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Summary 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.

This study was designed to explore the relationship between epidermal growth factor receptor (EGFR) copy number and EGFR protein expression in oral cavity squamous cell carcinoma (OSCCs) in Taiwan. A total of 160 oral cavity squamous cell carcinomas were examined for EGFR protein overexpression using immunohistochemistry and for copy number using a fluorescence in situ hybridization (FISH) assay. Overexpression and increased gene copy numbers of EGFR were found in 75 (46.88%) and 50 (31.25%) cases, respectively. The concordance rate for EGFR gene amplification and protein overexpression was 100%. EGFR overexpression was associated with a poor prognosis both in terms of disease-free survival (DFS) and overall survival (OS). On the other hand, the association between an increase in EGFR gene copies and DFS or OS was insignificant. This was despite the observed significant associations between gene copy number and tumor stage, depth of tumor invasion, lymph node metastasis, bone invasion and perineural invasion. EGFR protein overexpression is closely related to EGFR copy number. Standard methodological and interpretation criteria need to be established that allows EGFR copy number combined with EGFR protein expression to be determined in a manner that allows individualized EGFR targeted therapy in OSCC patients.

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], P0.001, HR=6.794, 95% CI=2.364-19.525). In pN+ patients, level IV/V neck nodal metastases (DFS, P0.001, HR=47.483, 95% CI=8.942-252.122; DSS, P0.001, 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.

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.

Summary 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.

We report the incidence, risk factor(s), and overall survival (OS) of second/multiple primary tumors (SPTs/MPTs) in oral cavity squamous cell carcinoma (OSCC) patients in betel quid chewing areas. Of 816 untreated OSCC patients who had radical surgery, 15.7% had either synchronous or metachronous SPTs. The SPTs (70.3%) were at the oral cavity. SPTs (18.8%) developed third primary tumors, with a significantly higher incidence in synchromous than metachronous SPTs (p=0.001). An optimal, but significantly lower, 5-year OS was observed in patients with SPTs/MPTs than without (54.0% vs. 67.2%, p=0.0195). By multivariate analyses, OSCC sub-sites (p=0.006) and lymphatic permeation (p=0.040) were independent risk factors for SPT rate. A significantly higher 5-year OS was observed in SPT patients receiving a second radical surgery at the oral cavity/soft palate than patients that did not (p=0.0001). A good survival rate can be obtained for OSCC patients with resectable SPTs/MPTs.

According to the AJCC 2002 staging system, squamous cell carcinoma of the oral cavity (OSCC) with T4b is unresectable. Herein, we report on our surgical outcome for T4b OSCC. All patients were enrolled before 2002. From January 1996 to December 2000, 45 consecutive untreated T4b OSCC patients were included. According to the trans-axial plane of the mandibular notch on CT/MRI, seven were supra-notch T4b and 38 were infra-notch T4b tumors. Significantly higher 5-year loco-regional control and survivals were observed in patients with infra-notch T4b than with supra-notch T4b. In the infra-notch group, pN0-1 patients had a significantly higher 5-year loco-regional control and survivals than pN2 patients. Nerve invasion was the sole significant adverse factor for loco-regional control and survivals in the infra-notch T4b group with pN0-1. Our retrospective study demonstrated that OSCC patients of infra-notch T4b with pN0-1 and no nerve invasion might have a favorable surgical outcome.

Summary Objectives We sought to investigate whether there is evidence of field cancerization in patients with oral cavity squamous cell carcinoma (OSCC) enrolled in a betel quid chewing area. We also assessed whether betel quid chewing is an independent risk factor for field cancerization in OSCC patients. Methods We retrospectively examined the records of 1570 OSCC patients who underwent radical tumor resection between 1996 and 2011. A total of 1243 study participants (79%) had a positive history of betel quid chewing before surgery. Of the 767 patients treated with surgery alone, 599 (78%) were preoperative chewers, whereas a history of preoperative betel quid chewing was identified in 644 (80%) of the 803 patients who received adjuvant therapy. The 5-year control, survival, and second primary tumors (SPTs) rates served as the main outcome measures. Results Regardless of the treatment modality, more than 70% of the SPTs were located in the oral cavity or soft palate. Despite a similar risk profile in terms of tumor depth, lymph node metastasis, and pathological margin status, preoperative chewers showed a significantly higher incidence of 5-year SPTs and local recurrences compared with non-chewers. Moreover, multivariate analysis demonstrated that preoperative betel quid chewing was an independent prognostic factor for 5-year local control and SPTs occurrence rates. Conclusions Our results demonstrate that preoperative betel quid chewers had a higher incidence of local recurrence and SPTs than non-chewers, suggesting that field cancerization may occur in OSCC patients with a history of betel quid chewing.

Summary Objectives To evaluate the prognostic value of maximum standardized uptake value (SUVmax) measured in [ 18 F]-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) for patients with non-disseminated nasopharyngeal carcinoma (NPC). Materials and methods From January 2002 to July 2008, 371 NPC patients who underwent 18 F-FDG-PET before radical intensity-modulated radiotherapy (IMRT) were recruited. The SUVmax was recorded for the primary tumor (SUVmax-T) and neck lymph nodes (SUVmax-N). Results The median follow-up was 64 months. The optimal cutoff value was 9.3 for SUVmax-T and 7.4 for SUVmax-N. Patients with a lower SUVmax-T or SUVmax-N had a significantly better 5-year distant metastasis-free survival (DMFS), but showed no significant difference in local control or regional control. Patients were divided into four groups by SUVmax, as follows: (a) both lower SUVmax-T and SUVmax-N, (b) higher SUVmax-T only, (c) higher SUVmax-N only, and d) both higher SUVmax-T and SUVmax-N. There were significant differences between these four groups in 5-year DMFS: (a) 95.5%, (b) 90.0%, (c) 83.3%, and (d) 79.9%, respectively ( p = 0.004). When looking at the stage of disease, the 5-year DMFSs in group a, b, c, d were 96.9%, 94.6%, 97.4%, and 84.3%, respectively in stage I–III patients ( p = 0.037) and were 91.6%, 82.9%, 68.5%, and 76.7% in stage IVA–B patients ( p = 0.145). Using multivariate analysis, the SUVmax grouping, gender, and stage were independent factors for DMFS. Conclusion The SUVmax of the primary tumor and neck lymph nodes were independent prognostic factors for DMFS in NPC patients treated with IMRT.

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

Summary The recently identified single nucleotide polymorphism in the MDM2 promoter (SNP 309) may contribute to the early onset of both sporadic and hereditary malignancies in patients with defective p53. We tested this hypothesis by examining the effects of combined MDM2 polymorphisms and somatic p53 mutations on 351 oral squamous cell carcinomas (OSCCs) associated with areca quid chewing. We found that the G allele of MDM2 SNP 309 was associated with early age of onset (p = 0.02) and poor differentiation of OSCC tumors (p = 0.01). The frequency of lymph node extracapsular spread (LNECS) was increased in individuals having both the MDM2 SNP 309 GG genotype and p53 mutation (χ2 for trend p = 0.04). MDM2 GG genotype and p53 mutations were associated with poor disease-free survival in both early and lymph node positive advanced stage OSCC patients (Hazard ratio = 2.77 and 1.93, respectively). Taken together, an interaction between MDM2 SNP 309 and p53 with respect to tumor behaviors (including disease onset, tumor differentiation, LNECS and disease-free survival) was observed in sporadic Taiwanese OSCCs.

The objective of this study was to understand if the age of the patient at onset of tongue cancer was an adverse factor for patient survival and distant metastasis (DM). Data were collected from a retrospective database (January 1996-June 2003, n=296). Local control rates, neck control rates, DM rates, and survival curves were assessed by the Kaplan-Meier method. Prognostic variables were assessed by the log-rank test and Cox proportional hazards regression method. For the young group (or=40 years, n=76), a significantly higher 5-year DM rate (p=0.014) was noted than the elderly group (40 years, n=220). No significant differences were seen in 5-year local and neck controls, disease-free, disease-specific and overall survivals between these two groups. We concluded that beingor=40 years of age at the onset of disease is a significant adverse factor for DM in tongue cancer.

Summary The aim was to analyze the survival and prognostic factors in 232 patients with squamous cell carcinoma of the buccal mucosa (BSCC) treated with radical surgery with or without neck dissection (ND). The 5-year survivals for local, locoregional control, overall, disease-free, and disease-specific were demonstrated. Pathologic nodal status was the independent risk factor for local and locoregional control. Both pathologic nodal status and cell differentiation were the significant prognostic factors of disease-free survival. For cT1N0, 11.1% had neck metastases. All were tumor depth of ≧6 mm. Our result showed a relatively better tumor control and survivals in BSCC with radical surgery with or without ND. The possible reason may be due to the benefit from widely surgical resection with ND and post-operative radiotherapy or concurrent chemoradiotherapy in those with risk factors. In treating early cT1N0, we suggest that elective ND is indicated only when tumor depth ≧6 mm.