< > Home : FAQ : Professional : Chlamydiales : Immunobiology : Infections : Diagnosis & Treatment : Links : Contact Us

Chlamydial genital tract infections

Chlamydia as a cofactor in cervical cancer.

Globally, cervical cancer is among the 3 most prevalent malignancies in women, with more than 400 000 cases reported in 1998, of which 12 800 were in the United States [Zenilman, 2001; see also background information from the US National Cancer Institute]. Oncogenic types of human papilloma (wart) virus (HPV) are major risk factors for cervical cancer but by no means totally explain the epidemiology of the condition.  However HPV infection is common and few such cases progress to cervical cancer, suggesting that other cofactors are involved. Identifying such co-factors is difficult, as sexually transmitted infections including HPV and C. trachomatis are subject to numerous behavioural and clinical confounder. Furthermore these may operate at different points in the long progression from initial HPV infection to cancer. Careful biological and behavioural data collection is essential, together with multivariate analysis. Large study populations are also necessary because of the relatively low incidence of cervical cancer. Smoking has been consistently identified as a risk factor and smoking status at the time of serum collection can be determined from serum levels of cotinine, a nicotine metabolite. Nevertheless, the literature on the aetiology of cervical cancer is full of examples of epidemiological confounders [Zenilman, 2001].

An early attempt by Schachter et al., 1982 to demonstrate an association between chlamydia and cervical cancer in the era before the role of HPV was discovered did not control for sexual behaviour and, in hindsight, was inconclusive [Zenilman, 2001]. In the post HPV era, Koutsky et al., 1992 found that cervical intraepithelial neoplasia (CIN), after adjustment for HPV status, was independently associated with serological evidence of chlamydial, gonococcal and cytomegalovirus (CMV) infection. Lehtinen et al 1996, working in Finland, found that prior chlamydial infection, particularly of organisms in a serovar G, F or K pool, was significantly associated with cervical carcinoma. However the Lehtinen study was limited by the small numbers of cancers and the lack of multivariate analysis. In Taiwan in a  community-based case-control study,  183 confirmed cervical cancer cases were compared with 293 healthy neighborhood controls.  Genus-specific antibodies to C. trachomatis, and antibodies to human cytomegalovirus and herpes simplex type 2 virus were determined by enzyme immunoassay. After adjustment for potential risk factors, parity and number of vaginal delivery were positively and significantly associated with an increased risk of invasive cervical cancer, as were antibodies to C. trachomatis (adjusted odds ratio = 7.0; 95% CI = 1.7 - 28.9), to HSV2 (OR = 2.3; 95% CI 1.1 - 4.6 and to CMV (OR = 4.1; CI 1.5 - 11.3). The use of a diaphragm for contraception was associated with a decreased risk of cervical cancer (OR = 0.4, 95% CI = 0.1 - 1.0) [Hsieh et al., 1999]. In Beirut Finan et al., 2002 and Tamim et al., 2002 in small studies found a higher rate of C. trachomatis infection in human papilloma virus-positive women. Within the papilloma virus-positive patients, there was no significant difference between those who were chlamydia positive or chlamydia negative with respect to the risk factors for cervical cancer that were studied. It was suggested that chlamydial infection might be a cofactor with papilloma virus in the aetiology of cervical cancer, possibly by modulating the host's immunity and/or precipitation of chronic inflammation [Tamim et al., 2002]. However other studies in Honduras, the US, Colombia and Spain failed to demonstrate any association between an agent of sexually transmitted infection, including C. trachomatis, and cervical cancer [Zenilman, 2001] and none of these studies is conclusive. 

A powerful longitudinal nested case control study [Hakama et al., 2000; Anttila et al., 2001] examined a cohort of 530,000 women in Finland, Norway and Sweden who had provided samples to serum banks over the years 1973 - 1994. Within this cohort, 128 women had developed invasive squamous cell cervical cancer at least 12 months after serum donation and, on average, 56 months before the diagnosis of cancer from a cervical smear [Anttila et al., 2001]. For each of these cases, serum from 3 matched controls were selected and studied for the prevalence of antibodies to 10 different C. trachomatis serotypes after adjusting for antibodies to cervical cancer-associated strains of HPV. The objective was to determine whether C. trachomatis might be a cofactor in the induction of cervical cancer. Serum cotinine was also measured to determine whether cigarette smoking played a role. After multivariate analysis, antibody to serotype G was most strongly associated with cervical cancer (adjusted odds ratio OR 6.6, 95% confidence interval CI 1. 6 - 27.0). Serotypes I and D were also significantly associated with  cervical cancer. Moreover the presence of serum IgG antibodies to more than 1 serotype  significantly increased the adjusted odds ratios for cervical cancer (P<.001 for trend). This finding was consistent with the previous study of Lehtinen et al., 1996 which included many of the same investigators and the same geographic region, but the number of individuals with antibody to many of the serotypes was small. While the evidence is suggestive of a link between past C. trachomatis infection and cervical cancer, the confidence intervals are wide and the number of cases of cervical cancer small. The amount of behavioural data collected was also limited. Thus the possibility that unknown behavioural or biological variables might have confounded the result cannot be excluded.  A smaller serological study found no association between circulating antichlamydial antibodies and the severity of cervical cancer [Reesinck-Peters et al., 2001].  [MEW comment: A number of smallish studies have reported an association between C. trachomatis serovar and different disease patterns. Such associations have yet to be widely accepted].

Mexico has one of the highest mortality rates of invasive cervical cancer in the world, particularly in the northern states bordering the USA. Women of Hispanic origin in the USA also have higher rates of cervical cancer than non - Hispanics. Research conducted on 2,436 women on both sides of the border (Sonora and Arizona) found a significantly higher prevalence of abnormal cervical cells on the Mexican side (11.4%) compared with the US (6.6%). There was no significant difference in prevalence of HPV between the two countries but the prevalence of C. trachomatis was higher in Mexico [Guilano et al., 2001]. Whether this was a chance event or was causally associated with the higher prevalence of cervical cancer in northern Mexico is unclear.

A large study in Brazil and the Phillippines of 499 women with invasive cervical cancer versus 539 control patients found serological evidence that C. trachomatis increased the risk of cervical cancer among HPV positive wormen (OR 2.1; 95% CI 1.1 - 4.0). [MEW comment: Note that the lowest confidence interval is close to 1]. There was a suggestion of increasing cervical cancer risk with increasing C. trachomatis antibody. It was concluded that C. trachomatis was a possible cofactor of HPV in the aetiology of cervical cancer, perhaps by causing  persistent, chronic, cervical inflammation [Smith et al., 2002]. In contrast another serological study, while observing that HPV, smoking and C. trachomatis infections were all risk factors for cervical cancer, concluded that jointly these factors had a strong antagonistic effect. This was not due to non-differential misclassification of serology for HPV16 [Hakama et al., 2001]. Ness et al., 2003,  measured antibodies by ELISA to C. trachomatis serovar D elementary bodies and to heat shock protein 60 (GroEL), and hsp10 (GroES). The Hawaiian study population was 117 women with ovarian cancer and 171 age- and ethnicity-matched population-based control subjects. They found that the probability of having ovarian cancer was 90% greater in women with the highest, compared with the lowest levels of antibody to whole chlamydiae (P=.05). There was also a monotonic trend (P=.09) in ovarian cancer risk associated with CHSP60-1 but not with CHSP60-2, CHSP60-3, or CHSP10. This is a small data and the results are only marginally significant in a statistical sense. However the data are consistent with the hypothesis that past or chronic persistent infection with C. trachomatis  may be a risk factor for ovarian cancer.

In Northern Sweden, the presence of C. trachomatis and of HPV DNA in cervical smears or cervical cancer biopsies as appropriate was assessed on 118 women with cervical cancer over a period up to 26 years versus 118 age and sample matched controls. At baseline, C. trachomatis DNA was present in 8% of cases but not among any of the controls. The relative risk for cervical cancer associated with past C. trachomatis infection, adjusted for concomitant HPV DNA positivity, was 17.1 (95% CI 2.6- infinity ).The presence of C. trachomatis and of HPV were not interrelated. Interestingly, whereas C. trachomatis was primarily found in specimens taken many years before cancer diagnosis, HPV DNA was associated with a short time interval before the diagnosis. Unlike HPV, none of the women were positive for C. trachomatis in both the prediagnostic smear and in the cervical cancer which subsequently developed. It was again concluded, this time using PCR, that prior cervical C. trachomatis infection was associated with an increased risk of development of invasive cervical cancer [Wallin et al., 2002].

It is usually assumed that chlamydial and other infections might play a role in the aetiology of cervical and other cancers  [Quirk & Kupinski, 2001] because of their ability to cause persistent inflammation. It has been suggested that active oxygen radicals from inflammatory cells might cause scission of host DNA that overwhelms repair mechanisms, while inflammatory cytokines might alter local immune surveillance of the cervix. In the laboratory, infection of HeLa cells, an immortalized human cervical tumour cell line, causes breakdown of N-cadherin: beta-catenin intercellular junctions and sequestration of beta-catenin to the region of the chlamydial inclusion [Prozialek et al., 2002]. The authors suggested that this might represent an important mechanism by which C. trachomatis alters epithelial function. [Comment: This is an interesting observation, but of uncertain relevance to the process of carcinogenesis].

[Comment: The larger serological studies suggest but do not prove that C. trachomatis might be a significant co-factor alongside HPV in the aetiology of cervical cancer. At the present time the number of large, well controlled and analysed epidemiological studies of this question is still relatively small. The role of chlamydiae in cervical cancer or indeed any other chronic disease is extremely difficult to prove conclusively. Further well designed epidemiological studies in a variety of geographical settings are indicated together with experimental work designed to elucidate whether there are plausible mechanisms to explain chlamydial-facilitated carcinogenesis].

[MEW] April 2003

NEXT: Urethritis in women

Infections index

References

Anttila, T., Saikku, P., Koskela, P., Bloigu, A., Dillner, J., Ikaheimo, I. et al.,  (2001). Serotypes of Chlamydia trachomatis and risk for development of cervical squamous cell carcinoma. Journal of the American Medical Association 285, 47-51. Full article [Plus comment in: JAMA. 285, 1703 - 1706 (2001).]

Finan, R. R., Tamim, H. & Almawi, W. Y. (2002). Identification of Chlamydia trachomatis DNA in human papillomavirus (HPV) positive women with normal and abnormal cytology. Archives of Gynecology and Obstetrics 266, 168 - 171.

Giuliano, A. R., Denman, C., Guernsey de Zapien, J., Navarro Henze, J. L., Ortega, L., Djambazov, B., Mendez Brown de Galaz, E. & Hatch, K. (2001). Design and results of the USA-Mexico border human papillomavirus (HPV), cervical dysplasia, and Chlamydia trachomatis study. Revista Panamerica Salud Publica 9, 172 - 181.

Hakama, M., Luostarinen, T., Hallmans, G., Jellum, E., Koskela, P., Lehtinen, M.  et al., (2000). Joint effect of HPV16 with Chlamydia trachomatis and smoking on risk of cervical cancer: antagonism or misclassification (Nordic countries). Cancer Causes and Control 11, 783 - 790.

Hsieh, C. Y., You, S. L., Kao, C. L. & Chen, C. J. (1999). Reproductive and infectious risk factors for invasive cervical cancer in Taiwan. Anticancer Research 19, 4495 - 4500.

Koutsky, L. A., Holmes, K. K., Critchlow, C. W., et al. (1992). A cohort study of the risk of cervical intraepithelial neoplasia grade 2 or 3 in relation to papillomavirus infection. New England Journal of Medicine 327, 1272 - 1278.

Lehtinen, M., Dillner, J., Knekt, P., et al. (1996). Serologically diagnosed infection with human papillomavirus type 16 and risk for subsequent development of cervical carcinoma: nested case-control study. British Medical Journal 312, 537 - 539. Full article

Ness, R. B., Goodman, M. T., Shen, C., Brunham, R. C. (2003). Serologic Evidence of Past Infection with Chlamydia trachomatis, in Relation to Ovarian Cancer. Journal of Infectious Diseases 187, 1147 - 1152.

Paavonen, J. (2001). Chlamydia trachomatis and cancer. Sexually Transmitted Infections 77, 154 - 156. [Editorial]

Prozialeck, W. C., Fay, M. J., Lamar, P. C., Pearson, C. A., Sigar, I. & Ramsey, K. H. (2002). Chlamydia trachomatis disrupts N-cadherin-dependent cell-cell junctions and sequesters beta-catenin in human cervical epithelial cells. Infection and Immunity 70, 2605 - 2613.

Quirk, J. T. &  Kupinski, J. M. (2001). Chronic infection, inflammation, and epithelial ovarian cancer. Medical Hypotheses 57, 426 - 428.

Reesink-Peters, N., Ossewaarde, J. M., Van Der Zee, A. G., Quint, W. G., Burger, M. P. & Adriaanse, A. H. (2001). No association of anti-Chlamydia trachomatis antibodies and severity of cervical neoplasia. Sexually Transmitted Infections 77, 101 - 102.

Schachter J., Hill, E. C., King, E. B., Heilbron, D. C., Ray, R. M., Margolis, A. J. & Greenwood, S. A. (1982).  Chlamydia trachomatis and cervical neoplasia. JAMA. 248, 2134 - 2138.

Smith, J. S., Munoz, N., Herrero, R., Eluf-Neto, J., Ngelangel, C., Franceschi, S., Bosch, F. X., Walboomers, J. M. & Peeling, R. W. (2002). Evidence for Chlamydia trachomatis as a human papillomavirus cofactor in the etiology of invasive cervical cancer in Brazil and the Philippines. Journal of Infectious Diseases 185, 324 - 331.

Tamim, H., Finan, R. R., Sharida, H. E., Rashid, M. & Almawi, W. Y. (2002). Cervicovaginal coinfections with human papillomavirus and Chlamydia trachomatis. Diagnostic Microbiology and Infectious Diseases 43, 277 - 281.

Wallin, K. L., Wiklund, F., Luostarinen, T., Angstrom, T., Anttila, T., Bergman F et al.,  (2002). A population-based prospective study of Chlamydia trachomatis infection and cervical carcinoma. International Journal of Cancer 101, 371 - 374.

Zenilman, J. M. (2001). Chlamydia and cervical cancer: a real association? JAMA 285, 81 - 83. [Editorial] Full text 

NEXT Urethritis

Infections index