Lymphatic mapping of the neck in oral cavity malignancies using ICG-nanocolloid

In 20-30% of the patients with squamous cell carcinoma of the oral cavity who
are staged clinically node negative occult metastasis are present.(1-3) In
experienced hands, the most sensitive method of staging the lymph nodes (LNs)
of the neck is ultrasound-guided fine needle aspiration cytology (USgFNAC) with
a sensitivity and specificity of 42-98% and 92-100%, respectively.(4,5) To
further improve the sensitivity of occult LN metastasis detection, patients
with USgFNAC negative LNs are generally scheduled for a SN biopsy.
The SN is defined as a LN receiving direct lymph drainage from the
primary tumor.(8) Assuming the orderly spread of tumor cells through the
lymphatic system, pathological evaluation of the SN allows accurate
determination of the tumor status of the LN and therefor the regional lymphatic
system.
Some authors have stated that the tumor load of the LNs can influence the
drainage route of the radiocolloid through the lymphatic system in such a way
that LNs saturated with tumor deviate the drainage pattern. This may ultimately
lead to the identification of a different SN than the true tumor-harboring node
SN. This phenomenon is called *rerouting*.(14,15) Another phenomenon that can
influence the false-negative rate in are the so-called *skip metastases*. The
term *skip metastases* refers to the presence of LN metastasis in the lower
neck levels (levels III-V) whereas the level I and II LNs (more close to the
tumor) are metastasis free. Byers et al. reported that *skip metastases* are
present in 16% of tongue carcinoma patients.(16)

Primary aim:
Lymphatic mapping of the neck in oral cavity malignancies using
ICG-nanocolloid.

Secondary aims:
- Analysis of lymphatic drainage of the head and neck area to determine the
extension of the neck dissection.
- Identification of the tumor draining lymph node(s).
- In case of lymph node metastasis: Evaluation of the rerouting phenomenon.

In the operation room a peritumoral injection ICG-nanocolloid will be given
after which the neck dissection will be performed. During the operation
fluorescence imaging will be performed to evaluate if there are fluorescent
lymph node present. Visualized fluorescent nodes will be collected after
excision of the neck dissection specimen and sent in separately for
pathological evaluation. Further inspection of the neck dissection specimen for
the presence of fluorescent lymph nodes will be performed ex vivo. All lymph
nodes will be sent to pathology for tumor status evaluation. Fluorescent lymph
nodes will be analyzed following the SN protocol. Non-SNs will be evaluated
following the normal pathology protocol.

At the NKI-AVL ICG-99mTc-nanocolloid is used as standard for SN biopsy
procedures of head and neck malignancies. In this study we will use the
non-radioactive counterpart, ICG-nanocolloid, to evaluate the tracer
distribution from the tumor via the lymphatic system to the lymph node(s). This
will be evaluated in 20 patients. Evaluation criteria are: 1) presence of
fluorescent lymph nodes in the neck dissection specimen; 2) cervical level at
which the fluorescent lymph node are found; 3) number of fluorescent lymph
nodes per cervical level; 4) is there unilateral or bilateral drainage (most
important in case of unilateral tumors); 5) tumor status of the fluorescent
lymph node(s); and 6) tumor status of non-fluorescent lymph nodes. In case of
tumor metastases: 1) size of metastasis 2) size of lymph node in which the
metastases is present.

Because ICG-nanocolloid is not radioactive, the surgeon/OR-personnel and
patients will not suffer from radiation burden. To lower the pain burden for
the patients, ICG-nanocolloid will be injected on the operation room when the
patient is already under general anesthesia. Fluorescence evaluation of lymph
nodes will be performed mainly ex vivo. Because of the intervention the
patients will be 20-30 minutes longer under general anesthesia.

In rare cases intravenously injected ICG will lead to nausea, urticaria and
anaphylactic shock (<1/10000). Because in this study a small amount of ICG will
be injected peritumoral, the expectation is that the chance on side-effects is
minimal.