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Splenectomy and increased subsequent cancer risk: a nationwide population-based cohort study
The American Journal of Surgery (2015) 210, 243-251
Clinical Science
Splenectomy and increased subsequent cancer risk: a nationwide population-based cohort study Li-Min Sun, M.D.a, Hsuan-Ju Chen, M.Sc.b,c, Long-Bin Jeng, M.D.d,e, Tsai-Chung Li, Ph.D.f,g, Shih-Chi Wu, M.D.e,h, Chia-Hung Kao, M.D.e,i,* a
Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; bManagement Office for Health Data, China Medical University Hospital, Taichung, Taiwan; cCollege of Medicine, China Medical University, Taichung, Taiwan; dDepartment of Surgery, Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan; e Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine and f Graduate Institute of Biostatistics, College of Management, China Medical University, Taichung, Taiwan; gDepartment of Healthcare Administration, College of Health Science, Asia University, Taichung, Taiwan; hTrauma and Emergency Center and iDepartment of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan KEYWORDS: Splenectomy; Malignancy; Population-based cohort study; The National Health Insurance system; Cox proportional hazard regression analysis
Abstract BACKGROUND: Splenectomy has been suggested to have an impact on immunological function, and subsequent development of cancer has been recognized as a possible adverse effect of splenectomy. This study evaluated the possible association between splenectomy and malignancy in Taiwan. METHODS: A cohort study consisted of including 2,603 patients with nontraumatic and 2,295 patients with traumatic splenectomy, and then randomly frequency matched with 4 participants without splenectomy. The Cox proportional hazard regression analysis was conducted to estimate the influence of splenectomy on cancer risk. RESULTS: Both nontraumatic and traumatic splenectomy had a significantly higher risk for overall cancer development (adjusted hazard ratios are 2.64 and 1.29 for nontraumatic and traumatic reasons, respectively). After adjusting for age, sex, and comorbidities, patients with splenectomy were associated with significantly higher risks for developing certain gastrointestinal tract cancers, other head and neck cancers, and hematological malignancies, and the phenomenon is more prominent in nontraumatic splenectomy group. CONCLUSION: This nationwide population-based study found that people with splenectomy have higher risks of developing overall cancer, as well as certain site-specific cancers, especially for patients with nontraumatic reasons. Ó 2015 Elsevier Inc. All rights reserved.
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and Health, and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW104TDU-B-212-124-002, Taiwan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. The authors declare no conflicts of interest. * Corresponding author. Tel.: 1886-4-22052121; fax: 1886-4-22336174. E-mail address: [email protected] Manuscript received October 3, 2014; revised manuscript January 6, 2015 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.01.017
244 The spleen is the largest lymphatic organ in the human body and serves a crucial role in immune function. It combines the innate and adaptive immune system, and is considered to be the most vital organ for antibacterial and antifungal immune reactivity.1,2 Splenectomy can be performed both as an emergency procedure following abdominal trauma and electively when indicated for hematological disorders.3,4 In addition to infection, cancer is thought to be related to human immunity.5,6 Splenectomy has been studied for its effects on tumor cell growth with inconsistent results,7–10 and controversial animal studies have revealed the influence on the antitumor immune system after splenectomy in vivo.11,12 Few studies have explored the clinical human cancer risk after splenectomy; however, epidemiologic studies have observed increased risks among certain solid tumors and hematological malignancies.13–15 Malignant neoplasm has been the leading cause of death for the Taiwanese general population since 1982, and is becoming a crucial public health problem with aging populations and changes in lifestyles.16 The Taiwan government has focused on this concern and launched primary and secondary prevention programs for major cancers, such as high-risk factor avoidance and periodic cancer screening to reduce cancer incidence and mortality rates.16 Therefore, population-based investigations regarding cancerpreventive epidemiology continue to be conducted. Based on the limited available clinical reports highlighting the association between splenectomy and subsequent cancer risk, we hypothesized that people with a splenectomy in Taiwan may be at increased risk of cancer. Our results were generated from a retrospective cohort study for people with a splenectomy. The original database was derived from the National Health Insurance (NHI) system in Taiwan.
Methods Data source The NHI program was initiated in Taiwan in 1995 and currently covers approximately 99% of the 23 million population of Taiwan. In this study, we established a longitudinal cohort study from the Taiwan National Health Institute Research Database (NHIRD), with hospital admissions of the entire population insured in Taiwan between 1996 and 2011, which contains the healthcare claims of each patient. To protect privacy, the NHIRD scrambled data cryptographically on patient identities and institutions. Each person in Taiwan has a unique personal identification number, and all NHI datasets can be interlinked with the personal identification number of each person. For this study, disease diagnosis was based on disease records according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) in inpatients and catastrophic registry files. This study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
The American Journal of Surgery, Vol 210, No 2, August 2015
Study population Initially, we identified 10,964 patients with newly received splenectomy (ICD-9-CM code 41.5) from 2000 to 2006 from the inpatient registry file. We excluded patients with less than 20 years of age (n 5 1,067), diagnosis of cancer at baseline (n 5 1,280), and less than 1-year of follow-up (n 5 3,719) from the analysis. The remaining 4,898 patients with newly received splenectomies were included in the splenectomy cohort, which was divided into 2 groups based on trauma status. Four study subjects in the no splenectomy cohort for every patient with a splenectomy were randomly selected from insured people without a history of splenectomy or cancer, and frequency matched with age (per 5 years), sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, and index year. Overall, 4,898 patients were included as the splenectomy cohort and 19,592 patients as the no splenectomy cohort. The sociodemographic status included sex and age (20 to 44 and R45 years). Information on pre-existing comorbidities, including diabetes (ICD-9-CM code 250.xx), hypertension (ICD-9-CM code 401.xx to 405.xx), hyperlipidemia (ICD-9-CM code 272.xx), and coronary artery disease (ICD-9-CM 410.xx to 414.xx), were also recorded. The primary outcome was cancer occurrence (ICD-9CM code 140.xx to 208.xx), which was determined by linking records with the catastrophic illness registry of the NHIRD. All subjects were followed until patient withdrawal from the NHI program, cancer development, death, or the end of 2011. We attempted to minimize the impact of any effect of existing medical conditions on splenectomy by excluding cancer that occurred in subjects during the first year of follow-up. We also investigated the risk of individual cancer sites between the splenectomy cohort and the no splenectomy cohort. The cancer sites were separated into head and neck cancers (ICD-9-CM code 147.xx for nasopharynx cancer; ICD-9-CM code 140.xx to 146.xx and 148.xx to 149.xx for other head and neck cancers), esophagus cancer (ICD-9-CM code 150.xx), stomach cancer (ICD-9-CM code 151.xx), colorectal cancer (ICD-9CM code 153.xx and 154.xx), liver cancer (ICD-9-CM code 155.xx), lung cancer (ICD-9-CM code 162.xx), breast cancer (ICD-9-CM code 174.xx), gynecologic cancer (ICD-9-CM code 179.xx to 184.xx), prostate cancer (ICD-9-CM code 185.xx), bladder cancer (ICD-9-CM code 188.xx), non-Hodgkin’s lymphoma (ICD-9-CM code 200.xx and 202.xx), Hodgkin’s disease (ICD-9-CM code 201.xx), leukemia (ICD-9-CM code 204.xx to 208.xx), and other cancers.
Statistical analysis We compared the distribution of sociodemographic factors and pre-existing comorbidities between the cohorts with and without a splenectomy using the chi-square test
L.-M. Sun et al. Table 1
Splenectomy and cancer
245
Demographic factors and comorbidity of study participants according to splenectomy status Splenectomy
Variables Sex Female Male Age (years) 20–44 R45 Mean (SD) Comorbidity Diabetes Hypertension Hyperlipidemia CAD Follow-up period (years), mean (SD)
No splenectomy (n 5 19,592)
All (n 5 4,898)
Nontrauma (n 5 2,603)
Trauma (n 5 2,295)
N
n
n
n
%
%
%
%
P value* .99
7,440 12,152
37.97 62.03
1,860 3,038
37.97 62.03
1,198 1,405
46.02 43.98
662 1,633
28.85 71.15 .99
10,368 52.92 9,224 47.08 45.20 (16.78)
2,592 52.92 2,306 47.08 45.29 (16.66)
1,181 45.37 1,422 54.63 48.35 (16.38)
1,411 61.48 884 38.52 41.82 (16.28)
1,640 1,828 820 784 7.90 (2.52)
410 8.37 457 9.33 205 4.19 196 4.00 7.41 (2.72)
307 322 148 137
103 135 57 59
8.37 9.33 4.19 4.00
11.79 12.37 5.69 5.26
4.49 5.88 2.48 2.57
.75 .99 .99 .99 .99 ,.001
CAD 5 coronary artery disease; SD 5 standard deviation. *Comparison between the cohorts with and without splenectomy.
for category variables and the t test for continuous variables. For estimating the cumulative incidence of cancer risk in the splenectomy cohort and the no splenectomy cohort, we performed survival analysis using the Kaplan– Meier method, with significance based on the log-rank test. The Cox proportional hazards model was used to assess the risk of the study population developing cancer and to produce hazard ratios (HRs) and 95% confidence intervals (95% CIs). Statistical analyses and data management were performed with SAS 9.3 (SAS Institute, Inc, Cary, NC), and the cumulative incidence curves were determined using R computer software (R Foundation for Statistical Computing, Vienna, Austria). The significance levels were set at a 2 tailed P value of .05.
hypertension, hyperlipidemia, and coronary artery disease (Table 2). Among patients receiving splenectomy, patients without and with trauma exhibited a significantly increased risk of overall cancer compared with the no splenectomy cohort (HR 2.64, 95% CI 2.30 to 3.05 and HR 1.29, 95% CI 1.05 to 1.60, respectively). Sex-specific analysis showed that women exhibited a 2.16-fold higher risk of developing cancer (95% CI 1.76 to 2.65) and men exhibited a 1.99-fold (95% CI 1.70 to 2.34) higher risk of developing cancer than the no splenectomy cohort. After age stratification, we observed that both the age groups of 20 to 44 years and 45 years and older of splenectomy patients exhibited a
Results We established 4,898 splenectomy patients and 19,592 subjects without splenectomy, with the same average age (mean 5 45 years) and more men than women (62.03% vs 37.97%) (Table 1). The distributions of age, sex, and comorbidities were the same in both groups. The mean follow-up periods for the splenectomy and nonsplenectomy groups were 7.41 (62.72) and 7.90 (62.52) years, respectively. The cumulative subsequent cancer incidence curves showed that the curve for the splenectomy cohort was significantly higher than that for the no splenectomy cohort (P , .001 for the log-rank test; Fig. 1). Patients with splenectomy were 1.94 times more likely than the no splenectomy cohort to experience cancer (9.73 vs 5.03 per 1,000 person-years), with an adjusted HR of 2.06 (95% CI 1.81 to 2.33) after adjusting for age, sex, and history of diabetes,
Figure 1 Cumulative incidence curves of all cancers for splenectomy and control groups.
246
The American Journal of Surgery, Vol 210, No 2, August 2015
Table 2 Incidence density rates and HR for cancers according to splenectomy status stratified by demographic factors and comorbidity Splenectomy No splenectomy
All
Nontrauma
Trauma
Variables
IR
HR
IR
Overall Sex Women Men Age (years) 20–44 R45 Comorbidity No Yes
5.03
1.00
9.73
HR† (95% CI)
IR
HR† (95% CI)
IR
2.06 (1.81–2.33)***
14.08
2.64 (2.30–3.05)***
5.36
1.29 (1.05–1.60)*
4.89 5.12
1.00 1.00
9.79 9.69
2.16 (1.76–2.65)*** 1.99 (1.70–2.34)***
13.00 15.05
2.75 (2.21–3.42)*** 2.51 (2.08–3.02)***
4.55 5.69
1.08 (.71–1.64) 1.41 (1.11–1.81)**
1.42 9.40 status‡ 4.16 9.81
1.00 1.00
4.28 16.88
3.09 (2.34–4.06)*** 1.83 (1.59–2.11)***
6.89 21.18
4.82 (3.54–6.57)*** 2.33 (1.98–2.73)***
2.25 10.85
1.66 (1.09–2.54)* 1.16 (.91–1.48)
1.00 1.00
8.13 19.40
2.04 (1.76–2.37)*** 2.10 (1.66–2.65)***
12.34 21.13
2.80 (2.36–3.31)*** 2.29 (1.77–2.97)***
4.41 15.40
1.23 (.96–1.57) 1.66 (1.09–2.52)*
HR† (95% CI)
*P , .05, **P , .01, ***P , .001. CI 5 confidence interval; HR 5 hazard ratio; IR 5 incidence density rates, per 1,000 person-years. † Mutually adjusted for age, sex, and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression. ‡ Patients with any one of diabetes, hypertension, hyperlipidemia, and coronary artery disease were classified as having comorbidity.
significantly higher risk of cancer than the no splenectomy cohort. Regardless of subjects without or with comorbidities, the risk of cancer was higher in the splenectomy cohort than that in the nonsplenectomy cohort. We observed a significantly positive association between splenectomy and the risks of site-specific cancer, including other head and neck, esophagus, stomach, liver, nonHodgkin’s lymphoma, and leukemia (Table 3). Splenectomy patients without trauma were at significantly increased cancer risk of head and neck, other head and neck, esophagus, stomach, liver, breast, non-Hodgkin’s lymphoma, and leukemia. On the other hand, splenectomy patients with trauma were only at significantly increased cancer risk of esophagus, stomach, liver, and leukemia. We calculated the HR for specific cancer types according to splenectomy status stratified by follow-up years, and the results are shown in Table 4. For overall cancer, higher risks for developing cancer were observed in the follow-up periods of 1 to 3, 4 to 6, and 7 years or more. In addition, the risks for developing cancer were observed in the followup periods of 1 to 3, 4 to 6, and 7 years or more for splenectomy patients without trauma, as well as in the follow-up periods of 7 years or more for splenectomy patients with trauma. For head and neck cancer, a 3.99-fold risk of developing cancer was found in the 7 year or more follow-up period. For other head and neck cancer, a 3.83-fold risk of developing cancer was found in the 7 year or more follow-up period. For esophagus cancer, a 4.54-fold risk of developing cancer was found in the follow-up period of 4 to 6 years. For stomach cancer, the risks for developing cancer were observed in the followup periods of 1 to 3 years and 7 years or more. For liver cancer, higher risks were observed for developing cancer in the follow-up periods of 1 to 3, 4 to 6, and 7 years or more. For non-Hodgkin’s lymphoma, a 15.23-fold risk of
developing cancer was found in the follow-up period of 4 to 6 years. For leukemia, higher risks for developing cancer were observed in the follow-up periods of 1 to 3 years.
Comments This population-based cohort study revealed that Taiwanese with splenectomy had a significantly higher risk of subsequent overall cancer, as well as certain gastrointestinal tract cancers, other head and neck cancers, and hematological malignancies. The phenomenon was more obvious for patients with nontraumatic reasons for splenectomy. Further stratified analysis by follow-up years revealed various patterns among diverse cancers, which are likely caused by the coincidence effect of splenectomy and cancer. The age-adjusted incidence rate of cancer in Taiwan has increased steadily, and overall cancer incidence rates increased by 2% per year between 2008 and 2011, reaching 295.1 (invasive cancers only) and 320.7 new cases (carcinoma in situ and invasive cancers) per 100,000 persons in 2011.17 Despite enhanced detection, much of the increased incidence may be associated with aging populations and a westernized lifestyle.16 In contrast, trend analysis from surveillance epidemiology and end results data showed that the overall cancer incidence rates for all racial and ethnic groups combined in the United States decreased by .6% per year between 2006 and 2010.18 This obstacle continues to be a challenge for public health in Taiwan, and has aroused the attention of the government to enact policies regarding cancer prevention. Prevention is the most costeffective long-term control strategy for cancer, with an estimated one third of all cases considered avoidable.19 One of the research topics in this field is to explore the possible
L.-M. Sun et al. Table 3
Splenectomy and cancer
247
Incidence density rates and HR for specific cancer types according to splenectomy status Splenectomy
Site of cancers
No splenectomy
All
IR
HR
IR
HR† (95% CI)
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
.72 .08 .63 .50 .47 .55 3.86 .80 1.44 .29 .36 .30 .41 .00 .30 .94
1.56 .70 1.87 3.84 3.11 .76 5.56 1.28 1.34 .49 .88 1.61 3.93 – 5.98 1.31
Head and neck .47 Nasopharynx .12 Other head and neck .35 Esophagus .14 Stomach .16 Colorectal .79 Liver .74 Lung .67 Breast (only women) 1.13 Gynecologic (only women) .63 Prostate (only men) .44 Bladder .20 NHL .11 Hodgkin’s disease .01 Leukemia .05 Other .75
(.99–2.45) (.21–2.35) (1.15–3.04)* (2.04–7.21)*** (1.68–5.76)*** (.48–1.22) (4.34–7.12)*** (.85–1.93) (.81–2.21) (.18–1.38) (.41–1.86) (.81–3.21) (1.96–7.87)***
Nontrauma
Trauma
IR
IR
.99 .11 .88 .50 .61 .83 6.33 .88 1.97 .12 .42 .28 .72 .00 (2.40–14.86)*** .39 (.90–1.92) 1.38
HR† (95% CI) 2.28 .99 2.70 3.86 3.36 .99 8.01 1.21 1.79 .20 .75 1.26 6.43 – 6.90 1.72
HR† (95% CI)
(1.36–3.83)*** .44 .91 (.44–1.90) (.23–4.29) .06 .43 (.06–3.25) (1.54–4.73)*** .39 1.09 (.50–2.41) (1.76–8.45)*** .50 3.82 (1.74–8.38)*** (1.65–6.94)*** .33 2.73 (1.11–6.67)* (.58–1.70) .28 .45 (.18–1.10) (6.18–10.39)*** 1.38 2.29 (1.48–3.54)*** (.72–2.06) .72 1.37 (.77–2.44) (1.05–3.05)* .57 .55 (.17–1.75) (.03–1.42) .57 1.01 (.31–3.29) (.27–2.09) .31 1.05 (.38–2.94) (.49–3.25) .33 2.11 (.87–5.07) (3.11–13.30)*** .11 1.11 (.26–4.81) .11 – (2.49–19.10)*** .22 4.84 (1.45–16.16)* (1.12–2.65)* .50 .79 (.40–1.56)
ICD-9-CM: nasopharynx cancer 147.xx; other head and neck cancer 140.xx to 146.xx and 148.xx to 149.xx; esophagus cancer 150.xx; stomach cancer 151.xx; colorectal cancer 153.xx and 154.xx; liver cancer 155.xx; lung cancer 162.xx; breast cancer 174.xx; gynecologic cancer 179.xx to 184.xx; prostate cancer 185.xx; bladder cancer 188.xx; non-Hodgkin’s lymphoma 200.xx and 202.xx; Hodgkin’s disease 201.xx; leukemia 204.xx to 208.xx. *P , .05, **P , .01, ***P , .001. CI 5 confidence interval; HR 5 hazard ratio; IR 5 incidence density rates, per 1,000 person-years; NHL 5 non-Hodgkin’s lymphoma. † Adjusted for age, sex, and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression.
risk/protective factors of cancer. The NHI program in Taiwan is a suitable resource for providing valuable materials with which to approach populated-based studies. Our research team recently performed a cohort study by using the NHIRD and found that Taiwanese patients with diabetes are at an elevated risk of cancer (particularly colorectal and pancreatic cancers), and the use of thiazolidinediones might decrease the risk of liver cancer in diabetic patients.20 This information inspires us to conduct studies to discover other factors that may be related to cancer. Infection is a well-known complication of splenectomy,21–23 and immunocompromised patients are also vulnerable to certain types of cancer. Therefore, it is plausible to hypothesize that people with splenectomy may have a higher risk of developing cancer. Besides age, sex, and index year, our control subjects were frequency matched to cases with comorbidity as well. Diabetes, hypertension, and hyperlipidemia are suggested to be a risk factor for certain types of cancer.22,24–29 In addition, we also adjusted these comorbidities and other factors in the multivariate analysis to eliminate possible bias. Table 2 shows that splenectomized patients had a significantly higher adjusted HR of overall cancer compared with the no splenectomy participants, and Table 4 shows that the significantly higher risks in the splenectomy group were consistent across various follow-up years. This finding is consistent with a cohort study from American veterans, which showed that the cancer risk in splenectomy patients was significantly higher across
various follow-up years [relative risks (95% CIs) are 2.05 (1.82 to 2.32), 1.44 (1.28 to 1.62), and 1.35 (1.24 to 1.47) for 2 to 5, 5 to 10, and greater than 10 years latency, respectively].13 Table 2 also highlights the higher risks of overall cancer in the splenectomy cohort, regardless of sex, age, and comorbidity. When divided splenectomy patients by trauma and nontrauma reasons, we found that both groups had a significantly higher risk of overall cancer compared with nonsplenectomy cohort, but the same pattern regarding consistently higher risk across sex, age, and comorbidity only limited to nontraumatic reasons. For specific cancer site analysis, we separated nasopharyngeal carcinoma from head and neck cancer because nasopharyngeal carcinoma is relatively common in Chinese people.30 Splenectomy patients were found to have significantly higher risks in other head and neck, esophagus, stomach, liver, non-Hodgkin’s lymphoma, and leukemia cancers (Table 3). Kristinsson et al13 conducted a cohort study to evaluate long-term risks after splenectomy among 8,149 cancerfree American veterans and found significantly higher risks of being hospitalized for all cancer, as well as for esophagus, liver, pancreas, lung, prostate, non-Hodgkin’s lymphoma, and leukemia cancers among splenectomy patients. Their further sensitivity analyses for subset of patients with diagnoses of autoimmune disease or trauma did not change the overall results.13 Although both trauma and nontrauma reasons had higher risks for developing some kinds of cancer in our splenectomy patients, Table 3 indicates that a significantly higher risk more likely occurred among those with
248
Table 4
Incidence density rates and HR for specific cancer types according to splenectomy status stratified by follow-up years Splenectomy No splenectomy
Variable
Nontrauma
Event
IR
HR
Event
IR
HR† (95% CI)
289 311 178
13.44 8.69 5.87
1.00 1.00 1.00
167 107 79
29.05 12.85 12.08
1.24 (1.03–1.51)* 1.49 (1.20–1.86)*** 2.25 (1.73–2.94)***
29 32 12
1.35 .89 .40
1.00 1.00 1.00
10 6 10
1.74 .72 1.53
7 10 2
.33 .28 .07
1.00 1.00 1.00
1 0 2
.17 .00 .31
22 22 10
1.02 .62 .33
1.00 1.00 1.00
9 6 8
6 9 6
.28 .25 .20
1.00 1.00 1.00
9 11 5
.42 .31 .16
40 48 34
Trauma
Event
IR
129 80 47
40.22 19.27 15.54
.77 (.37–1.57) .82 (.34–1.95) 3.99 (1.72–9.25)**
5 4 9
1.56 .96 2.98
.34 (.04–2.78) – 5.13 (.71–36.82)
0 0 2
.00 .00 .66
1.57 .72 1.22
.88 (.41–1.93) 1.19 (.48–2.93) 3.83 (1.51–9.72)**
5 4 7
1.56 .96 2.31
5 10 3
.87 1.20 .46
1.58 (.48–5.26) 4.54 (1.83–11.28)** 2.70 (.66–10.98)
1 6 2
.31 1.45 .66
1.00 1.00 1.00
11 2 4
1.91 .24 .61
2.93 (1.21–7.14)* .84 (.19–3.78) 4.21 (1.11–15.95)*
9 0 2
2.81 .00 .66
1.86 1.34 1.12
1.00 1.00 1.00
10 6 4
1.74 .72 .61
7 5 3
2.18 1.20 .99
39 45 31
1.18 1.26 1.02
1.00 1.00 1.00
71 39 30
12.35 4.68 4.59
62 33 20
19.33 7.95 6.61
44 38 21
2.05 1.06 .69
1.00 1.00 1.00
15 6 8
2.61 .72 1.22
.76 (.42–1.37) .64 (.27–1.52) 1.93 (.85–4.36)
9 4 3
2.81 .96 .99
15 11
.70 .31
1.00 1.00
4 6
.70 .72
.68 (.22–2.07) 2.47 (.91–6.70)
3 2
.94 .48
.57 (.28–1.13) .52 (.22–1.22) .61 (.22–1.73) 3.87 (2.62–5.73)*** 3.75 (2.43–5.77)*** 5.18 (3.13–8.59)***
HR† (95% CI)
Event
IR
HR† (95% CI)
1.37 (1.11–1.68)** 2.02 (1.58–2.58)*** 2.51 (1.82–3.46)***
38 27 32
14.95 6.47 9.10
.97 (.69–1.36) .84 (.56–1.24) 1.95 (1.34–2.85)***
.58 (.22–1.51) 1.13 (.40–3.22) 8.22 (3.45–19.63)***
5 2 1
1.97 .48 .28
1.12 (.43–2.89) .52 (.12–2.18) .70 (.09–5.41)
1 0 0
.39 .00 .00
.96 (.12–7.91) – –
.74 (.28–1.98) 1.58 (.54–4.60) 7.83 (2.96–20.70)***
4 2 1
1.57 .48 .28
1.15 (.40–3.36) .80 (.19–3.40) .83 (.11–6.51)
.46 (.05–3.83) 5.83 (2.07–16.43)*** 3.78 (.75–19.04)
4 4 1
1.57 .96 .28
4.01 (1.11–14.48)* 3.36 (1.01–11.16)* 1.70 (.20–14.54)
3.45 (1.36–8.79)** – 3.39 (.65–17.83)
2 2 2
.79 .48 .57
1.76 (.38–8.20) 2.05 (.45–9.38) 5.55 (1.04–29.49)*
.56 (.25–1.26) .78 (.31–1.98) .82 (.25–2.68)
3 1 1
1.18 .24 .28
9 6 10
3.54 1.44 2.85
1.70 (.82–3.52) 1.26 (.53–2.96) 4.04 (1.96–8.32)***
.64 (.31–1.31) .77 (.27–2.16) 1.33 (.39–4.47)
6 2 5
2.36 .48 1.42
1.06 (.45–2.50) .48 (.12–2.01) 2.65 (.99–7.08)
.75 (.22–2.63) 1.47 (.33–6.65)
1 4
.39 .96
– – 10.11 (1.40–73.18)*
4.76 (3.18–7.13)*** 5.77 (3.67–9.07)*** 6.01 (3.42–10.55)***
.58 (.18–1.87) .19 (.03–1.38) .35 (.05–2.54)
.53 (.07–4.04) 3.77 (1.19–11.97)*
The American Journal of Surgery, Vol 210, No 2, August 2015
Overall 1–3 (n 5 1,977) 4–6 (n 5 7,265) R7 (n 5 15,248) Head and neck 1–3 4–6 R7 Nasopharynx 1–3 4–6 R7 Other 1–3 4–6 R7 Esophagus 1–3 4–6 R7 Stomach 1–3 4–6 R7 Colorectal 1–3 4–6 R7 Liver 1–3 4–6 R7 Lung 1–3 4–6 R7 Bladder 1–3 4–6
All
1,262) 4,462) 9,466)
.16
1.00
1
.15
8 2 7
.37 .06 .23
1.00 1.00 1.00
6 7 2
1.04 .84 .31
3 5 0
.14 .14 .00
1.00 1.00 1.00
6 3 2
1.04 .36 .31
18 33 16
2.21 2.41 1.37
1.00 1.00 1.00
6 11 3
2.76 3.46 1.17
13 12 12
1.60 .88 1.02
1.00 1.00 1.00
1 2 1
13 20 9
.97 .91 .48
1.00 1.00 1.00
5 1 2
1.02 (.12–8.73)
0
.00
–
1
.28
2.38 (.27–20.90)
1.58 (.55–4.57) 15.23 (3.16–73.40)*** 1.43 (.30–6.88)
5 7 1
1.56 1.69 .33
1.89 (.62–5.82) 30.31 (6.26–148.87)*** 1.38 (.17–11.26)
1 0 1
.39 .00 .28
.87 (.11–6.97) – 1.47 (.18–12.12)
4.35 (1.06–17.78)* 2.77 (.66–11.63) –
5 2 0
1.56 .48 .00
5.41 (1.24–23.63)* 3.51 (.68–18.17) –
1 1 2
.39 .24 .57
2.28 (.23–22.27) 1.94 (.22–16.80) –
.65 (.26–1.65) 1.49 (.75–2.95) .86 (.25–2.97)
5 10 2
3.47 5.08 1.32
.71 (.26–1.92) 2.10 (1.03–4.26)* .96 (.22–4.17)
1 1 1
1.36 .82 .95
.47 (.06–3.54) .38 (.05–2.76) .72 (.10–5.43)
.46 .63 .39
.15 (.02–1.18) .72 (.16–3.21) .39 (.05–3.00)
1 0 0
.69 .00 .00
.19 (.03–1.48) – –
0 2 1
.00 1.65 .95
– 2.18 (.48–9.85) .93 (.12–7.14)
1.40 .19 .50
1.29 (.45–3.74) .21 (.03–1.60) 1.15 (.25–5.33)
3 0 1
1.70 .00 .66
1.13 (.31–4.04) – 1.05 (.13–8.37)
2 1 1
1.11 .34 .41
1.68 (.36–7.73) .45 (.06–3.39) 1.27 (.16–10.09)
Splenectomy and cancer
715) 2,803) 5,782)
5
L.-M. Sun et al.
R7 NHL 1–3 4–6 R7 Leukemia 1–3 4–6 R7 Only women‡ Breast 1–3 (n 5 4–6 (n 5 R7 (n 5 Gynecologic 1–3 4–6 R7 Only men‡ Prostate 1–3 (n 5 4–6 (n 5 R7 (n 5
ICD-9-CM: nasopharynx cancer 147.xx; other head and neck cancer 140.xx to 146.xx and 148.xx to 149.xx; esophagus cancer 150.xx; stomach cancer 151.xx; colorectal cancer 153.xx and 154.xx; liver cancer 155.xx; lung cancer 162.xx; breast cancer 174.xx; gynecologic cancer 179.xx to 184.xx; prostate cancer 185.xx; bladder cancer 188.xx; non-Hodgkin’s lymphoma 200.xx and 202.xx; Hodgkin’s disease 201.xx; leukemia 204.xx to 208.xx. *P , .05, **P , .01, ***P , .001. CI 5 confidence interval; HR 5 hazard ratio; IR 5 incidence density rates, per 1,000 person-years; NHL 5 non-Hodgkin’s lymphoma. † Adjusted for age, sex, and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression. ‡ Adjusted for age and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression.
249
250 nontraumatic reasons. The exact mechanism for the possible association between splenectomy and cancer risk remains unclear. A plausible mechanism is that the spleen is thought to be involved in immunologic defenses, and provides active immune response through humoral and cell-mediated pathways. Splenectomy may impair immune surveillance in the host.21,31 Cancer is suggested to be related to human immunity,5,6 and immunity may therefore partially account for the possible linkage between splenectomy and cancer risk. Our data show a significantly increased risk of gastric cancer in the splenectomy group. We conjecture that splenectomy patients are susceptible to bacterial infection. Infection with Helicobacter pylori causes chronic inflammation and is the strongest risk factor for the development of gastric cancer.32 Our data identified that a significantly higher risk of nonHodgkin’s lymphoma was only observed in the nontraumatic group, but both the traumatic and the nontraumatic groups had a significantly higher risk for leukemia. A previous population-based report from Denmark was conducted to evaluate cancer risk after splenectomy for both traumatic and nontraumatic reasons. The authors found no increased risk for cancer among patients who underwent splenectomy because of trauma. However, they indicated an increased risk for certain hematological malignancies in patients who underwent splenectomy for nontraumatic reasons.15 Another epidemiologic study with a long-term follow-up of 740 American veterans splenectomized because of trauma during World War II showed no increased risk of cancer.33 This null association between total or site-specific cancers and splenectomy for external trauma reason has also been reported in Swedish residents.14 On the other hand, Kristinsson et al13 performed subanalyses restricted to splenectomy patients for trauma and observed significantly elevated risks of cancer in splenectomy patients, which is consistent with our findings. Spleen is thought to be involved in immunologic defenses and splenectomy (no matter trauma or nontrauma reasons) may be possibly linked to the tumorigenesis. For nontraumatic reasons, splenectomy could result from certain benign hematological disorders, which are possibly related to subsequent development of hematological malignancies.34,35 This may partially explain the different risks of cancer in splenectomy patients with nontrauma and trauma reasons. In vitro and in vivo animal studies have yielded controversial results. Murine models have suggested that splenectomy is associated with increased tumor induction,31,36 but other studies have shown that splenectomy may improve the efficiency of cancer treatment in certain tumor host systems.37,38 Prehn performed a review and concluded that splenectomy on tumor growth is exceedingly complex, and splenectomy enhances or inhibits tumor growth based primarily on the spleen to tumor ratio.8 Table 4 shows the follow-up specific rates for cancer incidence and HR, and splenectomy patients were found to have a consistently significantly higher risk for overall cancer development among various follow-up times. Fig. 1 also illustrates that the difference in cumulative incidence curves of all cancers between the splenectomy and
The American Journal of Surgery, Vol 210, No 2, August 2015 control groups is widening over time. This finding supports that the existence of coincidence of cancer and splenectomy is unlikely. The cancer risk patterns by follow-up years among diverse cancers varied, and interpreting the discrepancies is difficult. The strength of this study is its nationwide populationbased design, which increases the generalizability of the results. The diagnoses of splenectomy and cancer were based on hospital records, which are highly reliable. Our study suggests that splenectomy may need to be employed more conservatively in medical practice in the future, with spleen-preserving techniques used more frequently in trauma care and with splenectomy performed less frequently in nontrauma indications. However, interpretation of our results should be tempered because of a couple of study limitations. First, information regarding the lifestyle or behavior of patients is lacking in the NHIRD, making it impossible to adjust for health behavior-related factors such as cigarette smoking and alcohol consumption. These unhealthy habits can increase the risk of cancer39; however, the relationship between health behaviors and splenectomy (and its reasons) remains undetermined. Second, surveillance bias may exist because of increased clinical check-ups in these patients after surgery, which could detect more cancers. In summary, this population-based retrospective cohort study found significantly increased risks of overall cancer and certain site-specific cancers in Taiwanese with splenectomy, compared with the general population. The phenomenon is more prominent when patients had splenectomy because of nontraumatic reasons. The possible association does not imply causation. The immune factor may play an essential role, and pre-existing hematological disorders may also be related to hematological malignancies. Further comprehensive investigations should explore other undetermined mechanisms.
References 1. Mebius RE, Kraal G. Structure and function of the spleen. Nat Rev Immunol 2005;5:606–16. 2. Wluka A, Olszewski WL. Innate and adaptive processes in the spleen. Ann Transplant 2006;11:22–9. 3. Davies I, Cho J, Lewis M. Splenectomy results from an 18-year single centre experience. Ann R Coll Surg Engl 2014;96:147–50. 4. Bickenbach KA, Gonen M, Labow DM, et al. Indications for and efficacy of splenectomy for haematological disorders. Br J Surg 2013; 100:794–800. 5. Hadden JW. Immunodeficiency and cancer: prospects for correction. Int Immunopharmacol 2003;3:1061–71. 6. Salavoura K, Kolialexi A, Tsangaris G, et al. Development of cancer in patients with primary immunodeficiencies. Anticancer Res 2008;28: 1263–9. 7. Chang RW, Turk JL. Increased resistance in splenectomized mice to a methylcholanthrene-induced tumour. Br J Cancer 1977;35:768–76. 8. Prehn RT. The paradoxical effects of splenectomy on tumor growth. Theor Biol Med Model 2006;3:23. 9. Kossoy G, Ben-Hur H, Lifschitz O, et al. Mammary tumors in splenectomized rats. Oncol Rep 2002;9:185–8.
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Splenectomy and cancer
10. Ben-Hur H, Kossoy G, Lifschitz O, et al. Splenectomy, chemicallyinduced mammary tumors and parathymic lymph nodes in rats: experimental and morphological studies. In Vivo 2002;16:275–80. 11. Sonoda K, Izumi K, Matsui Y, et al. Decreased growth rate of lung metastatic lesions after splenectomy in mice. Eur Surg Res 2006;38: 469–75. 12. Higashijima J, Shimada M, Chikakiyo M, et al. Effect of splenectomy on antitumor immune system in mice. Anticancer Res 2009;29: 385–93. 13. Kristinsson SY, Gridley G, Hoover RN, et al. Long-term risks after splenectomy among 8,149 cancer-free American veterans: a cohort study with up to 27 years follow-up. Haematologica 2014;99:392–8. 14. Linet MS, Nyre´n O, Gridley G, et al. Risk of cancer following splenectomy. Int J Cancer 1996;66:611–6. 15. Mellemkjoer L, Oslen JH, Linet MS, et al. Cancer risk after splenectomy. Cancer 1995;75:577–83. 16. Chiang CJ, Chen YC, Chen CJ, et al. Taiwan Cancer Registry Task Force. Cancer trends in Taiwan. Jpn J Clin Oncol 2010;40:897–904. 17. Cancer Statistics Annual Report. Taiwan Cancer Registry. Available at: http://tcr.cph.ntu.edu.tw/main.php?Page5N2. Accessed October 2, 2014. 18. Edwards BK, Noone AM, Mariotto AB, et al. Annual Report to the Nation on the status of cancer, 1975-2010, featuring prevalence of comorbidity and impact on survival among persons with lung, colorectal, breast, or prostate cancer. Cancer 2014;120:1290–314. 19. Cancer Prevention. World Health Organization. Available at: http:// www.who.int/cancer/prevention/en/. Accessed October 2, 2014. 20. Kao CH, Sun LM, Chen PC, et al. A population-based cohort study in Taiwanduse of insulin sensitizers can decrease cancer risk in diabetic patients? Ann Oncol 2013;24:523–30. 21. Altamura M, Caradonna L, Amati L, et al. Splenectomy and sepsis: the role of the spleen in the immune-mediated bacterial clearance. Immunopharmacol Immunotoxicol 2001;23:153–61. 22. Coignard-Biehler H, Lanternier F, de Montalembert M, et al. [Infections in splenectomized patient]. Rev Prat 2008;58:2209–14. 23. Glass JM, Gilbert JM. Splenectomy in a general hospital. J R Soc Med 1996;89:199–201. 24. de Beer JC, Liebenberg L. Does cancer risk increase with HbA1c, independent of diabetes? Br J Cancer 2014;110:2361–8.
251 25. Ronco AL, De Stefani E, Deneo-Pellegrini H, et al. Diabetes, overweight and risk of postmenopausal breast cancer: a case-control study in Uruguay. Asian Pac J Cancer Prev 2012;13:139–46. 26. Chow WH, Gridley G, Fraumeni Jr JF, et al. Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med 2000;343:1305–11. 27. Kaye JA, Meier CR, Walker AM, et al. Statin use, hyperlipidaemia, and the risk of breast cancer. Br J Cancer 2002;86:1436–9. 28. Herbey II, Ivankova NV, Katkoori VR, et al. Colorectal cancer and hypercholesterolemia: review of current research. Exp Oncol 2005;27: 166–78. 29. Pelton K, Freeman MR, Solomon KR. Cholesterol and prostate cancer. Curr Opin Pharmacol 2012;12:751–9. 30. Sun LM, Epplein M, Li CI, et al. Trends in the incidence rates of nasopharyngeal carcinoma among Chinese Americans living in Los Angeles County and the San Francisco metropolitan area, 1992-2002. Am J Epidemiol 2005;162:1174–8. 31. Hull CC, Galloway P, Gordon N, et al. Splenectomy and the induction of murine colon cancer. Arch Surg 1988;123:462–4. 32. Lamb A, Chen LF. Role of the Helicobacter pylori-induced inflammatory response in the development of gastric cancer. J Cell Biochem 2013;114:491–7. 33. Robinette CD, Fraumeni Jr JF. Splenectomy and subsequent mortality in veterans of the 1939-45 war. Lancet 1977;2:127–9. 34. Bertolino G, Noris P, Balduini CL. Qualitative and quantitative platelet defect with bleeding symptoms as presenting feature of non-Hodgkin’s lymphomas. Haematologica 1991;76:243–4. 35. Kirshner JF, Zamkoff KW, Gottlieb AJ. Idiopathic thrombocytopenic purpura and Hodgkin’s disease: report of two cases and a review of the literature. Am J Med Sci 1980;280:21–8. 36. Sato N, Michaelides MC, Wallack MK. Effect of splenectomy on the growth of murine colon tumors. J Surg Oncol 1983;22:73–6. 37. Kopel S, Michowitz M, Leibovici J. Effect of splenectomy on the efficiency of chemo-immunotherapy of melanoma-bearing mice. Int J Immunopharmacol 1985;7:801–10. 38. Yamagishi H, Oka T, Hashimoto I, et al. The role of the spleen in tumor bearing host: II. The influence of splenectomy in mice. Jpn J Surg 1984;14:72–7. 39. Schwarz S, Messerschmidt H, Doren M. Psychosocial risk factors for cancer development. Med Klin (Munich) 2007;102:967–79.
Clinical Science
Splenectomy and increased subsequent cancer risk: a nationwide population-based cohort study Li-Min Sun, M.D.a, Hsuan-Ju Chen, M.Sc.b,c, Long-Bin Jeng, M.D.d,e, Tsai-Chung Li, Ph.D.f,g, Shih-Chi Wu, M.D.e,h, Chia-Hung Kao, M.D.e,i,* a
Department of Radiation Oncology, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung, Taiwan; bManagement Office for Health Data, China Medical University Hospital, Taichung, Taiwan; cCollege of Medicine, China Medical University, Taichung, Taiwan; dDepartment of Surgery, Organ Transplantation Center, China Medical University Hospital, Taichung, Taiwan; e Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine and f Graduate Institute of Biostatistics, College of Management, China Medical University, Taichung, Taiwan; gDepartment of Healthcare Administration, College of Health Science, Asia University, Taichung, Taiwan; hTrauma and Emergency Center and iDepartment of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan KEYWORDS: Splenectomy; Malignancy; Population-based cohort study; The National Health Insurance system; Cox proportional hazard regression analysis
Abstract BACKGROUND: Splenectomy has been suggested to have an impact on immunological function, and subsequent development of cancer has been recognized as a possible adverse effect of splenectomy. This study evaluated the possible association between splenectomy and malignancy in Taiwan. METHODS: A cohort study consisted of including 2,603 patients with nontraumatic and 2,295 patients with traumatic splenectomy, and then randomly frequency matched with 4 participants without splenectomy. The Cox proportional hazard regression analysis was conducted to estimate the influence of splenectomy on cancer risk. RESULTS: Both nontraumatic and traumatic splenectomy had a significantly higher risk for overall cancer development (adjusted hazard ratios are 2.64 and 1.29 for nontraumatic and traumatic reasons, respectively). After adjusting for age, sex, and comorbidities, patients with splenectomy were associated with significantly higher risks for developing certain gastrointestinal tract cancers, other head and neck cancers, and hematological malignancies, and the phenomenon is more prominent in nontraumatic splenectomy group. CONCLUSION: This nationwide population-based study found that people with splenectomy have higher risks of developing overall cancer, as well as certain site-specific cancers, especially for patients with nontraumatic reasons. Ó 2015 Elsevier Inc. All rights reserved.
This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW104-TDU-B-212-113002); China Medical University Hospital, Academia Sinica Taiwan Biobank, Stroke Biosignature Project (BM104010092); NRPB Stroke Clinical Trial Consortium (MOST 103-2325-B-039 -006); Tseng-Lien Lin Foundation, Taichung, Taiwan; Taiwan Brain Disease Foundation, Taipei, Taiwan; Katsuzo and Kiyo Aoshima Memorial Funds, Japan; and Health, and welfare surcharge of tobacco products, China Medical University Hospital Cancer Research Center of Excellence (MOHW104TDU-B-212-124-002, Taiwan). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study. The authors declare no conflicts of interest. * Corresponding author. Tel.: 1886-4-22052121; fax: 1886-4-22336174. E-mail address: [email protected] Manuscript received October 3, 2014; revised manuscript January 6, 2015 0002-9610/$ - see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjsurg.2015.01.017
244 The spleen is the largest lymphatic organ in the human body and serves a crucial role in immune function. It combines the innate and adaptive immune system, and is considered to be the most vital organ for antibacterial and antifungal immune reactivity.1,2 Splenectomy can be performed both as an emergency procedure following abdominal trauma and electively when indicated for hematological disorders.3,4 In addition to infection, cancer is thought to be related to human immunity.5,6 Splenectomy has been studied for its effects on tumor cell growth with inconsistent results,7–10 and controversial animal studies have revealed the influence on the antitumor immune system after splenectomy in vivo.11,12 Few studies have explored the clinical human cancer risk after splenectomy; however, epidemiologic studies have observed increased risks among certain solid tumors and hematological malignancies.13–15 Malignant neoplasm has been the leading cause of death for the Taiwanese general population since 1982, and is becoming a crucial public health problem with aging populations and changes in lifestyles.16 The Taiwan government has focused on this concern and launched primary and secondary prevention programs for major cancers, such as high-risk factor avoidance and periodic cancer screening to reduce cancer incidence and mortality rates.16 Therefore, population-based investigations regarding cancerpreventive epidemiology continue to be conducted. Based on the limited available clinical reports highlighting the association between splenectomy and subsequent cancer risk, we hypothesized that people with a splenectomy in Taiwan may be at increased risk of cancer. Our results were generated from a retrospective cohort study for people with a splenectomy. The original database was derived from the National Health Insurance (NHI) system in Taiwan.
Methods Data source The NHI program was initiated in Taiwan in 1995 and currently covers approximately 99% of the 23 million population of Taiwan. In this study, we established a longitudinal cohort study from the Taiwan National Health Institute Research Database (NHIRD), with hospital admissions of the entire population insured in Taiwan between 1996 and 2011, which contains the healthcare claims of each patient. To protect privacy, the NHIRD scrambled data cryptographically on patient identities and institutions. Each person in Taiwan has a unique personal identification number, and all NHI datasets can be interlinked with the personal identification number of each person. For this study, disease diagnosis was based on disease records according to the International Classification of Disease, Ninth Revision, Clinical Modification (ICD-9-CM) in inpatients and catastrophic registry files. This study was approved by the Ethics Review Board of China Medical University (CMU-REC-101-012).
The American Journal of Surgery, Vol 210, No 2, August 2015
Study population Initially, we identified 10,964 patients with newly received splenectomy (ICD-9-CM code 41.5) from 2000 to 2006 from the inpatient registry file. We excluded patients with less than 20 years of age (n 5 1,067), diagnosis of cancer at baseline (n 5 1,280), and less than 1-year of follow-up (n 5 3,719) from the analysis. The remaining 4,898 patients with newly received splenectomies were included in the splenectomy cohort, which was divided into 2 groups based on trauma status. Four study subjects in the no splenectomy cohort for every patient with a splenectomy were randomly selected from insured people without a history of splenectomy or cancer, and frequency matched with age (per 5 years), sex, diabetes, hypertension, hyperlipidemia, coronary artery disease, and index year. Overall, 4,898 patients were included as the splenectomy cohort and 19,592 patients as the no splenectomy cohort. The sociodemographic status included sex and age (20 to 44 and R45 years). Information on pre-existing comorbidities, including diabetes (ICD-9-CM code 250.xx), hypertension (ICD-9-CM code 401.xx to 405.xx), hyperlipidemia (ICD-9-CM code 272.xx), and coronary artery disease (ICD-9-CM 410.xx to 414.xx), were also recorded. The primary outcome was cancer occurrence (ICD-9CM code 140.xx to 208.xx), which was determined by linking records with the catastrophic illness registry of the NHIRD. All subjects were followed until patient withdrawal from the NHI program, cancer development, death, or the end of 2011. We attempted to minimize the impact of any effect of existing medical conditions on splenectomy by excluding cancer that occurred in subjects during the first year of follow-up. We also investigated the risk of individual cancer sites between the splenectomy cohort and the no splenectomy cohort. The cancer sites were separated into head and neck cancers (ICD-9-CM code 147.xx for nasopharynx cancer; ICD-9-CM code 140.xx to 146.xx and 148.xx to 149.xx for other head and neck cancers), esophagus cancer (ICD-9-CM code 150.xx), stomach cancer (ICD-9-CM code 151.xx), colorectal cancer (ICD-9CM code 153.xx and 154.xx), liver cancer (ICD-9-CM code 155.xx), lung cancer (ICD-9-CM code 162.xx), breast cancer (ICD-9-CM code 174.xx), gynecologic cancer (ICD-9-CM code 179.xx to 184.xx), prostate cancer (ICD-9-CM code 185.xx), bladder cancer (ICD-9-CM code 188.xx), non-Hodgkin’s lymphoma (ICD-9-CM code 200.xx and 202.xx), Hodgkin’s disease (ICD-9-CM code 201.xx), leukemia (ICD-9-CM code 204.xx to 208.xx), and other cancers.
Statistical analysis We compared the distribution of sociodemographic factors and pre-existing comorbidities between the cohorts with and without a splenectomy using the chi-square test
L.-M. Sun et al. Table 1
Splenectomy and cancer
245
Demographic factors and comorbidity of study participants according to splenectomy status Splenectomy
Variables Sex Female Male Age (years) 20–44 R45 Mean (SD) Comorbidity Diabetes Hypertension Hyperlipidemia CAD Follow-up period (years), mean (SD)
No splenectomy (n 5 19,592)
All (n 5 4,898)
Nontrauma (n 5 2,603)
Trauma (n 5 2,295)
N
n
n
n
%
%
%
%
P value* .99
7,440 12,152
37.97 62.03
1,860 3,038
37.97 62.03
1,198 1,405
46.02 43.98
662 1,633
28.85 71.15 .99
10,368 52.92 9,224 47.08 45.20 (16.78)
2,592 52.92 2,306 47.08 45.29 (16.66)
1,181 45.37 1,422 54.63 48.35 (16.38)
1,411 61.48 884 38.52 41.82 (16.28)
1,640 1,828 820 784 7.90 (2.52)
410 8.37 457 9.33 205 4.19 196 4.00 7.41 (2.72)
307 322 148 137
103 135 57 59
8.37 9.33 4.19 4.00
11.79 12.37 5.69 5.26
4.49 5.88 2.48 2.57
.75 .99 .99 .99 .99 ,.001
CAD 5 coronary artery disease; SD 5 standard deviation. *Comparison between the cohorts with and without splenectomy.
for category variables and the t test for continuous variables. For estimating the cumulative incidence of cancer risk in the splenectomy cohort and the no splenectomy cohort, we performed survival analysis using the Kaplan– Meier method, with significance based on the log-rank test. The Cox proportional hazards model was used to assess the risk of the study population developing cancer and to produce hazard ratios (HRs) and 95% confidence intervals (95% CIs). Statistical analyses and data management were performed with SAS 9.3 (SAS Institute, Inc, Cary, NC), and the cumulative incidence curves were determined using R computer software (R Foundation for Statistical Computing, Vienna, Austria). The significance levels were set at a 2 tailed P value of .05.
hypertension, hyperlipidemia, and coronary artery disease (Table 2). Among patients receiving splenectomy, patients without and with trauma exhibited a significantly increased risk of overall cancer compared with the no splenectomy cohort (HR 2.64, 95% CI 2.30 to 3.05 and HR 1.29, 95% CI 1.05 to 1.60, respectively). Sex-specific analysis showed that women exhibited a 2.16-fold higher risk of developing cancer (95% CI 1.76 to 2.65) and men exhibited a 1.99-fold (95% CI 1.70 to 2.34) higher risk of developing cancer than the no splenectomy cohort. After age stratification, we observed that both the age groups of 20 to 44 years and 45 years and older of splenectomy patients exhibited a
Results We established 4,898 splenectomy patients and 19,592 subjects without splenectomy, with the same average age (mean 5 45 years) and more men than women (62.03% vs 37.97%) (Table 1). The distributions of age, sex, and comorbidities were the same in both groups. The mean follow-up periods for the splenectomy and nonsplenectomy groups were 7.41 (62.72) and 7.90 (62.52) years, respectively. The cumulative subsequent cancer incidence curves showed that the curve for the splenectomy cohort was significantly higher than that for the no splenectomy cohort (P , .001 for the log-rank test; Fig. 1). Patients with splenectomy were 1.94 times more likely than the no splenectomy cohort to experience cancer (9.73 vs 5.03 per 1,000 person-years), with an adjusted HR of 2.06 (95% CI 1.81 to 2.33) after adjusting for age, sex, and history of diabetes,
Figure 1 Cumulative incidence curves of all cancers for splenectomy and control groups.
246
The American Journal of Surgery, Vol 210, No 2, August 2015
Table 2 Incidence density rates and HR for cancers according to splenectomy status stratified by demographic factors and comorbidity Splenectomy No splenectomy
All
Nontrauma
Trauma
Variables
IR
HR
IR
Overall Sex Women Men Age (years) 20–44 R45 Comorbidity No Yes
5.03
1.00
9.73
HR† (95% CI)
IR
HR† (95% CI)
IR
2.06 (1.81–2.33)***
14.08
2.64 (2.30–3.05)***
5.36
1.29 (1.05–1.60)*
4.89 5.12
1.00 1.00
9.79 9.69
2.16 (1.76–2.65)*** 1.99 (1.70–2.34)***
13.00 15.05
2.75 (2.21–3.42)*** 2.51 (2.08–3.02)***
4.55 5.69
1.08 (.71–1.64) 1.41 (1.11–1.81)**
1.42 9.40 status‡ 4.16 9.81
1.00 1.00
4.28 16.88
3.09 (2.34–4.06)*** 1.83 (1.59–2.11)***
6.89 21.18
4.82 (3.54–6.57)*** 2.33 (1.98–2.73)***
2.25 10.85
1.66 (1.09–2.54)* 1.16 (.91–1.48)
1.00 1.00
8.13 19.40
2.04 (1.76–2.37)*** 2.10 (1.66–2.65)***
12.34 21.13
2.80 (2.36–3.31)*** 2.29 (1.77–2.97)***
4.41 15.40
1.23 (.96–1.57) 1.66 (1.09–2.52)*
HR† (95% CI)
*P , .05, **P , .01, ***P , .001. CI 5 confidence interval; HR 5 hazard ratio; IR 5 incidence density rates, per 1,000 person-years. † Mutually adjusted for age, sex, and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression. ‡ Patients with any one of diabetes, hypertension, hyperlipidemia, and coronary artery disease were classified as having comorbidity.
significantly higher risk of cancer than the no splenectomy cohort. Regardless of subjects without or with comorbidities, the risk of cancer was higher in the splenectomy cohort than that in the nonsplenectomy cohort. We observed a significantly positive association between splenectomy and the risks of site-specific cancer, including other head and neck, esophagus, stomach, liver, nonHodgkin’s lymphoma, and leukemia (Table 3). Splenectomy patients without trauma were at significantly increased cancer risk of head and neck, other head and neck, esophagus, stomach, liver, breast, non-Hodgkin’s lymphoma, and leukemia. On the other hand, splenectomy patients with trauma were only at significantly increased cancer risk of esophagus, stomach, liver, and leukemia. We calculated the HR for specific cancer types according to splenectomy status stratified by follow-up years, and the results are shown in Table 4. For overall cancer, higher risks for developing cancer were observed in the follow-up periods of 1 to 3, 4 to 6, and 7 years or more. In addition, the risks for developing cancer were observed in the followup periods of 1 to 3, 4 to 6, and 7 years or more for splenectomy patients without trauma, as well as in the follow-up periods of 7 years or more for splenectomy patients with trauma. For head and neck cancer, a 3.99-fold risk of developing cancer was found in the 7 year or more follow-up period. For other head and neck cancer, a 3.83-fold risk of developing cancer was found in the 7 year or more follow-up period. For esophagus cancer, a 4.54-fold risk of developing cancer was found in the follow-up period of 4 to 6 years. For stomach cancer, the risks for developing cancer were observed in the followup periods of 1 to 3 years and 7 years or more. For liver cancer, higher risks were observed for developing cancer in the follow-up periods of 1 to 3, 4 to 6, and 7 years or more. For non-Hodgkin’s lymphoma, a 15.23-fold risk of
developing cancer was found in the follow-up period of 4 to 6 years. For leukemia, higher risks for developing cancer were observed in the follow-up periods of 1 to 3 years.
Comments This population-based cohort study revealed that Taiwanese with splenectomy had a significantly higher risk of subsequent overall cancer, as well as certain gastrointestinal tract cancers, other head and neck cancers, and hematological malignancies. The phenomenon was more obvious for patients with nontraumatic reasons for splenectomy. Further stratified analysis by follow-up years revealed various patterns among diverse cancers, which are likely caused by the coincidence effect of splenectomy and cancer. The age-adjusted incidence rate of cancer in Taiwan has increased steadily, and overall cancer incidence rates increased by 2% per year between 2008 and 2011, reaching 295.1 (invasive cancers only) and 320.7 new cases (carcinoma in situ and invasive cancers) per 100,000 persons in 2011.17 Despite enhanced detection, much of the increased incidence may be associated with aging populations and a westernized lifestyle.16 In contrast, trend analysis from surveillance epidemiology and end results data showed that the overall cancer incidence rates for all racial and ethnic groups combined in the United States decreased by .6% per year between 2006 and 2010.18 This obstacle continues to be a challenge for public health in Taiwan, and has aroused the attention of the government to enact policies regarding cancer prevention. Prevention is the most costeffective long-term control strategy for cancer, with an estimated one third of all cases considered avoidable.19 One of the research topics in this field is to explore the possible
L.-M. Sun et al. Table 3
Splenectomy and cancer
247
Incidence density rates and HR for specific cancer types according to splenectomy status Splenectomy
Site of cancers
No splenectomy
All
IR
HR
IR
HR† (95% CI)
1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00 1.00
.72 .08 .63 .50 .47 .55 3.86 .80 1.44 .29 .36 .30 .41 .00 .30 .94
1.56 .70 1.87 3.84 3.11 .76 5.56 1.28 1.34 .49 .88 1.61 3.93 – 5.98 1.31
Head and neck .47 Nasopharynx .12 Other head and neck .35 Esophagus .14 Stomach .16 Colorectal .79 Liver .74 Lung .67 Breast (only women) 1.13 Gynecologic (only women) .63 Prostate (only men) .44 Bladder .20 NHL .11 Hodgkin’s disease .01 Leukemia .05 Other .75
(.99–2.45) (.21–2.35) (1.15–3.04)* (2.04–7.21)*** (1.68–5.76)*** (.48–1.22) (4.34–7.12)*** (.85–1.93) (.81–2.21) (.18–1.38) (.41–1.86) (.81–3.21) (1.96–7.87)***
Nontrauma
Trauma
IR
IR
.99 .11 .88 .50 .61 .83 6.33 .88 1.97 .12 .42 .28 .72 .00 (2.40–14.86)*** .39 (.90–1.92) 1.38
HR† (95% CI) 2.28 .99 2.70 3.86 3.36 .99 8.01 1.21 1.79 .20 .75 1.26 6.43 – 6.90 1.72
HR† (95% CI)
(1.36–3.83)*** .44 .91 (.44–1.90) (.23–4.29) .06 .43 (.06–3.25) (1.54–4.73)*** .39 1.09 (.50–2.41) (1.76–8.45)*** .50 3.82 (1.74–8.38)*** (1.65–6.94)*** .33 2.73 (1.11–6.67)* (.58–1.70) .28 .45 (.18–1.10) (6.18–10.39)*** 1.38 2.29 (1.48–3.54)*** (.72–2.06) .72 1.37 (.77–2.44) (1.05–3.05)* .57 .55 (.17–1.75) (.03–1.42) .57 1.01 (.31–3.29) (.27–2.09) .31 1.05 (.38–2.94) (.49–3.25) .33 2.11 (.87–5.07) (3.11–13.30)*** .11 1.11 (.26–4.81) .11 – (2.49–19.10)*** .22 4.84 (1.45–16.16)* (1.12–2.65)* .50 .79 (.40–1.56)
ICD-9-CM: nasopharynx cancer 147.xx; other head and neck cancer 140.xx to 146.xx and 148.xx to 149.xx; esophagus cancer 150.xx; stomach cancer 151.xx; colorectal cancer 153.xx and 154.xx; liver cancer 155.xx; lung cancer 162.xx; breast cancer 174.xx; gynecologic cancer 179.xx to 184.xx; prostate cancer 185.xx; bladder cancer 188.xx; non-Hodgkin’s lymphoma 200.xx and 202.xx; Hodgkin’s disease 201.xx; leukemia 204.xx to 208.xx. *P , .05, **P , .01, ***P , .001. CI 5 confidence interval; HR 5 hazard ratio; IR 5 incidence density rates, per 1,000 person-years; NHL 5 non-Hodgkin’s lymphoma. † Adjusted for age, sex, and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression.
risk/protective factors of cancer. The NHI program in Taiwan is a suitable resource for providing valuable materials with which to approach populated-based studies. Our research team recently performed a cohort study by using the NHIRD and found that Taiwanese patients with diabetes are at an elevated risk of cancer (particularly colorectal and pancreatic cancers), and the use of thiazolidinediones might decrease the risk of liver cancer in diabetic patients.20 This information inspires us to conduct studies to discover other factors that may be related to cancer. Infection is a well-known complication of splenectomy,21–23 and immunocompromised patients are also vulnerable to certain types of cancer. Therefore, it is plausible to hypothesize that people with splenectomy may have a higher risk of developing cancer. Besides age, sex, and index year, our control subjects were frequency matched to cases with comorbidity as well. Diabetes, hypertension, and hyperlipidemia are suggested to be a risk factor for certain types of cancer.22,24–29 In addition, we also adjusted these comorbidities and other factors in the multivariate analysis to eliminate possible bias. Table 2 shows that splenectomized patients had a significantly higher adjusted HR of overall cancer compared with the no splenectomy participants, and Table 4 shows that the significantly higher risks in the splenectomy group were consistent across various follow-up years. This finding is consistent with a cohort study from American veterans, which showed that the cancer risk in splenectomy patients was significantly higher across
various follow-up years [relative risks (95% CIs) are 2.05 (1.82 to 2.32), 1.44 (1.28 to 1.62), and 1.35 (1.24 to 1.47) for 2 to 5, 5 to 10, and greater than 10 years latency, respectively].13 Table 2 also highlights the higher risks of overall cancer in the splenectomy cohort, regardless of sex, age, and comorbidity. When divided splenectomy patients by trauma and nontrauma reasons, we found that both groups had a significantly higher risk of overall cancer compared with nonsplenectomy cohort, but the same pattern regarding consistently higher risk across sex, age, and comorbidity only limited to nontraumatic reasons. For specific cancer site analysis, we separated nasopharyngeal carcinoma from head and neck cancer because nasopharyngeal carcinoma is relatively common in Chinese people.30 Splenectomy patients were found to have significantly higher risks in other head and neck, esophagus, stomach, liver, non-Hodgkin’s lymphoma, and leukemia cancers (Table 3). Kristinsson et al13 conducted a cohort study to evaluate long-term risks after splenectomy among 8,149 cancerfree American veterans and found significantly higher risks of being hospitalized for all cancer, as well as for esophagus, liver, pancreas, lung, prostate, non-Hodgkin’s lymphoma, and leukemia cancers among splenectomy patients. Their further sensitivity analyses for subset of patients with diagnoses of autoimmune disease or trauma did not change the overall results.13 Although both trauma and nontrauma reasons had higher risks for developing some kinds of cancer in our splenectomy patients, Table 3 indicates that a significantly higher risk more likely occurred among those with
248
Table 4
Incidence density rates and HR for specific cancer types according to splenectomy status stratified by follow-up years Splenectomy No splenectomy
Variable
Nontrauma
Event
IR
HR
Event
IR
HR† (95% CI)
289 311 178
13.44 8.69 5.87
1.00 1.00 1.00
167 107 79
29.05 12.85 12.08
1.24 (1.03–1.51)* 1.49 (1.20–1.86)*** 2.25 (1.73–2.94)***
29 32 12
1.35 .89 .40
1.00 1.00 1.00
10 6 10
1.74 .72 1.53
7 10 2
.33 .28 .07
1.00 1.00 1.00
1 0 2
.17 .00 .31
22 22 10
1.02 .62 .33
1.00 1.00 1.00
9 6 8
6 9 6
.28 .25 .20
1.00 1.00 1.00
9 11 5
.42 .31 .16
40 48 34
Trauma
Event
IR
129 80 47
40.22 19.27 15.54
.77 (.37–1.57) .82 (.34–1.95) 3.99 (1.72–9.25)**
5 4 9
1.56 .96 2.98
.34 (.04–2.78) – 5.13 (.71–36.82)
0 0 2
.00 .00 .66
1.57 .72 1.22
.88 (.41–1.93) 1.19 (.48–2.93) 3.83 (1.51–9.72)**
5 4 7
1.56 .96 2.31
5 10 3
.87 1.20 .46
1.58 (.48–5.26) 4.54 (1.83–11.28)** 2.70 (.66–10.98)
1 6 2
.31 1.45 .66
1.00 1.00 1.00
11 2 4
1.91 .24 .61
2.93 (1.21–7.14)* .84 (.19–3.78) 4.21 (1.11–15.95)*
9 0 2
2.81 .00 .66
1.86 1.34 1.12
1.00 1.00 1.00
10 6 4
1.74 .72 .61
7 5 3
2.18 1.20 .99
39 45 31
1.18 1.26 1.02
1.00 1.00 1.00
71 39 30
12.35 4.68 4.59
62 33 20
19.33 7.95 6.61
44 38 21
2.05 1.06 .69
1.00 1.00 1.00
15 6 8
2.61 .72 1.22
.76 (.42–1.37) .64 (.27–1.52) 1.93 (.85–4.36)
9 4 3
2.81 .96 .99
15 11
.70 .31
1.00 1.00
4 6
.70 .72
.68 (.22–2.07) 2.47 (.91–6.70)
3 2
.94 .48
.57 (.28–1.13) .52 (.22–1.22) .61 (.22–1.73) 3.87 (2.62–5.73)*** 3.75 (2.43–5.77)*** 5.18 (3.13–8.59)***
HR† (95% CI)
Event
IR
HR† (95% CI)
1.37 (1.11–1.68)** 2.02 (1.58–2.58)*** 2.51 (1.82–3.46)***
38 27 32
14.95 6.47 9.10
.97 (.69–1.36) .84 (.56–1.24) 1.95 (1.34–2.85)***
.58 (.22–1.51) 1.13 (.40–3.22) 8.22 (3.45–19.63)***
5 2 1
1.97 .48 .28
1.12 (.43–2.89) .52 (.12–2.18) .70 (.09–5.41)
1 0 0
.39 .00 .00
.96 (.12–7.91) – –
.74 (.28–1.98) 1.58 (.54–4.60) 7.83 (2.96–20.70)***
4 2 1
1.57 .48 .28
1.15 (.40–3.36) .80 (.19–3.40) .83 (.11–6.51)
.46 (.05–3.83) 5.83 (2.07–16.43)*** 3.78 (.75–19.04)
4 4 1
1.57 .96 .28
4.01 (1.11–14.48)* 3.36 (1.01–11.16)* 1.70 (.20–14.54)
3.45 (1.36–8.79)** – 3.39 (.65–17.83)
2 2 2
.79 .48 .57
1.76 (.38–8.20) 2.05 (.45–9.38) 5.55 (1.04–29.49)*
.56 (.25–1.26) .78 (.31–1.98) .82 (.25–2.68)
3 1 1
1.18 .24 .28
9 6 10
3.54 1.44 2.85
1.70 (.82–3.52) 1.26 (.53–2.96) 4.04 (1.96–8.32)***
.64 (.31–1.31) .77 (.27–2.16) 1.33 (.39–4.47)
6 2 5
2.36 .48 1.42
1.06 (.45–2.50) .48 (.12–2.01) 2.65 (.99–7.08)
.75 (.22–2.63) 1.47 (.33–6.65)
1 4
.39 .96
– – 10.11 (1.40–73.18)*
4.76 (3.18–7.13)*** 5.77 (3.67–9.07)*** 6.01 (3.42–10.55)***
.58 (.18–1.87) .19 (.03–1.38) .35 (.05–2.54)
.53 (.07–4.04) 3.77 (1.19–11.97)*
The American Journal of Surgery, Vol 210, No 2, August 2015
Overall 1–3 (n 5 1,977) 4–6 (n 5 7,265) R7 (n 5 15,248) Head and neck 1–3 4–6 R7 Nasopharynx 1–3 4–6 R7 Other 1–3 4–6 R7 Esophagus 1–3 4–6 R7 Stomach 1–3 4–6 R7 Colorectal 1–3 4–6 R7 Liver 1–3 4–6 R7 Lung 1–3 4–6 R7 Bladder 1–3 4–6
All
1,262) 4,462) 9,466)
.16
1.00
1
.15
8 2 7
.37 .06 .23
1.00 1.00 1.00
6 7 2
1.04 .84 .31
3 5 0
.14 .14 .00
1.00 1.00 1.00
6 3 2
1.04 .36 .31
18 33 16
2.21 2.41 1.37
1.00 1.00 1.00
6 11 3
2.76 3.46 1.17
13 12 12
1.60 .88 1.02
1.00 1.00 1.00
1 2 1
13 20 9
.97 .91 .48
1.00 1.00 1.00
5 1 2
1.02 (.12–8.73)
0
.00
–
1
.28
2.38 (.27–20.90)
1.58 (.55–4.57) 15.23 (3.16–73.40)*** 1.43 (.30–6.88)
5 7 1
1.56 1.69 .33
1.89 (.62–5.82) 30.31 (6.26–148.87)*** 1.38 (.17–11.26)
1 0 1
.39 .00 .28
.87 (.11–6.97) – 1.47 (.18–12.12)
4.35 (1.06–17.78)* 2.77 (.66–11.63) –
5 2 0
1.56 .48 .00
5.41 (1.24–23.63)* 3.51 (.68–18.17) –
1 1 2
.39 .24 .57
2.28 (.23–22.27) 1.94 (.22–16.80) –
.65 (.26–1.65) 1.49 (.75–2.95) .86 (.25–2.97)
5 10 2
3.47 5.08 1.32
.71 (.26–1.92) 2.10 (1.03–4.26)* .96 (.22–4.17)
1 1 1
1.36 .82 .95
.47 (.06–3.54) .38 (.05–2.76) .72 (.10–5.43)
.46 .63 .39
.15 (.02–1.18) .72 (.16–3.21) .39 (.05–3.00)
1 0 0
.69 .00 .00
.19 (.03–1.48) – –
0 2 1
.00 1.65 .95
– 2.18 (.48–9.85) .93 (.12–7.14)
1.40 .19 .50
1.29 (.45–3.74) .21 (.03–1.60) 1.15 (.25–5.33)
3 0 1
1.70 .00 .66
1.13 (.31–4.04) – 1.05 (.13–8.37)
2 1 1
1.11 .34 .41
1.68 (.36–7.73) .45 (.06–3.39) 1.27 (.16–10.09)
Splenectomy and cancer
715) 2,803) 5,782)
5
L.-M. Sun et al.
R7 NHL 1–3 4–6 R7 Leukemia 1–3 4–6 R7 Only women‡ Breast 1–3 (n 5 4–6 (n 5 R7 (n 5 Gynecologic 1–3 4–6 R7 Only men‡ Prostate 1–3 (n 5 4–6 (n 5 R7 (n 5
ICD-9-CM: nasopharynx cancer 147.xx; other head and neck cancer 140.xx to 146.xx and 148.xx to 149.xx; esophagus cancer 150.xx; stomach cancer 151.xx; colorectal cancer 153.xx and 154.xx; liver cancer 155.xx; lung cancer 162.xx; breast cancer 174.xx; gynecologic cancer 179.xx to 184.xx; prostate cancer 185.xx; bladder cancer 188.xx; non-Hodgkin’s lymphoma 200.xx and 202.xx; Hodgkin’s disease 201.xx; leukemia 204.xx to 208.xx. *P , .05, **P , .01, ***P , .001. CI 5 confidence interval; HR 5 hazard ratio; IR 5 incidence density rates, per 1,000 person-years; NHL 5 non-Hodgkin’s lymphoma. † Adjusted for age, sex, and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression. ‡ Adjusted for age and history of diabetes, hypertension, hyperlipidemia, and coronary artery disease in Cox proportional hazards regression.
249
250 nontraumatic reasons. The exact mechanism for the possible association between splenectomy and cancer risk remains unclear. A plausible mechanism is that the spleen is thought to be involved in immunologic defenses, and provides active immune response through humoral and cell-mediated pathways. Splenectomy may impair immune surveillance in the host.21,31 Cancer is suggested to be related to human immunity,5,6 and immunity may therefore partially account for the possible linkage between splenectomy and cancer risk. Our data show a significantly increased risk of gastric cancer in the splenectomy group. We conjecture that splenectomy patients are susceptible to bacterial infection. Infection with Helicobacter pylori causes chronic inflammation and is the strongest risk factor for the development of gastric cancer.32 Our data identified that a significantly higher risk of nonHodgkin’s lymphoma was only observed in the nontraumatic group, but both the traumatic and the nontraumatic groups had a significantly higher risk for leukemia. A previous population-based report from Denmark was conducted to evaluate cancer risk after splenectomy for both traumatic and nontraumatic reasons. The authors found no increased risk for cancer among patients who underwent splenectomy because of trauma. However, they indicated an increased risk for certain hematological malignancies in patients who underwent splenectomy for nontraumatic reasons.15 Another epidemiologic study with a long-term follow-up of 740 American veterans splenectomized because of trauma during World War II showed no increased risk of cancer.33 This null association between total or site-specific cancers and splenectomy for external trauma reason has also been reported in Swedish residents.14 On the other hand, Kristinsson et al13 performed subanalyses restricted to splenectomy patients for trauma and observed significantly elevated risks of cancer in splenectomy patients, which is consistent with our findings. Spleen is thought to be involved in immunologic defenses and splenectomy (no matter trauma or nontrauma reasons) may be possibly linked to the tumorigenesis. For nontraumatic reasons, splenectomy could result from certain benign hematological disorders, which are possibly related to subsequent development of hematological malignancies.34,35 This may partially explain the different risks of cancer in splenectomy patients with nontrauma and trauma reasons. In vitro and in vivo animal studies have yielded controversial results. Murine models have suggested that splenectomy is associated with increased tumor induction,31,36 but other studies have shown that splenectomy may improve the efficiency of cancer treatment in certain tumor host systems.37,38 Prehn performed a review and concluded that splenectomy on tumor growth is exceedingly complex, and splenectomy enhances or inhibits tumor growth based primarily on the spleen to tumor ratio.8 Table 4 shows the follow-up specific rates for cancer incidence and HR, and splenectomy patients were found to have a consistently significantly higher risk for overall cancer development among various follow-up times. Fig. 1 also illustrates that the difference in cumulative incidence curves of all cancers between the splenectomy and
The American Journal of Surgery, Vol 210, No 2, August 2015 control groups is widening over time. This finding supports that the existence of coincidence of cancer and splenectomy is unlikely. The cancer risk patterns by follow-up years among diverse cancers varied, and interpreting the discrepancies is difficult. The strength of this study is its nationwide populationbased design, which increases the generalizability of the results. The diagnoses of splenectomy and cancer were based on hospital records, which are highly reliable. Our study suggests that splenectomy may need to be employed more conservatively in medical practice in the future, with spleen-preserving techniques used more frequently in trauma care and with splenectomy performed less frequently in nontrauma indications. However, interpretation of our results should be tempered because of a couple of study limitations. First, information regarding the lifestyle or behavior of patients is lacking in the NHIRD, making it impossible to adjust for health behavior-related factors such as cigarette smoking and alcohol consumption. These unhealthy habits can increase the risk of cancer39; however, the relationship between health behaviors and splenectomy (and its reasons) remains undetermined. Second, surveillance bias may exist because of increased clinical check-ups in these patients after surgery, which could detect more cancers. In summary, this population-based retrospective cohort study found significantly increased risks of overall cancer and certain site-specific cancers in Taiwanese with splenectomy, compared with the general population. The phenomenon is more prominent when patients had splenectomy because of nontraumatic reasons. The possible association does not imply causation. The immune factor may play an essential role, and pre-existing hematological disorders may also be related to hematological malignancies. Further comprehensive investigations should explore other undetermined mechanisms.
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