Koos Boeve

136 Chapter 7 Cortactin and FADD were both significantly associated with true N-status in pT1 patients with a tumor infiltration depth <4 mm and both genes are located at the 11q13 chromosome which is frequently amplified in HNSCC [25,26]. Cortactin had the highest predictive value in this study and is a candidate driver gene of the 11q13 amplification [23]. Cortactin has many binding sites and interactions with other proteins which play an important role in metastasis as was reviewed in 2019 [16]. Cortactin plays a key-role in the regulation of protrusive structures such as invadopodia and lamellipodia that enable respectively the invasion and migration of tumor cells by changing the actin cytoskeleton [16,27-29]. Also in-vitro studies showed that cell migration of OSCC cell lines was regulated by cortactin expression [29-31]. The pooled data of nine studies with OSCC patients showed an association between N-status and amplification or expression of CTTN/ cortactin with an OR 2.78 (95% CI 1.68-4.60) (reviewed in [32]). The authors stated that cortactin could assist in the selection of patients for a watchful waiting strategy, but that further research is needed to define optimal patient selection [32]. In the current study, we have shown that cortactin expression has additional clinical value in pT1cN0 patients by better selection of watchful waiting with lower risk for lymph node metastases with a NPV of 92%. This is similar to the pooled NPV of 94% for the SLNB procedure in a meta-analysis [8]. Our study is based on a relatively small cohort, but our findings warrant further research with large prospective data to validate the selection of low risk patients for a watchful waiting strategy using cortactin expression in tumor biopsy specimens of OSCC tumors. This is one of the first studies using SLNB data for the validation of molecular tumor biomarkers associated with lymph node status. Although this study is limited by a relatively small number of patients compared to non-SLNB OSCC studies [15,33,34], it shows that cortactin expression might have additional value in preoperative neck strategy decisions in a subgroup of early stage OSCC patients. CONCLUSION This study showed the association between cortactin and lymph node status in pT1cN0 OSCC patients with a tumor infiltration depth <4mm and SLNB neck staging. A combination of a tumor size smaller than 20 mm, a tumor infiltration depth smaller than 4 mm and a low cortactin expression might have clinical value to select patients for a watchful waiting strategy instead of subjecting patients to a SLNB procedure. Further prospective research is needed to confirm the clinical value of cortactin as a predictive marker next to the SLNB procedure in one neck staging protocol in early stage OSCC.