In-vivo sentinel lymph node mapping in patients with colorectal cancer

The presence of lymph node metastases remains the most reliable prognostic
predictor and the gold indicator for adjuvant treatment in colorectal cancer
(CRC). The presence of nodal involvement decreases the 5-year survival with
25-35%. The chance of cure in patients with nodal metastases (Dukes C) is less
than 50%. One third of these patients may cure by the addition of adjuvant
chemotherapy. In spite of potentially curative resection, about 10% of the
patients with Dukes A and 15-30% with Dukes B tumours will eventually develop
recurrent disease within 5 years. In fact, 20 to 30% of CRC patients testing
negative for lymph node metastasis will subsequently develop systemic
metastases within 5 years. False-negative pathology for (occult) metastases may
be one of the causes for this later systemic spread. Most of these N0 CRC
patients harbour occult nodal or micro metastases and may therefore benefit
from adjuvant treatment. 1-3
These nodal metastases are usually less than 2 mm in size and can be missed on
routine examination. With sentinel lymph node biopsy (SLNB) it is currently
possible to predict the nodal status in several solid tumours with a high
degree of certainty.
The main advantage in CRC nowadays is to assess more accurately the true
negative status of the nodal basin and to allow extensive examination on the
pathologic material of one to four SLNs, such as immunohistochemistry (IHC).
The biological implication of micro metastases generally referred as occult or
less than 2 mm in diameter, still has to be defined. Bases on currently
available non-randomised data, the significance of micro metastases is
difficult to determine. Due to different techniques used among trials it is not
possible to compare studies properly or to perform a good meta-analysis of
previously reported studies.
Clearly, further studies are indicated to identify whether micro metastases
detected by SLNB procedure are able to predict the advantage of adjuvant
treatment in CRC patients. The value of sentinel lymph node mapping (SLNM) is
twofold. It will provide more intensive pathological analysis and more accurate
staging and may show unusual lymphatic drainage leading to a modification of
the extend of the resection.

1. To determine the feasibility of SLNM in CRC.
2. To assess the accuracy of SLNM in the status of the regional nodes.
3. To identify aberrant mesenteric lymphatic drainage patterns.

Patent blue dye V 0.5 - 2 ml is injected in case of colon tumours subserosally
around the tumour immediately after laparatomy and intra-abdominal palpation
and exclusion of distant metastases. Some mobilisation of the bowel along the
paracolic gutter is needed to deliver the bowel adjoining the tumour near the
surface. In patients with a rectal tumour the blue dye V (0.5 - 2 ml) is
injected by a rigid scope through the anus submucosal around the tumour. The
mesenteric dissection should be limited to a minimum to prevent disruption of
the lymphatic vessels. The first two to six blue stained nodes are marked with
a suture (suture-tagged). The lymphatic vessel containing the blue dye is
followed proximally to the site of the primary neoplasm to ensure that there
are no SLNs hidden in the mesenteric fat. Other blue nodes may appear during
resection but these should not be marked as SLNs. After all SLNs are marked, an
en bloc resection is performed. SLNs are defined as the first 6 lymph nodes
that localized blue dye within the regional basin. Bases on the hypothesis that
the lymphatic drainage occurs in a step-wise fashion, these lymph nodes should
reflect the pathological status of the regional node basin.
The pathologist examines the specimen by conventional methods and selects the
blue stained nodes and put them into marked cassettes so that they can be
identified by microscopic examination. All of the nodes, sentinel and
non-sentinel nodes, are examined by conventional methods (H&E staining). If the
sentinel node is negative or the non-sentinel node is positive and the sentinel
node is negative additional staining with Cytokeratin (CK) is performed on the
sentinel nodes.

Due to the blue dye the urine and stool may be discoloured over 24 to 48 hours
after surgery. Transient intraoperative hypotension and tachycardia usually
responding rapidly to a fluid bolus, and transient skin rash (urticaria) that
responds to diphenhydramine as a result of allergic reactions may occur. In
series of over 2100 patients only 0.42% demonstrated allergic reactions
manifested by an initial wheal reaction at the injection site, followed by the
development of blue hives scatterd at the regional area. Generally there is a
rapid response to in intravenous diphenhydramine and occasionally methyl
prednisolone. Patients had to be followed for at least 60 minutes. Physicians
may be hesitant to inject a substance into the tumour because of fear for
causing dissemination. However, there are no known data indicating that
intratumoral injections may result in a decreased survival. Patent blue dye V
is registered in the Netherlands.