Appendicitis before age 20 years is associated with an...

1

Appendicitis before age 20 years is associated with

an increased risk of later prostate cancer

Henrik Ugge1, Ruzan Udumyan

2, Jessica Carlsson

1, Sabina Davidsson

1, Ove Andrén

1,

Scott Montgomery2,3,4

, Katja Fall2,5

1. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

2. Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro,

Sweden

3. Clinical Epidemiology Unit, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden

4. Department of Epidemiology and Public Health, University College London, UK.

5. Department of Medical Epidemiology, Karolinska Institutet, Stockholm, Sweden

Corresponding author

Henrik Ugge, M.D.

Department of Urology

Örebro University Hospital

701 85 Örebro

Sweden

Phone: +46733391196

Email: [email protected]

Funding: 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).

Running title: Appendicitis and prostate cancer risk

Keywords: Prostate cancer, inflammation, cancer epidemiology, appendicitis, prostatitis

Conflict of interest: The authors declare no potential conflicts of interest

Word count; Abstract: 246; Main text: 2,302.

Tables: 2

Figures: 0

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mailto:[email protected]

http://cebp.aacrjournals.org/

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Abstract

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 hazard ratios (HR) and 95% confidence intervals

(95% CI) 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.

Conclusion: 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.




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Introduction

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.




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Methods

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 18-19 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

ICD-8 (international classification of diseases, 8th revision) 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/).




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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.

Armonk, NY, USA). 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




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Chi square test, Mann-Whitney-U test or t-test respectively where applicable. Unadjusted and

multivariable-adjusted Hazard Ratios (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+), 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; 6 categories) and summary disease score

(categorical; 6 categories from no or non-significant 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% confidence

intervals not including 1.00.




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Results

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.

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).




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Discussion

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 non-significant 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,




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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




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interleukin 6 (IL-6) 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.




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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.




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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 1952-1965.

Characteristics History of

appendicitis

No history of

appendicitis P-value

n=2,093 n=240,480

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/m

2)

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.




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.

Outcome Appendicitis: yes/no n events / n subjects Unadjusted HR (95% CI) P-value Multivariable adj. HR (95% CI)a P-value

Total prostate cancer No 1664 / 240,480 1 1

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 1 1

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 1 1

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 1 1

Yes 4 / 2,086b 7.13 (2.6-19.54) p<0.001* 8.95 (2.98-26.91) p<0.001*

a Model 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; 6 categories), height at conscription (continuous,

cm), summary disease score (categorical; 5 categories: non-significant to very significant health problems).

b234 subjects excluded from analysis due to unknown tumor stage.




Published OnlineFirst March 27, 2018.Cancer Epidemiol Biomarkers Prev Henrik Ugge, Ruzan Udumyan, Jessica Carlsson, et al. increased risk of later prostate cancerAppendicitis before age 20 years is associated with an

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