title: Association between developmental steps in the organogenesis of the uterine cervix and locoregional progression of cervical cancer: a prospective clinicopathological analysis.
abstract: BACKGROUND
  Our previous work provided evidence that early cervical cancer is locally confined to the Müllerian compartment that develops in women from the embryonic paramesonephric-mesonephric complex. We aimed to investigate if the concept of tumour permeation within ontogenetic domains is also valid for tumour progression and advanced disease.
  
  
  METHODS
  Starting from Carnegie stage 13, four successive steps in the organogenesis of the human uterine cervix were defined and an ontogenetic staging system for cervical cancer based on organ development was described. Histopathological and clinical data of patients with cervical cancer FIGO stages IB-IVA were raised prospectively from Oct 16, 1999, until Dec 20, 2012, and from March 8, 2000, until April 4, 2013, for two surgical trials of ontogenetic compartment resection without adjuvant radiation at the University of Leipzig (total or extended mesometrial resection [TMMR or EMMR]; and [laterally] extended endopelvic resection [LEER]). The primary endpoints of these trials were pathological resection state and locoregional tumour control. Patients who underwent TMMR and EMMR had follow-up assessment every 3-6 months for 5 years, and yearly thereafter. Patients who had (L)EER, every 3-6 months for 10 years, and yearly thereafter. By analysing the presence of disease within the classified tissues and disease outcome in these patients, and by examining relapse patterns, we were able to observe whether surgical excision within developmental compartments was sufficient for disease control. Survival curves were compared using the log-rank test. The effect of ontogenetic tumour stage and pathological tumour stage on overall survival was assessed by Cox proportional hazard models. The trials are registered as an ongoing observational monocentric study at the University of Leipzig Cancer Centre (ULCC012-13-28012013).
  
  
  RESULTS
  367 patients were included in our analysis. Staged organogenesis of the uterine cervix and progressive local growth of cervical carcinoma occur in the same tissue domains. The neoplasm originating in the uterine cervix, ontogenetic tumour stage 1 (oT1, n=217), permeates successively during its malignant progression the tissues developed from the Müllerian compartment (oT2, n=101), the genital metacompartment (oT3, n=38), and the urogenitorectal metacompartment (oT4, n=11). Ontogenetic staging, when comparing patients with oT1 and oT2 disease to those with oT3 and oT4 disease (hazard ratio 5·9, 95% CI 2·2-15·5; p=0·00036) was a better prognostic indicator for survival than pathological staging when comparing pT1b and pT2a with pT2b and pT4 disease (2·0, 95% CI 0·7-5·5; p=0·170). Resection of the stage-related ontogenetically specified tissue domains and their associated regional lymphoid tissues achieved an R0 resection in 363 (99%) of 367 patients and locoregional tumour control at 5 years was 94% (95% CI 92-97). 13 patients had grade 3 or 4 adverse events, the majority of which were urinary (10, 77%).
  
  
  CONCLUSIONS
  Cervical cancer infiltrates the adult tissues established during ontogeny, pursuing the developmental steps in retrograde sequence. Clinical translation of these insights into ontogenetic tumour staging and compartment resection holds the potential to improve prognostic assessment and curative treatment.
  
  
  BACKGROUND
  University of Leipzig and Leipzig School of Radical Pelvic Surgery.
authors.affiliation: Department of Gynaecology, University of Leipzig, Leipzig, Germany. Electronic address: michael.hoeckel@uniklinik-leipzig.de.
authors.forename: Michael
authors.initials: M
authors.lastname: Höckel
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Hentschel
authors.affiliation: Division of Breast, Gynaecological and Perinatal Pathology, Institute of Pathology, University of Leipzig, Leipzig, Germany.
authors.forename: Lars-Christian
authors.initials: LC
authors.lastname: Horn
mesh_terms: D002584:Cervix Uteri / Q000196:embryology* / Q000473:pathology* / Q000601:surgery; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005858:Germany; D006801:Humans; D007044:Hysterectomy; D053208:Kaplan-Meier Estimate; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology* / Q000517:prevention & control; D009367:Neoplasm Staging; D038081:Organogenesis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D002583:Uterine Cervical Neoplasms / Q000401:mortality / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery