The biology and significance of tumour deposits in rectal cancer

Abstract

Introduction: Both pathological and radiological staging in rectal cancer are suboptimal in predicting prognosis. This thesis aims to explore pathways of spread in rectal cancer which result in recurrence. Tumour deposits (TDs) are a manifestation of tumour spread via an extranodal pathway, closely related to extramural venous invasion (EMVI), which have been neglected in staging and clinical decision making. This thesis aims to evaluate the prognostic impact of TDs in comparison with known pathological variables, validate their diagnosis on radiology and explore the problems associated with their diagnosis and classification.

Methods: A number of studies were carried out, including meta-analyses of existing studies, a retrospective cohort study validating the prognostic effect of TDs seen on magnetic resonance imaging (MRI), a prospective trial investigating the effect of EMVI on prognosis (the MARVEL trial), studies of interobserver variation in the diagnosis of TDs on pathology and radiology, a modified Delphi consensus study aimed at improving the diagnosis of TDs and a prospective trial attempting to validate the MRI diagnosis of TDs compared with pathology (the COMET trial).

Results: Two meta-analyses confirmed that TDs seen on pathology are a marker of poor prognosis in both treated and untreated patients. A retrospective cohort study showed that TDs and EMVI seen on MRI are strong markers of poor prognosis, in contrast to the usual staging parameters used in the tumour nodes metastasis (TNM) system which were not predictive of prognosis. The results of the MARVEL trial showed that EMVI was the only predictor of poor prognosis on MRI in a multicentre trial of 17 sites. We reported that interobserver agreement between pathologists in diagnosing TDs is only moderate, however on MRI the diagnosis appears to be more reproducible with high levels of agreement.

Conclusion: The evidence presented in this thesis supports the overarching hypothesis that vascular mediated spread is more important than spread via the lymphatic pathways in predicting prognosis. TDs are part of a vascular pathway and are prognostically worse than lymph node metastases (LNMs) on pathology and imaging. The COMET trial is currently recruiting, and results are awaited. We aim to confirm that the nodules called TDs on MRI correspond to pathological TDs. Proving that the extranodal pathway of spread (i.e., TDs and EMVI) is the true cause of metastatic disease through phylogenetic studies would add further weight to the hypothesis that nodal metastases have a minimal role in tumour spread and would necessitate a major change to staging. This project is currently in development.