196 Chapter 6 reliable measurement of DOI before initial cancer surgery for example in biopsies. However, DOI measured on diagnostic biopsies is not reliable as sampling may not be representative of the entire primary cancer (24, 27). Assessment of DOI by preoperative MRI or intraoral ultrasonography is an alternative. However, preoperative MRI has been reported to be not accurate in tumors with DOI < 5 mm (28-33). Another alternative is measuring DOI during specimen-driven intraoperative assessment using frozen sections (34-36). This would enable an elective END during initial surgery in cN0 cases with DOI > 4 mm. Although promising, further validation and optimization is necessary to implement intraoperative assessment of DOI using frozen sections in a routine diagnostic setting. However, intraoperative assessment of DOI also has its limitations entailing patient uncertainty concerning the decision on END prior to surgery and the unnecessary prescheduled OR time for all potential ENDs leading to inefficiency and additional costs. Moreover, the direct communication that is necessary between surgeon and pathologist is not always possible (24, 36). The current study shows that MET positivity is univariably associated with LNM in OTSCC. This result was expected given the established association of MET positivity with OS and DFS in OSCC (17, 23). The result also concurs with the fact that wildtype MET activity is known to increase cell death, invasion and distant metastasis (18). Receptor tyrosine kinase MET is a known orchestrator of invasive growth (16, 19, 37, 38) As LNM is one of the major determinants of patient outcome in HNSCC, we are not the first to investigate the association between MET expression and LNM. It has been shown that expression levels of MET are high in cancer tissues and in corresponding affected lymph nodes (39-41). Additionally, it was shown that the MET gene product is more sensitive in the detection of occult LNM compared to cytokeratins in OSCC (42). The PPV of MET on occult LNM was 36.8%, which meets the recommendation of performing an END if the risk of occult LNM is 20% (NPV 80%) (2). In this study, we also showed that MET positivity has a NPV of 88.5% for occult LNM. Depth of invasion > 4 mm is a known predictor for occult LNM (4), in accordance with our results (PPV 25.8%). The established PPVs of MET positivity and DOI > 4mm showed that MET outperforms DOI in predicting occult LNM. Multivariable analysis showed that only MET positivity is independently associated with LNM, pN+ and occult (p-value < 0.05). Although DOI > 4 mm did not significantly contribute to the multivariable model, it showed a strong relation with pN+ LNM (OR=2.05, p-value = 0.209) and occult LNM (OR=2.16, p-value = 0.274). The lack of significance of DOI > 4 mm can
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