241 General discussion, conclusion, and future perspective is independently associated with RLNM (pN+ and occult) when corrected for DOI, we do not wish to underestimate the association between DOI and RLNM seen the high ORs. The lack of significance for DOI is probably due to the low number of cancers with DOI ≤ 4 mm. The significant association between C-terminal MET uniform positivity and RLNM (pN+ and occult) indicates that MET immunoreactivity might be of value in the clinical decision whether or not to perform an END in both the preoperative as well as the post-operative setting. We foresee that performing routine immunohistochemistry using a C-terminal MET antibody (e.g. D1C2) on biopsies will facilitate the decision whether or not to perform an END during initial OSCC surgery. Ultimately, this improves logistics, cost-effectiveness, and reduces patient morbidity caused by two separate surgeries. However, to accomplish this a study design needs to be developed that extrapolates the results obtained using whole tissue sections to biopsies while taking tumor heterogeneity into account (74). Since there were less occult RLNMs for cancers showing < 10% C-terminal MET uniform positivity with DOI ≤ 4 mm compared to cancers showing ≥ 10% C-terminal MET uniform positivity with DOI ≤ 4 mm, illustrates that C-terminal MET uniform positivity could be of added value to DOI ≤ 4 mm for the clinical decision on the treatment of the cN0 neck i.e., whether regular follow-up, watchful waiting, or END is more appropriate. We can imagine that patients with cancers showing ≥ 10% C-terminal MET uniform positivity and DOI ≤ 4 mm should have a more stringent follow-up compared to patients in the same DOI group with < 10% C-terminal MET uniform positivity. We realize that this statement is based on very low numbers and independent validation in a larger cohort is necessary. Ideally, the validation cohort includes also patients that were treated with the watchful waiting protocol to increase the number of cancers with DOI ≤ 4 mm. Furthermore, as it is known that besides DOI, other histopathological characteristics (e.g. pT stage, degree of differentiation, growth pattern, perineural invasion, and lymphovascular invasion) are also associated with RLNM (75, 76), development of a multivariable binary logistic regression model incorporating all these variables in addition to C-terminal MET immunoreactivity could be of added value in the post-operative setting to facilitate the clinical decision on performing END in early OSCC. 8
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