Concordance in MRI and Pathology Diagnosis of Extranodal Tumour Deposits

Predicting prognosis in colorectal cancer (CRC) and determining indications for
neoadjuvant treatment is an ongoing challenge for CRC multidisciplinary teams.
Staging is almost universally based on the TNM system which is mainly focused
on lymph node status and is still flawed in its ability to stratify patients
and predict prognosis.(1-3) Therefore, determining which patients will benefit
most from neoadjuvant and adjuvant therapy is still controversial. Recent
evidence challenges the focus on lymph node metastases (LNM) as the gateway to
distant metastatic disease by showing that 65% of distant metastases were not
seeded by LNM.(4) Furthermore, other types of locoregional spread have been
proven to influence patient outcome, with extranodal tumour deposits (TD)
having the most prognostic impact.(5)

TD are aggregates of tumour cells in the fat surrounding the bowel (figure 1).
Although they were first described in 1935(6), there is still ongoing
controversy about their prevalence, nature, effect on prognosis and how they
should be differentiated from LNM. The definition of TD within the TNM system
is one of the major changes to have taken place over the years; They were
considered lymph nodes (or not) and stratified according to size, contour or
presence of other histological structures.(7-10) Currently, TD have to be
classified within the subcategory *N1c*. However, experts have argued that
there is not sufficient evidence to include TD as part of the N stage. A recent
meta-analysis found a strong link between TD and extramural venous invasion
(EMVI).(11) Therefore, it is possible that TD and EMVI are a continuation of
the same process where TD represent a more advanced form of EMVI with nodules
closely related to vessels but not in continuity with the tumour itself. These
nodules could be seen as metastases in transit which would make their
association with poorer survival and higher rates of recurrence not surprising.

Radiological diagnosis of tumour deposits
Given the prognostic importance of TD, it is imperative that these lesions are
accurately reported on pathology so that their presence can be taken into
account when making treatment decisions. Next to this, accurate diagnosis or
TD by radiological modalities is also important. Identifying adverse prognostic
features before surgery via imaging rather than on pathology has distinct
advantages in that it contributes to planning of surgery and can guide
decisions regarding neo-adjuvant therapy. MRI can accurately identify
pathological markers of poor prognosis pre-operatively to allow risk
stratification and aid decision-making. The group of Prof. Gina Brown at the
Royal Marsden Hospital (RMH) is able to accurately diagnose EMVI on MRI.(12-14)
Also TD can be diagnosed on MRI as well as on CT when they are defined as
nodules arising within venous channels, identified as signal void vessels, in
continuity with major venous branches within the mesorectum and discontinuous
with the main tumour.(15, 16) However, the diagnosis of TD has not been
prospectively validated against that of pathology, which is the gold standard.

Preliminary work within the South West London Cancer Network has shown that MRI
can detect TD in up to 51% of the rectal cancer cases, and CT can detect TD in
up to 20% of the colon cancer cases. This is higher than the average of 13% of
patients that are found to have TD on both pathology and CT/MRI. The ability to
visualize the entire mesocolon and -rectum in three dimensions is a great
advantage of imaging modalities which leads us to believe that TD can be more
easily identified on CT or MRI than on pathology. Therefore, we want to use
mapping of the resection specimen based on CT/MRI to accurately correlate
radiological findings with pathology. Ultimately, this will provide information
regarding the accuracy of radiological diagnosis of TD.

Biological characterization of tumour deposits
Molecular pathology techniques are widely utilised in current practice and can
give further information about tumour behaviour (e.g. KRAS testing to determine
likely response to certain chemotherapy agents). Knijn et al. have shown very
low discordance in KRAS mutation between the primary tumour and distant disease
(<5% for liver metastases, 7% for lung metastases) but high discordance between
lymph nodes and the primary tumour of 20-40%.(17) The concordance of KRAS
mutations and other markers such as EMVI and TD has never been reported. We
hypothesize that the profile of EMVI and TD will have a higher concordance with
the primary tumour and any metastases that develop than that of lymph nodes
because this is the primary route of metastasis. Furthermore, it is likely that
the concordance between EMVI and TD will be high. If this hypothesis is
correct, it would allow a better understanding of the metastatic process and
allow better prediction of those likely to suffer local and distant failure.
This would in turn take us a step closer to cancer treatment that can be
personalised to each patient taking multiple factors into consideration to
determine individual risk.

In this study, we want to prove the accuracy of detection of TD on MRI/CT by
correlating these findings with histopathology. Furthermore, this prospective
setting enables us to analyse the prognostic value of TD in CRC. This could
alter the way we stage patients currently. If we can prove the prognostic
importance of this CT/MRI findings, the TNM system will most likely need to be
modified in such a way that TD will play a larger role in guiding decisions
regarding the use of neoadjuvant therapy.

To prove the accuracy of MRI/CT diagnosis of tumour deposits and their adverse
effect on prognosis.

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 colon or rectum and undergoing surgical resection
(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.

1. Radiology:
Local Radiologists will be asked to complete a study imaging CRF for the
baseline MRI or CT scan, and post-preoperative treatment MRI scan, if
applicable. This CRF will include standard staging information and,
additionally, information on the presence of Tumour Deposits (mrTD/ctTD).
Prior to surgery, imaging CRFs and pre-operative MRI/CT 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
from the pre-op MRI/CT scan. Each mrTD/ctTD 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.

2. Histopathology:
As well as following standard local pathological procedures, sections that are
thought to be lymph node metastases or TD will be photographed on a numbered
grid and clearly labelled. The pathologist will assess the specimen and report
whether TD are present using a proforma. A photograph of the tissue slices on a
numbered grid will be sent into the Trial Office and used for mapping purposes.
All tissue (including slides, blocks and cassettes) can be sent to the Royal
Marsden COMET trial team to allow for further assessment with additional
examination, staining and DNA extraction for genetic testing. The slides
containing nodules will be scanned after which these images will be used for
central review of the nodules. Due to the known problems with inter-observer
variability in distinguishing TD from LNM, the Study Pathologist at the Royal
Marsden as well as another Pathologist at Radboudumc in the Netherlands will
identify whether any features of a lymph node 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 LNM will be given an *L*
score and those which suggest a lesion of non-lymphatic origin will be given an
*E* score.
After analysis, all tissue samples will be returned to local hospitals and kept
in the long term storage facility, for use in future research. All movement of
tissue samples between centres will be logged on a secure database at the Royal
Marsden Hospital so an accurate account of where the samples are is available
throughout the course of the study.

3. General follow-up:
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.

Correlation of diagnostic tests: MRI/CT scans will be correlated with samples
from the resection specimen that are photographed on a numbered grid.

The proposed intervention will be additional radiological and pathological
assessment and the reporting of supplementary diagnostic information which
would not otherwise have been available. Pathology is regarded as the gold
standard and the information gathered from this modality will therefore not
change. There will be extra information gathered during radiological
diagnostics regarding TD, but this won't be taken into account when treatment
decisions are made. Therefore, this study will ultimately not affect the
treatment of patients participating in the study.

The tissue collected for diagnostics will follow an alternative processing
route without any risk for the participant. The tissue will be available for
diagnostics at all times. After diagnosis, the tissue will be made available
for the COMET study.