title: Radiotherapy-induced vaginal fibrosis in cervical cancer survivors.
abstract: BACKGROUND
  Cervical cancer survivors treated with radiotherapy report vaginal inelasticity and decreased lubrication that may affect their sexual health, but it is unknown which normal tissue reactions mediate these symptoms. The aim of this study was to investigate the morphology of the connective tissue of the vaginal wall in cervical cancer survivors treated with radiotherapy.
  
  
  METHODS
  We recruited 34 cervical cancer survivors treated with radiotherapy and 37 age-matched controls. Via clinical examination the degree of vaginal atrophy and pelvic fibrosis were estimated. We collected vaginal biopsies, which underwent morphometric analysis focused on elastin and collagen. Additionally, radiation dose at biopsy site were calculated and correlated to the clinical and morphological findings.
  
  
  RESULTS
  The survivors had marked morphological vaginal changes, most prominent in the survivors that had received the highest radiation dose at the biopsy site. Mucosal atrophy was observed in 91% and pelvic fibrosis in 97%. A shorter vagina was measured; 7.0 cm versus 10.3 cm in controls (p < 0.001). The area fraction of elastin was greater in survivors; 10.0% (range 5.8-12.9), compared with controls; 3.4% (range 1.8-5.8), p < 0.001. The survivors had signs of elastosis with thick aggregated elastin fibers irregularly scattered throughout the connective tissue, while the controls had elastin fibers in a thin sub-epithelial layer. The area fraction of high density collagen in the connective tissue was larger among the survivors (p < 0.001). The collagen with the highest density (fibrosis) was more common in the group of cancer survivors that had received external radiation.
  
  
  CONCLUSIONS
  We found drastic differences in the vaginal wall between the irradiated cervical cancer survivors and the controls, indicating that radiotherapy-induced vaginal symptoms are mediated by connective tissue fibrosis and elastosis. Our results also support that patients treated with external radiation have the highest risk of developing vaginal fibrosis with impairment of their sexual health.
authors.affiliation: a Department of Oncology-Pathology, Karolinska Institutet, and Unit of Gynecological Oncology, Radiumhemmet , Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hofsjö
authors.affiliation: b Department of Clinical Sciences , Karolinska Institutet , Stockholm , Sweden.|c Department of Obstetrics and Gynecology , Danderyd Hospital , Stockholm , Sweden.
authors.forename: Nina
authors.initials: N
authors.lastname: Bohm-Starke
authors.affiliation: b Department of Clinical Sciences , Karolinska Institutet , Stockholm , Sweden.|d Department of Pathology , Karolinska University Hospital , Stockholm , Sweden.
authors.forename: Bo
authors.initials: B
authors.lastname: Blomgren
authors.affiliation: e Halmstad Hospital , Halmstad , Sweden.
authors.forename: Helen
authors.initials: H
authors.lastname: Jahren
authors.affiliation: f Department of Oncology , The Sahlgrenska Academy, Sahlgrenska University Hospital , Gothenburg , Sweden.|g Clinical Cancer Epidemiology, Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Steineck
authors.affiliation: g Clinical Cancer Epidemiology, Department of Oncology-Pathology , Karolinska Institutet , Stockholm , Sweden.|h Gynecological Oncology, Department of Oncology , The Sahlgrenska Academy, Sahlgrenska University Hospital , Gothenburg , Sweden.
authors.forename: Karin
authors.initials: K
authors.lastname: Bergmark
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000532:radiotherapy; D018262:Adenocarcinoma, Clear Cell / Q000473:pathology / Q000532:radiotherapy; D000328:Adult; D001918:Brachytherapy / Q000009:adverse effects*; D000073116:Cancer Survivors; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000532:radiotherapy; D016022:Case-Control Studies; D005260:Female; D005355:Fibrosis / Q000209:etiology* / Q000473:pathology; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D011379:Prognosis; D011795:Surveys and Questionnaires; D015996:Survival Rate; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D014623:Vaginal Diseases / Q000209:etiology* / Q000473:pathology