The impact of tumor budding and single-cell invasion on survival in patients with stage III/IV locally advanced oral squamous cell carcinoma- results from a prospective cohort study.

Introduction: Tumor budding (TB) refers to the presence of small clusters of tumor cells at the invasive front of a malignant tumor. Single tumor cell invasion (SCI) is an extreme variant of TB, in which individual loose tumor cells are present at the invasive front. Both TB and SCI are important histomorphologic risk factors postulated to indicate loss of cellular cohesion. In this study, we investigated the influence of TB and SCI on different survival outcomes in patients with locally advanced oral squamous cell carcinoma (OSCC). Methods: We included 129 patients with locally advanced OSCC (pT3-4) from a single-center, prospectively maintained cohort. We examined the association of TB and SCI with the presence of occult lymph node metastasis using a logistic regression model. Survival probabilities were estimated using the Kaplan-Meier method and cumulative incidence functions. The association of TB and SCI on overall survival (OS), oral cancer-specific survival (OCSS), and local recurrence-free survival (LRFS) was investigated using Cox's proportional hazards regression models. Results: TB was detected in 98 (76%) of the tumors, while SCI was observed in 66 (51%) patients. There was a significant association between TB and the occurrence of occult lymph node metastasis (OR=3.33, CI: 1.21-10.0). On multivariate analysis, TB had no detectable impact on survival outcomes. However, SCI showed a higher risk for local recurrence (Hazards ratio (HR): 3.33, CI: 1.19 - 9.27). Discussion: This study demonstrates that TB and SCI in locally advanced OSCC function as an independent risk factor for occult lymph node metastases, as well as local recurrences. Both histomorphologic risk factors could serve as an additional parameter for stratifying therapy and escalating multimodal treatment approaches.

Prognostic impact of the loss of E-cadherin and de novo expression of N-cadherin at the invasive front of primary and recurrent oral squamous cell carcinoma.

The epithelial-mesenchymal transition (EMT) is a biological mechanism in multiple pathophysiological diseases. Related alterations in cadherin expression play a crucial role in carcinogenesis, progression, angiogenesis, and immune response. EMT cells exhibit a transition from an epithelial to a mesenchymal phenotype (cadherin-switch). This process is characterized by the de novo development of N-cadherin (N-CAD), which replaces E-cadherin (E-CAD) and signifies an increased migratory capacity and malignant transformation. The cadherin switch is a hallmark of EMT and has been studied in various cancer entities. We predicted that the cadherin switch in the primary and recurrent oral squamous cell carcinoma (re-OSCC) tissues is an inherent characteristic of the tumor, affects the biologic behavior, and further reflects the post-recurrence survival outcome of these patients. Survival outcome was analyzed by calculating the post-recurrence survival of the high-risk group and correlating the standardized h-score-based IHC expression of both cadherin types with the clinical follow-up. 94 patients with re-OSCC were observed within the cohort. Tissue samples from both primary and recurring tumors were collected. There was a significant association between loss of E-CAD expression and both oral cancer-specific and overall survival, (HR=2.72, CI:1.50-4.95, p=0.001) and (HR=3.84, CI:1.93-7.63, p=0.001), respectively, for expression loss higher than 60%. There was no statistically significant correlation between N-CAD de novo expression and Overall, oral cancer-specific and disease-free post-recurrence survival. The current study clearly shows that cadherin-switch, identified as E-CAD loss and N-CAD de novo expression in the invasion front of a re-OSCC, appears to be an inherent histological hallmark that does not change from primary manifestation to recurrence within the same tumor, regardless of the form of adjuvant therapy used for the primary tumor. The loss of E-CAD expression in re-OSCC is an independent risk factor for poor survival, and may be used to stratify therapy and de/escalate the multimodal treatment.

The Benefit of Postoperative Radiotherapy and Extending Neck Dissection in pT1-2 Oral Squamous Cell Carcinoma With a Single Ipsilateral Cervical Lymph Node Metastasis (pN1).

BACKGROUND/AIM: We compared postoperative radiotherapy (PORT) to surgery only (SO), and supraomohyoidal neck dissection (SOHND) to modified radical neck dissection (MRND) in patients with pT1-T2 squamous cell carcinomas of the oral cavity (OSCC) and a single cervical lymph node metastasis (pN1) in terms of overall survival (OS), oral cancer specific survival (OCSS), and regional recurrence-free survival (RRFS), in a prospective cohort study. PATIENTS AND METHODS: We included patients with pT1-T2 pN1 OSCC with no distant metastasis and estimated the survival probabilities using the Kaplan-Meier method and calculated hazards ratios (HR) for PORT vs. SO and MRND vs. SOHND using adjusted Cox regression models. RESULTS: A total of 51 patients (26 SO vs. 25 PORT, 9 SOHND vs. 42 MRND) were evaluated. Patients who received PORT were more likely to be younger and healthier. OS at 5 years was 41% and 87% in the SO and PORT groups, respectively. OS at 5 years was 52% and 67% in the in the SOHND and MRND groups, respectively. Both OCSS and RRFS were improved by PORT. Extending neck dissection was not associated with improved OS (HR = 0.83). CONCLUSION: PORT is associated with preferable OS, OCSS, and RRFS in pT1-2 pN1 oral cancer and should be recommended regularly.

The sub-fascial pattern of the myocutaneous platysma flap - The anatomical basis and preliminary cases for oral reconstruction.

To verify the feasibility of the SF-MPF for oral reconstruction, the anatomic, sonographic and histologic features of the SF-MPF were investigated and the outcome in a series of patients was evaluated. The sonographic and histologic results showed a supra-fascial arterio-venous vascular blood supply to the sub-fascial design of the MPF. The clinical course of 12 consecutive patients who underwent oral reconstruction using the SF-MPF along with ipsi- or lateral neck dissection for treatment of oral cancer showed sufficient pedicle length and reliable blood supply. The SF-MPF is a reliable and safe pedicled myocutaneous flap. Therefore, it should be considered being an additional option when a pedicled flap has to be selected.

Impact of stratified resection margin classification on local tumor control and survival in patients with oral squamous cell carcinoma.

BACKGROUND: Guidelines recommended for resection of oral cancer define a free margin of ≥5 mm as clear and safe (R0). This statement was questioned recently based on the assumption that different surgical margins may hold different risk categories. The aim of this study was to investigate the impact of stratification of the surgical margins on the survival outcome of patients with oral cancer. METHODS: In a cohort of 753 patients, the hazard ratio for local recurrence-free survival (LRFS), overall survival (OS), and oral cancer-specific survival (OCSS) were estimated for R0 resection, the close margin of 1-4 mm, involved resection borders but with free frozen sections. Competing risk factors were considered in the statistical regression model. RESULTS: One hundred seventy-three (23%) patients developed local recurrence and 316 (42%) died in the 5 follow-up years. There was a gradual improvement in the LRFS, OCSS, OS with the increase of clear margin. OS showed a similar tendency. CONCLUSION: Not all patients with an R0cm status carry the same risk for impaired LRFS, OCSS, and OS. Their risk to develop recurrence is higher than those patients with R0 ≥5 mm but stratified risk management can be recommended according to the presented results.