cancer risk in patients with pyogenic liver abscess: a nationwide cohort study

Cancer risk in patients with pyogenic liver abscess:a nationwide cohort studyW.-Y. Kao*,†,‡, C.-Y. Hwang§,¶, Y.-T. Chang§,¶, C.-W. Su*,†,**, M.-C. Hou*,†, H.-C. Lin*,†, F.-Y. Lee*,†, S.-D. Lee†† &J.-C. Wu**,‡‡

*Division of Gastroenterology,Department of Medicine, TaipeiVeterans General Hospital, Taipei,Taiwan.†Faculty of Medicine, School ofMedicine, National Yang-MingUniversity, Taipei, Taiwan.‡Division of Gastroenterology,Department of Medicine, Taoyuanbranch, Taipei Veterans GeneralHospital, Taipei, Taiwan.§Department of Dermatology, TaipeiVeterans General Hospital, Taipei,Taiwan.¶Department of Dermatology,National Yang-Ming University, Taipei,Taiwan.**Institute of Clinical Medicine,School of Medicine, National Yang-Ming University, Taipei, Taiwan.††Cheng Hsin General Hospital, Taipei,Taiwan.‡‡Department of Medical Researchand Education, Taipei VeteransGeneral Hospital, Taipei, Taiwan.

Correspondence to:Dr C.-W. Su, Division ofGastroenterology, Department ofMedicine, Taipei Veterans GeneralHospital, 201 Shih-Pai Road, Sec. 2,Taipei 112, Taiwan.E-mail: [email protected]

Drs WY Kao and CY Hwang contributedequally to this work.

Publication dataSubmitted 25 February 2012First decision 4 April 2012Resubmitted 14 June 2012Accepted 20 June 2012

SUMMARY

BackgroundThere has been no large-scale population-based study on the relationshipbetween pyogenic liver abscesses (PLA) and subsequent cancer risk.

AimThis study aimed to estimate all cancer risk following a diagnosis of PLA.

MethodsBased on Taiwan’s National Health Insurance Research Database, 1257patients with PLA without prior cancers in the period 1996–2008 wereidentified and followed-up. The standard incidence ratio (SIR) of each can-cer was calculated as the number of observed cancer cases arising amongthe PLA patients divided by the expected case number of cancer casesaccording to the national cancer rates.

ResultsOf the 1257 PLA patients identified, 598 (47.6%) had diabetes mellitus.After a median (±s.d.) follow-up of 3.33 ± 3.45 years, 186 were diagnosedwith cancers, including 56 liver cancer, 22 biliary tract cancer and 40 colo-rectal cancer patients. Patients with PLA had a higher risk of all cancers(SIR, 3.83; 95% CI, 3.30–4.42), liver cancer (SIR, 7.87; 95% CI, 5.94–10.21),biliary tract cancer (SIR, 34.58; 95% CI, 21.67–52.36) and colorectal cancer(SIR, 5.27; 95% CI, 3.76–7.18). The highest SIRs of all cancers, liver cancer,biliary tract cancer and colorectal cancer occurred within 90 days of follow-up (360.82; 95% CI, 278.46–459.91, 257.28; 95% CI, 186.17–346.56,1153.38; 95% CI 694.08–1801.24, and 52.63; 95% CI 25.2–96.8 respectively).

ConclusionsPyogenic liver abscesses may herald the onset of cancer, especially hepato-biliary and colon cancer. Further surveys should be conducted for thedetection of occult cancers in such patients.

Aliment Pharmacol Ther

ª 2012 Blackwell Publishing Ltd 1

doi:10.1111/j.1365-2036.2012.05212.x

Alimentary Pharmacology and Therapeutics

INTRODUCTIONPyogenic liver abscess (PLA) is a rare, but life-threaten-ing disease that has an increasing global incidence rate.1

Even though its reported annual incidences in the Uni-ted States (3.6/100 000 population),2 Canada (2.3/100 000) 3 and Demark (1.1/100 000)4 are relatively low,incidence in Taiwan is much higher and has increasedsteadily from 11.2/100 000 in 1996 to 17.6/100 000 in2004.1 It is relatively common in diabetes mellitus (DM)patients5, 6 and Klebsiella pneumonia is the most com-mon pathogen.7, 8

Furthermore, PLA has been reported as the initialmanifestation of silent colorectal cancers (CRCs) andadvanced colonic polyps.9–12 Colonic mucosal defectsdue to CRCs or large adenomas may be a route for bac-terial invasion into the portal system, with subsequenthaematogenous spread to the liver, resulting in abscessformation. However, only one large-scale population-based study in Taiwan has shown cryptogenic PLA as asign of CRC, especially among female diabetic patients.9

Primary liver cancer presenting as PLA has beenreported,13 but the relationship between PLA and thesubsequent risk of hepato-biliary cancer has never beenassessed in large, population-based studies. This studyaimed to investigate if PLA raises the risk of developingCRC, hepato-biliary cancer and other cancers in thegeneral population of Taiwan.

METHODS

Data sourceThe Taiwan National Health Insurance Research Database(NHIRD) is a claims database maintained by the Depart-ment of Health and the National Health Research Insti-tutes of Taiwan. This database provides scrambled patientidentification number, patient birth date, gender and diag-nostic codes in the format of the International Classifica-tion of Diseases, 9th Revision, Clinical Modification(ICD-9-CM), medications and dates of visits to medicalinstitutes. By the end of 2008, it covered 22.9 million ofTaiwan’s 23.0 million people.14 For this study, 1 000 000subjects(about 5% of Taiwan’s population), were randomlyselected from the Taiwan NHIRD. All the enrollees werefollowed from 1996 to 2008. The accuracy of the diagnosesof major diseases in the NHIRD, such as DM andstroke,15, 16 has been validated, and there have been manystudies based on diagnostic coding from the NHIRD,14

including pyogenic liver abscess (ICD-9-CM: 572.0) stud-ies.1, 9, 17–19 As the dataset used in this study consisted ofde-identified secondary data released to the public for

research purposes, this study was exempted from institu-tional review board approval.

The diagnosis of cancer was defined according to theRegistry for Catastrophic Illness Patients, which is a sub-part of the National Health Insurance databases. Thosediagnosed with cancer can apply for a catastrophic ill-ness certification in Taiwan, which grants exemptionfrom co-payment as required under the National HealthInsurance program. All the cancers discussed in thisstudy are listed in the catastrophic illness category. Acatastrophic illness certification for cancer requires cyto-logical or histological evidence.

Patient selectionIn this study, PLA was designated when a patient hadbeen diagnosed with pyogenic liver abscess (ICD-9-CM:572.0) more than two times. Patients with amoebic liverabscess (ICD-9-CM: 006.3) were excluded, as well asthose already diagnosed with cancers prior to enrolment.All the study subjects were followed up until the diagno-sis of first cancer, death, loss to follow-up in the data-base, or end of 2008. Subjects followed up for less than90 days were excluded.

Several cancer- and hepato-biliary-related risk factorswere also identified. Co-morbidity was defined as a diag-nosis for a particular disease more than two times beforethe end of follow-up. The risk factors and ICD-9-CMcodes used were as follows: hepatitis B (070.2, 070.3 andV02.61), hepatitis C (070.41, 070.44, 070.51, 070.54 andV02.62), alcoholic liver disease (571.0–571.3), cirrhosis(571.5 and 571.6), cholangitis (575.8 and 576.1), chole-cystitis (575.0, 575.11 and 575.12), cholelithiasis (574),choledocholithiasis (574.5), hypertension (401), chronickidney disease (580–585) and hyper-lipidaemia (272).

Cancer risk analysisCases of malignancies were gathered from the cata-strophic illness database using the ICD-9-CM code of140–208.91. Metastatic cancers (ICD-9-CM 196-199) andmalignant neoplasm of ill-defined sites (ICD-9-CM 195)were excluded because the goal of our study was to eval-uate the risk of primary cancers. The standardised inci-dence ratio (SIR) of each cancer was calculated afterstratified analyses according to gender, age at diagnosisand follow-up duration.

Statistical analysisThe SIR was used to examine the cancer risk of patientswith PLA. The SIR was calculated as the number ofobserved cancer cases arising among the PLA patients

2 Aliment Pharmacol Ther

ª 2012 Blackwell Publishing Ltd

W.-Y. Kao et al.

divided by the expected case number of cancer casesaccording to the national cancer rates. The 95% CI wascalculated using Byar’s approximation, whereas theexpected cancer rates were obtained from the TaiwanCancer Registry. All analyses used the Microsoft OfficeExcel 2003 (Microsoft Corporation, Redmond, Washing-ton DC, USA) and SPSS statistics analysis package (SPSSfor Windows, version 17.0; Chicago, IL, USA).

RESULTS

Demographic characteristics of patients with PLAThe mean (±s.d.) age of all PLA patients was59.58 ± 15.85 years (Table 1). On the basis of their agedistribution, DM patients (60.85 ± 13.44 years) weresignificantly older than non-DM patients (58.42 ±17.70 years) (P = 0.007). (Figure 1 and Table 1) The ratesof cirrhosis (9.36% vs. 6.37%, P = 0.048) and chronic kid-ney disease (14.88% vs. 7.44%, P < 0.001) were higher inthe DM group than in the non-DM group. Moreover, DMpatients had a trend of higher incidences of cholangitis,but lower proportions of male patients and hepatitis Bvirus infection than non-DM patients.

Cancer risk in PLA patientsThe median (±s.d.) time of follow-up was 3.33 ±3.45 years in this cohort. During the study period, 186cancer cases were diagnosed, including 56 cases of livercancer, 40 colorectal cancer, 22 biliary cancer, 9 lungcancer, 9 gastric cancer, 8 renal cancer, 6 prostate cancer,6 pancreatic cancer, 5 breast cancer, 5 haematological

malignancies, 4 bladder cancer, 3 tongue cancer, 3 smallintestinal cancer, 2 hypopharyngeal cancer, 2 laryngealcancer, 2 nonmelanoma skin cancer, 1 oesophageal can-cer, 1 oropharyngeal cancer, 1 oral cancer and 1 cervicalcancer.

On the basis of the SIRs of cancers in PLA patients,the overall cancer risk was elevated compared with theexpected case number of cancer by the national cancerrates, with a SIR of 3.83 (95% CI, 3.3–4.42) (Table 2).When stratified by gender, the risk of cancer was higherin female patients (SIR, 4.14; 95% CI, 3.12–5.37) than inmale patients (SIR, 3.71; 95% CI, 3.10–4.40). Stratifiedby age, cancer risk was higher in patients aged� 60 years (SIR, 6.59; 95% CI, 5.18–8.27) than in thoseaged >60 years (SIR, 3.52; 95% CI, 2.89–4.23). Moreover,PLA patients with cirrhosis had higher SIRs than thosewithout cirrhosis [11.63 (95% CI, 8.10–16.17) and 3.31(95% CI, 2.81–3.89)] respectively.

The highest SIR was found within 90 days of follow-up [360.82 (95% CI, 278.46–459.91)]. Although the riskof cancer decreased gradually with prolonged follow-up,it remained elevated 5 years after the diagnosis of PLA,with a SIR of 1.52 (95% CI, 1.09–2.05).

Liver cancer risk in PLA patientsDuring the study period, 56 liver cancer cases were iden-tified. The risk of liver cancer was elevated after thediagnosis of PLA, with an SIR of 7.87 (95% CI, 5.94–10.21) (Table 3). Male PLA patients had a higher SIRthan female patients (8.18 vs. 6.77). Stratified by age, therisk of liver cancer was higher in patients aged

Table 1 | Demographic data of the liver abscess patients

All DM Non-DM P value*

N (%) 1257 (100%) 598 (47.57%) 659 (52.43%)Male (%) 827 (65.79%) 379 (45.83%) 448 (54.17%) 0.086Age (mean, s.d.) 59.58, 15.85 60.85, 13.44 58.42, 17.70 0.007Follow-up (years; median, s.d.) 3.33, 3.45 3.65, 3.39 3.19, 3.50 0.158Hepatitis B 13 (1.03%) 3 (0.50%) 10 (1.52%) 0.075Hepatitis C 31 (2.47%) 15 (2.51%) 16 (2.43%) 0.927Alcoholic liver disease 46 (3.66%) 25 (4.2%) 21 (3.19%) 0.349Cirrhosis 98 (7.80%) 56 (9.36%) 42 (6.37%) 0.048Cholangitis 87 (6.92%) 33 (5.52%) 54 (8.19%) 0.062Cholecystitis 31 (2.47%) 14 (2.34%) 17 (2.58%) 0.785Cholelithiasis 35 (2.78%) 18 (3.01%) 17 (2.58%) 0.643Choledocholithiasis 37 (2.94%) 17 (2.84%) 20 (3.03%) 0.841Chronic kidney disease 138 (10.98%) 89 (14.88%) 49 (7.44%) <0.001

DM, diabetes mellitus; s.d., standard deviation.

The bold values indicate statistical significance.

* The chi-squared or t-test was used to calculate the P values between the DM and non-DM group where applicable.

Aliment Pharmacol Ther 3


Pyogenic liver abscess and cancer

� 60 years (SIR, 11.86; 95% CI, 7.34–18.12) than inthose aged >60 years (SIR, 7.63; 95% CI, 5.32–10.62).Moreover, the PLA patients with cirrhosis had a higherSIR than patients without cirrhosis (59.77 vs. 4.21), andthe PLA patients with viral hepatitis (HBV or HCV) hadhigher SIRs than those with nonviral hepatitis (34.78 vs.6.97). Similarly, although the risk of cancer decreasedgradually with prolonged follow-up, it remained elevated1 year after the diagnosis of PLA.

Biliary tract cancer risk in PLA patientsDuring the study period, 22 biliary cancer cases wereidentified. The risk of biliary cancer was elevated, withan SIR of 34.58 (95% CI: 21.67–52.36) (Table 4). FemalePLA patients had a higher SIR than male patients (59.57vs. 21.54). Stratified by age, the risk of biliary cancer washigher in patients aged � 60 years (SIR, 75.86; 95% CI,27.7–165.12) than in those aged >60 years (SIR, 34.52;95% CI, 19.72–56.05). Similarly, although the risk of can-cer decreased gradually with prolonged follow-up, itremained elevated 1 year after the diagnosis of PLA.

Colorectal cancer risk in PLA patientsBased on the SIRs, the risk of CRC was elevated in PLApatients (SIR, 5.27; 95% CI, 3.76–7.18) regardless oflength of follow-up (Table 5). Stratified by gender, malePLA patients had a higher SIR than female patients [5.44(95% CI: 3.64–7.81) and 4.89 (95% CI: 2.44–8.75) respec-tively]. Cancer risk was also higher in patients aged� 60 years (SIR, 13.6; 95% CI, 7.92–21.78) than in thosewith age >60 years (SIR, 4.32; 95% CI, 2.73–6.48).

DISCUSSIONTo date, this is the first nationwide population-basedstudy that investigated the risk of cancer, especially

hepato-biliary cancer and CRC, following a diagnosis ofPLA. On follow-up, patients with PLA have significantlyhigher risks of developing overall cancers, liver cancer,biliary tract cancer and CRC compared with the generalpopulation. When stratified by gender, age, follow-upduration and cirrhosis status, PLA patients still have sig-nificantly higher risks of developing cancers during thefollow-up period. The risks are even higher in PLApatients within 90 days of follow-up in terms of all can-cer, liver cancer, biliary tract cancer and CRC. YoungerPLA patients (age � 60 years) also have higher risksthan older patients.

PLA usually originates from hepato-biliary tract infec-tion, including cholangitis and cholecystitis or from anadjacent septic focus like pyelophlebitis. Less commonly,bacteraemia arises from intra-abdominal diseases, includ-ing diverticulitis, appendicitis, perforated or penetratingpeptic ulcer, inflammatory bowel disease or peritonitis.On rare instances, it may come from bacterial endocardi-tis or penetration of a foreign body through the colonicwall.20, 21 Consequently, anatomical or functional defectsof bile flow, bacteraemia or persistent chronic inflamma-tion may predispose the occurrence of PLA.

The mechanism of higher cancer risk in PLA patientshas not been fully elucidated until now. Nevertheless, thehighest SIR occurred within 90 days after the diagnosisof PLA in our cohort. The risk of cancer decreased grad-ually with prolonged follow-up, but it remained elevatedeven 5 years after the diagnosis of PLA. The differentialearly- and long-term cancer risk results represent twohypotheses, PLA as the initial manifestation of occultcancers, or long-term cancer development followingPLA.

Multiple and complex factors may be involved in thetumorigenesis of PLA. First, chronic inflammatory

30All

Non-DM

Per

cent

age

(%)

DM25

20

15

10

5

00–9 10–19 20–29 30–39 40–49 50–59 60–69 70–79 80–89 90+

Age group (years)

Figure 1 | Age distribution of pyogenic liver abscess patients.



W.-Y. Kao et al.

Table2|Stan

dardised

incide

nceratio

(SIR)of

allcancersam

ongtheliver

abscesspa

tientsstratified

byagean

dfollow-upyears

All

Male

Female

Obs

Exp

SIR(95%

CI)

Obs

Exp

SIR(95%

CI)

Obs

Exp

SIR(95%

CI)

Age �

60years

7411.23

6.59

(5.18

–8.27)

557.80

7.05(5.31–9.18)

193.43

5.54

(3.33–

8.65

)>60

years

112

31.86

3.52

(2.89–

4.23)

7523

.183.24

(2.55–

4.06)

378.75

4.23(2.98–

5.83

)Follow-up

<90

days

650.18

360.82(278

.46–4

59.91)

43

0.15

287.3(207.9–

387.01)

220.04

615.98

(385

.89–

932.64

)90

days

–1year

310.95

32.79(22.27

–46.54

)23

0.66

34.83(22.07–

52.26)

80.28

28.84(12.42–

56.83)

1–3years

335.63

5.86

(4.03–

8.23

)21

4.09

5.14

(3.18

–7.85)

121.54

7.80

(4.03–13.63)

3–5years

157.14

2.10

(1.17

–3.46)

114.72

2.33

(1.16

–4.17

)4

2.43

1.65

(0.44–4

.22)

>5years

42

27.65

1.52

(1.09–

2.05)

3220

.02

1.60

(1.09–

2.26

)10

7.62

1.31

(0.63–2.41)

Livercirrho

sis

Cirrhosis

353.01

11.63(8.10

–16.17)

302.22

13.49(9.10

–19.26

)5

0.75

6.70

(2.16

–15.63

)Non

cirrho

sis

151

45.56

3.31

(2.81–3.89

)100

32.85

3.04(2.48–

3.70

)51

12.79

3.99

(2.97–

5.24

)DM Diabe

tic88

23.99

3.67

(2.94–4

.52)

6116.30

3.74

(2.86–

4.81)

277.62

3.54

(2.34–5

.16)

Non

diabetic

9821.79

4.5

(3.65–

5.48)

6915.89

4.34(3.38–

5.49)

295.95

4.87(3.26–7.00)

All

186

48.57

3.83

(3.3–4

.42)

130

35.05

3.71

(3.10

–4.40)

5613.54

4.14

(3.12

–5.37)

DM,d

iabe

tesmellitus;E

xp,e

xpectedcase

numbe

r;Obs,o

bservedcase

numbe

r;SIR,

standardised

incide

nceratio

.

Expe

cted

cancer

caseswerebasedon

estim

ates

ofgene

ralp

opulationin

Taiwan

(2007),a

fter

adjustmen

tsforageandgend

er.




Table3|Stan

dardised

incide

nceratio(SIR)of

liver

cancer

amon

gtheliver

abscesspa

tientsstratifi

edby

agean

dfollow-upyears

All

Male

Female

Obs

Exp

SIR(95%

CI)

Obs

Exp

SIR(95%

CI)

Obs

Exp

SIR(95%

CI)

Age �

60years

211.7

711.86(7.34–18.12)

201.56

12.82(7.83–19.80)

10.18

5.52

(0.07–

30.74)

>60

years

354.58

7.63

(5.32–

10.62)

253.40

7.35

(4.76–

10.86)

101.20

8.36

(4.00–15.38

)Follow-up

�1year

43

0.17

257.28

(186

.17–3

46.56

)34

0.12

272.28

(188

.53–

380.5)

90.04

218.89

(99.88

–415.55)

>1year

136.42

2.02(1.08–3

.46)

114.97

2.21

(1.10–3

.96)

21.4

51.38

(0.16

–4.99)

Livercirrho

sis

Cirrhosis

280.47

59.77(39.71–8

6.39

)25

0.37

68.46(44.29–

101.06)

30.09

32.75(6.58–9

5.68

)Non

cirrho

sis

286.65

4.21(2.80–6

.09)

203

3.90

(2.38–6

.02)

81.53

5.22

(2.25–

10.29)

Vira

lhep

atitis

HBV

orHCV

80.23

34.78(14.98–6

8.54

)6

0.2

30.00(10.95–

65.30)

20.03

58.82(6.61–212.38

)Non

-HBV

/HCV

48

6.89

6.97

(5.14–9

.24)

395.31

7.35

(5.23–10.05)

91.59

5.66

(2.58–

10.75)

DM Diabe

tic26

3.59

7.24

(4.73–10.62)

212.65

7.93

(4.90–12.12)

50.92

5.45(1.76–

12.72)

Non

diabetic

303.27

9.17

(6.18–13.09)

242.58

9.29

(5.95–13.82)

60.71

8.44(3.08–

18.37)

All

567.12

7.87

(5.94–10.21)

45

5.50

8.18

(5.97–10.95)

111.62

6.77

(3.38–12.12)

DM,d

iabe

tesmellitus;H

BV,h

epatitisBvirus;HCV,h

epatitisCvirusExp,

expe

cted

case

numbe

r;Obs,o

bservedcase

numbe

r;SIR,

standardised

incide

nceratio

.

Expe

cted

cancer

caseswerebasedon

estim

ates

ofthegene

ralp

opulationin

Taiwan

(2007),a

fter

adjustmen

tsforageandgend

er.

Thebo

ldvalues

indicate

statistic

alsign

ificance.



W.-Y. Kao et al.

Table4|Stan

dardised

incide

nceratio

(SIR)of

biliary

tractcancer

amon

gtheliver

abscesspa

tientsstratifi

edby

agean

dfollow-upyears

All

Male

Female

Obs

Exp

SIR(95%

CI)

Obs

Exp

SIR(95%

CI)

Obs

Exp

SIR(95%

CI)

Age �

60years

60.08

75.86(27.7–165.12)

20.06

36.17

(4.06–

130.58)

40.02

168.42(45.31–4

31.19)

>60

years

160.46

34.52(19.72

–56.05)

70.30

23.11(9.26–

47.63

)9

0.16

55.88(25.50

–106.08)

Follow-up

�1year

190.02

1153

.38(694

.08–

1801.24

)7

0.01

653.54

(261.83–1346.61)

120.01

2086

.73(1077.00–3

645.35

)>1year

30.55

5.48(1.10–16.02)

20.36

5.62

(0.63–

20.27)

10.19

5.24

(0.07–

29.15

)Livercirrho

sis

Cirrhosis

10.03

26.43(0.35–

147.03)

00.02

–1

0.01

78.92(1.03–

439

.08)

Non

cirrho

sis

210.60

35.07(21.7–

53.62)

90.39

22.89(10.44–4

3.45)

120.21

58.38(30.13

–101.99

)Vira

lhep

atitis

HBV

orHCV

00.01

00

0.01

00

0.003

0Non

-HBV

/HCV

220.62

35.49(22.23

–53.74

)9

0.41

22.21(10.14

–42.17)

130.21

60.56(32.21–103.57

)DM D

iabe

tic6

0.31

19.38(7.08–4

2.19)

10.19

5.3(0.07–

29.47)

50.12

41.34(13.32

–96.48)

Non

diabetic

160.28

56.65(32.36

–92.00)

80.18

43.46(18.71–8

5.64

)8

0.10

82.03(35.32

–161.65)

All

220.64

34.58(21.67

–52.36

)9

0.42

21.54(9.83–

40.89)

130.22

59.57(31.69

–101.87

)

DM,d

iabe

tesmellitus;E

xp,e

xpectedcase

numbe

r;HBV

,hep

atitisBvirus;HCV,h

epatitisCvirus;Obs,o

bservedcase

numbe

r;SIR,

standardised

incide

nceratio

.

Expe

cted

cancer

caseswerebasedon

estim

ates

ofthegene

ralp

opulationin

Taiwan

(2007),a

fter

adjustmen

tsforageandgend

er.

Thebo

ldvalues

indicate

statistic

alsign

ificance.




conditions associated with neoplasms have been observedin several cancers,22 which mainly arise from sites ofinfection, such as liver flukes with cholangiocarcinoma,23

Helicobacter pylori with gastric cancer and mucosa-asso-ciated lymphoid tissue lymphoma24 and hepatitis B or Cvirus with hepatocellular carcinoma (HCC).25 In con-trast, nonsteroidal anti-inflammatory drugs have beenproven to reduce the incidence of colon cancer inpatients with familial adenomatous polyposis, suggestingthat inflammation is a critical component of tumour ini-tiation and progression.26 Consequently, PLA mayincrease the incidence of cancers, especially hepato-bili-ary cancers, through persistent chronic inflammatory sta-tus by bile stasis or chronic irritation of the localmicroenvironment. They may also promote the emer-gence of remote cancer through cytokines, chemokines,growth factors and reactive oxygen species by immuneand inflammatory cells.22, 27

Second, previous studies have shown that DM patientsmay increase the risk of PLA because of impaired poly-morphonuclear neutrophil and phagocytosis func-tions,5, 6 which are considered important risk factors forK. pneumonia liver abscess.20, 28 In Taiwan, Foo et al.,as well as the current study, both reveal that the propor-tion of DM (48.3% and 49.6% respectively) in PLApatients is significantly higher than that of the generalpopulation (8.2–11.4%).6, 29 Similarly, a large nationwidestudy in Denmark also shows that DM patients have a3.6-fold increase in PLA risk compared to population

control subjects.5 For DM patients, hyper-insulinaemiamay facilitate the production of insulin-like growth fac-tor-1 (IGF-1). Furthermore, IGF-1 stimulates cell prolif-eration and inhibits apoptosis, which in turn increasesthe risk of tumorigenesis.30 Epidemiological studies haverevealed an elevated risk of several types of cancer(including pancreas, liver, breast, colorectal, urinary tractand female reproductive organ cancers) in DMpatients.31 Several meta-analysis studies further demon-strate that DM patients have a nearly twofold increasedrisk of cancers in different organs than the general popu-lation.31–33 Consequently, DM may play an importantand synergistic role in the tumorigenesis of PLA.

Third, the incidences of PLA are also higher in cir-rhotic patients who are immunocompromised and haveincreased intestinal permeability to bacteria with ascitesformation. A Danish nationwide study shows that therisk of liver abscesses is increased 15.4-fold in cirrhoticpatients compared to the general population.34 The asso-ciation between cirrhosis, regardless of liver disease aeti-ology, and increased risk of HCC is well documented.35

Previous population-based studies also show that theoverall risk for non-HCC cancer in patients with cirrho-sis is 2–3 times higher than that of the general popula-tion,36, 37 suggesting that cirrhosis may also contributeto the emergence of cancers, especially hepato-biliarycancer, for PLA patients.

Fourth, PLA are often polymicrobial, includingaerobic, anaerobic or fungal infections. The most

Table 5 | Standardised incidence ratio (SIR) of colorectal cancer among the liver abscess patients stratified by ageand follow-up years

All Male Female

Obs Exp SIR (95% CI) Obs Exp SIR (95% CI) Obs Exp SIR (95% CI)

Age� 60 years 17 1.25 13.6 (7.92–21.78) 12 0.93 12.9 (6.66–22.54) 5 0.32 15.63 (5.04–36.46)>60 years 23 5.33 4.32 (2.73–6.48) 17 3.71 4.58 (2.67–7.34) 6 1.62 3.7 (1.35–8.06)

Follow-up� 1 year 10 0.19 52.63 (25.2–96.8) 9 0.13 69.23 (31.59–131.43) 1 0.06 16.67 (0.22–92.73)>1 year 30 6.65 4.51 (3.04–6.44) 20 4.65 4.3 (2.63–6.64) 10 2 5 (2.39–9.2)

Liver cirrhosisCirrhosis 1 0.47 2.14 (0.03–11.89) 0 0.34 0 1 0.13 7.87 (0.10–43.81)Noncirrhosis 39 7.12 5.48 (3.89–7.49) 29 5.00 5.80 (3.88–8.33) 10 2.13 4.70 (2.25–8.65)

DMDiabetic 20 3.74 5.35 (3.27–8.26) 13 2.47 5.26 (2.8–9) 7 1.26 5.56 (2.23–11.45)Nondiabetic 20 3.4 5.88 (3.59–9.09) 16 2.41 6.64 (3.79–10.78) 4 0.99 4.04 (1.09–10.34)

All 40 7.59 5.27 (3.76–7.18) 29 5.33 5.44 (3.64–7.81) 11 2.25 4.89 (2.44–8.75)

DM, diabetes mellitus; Exp, expected case number; Obs, observed case number; SIR, standardised incidence ratio.

Expected cancer cases were based on estimates of general population in Taiwan (2007), after adjustments for age and gender.

The bold values indicate statistical significance.



W.-Y. Kao et al.

frequently isolated organisms are Escherichia coli andKlebsiella, Proteus, Pseudomonas and Streptococcus spe-cies.20 The association between Streptococcus bovis bac-teraemia and CRC has been well described.38 It is alsoassociated with extra-colonic malignancies, particularlyin cirrhotic patients.39 As regards K. pneumonia, it isthe most common agent responsible for liver abscessin Taiwan.6, 8 Some reports describe K. pneumonialiver abscess and the subsequent emergence ofCRC.40, 41 S. bovis and K. pneumonia are both colonis-ers of the human gastrointestinal tract and bacteraemiamay disrupt the colonic mucosa, which may promotetumorigenesis,42 or mucosal disruption and underlyingblood vessel exposure caused by CRC predisposing tomicrobial seeding of the portal venous system of theliver, resulting in abscess formation. Taken together, itcan be hypothesised that the tumorigenesis of PLA orthe association between PLA and cancers may be dueto chronic inflammation, bacteraemia, underlying DMor cirrhosis.32, 36–39, 43, 44 This implies that we mayneed to look harder to find a hidden or occult cancerin these patients.

In addition, one of the possible factors in the patho-genesis of hepato-biliary tract cancer presenting as PLAis spontaneous tumour necrosis, especially for large oneswhen they outgrow their blood supply and biliaryobstruction caused by tumour thrombi, superimposedwith bacterial infection, resulting in abscess formation.18

However, PLA and hepatic tumour necrosis are extre-mely difficult to distinguish by clinical presentationsalone. Verification by pathology is essential for thedifferential diagnoses of both diseases, especially fordelayed resolution of abscesses and in endemic areassuch as Taiwan.45

Ageing is associated with a number of events at themolecular, cellular and physiologic levels that influencecarcinogenesis and subsequent cancer growth. Carcino-genesis is a time-consuming process, and cancer is more

likely to occur in persons of advanced age, depending oncumulative exposure to environmental carcinogens.46

However, in our cohort, cancer risk was higher in theyounger patients with PLA than in the older patients.The higher relative risk in the young PLA patients maybe due to the extremely lower cancer risk in the youngsubjects of the general population. In contrast, a lowerrelative risk may translate to a higher absolute cancerrisk in the elderly.

The current study has several limitations. First, micro-biological data are deficient. The interaction between K.pneumoniae or S. bovis bacteraemia and specific types ofcancer development, especially CRC, has not been inves-tigated. Second, as PLA may be insidious, with nonspe-cific presentations at onset, the diagnosis may be difficultand underestimated and some hepato-biliary cancersmay be misdiagnosed initially as PLA.13, 47, 48

Furthermore, artificial registry bias when establishing thedataset may not entirely be excluded by screening withICD-9-CM codes, and incomplete records of dischargeICD codes may limit the investigation of someco-morbidities.

Despite such limitations, the strengths of this studyare its large, nationwide population-based sample size,the availability of data on complete histories of medicalservice utilisation for the sampled patients, and a broadrepresentation of the database. The Taiwan NHI data-base includes complete out-patient visits, hospital admis-sions, prescriptions, disease and vital status for 99% ofthe 23 million populations in Taiwan.49

In conclusion, pyogenic liver abscess may herald theonset of cancer, especially for hepato-biliary and coloncancer. Patients who are younger in age, with cirrhosis,and in the early follow-up period following PLAdiagnosis have a further increased risk of cancer.

ACKNOWLEDGEMENTDeclaration of personal and funding interests: None.

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cancer risk in patients with pyogenic liver abscess: a nationwide cohort study

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