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Background and Purpose: The aims of our study are to evaluate the diagnostic performance and prognostic value of radiological lymph node (LN) characteristics in pN+ oral cavity squamous carcinoma (OSCC)., Materials and Methods: pN+ OSCC treated between 2012 and 2020 were included. Preoperative imaging was reviewed by a single radiologist blinded to pathologic findings for the following nodal features: imaging-positive LN (iN+), laterality and total number, and image-identified extranodal extension (iENE). The sensitivity of iN+ for pN+ was calculated. The diagnostic performance of other nodal features was evaluated in the iN+ subgroup. The association of radiologic nodal features with overall survival (OS) was evaluated. Inter-rater kappa for radiologic nodal features was assessed in 100 randomly selected cases., Results: Of 406 pN+ OSCC, 288 were iN+. The sensitivity of iN+ for pN+ was 71% overall, and improved to 89% for pN+ LN >1.5 cm. Within iN+, sensitivity/specificity for LN size (>3 cm), total LN number (>4), and ENE were 0.44/0.95, 0.57/0.84, and 0.27/0.96, respectively. Sensitivity of iENE was higher in the subset, with major (>2 mm) versus minor (≤2 mm) pENE (43% vs. 13%, p = 0.001). Reduced OS was observed in iN+ versus iN- (p = 0.006), iENE+ versus iENE- (p = 0.004), LN size >3 versus ≤3 cm (p < 0.001), and higher LN number (p < 0.001). Inter-rater kappa for iN+, laterality, total LN number, and presence of iENE were 0.71, 0.57, 0.78, and 0.69, respectively., Conclusion: Our study shows that despite modest sensitivity of most radiological nodal features, the specificity of image-identified nodal features is high and their prognostic values are retained in pN+ OSCC., Level of Evidence: 3 (retrospective review comparing cases and controls) Laryngoscope, 134:4947-4955, 2024., (© 2024 The Author(s). The Laryngoscope published by Wiley Periodicals LLC on behalf of The American Laryngological, Rhinological and Otological Society, Inc.)

Despite the employment of extensive therapeutic strategies, OSCC recurrence and mortality rates persist at high levels. This underscores the shortcomings of current prognostic models and the urgency for refined biomarkers. This study explores the prognostic significance of tumor-draining lymph nodes (TDLNs) in OSCC, with a special focus on the quantification of T regulatory cells (Tregs) and the expression of immune checkpoints on T cells., Methods: Forty-nine OSCC patients were enrolled. One TDLN per patient was analysed using flow cytometry to profile immune-checkpoint expression (PD-1, CTLA-4, TIGIT, TIM-3, LAG-3) and other markers such as CD69, CXCR5 on CD4+, CD8+, and Tregs. Disease-free survival (DFS) and overall survival (OS) were assessed., Results: According to multivariate analysis, elevated levels of FoxP3+CD4+ and TIGIT+CD8+ cells in TDLNs correlated with significantly worse DFS, while high CXCR5+CD4+ levels were associated with better DFS. Notably, the expression of immune checkpoints on T cells within TDLNs showed significant associations with recurrence status. Patients experiencing recurrence exhibited heightened levels of T regulatory cells, CD4+PD-1+ and CD4+CTLA-4+, cells in TDLNs. Survival multivariate analyses revealed that T status emerged as an independent predictor of OS., Conclusion: The findings highlight the critical role of TDLNs in the immune microenvironment of OSCC and establish immune checkpoint expression on T cells as promising prognostic biomarkers. These insights upgrade the prognostic framework for OSCC and pave the way for individualized therapeutic strategies. The prognostic significance of TDLNs and a high expression of immune checkpoint inhibitors is a compelling argument for the adoption of neoadjuvant immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Piersiala, Hjalmarsson, Lagebro, Farrajota Neves da Silva, Bark, Elliot, Marklund, Margolin, Georén and Cardell.)

Selective neck dissection (SND) is the treatment of choice in patients with oral squamous cell carcinomas (OSCCs) and clinically node-negative necks (cN0). The treatment of patients with positive-staged necks (cN+) includes SND as well as comprehensive neck dissection (CND). The clear benefit of one or the other remains under debate. We aim to address this lack of clarity by analysing patients with OSCC staged with clinically node-positive necks, treated with either CND or SND using a level-by-level approach. This retrospective study included patients diagnosed with OSCC with clinically (cN+) and pathologically (pN+) positive cervical lymph nodes (LNs) with clear neck level categorization during the years 2010-2019. In total, 74 patients were analysed. Cox regression analysis found no significance for the type of ND being an independent risk factor, neither for overall survival (OS) nor for disease-free survival (DFS). Regional recurrence of CND cases (5.77%) was comparable to SND cases (9.09%). For OS, extracapsular spread (ECS) and male sex were identified as independent risk factors with poorer outcome. pT-stage and ECS were found to be independent risk factors for DFS. The results of this study suggest that both CND and SND may be viable treatment options for certain patients with OSCC pN+., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Jan Oliver Voss et al.)

Background: Studies suggest that neck dissections with a minimum of 16-18 yielded nodes are associated with better overall survival compared to neck dissections with lower yields., Aims: We aimed to identify factors affecting the lymph node yield and density in patients with oral cavity cancer undergoing elective neck dissection levels 1-3., Materials and Methods: Using prospectively registered data, we conducted a population-based cohort study on all patients surgically treated for oral cavity cancer including levels 1-3 neck dissection at our institution from 2018 to 2022. Uni and multivariate analyses were performed to identify factors associated with lymph node yields., Results: In total, 221 patients were included. The mean lymph nodes yield and density were 19 (95%CI 18-20) and 0.12 (95%CI 0.09-0.16), respectively. In multivariate analysis, increasing body weight ( p  = .034) was positively and previous radiotherapy ( p  = .006) were negatively correlated with the number of yielded lymph nodes. Lymph node density was positively correlated with body weight ( p  = .011) and body mass index ( p  = .032) in univariate analysis., Conclusions and Significance: Increasing body weight was positively and previous radiotherapy was negatively correlated to lymph node yield. These factors should be taken into consideration when interpreting the lymph node yield as an indicator of neck dissection quality.

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., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: We aimed to compare the predictive performance of pN-categories in oral squamous cell carcinoma (OSCC) encompassing the most recent 8th edition (TNM8), its predecessor (TNM7), and a newly proposed algorithm (pN-N + ), which classifies patients according to the number of positive lymph nodes and extranodal extension., Methods: Consecutive, primary OSCC patients from seven previously published cohorts were included and classified according to the three pN-classifications: TNM7, TNM8 and pN-N + . Overall survival probabilities were summarised with the Kaplan-Meier method. We added each of the three metrics to a Cox regression adjusted for pT-category, lymph nodal yield, age, sex, radiotherapy and chemotherapy, and trained these models in one institution. We evaluated the predictive performance in the remaining six institutions and assessed the predicted 5-year risk of death using the area under the receiver operating characteristics curve (AUC) and Brier scores., Results: All 1,905 included patients were classified according to TNM7 and pN-N + . A subset of 1,575 patients was additionally classified according to TNM8, leading to upstaging in 27.0%. The pN-N + ranked overall best determined by the obtained AUC and Brier scores. In contrast to pN-N + , TNM7 and TNM8 both suffered from disproportionate patient distribution across pN-categories and poor pN-categorial discrimination on overall survival., Conclusions: The TNM8 pN-classification designates a larger subset to more advanced disease stages but failed to show improvement of its predictive performance compared to TNM7. The pN-categories of TNM7/8 are disproportionate and inconsistently discriminated. The pN-N + conveyed the best measures of prognosis and should be considered in future TNM iterations., Competing Interests: Conflict of interest statement The authors declare no competing interests and have nothing to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The 8th TNM edition remarkably changed the classification of T and N categories for oral squamous cell carcinoma (OSCC). The present study aims at evaluating the improvement in prognostic power compared to the 7th edition, pros and cons of the modifications, and parameters deserving consideration for further implementations., Materials and Methods: All OSCCs treated with upfront surgery at our institution between 2002 and 2017 were included. Demographics, clinical-pathological and treatment variables were retrieved. All tumors were classified according to both the 7th and 8th TNM edition, and patients were grouped according to the shift in T category and stage. Survivals were calculated with the Kaplan-Meier method. Univariate and multivariate analysis were carried out. Receiver Operating Characteristics (ROC) curve analyses were performed to find the best cut-off of DOI (in patients with DOI > 10 mm) and number of involved nodes (in positive neck patients)., Results: 244 patients were included. T, N categories, and stage changed in 59.2%, 20.5%, and 49.1% patients, respectively; 41.5% of patients were upstaged. The new T classification well depicted prognosis according to OS. Five-year overall (OS), disease-specific, recurrence-free (RFS) survivals were 60.5%, 70.9%, 59.8%, respectively. According to ROC curves, DOI > 20 mm and 4 positive nodes were the best cutoffs for OS and RFS., Conclusion: The novelties introduced in 8th TNM edition were positive. DOI > 20 mm for T4 definition and number of positive nodes (0, <4, 4 or more) for N classification emerged as the most urgent factors to be implemented., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: To determine the effects of nodal yield on survival in early stage oral cavity squamous cell carcinoma (OCSCC) in the context of primary tumor depth of invasion (DOI)., Materials and Methods: Patients with early-stage clinically node-negative OCSCC who underwent upfront surgery at the primary site were identified using the National Cancer Database between 2004 and 2015., Results: There were 3384 patients with <4 mm DOI and 1387 patients with ≥4 mm DOI identified. Management of the neck included observation (40%), END with <18 nodes harvested ± postoperative radiation (ND < 18, 16%), and END with ≥18 nodes harvest ± postoperative radiation (ND ≥ 18, 44%). When adjusted for relevant covariates, ND ≥ 18 demonstrated statistically significant improvements in overall survival for both DOI < 4 mm and ≥4 mm (DOI < 4 mm: HR 0.67, 95%CI 0.54-0.85; DOI ≥ 4 mm: HR 0.47, 95%CI 0.34-0.64). However, ND < 18 showed no significant difference from observation of the neck regardless of DOI (DOI < 4 mm: HR 0.82, 95%CI 0.63-1.07; DOI ≥ 4 mm: HR 0.72, 95%CI 0.51-1.03). Of patients undergoing END, the most significant factors associated with obtaining a nodal yield of 18 or more were age less than 40 years (HR 2.58, 95%CI 1.84-3.63) and treatment at an academic facility (HR 2.47, 95%CI 2.06-2.96)., Conclusions: END with 18 or more nodes is associated with improved survival outcomes in patients with early stage OCSCC regardless of DOI. END with less than 18 nodes, however, does not appear significantly different than observation of the neck alone. Achieving a lymph node yield of 18 or more is multifactorial and includes both patient and provider factors., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: The management of occult lymph node metastasis (LNM) in head and neck squamous cell carcinoma has been a matter of controversy for decades. The vascular density within the tumor microenvironment, as an indicator of ongoing angiogenesis, could constitute an attractive predictor of LNM. The use of the panvascular endothelial antibody CD31 as a marker of occult LNM has never been reported. The aim of this study was to assess the predictive value of CD31 microvascular density for the detection of occult LNM in squamous cell carcinoma of the oral cavity and oropharynx., Study Design: Case series with chart review., Setting: Tertiary university hospital., Subjects and Methods: Intra- and peritumoral microvascular density values were determined in 56 cases of squamous cell carcinoma of the oral cavity (n = 50) and oropharynx (n = 6) with clinically negative necks using the CD31 marker. Statistical associations of CD31 microvascular densities with clinicopathologic data were then established., Results: Peritumoral CD31 microvascular density was significantly associated with occult LNM in multivariate analysis ( P < .01). Recursive partitioning analysis for this parameter found a cutoff of 19.33, which identified occult LNM with a sensitivity of 91%, a specificity of 65%, a positive predictive value of 40%, a negative predictive value of 97%, and an overall diagnostic accuracy of 71%., Conclusion: Peritumoral CD31 microvascular density in primary squamous cell carcinoma of the oral cavity and oropharynx allows accurate prediction of occult LNM.

Importance: Oral cavity squamous cell carcinoma (OCSCC) is associated with often-delayed clinical diagnosis, poor prognosis, and expensive therapeutic approaches. Prognostic accuracy is important in improving treatment outcomes of patients with this disease., Objectives: To assess lymph node ratio (LNR) and other factors in estimating response to treatment and provide prognostic information helpful for clinical decision making., Design, Setting, and Participants: A retrospective cohort study was conducted from January 1, 2000, to December 31, 2015, at an academic hospital in Denver, Colorado. Participants included 149 patients with primary OCSCC who received curative-intent surgery and/or postoperative adjuvant therapies. Analysis was performed from December 8, 2017, to August 15, 2018., Main Outcomes and Measures: Overall survival (OS), disease-free survival (DFS), locoregional disease-free survival (LRDFS), and distant metastasis-free survival (DMDFS) adjusted for known prognostic risk factors, as well as correlation of LNR with other histopathologic prognostic factors., Results: Of the 149 patients included in analysis, 105 were men (70.5%); the median age at diagnosis was 59 years (range, 28-88 years). Using the Kaplan-Meier method, the 5-year survival estimates for OS rate was 40.4% (95% CI, 31.3%-49.3%); DFS, 48.6% (95% CI, 38.6%-58.0%); LRDFS, 57.7% (95% CI, 46.6%-67.2%); and DMDFS, 74.7% (95% CI, 65.1%-82.0%). The median follow-up was 20 months for all patients and 34.5 months (range, 0-137 months) for surviving patients. Nonwhite race (hazard ratio [HR], 2.15; 95% CI, 1.22-3.81), T3-T4 category (HR, 1.99; 95% CI, 1.18-3.35), and LNR greater than 10% (HR, 2.71; 95% CI, 1.39-5.27) were associated with poorer OS. Nonwhite patients also had higher risk of locoregional failures (HR, 2.47; 95% CI, 1.28-4.79), whereas women were more likely to have distant metastasis (HR, 2.55; 95% CI, 1.14-5.71). Floor-of-mouth subsite had fewer locoregional recurrences than did other subsites (HR, 0.45, 95% CI, 0.21-0.99). An LNR greater than 10% independently was associated with worse OS (HR, 2.71; 95% CI, 1.39-5.27), DFS (HR, 2.48; 95% CI, 1.18-5.22), and DMDFS (HR, 6.05; 95% CI, 1.54-23.71). The LNR was associated with N-stage (Cramer V, 0.69; 95% CI, 0.58-0.78), extracapsular extension (Cramer V, 0.55; 95% CI, 0.44-0.66), lymphovascular invasion (Cramer V, 0.46; 95% CI, 0.27-0.61); number of excised lymph nodes (Cramer V, 0.24; 95% CI, 0.06-0.37), margin (Cramer V, 0.22; 95% CI, 0.05-0.38), and tumor thickness combined with depth of invasion (Cramer V, 0.25; 95% CI, 0.05-0.38)., Conclusions and Relevance: Locoregional treatment failure remained the predominant pattern of failure. An advanced pathologic stage and nonwhite race were found to be associated with worse outcomes. The findings from this study suggest that LNR is the most robust prognostic factor and appears to have implications for risk stratification in this disease.

Background: The treatment failure for oral squamous cell carcinoma (SCC) frequently takes the form of local and regional recurrences. We investigated the role of lingual lymph nodes (LLNs) in the recurrence of SCC of the tongue and the floor of the mouth., Methods: A total of 111 patients with SCC of the tongue and the floor of the mouth who received treatment between 2012 and 2017 were included in this study. The patients with lingual lymph nodes that were confirmed to be metastasis on pathological examination were classified into the LNN group. The demographic and clinical data differences between the No-LLN group and the LLN group were compared. Statistical analyses were performed using the Pearson chi-square test RESULTS: The total incidence of LLNs was 17.12% (19/111) and 5 patients (4.5%) demonstrated LLN metastases. All the patients with LLN metastases had a neck lymph node status of N2 classification. The incidence and metastasis of the LLNs were associated with pathological classifications of SCC of the tongue and the floor of the mouth., Conclusions: LLNs are rare in patients with SCC of the tongue and the floor of the mouth, and they would be ready to be omitted. The dissection of these LLNs would be of benefit to those patients with advanced pathological grade., (© 2018 Wiley Periodicals, Inc.)

Objective: According to the AJCC 2017 Staging Manual, oral cavity squamous cell carcinoma (OCSCC) with pN2 disease (based on the AJCC 2010 criteria) and extra-nodal extension (ENE) should be classified as pN3b. We performed a detailed outcome analyses in this patient subgroup., Material and Methods: We retrospectively reviewed the clinical records of consecutive OCSCC patients who underwent radical surgery between 1996 and 2017. Patients with pN3b disease (n = 365) were divided into a pN+ ≥8/ENE ≥5 subgroup (defined by the presence of pN+ ≥8 nodes or ENE ≥5 nodes, n = 77) and a pN+ ≤7/ENE ≤4 subgroup (defined by the presence of pN+ ≤7 nodes and ENE ≤4 nodes, n = 288). Patients with pN0/pN1/pN2 (n = 1192/179/197) disease were included for comparison purposes., Results: Patients in the pN+ ≥8/ENE ≥5 subgroup had less favorable 5-year outcomes than those in the pN+ ≤7/ENE ≤4/pN2/pN1/pN0 groups (local control, 64%/79%/86%/83%/88%, p < 0.001; neck control, 55%/75%/80%/86%/93%, p < 0.001; distant metastases, 67%/28%/20%/12%/3%, p < 0.001; disease-free survival, 21%/51%/64%/72%/82%, p < 0.001; disease-specific survival, 25%/55%/71%/82%/92%, p < 0.001; overall survival, 19%/40%/54%/64%/82%, p < 0.001; respectively). Among patients with pN3b disease, multivariable analysis identified the pN+ ≥8/ENE ≥5 subgroup, lower neck (level IV/V) metastases, and depth of invasion ≥25 mm as independent adverse prognostic factors for 5-year distant metastases and survival rates., Conclusions: Patients in the pN+ ≥8/ENE ≥5 subgroup have an unfavorable prognosis and their classification as pN3b is advisable. In contrast, patients in the pN+ ≤7/ENE ≤4 subgroup should be classified as pN3a., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Recently, the genetic alterations associated with tumor progression and impaired host immunity against transformed cells draw increased attention. Here, we characterized the differential gene expression patterns and protein expression in tumor-free lymph node from recurrent and non-recurrent tumors to identify independent prognostic markers for oral squamous cell carcinoma (OSCC)., Methods: A cDNA microarray analysis was performed to identify the differentially expressed genes in regional tumor-free lymph nodes from OSCC patients with and without recurrence. Then, the protein expression of the selected genes was analyzed by immunohistochemistry in 60 OSCC patients to determine their association with survival., Results: Widespread down-regulation of genes involved in antigen processing and recognition in lymph nodes was a distinctive feature. In univariate Kaplan-Meier analysis, lower expression of CD40L and CD80 in tumor-free lymph nodes was significantly correlated with poorer survival. In multivariate Cox regression analysis, CD40L was identified as an independent prognostic marker of disease-free survival., Conclusion: Our data indicate that impaired host immunity (decreased CD40L expression) along with the TNM staging might be an important factor determining the prognosis of OSCC.

Background: Oral squamous cell carcinoma (OSCC) containing single lymph node metastasis (pN1) with extra nodal extension (ENE) is a rare clinical situation. Therefore, it is unclear whether pN1 with ENE is at high risk of recurrence among the OSCC population, or whether postoperative radiotherapy (RT)/concomitant chemoradiotherapy (CCRT) is effective in these cases., Objectives: The purpose of this retrospective study was to investigate the prognosis and compare between no postoperative therapy and postoperative RT/CCRT in pN1 with ENE OSCC patients., Methods: Clinicopathological data and treatment modalities were investigated. The evaluated endpoints were overall survival (OS) and type of recurrence., Results: The 3-year cumulative OS rates for the pN1 only, multiple lymph node metastasis (MLM) only, ENE + MLM, and ENE + pN1 groups were 77.2%, 66.8%, 43.3%, and 66.6%, respectively. In the ENE + pN1 group, the most common cause of death in the surgery only group was from regional failure. The surgery + RT/CCRT group was associated with better disease-specific survival and OS rates than the surgery only groups (P < 0.05)., Conclusions: The prognosis of ENE + pN1 was not as poor as that of ENE + MLM, although both these groups feature ENE. Adjuvant therapy (RT/CCRT) after surgery is recommend for cases of ENE + pN1., (© 2018 Wiley Periodicals, Inc.)

Background: Few studies have examined the frequency and survival implications of clinicopathologic stage discrepancy in oral cavity squamous cell carcinoma (SCC)., Methods: Oral cavity SCC cases with full pathologic staging information were identified in the National Cancer Database (NCDB). Clinical and pathologic stages were compared. Multivariate logistic regressions were performed to identify factors associated with stage discrepancy., Results: There were 9110 cases identified, of which 67.3% of the cases were stage concordant, 19.9% were upstaged, and 12.8% were downstaged. The N classification discordance (28.5%) was more common than T classification discordance (27.6%). In cases of T classification discordance, downstaging is more common than upstaging (15.4% vs 12.1% of cases), but in cases of N classification discordance, the reverse is true; upstaging is much more common than downstaging (20.1 vs 8.4% of cases)., Conclusion: Clinicopathologic stage discrepancy in oral cavity SCC is a common phenomenon that is associated with a number of clinical factors and has survival implications., (© 2018 Wiley Periodicals, Inc.)

Background: Recently, lymph node ratio (LNR) has been recognized as an important prognosticator for oral squamous cell carcinoma (OSCC). However, its relevance for the specific subsite floor of mouth (FOM) has not been investigated. This study was conducted to elucidate the prognostic significance of LNR for the subsite FOM among other prognostic factors., Methods: A retrospective study of 155 patients with FOM SCC who received primary curative resection and neck dissection was conducted. We analyzed the impact of LNR among other clinicopathologic variables on overall survival (OS) in univariate and multivariate analysis., Results: In univariate analysis, patients detected with LNR ≤ 0.07 (cutoff-point: 0.07) showed an 85% 5-year OS rate, whereas for patients with LNR > 0.07 the OS rate reached 25% after 5-years (p < 0.001). The 5-year DFS rate was 72% for patients with LNR ≤ 0.07; on the contrary, patients with LNR > 0.07 the 5-year DFS rate was 17% (p < 0.001). LNR was detected as an independent predictor of OS in multivariate analysis (p = 0.032) for the subsite FOM., Conclusion: We concluded that LNR is an important predictor of prognosis in patients with FOM SCC, LNR should be considered in the choice of adjuvant treatment for these patients., (Copyright © 2017 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)

Context: Lymph node metastasis (LNM) influences survival of oral squamous cell carcinoma (OSCC). Evidence supports the value of prognostic information provided by most aggressive cells that lie in the tumor invasive front., Aims: This study evaluated the clinical and histological parameters (C and HP) that would best associate with LNM in OSCC., Settings and Design: A review of records and histological examination of nonrecurrent surgically treated 182 cases., Subjects and Methods: A review of records and histological examination according to the Bryne's invasive front grading system of nonrecurrent surgically treated 182 cases (pN- =100; pN+ =82) was undertaken. The data were subjected to suitable statistical analysis to check the agreement between observers, association of the parameters to LNM, and to identify the best among all of them., Statistical Analysis Used: Kappa statistics, Pearson's Chi-square, Fisher's exact test, multiple logistic regression analysis., Results: None of the C and HP, with the exception of pattern of invasion (PI) (P = 0.000), modified degree of keratinization and nuclear polymorphism (P = 0.041, 0.022), and total malignancy score for survival (P = 0.013) showed a significant association with nodal status. PI was identified as the most influencing parameter of all., Conclusions: Factor that is primarily the manifestation of tumor and its microenvironment has taken the prime seat followed by the ones that are dictated by the tumor. The factors that are basically quantified were not able to show association. Site influences the nodal status alongside PI., Competing Interests: There are no conflicts of interest.

Background: There is no published study on the influence of lymph node ratio on locoregional recurrence of squamous cell carcinoma (SCC) of the buccal mucosa. Therefore, we focused in our study on this specific anatomic subsite., Methods: We conducted a retrospective chart review of 95 patients from 2003-2013 with treatment-naive SCC of the buccal mucosa. Exclusion criteria were neoadjuvant chemoradiotherapy, perioperative death, N3 disease, unresectable disease, synchronous malignancy, and follow-up <3 months. Statistical analysis was performed using univariate and multivariate analysis., Results: Significant correlations were found between locoregional recurrence and pathologic N classification (P < .001), grading (P = .001), and lymph node ratio (P < .001). Multivariate analysis indicated lymph node ratio as an independent risk factor for locoregional recurrence (P = .002). A cutoff value under 7% led to a 10.383-fold higher risk of incurring a locoregional recurrence., Conclusion: Lymph node ratio is a useful parameter to stratify the risk of locoregional recurrence in patients with SCC of the buccal mucosa., (© 2017 Wiley Periodicals, Inc.)

Purpose Current staging systems for oral cavity cancers incorporate lymph node (LN) size and laterality, but place less weight on the total number of positive metastatic nodes. We investigated the independent impact of numerical metastatic LN burden on survival. Methods Adult patients with oral cavity squamous cell carcinoma undergoing upfront surgical resection for curative intent were identified in the National Cancer Data Base between 2004 and 2013. A neck dissection of a minimum of 10 LNs was required. Multivariable models were constructed to assess the association between the number of metastatic LNs and survival, adjusting for factors such as nodal size, laterality, extranodal extension, margin status, and adjuvant treatment. Results Overall, 14,554 patients met inclusion criteria (7,906 N0 patients; 6,648 node-positive patients). Mortality risk escalated continuously with increasing number of metastatic nodes without plateau, with the effect most pronounced with up to four LNs (HR, 1.34; 95% CI, 1.29 to 1.39; P < .001). Extranodal extension (HR, 1.41; 95% CI, 1.20 to 1.65; P < .001) and lower neck involvement (HR, 1.16; 95% CI, 1.06 to 1.27; P < .001) also predicted increased mortality. Increasing number of nodes examined was associated with improved survival, plateauing at 35 LNs (HR, 0.98; 95% CI, 0.98 to 0.99; P < .001). In multivariable models accounting for the number of metastatic nodes, contralateral LN involvement (N2c status) and LN size were not associated with mortality. A novel nodal staging system derived by recursive partitioning analysis exhibited greater concordance than the American Joint Committee on Cancer (8th edition) system. Conclusion The number of metastatic nodes is a critical predictor of oral cavity cancer mortality, eclipsing other features such as LN size and contralaterality in prognostic value. More robust incorporation of numerical metastatic LN burden may augment staging and better inform adjuvant treatment decisions.

Purpose: Lymph node density(LND) has been shown to be a better prognosticator than conventional nodal classification to predict prognosis for squamous cell carcinoma(SCC) of the oral cavity. However, studies focusing on subsites of oral cancer are meager. The role of LND for buccal SCC was evaluated in this study., Methods: A total of 39 patients with buccal SCC primarily treated surgically with neck dissection were identified. LND was defined as the number of positive nodes over the number of nodal yield. The cut-off of LND was ≤0.07 or >0.07. Patient demographic data and clincopathologic parameters were described. Survival was expressed by Kaplan-Meier method and correlation with survival is analyzed with log-rank test. IBM SPSS Statistics version 22 was used for data computation., Results: The median follow-up was 79.0months and median nodes removed was 23 (range 8-93). Positive nodal involvement was found in 19(48.7%) patients. The 5-year and 10-year OS were 67.4% and 42.5% whilst for DSS were 69.2% and 65.5%, respectively. When pT-, pN-, LND-classification and AJCC stage were analyzed for the whole series, only pN- (p=0.006) and LND-classification (p=0.002) were significant factors for OS, while pT-, pN-, LND-classification and AJCC stage were all significant factors for DSS. When only cases with positive nodal spread were considered, the pN-classification (pN1 vs pN2) was not a significant risk factor for either OS (p=0.075, HR 3.10(CI 0.89-10.76)) and DSS (p=0.074, HR 3.58(CI 0.88-14.56)). By contrast, LND-classification (≤0.07 vs >0.07) remained a significant predictor for OS (p=0.03, HR 3.95(CI 1.15-13.63)), but not for the DSS (p=0.112, HR 2.92(CI 0.78-10.99))., Conclusion: The prognostic value of LND on buccal SCC is supported in this study. The results also suggest that LND is better than the conventional pN-classification to predict OS. Further studies on LND with big sample size for buccal SCC or other subsites of OSCC are worthwhile., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The lymph node ratio(LNR) has been described as a novel predictor of the survival of patients with oral and oropharyngeal squamous cell carcinoma(O/OPSCC). The purpose of this study was to evaluate whether LNR is better at predicting survival and the need for adjuvant treatment than traditional tumour-nodal-metastasis(TNM) staging. Eight hundred nine patients with O/OPSCC and positive lymph node disease were retrospectively enrolled in this study. LNR equal to 0.075 is the best cut-off value for stratifying 5-year disease-free survival(DFS). High LNR is closely associated with more advanced T stage, higher N stage, more severe pathological grade, the presence of diffuse infiltration and extracapsular spread(ECS). LNR is better for evaluating prognosis than the pathological N stage. Patients with high LNR coupled with high number of positive lymph nodes who received adjuvant concurrent chemo-radiotherapy(CCRT) had a better 5-year DFS than patients who received surgery alone. Multivariate analyses revealed that T stage, ECS and LNR are independent prognostic factors of 5-year DFS and disease-specific survival(DSS). Therefore, high LNR is closely correlated with adverse parameters that markedly hinder prognosis. LNR is superior to traditional TNM staging for the evaluation of prognosis,and the combination of the LNR with the number of positive lymph nodes can predict the benefits of adjuvant CCRT.

The aim of this study was to evaluate the histopathologic parameters that predict lymph node metastasis in patients with oral squamous cell carcinoma (OSCC) and to design a new assessment score on the basis of these parameters that could ultimately allow for changes in treatment decisions or aid clinicians in deciding whether there is a need for close follow-up or to perform early lymph node dissection. Histopathologic parameters of 336 cases of OSCC with stage cT1/T2 N0M0 disease were analyzed. The location of the tumor and the type of surgery used for the management of the tumor were recorded for all patients. The parameters, including T stage, grading of tumor, tumor budding, tumor thickness, depth of invasion, shape of tumor nest, lymphoid response at tumor-host interface and pattern of invasion, eosinophilic reaction, foreign-body giant cell reaction, lymphovascular invasion, and perineural invasion, were examined. Ninety-two patients had metastasis in lymph nodes. On univariate and multivariate analysis, independent variables for predicting lymph node metastasis in descending order were depth of invasion (P=0.003), pattern of invasion (P=0.007), perineural invasion (P=0.014), grade (P=0.028), lymphovascular invasion (P=0.038), lymphoid response (P=0.037), and tumor budding (P=0.039). We designed a scoring system on the basis of these statistical results and tested it. Cases with scores ranging from 7 to 11, 12 to 16, and ≥17 points showed LN metastasis in 6.4%, 22.8%, and 77.1% of cases, respectively. The difference between these 3 groups in relation to nodal metastasis was very significant (P<0.0001). A patient at low risk for lymph node metastasis (score, 7 to 11) had a 5-year survival of 93%, moderate-risk patients (score, 12 to 16) had a 5-year survival of 67%, and high-risk patients (score, 17 to 21) had a 5-year survival of 39%. The risk of lymph node metastasis in OSCC is influenced by many histologic parameters that are not routinely analyzed in pathologic reports. These significant independent factors were graded to design a scoring system that permits accurate evaluation of the risk of metastasis with accuracy independent of the traditional TNM system or isolated histologic parameters. The need for neck node dissection can be predicted depending upon the scores obtained.

Background: The purpose of this study was to identify clinicopathological and immunohistochemical factors predicting delayed lymph node metastases and survival in early oral squamous cell carcinoma (OSCC)., Methods: The study included 85 consecutive patients with clinically T1 to T2N0 OSCC who were primarily surgically treated between 2000 and 2004., Results: There were 68 men and 17 women (median age, 61 years; range, 34-82 years). Of all the patients, 25 (29.4%) developed delayed lymph node metastases within 3 to 42 months after treatment of the primary tumor. Multivariate logistic regression analysis identified poorly differentiated tumors, low laminin, and high fibronectin expression as prognosticators of delayed lymph node metastases. Cox's proportional hazards regression analysis demonstrated that moderately differentiated tumors and delayed lymph node metastases had predictive value regarding survival., Conclusion: Large prospective investigations with reproducibility and the clinical translatability of immunohistochemical methods are needed in order to provide new and effective therapeutic strategies in the future. © 2016 Wiley Periodicals, Inc. Head Neck 39: 694-701, 2017., (© 2016 Wiley Periodicals, Inc.)

Downregulated expression of KiSS-1 has been correlated with tumor progression, metastasis, and patient prognosis in various human malignancies. However, there is no information regarding the expression of KiSS-1 in oral squamous cell carcinoma (OSCC). Our aims were to examine KiSS-1 expression in OSCC tissue samples and cell lines and to determine its prognostic significance. KiSS-1 expression was significantly lower in lymph node (LN) metastases than in primary tumor tissues. Five of six OSCC cell lines showed absence or relatively low expression of KiSS-1. Correlations between KiSS-1 expression and clinicopathological parameters were statistically assessed. There were significant correlations between KiSS-1 expression and LN metastasis (p = 0.007), TNM stage (p = 0.024), and local recurrence (p = 0.012). In the Kaplan-Meier survival analysis, negative KiSS-1 expression significantly correlated with poorer overall survival (OS) and disease-free survival (DFS) (p = 0.000 and 0.000, respectively). Multivariate analysis using Cox regression modeling revealed that KiSS-1 expression was an independent prognostic factor for both OS and DFS (p = 0.001 and 0.000, respectively). Our findings suggested that KiSS-1 downregulation may play a role in tumor progression and metastasis of OSCC and may be a reliable biomarker for predicting clinical outcome in OSCC., (© 2016 APMIS. Published by John Wiley & Sons Ltd.)

Objective: To investigate the cutoff value and significance of lymph node ratio (LNR) in oral squamous cell carcinoma., Methods: This retrospective study included 286 patients with oral cancer and pathological positive lymph nodes. Used time-dependent receiver operating characteristic (ROC) curves to determine which LNR best defines different risk groups of oral squamous cell carcinoma (OSCC) patients. All the variables were subjected to the univariate analysis, then only the variables that had prognostic potential were subjected to multivariate analysis by the COX proportional hazards regression model., Results: The cutoff value of LNR was 0.092. When LNR was greater than 0.092, the overall survival rate was 24.2%, when LNR was less than 0.092, the overall survival rate was 45.8% (P<0.05)., Conclusions: Lymph node ratio is a predictor of outcome in patients with oral squamous cell carcinoma, and the cutoff value is 0.092.

To investigate the incidence of metastasis to facial lymph nodes (FLNs) and to determine its impact on the prognosis and survival of patients at onset of oral cavity squamous cell carcinoma (OSCC). A retrospective review of 641 patients with OSCC treated with curative surgery (CS) alone or CS + postoperative radiotherapy (PORT) was performed. Based on FLN status, an analysis of clinicopathologic parameters, prognosis, and survival was conducted. By classifying patients according to FLN status, a reasonable treatment modality was identified in the low-risk group, which was defined as those who had N0-1 disease, negative margin, and no extracapsular nodal spread (ENS). FLN involvement was identified in 103 patients (16 %), which showed statistically significant associations with several established risk factors and negatively affected local controls (P < 0.001), neck controls (P < 0.001), and disease-specific survival (P < 0.001). Compared to CS alone, CS + PORT increased the 5-year neck control rate (76.8 vs. 30.7 %, P = 0.006) and disease-specific survival rate (67.8 vs. 30.7 %, P = 0.037) of the OSCC patients with FLN metastasis in the low-risk group. Metastasis to FLNs is strongly associated with poor disease control and lower survival rate of OSCC patients. PORT minimized the residual risk of involved FLN in the low-risk group.

Background: The current head and neck squamous cell carcinoma (HNSCC) staging system may not capture the full prognostic implications of regional lymph node involvement. This study investigated the impact of the level of lymph node metastasis (LNM) on survival., Methods: The Surveillance, Epidemiology, and End Results registry was queried for oral cavity (OC), oropharynx (OP), larynx (LAR), and hypopharynx (HP) HNSCC. A multivariate Cox proportional hazards model was used to evaluate whether the level of LNM was an independent prognostic factor. Site-specific recursive-partitioning analysis was performed to classify patients into different risk groups., Results: In all, 14,499 patients, including OC (n = 2463), OP (n = 8567), LAR (n = 2332), and HP patients (n = 1137), were analyzed. Both the American Joint Committee on Cancer (AJCC) N classification and the level of LNM showed significant effects on overall survival (OS) in patients with OC, OP, or LAR HNSCC but not in patients with HP HNSCC. In patients with N2 disease, the AJCC subclassification (N2a, N2b, or N2c) was significantly associated with the OS of patients with OP and LAR HNSCC but not with the OS of patients with OC or HP HNSCC, whereas the level of LNM (primary, secondary, or tertiary) was significantly associated with the OS of patients with OC, OP, and LAR HNSCC but not HP HNSCC. With recursive-partitioning analysis, a simple, primary site-specific prognostic tool integrating the AJCC T and N classifications and the level of LNM was designed, and it could be easily used by health care providers in clinic., Conclusions: The level of LNM is an independent prognostic factor for patients with locally advanced HNSCC and could add to the prognostic value of AJCC T and N classifications in patients with locally advanced HNSCC., (© 2015 American Cancer Society.)

Objective: The tumour-node-metastasis staging system has a dynamic structure that is continuously being updated as scientific data develops. This review discusses some suggested revisions on tumour-node-metastasis staging of human papillomavirus negative upper aerodigestive tract cancers., Methods: The seventh edition of The American Joint Committee on Cancer Staging Manual was reviewed and important issues that could be considered for revision were identified and discussed., Results: According to our assessment of the oncological outcomes of previous studies, the following factors should be considered for revision: anterior commissure involvement and subglottic extension in laryngeal cancers; underlying bone involvement in hard palate and upper alveolar ridge cancers; tumour thickness in oral cancers; and extracapsular spread and carotid artery involvement in neck metastases., Conclusion: Sufficient data on the prognostic importance of these issues have been reported. Suggested revisions in line with current knowledge on the clinical behaviour of upper aerodigestive tract cancers would improve the relevancy of staging.

Purpose: Optimum management of the N0 neck is unresolved in oral cancer. Sentinel node biopsy (SNB) can reliably detect microscopic lymph node metastasis. The object of this study was to establish whether the technique was both reliable in staging the N0 neck and a safe oncological procedure in patients with early-stage oral squamous cell carcinoma., Methods: An European Organisation for Research and Treatment of Cancer-approved prospective, observational study commenced in 2005. Fourteen European centres recruited 415 patients with radiologically staged T1-T2N0 squamous cell carcinoma. SNB was undertaken with an average of 3.2 nodes removed per patient. Patients were excluded if the sentinel node (SN) could not be identified. A positive SN led to a neck dissection within 3 weeks. Analysis was performed at 3-year follow-up., Results: An SN was found in 99.5% of cases. Positive SNs were found in 23% (94 in 415). A false-negative result occurred in 14% (15 in 109) of patients, of whom eight were subsequently rescued by salvage therapy. Recurrence after a positive SNB and subsequent neck dissection occurred in 22 patients, of which 16 (73%) were in the neck and just six patients were rescued. Only minor complications (3%) were reported following SNB. Disease-specific survival was 94%. The sensitivity of SNB was 86% and the negative predictive value 95%., Conclusion: These data show that SNB is a reliable and safe oncological technique for staging the clinically N0 neck in patients with T1 and T2 oral cancer. EORTC Protocol 24021: Sentinel Node Biopsy in the Management of Oral and Oropharyngeal Squamous Cell Carcinoma., (Copyright © 2015. Published by Elsevier Ltd.)

Death-associated protein 1 (DAP1) is a member of the DAP family. Its expression is associated with cell growth and normal death of the neoplastic cells, regulated by the mammalian target of the rapamycin protein. Activated DAP1 negatively regulates autophagy, which has been associated with the development and progression of several diseases, such as cancer, and with prognosis and survival of diverse tumor types. Therefore, in this study we analyzed DAP1 expression in 54 oral squamous cell carcinoma tumor samples and in 20 non-tumoral margins by immunohistochemistry. The results showed that DAP1 is more frequently expressed in tumor tissues compared with marginal non-tumoral cells. Additionally, high DAP1 expression is associated with a 4-fold increase in the risk of lymph node metastases. Our results suggest that the DAP1 protein can be used as a potential marker of lymph node metastases predisposition, helping define the best therapy for each patient to minimize risk of developing metastases.

Recently, log odds of positive lymph nodes (LODDS) was proven a better prediction of outcomes than other methods in gastric cancer, pancreatic cancer, and colon cancer. However, the validity is not yet tested in oral cavity squamous cell carcinoma (OSCC). We conducted a retrospective study to compare the predictive ability of LODDS, traditional pN classification and lymph node ratio (rN) in OSCC patients.In total, 347 OSCC patients receiving surgery with or without adjuvant therapy at the time of diagnosis between 2004 and 2013 were identified from the cancer registry database of the Dalin Tzu Chi Hospital. Cox proportional hazards models were used to compare the disease-specific survival (DSS) rates for pN, rN, and LODDS after adjusting for possible confounding risk factors. The discriminatory ability of different classification systems was evaluated using the adjusted hazard ratio and Akaike information criterion (AIC) by multivariate regression model. The prediction accuracy of the model was assessed by Harrell's c-statistic.The 347 OSCC patients had a mean age of 57 years old. Among them, 322 patients (92.8%) were male and 189 patients (54.5%) were in stages III to IV. LODDS showed better discriminatory ability for patients with <5 pathological cervical metastatic nodes and those with rN < 0.2. The hypothetical T-LODDS-M staging system had higher linear trend Chi-square, lower AIC, and higher prediction accuracy compared with the American Joint Committee on Cancer (AJCC) TNM, or hypothetical T-rN-M system. After adjusting for other factors, the LODDS unfavorable group had the highest adjusted hazard ratio (HR, 5.42; 95% confidence interval [CI], 3.19-9.12) and LODDS-based model lowest AIC of 704, comparing with pN and rN-based model. The LODDS-based system had the highest prediction accuracy for 3-year DSS (Harrell's c-statistic, 0.803).In our series, LODDS shows great promise as a prognostic tool for OSCC. Compared with the AJCC pN classification and the rN classification, LODDS can stratify OSCC patients and help to identify high-risk patients missed by the other systems.

Introduction: Elective neck dissection is recommended in cases of oral cavity squamous cell carcinoma without lymph node metastasis because of the risk of occult metastasis., Objective: The present study aimed to evaluate predictive factors for occult lymph node metastasis in patients with oral cavity squamous cell carcinoma treated with elective neck dissection and their impact on overall and disease-free survival., Methods: Forty surgically treated patients were retrospectively included., Results: Ten cases (25%) had lymphatic metastasis. Of the studied variables, perineural and angiolymphatic invasion in addition to tumor thickness were statistically associated with lymph node metastasis. Only angiolymphatic invasion was identified as an independent risk factor for occult metastasis in the logistic regression (OR=39.3; p=0.002). There was no association between overall and disease-free survival with the presence of occult lymph node metastasis., Conclusion: Metastatic disease rate was similar to that found in the literature. Perineural and angiolymphatic invasion and tumor thickness were associated with occult metastasis, but only angiolymphatic invasion showed to be an independent risk factor., (Copyright © 2015 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.)

Background: The overall mortality rate in cases of head and neck squamous cell carcinoma (HNSCC) has not improved over the past 30 years, mostly because of the high treatment failure rate among patients with regionally metastatic disease. To better understand the pathobiologic processes leading to lymphatic metastasis development, there is an urgent need for relevant animal models., Methods: HNSCC cell lines were implanted into the tongues of athymic nude mice. Histology, immunohistochemistry, and ex vivo 2-photon microscopy were used to evaluate tumor progress and spread., Results: Orthotopic xenografts of different HNSCC cell lines produced distinct patterns of survival, tumor histology, disease progression rate, and lymph node metastasis development. Remarkably, all injected cell types reached the lymph nodes within 24 hours after injection, but not all developed metastasis., Conclusion: This orthotopic xenograft model closely mimics several characteristics of human cancer and could be extremely valuable for translational studies focusing on lymphatic metastasis development and pathobiology., (© 2014 Wiley Periodicals, Inc.)

Background: A study was conducted to assess for prognostic heterogeneity within the N2b and N2c classifications for oral cancer based on the number of metastatic lymph nodes and to determine whether laterality of neck disease provides additional prognostic information., Methods: An international multicenter study of 3704 patients with oral cancer undergoing surgery with curative intent was performed. The endpoints of interest were disease-specific survival and overall survival. Model fit was assessed by the Akaike Information Criterion and comparison of models with and without the covariate of interest using a likelihood ratio test., Results: The median number of metastatic lymph nodes was significantly higher in patients with N2c disease compared to those with N2b disease (P < .001). In multivariable analyses stratified by study center, the addition of the number of metastatic lymph nodes improved model fit beyond existing N classification. Next, the authors confirmed significant heterogeneity in prognosis based on the number of metastatic lymph nodes (≤ 2, 3-4, and ≥ 5) in patients with both N2b and N2c disease (P < .001). A proposed reclassification combining N2b and N2c disease based on the number of metastatic lymph nodes demonstrated significant improvement in prognostic accuracy compared with the American Joint Committee on Cancer staging system, and no improvement was noted with the addition of a covariate for contralateral or bilateral neck disease (P = .472)., Conclusions: The prognosis of patients with oral cancer with N2b and N2c disease appears to be similar after adequate adjustment for the burden of lymph node metastases, irrespective of laterality. Based on this finding, the authors propose a modified lymph node staging system that requires external validation before implementation in clinical practice., (© 2014 American Cancer Society.)

Introduction: TNM status is questioned as an exact predictor of survival in different tumour entities. Recently, lymph node ratio (LNR) has been described as a predictor of survival in patients with HNSCC. The purpose of this study was to evaluate to which degree LNR could be used as a more accurate predictor than TNM staging?, Methods: A total of 291 patients, with a follow-up of at least 3 years, were analyzed using log-rank statistic, univariate and multivariate data analyzes, and p values, for prediction of lymph node ratio on overall and recurrence-free survival., Results: Survival differed significantly if patients were stratified for LNR. Impact of LNR on survival was significantly different even in patients with extracapsular spread. Patients with pN0 had no survival benefit compared with patients with pN1 or higher with a LNR lower than 6 %., Conclusions: LNR is a prognostic tool in patients with a lymph node status pN0-pN2b. LNR remained significant even in patients with extracapsular spread, contrary to TNM status. With LNR, stratification for high-risk patients (higher than 6 % LNR) can be evaluated easily. We would suggest using LNR in the clinical routine.

Regional lymph node (LN) metastasis in oral cancer patients is the most significant grave prognostic factor. We evaluated the relationship between clinical outcomes and different histopathological changes in tumor-negative LNs (LN0) selected from neck dissections without metastatic disease (pN0). A total of 435 LN0 selected from pN0 neck dissections (up to three nodes in each level) were scored for histopathological parameters of LN areas, capsule thickness, subcapsular and medullary sinus ectasia, lobular architecture and percent of cortical reactive follicles. These were compared to 328 LN0 selected from neck dissections with metastases (pN+) after exclusion of metastatic LNs. Data were presented by maximum scores of each parameter in I-III (close) and in IV-V (distant) levels. Limited data from level V and regression analyses inferred that the values in level IV represented the worst changes for most patients. Cox proportional hazard regression on each parameter in close and distant levels demonstrated that capsule thickness, number of lobules and percent of reactive follicles were significantly associated with time to death from disease. The higher the change in distant levels, the shorter the time to death, while the higher the change in close levels (given a stable change in distant levels), the longer the time to death. After adjustment for gender, age and location, only the effect of the percent of reactive follicles retained their significant effect. Logistic regression of metastases demonstrated that all parameters except for percent of reactive follicles were significantly associated with risk of metastases, with differences between close and distant levels similar to those found for time to death. After adjustment for gender, age and location, only the area and number of lobes retained their significance. The findings of this study suggested that selective histopathological changes in tumor-negative LNs in metastatic-free patients provide new valuable prognostic parameters.

Purpose: Retropharyngeal lymph node (RPLN) metastasis is an uncommon finding in patients with oral cavity squamous carcinoma (OSCC). We sought to investigate the clinical outcomes, clinicopathological characteristics, and the priority of treatment with curative intent in OSCC patients with RPLN involvement., Methods and Materials: Between January 2007 and January 2011, we identified 36 patients with primary RPLN metastases (n = 10) or RPLN relapse (n = 26). The follow-up continued until June 2013. Disease-specific survival (DSS), disease-free survival (DFS), and the potential benefits of salvage therapy served as the main outcome measures., Results: The 2-year DSS and DFS rates of untreated patients with RPLN involvement were 20% and 24%, respectively. Level IV/V neck lymph node involvement was an adverse prognostic factor for DSS (P = 0.048) and DFS (P = 0.018). All of the patients presenting with neck lymph node involvement at level IV/V died within 6 months. Among patients who were treated for RPLN relapse, the 2-year DSS and DFS rates from the relapse day were 12.8% and 9.6%, respectively. Concomitant contralateral neck lymph node metastases (N2c) were associated with lower 2-year DSS (P = 0.005) and DFS (P = 0.011) rates. Moreover, five (55%) of the nine patients with recurrent disease in the contralateral RPLN had distant metastases within 6 months. Salvage therapy yielded the maximum survival benefit in patients without N2c disease and ipsilateral RPLN involvement alone (P = 0.005)., Conclusion: OSCC patients with RPLN involvement have poor outcomes. The risk factor for definitive treatment in OSCC patients with FDG PET/CT defined RPLN disease in primary disease was neck lymph node involvement at level IV/V and N2c and/or contralateral RPLN disease in recurrent disease. Treatment efforts with curative intent should be tailored according to individual risk factors.

Background: We aimed to study the importance of clinical N classification (cN) in a subgroup of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically negative neck nodes (pN-)., Methods: A total of 2,258 patients from 11 cancer centers who underwent neck dissection for OSCC (1990-2011) had pN- disease. The median follow-up was 44 months. 5-year overall survival (OS), disease-specific survival (DSS), disease free survival, local control, locoregional control, and distant metastasis rates were calculated by the Kaplan-Meier method. cN classification and tumor, node, metastasis classification system staging variables were subjected to multivariate analysis., Results: A total of 345 patients were preoperatively classified as cN+ and 1,913 were classified as cN-. The 5-year OS and DSS of cN- patients were 73.6 and 82.2 %, respectively. The 5-year OS and DSS of cN+ patients were 64.9 and 76.9 %, respectively (p < 0.0001 each). A cN+ classification was a significant predictor of worse OS (p = 0.03) and DSS (p = 0.016), regardless of treatment, depth of invasion, or extent of neck dissection. cN classification was associated with recurrence-free survival (p = 0.01) and locoregional (neck and primary tumor) control (p = 0.004), but not with local (p = 0.19) and distant (p = 0.06) recurrence rates., Conclusions: Clinical evidence of neck metastases is an independent predictor of outcome, even in patients with pN- nodes.

Objectives: To evaluate the prognostic role of the lymph node ratio (LNR; ratio of total positive nodes to total dissected nodes) in oral squamous cell carcinoma (OSCC) as compared to pN staging with an aim to provide an optimal cut-off value., Methods: 1,408 OSCC previously untreated patients who underwent treatment (surgery + neck dissection + adjuvant treatment). LNR sensitivity with respect to survival was calculated using receiver operating characteristic (ROC) curves and Cox regression method. LNR and TNM staging variables were subjected to multivariate analysis., Results: LNR (0.088) showed significant association with survival outcomes. For patients with LNR ≤0.088, the OS, DFS, local control, regional control and distant metastasis rates were 64%, 70%, and 89%; for LNR >0.088 it was 22%, 19%, and 52%, respectively (P < 0.001). On multivariate analysis LNR of 0.088 was seen to be an independent prognostic factor for 5-year regional control (p, hazard ratio [95% confidence interval]; 0.044, 2.016 (1.019-3.990), DFS, 0.032, 1.858 (1.054-3.276), and OS, 0.040, 1.195 (1.033-1.144). On multivariate analysis LNR categorization showed a statistically significant [0.032, 1.858, (1.054-3.276)] advantage over pN staging [0.527, 1.208 (1.054-3.276)] in predicting survival., Conclusions: LNR is a better prognostic marker than the current N staging of TNM classification., (Copyright © 2013 Wiley Periodicals, Inc.)

Objective: Evaluate the impact of cervical metastasis on the survival of patients with squamous cell carcinoma (SCC) of the hard palate., Methods: 155 cases of SCC of the hard palate hospitalized in Cancer Center, Sun Yat-sen University, from 1964 to 2008 were reviewed retrospectively., Results: The 5-year DSS rates for N+ and N0 patients were 21.54% and 47.36% (P = .048). The 5-year DSS rates were 47.36%, 27.48%, 15.55% and 0 for N0-N3 lesions, respectively (P = .041). Cervical metastasis was detected in 40% patients for initial consultation. After therapy, those individuals who presented with clinically negative necks had a 9.03% rate of cervical metastasis. Ultimately, 49.03% of patients manifested disease to the cervical lymph nodes., Conclusion: The presence of cervical nodal disease in patients is associated with the decreased survival rates. SCC of the hard palate should be treated aggressively, and elective neck dissection should be considered because of the high rate of cervical metastasis., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The presence of lymph node (LN) metastasis significantly affects the survival of patients with oral squamous cell carcinoma (OSCC). Successful detection and removal of positive LNs are crucial in the treatment of this disease. Current evaluation methods still have their limitations in detecting the presence of tumor cells in the LNs, where up to a third of clinically diagnosed metastasis-negative (N0) patients actually have metastasis-positive LNs in the neck. We developed a molecular signature in the primary tumor that could predict LN metastasis in OSCC. A total of 211 cores from 55 individuals were included in the study. Eleven proteins were evaluated using immunohistochemical analysis in a tissue microarray. Of the 11 biomarkers evaluated using receiver operating curve analysis, epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (HER-2/neu), laminin, gamma 2 (LAMC2), and ras homolog family member C (RHOC) were found to be significantly associated with the presence of LN metastasis. Unsupervised hierarchical clustering-demonstrated expression patterns of these 4 proteins could be used to differentiate specimens that have positive LN metastasis from those that are negative for LN metastasis. Collectively, EGFR, HER-2/neu, LAMC2, and RHOC have a specificity of 87.5% and a sensitivity of 70%, with a prognostic accuracy of 83.4% for LN metastasis. We also demonstrated that the LN signature could independently predict disease-specific survival (P = .036). The 4-protein LN signature validated in an independent set of samples strongly suggests that it could reliably distinguish patients with LN metastasis from those who were metastasis-free and therefore could be a prognostic tool for the management of patients with OSCC., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The aim of this article was to assess the management of the neck and regional recurrence for squamous cell carcinoma of the maxillary alveolus and hard palate (n = 43) and compare that to the rest of the oral cancer sites (n = 465)., Methods: This is a retrospective report through database and case note review., Results: The incidence of nodal metastases (pathologic node-positive necks added to regional recurrence for clinical N0 and pathologic N0) was 37% (16/43) for maxillary alveolus and hard palate compared with 40% (187/465) for the oral cavity in general. Regional recurrence occurred in 26% (11/43) in the maxillary alveolus and hard palate compared with 7% (31/465) in the remaining oral cavity sites (p = .001)., Conclusions: Squamous cell carcinoma arising in the maxillary alveolus and hard palate has a similar risk of regional metastasis as the rest of the oral cavity, and a lower propensity for selective neck dissection is resulting in higher regional recurrence and lower survival rates., (Copyright © 2012 Wiley Periodicals, Inc.)

Unlabelled: Neck staging in oral cancer depends on the number of compromised nodes, their size and side of occurrence., Objective: This paper aims to evaluate risk factors for metastatic nodes in levels IV/V and their prognostic impact on patients with oral carcinoma., Method: Retrospective study., Inclusion Criteria: pathologist's diagnosis of squamous cell carcinoma, primary tumor in the lower oral cavity, no extension into extraoral sites, no previous treatment, synchronous neck dissection and presence of metastatic nodes. Risk factors for metastasis were evaluated through logistic regression and disease-specific survival and recurrence by survival analysis. Classificatory analysis was performed through recursive partitioning., Results: 307 patients met the inclusion criteria. Univariate logistic regression identified pN stage, vascular invasion, and multiple metastatic nodes as risk factors for metastases in levels IV/V. Multivariate analysis found vascular invasion and multiple metastatic nodes were significant. Survival analysis revealed pT, pN, neural infiltration, vascular invasion, number of metastatic nodes, metastases in levels IV/V, and node ratio were significant factors. In multivariate survival analysis, pT, pN, vascular invasion and metastases in levels IV/V were significant. Classificatory analysis showed that pN is non-significant in patients with level IV/V metastases., Conclusion: The occurrence of metastases in levels IV/V was significant for disease-specific survival.

Pathological lymph node metastases (pN+) are an established prognostic factor in oral cavity squamous cell carcinoma (OSCC). We retrospectively examined the prognostic significance of lymph node (LN) density in pN+ OSCC patients who underwent neck dissection (ND) and postoperative adjuvant therapy. We examined 309 pN+ patients who underwent levels I-III ND and 148 pN+ patients treated with levels I-V ND. The 5-year control and survival rates served as the main outcome measures. The 5-year rates for patients treated with levels I-III and I-V NDs were as follows: local control, 79%, 74% (p=0.0630); neck control, 81%, 68% (p=0.0014); distant metastasis, 21%, 36% (p=0.0003); disease-free survival (DFS), 59%, 43% (p=0.0001); disease-specific survival (DSS), 66%, 46% (p<0.0001); and overall survival (OS), 49%, 37% (p=0.0048), respectively. Multivariate analysis demonstrated that an LN density ≥0.16 was an independent prognostic factor for 5-year neck control (all data presented as p, hazard ratio [95% confidence interval]) (0.003, 2.691 [1.412-5.128]), distant metastases (0.001, 2.831 [1.520-5.270]), DFS (<0.001, 2.464 [1.571-3.866]), and DSS (0.036, 1.781 [1.040-3.052]) in levels I-III ND patients. An LN density ≥0.048 was an independent predictor of 5-year local control (0.004, 4.871 [1.654-14.344]), neck control (0.002, 24.738 [3.367-181.771]), DFS (<0.001, 4.151 [2.264-7.610]), DSS (<0.001, 3.791 [2.017-7.125]), and OS (<0.001, 2.806 [1.706-4.613]) in levels I-V ND patients. Our findings demonstrate the prognostic value of LN density for guiding treatment strategies in OSCC patients who are to receive adjuvant therapy., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Purpose: The objective of this retrospective study was twofold: (1) to investigate prognostic factors for clinical outcomes in patients with poorly differentiated oral cavity squamous cell carcinoma and (2) to identify specific prognostic subgroups that may help to guide treatment decisions., Methods and Materials: We examined 102 patients with poorly differentiated oral cavity squamous cell carcinoma. All patients were followed for at least 24 months after surgery or until death. The 5-year rates of local control, neck control, distant metastasis, disease-free, disease-specific, and overall survival served as main outcome measures., Results: The 5-year rates were as follows: local control (79%), neck control (64%), distant metastases (27%), disease-free survival (48%), disease-specific survival (52%), and overall survival (42%). Multivariable analysis showed that the number of pathologically positive nodes (≥4 vs. ≤3) was a significant predictor of neck control, distant metastasis, and disease-free, disease-specific, and overall survival rates. In addition, the presence of tumor depth of ≥11 mm (vs. <11 mm) was a significant predictor of distant metastasis, disease-specific survival, and overall survival rates. The combination of the two predictors (26.5%, 27/102) was independently associated with poorer neck control (p = 0.0319), distant metastasis (p < 0.0001), and disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p < 0.0001) rates., Conclusions: In patients with poorly differentiated oral cavity squamous cell carcinoma, the presence of at least 4 pathologically positive lymph nodes and of a pathological tumor depth ≥11 mm identifies a subset of subjects with poor clinical outcomes. Patients carrying both risk factors are suitable candidates for the development of novel therapeutic approaches., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Purpose: Extracapsular spread (ECS) in neck lymph nodes is a major adverse prognostic factor in patients with oral cavity squamous cell carcinoma (OSCC). We conducted a retrospective analysis of prognostic factors in this patient group and tried to identify a subset of patients with a worse prognosis suitable for more aggressive therapeutic interventions., Methods and Materials: Enrolled in the study were 255 OSCC patients with ECS in neck nodes and without evidence of distant metastasis. All participants were followed-up for at least 2 years or censored at last follow-up. The 5-year rates of control, distant metastasis, and survival were the main outcome measures., Results: Level IV/V lymph node metastases and tumor depth ≥12 mm were independent predictors of 5-year survival and identified three prognostic groups. In the low-risk group (no level IV/V metastases and tumor depth <12 mm), the 5-year disease-free, disease-specific, and overall survival rates were 60%, 66%, and 50%, respectively. In the intermediate-risk group (no level IV/V metastases and tumor depth ≥12 mm), the 5-year disease-free, disease-specific, and overall survival rates were 39%, 41%, and 28%, respectively. In the high-risk group (evidence of level IV/V metastases), the 5-year disease-free, disease-specific, and overall survival rates were 14%, 12%, and 10%, respectively., Conclusions: Among OSCC patients with ECS, those with level IV/V metastases appear to have the worst prognosis followed by without level IV/V metastases and tumor depth ≥12 mm. An aggressive therapeutic approach may be suitable for intermediate- and high-risk patients., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: This multicenter study was undertaken to characterize the metastatic behavior of oral maxillary squamous carcinoma and to determine the role of selective neck dissection., Methods: A retrospective, multicenter study of patients surgically treated for oral maxillary squamous carcinoma was completed. Data collected included primary tumor location, cervical lymph node status, and neck failure rate., Results: The study included 146 patients. The adjusted regional metastatic rate was 31.4%. Of those N0 (clinically negative) necks treated with or without neck dissection, 14.4% developed cervical metastasis. Within the cohort, 7.5% of patients died with distant disease. The regional salvage rate was 52.9%. None of the patients with locoregional failures were salvaged., Conclusions: Maxillary palatal, alveolar, and gingival squamous carcinomas exhibit aggressive regional metastatic behavior. Surgical salvage rates for neck failure are low; therefore, selective neck dissection (levels I-III) is recommended at the time of resection of T2, T3, and T4 maxillary squamous carcinomas., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: We aimed to validate the lymph node ratio (LNR) as an independent prognostic factor in oral squamous cell carcinoma (OSCC) and compare its utility with the current nodal staging system., Methods: We conducted a retrospective analysis of 313 patients with OSCC undergoing neck dissection. The LNR was adjusted by relevant covariates in a multivariable Cox regression model., Results: LNR displaced conventional nodal staging and was shown to be an independent predictor of regional failure (p = .020), disease-specific (p = .003) and overall survival (p = .001). Patients with an LNR of 2.5% to 7.5%, 7.5% to 20%, and >20% had 2.6, 3.7, and 4.4 times the risk of death from OSCC, respectively, when compared with patients with an LNR <2.5%., Conclusions: The LNR is an independent prognostic factor in OSCC and may be used in conjunction with the current TNM staging to enable better risk stratification and selection for adjuvant therapy., (Copyright © 2010 Wiley Periodicals, Inc.)

Background: Lymph node density (LND) is superior to TNM nodal status in predicting survival after surgery for bladder and other cancers. Little is known, however, about whether LND can predict survival in patients with oral squamous cell carcinoma (OSCC). We therefore evaluated the utility of LND for predicting survival for patients with OSCC and positive nodes (pN+)., Methods: We reviewed the clinical, pathologic, and follow-up data of 211 OSCC patients who underwent surgery. All lymph nodes harvested from neck dissection were carefully examined, with LND calculated as the ratio of positive lymph nodes to total lymph nodes removed. Univariate and multivariate analyses of variables predicting overall survival (OS) and disease-specific survival (DSS) were performed for all patients and in pN+ patients., Results: Kaplan-Meier analyses showed that the 5-year OS and DSS rates in all patients were 72% and 79%, respectively. Multivariate analysis showed that variables independently prognostic for DSS were T classification (hazard ratio [HR] = 2.97, 95% confidence interval [95% CI] = 1.59-5.57; P = .001), and N classification (HR = 4.91, 95% CI = 2.47-9.75; P < .001). In pN+ patients, univariate analysis showed that T classification, >2 positive nodes, and LND >0.06 (median) were significant predictors of DSS (P < .015 each), and multivariate analysis showed that LND was an independent predictor of DSS (HR = 3.24, 95% CI = 1.61-6.53; P = .001)., Conclusions: LND may be useful in stratifying the likelihood of survival in patients with OSCC.

Background: Elective neck dissection (END) is commonly used as a staging and therapeutic procedure for oral squamous cell carcinoma (SCC) at high risk of nodal metastases. The authors aimed to determine whether the extent of lymphadenectomy, as defined by nodal yield, is a prognostic factor in this setting., Methods: A retrospective database review identified 225 patients undergoing END with curative intent for oral SCC between 1987 and 2009. Nodal yield was studied as a categorical variable for association with overall, disease-specific, and disease-free survival in univariate and multivariate analyses., Results: Nodal yield <18 was associated with 5-year overall survival of 51% compared with 74% in those with nodal yield ≥ 18 (P = .009). Five-year disease-specific survival rates were 69% in those with <18 nodes and 87% in patients with ≥ 18 nodes (P = .022). Similar results were obtained for disease-free survival, with 5-year rates of 44% with <18 nodes versus 71% with ≥ 18 nodes (P = .043). After adjusting for the effect of age, nodal status, T stage, and adjuvant radiotherapy on multivariate analysis, nodal yield <18 was associated with reduced overall (hazard ratio [HR], 2.0; 95% confidence interval [CI], 1.1-3.6; P = .020), disease-specific (HR, 2.2; 95% CI, 1.1-4.5; P = .043), and disease-free survival (HR, 1.7; 95% CI, 1.1-2.8; P = .040). In the pathologically lymph node-negative subgroup (n = 148), similar results were obtained., Conclusions: Nodal yield is an independent prognostic factor in patients undergoing END for oral SCC. These results suggest that an adequate lymphadenectomy in this setting should include at least 18 nodes., (Copyright © 2011 American Cancer Society.)