Vaginal morphological changes in cervical cancer survivors

Abstract: Background: Cervical cancer is globally the fourth most common cancer in women and has generally a good prognosis. Cervical cancer survivors report persistent changes in their sexual function, which result in considerable distress. The majority of new cases are diagnosed in young or middle-aged women. Consequently, a rising number of women are at risk for chronic side effects of the treatment. The aim of this thesis was to investigate the morphology of the vaginal wall and the expression of sex steroid receptors in cervical cancer survivors treated with radiotherapy. Methods: Via clinical examination the degree of vaginal atrophy, pelvic fibrosis and telangiectasia were estimated. We collected vaginal biopsies, which underwent morphometric analyses focused on elastin, collagen, epithelial structures, blood vessels and nerve fibers. Radiation dose at biopsy site was calculated and sex steroid hormone levels were analyzed. We also analyzed the expression and distribution of sex steroid hormone receptors by real-time PCR and immunohistochemistry (IHC). Additionally, a questionnaire designed to assess sexual function was filled out. Results: The survivors had marked morphological vaginal changes, most prominent in the survivors that had received the highest radiation dose at the biopsy site. Clinical findings of atrophy, pelvic fibrosis and shortened vagina were present in most cancer survivors. Signs of elastosis with thick aggregated elastin fibers were found throughout the connective tissue. High-density collagen (fibrosis) in the connective tissue was more common among the survivors, most prominent in survivors that had received external radiation. The vaginal epithelium volume was reduced despite no difference in serum estradiol between cancer survivors and controls. In biopsies from the vaginal wall, lower expression of estrogen receptor alpha (ERα) at both mRNA and protein levels was found. In the survivors with high radiation dose at biopsy site, the immunostaining of ERα and androgen receptor (AR) was lower in the epithelium and the stroma, compared to survivors with minimal radiation dose. The cervical cancer survivors reported more physical sexual symptoms. The highest relative risk was found for insufficient vaginal lubrication, vaginal inelasticity, reduced genital swelling when sexually aroused and for reduction of vaginal length. Conclusion: The vaginal wall is markedly changed in irradiated cervical cancer survivors. The connective tissue is re978-91-7676-897-6modeled with elastosis and radiotherapy-induced fibrosis, and the vaginal epithelium volume is reduced, compared to controls with similar levels of estradiol. Reduction in ERα and AR expression in the vaginal mucosa after radiotherapy may alter the responsiveness to hormonal treatment. The morphological changes in the vaginal wall correspond to the clinical findings of fibrosis and atrophy and can be one important explanation of the sexual dysfunction in the cervical cancer survivors.