11 691 (77.8) 2 741 (18.2) 592 (3.9)

0.56 1.75 1.20 0.61

72/128.8 1512/865.6 139/115.8 24/39.2

1.52 (1.45–1.59) 2.28 (0.84–4.96)

1.48 (1.41–1.55) 2.16 (1.82–2.55)

1.48 (1.41–1.56) 2.24 (1.86–2.66)

1.52 (1.45–1.59) 1.54 (1.27–1.83)

1.50 (1.42–1.58) 1.57 (1.41–1.74) 1.76 (1.33–2.29)

(0.44–0.70) (1.66–1.84) (1.01–1.42) (0.39–0.91)

1.75 (1.66–1.84) 0.83 (0.73–0.94)

1.64 (1.53–1.76) 1.34 (1.23–1.44) 1.68 (1.48–1.90)

1.54 1.12 1.54 1.63 1.46 1.59

1.36 (1.26–1.47) 1.65 (1.55–1.75)

1.52 (1.45–1.59) 1.29 (1.22–1.36) 3.40 (3.09–3.74)

SIR (95%CI)

1512/865.6 235/283.9

852/518.6 640/479.4 255/151.5

12/7.8 73/65.3 290/188.1 555/341.0 589/403.6 228/143.6

699/513.7 1048/635.7

1747/1149.4 1318/1023.4 429/126.0

Cancers observed/expected

Country of origin: Denmark Yes 9 462 (63.0) No 5 562 (37.0) Country of origin Asia 2 204 (14.7) Denmark 9 462 (63.0) Other 1 644 (10.9) Somalia 1 714 (11.4)

(9.0) (19.5) (23.7) (20.1) (17.4) (10.27)

1 2 3 3 2 1

Age, years 0–14 15–29 30–44 45–59 60–74 775

345 936 567 020 613 543

6 596 (43.9) 8 428 (56.1)

15 024

Sex Women Men

All Extra-pulmonary cancer Lung cancer

TB patients n (%)

All years

274/24.7 1/0.1

257/22.9 18/1.9

259/23.2 16/1.6

246/21.2 29/3.6

183/15.4 76/7.7 16/1.7

13/1.9 239/20.3 19/1.9 4/0.7

239/20.3 36/4.5

116/8.1 96/9.6 63/7.1

2/0.1 9/0.4 26/1.4 65/4.3 120/10.2 53/8.4

113/10.1 162/14.7

275/24.8 155/21.9 120/2.9

Cancers observed/expected

(3.96–118.27) (10.41–43.20) (11.84–26.56) (11.69–19.30) (9.77–14.09) (4.71–8.22)

(3.66–11.77) (10.31–13.34) (5.94–15.42) (1.66–15.63)

11.08 (9.81–12.48) 12.34 (0.31–68.74)

11.20 (9.87–12.66) 9.67 (5.73–15.28)

11.15 (9.83–12.59) 10.18 (5.82–16.54)

11.58 (10.18–13.12) 8.14 (5.45–11.69)

11.92 (10.25–13.77) 9.88 (7.78–12.36) 9.15 (5.23–14.86)

6.88 11.75 9.87 6.11

11.75 (10.31–13.34) 8.06 (5.64–11.15)

14.37 (11.87–17.24) 10.02 (8.11–12.23) 8.82 (6.78–11.28)

32.76 22.74 18.12 15.14 11.78 6.28

11.17 (9.20–13.43)) 11.03 (9.40–12.87)

11.09 (9.82–12.48) 7.09 (6.02–8.29) 40.94 (33.95–48.96)

SIR (95%CI)

0–3 months

581/367.4 4/1.2

529/341.8 56/26.8

533/345.8 52/22.8

527/326.2 58/42.5

399/249.9 156/100.2 30/18.5

17/33.2 523/289.7 38/32.4 7/13.3

523/289.7 62/78.9

219/120.2 227/150.5 139/98.0

2/1.1 12/8.7 48/30.4 158/81.6 237/157.5 128/89.3

233/156.6 352/212.1

585/368.6 437/326.2 148/42.4

(0.22–6.58) (0.71–2.41) (1.16–2.09) (1.65–2.26) (1.32–1.71) (1.20–1.70)

(0.30–0.82) (1.65–1.97) (0.83–1.61) (0.21–1.08)

1.58 (1.46–1.72) 3.30 (0.90–8.45)

1.55 (1.42–1.69) 2.09 (1.58–2.71)

1.54 (1.41–1.68) 2.28 (1.70–2.99)

1.62 (1.48–1.76) 1.37 (1.04–1.77)

1.60 (1.44–1.76) 1.56 (1.32–1.82) 1.62 (1.09–2.32)

0.51 1.81 1.17 0.53

1.81 (1.65–1.97) 0.79 (0.60–1.01)

1.82 (1.59–2.08) 1.51 (1.32–1.72) 1.42 (1.19–1.68)

1.82 1.38 1.58 1.94 1.50 1.43

1.49 (1.30–1.69) 1.66 (1.49–1.84)

1.59 (1.46–1.72) 1.34 (1.22–1.47) 3.49 (2.95–4.10)

SIR (95%CI)

3 months–5 years Cancers observed/expected

Table 1 SIRs for cancer in 15 024 individuals with a first hospital presentation with TB, overall and according to risk factors

886/754.6 1/1.3

817/718.0 70/37.9

828/723.6 59/32.4

852/722.5 35/33.4

761/630.4 117/114.6 9/11.0

42/93.7 750/555.5 82/81.5 13/25.3

750/555.5 137/200.5

517/390.3 317/319.3 53/46.3

8/6.6 52/56.2 216/156.3 332/255.2 232/236.0 47/45.8

353/347.0 534/408.9

887/756.0 726/675.3 161/80.7

Cancers observed/expected

(0.52–2.38) (0.69–1.21) (1.20–1.58) (1.16–1.45) (0.86–1.12) (0.75–1.37)

(0.32–0.61) (1.26–1.45) (0.80–1.25) (0.27–0.88)

1.17 (1.10–1.25) 0.75 (0.02–4.15)

1.14 (1.06–1.22) 1.84 (1.44–2.33)

1.14 (1.07–1.22) 1.82 (1.39–2.35)

1.18 (1.10–1.26) 1.05 (0.73–1.46)

1.21 (1.12–1.30) 1.02 (0.84–1.22) 0.82 (0.37–1.55)

0.45 1.35 1.01 0.51

1.35 (1.26–1.45) 0.68 (0.57–0.81)

1.32 (1.21–1.44) 0.99 (0.89–1.11) 1.14 (0.86–1.50)

1.21 0.93 1.38 1.30 0.98 1.03

1.02 (0.91–1.13) 1.31 (1.20–1.42)

1.17 (1.10–1.25) 1.08 (1.00–1.16) 2.00 (1.70–2.33)

SIR (95%CI)

75 years

1214 The International Journal of Tuberculosis and Lung Disease

TB patients n (%)

731/319.9 4/0.6

(1.80–2.52) (2.22–2.55) (1.21–1.48) (0.89–1.11)

2.29 (2.12–2.46) 6.90 (1.88–17.66)

2.14 2.38 1.34 0.99

1.09 (0.97–1.22) 1.39 (0.99–1.90) 1.05 (0.93–1.19)

1.66 (1.57–1.75) 3.98 (3.60–4.40) 1.36 (1.28–1.45)

1.10 (1.01–1.19) 2.02 (1.88–2.17)

SIR (95%CI)

155/7.4 1/0.02

29/1.5 152/7.9 28/6.0 24/6.3

30/5.1 6/0.5 24/4.6

245/19.7 114/2.4 131/17.3

49/12.0 173/8.5

Cancers observed/expected

(13.09–28.08) (16.25–22.48) (3.07–6.69) (2.44–5.67)

21.07 (17.88–24.66) 51.93 (1.31–289.25)

19.55 19.18 4.63 3.81

5.83 (3.93–8.32) 11.16 (4.10–24.33) 5.20 (3.33–7.74)

12.47 (10.95–14.13) 47.64 (39.29–57.23) 7.59 (6.35–9.01)

4.11 (3.04–5.43) 20.42 (17.49–23.71)

SIR (95%CI)

0–3 months

256/107.0 2/0.3

55/22.0 267/114.2 132/90.5 113/97.0

92/84.1 10/8.6 82/75.5

493/284.5 138/33.8 355/250.7

214/179.2 250/123.1

Cancers observed/expected

(1.88–3.25) (2.07–2.64) (1.22–1.73) (0.96–1.40)

2.39 (2.11–2.70) 7.38 (0.89–26.63)

2.50 2.34 1.46 1.16

1.09 (0.88–1.34) 1.16 (0.55–2.13) 1.09 (0.86–1.35)

1.73 (1.58–1.89) 4.09 (3.43–4.83) 1.42 (1.27–1.57)

1.19 (1.04–1.37) 2.03 (1.79–2.30)

SIR (95%CI)

3 months–5 years

320/205.5 1/0.3

57/42.5 377/212.0 223/188.9 183/219.4

182/190.5 23/18.9 159/171.5

705/565.5 138/61.7 567/503.8

355/371.7 318/234.7

Cancers observed/expected

(1.01–1.74) (1.60–1.97) (1.03–1.35) (0.72–0.96) 1.56 (1.39–1.74) 3.46 (0.09–19.25)

1.34 1.78 1.18 0.83

0.96 (0.82–1.10) 1.21 (0.77–1.82) 0.93 (0.79–1.08)

1.25 (1.16–1.34) 2.24 (1.88–2.64) 1.13 (1.03–1.22)

0.96 (0.86–1.06) 1.36 (1.21–1.51)

SIR (95%CI)

75 years

SIR ¼ standardised incidence ratio; TB ¼ tuberculosis; CI ¼ confidence interval; CCI ¼ Charlson Comorbidity Index; COPD ¼ chronic obstructive pulmonary disease; HIV ¼ human immunodeficiency virus; AIDS ¼ acquired immunodeficiency syndrome.

14 904 (99.2) 120 (0.8)

HIV/AIDS-related cancers HIV: no HIV: yes

304/279.7 39/28.1 265/251.6

141/66.0 796/334.1 383/285.5 320/322.7

3 552 (23.6)

1443/869.7 390/97.9 1053/771.8

618/562.9 741/366.3

Cancers observed/expected

All years

Cancers according to aetiology Haematological cancers Tobacco-related cancers Alcohol-related cancers Immune-related cancers

All Lung cancer Extra-pulmonary cancer

Non-respiratory TB

All 11 472 (76.4) Lung cancer Extra-pulmonary cancer

Respiratory TB

Metastases No Yes

Table 1 (continued)

TB and cancer risk

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The International Journal of Tuberculosis and Lung Disease

Figure 2 SIRs for lung cancer calculated for each year after diagnosis. SIR ¼ standardised incidence ratio.

these two cancer groups are worthy of note. Beyond 5 years, tobacco-related cancers still showed an increased SIR of 1.78 (95%CI 1.60–1.97). The SIR for alcohol-related cancers was 4.6-fold higher in the first 3 months, and remained elevated beyond 5 years of follow-up. Immune-related cancers were 3.8-fold higher during the first 3 months but showed no substantial increase in all-time risk.

DISCUSSION This nationwide population-based cohort study including 15 024 TB patients provides strong evidence that TB is an important marker for occult lung cancer, haematological cancer and several other extra-pulmonary cancers. The risk of cancer remained substantially increased in the first 5 years, most markedly for MPM, lung cancer, oral and haematological cancers. Beyond 5 years, increased risk remained, especially for lung cancer, other tobacco-related cancers and haematological cancers. Our findings are in line with previous observations of a high short-term risk of cancer in general and particularly lung cancer in TB patients.10 In line with our 1-year lung cancer SIR of 16.87, the 1-year RR of lung cancer in the recent Taiwanese study was 12.39 (95%CI 9.90–15.33) in men and 17.24 (95%CI 10.67–26.36) in women.10 Our finding of a 3.3-fold increased 1-year risk of extra-pulmonary cancer following TB is also very similar to their findings (RR 3.03, 95%CI 2.54–3.59). The high short-term risk of cancer is likely due to prevalent undiagnosed cancer at the time of TB diagnosis. The fact that short-term risk of metastatic disease was several fold higher than for localised cancer may underline the

importance of the TB propensity of the lung metastases frequently seen in advanced cancer disease. Alternatively, it may underline the importance of advanced malignancy in causing infection due to general immunosuppression. Such reverse causality (i.e., occult cancer causing subsequent TB) is consistent with the findings of a Taiwanese nationwide population-based matched cohort study of 16 487 cancer patients and 65 948 non-cancer controls.21 This study found that cancer in general increased the risk of TB (incidence rate ratio [IRR] 1.67, 95%CI 1.42–1.96). Furthermore, increased risk was especially seen for patients with cancers of the aerodigestive tract, including oral, nasopharynx, oesophagus and lung cancer (hazard ratio [HR] 3.09, 95%CI 2.42–3.94), as well as haematological cancers, including non-Hodgkin’s malignant lymphoma and leukaemia (HR 3.22, 95%CI 1.98–5.22), corroborating our observations. Reverse causality is unlikely to explain the increased long-term risk of cancer. These findings are more likely explained by TB promoting cancer growth or by shared risk factors. TB may stimulate cancer growth through chronic inflammation and, more specifically, by increased circulating levels of tumour necrosis factor-alpha (TNF-a).22 TNF-a is not only essential in controlling mycobacterial infection, it also promotes tumour cell survival, angiogenesis and stimulation of the production of carcinogenic molecules such as nitric oxide and reactive oxygen species.23 The particularly increased long-term risk of metastatic cancer might be due to the increased circulating levels of TNF-a, which could generate micro-environments that are more suitable for metastatic growth.24 Both respiratory TB and

TB and cancer risk

Table 2

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SIRs for selected specific cancer sites in patients with TB, presented for different of follow-up periods* All years

Cancer diagnosis

n

All cancers

SIR (95%CI)

0–3 months n

1747 1.52 (1.45–1.59) 275

Site-specific cancers Oral cavity Oesophagus Stomach Large intestine, including rectosigmoid colon Rectum Liver Gallbladder and biliary tract Pancreas Larynx Lung, bronchi and trachea Malignant pleural mesothelioma Malignant melanoma Other skin cancer (excluding basal cell carcinoma) Breast Uterus Ovary Prostate Kidney Urinary bladder Membrane of the brain and spinal meninx Brain Non-Hodgkin’s malignant lymphoma Lymphoid leukaemia Myeloid leukaemia Metastases and non-specified cancer in lymph nodes Other cancers with poorly specified localisation and non-specified cancer Basal cell carcinoma

SIR (95%CI) 1.59 (1.46–1.72)

4.09 2.16 1.45 1.30

(2.69–5.95) (1.42–3.14) (0.99–2.05) (1.07–1.58)

44 36 16 43 20 429 51

0.99 3.79 2.42 1.62 2.08 3.40 15.8

(0.72–1.33) 2 1.90 (0.23–6.86) 17 1.13 (2.66–5.25) 4 18.0 (4.9–46.0) 11 3.45 (1.38–3.93) 3 17.4 (3.6–50.8) 5 2.10 (1.17–2.18) 7 11.3 (4.5–23.2) 13 1.46 (1.27–3.21) 0 0 5 1.49 (3.09–3.74) 120 40.9 (34.0–49.0) 148 3.49 (11.8–20.8) 27 368.4 (242.7–536.0) 21 19.61

103 17 29 87 31 65 12

0.89 0.83 1.70 0.94 1.65 1.08 1.59

0 0

0 3.84 (0.10–21.38) 3.13 (0.38–11.31) 4.27 (1.84–8.41)

n 585

27 27 32 107

22 0.61 (0.38–0.93) 32 0.92 (0.63–1.30)

0 1 2 8

SIR (95%CI) 11.1 (9.8–12.5)

3 months–5 years

0 0

12 9 9 39

5.70 2.30 1.06 1.44

(2.94–9.96) (1.05–4.36) (0.49–2.02) (1.02–1.97)

75 years n

SIR (95%CI)

887 1.17 (1.10–1.25) 15 17 21 60

3.44 2.04 1.62 1.13

(1.92–5.68) (1.19–3.27) (1.00–2.47) (0.86–1.46)

(0.66–1.82) 25 0.88 (1.72–6.17) 21 3.45 (0.68–4.89) 8 1.97 (0.78–2.50) 23 1.35 (0.48–3.48) 15 2.49 (2.95–4.10) 161 2.00 (12.13–29.97) 3 1.44

(0.57–1.30) (2.14–5.28) (0.85–3.89) (0.86–2.03) (1.39–4.10) (1.70–2.33) (0.30–4.21)

9 10

0.83 (0.38–1.57) 1.00 (0.48–1.85)

13 0.53 (0.28–0.91) 22 0.91 (0.57–1.38) 61 12 12 57 15 44 9

(0.72–1.08) (0.48–1.33) (1.14–2.45) (0.75–1.16) (1.12–2.34) (0.84–1.38) (0.82–2.78)

9 1 10 6 6 4 1

4.13 2.24 26.4 3.01 14.1 2.75 7.34

(1.89–7.85) (0.06–12.45) (12.7–48.6) (1.10–6.56) (5.2–30.6) (0.75–7.04) (0.19–40.89)

33 4 7 24 10 17 2

0.96 0.60 1.23 0.84 1.60 0.82 0.91

(0.66–1.35) (0.16–1.52) (0.49–2.53) (0.54–1.25) (0.76–2.94) (0.48–1.31) (0.11–3.29)

32 1.22 (0.83–1.72) 81 2.17 (1.73–2.70)

2 19

3.63 (0.44–13.10) 23.8 (14.3–37.1)

7 31

0.81 (0.33–1.67) 2.58 (1.75–3.66)

23 1.35 (0.85–2.02) 31 1.27 (0.86–1.80)

18 1.39 (0.82–2.20) 31 3.24 (2.20–4.60) 63 2.68 (2.06–3.43)

4 2 14

13.0 (3.5–33.2) 8.72 (1.05–31.46) 26.9 (14.7–45.2)

6 16 19

1.35 (0.49–2.94) 4.80 (2.74–7.79) 2.47 (1.49–3.86)

8 0.98 (0.42–1.93) 13 2.17 (1.15–3.71) 30 1.96 (1.32–2.80)

27 2.35 (1.55–3.41)

8

28.3 (12.2–55.8)

12

2.97 (1.53–5.19)

7 0.97 (0.39–2.01)

130 0.68 (0.57–0.81)

1

0.28 (0.01–1.55)

44

0.79 (0.57–1.06)

85 0.65 (0.52–0.80)

* Data are not presented for cancers with fewer than 15 diagnoses recorded. Full table available online in Appendix Table A.2. SIR ¼ standardised incidence ratio; TB ¼ tuberculosis; CI ¼ confidence interval.

Figure 3 SIRs for extra-pulmonary cancer calculated for each year after diagnosis. SIR ¼ standardised incidence ratio.

0.77 0.90 1.10 0.92 1.24 1.16 1.73

(0.59–0.99) (0.47–1.58) (0.57–1.92) (0.69–1.19) (0.69–2.05) (0.84–1.56) (0.79–3.29)

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non-respiratory TB showed a stronger association with lung cancer than with extra-pulmonary cancer, whereas respiratory TB generally showed the strongest associations with both cancer groups. This could be because most primary TB infections are pulmonary, with subsequent lymphatic or haematogenous spread to extra-pulmonary locations.25 It could also be that inflammation, both locally and systemically, is much greater in respiratory TB than in non-respiratory TB. Local lung inflammation due to TB might account for the so-called scar cancers observed in old mycobacterial tubercles.26 These scar cancers are predominantly found in peripheral or subpleural lung tissue. Subpleural inflammation may explain our findings of a high all-time SIR for MPM. While the association between asbestos exposure and MPM is universally accepted,27,28 less importance has been given to the connection between MPM and chronic pleural disease, particularly TB.29 The very high MPM SIRs support the association between TB and MPM, as only one of the 51 patients with MPM had a diagnosis of asbestosis preceding TB diagnosis. We cannot, however, rule out asbestos exposure as an important confounder. The high long-term RRs of tobacco-related cancers and lung cancer indicate that tobacco smoking is an important shared risk factor. The increases in the risk of cancer were much higher among Danish citizens, males and substance users than in immigrants, women and non-users, and in the former subgroups, lifestyle factors may be more dominant risk factors for TB than in the latter groups. The lower all-time risks of cancer in immigrants from areas of high TB endemicity may indicate a ‘healthy immigrant bias’. The prevalence of TB is low in Denmark, with 300– 400 annual incident cases,30 and most native Danish citizens who contract TB have strong risk factors, including tobacco smoking, chronic lung disease, immunosuppression and substance use. This supports our hypothesis of shared risk factors in cancer development. However, previous studies restricted to never smoking women have shown an association between TB and lung cancer.31–33 When stratified for CCI, COPD, alcoholism, substance use or HIV/AIDS, the risk of any and extra-pulmonary cancer remained increased. This is consistent with TB independently altering the risk of cancer. The initial misinterpretation of cancer as TB may partly explain the high short-term risk, particularly of lung cancer, MPM and lymphomas, but such misclassification is unlikely to explain the highly increased risk of pulmonary and haematological cancer during intermediate- and long-term followup. We had no available data on microbiological confirmation, but the high PPV of primary TB diagnoses in the Danish registry argues against misclassification as the primary explanation for our observations.

Surveillance bias with heightened diagnostic activity might explain some of the increased short-term cancer risk following TB, but is unlikely to explain the long-term risks. The Danish health care system guarantees free access to medical care and high completeness of the databases used in the study, with ongoing follow-up of the entire population. If surveillance bias was substantial, the increased short-term risks of cancer would be followed by compensatory lower risks, which was not the case. We lacked data to examine the role of tobacco smoking and other individual lifestyle and environmental factors associated with both TB and cancer. Furthermore, the slight decrease in the long-term any cancer SIR in recent years may be biased by shortened long-term follow-up. Finally, even in this large nationwide study, the statistical precision of risk estimates for some rare cancers was limited. In conclusion, patients with hospital-diagnosed TB are at substantially increased risk of occult lung cancer and haematological or other extra-pulmonary cancers. As early detection of cancer is related to improved prognosis, physicians should be aware of this association in their diagnostic work-up. TB also predicts an increased long-term risk of specific cancers, likely due to chronic inflammation or shared risk factors, including immunosuppression and smoking. Further research is needed to determine whether the observed increased cancer risk justifies a special surveillance programme or a more active case finding approach by the treating physicians. Acknowledgements This study was financially supported by the Danish Cancer Society, Copenhaven, (R73-A4284-13-S17), the Karen Elise Jensen Foundation, Copenhaven, the Aarhus University Research Foundation, Aarhus, the A P Møller Foundation for the Advancement of Medical Science, Copenhaven, the Oticon Foundation, Smørum, the Dansk Tennis Fond, Copenhaven, and the Institute of Clinical Medicine at Aarhus University, Aarhus, Denmark. Conflict of interest: none declared.

References 1 World Health Organization. Global tuberculosis report, 2013. WHO/HTM/TB/2013.11. Geneva, Switzerland: WHO, 2013. http://www.who.int/tb/publications/global_report/en/index. html. Accessed June 2014. 2 Yu Y H, Liao C C, Hsu W H, et al. Increased lung cancer risk among patients with pulmonary tuberculosis: a population cohort study. J Thorac Oncol 2011; 6: 32–37. 3 Wu C, Hu H, Pu C, et al. Pulmonary tuberculosis increases the risk of lung cancer. Cancer 2011; 117: 618–624. 4 Brenner D R, McLaughlin J R, Hung R J. Previous lung diseases and lung cancer risk: a systematic review and meta-analysis. PLOS ONE 2011; 6: e17479. 5 Liang H Y, Li X L, Yu X S, et al. Facts and fiction of the relationship between preexisting tuberculosis and lung cancer risk: a systematic review. Int J Cancer 2009; 125: 2936–2944. 6 Vento S, Lanzafame M. Tuberculosis and cancer: a complex and dangerous liaison. Lancet Oncol 2011; 12: 520–522. 7 Slama K, Chiang C Y, Enarson D A, et al. Tobacco and

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tuberculosis: a qualitative systematic review and meta-analysis. Int J Tuberc Lung Dis 2007; 11: 1049–1061. Ferrara G, Murray M, Winthrop K, et al. Risk factors associated with pulmonary tuberculosis: smoking, diabetes and anti-TNF alpha drugs. Curr Opin Pulm Med 2012; 18: 233–240. Lawn S D, Zumla A I. Tuberculosis. Lancet 2011; 378: 57–72. Kuo S C, Hu Y W, Liu C J, et al. Association between tuberculosis infections and non-pulmonary malignancies: a nationwide population-based study. Br J Cancer 2013; 109: 229–234. Pedersen C B. The Danish Civil Registration System. Scand J Public Health 2011; 39 (Suppl): 22–25. Lynge E, Sandegaard J L, Rebolj M. The Danish National Patient Register. Scand J Public Health 2011; 39 (Suppl): S30– S33. Leegaard A, Riis A, Kornum J B, et al. Diabetes, glycemic control, and risk of tuberculosis: a population-based casecontrol study. Diabetes Care 2011; 34: 2530–2535. Gjerstorff M L. The Danish Cancer Registry. Scand J Public Health 2011; 39 (Suppl): S42–S45. Charlson M E, Pompei P, Ales K L, MacKenzie C R. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987; 40: 373–383. Kornum J B, Svaerke C, Thomsen R W, Lange P, Sørensen H T. Chronic obstructive pulmonary disease and cancer risk: a Danish nationwide cohort study. Respir Med 2012; 106: 845– 852. Thomsen R W, Farkas D K, Friis S, et al. Endocarditis and risk of cancer: a Danish nationwide cohort study. Am J Med 2013; 126: 58–67. Secretan B, Straif K, Baan R, et al. A review of human carcinogens. Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 2009; 10: 1033–1034. Baan R, Straif K, Grosse Y, et al. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007; 8: 292–293. Pinzone M R, Fiorica F, Di Rosa M, et al. Non-AIDS-defining

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i

APPENDIX Table A.1 ICD-8 and ICD-10 diagnostic codes used in the Danish cohort study of cancer risk in patients with a first hospital contact with tuberculosis Disease category

ICD-8

Main exposure: TB

01100–01904

Main outcome: any cancer

NA

Previous substance abuse-related disorder (previous hospital contact with psychiatric disease, including substance dependence, intoxication or alcoholism-related disorder)

291, 303, 304, 979, 980.09, E860, 571.09, 571.10, 577.10, 070.01

HIV-positive: one or more of the following diagnoses within 30 days of TB diagnosis: HIV, AIDS (with related diseases), dementia in HIV disease, HIV disease complicating pregnancy, childbirth and the puerperium, consultations about AIDS Alcoholism related disorders: alcohol psychosis, alcoholic liver disease, acute alcoholic pancreatitis, chronic alcoholic pancreatitis, alcohol-induced pseudo-Cushings syndrome, alcohol addiction and psychiatric consequences, alcoholic polyneuropathia, alcoholic myopathia, degenerative changes in the nervous system caused by alcohol, alcoholic cardiomyopathia, alcoholic gastritis, problems with alcohol abuse, alcoholic liver disease, disulfiram-alcohol reaction, alcoholic pellagra, contact about rehabilitation after alcohol abuse, advice and control of alcohol abuse COPD Diseases included in the Charlson Comorbidity Index: myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, connective tissue disease, ulcer disease, mild liver disease, type 1 or 2 diabetes, hemiplegia, moderate to severe renal disease, type 1 or 2 diabetes with end-organ damage, any tumour, leukaemia, lymphoma, moderate to severe liver disease, metastatic solid tumour, AIDS

07983, Y4049

Tobacco-related cancers: lip, tongue, oral cavity, oropharynx, nasopharynx, other parts of pharynx, other and ill-defined sites in the lip, oral cavity and pharynx, oesophagus, stomach, liver, pancreas, nasal cavity and accessory sinuses, larynx, lung, bronchus and trachea, cervix uteri, kidney, renal pelvis, ureter, urinary bladder, myeloid leukaemia Alcohol-related cancers: larynx, oral cavity, oropharynx, nasopharynx, other parts of pharynx, oesophagus, liver, breast, colon, rectum Immune-related cancers: liver, cervix, malignant melanoma, Kaposi’s sarcoma, non-Hodgkin 0 s lymphoma, non-melanoma skin cancer Haematological cancers: Hodgkin’s disease, nonHodgkin 0 s lymphoma, multiple myeloma, malignant immunoproliferative diseases, lymphoid leukaemia, myeloid leukaemia, monocytic leukaemia, other leukaemias

ICD-10 A15–A19, K230, K673, K930, M011, M490, M900, N330, N740, N741 B210, C00–C96, D090–091, D301–309, D411–419, D32–33, D352–354, D42– 43, D443–445, D44, D05, N87, D06, O01, D392, D45.9, D46, D471, D473 K70x, K852, K860, DE244, F100– F109,G621, G721, G312x, I426, K292, Z721x, K70x, T500A, E529A, Z502, Z714, T510, T39, T40, T436, F10, R780– R785 B20–B24, F024, O987

291, 303, 979.59, 571.0, 577.10

K70, K852, K860, F101–F109, G621, G721, G312x, I426, K292, Z721, K70, T500A, E244, E529A, Z502, Z714

490–492 410, 427.09, 427.10, 427.11, 427.19, 428.99, 782.49, 440, 441, 442, 443, 444, 445, 430–438, 290.09– 290.19, 293.09, 490–493, 515–518, 712, 716, 734, 446, 135.99, 530.91, 530.98, 531–534, 571, 573.01, 573.04, 249.00, 249.06, 249.07, 249.09, 250.00, 250.06, 250.07, 250.09, 344, 403, 404, 580–583, 584, 590.09, 593.19, 753.10–753.19, 792, 249.01– 249.05, 249.08, 250.01–250.05, 250.08, 140–194, 204–207, 200– 203, 275.59, 070.00, 070.02, 070.04, 070.06, 070.08, 573.00, 456.00–456.09, 195–198, 199, 079.83 NA

J41–J44 I21, I22, I23, I50, I11.0, I13.0, I13.2, I70, I71, I72, I73, I74, I77, I60–I69, G45, G46, F00–F03, F05.1, G30, J40–J47, J60–J67, J68.4, J70.1, J70.3, J84.1, J92.0, J96.1, J98.2, J98.3, M05, M06, M08, M09, M30, M31, M32, M33, M34, M35, M36, D86, K22.1, K25– K28, B18, K70.0–K70.3, K70.9, K71, K73, K74, K76.0, E10.0, E10.1, E10.9, E11.0, E11.1, E11.9, G81, G82, I12, I13, N00–N05, N07, N11, N14, N17–N19, Q61,E10.2–E10.8, E11.2–E11.8, C00– C75, C91–C95, C81–C85, C88, C90, C96, B15.0, B16.0, B16.2, B19.0, K70.4, K72, K76.6, I85, C76–C80, B20– B24

NA

C32, C03–06, C10, C11, C12–13, C15, C22, C50, C18–19, C20

NA

C22, C53, C43, C46, B210, C82–85, C44

NA

C81, C82–85, C88, C90, C91–C95, morphology codes: 965–966, 959, 967– 972

C00, C01–02, C03–06, C10, C11, C12– 13, C14, C15, C16, C22, C25, C30.0, C31, C32, C33–C34, C53, C64, C65, C66, C76, C92

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The International Journal of Tuberculosis and Lung Disease

Table A.1 (continued) Disease category

ICD-8

HIV-associated cancers (AIDS-defining: Kaposi’s sarcoma, non-Hodgkin’s lymphoma, cervix of uterus; HIV-related but non-AIDS-defining: liver, anal cancer, lung cancer, colon, rectum, Hodgkin’s lymphoma) Respiratory TB Extra-pulmonary TB

ICD-10

NA

C46, B210, C82–85, C90, C53, C22, C21, C33–34, C18–19, C20, C81

01100–01199, 01200–01299, 01900– 01904 01300–01899

A15–A16 A17–A19, K230, K673, K930, M011, M490, M900, N330, N740, N741

ICD ¼ International Classification of Disease; TB ¼ tuberculosis; NA ¼ not applicable; HIV ¼ human immunodeficiency virus; AIDS ¼ acquired immune-deficiency syndrome; COPD ¼ chronic obstructive pulmonary disease.

Table A.2 SIRs for selected specific cancer sites in patients with TB, presented for different of follow-up periods (full table)* All years Cancer diagnosis All cancers Site-specific cancers Tongue Oral cavity Pharyngeal tonsil and cavity of pharynx Nasal part of pharynx Other parts of pharynx Oesophagus Stomach Large intestine, including rectosigmoid colon Rectum Anal canal Liver Gallbladder and biliary tract Pancreas Nasal cavity, middle ear and sinuses Larynx Lung, bronchi and trachea Malignant pleural mesothelioma Malignant melanoma Other skin cancer (excluding basal cell carcinoma) Kaposi’s sarcoma Other connective tissue Breast Cervix of uterus Uterus Ovary Prostate Kidney Urinary bladder Membrane of the brain and spinal meninx Brain Thyroid gland Hodgkin malignant lymphoma Non-Hodgkin’s malignant lymphoma Lymphoid leukaemia Myeloid leukaemia Metastases and non-specified cancer in lymph nodes Other cancers with poorly specified localisation and non-specified cancer Basal cell carcinoma

n

SIR (95%CI)

0–3 months

SIR (95%CI)

11.1 (9.8–12.5)

585

1.59 (1.46–1.72)

887 1.17 (1.10–1.25)

9 2.49 (1.14–4.72) 27 4.09 (2.69–5.95)

1 14.05 (0.36–78.28) 0 0.00

2 12

1.80 (0.22–6.50) 5.70 (2.94–9.96)

6 2.46 (0.90–5.36) 15 3.44 (1.92–5.68)

14 6 10 27 32

2.52 7.29 4.39 2.16 1.45

(1.38–4.23) (2.68–15.90) (2.10–8.08) (1.42–3.14) (0.99–2.05)

0 2 2 1 2

99.2 47.6 3.84 3.13

7 0 5 9 9

4.37 (1.75–9.01) 0.00 7.49 (2.43–17.45) 2.30 (1.05–4.36) 1.06 (0.49–2.02)

7 4 3 17 21

1.81 7.96 1.91 2.04 1.62

(0.73–3.74) (2.17–20.39) (0.39–5.59) (1.19–3.27) (1.00–2.47)

107 44 10 36 16 43

1.30 0.99 3.51 3.79 2.42 1.62

(1.07–1.58) (0.72–1.33) (1.68–6.46) (2.66–5.25) (1.38–3.93) (1.17–2.18)

8 2 0 4 3 7

4.27 (1.84–8.41) 1.90 (0.23–6.86) 0.00 18.0 (4.9–46.0) 17.4 (3.6–50.8) 11.3 (4.5–23.2)

39 17 2 11 5 13

1.44 1.13 2.36 3.45 2.10 1.46

60 25 8 21 8 23

1.13 0.88 4.11 3.45 1.97 1.35

(0.86–1.46) (0.57–1.30) (1.77–8.10) (2.14–5.28) (0.85–3.89) (0.86–2.03)

5 2.29 (0.74–5.33) 20 2.08 (1.27–3.21) 429 3.40 (3.09–3.74)

0 0 120

0.00 0.00 40.9 (34.0–49.0)

1 5 148

51 15.8 (11.8–20.8) 22 0.61 (0.38–0.93)

275

SIR (95%CI)

75 years

n

1747 1.52 (1.45–1.59)

n

3 months–5 years

0.00 (12.0–358.0) (5.8–171.9) (0.10–21.38) (0.38–11.31)

(1.02–1.97) (0.66–1.82) (0.29–8.51) (1.72–6.17) (0.68–4.89) (0.78–2.50)

1.36 (0.03–7.57) 1.49 (0.48–3.48) 3.49 (2.95–4.10)

n

SIR (95%CI)

4 2.86 (0.78–7.32) 15 2.49 (1.39–4.10) 161 2.00 (1.70–2.33)

27 368.4 (242.7–536.0) 0 0.00

21 19.61 (12.13–29.97) 9 0.83 (0.38–1.57)

3 1.44 (0.30–4.21) 13 0.53 (0.28–0.91)

0 0.00 0 0.00 2 23.05 (2.79–83.21) 9 4.13 (1.89–7.85) 0 0.00 1 2.24 (0.06–12.45) 10 26.4 (12.7–48.6) 6 3.01 (1.10–6.56) 6 14.1 (5.2–30.6) 4 2.75 (0.75–7.04)

10 1.00 (0.48–1.85) 2 11.34 (1.37–40.93) 1 0.74 (0.02–4.15) 33 0.96 (0.66–1.35) 6 1.18 (0.43–2.57) 4 0.60 (0.16–1.52) 7 1.23 (0.49–2.53) 24 0.84 (0.54–1.25) 10 1.60 (0.76–2.94) 17 0.82 (0.48–1.31)

22 3 3 61 8 12 12 57 15 44

0.91 12.3 1.05 0.77 0.93 0.90 1.10 0.92 1.24 1.16

(0.57–1.38) (2.5–35.9) (0.22–3.08) (0.59–0.99) (0.40–1.82) (0.47–1.58) (0.57–1.92) (0.69–1.19) (0.69–2.05) (0.84–1.56)

9 23 3 4

1.73 1.35 0.91 1.67

(0.79–3.29) (0.85–2.02) (0.19–2.67) (0.45–4.28)

32 5 6 103 14 17 29 87 31 65

0.92 11.6 1.40 0.89 1.00 0.83 1.70 0.94 1.65 1.08

(0.63–1.30) (3.8–27.0) (0.52–3.06) (0.72–1.08) (0.54–1.67) (0.48–1.33) (1.14–2.45) (0.75–1.16) (1.12–2.34) (0.84–1.38)

12 32 7 9

1.59 1.22 1.40 2.26

(0.82–2.78) (0.83–1.72) (0.56–2.89) (1.03–4.29)

1 2 0 3

7.34 (0.19–40.89) 3.63 (0.44–13.10) 0.00 30.6 (6.3–89.3)

2 7 4 2

81 2.17 (1.73–2.70) 18 1.39 (0.82–2.20) 31 3.24 (2.20–4.60)

19 4 2

23.8 (14.3–37.1) 13.0 (3.5–33.2) 8.72 (1.05–31.46)

31 6 16

2.58 (1.75–3.66) 1.35 (0.49–2.94) 4.80 (2.74–7.79)

31 1.27 (0.86–1.80) 8 0.98 (0.42–1.93) 13 2.17 (1.15–3.71)

63 2.68 (2.06–3.43)

14

26.9 (14.7–45.2)

19

2.47 (1.49–3.86)

30 1.96 (1.32–2.80)

27 2.35 (1.55–3.41) 130 0.68 (0.57–0.81)

8 1

28.3 (12.2–55.8) 0.28 (0.01–1.55)

12 44

2.97 (1.53–5.19) 0.79 (0.57–1.06)

7 0.97 (0.39–2.01) 85 0.65 (0.52–0.80)

*Data for cancers with fewer than five diagnoses recorded are not presented. TB ¼ tuberculosis; SIR ¼ standardised incidence ratio; CI ¼ confidence interval.

0.91 0.81 2.50 1.34

(0.11–3.29) (0.33–1.67) (0.68–6.39) (0.16–4.84)

TB and cancer risk

iii

RESUME O B J E C T I F S : Etudier les risques de cancer a` court et a` long terme chez des patients ayant une tuberculose (TB) active. S C H E´ M A : Nous avons quantifi´e le risque de cancer chez les patients tuberculeux grace ˆ aux bases de donn´ees nationales du Danemark pour la p´eriode 1978–2011 par comparaison a` la population g´en´erale. R E´ S U LT A T S : Nous avons observ´e 1747 cancers chez 15 024 patients tuberculeux (suivi m´edian 8,5 ans), soit un taux d’incidence standardis´e (SIR) de 1,52 (IC95% 1,45–1,59). Le taux d’incidence tout temps de cancer extra-pulmonaire e´ tait de 1,29 (IC95% 1,22–1,36) et le taux de cancer bronchique de 3,40 (IC95% 3,09–3,74). Le risque absolu de cancer 3 mois apr`es la TB e´ tait de 1,83% (SIR 11.09 ; IC95% 9,82–12,48), avec un taux tr`es augment´e de m´esoth´eliome malin de la pl`evre (368,4), de cancer bronchique (40,9), de lymphome de

Hodgkin (30,6), de cancer de l’ovaire (26,4) et de lymphome malin non-Hodgkinien (23,8). Entre 3 mois et 5 ans de suivi, le taux d’incidence pour un cancer quelconque e´ tait de 1,59 (IC95% 1,46–1,72), incluant une multiplication par 19 et par 3 du m´esoth´eliome malin et du cancer bronchique. Au-dela` de 5 ans, le taux de cancer e´ tait de 1,17 (IC95% 1,10–1,25). Les risques plus e´ lev´es a` long terme persistaient pour les cancers h´ematologiques (SIR 1.34 ; IC95% 1,01–1,74), et ceux li´es au tabac (SIR 1,78 ; IC95% 1,60–1,97). C O N C L U S I O N : La TB est un marqueur de cancer bronchique occulte et de plusieurs cancers extrapulmonaires. La TB pr´edit e´ galement un risque accru de cancer a` long terme, peut-ˆetre li´e a` une inflammation chronique et a` des facteurs de risque communs comme l’immunosuppression et le tabac.

RESUMEN

Investigar el riesgo de padecer ca´ncer a corto y largo plazo que presentan los pacientes con tuberculosis (TB) activa. M E´ T O D O: A partir de las bases de datos nacionales en Dinamarca, se cuantifico´ el riesgo de padecer ca´ncer en los pacientes con diagnostico ´ de TB entre 1978 y el 2011 y se comparo´ con el riesgo de la poblacion ´ general. R E S U LT A D O S: Se observaron 1747 casos de ca´ncer en 15 024 pacientes con diagnostico ´ de TB (mediana del seguimiento 8,5 anos), lo cual corresponde a una razon ´ ˜ de incidencia normalizada (SIR) de 1,52 (IC95% 1,45– 1,59). La SIR de carcinoma extrapulmonar durante todo el tiempo fue 1,29 (IC95% 1,22–1,36) y de carcinoma broncopulmonar fue 3,40 (IC95% 3,09–3,74). El riesgo absoluto de padecer ca´ncer 3 meses despu´es de la TB fue 1,83% (SIR 11,09; IC95% 9,82–12,48), con un riesgo mayor de mesotelioma pleural maligno (368,4), carcinoma broncopulmonar (40,9), linfoma de O B J E T I V O S:

Hodgkin (30,6), ca´ncer de ovario (26,4) y linfoma maligno no Hodgkin (23,8). Entre los 3 meses y los 5 anos de seguimiento, la SIR de todo ca´ncer fue 1,59 ˜ (IC95% 1,46–1,72), con un incremento de 19 veces del mesotelioma pleural maligno y de tres veces del carcinoma broncopulmonar. Despu´es de los 5 anos, la ˜ SIR de ca´ncer fue 1,17 (IC95% 1,10–1,25). Se observo´ la persistencia de un riesgo a largo plazo para las neoplasias hema´ticas (SIR 1,34; IC95% 1,01–1,74) y las neoplasias asociadas con el tabaquismo (SIR 1,78; IC95% 1,60–1,97). ´ N: La TB constituye un marcador de CONCLUSIO carcinoma broncopulmonar y de varios tipos de ca´ncer extrapulmonar ocultos. La TB implica adema´s un mayor riesgo a largo plazo de padecer ca´ncer, tal vez en relacion ´ con la inflamacion ´ cronica ´ y los factores de riesgo compartidos como la inmunodepresion ´ y el tabaquismo.