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Prognostic factors for squamous cell cervical cancer: tumor markers, hormones, smoking, and S-phase fraction
Umeå University, Faculty of Medicine, Department of Radiation Sciences.
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cervical cancer is the second most common malignancy in women worldwide and one of the leading causes of cancer mortality globally. In patients with invasive cervical cancer prognostic factors are of value for the choice of treatment, monitoring of treatment and follow-up. The most important clinical prognostic factors are stage, tumor volume, parametrial infiltration, vascular invasion, lymph node metastases, and distant metastases. An improved estimation of the prognosis of cervical cancer is desirable, especially in early cancer stages.

The aim of this research was to study possible associations between tumor markers, female sex steroids, smoking, S-phase fraction (SPF), and prognosis in invasive squamous cell cervical cancer (SCC). The study comprised 190 patients with SCC, stages IB-IV, admitted to the Department of Gynecologic Oncology at Norrland University Hospital in Umeå between September 1984 and October1990. Ten year mortality was estimated.

In study I, of a total of 103 patients, it was found that increased tumor growth, measured by the DNA SPF, was associated with elevated serum progesterone and smoking in the premenopasual patients and with aneuploidy in the whole group.

In study II, comprising 128 patients, survival length related to hormone levels and SPF was evaluated in women who died of cervical cancer. In both pre- and postmenopausal women, who died of cervical cancer, SPF at or above 12% was correlated with reduced survival. There was significant positive correlation between a low serum estradiol/progesterone ratio and short survival in those premenopausal women who died of cancer (p=0.02).

In study III, ten-year follow-up results in 128 women were compared with the expression of ten relevant tumor markers, assessed by immunohistochemistry. The overall ten-year survival rate in patients with low COX-2 and high CD4+ expression was 76%, versus 53% in the remaining women. The survival rate with absent p53 and high COX-2 expression in the tumors was 42%, versus 71%, while the corresponding figure for the combination of high COX-2 intensity and expression of c-myc was 27%, versus 62%. None of the single markers correlated significantly with outcome in the final Cox regression analyses, while five combinations did.

Study IV addressed possible associations between selected tumor markers and cofactors in SCC. Ten tumor markers were examined in 128 patients. Smoking habits and previous oral contraceptive use were recorded. Serum estradiol and progesterone levels were evaluated in 80 women. Highly significant associations were found between strong c-myc staining and increased progesterone, low EGFR staining and high serum estradiol, and absence of p53 staining and smoking. There was an association between absence of p53 and high serum progesterone.

In study V, LRIG1 expression was studied in 128 patients and was compared with expression of nine other tumor markers, smoking history, hormone levels, and prognosis. LRIG1 appears to be a significant prognostic predictor in early stage SCC, independent of the other tumor markers that were studied.  Diminished expression in advanced cancer stages and the inverse correlation to serum progesterone and smoking indicate that LRIG1 is a tumor suppressor in squamous cell cervical cancer.

Conclusion: The results of these studies support a role of progesterone as a promoter of cervical cancer and indicate that smoking is associated with tumor progression. A combination of tumor markers might be of help in prognostic prediction. LRIG1 acts as a tumor suppressor. These findings might contribute towards greater understanding of prognostic prediction of squamous cell cervical cancer.

Place, publisher, year, edition, pages
Umeå: Umeå university , 2010. , 67 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1350
Keyword [en]
Cervical cancer, squamous cell carcinoma, sex steroid hormones, smoking, S-phase fraction, tumor markers, LRIG1, prognosis.
National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
URN: urn:nbn:se:umu:diva-33939ISBN: 978-91-7264-998-9 (print)OAI: oai:DiVA.org:umu-33939DiVA: diva2:318860
Public defence
2010-06-12, Sal 244 Lionssalen, By 7, Norrlands universitetssjukhus, Umeå, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2010-05-20 Created: 2010-05-11 Last updated: 2010-05-20Bibliographically approved
List of papers
1. Correlations between serum progesterone and smoking, and the growth fraction of cervical squamous cell carcinoma
Open this publication in new window or tab >>Correlations between serum progesterone and smoking, and the growth fraction of cervical squamous cell carcinoma
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2000 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 20, no 5C, 3637-3640 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Possible correlations between growth fraction of squamous cervical carcinomas and serum progesterone (se-P) concentrations, smoking habits and DNA ploidy were studied. MATERIALS AND METHODS: The DNA S-phase fraction (SPF), measured by flow cytometry was used as a marker of tumour growth in 103 cases of squamous cervical cancer stage IB-IV. DNA-ploidy (peridiploidy vs. aneuploidy), Se-P, se-Estradiol, smoking habits, parity, menopausal status, clinical stage and histopathological grading were compared to SPF < 14% vs. SPF > or = 14%. RESULTS: Aneuploidy, (odds ratio (OR) 10.0), se-P > or = 2.6 nmol/l (OR 7.5) and smoking (OR 3.0) were significantly associated with SPF > or = 14%, after adjustments for all factors included in the study. The association with se-P and smoking was attributed to an increased risk for the premenopausal women in the study. DISCUSSION: In this study an increased tumour growth was associated with increased leves of se-P, smoking and aneuploidy in women with invasive squamous cervical carcinoma. This study seems to experimentally confirm epidemiological studies, where smoking and long-term use of oral contraceptives have been linked to cervical neoplasms.

National Category
Medical and Health Sciences
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-32590 (URN)11268431 (PubMedID)
Available from: 2010-03-17 Created: 2010-03-17 Last updated: 2017-12-12Bibliographically approved
2. Correlation between serum estradiol/progesterone ratio and survival length in invasive squamous cell cervical cancer
Open this publication in new window or tab >>Correlation between serum estradiol/progesterone ratio and survival length in invasive squamous cell cervical cancer
2005 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 25, no 1B, 611-616 p.Article in journal (Refereed) Published
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-14398 (URN)15816635 (PubMedID)
Available from: 2006-11-09 Created: 2006-11-09 Last updated: 2017-12-14Bibliographically approved
3. Predicting the outcome of squamous cell carcinoma of the uterine cervix using combinations of individual tumor marker expressions
Open this publication in new window or tab >>Predicting the outcome of squamous cell carcinoma of the uterine cervix using combinations of individual tumor marker expressions
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2007 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 27, no 3B, 1609-1615 p.Article in journal (Refereed) Published
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-8691 (URN)17595784 (PubMedID)
Available from: 2008-02-05 Created: 2008-02-05 Last updated: 2017-12-14Bibliographically approved
4. Associations between ten biological tumor markers in squamous cell cervical cancer and serum estradiol, serum progesterone and smoking
Open this publication in new window or tab >>Associations between ten biological tumor markers in squamous cell cervical cancer and serum estradiol, serum progesterone and smoking
2007 (English)In: Anticancer Research, ISSN 0250-7005, E-ISSN 1791-7530, Vol. 27, no 3B, 1401-1406 p.Article in journal (Refereed) Published
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-8687 (URN)17595754 (PubMedID)
Available from: 2008-02-05 Created: 2008-02-05 Last updated: 2017-12-14Bibliographically approved
5. LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking
Open this publication in new window or tab >>LRIG1 and squamous epithelial uterine cervical cancer: correlation to prognosis, other tumor markers, sex steroid hormones, and smoking
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2008 (English)In: International Journal of Gynecological Cancer, ISSN 1048-891X, E-ISSN 1525-1438, Vol. 18, no 2, 312-317 p.Article in journal (Refereed) Published
Abstract [en]

The aim is to evaluate LRIG1 as a prognosis predictor and correlations to cofactors in squamous cell cervical cancer. LRIG1 expression was studied in 128 cervical carcinomas and was compared with expression of nine other tumor markers. Smoking history was registered and pretreatment serum estradiol and progesterone levels were evaluated in 79 women. At clinical stage IB, 58% of the tumors showed LRIG1 expression, but there was a decline by increasing stage (33% in stage IV). Ninety percent of women with stage IB cancer and LRIG1 positivity survived, as compared to 64% without expression (P = 0.02). LRIG1 expression did not predict prognosis in advanced stages, but in stage IIA there was a marked relative difference, with 75% survival in tumors expressing LRIG1, as compared to 43% in those without. No correlation was found between LRIG1 and the other nine tumor markers studied. A high serum progesterone and smoking correlated to absent LRIG1 expression. We conclude that LRIG1 appears to be a significant prognosis predictor in early-stage cervical cancer, independent of the other tumor markers that were studied. Diminished expression in advanced stages and the inverse correlation to serum progesterone and smoking indicates that LRIG1 is a tumor suppressor in cervix.

Keyword
cervix cancer, hormones, LRIG, prognosis, smoking
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:umu:diva-9253 (URN)10.1111/j.1525- 1438.2007.01021.x (DOI)17624990 (PubMedID)
Available from: 2008-03-13 Created: 2008-03-13 Last updated: 2017-12-14Bibliographically approved

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