Appendectomy and subsequent cancer risk

J Chron Dis Vol. 36. No. 5. pp. 391-396, 1983 Printed in Great Britain. All rights reserved

APPENDECTOMY

0021-9681/83/050391-06$03.OWO

Copyright 0 1983Pergamon Press Ltd

AND SUBSEQUENT

CANCER

RISK

CHRISTOPHER P. HOWSON Division

of Epidemiology, School of Public Health, University of California Los Angeles, CA 90024, U.S.A. (Received

in revised

form 23

September

1982)

Abstract-Although earlier epidemiologic studies reported a positive association between appendectomy and certain cancers, interest was limited due to lack of confidence in the study findings. However, recent morphologic studies on the immune structure of the vermiform appendix in the rabbit and man argue for a reevaluation of the appendectomy-cancer association. This paper reviews briefly the morphologic and epidemiologic literature on the subject to date. The validity of the earlier epidemiologic findings is discussed and avenues for further research assessing the relationship of appendectomy to subsequent cancer risk are proposed.

INTRODUCTION IN THE 1960’s, a number of researchers using case-control techniques to study various neoplastic diseases reported a higher prevalence of prior appendectomy among their index case populations than among their control populations. Subsequent epidemiologic investigation focused on the relationship between appendectomy and increased cancer risk. Although the results indicated a positive association for certain cancers, the findings were inconclusive and interest in the appendectomy-cancer connection slowly waned. However, the findings of recent morphologic and immunologic studies of the vermiform appendix of both the rabbit and man have confirmed earlier findings and suggest that the organ may play an integral role in the functioning of the immune system. The nature of this role is not yet clear but the recent evidence is worthy of review as it lends new biologic plausibility to the earlier epidemiologic observations. The question of whether or not appendectomy promotes future cancer risk through immune dysfunction in individuals is still unanswered. Neither the morphologic nor the epidemiologic evidence alone is strong enough to present a case for an appendectomycancer association. But taken together, the study findings are provocative and merit a closer look particularly in view of the high rate of appendectomy in the United States today [I]. This paper will review briefly both the recently published morphologic studies on the immune structure of the vermiform appendix and the epidemiologic literature assessing the association between appendectomy and subsequent cancer risk. The author will discuss the validity of the study findings and will suggest ways in which the putative association between appendectomy and subsequent cancer risk can be more accurately assessed. MORPHOLOGIC

AND

EPIDEMIOLOGIC

EVIDENCE

Morphologic evidence

While the immunologic role of the appendix in mammals has not been defined, the appendix of both the rabbit, the most studied model, and man contains significant amounts of lymphoid tissue, the former exhibiting a mitotic index similar to that of the rabbit thymus [2]. In the rabbit appendix, two morphologically distinct sections have 391

392

CHRISTOPHERP. H~WSON

been identified which contain functional IgM and IgA bearing cells [3-53. These sections are thought to be germinal centers, a kind of antigen-dependent microenvironment where immature B cells undergo a selective or nonselective amplification becoming after subsequent maturation part of the immunologic pool of either memory or virgin mature B cells respectively [6]. Rabbit appendiceal tissue has also been shown to contain both lymphocytes which bind complement [7] as well as cells capable of suppressing an in vitro secondary IgG and IgM response to antigen. Evidence suggests that these “suppressor” cells are part of a T cell population which exerts a general rather than an antigen-specific suppressor function in the rabbit immune system [S]. The human appendix also contains B cell dependent lymphoid tissue [9]. Its appenditeal lymphocyte population includes Ig’s of various types as well as a precursor cell, which after migration via the lymphatics and blood stream, is thought to settle in the intestinal lamina propria producing IgA [lo]. Approximately 3+60% of the lymphocytes in the human appendix are B cells while 40-50% are T cells. The lymphoid cells exhibit a poor plaque-forming response to sheep red blood cells but this may only be a result of suppressor activity similar to that shown in the rabbit appendix [ 111. There are no published data as to the effect of appendectomy on subsequent in vioo or in citro immune function in either animals or man. Epidemiologic

evidence

In 1964, the first epidemiologic study specifically investigating the relationship between appendectomy and subsequent cancer risk was published. McVay, in a case-control study of major cancer sites, observed the prevalence of appendectomy to be higher among colon cancer patients than among controls with cardiovascular disease [12] ; see Table 1. These findings piqued further epidemiologic interest. In relatively short order the results of several case-control series were published. Berndt replicated McVay’s findings in a study of German patients with cancer of the colon and rectum. He observed a higher prevalence of prior appendectomy among his cases than among his controls [13]. Howie and Timperly, on the other hand, found no association with appendectomy in a case-control study of patients with cancer of the colon, breast and uterus [14]. Hyams and Wynder reported a much higher prevalence of appendectomy among 100 male Hodgkin’s disease cases in New York than among 815 matched controls. They noted that the prevalence of appendectomy was not elevated among their female Hodgkin’s disease cases but suggested that their female case population (33 individuals) may have been too small to permit any definite conclusions [15]. Gross, in a case-control study of 300 cancer cases, observed that a greater proportion of cases had undergone appendectomy at age 40 and above than had controls. He later reported that the case frequency of appendectomy within 16 yr prior to the onset of cancer was significantly higher than the frequency in controls 1161. Cassimos et al. identified 500 individuals with cancers of various sites and matched each case to a non-cancer control by age, sex, and race. A significantly larger number of female cases with cancers of the breast and ovary had had a previous appendectomy than had their matched controls [17]. Bierman reported that the association with cancers of various sites appeared to be high or low depending on the specific malignant neoplasm. He singled out carcinomas of the large intestine, stomach, lung, breast, and ovary, as well as leukemia and lymphoma as the sites most strongly associated with past appendectomy

C181. Other epidemiologic evidence supporting the theory of appendectomy as a risk factor in cancer was presented by Robinson in a study of cancer patients in Israel. He reported a significantly higher prevalence of appendectomy among his cancer patients than among his controls. Comparison by sex showed the prevalence to be higher in females than in males although this difference was observed only in the index cases and not among the controls [19].

*Derived

from published

McVay Jr., I964 [ 121 Berndt, 1970 [13] Howie PI ul., 1966 [I41 Hyams et al., 1968 [I 53 Gross, 1966 [I61 Cassimos et ul.. 1973 [l7] Bierman, 1970 [I81 Robinson, 1968 [I91 Howson et al., 1975 [20] Haines et ~11..1982 1211 Moertel c’t al., 1974 [22]f

Ref.

data;

Registry

I.

interval.

Autopsy Hospital Interviews Hospital Interviews Hospital Autopsy Interviews Hospital Hospital Hospital RR = risk ratio;

records records records

records

records

records

source

tCohort

STUDIES OF APPENDECTOMY

Data

PUBLISHED

OR = odds ratio. CI = 95”,, confidence

Kansas City Germany Scottish Cancer New York City New York City Greece Los Angeles Israel Oklahoma City England Rochester. MN

Population

TABLE

Cancer

CANCER

site(s)

RISK

study.

Colon Colon, rectum Breast. cervix. colon Hodgkin’s disease (males) Mixed Breast (female), ovary Mixed Mixed Pancreas Pancreas Mixed

AND

229 215 1019 100 300 66 608 435 201 116 1770

Number of cases OR OR OR OR OR OR OR OR OR OR RR

= = = = = = = = = = =

1.9; 0.5: 0.8; 3.6; 0.9: 1.2. 1.7: 1.5; 2.1: 0.9; 1.1

CI(l.2.2.9) Cl(O.3,l.O) CI(0.6,1.1) Cl(2.0.6.3) CI(O.6.1.4) CI(O.7.2.2) CI(l.3.2.1) CI(1.1.2.1) CI(l.2.3.7) C-1(0.5.1.6)

Measure of Association*

>

z ;o” a B e 0 S 81 S ; jr

z a

S W

: ”

z

394

CHRISTOPHERP. HOWSON

Howson and Asal compared 201 pancreatic cancer cases to an equal number of matched controls and reported a higher prevalence of appendectomy among the cases. Their exposure criterion was strict; only those cases who had an appendectomy at least 10 yr prior to the onset of cancer symptoms were labelled exposed and included in the analysis [20]. Haines et al. in a study of 116 cases of pancreatic cancer observed no association with appendectomy. They excluded cases whose appendectomies were performed within 5 yr of their cancer diagnosis [21]. Moertal et al. in the only cohort study of appendectomy and cancer risk published to date followed 1779 residents of Rochester, Minn. who had had appendectomies between the years of 1925 and 1944. The comparison group was 1943 residents of Rochester who had had dental extraction within the same time interval. The comparison cohort was matched to the appendectomy cohort by age, sex, and calendar years of observation. Both the appendectomy and comparison populations were followed up through 1 January, 1972. No significant differences in the overall cancer rate were observed between the two groups [22]. DISCUSSION

The concept of the vermiform appendix as a vestigial pouch whose sole purpose in life is to become inflamed at the most inopportune times is prevalent within both the medical and lay establishments. Appendectomy is often performed incidentally in the course of abdominal surgery. While the existing immunologic data supporting the hypothesis that appendectomy promotes cancer risk through some intervening immune dysfunction are incomplete and the epidemiologic data inconclusive, the data are by no means sufficient to reject the hypothesis outright. In fact, inference from the totality of the evidence cited above argue strongly for further immunologic and epidemiologic studies especially given that the prognosis for most cancers remains poor [23]. For example, the morphologic studies have demonstrated that the vermiform appendix of both the rabbit and man contains significant amounts of lymphoid cells. While this finding is intriguing in view of the epidemiologic link between appendectomy and cancer risk, the importance of this lymphoid cell population in maintaining a patent immune system is not known. Perhaps the appendix is merely a passive trap or repository for circulating lymphoid cells and has no active role in immune regulation. Clearly, further investigation into the structure and immune function of the vermiform appendix is needed. Studies assessing immune regulation and competency, pre-and post-appendectomy, in a suitable animal model are the next logical step. If appendectomy were found to adversely affect immunocompetency in animals, it would lend credence to the possibility of an appendectomy-cancer association in man particularly in view of the high incidence of neoplasia in immunosuppressed individuals [24]. The epidemiologic issue of whether or not appendectomy in man is specifically related to increased cancer risk also awaits resolution. The earlier epidemiologic studies attempted to address this issue but methodologic concerns led to questions over the validity of their findings. In the case-control studies, most of which show a positive association between appendectomy and certain neoplasias, the major concern is internal validity: whether or not the studies adequately controlled for variables which may have confounded the levels of the observed association. For example, Berndt felt that the high prevalence of appendectomy observed in his case as compared to his control population may have been a result of confounding by social class. Since both the frequency of appendectomy and the incidence of bowel cancer are proportional to social class and since he did not control for social class in the design of his study, Berndt acknowledged that his positive measure of association may have been biased upwards. He concluded that observed differences in prevalence of appendectomy over various cancer sites can be explained by differences in socioeconomic class alone [ 131. Another important variable uncontrolled for in the design of earlier studies was age. Many of the case series compared case and control populations of different mean ages

Appendectomy and Subsequent Cancer Risk

395

[ 12, I 7. I 81. Since cancer risk and the rate of appendectomy both differ with age [35], the validity of the study findings may have been weakened. A further concern with past case-control studies centers on the problem of potential misclassification of cases in regard to exposure category (appendectomy). Several of the studies did not specify their criteria for exposure [ 12 14. 17 191. Thus cases who had appendectomies as a direct result of the early cancer process may have been erroneousI> labeled exposed. A misclassification of this type would be more likely to bias studies of gastrointestinal cancer and would serve to attenuate a positive measure of association. Of the two studies that did strictly define exposure in the case population. however. one reported a positive association between appendectomy and pancreatic cancer [ZO] while the other observed no association 1211. Finally, the issues of selection bias and differential recall were not addressed in man) of the caseecontrol studies. For example, the use of autopsy series [12,18] and hospital based records [l3, 15. 17,20.21] may have diminished the validity of the study findings. Similarly, differential recall on the part of cases and controls when interviews and questionnaires were employed may have also affected validity by conceivably augmenting the differences in prevalence of appendectomy observed between the two groups [14. 16. 18. 193. The sole cohort study presented [21] had itself two potential sources of bias. First. while Moertel rt LII. correctly excluded from their analyses those persons who had a malignant neoplasm diagnosed prior to or concurrent with their appendectomy or control procedure. they did not exclude individuals whose malignant neoplasms were diagnosed within a specified period of time just after their appendectomy. Thus. they risked including in their case population persons whose appendectomy may have resulted from an existing but as yet undiagnosed malignancy. Such a bias could lead to an overenumeration of observed cancer cases among those exposed. Second. the authors did not distinguish those individuals who had a primary appendectomy as a direct result of inflammation from those who received an incidental appendectomy in the course of other abdominal surgery. The risk of cancer in these two groups could conceivably differ. A review of the literature relating to appendectomy and cancer risk leaves us with more questions than answers. For example, is the appendix in man involved in immune regulation’? Does appendectomy leave a person immunologically handicapped? If so, the most important question is. does appendectomy increase an individual’s cancer risk? By how much’? Does age at appendectomy affect cancer risk‘! The answers to these questions can be answered only through further immunologic and epidemiologic research. For example. if appendectomy were found to affect immunocompetency by decreasing the ‘*carcinogenic threshold” in a suitable animal model, the rationale for further epidemiologic studies of a more sophisticated analytic design would be provided. An example of such would be a historical cohort study whose design WOLII~ control for key demographic characteristics as well as such variables as family and personal medical history, age at appendectomy, reason for appendectomy. socioeconomic status. time between appendectomy and first cancer diagnosis. and accessibility of health care. While there is no direct evidence suggesting that the removal of a non-diseased appendix in an otherwise healthy person is harmful, the weight of the findings presented here argues the need for further investigation of a more sophisticated nature into the putative association between appendectomy and subsequent cancer risk.

CONCLUSION

The long-term health effect of appendectomy, a relatively prevalent and low risk procedure in humans, is not known. However, enough morphologic and epidemiologic evidence exists to suggest that appendectomy may influence subsequent cancer risk. Clearly, further immunologic and epidemiologic research of a more sophisticated and rigorous nature is needed before we can reject the possibility of an appendectomyPcancer connection.

396

CHRISTOPHERP. HOWSON

Ack,low/edyenlent-The author wishes to thank Dr Ralph R. Frerichs, Professor Public Health, University of California, Los Angeles, for his guidance in revising

of Epidemiology, this manuscript,

School

of

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