New developments in sentinel lymph node biopsy for early-stage oral cancer

In 2007, sentinel lymph node biopsy (SLNB) was applied for the first time in the Netherlands in a patient with early-stage oral cavity carcinoma without any signs of lymph node metastasis on clinical and radiological examination (clinically negative neck). In the following years, SLNB was increasingly applied in most Dutch head and neck cancer centers, on account of its less invasive nature compared to an elective neck dissection, as well as its ability to detect individual lymphatic drainage patterns. In doing so, SLNB is able to reveal aberrant lymphatic drainage and detect any lymph node metastases beyond the cervical nodal levels generally addressed by elective neck dissection. As a result, elective neck dissection was gradually abandoned as a treatment strategy for the clinically negative neck in patients with early-stage oral cancer.
However, challenges remain for SLNB, especially in oral cancer due to the complex lymphatic system and abundance of lymph nodes in the neck. The main limitations of SLNB in oral cancer arise from the relatively low resolution of lymphoscintigraphy: an imaging technique that is able to assess the lymphatic drainage pattern of a tumor by injecting a radioactive tracer around the respective tumor. In situations where sentinel lymph nodes (SLNs) are located in close vicinity of the primary tumor, the radioactivity of the injection site can conceal the activity in nearby SLNs, making them undetectable.
This particular circumstance, known as the shine-through phenomenon, considerably increases the risk of missing metastatic SLNs. Especially tumor subsites with close spatial relation to SLNs, such as the floor-of-mouth or vestibule-of-mouth, are prone to the shine-through phenomenon. As a consequence, patients may be incorrectly staged negative for the presence of nodal disease (i.e., false-negative outcome), thereby erroneously omitting the treatment required for the regional nodal basin.
In addition, often multiple lymph nodes with radioactive uptake (i.e., hotspots) are revealed on lymphoscintigraphy. Although multiple true SLNs exist in many oral cancer patients, some hotspots may actually represent irrelevant higher echelon nodes. Falsely considering higher echelon nodes as SLNs can induce unnecessary surgical exploration of the neck, with its accompanying morbidity and risk of complications, which may hamper a complementary neck dissection in case of metastatic involvement of SLNs. Moreover, mistakenly designating SLNs as higher echelon nodes can lead to the neglect of true SLNs that are potentially harboring metastases.
Considering that any untreated nodal metastasis will inevitably develop into clinical manifestation of disease, which usually entails more comprehensive surgery as well as more frequently adjuvant radiotherapy and even reduced chances of survival, there is a need for technological advancements to overcome these limitations of SLNB in oral cancer.
This thesis is dedicated to improving the accuracy of SLNB and thereby improving the prognosis and quality-of-life for patients with early-stage oral cancer and a clinically negative neck. To that end, several new techniques for SLNB were investigated: SLNB with [99mTc]Tc-tilmanocept as tracer, MR lymphography with gadobutrol, CT lymphography with Lipidiol® and PET/CT lymphoscintigraphy with [68Ga]Ga-tilmanocept.