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Objectives/Hypothesis The benefits of elective neck dissection (END) in early-stage tongue cancer have been widely discussed but are still controversial regarding early-stage buccal cancer. In this study, we evaluate the role of END and the treatment outcome in early-stage buccal cancer in an areca-quid endemic area. Study Design Retrospective case-control study. Methods One hundred seventy-three cT1-2N0M0 buccal cancer patients all staged by computed tomography or magnetic resonance imaging were recruited. A total of 151 patients received radical surgery with END, whereas 22 received observation (OBS). Adjuvant radiotherapy with or without chemotherapy was given in selected high-risk patients. Results The 5-year overall survival (OS) rates for cT1 lesions and cT2 lesions were 86.14% and 75.45%, respectively (P = .105). In the END group, the occult metastasis rate was 1.8% for cT1 lesions and 10.6% for cT2 lesions (P = .053). The 5-year neck control rate rates (P = .001) and disease-free survival rates (P = .0101) were significantly better in the END group compared to the OBS group but were not significant in OS (P = .689). Eighteen (10.41%) patients developed a second primary tumor (SPT), and five (2.89%) patients developed a third primary tumor. Ninety-four percent of SPTs were located within the oral cavity. Conclusions END was suggested in T1–T2N0 buccal cancer to improve the neck control rate. In patients for whom END is not performed at the time of tumor excision, regular follow-up of neck status is necessary because the metastatic lesions are mostly salvageable and do not influence the OS. Level of Evidence 4 Laryngoscope, 125:128–133, 2015

Objectives/Hypothesis The role of tumor volume in T4a laryngeal cancer remains unclear among different treatment modalities. Using tumor volumetry, we investigated the impact of primary tumor volume on this subset of patients. Study Design Retrospective cohort study of 62 T4a laryngeal cancer patients. Methods From October 2002 to September 2010, 48 patients were treated with definitive chemoradiation therapy (CRT), and 14 patients had undergone total laryngectomy. Tumor volume was calculated and was correlated with the overall survival (OS), progression-free survival (PFS), and local control rate (LCR) data of each treatment group. Results The 5-year OS, PFS, and LCR were significantly lower in the CRT group with tumor volume ≥ 15 cm3 (22.5% vs. 48.7%, P = 0.009; 32.2% vs. 64.3%, P = 0.003; 45.2% vs. 67.3%, P = 0.039). Multivariate analysis showed that tumor volume was an independent poor prognosticator for OS, PFS, and LCR in the CRT group. For tumor volume ≥ 15 cm3, total laryngectomy provided a significantly higher 5-year OS and PFS (54.5% vs. 22.5%, P = 0.039; 80.0% vs. 32.2%, P = 0.017) than for those tumors treated with definitive CRT. Conclusions Patients with T4a laryngeal cancer with primary tumor volume ≥ 15 cm3 had poorer survival outcomes after definitive CRT compared with total laryngectomy. It was also an independent poor prognosticator on LCR, PFS, and OS for those receiving definitive CRT. For patients with tumor volume ≥ 15 cm3, total laryngectomy provided a better survival outcome than definitive CRT. Level of Evidence 4. Laryngoscope, 124:1134–1140, 2014

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.

Objectives/Hypothesis Elevated inflammatory biomarkers such as C-reactive protein (CRP) and the recently identified neutrophil/lymphocyte ratio (NLR) were demonstrated to be associated with prognosis in human cancers. The aim of our present study is to analyze the relationship of preoperative levels of CRP and NLR with clinicopathological factors and prognosis in oral squamous cell carcinoma (OSCC) patients. Study Design Retrospective study. Methods This study was performed on 226 OSCC patients between July 2007 and April 2012. Their serum CRP levels and NLR were measured preoperatively. Results CRP level ≥ 5.0 mg/L was significantly associated with NLR ≥ 2.44 (linear regression, P

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.

Squamous cell carcinoma antigen (SCC-Ag) level and C-reactive protein (CRP) have been shown to be associated with tumor invasion, lymph node metastasis, staging and survival in patients with oral squamous cell carcinoma (OSCC). The purpose of the present study was to analyze the relationship between preoperative levels of both SCC-Ag and CRP, with clinicopathologic factors and prognosis in OSCC patients. A retrospective study was performed on 142 OSCC patients between March 2008 and March 2011. Their serum SCC-Ag and CRP levels were measured preoperatively. SCC-Ag level of ≥2.0 ng/ml and CRP level ≥5.0 mg/L were significantly associated with pathologic tumor status (P

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.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.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 (p0.0001), disease-free (p0.0001), disease-specific (p0.0001), and overall survival (p = 0.0046) rates.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.

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 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.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.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 (p0.0001), and disease-free (p0.0001), disease-specific (p0.0001), and overall survival (p0.0001) rates.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.

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.

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.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.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 depth12 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.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.

Objectives/Hypothesis: Previous studies have demonstrated a relationship between elevated serum squamous cell carcinoma (SCC) antigen (SCC-Ag) levels and shorter survival in cancer patients. Few studies, however, have investigated the role of serum SCC-Ag levels in oral SCC (OSCC). This study was conducted to analyze the relationship between preoperative SCC-Ag levels, clinicopathologic factors, and prognosis in OSCC patients. Study Design: Retrospective case-control study. Methods: Seventy-nine OSCC patients from Chang Gung Memorial Hospital were retrospectively recruited between April 2008 and March 2010. Serum SCC-Ag levels were measured preoperatively. Results: An SCC-Ag level of ≥2.0 ng/mL was significantly associated with the pathologic tumor status (P 10 mm vs. ≤10 mm, P < .001). It was not significantly associated with histologic differentiation (P = 1.000). A univariate analysis revealed that positivity for SCC-Ag was associated with disease-free survival (DFS) (P = .034) and overall survival (OS) (P < .001). In SCC-Ag-positive patients, the distant metastatic rate was higher than in the SCC-Ag-negative patients (P = .053). Conclusions: This study demonstrated that preoperative SCC-Ag is a good marker of pathologic lymph node metastasis, an advanced tumor stage, and a higher rate of distant metastasis. The preoperative SCC-Ag level is a potential prognostic indicator in DFS and OS, but studies with a longer follow-up period are needed to confirm these results.

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.

Background The purpose of this study was to evaluate the Model for Endstage Liver Disease (MELD) scoring system for predicting the morbidity and mortality of patients with head and neck cancer with liver cirrhosis undergoing tumor resection with microsurgical free-tissue transfer. Methods Between January 2000 and December 2008, 3108 cases were retrospectively reviewed. Results There were 59 men and 2 women enrolled in this study. Preoperatively, 31 and 30 patients were classified as having lower ( 9.73) MELD scores, respectively. Patients with higher MELD scores had significantly more postoperative medical morbidities including pulmonary complications and gastrointestinal bleeding. The mortality rate was also significantly higher for higher MELD scorers (23.3% vs 3.2%; p = 0.026). By logistic regression model, preoperative MELD score was a significant predictive factor for morbidity and mortality in multivariate analysis. Conclusion MELD score could be used to predict morbidity and mortality for patients with head and neck cancer with liver cirrhosis undergoing tumor resection with microsurgical free tissue transfer. © 2010 Wiley Periodicals, Inc. Head Neck, 2011

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 prospectively evaluated the sensitivity and specificity of 18F-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 18F-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:18F-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.

Background This study was undertaken to identify the genes in response to areca nut extract, a potential carcinogen of oral cancer. Methods Two oral cancer sublines chronically treated with areca nut extract were established. Methods such as microarray and immunohistochemistry were used to screen and validate the genes' altered expressions in areca nut extract-sublines or in cancer tissues. Results A total of 35 genes were differentially expressed in both sublines. Several functional pathways were significantly altered. Six genes were confirmed over 2-fold of changes, including Ches1. Functional analyses showed that overexpression of Ches1 suppressed cell growth and arrested cells in the G2/M phase. Consistently, this gene has reduced expression in 52% of oral cancer tissues, which was significantly correlated with the areca nut chewing habit of patients (p = .04). Conclusion We identified 35 candidates and validated 6 genes that may be associated with areca nut-induced oral cancer. Loss of Ches1 may be attributed to areca nut extract–induced oral carcinogenesis. © 2010 Wiley Periodicals, Inc. Head Neck, 2011

In our experience, the prognosis for parotid gland acinic cell carcinoma (AciCC) is good. Surgery alone would be sufficient in early-stage tumor. Postoperative adjuvant treatment in advanced-stage patients or those with positive resection margins usually gives satisfactory control of the disease.AciCC is a rare tumor in parotid gland malignancy. The aim of this study was to retrospectively analyze the experience in our hospital in treating this malignancy.Twenty-five patients with AciCC diagnosed from 1983 to 2007 at the Chang Gung Memorial Hospital were retrospectively reviewed.Thirteen male and 12 female patients ranged in age from 16 to 84 years (mean 37.5 years) at the time of diagnosis. Most patients (92%) presented with symptoms of infra-auricular mass. The tumor stage distributions of the patients were 24%, 44%, 28%, and 4% for stages I, II, III, and IV, respectively. Thirteen patients underwent superficial parotidectomy and 12 patients underwent total parotidectomy. Four patients had positive resection margins. Ten patients had surgery and postoperative radiotherapy; one received surgery and postoperative chemo/radiotherapy. The 10-year disease-free and overall actuarial survivals were both 84% in a mean follow-up of 75.8 months.

Purpose Radiotherapy is an integral part of the treatment modality for head-neck cancer (HNC), but in some cases the disease is radioresistant. We designed this study to identify molecules that may be involved in this resistance. Methods and Materials Two radioresistant sublines were established by fractionated irradiation of the HNC cell lines, to determine differentially proteins between parental and radioresistant cells. Proteomic analysis and reverse-transcription polymerase chain reaction were used to identify and confirm the differential proteins. The siRNA knockdown experiments were applied to examine cellular functions of a radioresistant gene, with investigation of the alterations in colonogenic survival, cell cycle status, and reactive oxygen species levels. Xenografted mouse tumors were studied to validate the results. Results IN all, 64 proteins were identified as being potentially associated with radioresistance, which are involved in several cellular pathways, including regulation of stimulus response, cell apoptosis, and glycolysis. Six genes were confirmed to be differentially expressed in both radioresistant sublines, with Gp96, Grp78, HSP60, Rab40B, and GDF-15 upregulated, and annexin V downregulated. Gp96 was further investigated for its functions in response to radiation. Gp96-siRNA transfectants displayed a radiation-induced growth delay, reduction in colonogenic survival, increased cellular reactive oxygen species levels, and increased proportion of the cells in the G2/M phase. Xenograft mice administered Gp96-siRNA showed significantly enhanced growth suppression in comparison with radiation treatment alone ( p = 0.009). Conclusions We identified 64 proteins and verified 6 genes that are potentially involved in the radioresistant phenotype. We further demonstrated that Gp96 knockdown enhances radiosensitivity both in cells and in vivo , which may lead to a better prognosis of HNC treatment.

We sought to determine the differences in clinical outcome of tongue and buccal carcinomas. Five-year locoregional control, distant metastasis, and survival rates were examined in 456 patients with tongue cancer and 407 patients with buccal cancer. 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. 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.

A better understanding of the prognostic factors in oral cavity squamous cell carcinoma (OSCC) may optimize the therapeutic approach. In this study, we sought to investigate whether the combination of clinical information, pathologic results, and preoperative maximal standardized uptake value (SUVmax) at the primary tumor and regional lymph nodes might improve the prognostic stratification in this patient group.A total of 347 consecutive OSCC patients were investigated. All participants underwent fluorodeoxyglucose-positron emission tomography within 2 weeks before surgery and neck dissection. The duration of follow-up was at least 24 months in all surviving patients. The optimal cutoff values for SUVmax at the primary tumor (SUVtumor-max) and regional lymph nodes (SUVnodal-max) were selected according to the 5-year disease-free survival (DFS) rate. Independent prognosticators were identified by Cox regression analysis.In multivariate analysis, a cutoff SUVtumor-max of 8.6, a cutoff SUVnodal-max of 5.7, and the presence of pathologic lymph node metastases were found to be significant prognosticators for the 5-year DFS. A scoring system using these three prognostic factors was formulated to define distinct prognostic groups. The 5-year rates for patients with a score between 0 and 3 were as follows: neck control, 94%, 86%, 77%, 59% (p0.0001); distant metastases, 1%, 7%, 22%, 47% (p0.0001); disease-specific survival, 93%, 85%, 61%, 36%, respectively (p0.0001).Based on the study findings, the combined evaluation of pathologic node status and SUVmax at the primary tumor and regional lymph nodes may improve prognostic stratification in OSCC patients.

The aim of this study was to clarify relevant alterations of gene expression associated with the invasive phenotype of oral cancer. To reduce heterogeneity and to obtain data on genes specifically involved in invasive mechanism, we established a highly invasive ORC subline through in vitro Matrigel invasion method. Affymetrix microarrays were used for transcriptome profiling between parental and the highly invasive subline. Seventy-nine genes were differentially expressed at least 2-fold, including 38 up-regulated and 41 down-regulated. After analyzing the microarray data by MetaCore algorithm, a total of 12 regulatory pathways were found to be associated with invasive phenotype (p

Background. Epidermal growth factor receptor (EGFR)-targeted therapy has been extensively assessed in human cancer treatment. We appraised the possible role of tyrosine kinase inhibitors (TKIs) in areca quid (AQ)-associated oral cavity squamous cell carcinomas (OSCCs) by examining EGFR protein overexpression and its tyrosine kinase domain mutations. Methods. EGFR overexpression was evaluated by immunohistochemical staining, and tyrosine kinase mutations was determined by direct sequencing of DNAs from 172 OSCC tumors. Results. Overexpression of EGFR was found in 27.9% (48 of 172) of the OSCCs and was associated with lymph node metastasis (p = .013) and extracapsular spread (p = .022). Only 1 (0.58%) OSCC displayed somatic EGFR mutation but in a silent form (T725T, ACGACA). Conclusion. EGFR-targeted therapy might have some potential in AQ-associated OSCCs for their EGFR frequently overexpressed, although EGFR mutations were rare. However, the feasibility of TKIs in AQ-associated OSCCs needs further clinical testing. © 2009 Wiley Periodicals, Inc. Head Neck, 2009

Purpose Survival in oral cavity squamous cell carcinoma (OSCC) depends heavily on locoregional control. In this prospective study, we sought to investigate whether preoperative maximum standardized uptake value of the neck lymph nodes (SUVnodal-max) may predict prognosis in OSCC patients. Methods and Materials A total of 120 OSCC patients with pathologically positive lymph nodes were investigated. All subjects underwent a [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scan within 2 weeks before radical surgery and neck dissection. All patients were followed up for at least 24 months after surgery or until death. Postoperative adjuvant therapy was performed in the presence of pathologic risk factors. Optimal cutoff values of SUVnodal-max were chosen based on 5-year disease-free survival (DFS), disease-specific survival (DSS), and overall survival (OS). Independent prognosticators were identified by Cox regression analysis. Results The median follow-up for surviving patients was 41 months. The optimal cutoff value for SUVnodal-max was 5.7. Multivariate analyses identified the following independent predictors of poor outcome: SUVnodal-max ≥5.7 for the 5-year neck cancer control rate, distant metastatic rate, DFS, DSS, and extracapsular spread (ECS) for the 5-year DSS and OS. Among ECS patients, the presence of a SUVnodal-max ≥5.7 identified patients with the worst prognosis. Conclusion A SUVnodal-max of 5.7, either alone or in combination with ECS, is an independent prognosticator for 5-year neck cancer control and survival rates in OSCC patients with pathologically positive lymph nodes.

Purpose The pathologic tumor depth is an independent prognosticator for local control (LC) and survival in patients with oral cavity squamous cell carcinoma (OSCC). We sought to investigate the prognostic value of the preoperative maximal standardized uptake value (SUVmax) at the primary tumor in OSCC patients with pathologically positive lymph nodes. Methods and Materials A total of 109 OSCC patients with pathologically positive lymph nodes were investigated. All patients underwent 2-deoxy-2[(18)F]fluoro-d-glucose–positron emission tomography within 2 weeks before surgery and neck dissection. All patients were followed for ≥24 months after surgery or until death. The optimal cutoff value for the primary tumor SUVmax was selected according to the 5-year LC rate. Independent prognosticators were identified by Cox regression analysis. Results The median follow-up for all patients was 26 months (39 months for surviving patients). A cutoff SUVmax of 19.3 provided the greatest prognostic information for the 5-year LC rate (55% vs. 88%, p = 0.0135). A tumor depth ≥12 mm appeared to be the most appropriate cutoff for predicting the 5-year LC rate (76% vs. 95%, p = 0.0075). A scoring system using the primary tumor SUVmax and tumor depth was formulated to define distinct prognostic groups. Patients with both a SUVmax of ≥19.3 and tumor depth of ≥12 mm ( n = 8) had significantly poorer 5-year LC, 5-year disease-free, 5-year disease-specific, and 5-year overall survival rates compared with the other patient groups. Conclusion The combination of the primary tumor SUVmax (≥19.3) and pathologic tumor depth (≥12 mm) identified a subgroup of OSCC patients at greatest risk of poor LC and death.

Purpose The criteria for administration of adjuvant radiation therapy (RT) in oral cavity squamous cell carcinoma (OSCC) remain controversial, and it is unclear whether patients with pT1-3N0 disease benefit from adjuvant radiation in the presence of free margins and perineural invasion. The goal of this report was to determine whether this group would benefit from adjuvant radiation therapy in terms of 5-year local control rate and overall survival rate. Methods and Materials We retrospectively reviewed our case records from January 1996 to May 2005. In all, 460 pT1-3N0 OSCC patients had tumor-free margins, of whom 68 had perineural invasion. Postoperative adjuvant RT was performed in patients with pT4 tumors, positive lymph nodes, or close margins (≤4 mm). In addition, selected OSCC patients with large pT3 tumors or perineural invasion received postoperative adjuvant RT. Local control and overall survival rates were plotted by Kaplan-Meier analysis. Results There were no significant differences in 5-year local control ( p = 0.1936) and overall survival ( p = 0.5580) rates between patients with perineural invasion compared with those without. Among patients with perineural invasion, the addition of adjuvant radiotherapy did not significantly alter the 5-year local control rate ( p = 0.3170) or the overall survival rate ( p = 0.0935). Conclusion Altogether, these data seem to indicate that radical surgical resection alone should be considered a sufficient treatment for OSCC patients with pT1-3N0 disease, even in the presence of perineural invasion.

Purpose To evaluate the outcome of treatment for buccal cancers and assess the impact of unilateral vs. bilateral adjuvant neck radiation. Methods and Materials We retrospectively reviewed the course of 145 patients newly diagnosed with buccal squamous cell carcinoma without distant metastases who completed definitive treatment between January 1994 and December 2000. Of 145 patients, 112 (77%) had Stage III or IV disease. All underwent radical surgery with postoperative radiotherapy (median dose, 64 Gy), including unilateral neck treatment in most ( n = 120, 82.8%). After 1997, cisplatin-based concomitant chemoradiotherapy was given for high-risk patients with more than two involved lymph nodes, extracapsular spread, and/or positive margins. Results The 5-year disease-specific survival rate for Stages I–IV was 87%, 83%, 61%, and 60%, respectively ( p = 0.01). The most significant prognostic factor was N stage, with the 5-year disease-specific survival rate for N0, N1, and N2 being 79%, 65%, and 54%, respectively ( p = 0.001). For patients with more than two lymph nodes or positive extracapsular spread, cisplatin-based concomitant chemoradiotherapy improved locoregional control ( p = 0.02). Locoregional control did not differ between patients undergoing unilateral or bilateral neck treatments ( p = 0.95). Contralateral neck failure occurred in only 2.1%. Conclusions In patients with buccal carcinoma after radical resection, ipsilateral neck radiation is adequate. Bilateral prophylactic neck treatment does not confer an added benefit.

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.

Objectives: There is no plasma marker for detecting nasopharyngeal cancer (NPC). We developed a bead-based affinity fractionated proteomic method to search potential plasma markers for NPC. Design and methods: Affinity purification of heparinized plasma with Cu-chelated beads and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) analysis were used to screen potential NPC markers. We compiled MS protein profiles for 47 patients with NPC and compared them to profiles from 28 healthy controls. The spectra were statistically analyzed using flexAnalysis ™ and ClinProt ™ bioinformatics software. Diagnostic efficacy was evaluated by determination of the assay sensitivity and specificity of each marker. Results: Twelve mass fingerprint markers differing between cancer and control spectra were found. The sensitivities of these NPC markers are various ranging from 36% to 83%, and the specificities were all over 90%. Combine use of these markers significantly increases diagnostic efficacy. In which, the combined markers (2020 Da and 4635 Da) possess best discriminator with high sensitivity (94%) and specificity (93%). We further identify a C3 fragment, C3f, that may serve as a biomarker for NPC. Conclusion: The combined use of mass fingerprint markers in plasma proteome will enhance diagnostic efficacy for NPC. This method can be applied to search for novel plasma markers for cancers.

BACKGROUND The goal of the current study was to evaluate the efficacy and toxicity of paclitaxel, cisplatin (P), tegafur (T), and leucovorin (L) as a neoadjuvant chemotherapy (CT) for patients with advanced, unresectable squamous cell carcinoma of the head and neck. METHODS From November 1999 to January 2001, 21 consecutive patients (Stage IV, 100%; T4, 86%; and N3, 41%) were treated with paclitaxel-PTL (Day 1: paclitaxel, 120 mg/m2 intravenous infusion for 3 hours; Day 1: P, 50 mg/m2; T, 800 mg; and L, 60 mg orally daily over a 14-day cycle). Evaluation after three cycles led to CT termination if primary tumor responses were less than partial responses. Otherwise, paclitaxel-PTL was continued for up to six cycles before commencement of locoregional therapy. RESULTS CT responses were analyzed on an intent-to-treat basis. Response rates (RR) for the primary tumors were 81% (17 of 21), with 28.6% (6 of 21) showing a complete response (CR). RR and CR rates for the neck lymph nodes were 85.3% (15 of 18) and 22% (4 of 18), respectively. The combined RR for primary tumors and neck lymph nodes was 81% (95% confidence interval, 62.9–99.3%) with a CR rate of 19%. Grade 3/4 toxicities according to World Health Organization criteria included leukopenia, 19.0%; emesis, 9.5%; asthenia, 9.5%; mucositis, 4.8%; and neuropathy, 4.8%. Both the overall and disease-free survival rates were 14.3% (3 of 21), with a median follow-up of 41 months. CONCLUSIONS The relatively low toxicities and encouraging response rates demonstrated in the current study suggested that paclitaxel-PTL merits future trials in the setting of resectable tumors with more favorable characteristics. Cancer 2004. © 2004 American Cancer Society.

Most adults have been infected with EBV. Many studies have indicated that antibodies against specific EBV antigens, particularly IgA antibodies, can be predictive or prognostic of EBV-associated malignancies, such as NPC. We hypothesized that healthy individuals from families with a history of multiple members affected with NPC (who therefore might be genetically susceptible to NPC themselves) might have an EBV antibody profile that is distinct from that seen in healthy individuals from the community at large. To explore this possibility and examine determinants of anti-EBV antibody levels in healthy, high-risk individuals, we evaluated data from 2 parallel studies of NPC in Taiwan, which included 1,229 healthy members of families in which 2 or more individuals were affected with NPC and 320 controls from the community at large. Blood collected from participants was tested for IgA antibodies against EBV VCA and EBNA-1 and for neutralizing antibodies against EBV DNase using standard assays. We observed evidence of familial aggregation of EBV seroreactivity among individuals from high-risk, multiplex NPC families. Anti-VCA IgA and anti-EBNA-1 IgA antibody seroprevalence in unaffected family members of NPC cases was 5-6 times higher than in members of the community (p < 0.01). This elevated seroprevalence among unaffected individuals from high-risk families was observed regardless of the relationship of the unaffected individual to the closest affected relative (siblings, parents, children or spouses). No sociodemographic or environmental factors examined were found to strongly and consistently correlate with elevated seroprevalence, but patterns emerged of increasing seroprevalence among older individuals and among females. Unaffected individuals from high-risk NPC families have elevated anti-EBV IgA antibody titers. The etiologic and clinical implications of this finding remain to be established.

Reconstruction of composite defects of the mandible is a challenging problem. Although the use of an osteocutaneous free flap, alone or in combination with another soft-tissue free flap, is generally accepted to be optimal, the bony reconstruction is sometimes undervalued, especially when the cancer is advanced. In such situations, reconstruction is often performed with a reconstruction plate covered with a soft-tissue free flap. Between January of 1997 and July of 2000, 80 patients with composite or extensive composite oromandibular defects underwent treatment with a reconstruction plate and a soft-tissue free flap. All of the patients were male, and the ages of the patients at the time of treatment ranged from 32 to 78 years (mean, 51 years). Tumors were classified as stage IV in 56 patients (70 percent), whereas the remaining 24 patients (30 percent) had recurrent carcinomas. The titanium mandibular reconstruction system manufactured by Stryker (Freiburg, Germany) was used to bridge the mandibular defects. The soft-tissue free flaps used for wound and plate coverage were as follows: anterolateral thigh flap (n = 75), radial forearm flap (n = 3), transverse rectus abdominis myocutaneous flap (n = 1), and tensor fasciae latae flap (n = 1). Five patients with recurrent carcinomas and 10 with stage IV carcinomas (18.75 percent) died 2 to 6 months after the operation and were excluded from the study. The remaining 65 patients were monitored for an average follow-up period of 22 months (range, 6 to 40 months). During that period, one or more complications occurred for 45 patients (69.2 percent). Plate exposure was the most common complication and was observed for 30 patients (46.15 percent). Twenty of the 65 patients (30.8 percent) required secondary salvage reconstruction with a fibula osteoseptocutaneous flap. The decision to perform a secondary salvage procedure was based on the general health of the patient, the extent of local disease, and the severity of the complications. Patients underwent salvage operations after an average of 11.5 months (range, 6 to 26 months). The major reasons for the second operation were as follows: reconstruction plate exposure (n = 12), soft-tissue deficiency and mandibular contour deformation of the lateral face (n = 7), intraoral contracture and lack of a gingivobuccal sulcus (n = 6), trismus (n = 4), and osteoradionecrosis of the mandible (n = 2). The total flap survival rate was 90 percent (18 of 20 free flaps). In two cases, the skin paddles of the fibula osteoseptocutaneous flaps exhibited partial failure and were revised with pedicled pectoralis major and deltopectoral flaps. The reconstruction plate and free soft-tissue flap procedure for the reconstruction of composite defects of the oromandibular region has many late complications, which eventually necessitate reconstruction of the mandible with an osteocutaneous free flap.

Progression of head and neck cancer is always associated with changes of gene expression profile. In this study, we characterized the expression of multidrug‐resistance mdr1 gene, which may play a role in tumorigenesis and multidrug resistance in head and neck cancer. A TaqMan one‐step RT‐PCR with a linear range for quantification across at least a 5 log scale of concentration of mdr1 mRNA was designed to determine the level of mdr1 expression in 50 pairs of normal vs. malignant head and neck tissues. Both the absolute level of mdr1 mRNA in tumor (T) and the relative mdr1 expression between tumor and its normal counterpart (T/N) were measured and their associations with several clinical variables were analyzed. Among the clinical variables analyzed, only the clinical stage of tumor was found to be associated with mdr1 expression. The distribution of clinical stages differed significantly (P1, with 59.3%, 22.2%, 14.8% and 3.7% in stage IV, III, H, and I, respectively. In addition, 76% of stage IV and 75% of stage III tumors had a T/N>1 compared to 25% of stage II and 20% of stage I tumors (P=0.004). Multivariate logistic regression analysis also indicated a significant difference of mdr1 expression between the early (I and II) and advanced (III and IV) stages tumors. The adjusted odds ratios (95% confidence intervals) were 1.477 (1.084–2.012) and 1.001 (1.000–1.002) for T/N (P

Nasopharyngeal carcinoma (NPC) is endemic among well-defined ethnic groups in several world regions, such as Southeastern China and Taiwan. Glucose-6-phosphate-dehydrogenase (G6PD)- deficiency, a sex-linked disorder, is one of the most common enzymopathies in Taiwan. The major role of G6PD is to generate NADPH to protect cells from oxidative damage, which is a major contributing factor to certain degenerative diseases, such as aging and cancer. In view of the coincidence of epidemic distribution of NPC and G6PD deficiency, as well as the house-keeping function of G6PD in cellular oxidative defense, we investigated the correlation of G6PD activity with NPC. The stage of NPC was classified by AJCC (1997) criteria. G6PD levels were determined in 108 NPC male patients and 75 healthy male individuals. The mean G6PD level of NPC patients was 218.9 U/10(12) RBC or 7.53 U/g hemoglobin (Hb), being much lower than in normal individuals (260.6 U/10(12) erythrocytes (RBC) or 8.92 U / gHb). The level of G6PD activity had no correlation with tumor stage or lymph node or distant metastasis, but was significantly correlated with tumor recurrence (P = 0.004 when using G6PD = 130 U/10(12) RBC as cutoff value). These results indicated that low G6PD activity in patients with NPC is associated with poor prognosis.

Background Nasopharyngeal carcinoma (NPC) is the most common head and neck malignancy in southeastern China and Taiwan. Early detection of the local disease followed immediately by proper treatment is essential to increase the cure and survival rates. Because every NPC tumor cell carries Epstein-Barr Virus (EBV) genomes, detection of EBV genomic DNA such as latent membrane protein 1 gene (LMP1) might indicate the presence of NPC. We developed a simple and noninvasive technique of nasopharyngeal swabbing to acquire nasopharyngeal cells for detecting the presence of EBV genome. The aim of this study was to investigate the feasibility and reliability of this technique. Methods We collected nasopharyngeal cells by means of a nasopharyngeal swabbing technique and detected the presence of EBV LMP1 with polymerase chain reaction (PCR). Thirty-eight swab specimens were obtained from patients with NPC who were newly diagnosed or were just beginning radiotherapy. Two groups of control subjects were recruited, including 20 patients with other head and neck cancers and eight family members of the NPC patients. An additional group of 65 NPC patients were enrolled in the course of regular follow-up after definitive radiotherapy. Results All of the samples yielded sufficient DNA for PCR amplification. Thirty-six of 38 NPC swab samples were positive for EBV LMP1, and all the control subjects had swab sample results negative for EBV. All five patients with suspected local recurrence exhibited positive EBV test results. Conclusions Demonstration of EBV LMP1 in the nasopharyngeal swab specimens detected NPC with a sensitivity of 94.7% and specificity of 100%. This study confirms the reliability and feasibility of nasopharyngeal swab in the predicting and screening of NPC. © 2001 John Wiley & Sons, Inc. Head Neck 23: 194–200, 2001.

Previous studies of nasopharyngeal carcinoma (NPC) have found elevated risks with higher consumption of salted fish and preserved foods, particularly during childhood. These foods can contain high levels of nitrosamines; however, most studies have not estimated exposure to nitrosamines directly. We conducted a case-control study in Taiwan to evaluate dietary intakes and NPC risk. A total of 375 cases (99% response rate) and 327 controls (88% response rate) were interviewed about their diet as an adult and at age 10 using a food-frequency questionnaire. We interviewed mothers of participants about their child's diet at age 10, age 3 and during weaning and the mother's diet while she was breast-feeding. Mothers of 96 cases and 120 controls were interviewed. Nitrosamine and nitrite levels were assigned to 66 foods based on published values. Intake of nitrosamines and nitrite as an adult was not associated with risk of NPC. High intakes of nitrosamines and nitrite during childhood and weaning were associated with increased risks of NPC for foods other than soy products. Adjusted odds ratios for the highest quartile were 2.2 [95% confidence interval (CI) 0.8–5.6] for age 10, 2.6 (95% CI 1.0–7.0) for age 3 and 3.9 (95% CI 1.4–10.4) for weaning diet. Intakes of nitrite and nitrosamines from soybean products during childhood and weaning were inversely associated with risk. Soybeans contain known inhibitors of nitrosation, and thus may explain the inverse association we observed. Our results suggest that nitrosamine and nitrite intake during childhood may play a role in the development of NPC. Int. J. Cancer 86:603–609, 2000. Published 2000 Wiley-Liss, Inc.