Background: Appendicitis before age 20 years has been observed to influence the risk of several inflammatory conditions, possibly through underlying immunological mechanisms. Inflammation has further been suggested to be involved in prostate cancer development. We therefore hypothesized that immunological characteristics signaled by appendicitis before late adolescence might influence the risk of later prostate cancer, and aimed to evaluate this association in a population-based study.

Methods: We identified a large cohort of Swedish men who underwent assessment for military conscription around the age of 18 years (n = 242,573). Medical diagnoses at time of conscription were available through the Swedish Military Conscription Register. The Swedish Cancer Register was used to identify diagnoses of prostate cancer. Multivariable adjusted Cox regression analyses were used to estimate HR and 95% confidence intervals (95% CIs) for the association between appendicitis and prostate cancer.

Results: During a median of 36.7 years of follow-up, 1,684 diagnoses of prostate cancer occurred. We found a statistically significant association between appendicitis and overall prostate cancer (adjusted HR 1.70; 95% CI, 1.08–2.67). The risk was notably increased for advanced (HR 4.42; 95% CI, 1.74–11.22) and lethal (HR 8.95; 95% CI, 2.98–26.91) prostate cancer.

Conclusions: These results suggest that a diagnosis of appendicitis before adulthood potentially signals underlying immune characteristics and a pattern of inflammatory response relevant to prostate cancer risk.

Impact: The study lends support to the proposed role of inflammation in prostate carcinogenesis, and adds another area of investigation potentially relevant to prostate cancer development. Cancer Epidemiol Biomarkers Prev; 27(6); 660–4. ©2018 AACR.

This article is featured in Highlights of This Issue, p. 617

Chronic inflammation has been identified as a driving force in the development of several cancer types (1), and a possible role has been suggested also in the pathogenesis of prostate cancer (2). While prostatic inflammation is common, far from all men with prostatic inflammation develop prostate cancer, and individual variation in the immune response has been proposed as a determinant of outcome (2, 3). One approach to exploring components of the immune response relevant to prostate carcinogenesis is to examine the association between specific inflammatory or immunologic conditions and prostate cancer. Asthma has, for example, been observed to be inversely associated with the occurrence of lethal prostate cancer, which may suggest a favorable influence of a type 2 T-helper cell (Th2)-skewed immune response (4).

Appendicitis, a common inflammatory condition with the highest incidence among young males (5) has been proposed as a useful human model of immunological characteristics relevant to the risk for some diseases. Although its etiology is not completely understood, microbial agents and obstruction by fecalithis or lymphoid hyperplasia are thought to be involved (6–8). Variation in the individual's immune-response profile has further been identified as a determinant of appendicitis outcome (9–11), where a Th1-skewed response for example characterized more severe appendicitis.

A history of appendicitis or appendectomy, particularly before the age of 20 years, has previously been linked to variation in the risk of several inflammatory diseases (12–17). No population-based study has, however, yet evaluated the association between appendicitis and the potential consequences of chronic prostatic inflammation. In this nationwide study, we thus for the first time examine the association between appendicitis before age 20 years and subsequent prostate cancer development.

Ethical statement

The study was approved by the regional Ethical Review Board, Uppsala, Sweden (2014/324).

Study population

Through the Swedish Military Conscription Register, we identified a cohort of 284,198 Swedish men, born between 1952 and 1956, who underwent mandatory military conscription at age 18 to 19 years. At conscription examination, participants were subject to standardized tests for physical fitness and cognitive function, resulting in a score (low to high; 0–9 for physical fitness, 1–9 for cognitive function). Trained personnel performed measurements of height and weight, and a blood test was performed, analyzed for erythrocyte sedimentation rate (ESR, a measure of systemic inflammation) and erythrocyte volume fraction (EVF). The examination also included a health questionnaire, sent to the participant in advance, and an interview as well as physical examination, both performed by a physician. Diagnoses were recorded by the examining physician, based on health questionnaire and interview. The recording of diagnoses was performed on a practical clinical basis, with emphasis on conditions potentially affecting the participant's capacity to undertake military service, using international classification of diseases, 8th revision(ICD-8) codes. A summary disease score, summarizing presence and severity of health problems relevant to performance during military service, was further determined by the examining physician. Socioeconomic and demographic variables, including region of residence in 1970, household head's occupation in 1960 and household crowding in 1960 (measured in persons per room) were obtained from population-based registers held by the government agency Statistics Sweden (https://www.scb.se/en/services/).

Of the 284,198 available subjects, we excluded 2,564 due to errors in personal identification number, female sex, or uncertain vital status, 182 due to improbable anthropometric measures, and 35 due to ill-defined summary disease score. We further omitted subjects with neoplasms at time of conscription (n = 599) as well as those with other malignant neoplastic diagnosis prior to prostate cancer diagnosis (n = 47). We also excluded men with missing information on variables used in the analyses (n = 38,198), making 242,537 subjects available for complete case-analysis. For secondary analyses, using outcome based on prostate cancer stage, 234 subjects with prostate cancer were excluded due to unknown tumor stage.

Exposure assessment

Exposure was assessed using the Swedish Military Conscription Register and determined as having a recorded diagnosis of previous appendicitis (ICD-8 codes 540, 541, 542, or 543.02) from conscription examination.

Assessment of outcome

We used the Swedish Cancer Register, with a completeness exceeding 95% for common cancer types (18), to identify prostate cancer diagnoses and corresponding TNM-stages. ICD7-code 177 was used to identify prostate cancer diagnoses. T1-T2, M0, N0 was classified as localized disease and T3-T4 or M1 or N1 as advanced. Lethal prostate cancer was defined as M1/N1 or prostate cancer as underlying cause of death from the Cause of Death Register.

Statistical analysis

We performed the statistical analyses using IBM SPSS Statistics version 22 (IBM Corp.). Descriptive statistics included frequencies, proportions, means, and standard deviations. Normal distribution of continuous variables was assessed using QQ plot, histogram, and box plot. Comparisons between exposed and unexposed men were made using Chi square test, Mann–Whitney U test or t test respectively where applicable. Unadjusted and multivariable-adjusted HRs and 95% confidence intervals (95% CIs) for the association between appendicitis diagnosed before conscription and time to prostate cancer diagnosis was estimated using Cox regression. The adjusted model included the categorical variables ESR (mm/h: <10, 10 to <15, 15+), body mass index [BMI (kg/m2: <18.5, 18.5 to <25, 25 to <30, 30+)], household crowding (persons per room divided into quartiles), region of residence, cognitive test score (low, moderate, high), physical capacity score (low, moderate, high), household head's occupation (categorical; six categories), and summary disease score (categorical; six categories from no or nonsignificant health problem to very severe health problem), as well as continuous variables EVF and height at conscription (cm). The functional form of the measures was explored using multivariable fractional polynomial modeling, which indicated a linear relationship with the log hazard of the outcome for both continuous variables. Statistical significance was defined as P < 0.05 and 95% CIs not including 1.00.

Among the 242,573 subjects eligible for analysis, 1,684 (0.7%) were later diagnosed with prostate cancer, over a total follow-up time including almost 8.6 million person-years. Median age at prostate cancer diagnosis was 53 years, and the median follow-up time was 36.7 years (median age at the end of follow-up was 55.5 years). Of the 1,450 cancer cases with known stage, 1,256 (86.6%) were classified as localized, 194 (13.4%) as advanced, and 82 (5.7%) as lethal.

At time of conscription assessment, 2,093 (0.9%) men had, according to records from conscription examination, been diagnosed with appendicitis. Characteristics of exposed and unexposed subjects are listed in Table 1. Men with a history of appendicitis were less likely to be sons of office workers, but more likely to be sons of farm owners compared with men without a history of appendicitis. Exposed men were also less likely to come from crowded households, and tended to perform better on physical tests. No difference between the groups was found for BMI or cognitive performance test score, but men with a history of appendicitis had a higher ESR at time of conscription assessment.

Table 1.

Characteristics of the exposed and unexposed subjects (history of appendicitis at time of conscription), in a cohort of Swedish men (n = 242,573) born 1952 to 1965

History of appendicitisNo history of appendicitis
Characteristicsn = 2,093n = 240,480P-value
Age at conscription (years) 
 Median (min–max) 18 (17–23) 19 (16–28) P < 0.001a 
Erythrocyte sedimentation rate (mm/h) 
 Median (min–max) 3.0 (1.0–51.0) 2.0 (1.0–89.0) P < 0.001a 
Height at conscription (cm) 
 Mean (SD) 178.7 (6.5) 178.7 (6.4) P = 0.935b 
Household crowding (persons per room) n (%) n (%)  
 ≤2 1,333 (63.7) 140,664 (58.5) P < 0.001c 
 >2 760 (36.3) 99,816 (41.5)  
Household head's occupation. Census 1960 
 Manual worker 864 (41.3) 99,585 (41.4) P < 0.001c 
 Agricultural worker 57 (2.7) 9,331 (3.9)  
 Farm owner/manager 303 (14.5) 23,753 (9.9)  
 Office worker 519 (24.8) 67,089 (27.9)  
 Business owner/manager 244 (11.7) 25,964 (10.8)  
 Others 106 (5.1) 14,758 (6.1)  
Physical working capacity score 
 Lowest (0–3) 76 (3.6) 13,370 (5.6) P < 0.001c 
 Moderate (4–6) 994 (47.5) 119,809 (49.8)  
 Highest (7–9) 1,023 (48.9) 107,301 (44.6)  
Cognitive function score 
 Lowest (1–3) 418 (20.0) 49,103 (20.4) P = 0.869c 
 Moderate (4–6) 1,104 (52.7) 126,494 (52.6)  
 Highest (7–9) 571 (27.3) 64,883 (27.0)  
BMI at conscription (kg/m2
 Underweight (<18.5) 251 (12.0) 27,933 (11.6) P = 0.427c 
 Normal weight (18.5 to <25) 1,677 (80.1) 194,455 (80.9)  
 Overweight (25.0 to <30) 137 (6.5) 15,691 (6.5)  
 Obese (30+) 28 (1.3) 2,401 (1.0)  
History of appendicitisNo history of appendicitis
Characteristicsn = 2,093n = 240,480P-value
Age at conscription (years) 
 Median (min–max) 18 (17–23) 19 (16–28) P < 0.001a 
Erythrocyte sedimentation rate (mm/h) 
 Median (min–max) 3.0 (1.0–51.0) 2.0 (1.0–89.0) P < 0.001a 
Height at conscription (cm) 
 Mean (SD) 178.7 (6.5) 178.7 (6.4) P = 0.935b 
Household crowding (persons per room) n (%) n (%)  
 ≤2 1,333 (63.7) 140,664 (58.5) P < 0.001c 
 >2 760 (36.3) 99,816 (41.5)  
Household head's occupation. Census 1960 
 Manual worker 864 (41.3) 99,585 (41.4) P < 0.001c 
 Agricultural worker 57 (2.7) 9,331 (3.9)  
 Farm owner/manager 303 (14.5) 23,753 (9.9)  
 Office worker 519 (24.8) 67,089 (27.9)  
 Business owner/manager 244 (11.7) 25,964 (10.8)  
 Others 106 (5.1) 14,758 (6.1)  
Physical working capacity score 
 Lowest (0–3) 76 (3.6) 13,370 (5.6) P < 0.001c 
 Moderate (4–6) 994 (47.5) 119,809 (49.8)  
 Highest (7–9) 1,023 (48.9) 107,301 (44.6)  
Cognitive function score 
 Lowest (1–3) 418 (20.0) 49,103 (20.4) P = 0.869c 
 Moderate (4–6) 1,104 (52.7) 126,494 (52.6)  
 Highest (7–9) 571 (27.3) 64,883 (27.0)  
BMI at conscription (kg/m2
 Underweight (<18.5) 251 (12.0) 27,933 (11.6) P = 0.427c 
 Normal weight (18.5 to <25) 1,677 (80.1) 194,455 (80.9)  
 Overweight (25.0 to <30) 137 (6.5) 15,691 (6.5)  
 Obese (30+) 28 (1.3) 2,401 (1.0)  

aP-value from Mann–Whitney U test.

bP-value from t test.

cP-value from Chi-square test.

Men with a history of appendicitis at conscription were more likely to develop prostate cancer later in life (crude HR 1.79; 95% CI, 1.15–2.79). Multivariable adjustment for potential confounders attenuated the risk estimate somewhat (HR 1.70; 95% CI, 1.08–2.67). Although the analysis was limited by small numbers, the results indicate a higher magnitude association for advanced (HR 4.42; 95% CI, 1.74–11.22) and lethal (HR 8.95; 95% CI, 2.98–26.91) prostate cancer (Table 2). Inclusion of men without complete covariate information rendered an essentially unchanged unadjusted estimate (HR 1.76; 95% CI, 1.13–2.73).

Table 2.

HR and 95% CI for subsequent prostate cancer, total and by stage, among subjects (n = 242,573) with and without history of appendicitis at time of conscription

OutcomeAppendicitis: yes/non events/n subjectsUnadjusted HR (95% CI)P-valueMultivariable adj. HR (95% CI)aP-value
Total prostate cancer No 1664/240,480   
 Yes 20/2,093 1.79 (1.15–2.79) P = 0.01* 1.70 (1.08–2.67) P = 0.02* 
Localized prostate cancer No 1248/240,253b   
 Yes 8/2,086b 0.98 (0.49–1.97) P = 0.96 0.81 (0.4–1.63) P = 0.55 
Advanced prostate cancer No 189/240,253b   
 Yes 5/2,086b 3.78 (1.55–9.22) P = 0.003* 4.42 (1.74–11.22) P = 0.002* 
Lethal prostate cancer No 78/240,253b   
 Yes 4/2,086b 7.13 (2.6–19.54) P < 0.001* 8.95 (2.98–26.91) P < 0.001* 
OutcomeAppendicitis: yes/non events/n subjectsUnadjusted HR (95% CI)P-valueMultivariable adj. HR (95% CI)aP-value
Total prostate cancer No 1664/240,480   
 Yes 20/2,093 1.79 (1.15–2.79) P = 0.01* 1.70 (1.08–2.67) P = 0.02* 
Localized prostate cancer No 1248/240,253b   
 Yes 8/2,086b 0.98 (0.49–1.97) P = 0.96 0.81 (0.4–1.63) P = 0.55 
Advanced prostate cancer No 189/240,253b   
 Yes 5/2,086b 3.78 (1.55–9.22) P = 0.003* 4.42 (1.74–11.22) P = 0.002* 
Lethal prostate cancer No 78/240,253b   
 Yes 4/2,086b 7.13 (2.6–19.54) P < 0.001* 8.95 (2.98–26.91) P < 0.001* 

aModel adjusted for year of birth (categorical), ESR (categorical; mm/h: <10, 10 to <15, 15+), EVF (continuous), BMI (categorical; kg/m2: <18.5, 18.5 to <25, 25 to <30, 30+), household crowding (categorical; persons per room divided into quartiles), region of residence in 1970 census (categorical), cognitive test score (categorical: low, moderate, and high), physical capacity score (categorical: low, moderate, and high), household head's occupation from 1960 census (categorical; six categories), height at conscription (continuous, cm), summary disease score (categorical; five categories: nonsignificant to very significant health problems).

bTwo hundred and thirty-four subjects excluded from analysis due to unknown tumor stage.

*Denotes statistically significant result.

In this population-based prospective cohort study, we found that men with a history of appendicitis at time of military conscription assessment in late adolescence had a higher risk of developing prostate cancer later in life. Higher magnitude associations were further observed between appendicitis and advanced and lethal prostate cancer, lending support to the hypothesis that sensitivity to inflammation during childhood, and the related inflammatory response, may play a role in prostate carcinogenesis.

Previous studies examining the association between appendicitis or appendectomy and risk for neoplastic disease have reported contradictory results (19–22). To our knowledge only two previous studies have addressed the association between appendicitis or appendectomy and prostate cancer risk, none of which reported a significant association. The inconsistency with our finding could possibly be explained in one case by retrospectively collected data (23) and in the other, showing a statistically nonsignificant positive association (HR 1.2; 95% CI, 0.4–2.9), by shorter follow-up time and few cases of prostate cancer (n = 17) (24). The increased risk observed in this study, between a history of appendicitis by late adolescence and prostate cancer later in life, might also not be generalizable to appendicitis at any age.

Accumulating evidence supports an important influence of local prostatic inflammation on prostate carcinogenesis (2). Associations have been found between polymorphisms in genes related to immune response, such as Toll-like receptor (TLR) and T-helper influencing cytokines, and prostate cancer risk (25), suggesting that both the microbial environment and characteristics of the immune response might play a role in prostate carcinogenesis. Studies of prostate cancer in relation to other conditions associated with specific immune profiles might add to our understanding of what inflammatory processes are involved (26). A large prospective cohort study reported an inverse association between asthma and prostate cancer, which might be related to the Th2-skewed immune response characteristic for asthma (4), but other studies have reported contradictory findings and the link between asthma and prostate cancer remains unclear (27).

Associations have been observed between appendicitis or appendectomy and several inflammatory or immune-related conditions: inverse for ulcerative colitis (12, 14, 28), MS (16), and coeliac disease (15); and positive for Crohn's disease (13, 28). Generally, associations are exclusive to or stronger for appendicitis, compared to appendectomy per se (which may not be due to appendicitis), and for appendectomy due to perforated appendicitis (which is more likely to signal acute appendicitis) compared to appendectomy due to other causes (12–16, 20). This has been interpreted as implying an underlying biological, possibly immunological, mechanism, rather than an immune-modulating or other effect of appendectomy.

Earlier studies have, in analogy with our results, found an inverse association between appendicitis and ulcerative colitis restricted to subjects with appendicitis before age 20 years (12, 14). A possible explanation is an underlying immunologic mechanism specifically associated with appendicitis at a young age, for example an increased immune sensitivity to infections. Similar mechanisms have been suggested to explain associations between a history of acne vulgaris, rheumatic fever or tonsillectomy before young adulthood and prostate cancer risk (29–32). Results from migration studies further indicate that early-life environmental exposures influence the risk of prostate cancer, suggesting vulnerability to carcinogenic exposures during the development and maturation of the prostate in childhood and puberty (33).

Evidence suggests that the pathology of appendicitis is immunologically driven, and that underlying biological mechanisms might distinguish phlegmonous from gangrenous appendicitis (9–11). Polymorphisms in the gene coding the pro-inflammatory cytokine IL6 have been associated with a higher risk for gangrenous appendicitis (11). Gangrenous appendicitis has, compared to phlegmonous appendicitis, also been associated with a distinct cytokine pattern suggestive of pro-inflammatory type 17 T-helper cell (Th17) activation (9), as well as signs of a Th1-shifted immune response (10).

The association between appendicitis and a Th1-shifted immune-response has previously been suggested as an explanation for the inverse association with ulcerative colitis (Th2-associated) and positive association with Crohn's disease (Th1-associated) (12, 14). A similar explanation has been proposed to account for the inverse association previously observed between asthma and prostate cancer (4), and could possibly play an underlying role in the association observed in this study. The activation of another type of T-helper cell, Th17, has further been suggested to play a role in appendicitis (9) and potentially also prostate cancer (2, 4), and constitutes another conceivable underlying mechanism.

The number of exposed men in the study is in an order of magnitude consistent with incidence of appendicitis (5, 34) and the diagnostic accuracy in Sweden at the time was estimated to 79% (34). Also, young and adolescent men have been shown to have the lowest incidence of negative appendectomies and incidental appendectomies, reducing potential misclassification of the diagnosis (5, 34).

The men in our cohort had a median age of 55 years at end of follow-up, which is clearly below the median age of prostate cancer diagnosis in Western countries (35). The study could thus be argued to specifically examine the association between appendicitis before late adolescence and early onset prostate cancer, which may constitute a separate entity with a more prominent hereditary component and higher cause-specific mortality (36). Even if the association may not be generalizable to prostate cancer at later ages, early prostate cancer remains a clinically important outcome.

The strengths of this study include its large study-population and prospectively collected data from national registers covering almost all Swedish residents. The use of appendicitis as a measure of immune response profile is unspecific and indirect, but underlying immunologic mechanisms reflected in clinically identifiable diseases may offer new insight into immune mechanisms of relevance to prostate carcinogenesis. A proportion of men were excluded from the analyses due to missing information; the majority because of conditions that classified them as unfit for military service and thus from further conscription assessments. The study sample thus represents a slightly healthier subset of the study population. Alleviating potential concerns about selection bias, inclusion of men with missing covariate values, however, left the results essentially unchanged. As in all observational studies, we cannot entirely exclude the possibility of residual confounding by socioeconomic or other factors, but the higher magnitude association observed for advanced and lethal prostate cancer suggests a biologic explanation.

In conclusion, we observed a statistically significant increased risk for prostate cancer, especially advanced and lethal prostate cancer, for men with a history of appendicitis by late adolescence. We propose that appendicitis at an early age might mark a specific immune profile, which in turn is associated with an increased risk for prostate cancer. Although further research is required regarding mechanisms underlying this association, this study adds another area of investigation potentially relevant to prostate carcinogenesis.

No potential conflicts of interest were disclosed.

Conception and design: H. Ugge, R. Udumyan, O. Andrén, S. Montgomery, K. Fall

Development of methodology: H. Ugge, R. Udumyan, K. Fall

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): S. Montgomery, K. Fall

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): H. Ugge, R. Udumyan, O. Andrén, K. Fall

Writing, review, and/or revision of the manuscript: H. Ugge, R. Udumyan, J. Carlsson, S. Davidsson, O. Andrén, S. Montgomery, K. Fall

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): O. Andrén

Study supervision: J. Carlsson, S. Davidsson, O. Andrén, K. Fall

Other (prepared data for the analysis): R. Udumyan

S. Montgomery has received support from the UK Economic and Social Research Council (ESRC) as grants to the International Centre for Life Course Studies (grants RES-596-28-0001 and ES/JO19119/1).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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