Locoregional Progression of Cervical Cancer Follows Reverse Ontogenetic Sequence


Key Points

  • Locoregional progression of cervical cancer follows the reverse course of ontogenetic tissue development.
  • Ontogenetic staging was a better predictor of survival than pathologic staging.

In a study reported in The Lancet Oncology, Höckel et al demonstrated that locoregional progression of cervical cancer follows the reverse sequence of establishment of adult tissues in ontogeny. Ontogenetic staging was a better predictor of survival than pathologic staging. Previous work by these investigators suggested that early cervical cancer is locally confined to the Müllerian compartment developing in women from the embryonic paramesonephric-mesonephric complex.

Study Details

In the study, four successive steps in organogenesis of the cervix were defined starting from Carnegie stage 13, and an ontogenetic staging system for cervical cancer based on organ development was specified. Histologic and clinical data were obtained from 367 patients with FIGO (International Federation of Gynecology and Obstetrics) stage IB to IVA cervical cancer enrolled in trials of total mesometrial resection (88% of patients), extended mesometrial resection (6%), and laterally extended endopelvic resection (6%) conducted at the University of Leipzig since 1999. Patients received no adjuvant radiation, 59 received adjuvant chemotherapy, and patients who received and responded to neoadjuvant chemotherapy were excluded.

The primary endpoints of the trials were pathologic resection status and locoregional tumor control. Patients who underwent total mesometrial resection and extended mesometrial resection were assessed every 3 to 6 months for 5 years and yearly thereafter and those undergoing laterally extended endopelvic resection were assessed every 3 to 6 months for 10 years and yearly thereafter. The presence of disease within the ontogenetically classified tissues and disease outcomes were examined to determine whether surgical excision within developmental compartments was sufficient for disease control.

Ontogenetic Staging and Progression

The investigators found that staged organogenesis of the cervix and progressive local growth of cervical cancer occurred in the same tissue domains. During malignant progression, disease originating in the cervix, classified as ontogenetic tumor stage 1 (oT1, n = 217), successively permeated tissues developed from the Müllerian compartment (oT2, n = 101), genital metacompartment (oT3, n = 38), and urogenitorectal metacompartment (oT4, n = 11).

Higher ontogenetic tumor stage was associated with increased risk of recurrence, with recurrence observed in 5% of patients at oT1, 19% at oT2, 42% at oT3, and 55% at oT4. More than half of relapses in patients with oT1 occurred in the pelvis only, with distant metastasis with or without pelvic involvement being more common at later stages.

Association With Survival

Overall survival was markedly reduced in patients with tumors showing the ability to leave their developmental compartment, with 5-year overall survival rates being 97% in those with oT1 tumors, 94% for oT2 tumors, 60% for oT3 tumors, and 47% for oT4 tumors.

On multivariate models including ontogenetic staging or pathologic staging and adjusting for nodal status, tumor size, lymphangiosis, hemangiosis, grading, and resection margin, ontogenetic staging comparing patients with oT3 and oT4 disease vs those with oT1 and oT2 disease (hazard ratio [HR] for death = 5.9, P = .00036) was a better predictor of survival than pathologic staging comparing pT2b and pT4 vs pT1b and pT2a disease (HR = 2.0, P = .170).

Nodal stage was the strongest prognostic factor in the pathologic staging model (HR = 3.7, P = .007) but had a reduced effect in the ontogenetic staging model (HR = 2.4, P = .091). Comparison of the two models using Akaike’s information criterion for global model fit showed better fit for the model including ontogenetic tumor stage.

Resection of the ontogenetically staged tissue domains and regional lymphoid tissues resulted in an R0 resection rate of 99%, and locoregional tumor control at 5 years was 94%.

The investigators concluded, “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.”

Michael Höckel, MD, of the University of Leipzig, is the corresponding author of The Lancet Oncology article.

The study was funded by the University of Leipzig and Leipzig School of Radical Pelvic Surgery. The study authors reported no potential conflicts of interest.

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