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Background: While several studies have indicated that a margin status of < 1 mm should be classified as a positive margin in oral cavity squamous cell carcinoma (OCSCC), there is a lack of extensive cohort studies comparing the clinical outcomes between patients with positive margins and margins < 1 mm., Methods: Between 2011 and 2020, we identified 18,416 Taiwanese OCSCC patients who underwent tumor resection and neck dissection. Of these, 311 had margins < 1 mm and 1013 had positive margins. To compare patients with margins < 1 mm and those with positive margins, a propensity score (PS)-matched analysis (n = 253 in each group) was conducted., Results: The group with margins < 1 mm displayed a notably higher prevalence of several variables: 1) tongue subsite, 2) younger age, 3) smaller depth of invasion), 4) early tumor stage, and 5) treatment with surgery alone. Patients with margins < 1 mm demonstrated significantly better disease-specific survival (DSS) and overall survival (OS) rates compared to those with positive margins (74 % versus 53 %, 65 % versus 43 %, both p < 0.0001). Multivariable analysis further confirmed that positive margins were an independent predictor of worse 5-year DSS (hazard ratio [HR] = 1.38, p = 0.0103) and OS (HR = 1.28, p = 0.0222). In the PS-matched cohort, the 5-year outcomes for patients with margins < 1 mm compared to positive margins were as follows: DSS, 71 % versus 59 %, respectively (p = 0.0127) and OS, 60 % versus 48 %, respectively (p = 0.0398)., Conclusions: OCSCC patients with a margin status < 1 mm exhibited distinct clinicopathological characteristics and a more favorable prognosis compared to those with positive resection margins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Objectives: According to the NCCN guidelines, there is weak evidence to support the use of elective neck dissection (END) in early-stage oral cavity squamous cell carcinoma (OCSCC). We sought to examine the indications for END in patients with cT1N0M0 OCSCC defined according to the AJCC Staging Manual, Eight Edition., Methods: Of the 3886 patients diagnosed with cT1N0M0 included in the study, 2065 underwent END and 1821 neck observation., Results: The 5-year outcomes for patients who received END versus neck observation before and after propensity score matching (n = 1406 each) were as follows: neck control, 96 %/90 % (before matching), p < 0.0001; 96 %/90 % (after matching), p < 0.0001; disease-specific survival (DSS), 93 %/92 % (before matching), p = 0.0227; 93 %/92 % (after matching), p = 0.1436. Multivariable analyses revealed that neck observation, depth of invasion (DOI) > 2.5 mm, and poor differentiation were independent risk factors for 5-year outcomes. Upon the application of a scoring system ranging from 0 (no risk factor) to 3 (presence of the three risk factors), the following 5-year rates were observed: neck control, 98 %/95 %/84 %/85 %; DSS, 96 %/93 %/88 %/85 %; and overall survival, 90 %/86 %/79 %/59 %, respectively (all p < 0.0001). The survival outcomes of patients with scores of 0 and 1 were similar. The occult metastasis rates in the entire study cohort, DOI > 2.5 mm, and poor differentiation were 6.8 %/9.2 %/17.1 %, respectively., Conclusion: Because all patients who received neck observation had a score of 1 or higher, END should be performed when a DOI > 2.5 mm or poorly differentiated tumors are present. Under these circumstances, 48.6 % (1888/3886) of cT1N0M0 patients may avoid END without compromising oncological outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: The prognostic significance of the relapse interval in patients with resected oral cavity squamous cell carcinoma (OCSCC) is a matter of ongoing debate. In this large-scale, registry-based, nationwide study, we examined whether the time interval between surgery and the first disease relapse may affect survival outcomes in Taiwanese patients with OCSCC., Methods: Data made available by the Taiwan Health Promotion Administration as of 2004 were obtained. The study cohort consisted of patients who were included in the registry between 2011 and 2017. Disease staging was performed according to the American Joint Committee on Cancer (AJCC) Staging Manual, Eight Edition. We retrospectively reviewed the clinical records of 13,789 patients with OCSCC who received surgical treatment. A total of 2327 (16.9%) patients experienced a first disease relapse. The optimal cutoff value for the relapse interval was 330 days when both 5-year disease-specific survival (DSS) and overall survival (OS) (≤ 330/>330 days, n = 1630/697) were taken into account. In addition, we undertook a propensity score (PS)-matched analysis of patients (n = 654 each) with early (≤ 330 days) versus late (> 330 days) relapse., Results: The median follow-up time in the entire study cohort was 702 days (433 and 2001 days in the early and late relapse groups, respectively). Compared with patients who experienced late relapse, those with early relapse showed a higher prevalence of the following adverse prognostic factors: pT4, pN3, pStage IV, poor differentiation, depth of invasion ≥ 10 mm, and extra-nodal extension. Multivariable analysis revealed that early relapse was an independent adverse prognostic factor for both 5-year DSS and OS (average hazard ratios [AHRs]: 3.24 and 3.91, respectively). In the PS-matched cohort, patients who experienced early relapse showed less favorable 5-year DSS: 58% versus 30%, p < 0.0001 (AHR: 3.10 [2.69 - 3.57]) and OS: 49% versus 22%, p < 0.0001 (AHR: 3.32 [2.89 - 3.81])., Conclusion: After adjustment for potential confounders and PS matching, early relapse was an adverse prognostic factor for survival outcomes in patients with OCSCC. Our findings may have significant implications for risk stratification., (© 2023. The Author(s).)

Objectives: Perineural invasion (PNI) was quantitatively analyzed in oral squamous cell carcinoma (OSCC) specimens obtained by radical surgery to correlate with survival outcomes. Methods: This is a retrospective study that reviewed the Cancer registry data between 2009 and 2015. Inclusion criteria were oral cavity cancer, treatment by radical surgery, presence of PNI, and available pathologic samples for S100 staining. Patients with M1 disease and those with synchronous or metachronous cancer during staging work-up were excluded. All pathologic samples were reviewed to confirm PNI status and processed by immunohistochemical staining for S100 to quantify PNI. Pathologic information and staging results were also reviewed, and clinical outcomes were analyzed. Results: The retrospective study included 92 patients; 63 had intratumoral PNI (IPNI) and 29 had extratumoral PNI (EPNI). The average number of PNI foci (APNI) was higher in the EPNI group than in the IPNI group (6.7 vs 3.8, t -test 2-tail significance  =  0.021). The 3-year overall survival (OS) and time-to-recurrence (TTR) rates of all patients were 82.5% and 81.2%, respectively. Univariate analysis showed that pathological T4 or N2-3 stage correlated with poor OS, whereas APNI ≥4 correlated with poor TTR. In multivariate analysis, only the pathological N2-3 stage was significantly correlated with poor OS, whereas only APNI ≥ 4 was an independent factor of poor TTR. The 3-year TTR rates were 92.4% and 65.6% for diseases with APNI < 4 and ≥ 4, respectively ( P   =  .008). Conclusions: In patients with OSCC with PNI, a greater amount of PNI identified by S100 staining indicated a poorer TTR regardless of stage and other prognostic factors. Quantification of PNI by S100 immunohistochemistry is a potential method for prognosis prediction.

Objectives: While the NCCN guidelines maintain that T4b oral cavity squamous cell carcinoma (OCSCC) should undergo either non-surgical treatments or clinical trials, promising outcomes of T4b OCSCC having surgical excision have been reported. We analyzed and compared the clinical outcomes of Taiwanese patients with pT4a and pT4b OCSCC who had undergone surgical treatment., Methods: From 2011 to 2017, a total of 4031 and 355 patients with first primary pT4a and pT4b OCSCC were identified. A propensity score (PS)-matched analysis of patients (n = 351 each) for pT4a and pT4b tumors was also performed., Results: The 5-year disease-specific and overall survival (DSS/OS) rates were more favorable in patients with pT4a than in those with pT4b OCSCC (64%/55%, p < 0.0001; 55%/43%, p < 0.0001, respectively). Compared with pT4a, those with pT4b tumors had a higher burden of the following risk factors: buccal/retromolar/hard palate subsite, male sex, depth ≥ 10 mm, and positive margins. Before PS matching, multivariable analyses revealed that pT4b tumors (versus pT4a) were an adverse prognosticator for both 5-year DSS and OS (hazard ratios: 1.32 and 1.39, respectively). However, in the PS-matched cohort, no significant differences in 5-year DSS and OS rates were observed between pT4a and pT4b OCSCC (57%/56%, p = 0.4024; 48%/44%, p = 0.1807, respectively) CONCLUSIONS: No significant outcome differences were evident between pT4b and pT4a OCSCC after PS matching. The most plausible hypothesis for the observed survival difference between T4a and T4b tumors is that it was driven by positive margins. We suggest that T4b OCSCC should undergo initial surgical excision if adequate resection is possible., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objectives: pStage IVB oral cavity squamous cell carcinoma (OCSCC) is defined as either pT4b or pN3 disease. We sought to devise an improved prognostic stratification of this patient group., Methods: Between December 2003 and January 2018, we retrospectively reviewed the clinical records of 1331 consecutive patients with OCSCC who received tumor excision and neck dissection. The number of patients with pT4a/pT4b, pT1N3b/pT2N3b/pT3N3b/pT4N3b, and pStage IVA/IVB was 370/83, 3/49/42/142, and 332/295, respectively., Results: The 5-year rates of disease-free survival (DFS) and disease-specific survival (DSS) for patients with pT4a/pT4b disease were 64%/63% (p = 0.973) and 72%/69% (p = 0.672), respectively. The 5-year DFS and DSS rates for patients with pT1N3b/pT2N3b/pT3N3b/pT4N3b disease were 67%/65%/40%/42% (p < 0.001; pT1-2N3b versus pT3-4N3b, p = 0.002) and 100%/68%/45%/49% (p < 0.001; pT1-2N3b versus pT3-4N3b, p = 0.002), respectively. We devised a new definition for pStage IV by considering patients with pT4bN0-2 and pT1-2N3b diseases as pStage-IVA. The number of patients with pStage IVA/IVB (pT3-4N3b) was 443/184. The 5-year rates of AJCC pStage IVA/IVB and the newly proposed pStage IVA/IVB (pT3-4N3b) were as follows: DFS, 74%/52% and 72%/42%; DSS, 83%/58% and 81%/47%; respectively, all p value < 0.001., Conclusions: The clinical outcomes of pT4b and pT4a OCSCC are similar. However, patients with pT3-4N3b disease have a less favorable 5-year prognosis compared with cases with pT1-2N3b. In light of the unfavorable outcomes, pT3-4N3b disease should continue to be classified as pStage IVB. Conversely, pT4bN0-2 and pT1-2N3b diseases portend a less adverse prognosis and should therefore be downstaged to pStage IVA., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: This large-scale cohort study was designed to compare the clinical outcomes of Taiwanese patients with squamous cell carcinoma (SCC) of the upper versus lower gum., Methods: Between 2004 and 2017, we identified 4244 patients with first primary SCC of the gum (694 upper gum; 3550 lower gum) who were treated with surgery either with or without adjuvant therapy. Of them, 1990 patients (329 upper gum; 1661 lower gum) enrolled from 2011 to 2017 had a higher number of histopathological variables and entered subgroup analyses. Five-year disease-specific survival (DSS) and overall survival (OS) rates served as outcome measures., Results: The 5-year DSS and OS rates of patients with upper gum SCC were lower than those of cases with lower gum SCC (65%/74%, p < 0.0001; and 55%/65%, respectively, p < 0.0001). Compared with lower gum SCC, upper gum SCC had a higher prevalence of the following variables: female sex, age ≥ 65 years, pNx (without neck dissection), no-betel chewing (2011-2017), no-smoking (2011-2017), and margin status ≤ 4 mm (positive and close margins, 2011-2017). On multivariable analysis, gum subsite (upper versus lower), age (≥65 versus < 65 years), pT (T3 - 4 versus T1 - 2), pN (N1 - 3 versus N0/Nx), depth (≥10 mm versus < 10 mm, 2011-2017), ENE (present versus absent, 2011-2017), and margins (≤4 mm versus > 4 mm 2011-2017, only DSS) were identified as independent adverse prognostic factors for 5-year DSS and OS., Conclusions: Compared to lower gum SCC, upper gum SCC had less favorable 5-year outcomes. Wide resection margins are recommended to improve prognosis of upper gum SCC., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Oral dysfunction is a common adverse event of treatment and may affect oral health-related quality of life (OHRQoL). This study aimed to identify factors associated with OHRQoL in patients with oral squamous cell carcinoma (OSCC) within the first three months posttreatment., Methods: This cross-sectional study examined OSCC patients who received treatment from the outpatient radiation department of a single cancer center in northern Taiwan. Demographic and clinical characteristics were recorded, and patients were assessed using the Self-Care Behaviors Scale (SCB), Oral Health Impact Profile (OHIP), and Karnofsky Performance Status (KPS) questionnaires., Results: Among 148 OSCC patients, 11.5% reported being underweight and 70.3% reported normal weight. The most common self-care factors associated with adverse effects were decreased appetite and fatigue. Psychological disability, functional limitation, and physical pain were the most negative OHRQoL factors. Poor OHRQoL was associated with more severe adverse effects after self-care behaviors, using feeding tubes during treatment, and having BMI less than 25, which together explained 33.5% of the variance in OHRQoL., Conclusions: The severity of adverse effects after self-care behaviors and using feeding tubes during treatment strongly influenced overall OHRQoL and seven specific dimensions of OHRQoL.

Purpose: Perineural invasion (PNI) is an adverse prognostic factor in patients with oral cavity squamous cell carcinoma (OCSCC). The American Joint Committee on Cancer Staging Manual, eighth edition, introduced a subdivision of PNI into two distinct forms, that is, extratumoral and intratumoral PNI (EPNI and IPNI, respectively). We designed the current study to assess whether EPNI and IPNI have different prognostic implications in terms of disease control and survival outcomes in patients with OCSCC., Materials and Methods: We retrospectively examined 229 consecutive patients with OCSCC and PNI who underwent radical surgery between July 2003 and November 2016. EPNI and IPNI were identified in 76 and 153 patients, respectively. The 5-year locoregional control (LRC), distant metastasis, disease-free survival (DFS), and overall survival (OS) rates served as the main outcome measures., Results: Compared with patients showing IPNI, those with EPNI had a higher prevalence of worst pattern of invasion type-5 (P < 0.001), alcohol consumption (P = 0.03), and close margins (P = 0.002). Univariate analysis revealed that EPNI was a significant predictor of 5-year LRC (P = 0.024), DFS (P = 0.007), and OS (P = 0.034) rates. After allowance for potential confounders in multivariable analysis, ENPI was retained in the model as an independent predictor of 5-year LRC (P = 0.028), DFS (P = 0.011), and OS (P = 0.034) rates., Conclusion: Compared with IPNI, the presence of EPNI in OCSCC portends less favorable outcomes. Patients with EPNI are potential candidates for definite aggressive treatment modalities aimed at improving prognosis., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: According to the AJCC third to seventh edition staging manuals (1988-2010), the presence of through cortex and/or skin invasion in oral cavity squamous cell carcinoma (OCSCC) identifies T4a tumors. The AJCC eighth edition (2018) introduced a depth of invasion (DOI) > 20 mm as a criterion for pT4a. Subsequently, a revision maintained that tumors > 4 cm with a DOI > 10 mm should be classified as pT4a. We sought to analyze the prognostic impact of the three distinct criteria identifying pT4a disease., Methods: We examined 667 consecutive patients with pT3-4 buccal/gum/hard palate/retromolar SCC who underwent surgery between 1996 and 2016. pT1/pT2 (n = 108/359) disease were included for comparison purposes., Results: The 5-year outcomes of patients with pT1/pT2/without (n = 406)/with tumor > 4 cm/DOI > 10 mm (n = 261), pT1/pT2/DOI ≤ 20 mm (n = 510)/> 20 mm (n = 157), and pT1/pT2/without (n = 305)/with through cortex/skin invasion (n = 362) were as follows: disease-specific survival (DSS), 98%/89%/79%/65%, p < 0.001, 98%/89%/78%/59%, p < 0.001, and 98%/89%79%/69%, p < 0.001; overall survival (OS), 90%/79%/63%/51%, p < 0.001, 90%/79%/63%/42%, p < 0.001, and 90%/79%/65%/52%, p < 0.001. In pT3-4 disease, a tumor > 4 cm/DOI > 10 mm was an independent adverse prognosticator for 5-year DSS rate, DOI > 20 mm was an independent adverse prognosticator for 5-year DSS and OS rates, whereas through cortex/skin invasion independently predicted 5-year OS rates., Conclusions: All of the three criteria (tumor > 4 cm/DOI > 10 mm, DOI > 20 mm, and through cortex/skin invasion) identify high-risk patients, which should be reflected in further revisions of pT4a classification in OCSCC.

Objectives: Human papillomavirus-negative oropharyngeal squamous cell carcinoma (OPSCC) has unfavorable survival outcomes. Two outcomes have been identified based on smoking history and tumor stage. We investigate the prognostic role of pre-treatment positron emission tomography (PET) in high-risk OPSCC., Materials and Methods: We enrolled 147 M0 OPSCC patients with p16-negative staining and a history of heavy smoking (>10 pack-years) or T4 disease. All patients completed primary chemoradiotherapy, and 42% maximum standard uptake values (SUV max ) were used as the threshold for primary tumor. Patients were classified into training and validation cohorts with a ratio of 1:1.5 according to the PET date. Heterogeneity and irregularity indices were obtained. PET parameters with significant impact on progression-free survival (PFS) in receiver operating characteristic curves and univariate Cox models were identified and included in recursive partitioning analysis (RPA) for constructing a prognostic model. The RPA-based prognostic model was further tested in the validation cohort using multivariate Cox models., Results: Fifty-eight and 89 patients were in the training and validation groups, respectively. Heterogeneity parameter, SUV-entropy (derived from histogram analysis), and irregularity index, and asphericity were significantly associated with PFS. The RPA model revealed that patients with both high SUV-entropy and high asphericity experienced the worst PFS. Results were confirmed in the validation group. The overall concordance index for PFS of the model was 0.75, which was higher than the clinical stages, performance status, SUV max , and metabolic tumor volume of PET., Conclusions: PET prognostic model provided useful prediction of PFS for patients with high-risk OPSCC., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: To investigate the advantage of concurrent chemotherapy with postoperative radiotherapy (RT) of oral squamous cell carcinoma (OSCC) in patients with three or more minor risk factors., Methods: Minor risk factors included pT4 disease, pN1 disease, margin ≤ 4 mm, poor differentiation, perineural invasion, vessel or lymphatic invasion, and tumor invasion depth ≥ 11 mm. Surgery was the primary treatment, followed by RT or concurrent chemoradiation (CCRT). After propensity score matching, 34 patients in each treatment group were selected for comparison., Results: The median follow-up for living patients was 86.4 months (range: 47-189 months). The 5-year overall survival of the RT and CCRT groups was 35.3% and 67.2% (p = 0.018), respectively. The 5-year recurrence-free survival of the RT group and CCRT group was 42.6% and 75.4% (p < 0.01)., Conclusion: Postoperative CCRT for patients with three or more minor risk factors increased recurrence-free and overall survival.

Background: The identification of extrinsic tongue muscle invasion in oral cavity cancer remains challenging. Notably, the most recent American Joint Committee on Cancer (AJCC 2017, 8th edition) staging manual indicates that extrinsic muscle invasion does not lead to the diagnosis of a T4 tumor. Because this approach carries the risk of tumor downstaging, we compared the clinical outcomes of patients with oral tongue squamous cell carcinoma (SCC) staged as pT3 vs. pT4 according to the AJCC 2010, 7th edition criteria., Methods: We retrospectively examined the records of consecutive patients with pT3 (n = 135) and pT4 (n = 68) tongue SCC who underwent radical surgery. Of the 68 pT4 tongue SCC, 63 (93%) had extrinsic muscle involvement alone. The 5-year locoregional control (LRC), distant metastasis (DM), and disease-free survival (DFS) rates served as outcome measures., Results: Compared with pT3 tongue SCC, pT4 patients presented significantly more frequently with pN2 disease, extranodal extension, poor tumor differentiation, tumor depth >15 and >20 mm, margin status ≤4 mm, perineural invasion, vascular invasion, and were more frequently treated with surgery plus concurrent chemoradiotherapy. Less favorable 5-year outcomes were observed in patients with pT4 than pT3 tumors (LRC 50 vs. 75%, p < 0.001; DM 27 vs. 14%, p = 0.013; DFS 43 vs. 69%, respectively, p < 0.001). We identified pT4 disease (vs. pT3) as an independent adverse prognostic factor for LRC and DFS., Conclusions: We suggest classifying patients with tongue SCC and extrinsic muscle invasion as having pT4 disease.

Purpose: This single-center retrospective study of prospectively collected data was aimed at comparing the clinical outcomes of positron emission tomography/computed tomography (PET/CT) for patients with oral cavity squamous cell carcinoma (OSCC) with symptomatic recurrences identified by PET/CT imaging following adjuvant therapy (Group A) versus those of cases with asymptomatic recurrences diagnosed through periodic post-adjuvant therapy PET/CT surveillance (Group B). We also sought to establish the priority of salvage therapy in the two study groups., Methods: We identified 111 patients with advanced resected OSCC who developed recurrences following adjuvant therapy (51 in Group A and 60 in Group B). Histopathology served as the gold standard for recurrent lesions. The impact of post-adjuvant therapy PET/CT surveillance was examined with Kaplan-Meier curves and Cox proportional hazards regression models., Results: The 2-year DSS and OS rates were marginally or significantly higher in Group B than in Group A (P = 0.073 and P = 0.025, respectively). Time-dependent ROC curve analysis demonstrated that the optimal cutoff values for time to positive PET/CT findings in relation to OS were 12 months for Group A and 9 months for Group B, respectively. Independent risk factors identified in multivariate analyses were used to devise two prognostic scoring systems for 2-year DSS and OS in each study group (all P < 0.001)., Conclusions: Scheduled periodic PET/CT surveillance is a valuable tool for early detection of recurrent lesion(s) in asymptomatic OSCC patients who bear risk factors for disease recurrence. The presence of clinical symptoms and a short time to positive PET/CT findings were adverse prognostic factors for clinical outcome in patients with advanced OSCC. The priority of salvage therapy is discussed in each patient subgroup according to the devised prognostic scoring systems.

Human papillomavirus (HPV) infections predict mortality in Taiwanese patients with oral cavity squamous cell carcinoma (OCSCC). To address their prognostic significance for local recurrence (LR), in this retrospective cohort study we investigated different serologic and molecular markers of HPV 16 infection in 85 consecutive patients with primary OCSCC who received standard treatment and had their sera stored before treatment. Resected tumor specimens were examined with PCR-based assays for HPV 16 E6/E7 mRNA expression. Sera were tested with suspension arrays for the presence of HPV-specific antibodies using synthetic L1 and E6 peptides as well as a synthetic E7 protein. HPV 16 E6/E7 mRNA, anti-L1, anti-E6, and anti-E7 antibodies tested positive in 12%, 25%, 38%, and 41% of the study patients, respectively. Multivariate analysis identified pathological T3/T4, E6/E7 mRNA, and anti-E7 antibodies as independent risk factors for LR, whereas anti-E6 antibodies were an independent protective factor. In patients with ≥ 3 (high-risk group), 2 (intermediate-risk), and ≤ 1 (low-risk) independent risk factors (predictors), the 5-year LR rates were 75%, 42%, and 4%, respectively. Results were validated in an independent cohort. Together, our preliminary data indicate that HPV 16 infections as well as low and high serum levels of anti-E6 and anti-E7 antibodies, respectively, can serve as biomarkers of LR in patients with OCSCC, whereas the clinical usefulness of anti-HPV 16 antibodies for risk stratification of newly diagnosed cases deserves further scrutiny.

Objectives: Although patients with buccal squamous cell carcinoma (SCC) usually show acceptable outcomes, local control and survival rates are generally lower than those observed for tongue SCC. This study was designed to compare the clinical outcomes of Taiwanese patients with these two common oral cavity malignancies., Methods: Patients with first primary buccal or tongue SCC who were included in the Taiwanese Cancer Registry Database between 2004 and 2012 were eligible. The study sample consisted of 16,379 patients (7870 buccal SCC and 8509 tongue SCC) who received surgery with or without adjuvant therapy. The 5-year disease-specific survival (DSS) and overall survival (OS) rates served as the outcome measures., Results: Compared with tongue SCC, patients with buccal SCC had a higher prevalence of males (95.7% vs. 86.4%, p<0.0001), pT4 disease (21.4% vs. 12.7%, p<0.0001), and p-Stage IV (30.4% vs. 24.8%, p<0.0001) but a lower frequency of pN2 disease (15.2% vs. 18.5%, p<0.0001). The 5-year DSS and OS rates of buccal SCC patients were slightly higher than those of tongue SCC (78% vs. 77%, p=0.0297; and 71% vs. 69%, p=0.0231, respectively). Multivariate analysis identified tumor site (tongue vs. buccal SCC), sex (male vs. female), age (≥65 vs. <65years), pT classification (T4/T3/T2 vs. T1), and pN classification (N3/N2/N1vs. N0) as independent prognostic factors in the entire study cohort., Conclusions: The survival advantage of buccal SCC over tongue SCC appears significant in large clinical samples, despite a higher prevalence of p-Stage IV disease in the former., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The National Comprehensive Cancer Network guidelines recommend that patients with oral cavity squamous cell carcinoma (OSCC) and cT4b disease should be either included in clinical trials or treated with a nonsurgical approach. However, surgery may be feasible in selected patients with adequate safety margins. Using the nationwide Taiwanese Cancer Registry Database, we examined the prognosis of cT4b OSCC patients in relation to their treatment approach., Methods: Of the 18,910 patients with previously untreated first primary OSCC identified between 2004 and 2010, 492 (2.6 %) had cT4b tumors. Of them, 327 (66 %) received initial treatment with surgery, whereas 165 (34 %) were initially treated with a nonsurgical approach. Of the latter group, 78 patients subsequently underwent surgery. A 5-year disease-specific survival (DSS) ≥45 % was considered as a favorable outcome., Results: Better 5-year DSS and overall survival (OS) rates were observed in cT4b patients initially treated with surgery (vs. nonsurgery; DSS, 51 vs. 38 %; OS, 43 vs. 27 %, respectively, p < 0.001). Of the participants initially treated with surgery, patients with cN0-2 disease had better 5-year survival rates (DSS: cN0, 59 %; cN1, 53 %; cN2, 46 %; OS: cN0, 49 %; cN1, 50 %; cN2, 37 %) than those with cN3 disease (DSS: 0 %; OS: 0 %). Among cT4b patients who initially received a nonsurgical treatment, subjects who subsequently underwent surgery showed better outcomes., Conclusions: Primary surgery is performed in approximately two-thirds of cT4b OSCC patients, with cN0-2 cases showing a good prognosis. Patients who initially received a nonsurgical approach can subsequently be treated with surgery and achieve favorable outcomes.

Background: To investigate the association between the diagnosis-to-treatment interval (DTI) and overall survival (OS) in patients with oral cavity squamous cell carcinoma (OSCC)., Methods: A total of 18,677 patients with first primary OSCC identified in the Taiwanese Cancer Registry Database between 2004 and 2010 were examined. The effect of DTI on 5-year OS rates was investigated with multivariate Cox regression analysis. After the identification of the optimal cutoff for DTI based on the 5-year OS rates, DTI was classified in the following 20-day groups: ≤20 days (57% of the study patients), 21-45 days (34%), 46-90 days (6%) and ≥91 days (3%). In additional exploratory analyses, DTI was reclassified in the following 30-day interval groups: ≤30 days (81% of the study patients), 31-60 days (14%), 61-90 days (2%) and ≥91 days (3%)., Results: Multivariate analyses identified DTI (≤20 days versus other subgroups), sex (female versus male), age (<65 versus ≥65 years), clinical stage (p-stage I versus p-stage II, III, IV) and treatment modality (initial surgery versus initial non-surgery) as independent prognostic factors for 5-year OS. Compared with a DTI ≤20 days, the DTI categories ≥91 days (hazard ratio [HR]: 1.28, P < 0.001), 46-90 days (HR: 1.25, P < 0.001) and 21-45 days (HR: 1.07, P = 0.007) were independently associated with a higher risk of 5-year mortality. Similar results were obtained for DTI ≤30 days groups., Conclusions: DTI is independently associated with 5-year OS in OSCC patients. A DTI longer than 30 days or even 20 days may potentially decrease survival., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Patients with resected oral squamous cell carcinoma (OSCC) harboring extracapsular extension (ECE) of the involved lymph node, show poor and heterogeneous outcomes. We aim to improve their prognostic stratification by combining genetic information from next-generation sequencing (NGS) using traditional clinicopathological prognosticators. The hotspot mutation regions of 45 cancer-related genes were investigated using NGS with an ultra-deep (>1000×) sequencing approach in formalin-fixed paraffin-embedded samples obtained from 201 patients with resected OSCC harboring ECE. Adjuvant chemoradiotherapy (CRT) and the number of nodes with ECE were the most important traditional prognosticators for disease-specific survival (DSS). The 5-year DSS for patients with CRT versus without, was 55% versus 21% (P < 0.001), and that for 1-3 versus ≥ 4 ECEs was 60% versus 25% (P = 0.001), respectively. Multivariate analysis in patients who received adjuvant CRT for 1-3 ECEs (i.e., those with a favorable expected prognosis) identified the following adverse prognostic factors: 1) margin of < 5 mm for locoregional failure (66% versus 30%, P = 0.007) and DSS (42% versus 63%, P = 0.039); 2) HRAS mutation for distant failure (55% versus 25%, P = 0.007) and DSS (36% versus 63%, P = 0.024); and 3) TP53 DNA-binding domain missense mutations for DSS (52% versus 71%, P = 0.025) and overall survival (39% versus 61%, P = 0.007).We conclude that genetic information from NGS may improve the prognostic stratification offered by traditional prognosticators in resected OSCC patients with ECE. Our findings will contribute to implementation of precision medicine in OSCC patients.

TP53 mutations have been linked to reduced survival in patients with oral cavity squamous cell carcinoma (OSCC). However, the impact of different types of TP53 mutations remains unclear. Here, we demonstrate that the carriage of missense mutations in the TP53 DNA binding domain (DBD missense mutations) is associated with decreased disease-specific survival (DSS) compared with wild-type TP53 (P=0.002) in a cohort of 345 OSCC patients. In contrast, DSS of patients bearing all of the remaining TP53 mutations did not differ from that observed in wild-type TP53 patients (P=0.955). Our classification method for TP53 mutations was superior to previously reported approaches (disruptive, truncating, Evolutionary Action score, mutations in L2/L3/LSH) for distinguishing between low- and high-risk patients. When analyzed in combination with traditional clinicopathological factors, TP53 DBD missense mutations were an independent prognostic factor for shorter DSS (P=0.014) alongside with advanced AJCC T- and N-classifications and the presence of extracapsular spread. A scoring system that included the four independent prognostic factors allowed a reliable patient stratification into distinct risk groups (high-risk patients, 16.2%). Our results demonstrate the usefulness of TP53 DBD missense mutations combined with clinicopathological factors for improving the prognostic stratification of OSCC patients., Competing Interests: Nina Lapke, Yen-Jung Lu, and Shu-Jen Chen are employees of ACT Genomics.

Background: The purpose of this study was to investigate whether multidisciplinary team care (MDTC) is associated with outcomes in oral cavity squamous cell carcinoma (SCC)., Methods: We retrospectively examined 1616 patients with oral cavity SCC who underwent radical surgery between 1996 and 2011. The study participants were classified into 2 subgroups according to the use of MDTC., Results: Five-year outcomes were significantly better in the MDTC group than in the no-MDTC group (neck control, 88% vs 84%, p = .0397; disease-specific survival [DSS], 83% vs 78%, p = .0114; and overall survival [OS], 70% vs 64%, p = .0002, respectively). Among patients who were scheduled to undergo adjuvant therapy, the number who completed their adjuvant treatment was significantly higher in the MDTC group than in the no-MDTC group (90% vs 60% to 70%, p < .001)., Conclusion: The association of MDTC with improved outcomes may be potentially explained by a better therapeutic alliance between the patient and the tumor board, and/or a greater thoroughness in clinical management. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1544-E1553, 2016., (© 2016 Wiley Periodicals, Inc.)

The aim of this study was to explore the incidence and outcomes of patients with oral cavity squamous cell carcinoma (OSCC) and fourth primary tumors (PTs) in a betel-chewing endemic area.We retrospectively examined the records of 1836 OSCC patients who underwent radical tumor resection between 1996 and 2014. The outcome measures included the incidence and number of multiple PTs, the main risk factors, and their associations with overall survival (OS).Of the 1836 patients, 1400 (76.3%) had a single PT, 344 (18.7%) a second PT, 67 (3.6%) a third PT, and 25 (1.4%) a fourth PT. Univariate analyses (log-rank test) identified the following factors as significantly associated with a fourth PT: simultaneous first and second PTs, betel quid chewing, buccal subsite, and pT3-4 status. After allowance for the potential confounding effect of other risk factors, all of these factors retained their independent prognostic significance in stepwise multivariate analyses, the only exception being betel chewing. The incidences of second, third, and fourth PTs at 5 and 10 years were 20.2%/34.6%, 4.0%/8.6%, and 1.0%/2.3%, respectively. The 5 and 10-year OS rates (calculated from the diagnosis of each PTs) for patients with a single, second, third, and fourth PTs were 68%/61%, 43%/37%, 45%/39%%, and 30%/30%, respectively (P < 0.0001). Among patients with a fourth PT, those who underwent radical surgery showed a significantly higher 3-year OS than those who did not (57% vs 13%; P = 0.0442).Fourth PTs are rarely observed in OSCC patients in a betel quid-chewing endemic area. Long-term survival rates of patients treated with radical surgery seems acceptable, being 4-fold higher than their counterparts., Competing Interests: This study did not receive any specific funding. The authors report no conflicts of interest.

An improved prognostic stratification of patients with oral cavity squamous cell carcinoma (OSCC) and pathologically positive (pN+) nodes is urgently needed. Here, we sought to examine whether an ultra-deep targeted sequencing (UDT-Seq) gene panel may improve the prognostic stratification in this patient group.A mutation-based signature affecting 10 genes (including genetic mutations in 6 oncogenes and 4 tumor suppressor genes) was devised to predict disease-free survival (DFS) in 345 primary tumor specimens obtained from pN+ OSCC patients. Of the 345 patients, 144 were extracapsular spread (ECS)-negative and 201 were ECS-positive. The 5-year locoregional control, distant metastases, disease-free, disease-specific, and overall survival (OS) rates served as outcome measures.The UDT-Seq panel was an independent risk factor (RF) for 5-year locoregional control (P = 0.0067), distant metastases (P = 0.0001), DFS (P < 0.0001), disease-specific survival (DSS, P < 0.0001), and OS (P = 0.0003) in pN+ OSCC patients. The presence of ECS and pT3-4 disease were also independent RFs for DFS, DSS, and OS. A prognostic scoring system was formulated by summing up the significant covariates (UDT-Seq, ECS, pT3-4) separately for each survival endpoint. The presence of a positive UDT-Seq panel (n = 77) significantly improved risk stratification for all the survival endpoints as compared with traditional AJCC staging (P < 0.0001). Among ECS-negative patients, those with a UDT-Seq-positive panel (n = 31) had significantly worse DFS (P = 0.0005) and DSS (P = 0.0002). Among ECS-positive patients, those with a UDT-Seq-positive panel (n = 46) also had significantly worse DFS (P = 0.0032) and DSS (P = 0.0098).Our UDT-Seq gene panel consisting of clinically actionable genes was significantly associated with patient outcomes and provided better prognostic stratification than traditional AJCC staging. It was also able to predict prognosis in OSCC patients regardless of ECS presence.

This study evaluated the associations between lymphatic and vascular invasion of oral cavity squamous cell carcinoma (OSCC) and clinicopathological manifestations, as well as their impact on patient outcomes after treatment.In total, 571 patients with primary OSCC who underwent surgery with or without adjuvant therapy were enrolled.Lymphatic and vascular invasion were found in 28 (5%) and 16 (3%) patients, respectively. Significant associations were found between lymphatic and vascular invasion and overall stage (P < 0.001 and P = 0.020, respectively), tumor stage (P = 0.009 and P = 0.025, respectively), nodal metastasis (both P < 0.001), extracapsular spread (both P < 0.001), perineural invasion (both P < 0.001), bone invasion (P = 0.004 and P = 0.001, respectively), depth of invasion (P < 0.001 and P = 0.001, respectively), and pathologic differentiation (P = 0.002 and P < 0.001, respectively). In the analysis of adverse events during follow-up, neither lymphatic nor vascular invasion was statistically associated with local recurrence, neck recurrence, and distant metastasis. Although lymphatic invasion exhibited significant associations with poorer overall survival (P < 0.001), disease-specific survival (P < 0.001), and disease-free survival (P = 0.01), it was not demonstrated to be an independent prognostic factor in all multivariate analyses.Although both lymphatic and vascular invasion are associated with many clinicopathological manifestations, neither affects the occurrence of locoregional recurrence and distant metastasis in patients with OSCC after treatment.

Objectives: Simultaneous second primary tumors (SSPT) are not uncommon in patients with oral cavity squamous cell carcinoma (OSCC) living in areas where the habit of betel quid chewing is widespread. We sought to identify the main prognostic factors in OSCC patients with SSPT and incorporate them into a risk stratification scheme., Methods: A total of 1822 consecutive patients with primary OSCC treated between January 1996 and February 2014 were analyzed for the presence of SSPT. The 18-month and 5-year overall survival (OS) rates served as the main outcome measures., Results: Of the 1822 patients, 77 (4%) were found to have SSPT (i.e, two malignancies identified within one month of each other). The 18-month and 5-year OS rates in patients without SSPT and with SSPT were 82% and 69%, and 72% and 53%, respectively (p = 0.0063). Patients with SSPT were further divided into patients with either esophageal cancer or hepatocellular carcinoma (eso-HCC subgroup, n = 8) and other tumors (NO eso-HCC subgroup, n = 69). After multivariate analysis, neck nodal extracapsular spread (ECS, n = 18) and the presence of eso-HCC were identified as independent adverse prognostic factors. The 18-month OS rates of SSPT patients with both eso-HCC and ECS (n = 5) vs. the remaining patients (n = 72) were 0% and 78%, respectively (p < 0.0001)., Conclusion: OSCC patients with neck nodal ECS and esophageal cancer or hepatocellular carcinoma as SSPT have a dismal short-term prognosis.

Purpose: The question as to whether the regional textural features extracted from PET images predict prognosis in oropharyngeal squamous cell carcinoma (OPSCC) remains open. In this study, we investigated the prognostic impact of regional heterogeneity in patients with T3/T4 OPSCC., Methods: We retrospectively reviewed the records of 88 patients with T3 or T4 OPSCC who had completed primary therapy. Progression-free survival (PFS) and disease-specific survival (DSS) were the main outcome measures. In an exploratory analysis, a standardized uptake value of 2.5 (SUV 2.5) was taken as the cut-off value for the detection of tumour boundaries. A fixed threshold at 42 % of the maximum SUV (SUVmax 42 %) and an adaptive threshold method were then used for validation. Regional textural features were extracted from pretreatment (18)F-FDG PET/CT images using the grey-level run length encoding method and grey-level size zone matrix. The prognostic significance of PET textural features was examined using receiver operating characteristic (ROC) curves and Cox regression analysis., Results: Zone-size nonuniformity (ZSNU) was identified as an independent predictor of PFS and DSS. Its prognostic impact was confirmed using both the SUVmax 42 % and the adaptive threshold segmentation methods. Based on (1) total lesion glycolysis, (2) uniformity (a local scale texture parameter), and (3) ZSNU, we devised a prognostic stratification system that allowed the identification of four distinct risk groups. The model combining the three prognostic parameters showed a higher predictive value than each variable alone., Conclusion: ZSNU is an independent predictor of outcome in patients with advanced T-stage OPSCC, and may improve their prognostic stratification.

Unlabelled: The aim of this single-center study was to investigate whether obtaining an additional PET/CT scan before adjuvant radiotherapy or concurrent chemoradiotherapy (CCRT) could meaningfully improve 2-y disease-free survival (DFS) and disease-specific survival (DSS) rates., Methods: Six hundred seventy-four patients with oral cavity squamous cell carcinoma who received adjuvant therapy after radical surgery were included. Of these, 152 patients were initially scheduled to receive an additional preradiotherapy/CCRT PET/CT scan within 1 wk of starting adjuvant therapy. However, 16 patients were excluded because of either medical problems or refusal. Therefore, 136 patients underwent a preradiotherapy/CCRT PET/CT scan (PET group), and 522 did not (NO-PET group). All of the participants were followed up for at least 2 y or censored at the last follow-up. The impact of preradiotherapy/CCRT PET/CT imaging was examined using Kaplan-Meier curves and Cox proportional hazards models., Results: Two-year DFS (80% vs. 70%, P = 0.033) and DSS (84% vs. 75%, P = 0.010) rates were significantly higher in the PET than in the NO-PET group. In the PET group, both DFS and DSS were higher in patients with negative findings than in those without (88% vs. 22% and 91% vs. 36%, respectively; both P < 0.001). A prognostic scoring system based on the presence of the 2 independent risk factors in the PET group (extracapsular spread and lymphatic invasion) predicted both DFS (P = 0.001 and P < 0.001, respectively) and DSS (P = 0.001 and P < 0.001, respectively). Nineteen patients (14%) had their treatment modified by preradiotherapy/CCRT PET/CT findings. Of these, 15 were treated with curative intent due to the presence of locoregional disease, and 4 received palliative care due to distant metastases. Seven of the 15 patients are currently alive without disease., Conclusion: An additional preradiotherapy/CCRT PET/CT scan improves both DFS and DSS in patients with advanced oral cavity squamous cell carcinoma., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Human papillomaviruses (HPV) seem to be related to distant metastasis (DM) in advanced oral cavity squamous cell carcinoma (OSCC) patients., Objectives: This study aimed to investigate whether high-risk HPV viral load may predict DM among OSCC patients and stratify patients for risk-adapted treatment., Study Design: Viral loads of E7 oncogenes for HPV 16/18 were measured by quantitative PCR tests in paraffin-embedded lesional specimens from 312 OSCC of which the HPV genotypes had been determined previously. Multivariable Cox regression analysis was used to identify the independent prognostic factors for 5-year DM and C statistics were further computed., Results: By multivariable analysis, high HPV 16 E7 viral load (≥15.0 copies/genome); high HPV 18 E7 viral load (≥15.0 copies/genome); pathological N2 status (pN2); tumor depth ≥11 mm; extracapsular spread (ECS); and level IV/V metastases were independent risk factors for DM. We further identified three prognostic groups. In the high-risk group (level IV/V metastases or high HPV 16/18 E7 viral load plus pN2, tumor depth ≥11 mm, or ECS), the 5-year distant metastasis rate was 74%. In the intermediate-risk group (high HPV 16/18 E7 viral load, pN2, tumor depth ≥11 mm, or ECS), the 5-year DM rate was 17%. Finally, the 5-year DM rate was 1% in the low-risk group (no risk factors). The value of the C statistics was 0.78., Conclusions: Among OSCC patients, high HPV 16/18 E7 viral load identifies a small subgroup of patients at high-risk of 5-year DM and suggest the need for more intensive treatments and follow-up strategies., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: The fibula osteoseptocutaneous free flap is generally used for segmental mandibular reconstructions following resection of oral cavity squamous cell carcinoma (OSCC). However, less complex reconstructions may be feasible for patients with predicted poor survival. Herein, we sought to identify the main risk factors (RFs) associated with poor prognosis in OSCC patients undergoing segmental mandibulectomy to help decide between fibular and non-fibular reconstructions., Methods: Between 1996 and 2011, we examined the 5-year control, distant metastases, and survival rates in 310 consecutive, previously untreated patients with primary OSCC who underwent segmental mandibulectomy., Results: Margin status was the only independent RF for 5-year local control. Level IV/V metastases, extracapsular spread, and tumor depth ≥15 mm were independent RFs for poor 5-year survival. In the entire study cohort, 23% of the patients had 2 or 3 adverse RFs; such a high-risk group was characterized by a poor prognosis and may be suitable for non-fibular reconstructions. Overall, 70% of the study patients were cT1-4N0, cT1N2, cT2N1, or had tumor depth <15 mm; less than 5% of patients in this subgroup had 2 or 3 adverse RFs and were thus candidates for fibular reconstructions. Among the remaining 30% of patients who showed both advanced clinical stage (cT2N2, cT3-4N1-2) and tumor depth ≥15 mm, 70% exhibited 2 or 3 adverse RFs., Conclusions: Level IV/V metastases, extracapsular spread, and tumor depth ≥15 mm were independent predictors of poor prognosis in OSCC patients undergoing segmental mandibulectomy. The preoperative or intraoperative identification of adverse RFs may help decide between fibular and non-fibular mandibular reconstruction. High-risk patients bearing 2 or 3 adverse RFs have poor prognosis and should not be considered as candidates for fibular reconstructions.

Problem Presented: Sarcomatoid carcinoma (SaCa) is a rare variant of squamous cell carcinoma (SCC) with sarcomatoid features. This study investigated the clinical presentation and outcomes of head and neck SaCa. In addition, reconstructive outcome for a subset of patients was also evaluated., Studies Undertaken: Seventy-eight SaCa cases including 72 men and 6 women were identified from 13,777 head and neck SCC cases. Clinical outcomes were evaluated based on locoregional control, distant metastases, and multivariate analyses. Reconstructive outcome was evaluated by flap survival rate., Result: Of the 78 cases, 71% (55) of cases were located in the oral mucosa; 64% (50) of patients were classified as T3 or T4 at the time of diagnosis. The 5-year survival was only 16%. Multivariate analysis revealed better outcomes only when the patient had a history of previous SCC. Forty-five patients underwent flap reconstruction, with 98% flap survival rate but the functional result varied because of the inevitable adjuvant radiotherapy and advanced stage of tumor., Conclusions: Sarcomatoid carcinoma is a different entity from the conventional SCC of the head and neck. Sarcomatoid carcinoma carries a poorer prognosis despite aggressive surgical intervention and concurrent adjuvant therapies. It remains a great challenge for clinical oncologists, and the optimal treatment strategy requires further studies. Free flap is still preferred for defect reconstruction but the design should be simplified to avoid complications.

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: Although human papillomavirus (HPV) infections have been causally linked to oral cavity squamous cell carcinoma (OSCC), the potential role of low-risk HPV (LR-HPV) types in the pathogenesis of this malignancy remains unclear., Objectives: We sought to investigate the distribution of HPV genotypes and their prognostic significance in OSCC patients treated by radical surgery, either with or without adjuvant therapy., Study Design: We studied two non-overlapping OSCC cohorts for the periods 2005-2006 (2005 cohort, n = 204) and 2010-2011 (2010 cohort, n = 206). Paraffin-embedded tissue blocks were collected, and the HPV genotype was determined using PCR plus HPV blot tests. The primary study endpoint was the prevalence of HPV genotypes. The secondary endpoints were the 2-year therapeutic outcomes., Results: The overall prevalence of HPV infections did not differ significantly in the two study cohorts. However, the prevalence of LR-HPV was significantly higher in the 2010 cohort than in the 2005 cohort (p = 0.002). The overall prevalence of HPV infections was not significantly associated with the 2-year outcomes. However, multivariate analysis demonstrated that LR-HPV infection was a predictor of poor 2-year disease-free survival (p = 0.036, hazard ratio [HR] = 3.1), disease-specific survival (p = 0.014, HR = 3.8), and overall survival (p = 0.016, HR = 3.2) in the subgroups of OSCC patients with poor differentiation, pN2 lymph node metastases, or extracapsular spread (n = 150)., Conclusions: LR-HPV infections may have an important role in determining the clinical outcomes of certain OSCC patients bearing specific risk factors., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objectives: We have previously shown that the resection outcomes of cT4a and cT4b oral cavity squamous cell carcinoma (OSCC) are comparable, but whether similar conclusions can be applied for the pathological stage of this disease needs investigation. In this study, we sought to compare the outcomes and to identify the risk factors for both pT4a and pT4b tumors., Methods: We retrospectively examined 181 pT4 OSCC patients who had radical resections between 2003 and 2010. The 5-year control and survival rates were the main outcome measures., Results: Of the 181 resected pT4 OSCC patients, 133 (73%) had pT4a disease, and 48 (27%) had pT4b disease. All of the resected T4b tumors were below the mandibular notch (infra-notch pT4b). The 5-year outcomes of the patients with infra-notch pT4b and pT4a were comparable: local control, 80% vs. 78%, p=0.7275; neck control, 87% vs. 82%, p=0.4798; distant metastases, 22% vs. 23%, p=0.8871; disease-free survival, 63% vs. 55%, p=0.2813; disease-specific survival, 68% vs. 60%, p=0.3526; and overall survival, 62% vs. 44%, p=0.2643, respectively. Extracapsular spread was the only independent prognostic factor for 5-year survival rates in pT4a patients. Poor tumor differentiation and pN2 status were the independent 5-year survival prognostic factors for the infra-notch pT4b tumor patients., Conclusions: Infra-notch pT4b had outcomes comparable with those of pT4a tumors, although they displayed different risk factors. We therefore recommend that resectable infra-notch pT4b tumors should be classified as pT4a disease in the AJCC tumor staging., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aim: To understand the frequency, clinical significance, and benefits of salvage therapy in oral cavity squamous cell carcinoma (OSCC) patients with regional nodal recurrence at unusual sites (prelaryngeal area, parotid area, and retropharyngeal area)., Methods: We examined 178 patients with neck recurrence at levels I-V (usual group) and 26 patients outside levels I-V (unusual group). The 5-year survival rates served as the main outcome measure., Results: Of the 26 unusual group patients, the neck recurrence sites were as follows: 5 at the prelaryngeal area, 13 at the parotid area, and 8 at the retropharyngeal area. Multivariate analyses demonstrated that poor differentiation, pN2, extracapsular spread (ECS), tumor depth≥10 mm, relapse time≤10 months, local recurrence, neck recurrence at unusual sites, and distant metastases were independent prognostic factors for 5-year disease-specific survival (DSS), whereas pN2, ECS, tumor depth≥10 mm, relapse time≤10 months, neck recurrence at unusual sites, and distant metastases were independent prognostic factors for 5-year overall survival (OS). The 6-month and 18-month survival rates after the N-relapse date for the salvaged-usual group, the salvaged-unusual group, and the nonsalvaged patients were 73%/46%, 40%/0%, and 10%/0% (P<0.0001), respectively [DSS: salvaged-unusual group (hazard ratio/95 % confidence interval), 2.060/1.058-4.008, P=0.033; salvaged-usual group, 6.420/4.340-9.496, P<0.001; OS: salvaged-unusual group, 2.100/1.080-4.081, P=0.029; salvaged-usual group, 6.514/4.418-9.606, P<0.001]., Conclusions: Our findings demonstrate that OSCC patients with regional nodal recurrence at unusual sites had poor outcomes.

Background: The aim of this study was to compare the outcomes of postoperative adjuvant concomitant chemoradiotherapy using two different schedules of cisplatin for patients with high-risk oral squamous cell carcinoma (OSCC)., Methods: From Feb. 2008 to Aug. 2010, 55 patients with high-risk OSCC were included in this study. Patients were randomized into treatment groups that either received 100 mg/m2 cisplatin once every 3 weeks (arm A) or 40 mg/m2 cisplatin once per week (arm B). All patients were irradiated with 66 Gy in 33 fractions., Results: Of the 50 eligible patients, 26 were assigned to arm A, and 24 were assigned to arm B. Both groups of patients received the same mean doses of radiotherapy and cisplatin. However, 88.5% of patients in arm A and 62.5% of those in arm B (p=0.047) received ≥ 200 mg/m2 of cisplatin in total. The overall toxicity was significantly greater in arm B (p=0.020), and all of the grade 4 toxicities occurred in patients in arm B., Conclusions: Three-weekly high-dose cisplatin treatment showed higher compliance, and lower acute toxicity compared to weekly low-dose cisplatin treatment.

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: In the American Joint Committee on Cancer 2010 classification system, pT1-2N0 oral cavity squamous cell carcinoma (OSCC) is considered an early-stage cancer treatable with surgery alone (National Comprehensive Cancer Network 2010 guidelines). Our aim was to evaluate the feasibility of surgery alone for pT1-2N0 OSCC patients., Methods and Materials: Among 1279 previously untreated OSCC patients referred to our hospital between January 1996 and May 2008, we identified 457 consecutive patients with pT1-2N0 disease. All had radical tumor excision with neck dissection. A total of 387 patients showing pathologic margins greater than 4 mm and treated by surgery alone were included in the final analysis. All were followed up for at least 24 months after surgery or until death. The 5-year rates of control, distant metastasis, and survival were the main outcome measures., Results: The 5-year rates in the entire group of pT1-2N0 patients were as follows: local control, 91%; neck control, 92%; distant metastases, 1%; disease-free survival, 85%; disease-specific survival, 93%; and overall survival, 84%. Multivariate analysis identified poor differentiation and pathologic tumor depth of 4 mm or greater as independent risk factors for neck control, disease-free survival, and disease-specific survival. A scoring system using poor differentiation and tumor depth was formulated to define distinct prognostic groups. The presence of both poorly differentiated tumors and a tumor depth of 4 mm or greater resulted in significantly poorer 5-year neck control (p < 0.0001), disease-free (p < 0.0001), disease-specific (p < 0.0001), and overall survival (p = 0.0046) rates., Conclusion: The combination of poor differentiation and pathologic tumor depth of 4 mm or greater identified a subset of pT1-2N0 OSCC patients with poor outcome, who may have clinical benefit from postoperative adjuvant radiotherapy., (Copyright © 2012 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.)

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.)

Cervical lymph node metastasis represents the major prognosticator for oral cavity squamous cell carcinoma (OSCC). Here, we used an iTRAQ-based quantitative proteomic approach to identify proteins that are differentially expressed between microdissected primary and metastatic OSCC tumors. The selected candidates were examined in tissue sections via immunohistochemistry, and their roles in OSCC cell function investigated using RNA interference. Seventy-four differentially expressed proteins in nodal metastases, including PRDX4 and P4HA2, were identified. Immunohistochemical analysis revealed significantly higher levels of PRDX4 and P4HA2 in tumor cells than adjacent non-tumor epithelia (P < 0.0001 and P < 0.0001, respectively), and even higher expression in the 31 metastatic tumors of lymph nodes, compared to the corresponding primary tumors (P = 0.060 and P = 0.002, respectively). Overexpression of PRDX4 and P4HA2 was significantly associated with positive pN status (P = 0.048 and P = 0.021, respectively). PRDX4 overexpression was a significant prognostic factor for disease-specific survival in both univariate and multivariate analyses (P = 0.034 and P = 0.032, respectively). Additionally, cell migration and invasiveness were attenuated in OEC-M1 cells upon in vitro knockdown of PRDX4 and P4HA2 with specific interfering RNA. Novel metastasis-related prognostic markers for OSCC could be identified by our approach.

The prognosis of well-differentiated oral cavity squamous cell carcinoma (OSCC) is better than less-well-differentiated neoplasms. The aim of this retrospective study was to identify prognostic factors in patients with well-differentiated OSCC. The 5-year outcomes of 467 patients with well-differentiated OSCC who underwent radical surgery and neck dissection were analyzed. In the entire cohort, the presence of pathological node metastases (pN+ vs. pN0) was an independent predictor of 5-year outcomes. In pN0 patients, tumor depth (≥8 mm) was the only independently prognostic factor for 5-year survival rates on multivariable analysis (disease-free survival [DFS], P=0.001, hazard ratio [HR]=2.634, 95% confidence interval [95% CI]=1.496-4.636; disease-specific survival [DSS], P<0.001, HR=6.794, 95% CI=2.364-19.525). In pN+ patients, level IV/V neck nodal metastases (DFS, P<0.001, HR=47.483, 95% CI=8.942-252.122; DSS, P<0.001, HR=14.301, 95% CI=5.337-38.323), and ≥3 positive nodes (DFS, P=0.037, HR=2.107, 95% CI=1.047-4.242; DSS, P=0.044, HR=2.093, 95% CI=1.020-4.295) were independently associated with 5-year outcomes. Our results suggest that a tailored treatment approach in well-differentiated OSCC patients should take into account the presence of either pN0 or pN+ disease., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: The NCCN 2010 guidelines recommend the use of postoperative adjuvant radiotherapy (RT) for patients with pT3 oral cavity squamous cell carcinoma (OSCC). We sought to determine whether postoperative adjuvant RT improves outcomes in pT3N0 OSCC patients., Methods: A total of 119 consecutive patients with pT3N0 disease were involved. A total of 42 patients received postoperative adjuvant RT, while the remaining 77 did not. The 5-year rates of control, distant metastasis, and survival were the main outcome measures., Results: We found no differences in the risk profile of patients with and without postoperative adjuvant RT, the only exceptions being a higher frequency of tumor depth ≥10 mm (78.6% vs. 48.0%, P = .001) and close margins ≤4 mm (11.9 % vs. 2.7%, P = .043) in those treated by adjuvant RT. Tumor depth ≥10 mm was the only independent prognostic factor for 5-year local control, disease-free survival, and disease-specific survival in multivariable analysis. Tumor depth ≥13 mm was the only independent prognostic factor for the 5-year rate of distant metastases (16% [7 of 50] vs. 2% [1 of 67]). After stratification for tumor depth and adjuvant RT, patients with pT3N0 disease who received adjuvant RT did not show a survival advantage., Conclusions: Tumor depth ≥10 mm was the only prognostic factor identified in patients with pT3N0 disease. Adjuvant RT did not improve outcomes in pT3N0 patients, regardless of tumor depth. Patients with pT3N0 and tumor depth ≥13 mm (43% of pT3N0) were at the highest risk for distant metastases.

Objectives: Previous studies have demonstrated a relationship between elevated serum C-reactive protein (CRP) levels and shorter survival in cancer patients. Few studies, however, have investigated the role of serum CRP levels in oral squamous cell carcinoma. The present study was conducted to analyze the relationship between preoperative CRP levels, clinicopathologic factors, and prognosis in oral squamous cell carcinoma patients., Design: Retrospective clinical study., Setting: University teaching hospital., Participants: Eighteen oral cavity leukoplakia and 59 oral squamous cell carcinoma patients between November 2006 and November 2009 from the Chang Gung Memorial Hospital., Outcome Measures: Clinicopathologic parameters, disease-free survival and overall survival were correlated with CRP levels., Methods: Serum CRP levels were measured preoperatively, and all oral cavity cancer patients underwent curative intent radical surgery with or without postoperative adjuvant therapy., Results: The CRP levels in leukoplakia patients were used to analyze if factors (including diabetes and liver cirrhosis, smoking, alcohol drinking and areca quid chewing) influence CRP levels, and the results demonstrated they were not associated with CRP elevation (> 5.0 mg/L) (P > 0.05). In oral cancer patients, elevated CRP levels were associated with tumor status (P = 0.005), tumor stage (P = 0.054), bone invasion (P = 0.033), lymph node metastasis (P = 0.004) and lymph node extra-capsular spread (P = 0.018). Patients with higher CRP levels showed poorer disease-free survival (log rank test, P < 0.001) and overall survival (log rank test, P = 0.013)., Conclusions: Preoperative serum CRP levels are associated with advanced tumor stage, bone invasion, lymph node metastasis, lymph node extra-capsular spread and patients' survival. CRP is thus potentially a prognostic indicator, but studies with longer follow-up will be needed to confirm its reliability., (© 2011 Blackwell Publishing Ltd.)

Our aim was to retrospectively assess the diagnostic performance from combined positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) for the detection of bone marrow invasion of the mandible or maxilla in patients with oral cavity squamous cell carcinoma (OCSCC). A total of 114 patients with OCSCC, arising from or abutting the upper or lower alveolar ridge, underwent staging PET/CT and MRI studies before surgery. The possibility of bone marrow invasion on PET/CT and MRI was graded retrospectively on a 5-point score. Histopathology was taken as the reference standard. Sensitivity, specificity, predictive values and likelihood ratios were calculated. Clinical factors affecting the performance, like tumor origin and dentate status were also explored. PET/CT was found to be more specific than MRI (83% vs. 61%, respectively, p=0.0015) but less sensitive (78% vs. 97%, respectively, p=0.0391). Dentate status and tumor origin affected the diagnostic performance of PET/CT. In patients with positive MRI, sensitivity and specificity of PET/CT were 78% and 100% in dentate patients with alveolar ridge tumors, 75% and 80% in dentate patient with buccal tumors, 90% and 33% in edentulous patients with alveolar ridge tumors and 0% and 63% for edentulous patients with buccal tumors, respectively. PET/CT is more specific than MRI and can be used to complement the role of MRI. A negative MRI result can confidently exclude the presence of bone marrow invasion, while in patients with positive MRI findings, a negative PET/CT may be useful to rule out bone marrow invasion in dentate patients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Unlabelled: We prospectively evaluated the sensitivity and specificity of (18)F-FDG PET in the detection of neck lymph node metastases in patients with oral cavity squamous cell carcinoma (OSCC). We also sought to evaluate whether pretreatment PET visual scores in the neck lymph nodes may improve risk stratification., Methods: We enrolled 473 OSCC patients (445 men and 28 women; mean age ± SD, 50.9 ± 11.7 y) without distant metastases. All participants underwent (18)F-FDG PET within 2 wk before surgery and neck dissection. Histopathology was taken as the reference standard for neck lymph node status. The duration of follow-up was at least 24 mo in all surviving patients., Results: (18)F-FDG PET correctly diagnosed 164 of 211 patients with neck metastases and 152 of 262 subjects without pathologic neck metastases, resulting in a patient-based sensitivity and specificity of 77.7% and 58.0%, respectively. In Cox models adjusting for age, sex, traditional risk factors, and treatment modality, PET results at the neck lymph nodes were significantly and independently associated with rates of neck control, distant metastasis, disease-free survival, disease-specific survival, and overall survival. Notably, the results of the c-statistics demonstrated that PET score improved the accuracy of risk prediction in terms of overall and disease-free survival rates., Conclusion: PET findings at the neck lymph nodes have limited sensitivity and specificity for primary staging of OSCC but improve risk stratification beyond that of traditional risk factors.

We examined the role of macrophage inflammatory protein (MIP)-3α on oral cavity squamous cell carcinoma (OSCC) and whether it was involved in modulating OSCC cell functions. The study population was comprised of 102 patients with OSCC. MIP-3α levels in tissues were examined by immunohistochemistry and quantitative real-time RT-PCR. Effects of MIP-3α on OSCC cell function were investigated by cell proliferation assays, trans-well migration/invasion assays, and RNA interference. We found that MIP-3α was overexpressed in OSCC tumor cells. MIP-3α expression was significantly higher in tumor cells vs. normal epithelial cells, as determined by both quantitative real-time RT-PCR and immunohistochemistry. Overexpression of MIP-3α was significantly correlated with positive pN status (P=0.036). Nevertheless, there were no correlations related to patient age, pT status, overall pathological stage, cell differentiation, or perineural invasion. The long-term disease-specific survival for patient subgroups stratified by the absence or presence of MIP-3α overexpression was 70.9% vs. 54.7% (P=0.041). Multivariate analysis indicated that MIP-3α overexpression had a significantly lower disease-specific survival (hazard ratio: 2.158; P=0.037). Additionally, in vitro suppression of MIP-3α expression in OECM-1 cells using specific interfering RNAs attenuated cell migration and invasiveness. These findings suggest that MIP-3α overexpression in OSCC is associated with a poorer prognosis for patient survival and contributes to tumor metastasis., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the outcome of definitive radiotherapy (RT) for oral cavity cancers and to assess prognostic factors., Methods and Materials: Definitive RT was performed on 115 patients with oral cavity cancers at Stages III, IVA, and IVB, with a distribution of 6%, 47%, and 47%, respectively. The median dose of RT was 72 Gy (range, 62-76 Gy). Cisplatin-based chemotherapy was administered to 95% of the patients. Eleven patients underwent salvage surgery after RT failure., Results: Eight-eight (76.5%) patients responded partially and 23 (20%) completely; of the patients who responded, 18% and 57%, respectively, experienced a durable effect of treatment. The 3-year overall survival, disease-specific survival, and progression-free survival were 22%, 27%, and 25%, respectively. The 3-year PFS rates based on the primary tumor sites were as follows: Group I (buccal, mouth floor, and gum) 51%, Group II (retromolar and hard palate) 18%, and Group III (tongue and lip) 6% (p < 0.0001). The 3-year progression-free survival was 41% for N0 patients and 19% for patients with N+ disease (p = 0.012). The T stage and RT technique did not affect survival. The patients who underwent salvage surgery demonstrated better 3-year overall survival and disease-specific survival (53% vs. 19%, p = 0.015 and 53% vs. 24%, p = 0.029, respectively). Subsite group, N+, and salvage surgery were the only significant prognostic factors for survival after multivariate analysis., Conclusion: The primary tumor site and neck stage are prognostic predictors in advanced-stage oral cancer patients who received radical RT. The primary tumor extension and RT technique did not influence survival., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: We sought to determine the differences in clinical outcome of tongue and buccal carcinomas., Methods: Five-year locoregional control, distant metastasis, and survival rates were examined in 456 patients with tongue cancer and 407 patients with buccal cancer., Results: Five-year rates for patients with tongue and buccal carcinomas were as follows: local control, 85% and 87% (P = 0.9366); neck control, 81% and 87% (P = 0.0304); distant metastasis, 8% and 14% (P = 0.0052); disease-free survival, 70% and 72% (P = 0.9978); disease-specific survival, 79% and 78% (P = 0.2435), respectively. After stratification according to pathological lymph node status, patients with buccal cancer and pN0/pNx disease (without neck dissection) had a higher 5-year neck control rate than those with tongue cancer (93% versus 86%, P = 0.0115). In contrast, buccal cancer with pN+ disease had a higher 5-year distant metastasis rate compared with tongue cancer (30% versus 18%, P = 0.0231). In pN0/pNx subjects, neck control was predicted by perineural invasion and the absence of neck dissection in tongue cancer, and by poor differentiation in buccal cancer. In pN+ patients, distant metastases were predicted by pT3-4 disease, age at onset ≤40 years, poor differentiation, and pN+ ≥ 5 nodes in tongue cancer, and by poor differentiation and pN+ ≥ 5 nodes in buccal cancer., Conclusions: There are significant differences in the failure pattern of tongue and buccal carcinomas. Prognostic models for these malignancies should allow stratification of patients for a risk-adapted approach to treatment.

Background: Our aim was to examine the potential role of glucose-regulated protein (GRP)78 during oral cancer progression and the prognostic value in oral precancerous lesions., Methods: A total of 204 patients with oral cancer and 86 with precancerous lesions were investigated. GRP78 expression was determined in the lesion tissues by Western blot analysis. Association of GRP78 with clinicopathology or disease prognosis was examined using Fisher's exact, Kaplan-Meier, or Cox regression method., Results: Hyperexpression of GRP78 was found to be correlated with increasing malignant potential of oral lesions, with 14% in leukoplakia, 27% in erythroplakia, 50% in verrucous lesion, and 74% in oral cancer (p < .0001), suggesting this molecule plays a crucial role in the early steps of oral oncogenesis. In patients with precancerous lesions of the oral cavity, GRP78 expression predicts poorer same-site premalignancy-free survival (p = .002) and malignancy-free survival rates (p = .002)., Conclusion: Determination of GRP78 expression levels might enable a better risk stratification for patients with oral premalignant lesions., (2009 Wiley Periodicals, Inc. Head Neck, 2010.)

Purpose: The aim of this study was to investigate the treatment results of postoperative radiotherapy (PORT) on squamous cell carcinoma of the oral cavity (OSCC)., Materials and Methods: This study included 302 OSCC patients who were treated by radical surgery and PORT. Indications for PORT include Stage III or IV OSCC according to the 2002 criteria of the American Joint Committee on Cancer, the presence of perineural invasion or lymphatic invasion, the depth of tumor invasion, or a close surgical margin. Patients with major risk factors, such as multiple nodal metastases, a positive surgical margin, or extracapsular spreading, were excluded. The prescribed dose of PORT ranged from 59.4 to 66.6 Gy (median, 63 Gy)., Results: The 3-year overall and recurrence-free survival rates were 73% and 70%, respectively. Univariate analysis revealed that differentiation, perineural invasion, lymphatic invasion, bone invasion, location (hard palate and retromolar trigone), invasion depths > or =10mm, and margin distances < or =4mm were significant prognostic factors. The presence of multiple significant factors of univariate analysis correlated with disease recurrence. The 3-year recurrence-free survival rates were 82%, 76%, and 45% for patients with no risk factors, one or two risk factors, and three or more risk factors, respectively. After multivariate analysis, the number of risk factors and lymphatic invasion were significant prognostic factors., Conclusion: PORT may be an adequate adjuvant therapy for OSCC patients with one or two risk factors of recurrence. The presence of multiple risk factors and lymphatic invasion correlated with poor prognosis, and more aggressive treatment may need to be considered., (Copyright 2010 Elsevier Inc. All rights reserved.)