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Pelvic inflammatory disease and epithelial ovarian tumors
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Obstetrics and Gynecology. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.ORCID iD: 0009-0005-1288-4645
2023 (English)Doctoral thesis, comprehensive summary (Other academic)Alternative title
Bäckeninflammation och epiteliala ovarialtumörer (Swedish)
Abstract [en]

Background: Epithelial ovarian cancer and borderline ovarian tumors consist of several histotypes in which high-grade serous carcinoma is the most common. The majority of epithelial ovarian tumors are considered to originate in the fimbriated end of the fallopian tubes. What initiates these tumors is far from completely understood. Pelvic inflammatory disease has been proposed as a modifiable risk factor for epithelial ovarian tumors. A major cause of pelvic inflammatory disease is Chlamydia trachomatis which has been shown to have cancer-causing potential. The overall purpose of this thesis was to study associations of pelvic inflammatory disease and C. trachomatis with risk of epithelial ovarian tumors.

Methods: In a cross-sectional study (Paper I) we collected ovarian tissue and corresponding blood samples from 69 women undergoing surgery due to suspected ovarian pathology. C. trachomatis specific protein (immunohistochemistry) and C. trachomatis DNA (qPCR) in ovarian tissue were analyzed (Paper I). In a nested case-control study (Paper II) prospective blood samples from 92 women diagnosed with high-grade serous ovarian cancer were matched to four controls each for age and date of plasma sampling. C. trachomatis specific plasma antibodies were analyzed by commercial Enzyme-Linked ImmunoSorbent Assay (ELISA) and Micro-ImmunoFluorescence (MIF) (Paper I and Paper II). We performed a nationwide register-based case-control study where we included 15 072 women diagnosed with epithelial ovarian cancer (Paper III), 4782 women diagnosed with borderline ovarian tumors (Paper IV), and ten controls each matched for age and residential district. Using national Swedish registers, we retrieved data on historyof pelvic inflammatory disease and the potential confounding factors parity, educational level, previous gynecological surgery, and hormonal therapy.

Results: We found C. trachomatis DNA in ovarian tissue of eight women with ovarian carcinoma, but not in ovarian tissue from women with borderline ovarian tumors or benign disease (Paper I). The prevalence of the C. trachomatis specific protein did not differ in benign and malignant tissue (Paper I). Prevalence of C. trachomatis specific plasma antibodies was similar in cases and controls at diagnosis (Paper I) and prospectively (Paper II). A history of clinically verified pelvic inflammatory disease was associated with an increased risk of epithelial ovarian cancer overall (Paper III) and borderline ovarian tumors overall (Paper IV). Histotype-specific analyses showed an increased risk of serous carcinoma (Paper III), high-grade serous carcinoma (Paper III), clear cell carcinoma (Paper III), and serous borderline ovarian tumors (Paper IV) but not significantly with other histotypes. A dose-response relationship was seen between an increased number of pelvic inflammatory disease episodes and epithelial ovarian cancer (Paper III), as well as borderline ovarian tumors (Paper IV).

Conclusions: This thesis contributes to an improved understanding of the association between pelvic inflammatory disease and epithelial ovarian tumors. The results regarding C. trachomatis are inconclusive and suggests that the association of pelvic inflammatory disease with epithelial ovarian tumors acts through mechanisms other than Chlamydia alone.

Abstract [sv]

Bakgrund: Epitelial ovarialcancer och ovariella borderlinetumörer består av flera histotyper där höggradigt seröst karcinom är den vanligaste. Majoriteten av epiteliala ovarialtumörer anses ha sitt ursprung i äggledarnas yttersta del, men vad som initierar dessa tumörer är inte klarlagt. Bäckeninflammation har föreslagits vara en modifierbar riskfaktor. Chlamydia trachomatis har visats ha cancerframkallande egenskaper och är en viktig orsak till bäckeninflammation. Syftet med denna avhandling var att studera om C. trachomatis och bäckeninflammation har samband med risk för epiteliala ovarialtumörer.

Metod: I en tvärsnittsstudie samlades ovarialvävnad och blodprover från 69 kvinnor som genomgått operation på grund av misstänkt sjukdom i äggstocken (Studie I). C. trachomatis-specifikt protein (immunhistokemi) och C. trachomatis-DNA (qPCR) analyserades i ovarialvävnad. I en nestad fall-kontroll studie analyserades prospektiva blodprover från 92 kvinnor som diagnostiserats med höggradigt serös ovarialcancer, samt prover från fyra kontroller vardera matchade med avseende på ålder och datum för provtagning (Studie II). C. trachomatis-specifika plasmaantikroppar analyserades med hjälp av ELISA (Enzyme-Linked ImmunoSorbent Assay) och MIF-analyser (Micro-ImmunoFlourescence) (Studie I och Studie II). I en rikstäckande registerbaserad fall-kontroll studie inkluderades 15 072 kvinnor som diagnostiserats med epitelial ovarialcancer (Studie III) och 4 782 kvinnor som diagnostiserats med borderlinetumörer (Studie IV) samt tio kontroller per fall som matchades med avseende på ålder och boendedistrikt. Från nationella svenska register hämtades uppgifter om tidigare bäckeninflammation och de potentiella förväxlingsfaktorerna paritet, utbildningsnivå, tidigare gynekologisk kirurgi och hormonell behandling.

Resultat: C. trachomatis-DNA identifierades i ovarialvävnad från åtta kvinnor med ovarialcancer, men inte i ovarialvävnad från kvinnor med borderlinetumörer eller godartade ovarialtumörer. Förekomsten av det C. trachomatis-specifika proteinet skiljde sig inte åt mellan godartad, borderline eller malign vävnad. Prevalensen av C. trachomatis-specifika plasmaantikroppar var likartad hos fall och kontroller såväl vid diagnos som prospektivt. En historia av bäckeninflammation var associerad med en ökad risk för epitelial ovarialcancer och borderlinetumörer. Histotypspecifika analyser visade en ökad risk för serösa, höggradigt serösa och klarcells karcinom samt serösa borderlinetumörer men inte signifikant med andra andra histotyper. Ett dos-respons förhållande sågs för antal episoder av bäckeninflammation och risk för epitelial ovarialcancer samt borderlinetumörer.

Slutsats: Denna avhandling bidrar till en förbättrad förståelse av sambandet mellan bäckeninflammation och epiteliala ovarialtumörer. Resultaten avseende C. trachomatis är inte entydiga och tyder på att sambandet mellan bäckeninflammation och epiteliala ovarialtumörer medieras genom andra mekanismer än enbart C. trachomatis.

Place, publisher, year, edition, pages
Umeå: Umeå University , 2023. , p. 65
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2242
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Identifiers
URN: urn:nbn:se:umu:diva-208116ISBN: 978-91-8070-051-1 (print)ISBN: 978-91-8070-052-8 (electronic)OAI: oai:DiVA.org:umu-208116DiVA, id: diva2:1755856
Public defence
2023-06-02, Hörsal B, Målpunkt T, byggnad 1D 9 trp, Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Funder
Cancerforskningsfonden i NorrlandRegion VästerbottenUmeå UniversityAvailable from: 2023-05-12 Created: 2023-05-09 Last updated: 2023-05-10Bibliographically approved
List of papers
1. Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors
Open this publication in new window or tab >>Chlamydia trachomatis, Chlamydial Heat Shock Protein 60 and Anti-Chlamydial Antibodies in Women with Epithelial Ovarian Tumors
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2018 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 11, no 2, p. 546-551Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Chlamydia trachomatis (C. trachomatis) infection has been suggested to promote epithelial ovarian cancer (EOC) development. This study sought to explore the presence of C. trachomatis DNA and chlamydial heat shock protein 60 (chsp60) in ovarian tissue, as well as anti-chlamydial IgG antibodies in plasma, in relation to subtypes of EOC. METHODS: This cross-sectional cohort consisted of 69 women who underwent surgery due to suspected ovarian pathology. Ovarian tissue and corresponding blood samples were collected at the time of diagnosis. In ovarian tumor tissue, p53, p16, Ki67 and chsp60 were analyzed immunohistochemically, and PCR was used to detect C. trachomatis DNA. Plasma C. trachomatis IgG and cHSP60 IgG were analyzed with a commercial MIF-test and ELISA, respectively. RESULTS: Eight out of 69 women had C. trachomatis DNA in their ovarian tissue, all were invasive ovarian cancer cases (16.7% of invasive EOC). The prevalence of the chsp60 protein, C. trachomatis IgG and cHSP60 IgG in HGSC, compared to other ovarian tumors, was 56.0% vs. 37.2% P = .13, 15.4% vs. 9.3% P = .46 and 63.6% vs. 45.5% P = .33 respectively. None of the markers of C. trachomatis infection were associated with p53, p16 or Ki67. CONCLUSIONS: C. trachomatis was detected in invasive ovarian cancer, supporting a possible role in carcinogenesis of EOC. However, there were no statistically significant associations of chsp60 in ovarian tissue, or plasma anti-chlamydial IgG antibodies, with any of the subtypes of ovarian tumors.

Place, publisher, year, edition, pages
Elsevier, 2018
National Category
Cancer and Oncology Clinical Laboratory Medicine
Identifiers
urn:nbn:se:umu:diva-148647 (URN)10.1016/j.tranon.2018.02.008 (DOI)000428690100041 ()29524832 (PubMedID)2-s2.0-85045732126 (Scopus ID)
Available from: 2018-06-26 Created: 2018-06-26 Last updated: 2023-05-09Bibliographically approved
2. Chlamydia trachomatis and Anti-MUC1 Serology and Subsequent Risk of High-Grade Serous Ovarian Cancer: A Population-Based Case-Control Study in Northern Sweden
Open this publication in new window or tab >>Chlamydia trachomatis and Anti-MUC1 Serology and Subsequent Risk of High-Grade Serous Ovarian Cancer: A Population-Based Case-Control Study in Northern Sweden
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2020 (English)In: Translational Oncology, ISSN 1944-7124, E-ISSN 1936-5233, Vol. 13, no 1, p. 86-91Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Chlamydia trachomatis salpingitis causes inflammatory damage to the fallopian tube and could potentially cause initiation and progression of high-grade serous ovarian cancer (HGSC). Furthermore, C. trachomatis infection may stimulate mucin 1 (MUC1) protein production, possibly affecting anti-MUC1 antibody levels. The aim of this study was to examine if serology indicating past infection with C. trachomatis as well as anti-MUC1 production was associated with subsequent risk of HGSC.

MATERIALS AND METHODS: In a prospective nested case-control study within the Northern Sweden Health and Disease Study and the Northern Sweden Maternity Cohort, the prevalence of chlamydial and anti-MUC1 antibodies was analyzed in blood samples drawn more than one year before diagnosis from 92 women with HGSC and 359 matched controls. Matching factors were age, date at blood draw, and sampling cohort. Plasma C. trachomatis IgG was analyzed using commercial micro-immunofluorescence test; chlamydial Heat Shock Protein 60 IgG (cHSP60) and anti-MUC1 IgG were analyzed with ELISA technique.

RESULTS: The prevalence of C. trachomatis IgG and cHSP60 IgG antibodies, as well as the level of anti-MUC1 IgG was similar in women with HGSC and controls (16.3% vs. 17.0%, P = 0.87; 27.2% vs. 28.5%, P = 0.80; median 0.24 vs. 0.25, P = 0.70). Anti-MUC1 IgG and cHSP60 IgG levels were correlated (r = 0.169; P < 0.001).

CONCLUSIONS: The findings of this prospective nested case-control study did not support an association between C. trachomatis infection, as measured by chlamydial serology, or anti-MUC1 IgG antibodies, and subsequent risk of HGSC.

Place, publisher, year, edition, pages
Elsevier, 2020
National Category
Obstetrics, Gynecology and Reproductive Medicine
Identifiers
urn:nbn:se:umu:diva-174272 (URN)10.1016/j.tranon.2019.09.007 (DOI)000502822300010 ()31805519 (PubMedID)2-s2.0-85075720208 (Scopus ID)
Available from: 2020-08-19 Created: 2020-08-19 Last updated: 2023-05-10Bibliographically approved
3. Inflammatory disease and epithelial ovarian cancer risk: a national population-based case-control study in Sweden
Open this publication in new window or tab >>Inflammatory disease and epithelial ovarian cancer risk: a national population-based case-control study in Sweden
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(English)Manuscript (preprint) (Other academic)
Keywords
EOC, epithelial ovarian cancer, HGSC, high-grade serous carcinoma, ovarian cancer, pelvic inflammatory disease, PID, population-based case-control study
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-208132 (URN)
Funder
Umeå University
Available from: 2023-05-10 Created: 2023-05-10 Last updated: 2023-05-10
4. Pelvic inflammatory disease and risk of borderline ovarian tumors: a national population-based case-control study in Sweden
Open this publication in new window or tab >>Pelvic inflammatory disease and risk of borderline ovarian tumors: a national population-based case-control study in Sweden
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(English)Manuscript (preprint) (Other academic)
Keywords
BOT, borderline ovarian tumor, serous BOT, pelvic inflammatory disease, PID, population-based case-control study
National Category
Obstetrics, Gynecology and Reproductive Medicine Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-208135 (URN)
Funder
Umeå University
Available from: 2023-05-10 Created: 2023-05-10 Last updated: 2023-05-10

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