Patient case: 45-year-old female with colon cancer; genetic feature: PIK3CA (E545K)

Clinical trial: Concordance in MRI and Pathology Diagnosis of Extranodal Tumour Deposits

Summary: Predicting prognosis in rectal cancer and determining indications for neoadjuvant treatment is an ongoing challenge for colorectal multidisciplinary teams (MDTs). Staging is almost universally based on the TNM system which, despite multiple changes and increasing levels of sub-classification and complexity, is still flawed in its ability to stratify patients and predict prognosis(1-3). Determining which patients will benefit most from neoadjuvant and adjuvant therapy is still controversial; NICE guidelines are open to interpretation(4) and there is significant geographic variation in the way patients are managed. The Aim of this study is to prove the accuracy of MRI diagnosis of ENTD and its adverse effect on prognosis.

Detailed description: This will be a prospective interventional, multi-centre study. Patients will be identified from multidisciplinary team meetings. All patients presenting with primary adenocarcinoma of the rectum and undergoing resectional surgery (with or without prior neo-adjuvant treatment) will be eligible for inclusion in the study. Patients will be approached following the MDT at their pre-op clinic and asked to participate in the trial. If they agree, they will be asked to sign a consent form before surgery.
  Local Radiologists will be asked to complete a study Imaging CRF for the baseline MRI scan, and post-preoperative treatment MRI scan, if applicable, which will include standard staging information and, additionally, information on the presence of Tumour Deposits (mrTD). (Before site initiation, local study Radiologists will be offered training in identifying mrTDs and asked to complete an assessment for quality assurance purposes.)
  Prior to surgery, imaging CRFs and pre-operative MRI scans will be sent to the Royal Marsden so that the COMET Chief Investigator (or one of her Radiology Registrars) can create an array of images and complete a central review CRF (see Figures 1 and 2) from the pre-op MRI scan. Each mrTD will be labelled (e.g E1, E2, E3). These images will be sent to the site study pathologist prior to histopathology processing of the specimen.
  Histopathology
  As well as following standard pathological procedures, additional sections will be taken from the area mrTD are thought to be present on MRI, and these will be kept separately from lymph nodes and clearly labelled. Deeper sections and elastin staining will only be carried out if the pathologist would do this as standard practice (i.e. it will not be requested as part of the trial). The pathologist will assess the specimen and report whether TD are present using a proforma. Tumour differentiation, CRM, T and N stage and the presence of EMVI will also be reported as standard. All pathology reporting will adhere to the Royal College of Pathologists Dataset Requirements for Reporting in Colorectal Cancer(19) to ensure standardisation between sites. A photograph of the tissue slices on a numbered grid will be sent into the Trial Office and used for mapping purposes. This should be accompanied by a completed Pathology CRF and anonymised histopathology report.
  All tissue (including slides, blocks and cassettes) will be sent to the Royal Marsden COMET trial team for central review and to allow for further assessment with additional examination, staining and DNA extraction for genetic testing and KRAS, NRAS, BRAF and PIK3CA analysis. Due to the known problems with inter-observer variability in distinguishing TD from LN(17), we will attempt to objectify this by specifically asking the Study Pathologist at the Royal Marsden as well as another Pathologist at Radboud University Medical Centre in the Netherlands to identify whether any features of a LN are present for each nodule examined as well as recording the presence of vascular and neural invasion. Features which would be specific to the lesion being a LN will be given an "L" score and those which suggest a lesion of non-LN origin will be given an "E" score. If the patient subsequently presents with metastatic disease and a pathology specimen is available (either in the form of a resection or a biopsy), this will also be obtained for the same testing. Scanned-in images of slides taken from the nodules will be used for their LN assessment and central review.
  Patients will undergo standard clinical follow up for a minimum of 5 years from the date of surgery. Clinic visits, imaging, blood tests and endoscopic follow-up will be carried out according to local protocols.

Eligibility: Inclusion Criteria:
  -  Patients aged 18 years of age and over presenting with primary adenocarcinoma of the rectum amenable to surgical resection. This will be diagnosed on tissue biopsy and disease spread assessed on CT and MRI. Both patients having primary surgery and those undergoing neoadjuvant treatment will be included. All must have had a baseline staging MRI and those undergoing neoadjuvant therapy must also have had a post-treatment MRI.
  Exclusion Criteria:
  -  Patients with recurrent or synchronous tumours, those who are unable to have an MRI scan (e.g pacemaker, contrast allergy, severe claustrophobia) and those under the age of 18 years or unable to give informed consent will be excluded.

Relevance to patient case: not relevant