Oral Squamous Cell Carcinoma

Forty tumours were diagnosed in 35 (53%) of 66 captive African hedgehogs documented at Northwest ZooPath (NZP) between 1994 and 1999. Three hedgehogs had more than one type of tumour and the remaining 32 had a single type. Of the 35 hedgehogs with tumours, 14 were female, 11 were male, and 10 were of unknown gender; 21 were from zoological parks and 14 were privately owned. Twenty of the hedgehogs with tumours were adult (>1 year old) with a median age of 3•5 years (range 2-5•5 years); 15, of unreported age, were classified as adult. Thirty-four (85%) of the 40 tumours were classified as malignant and six (15%) as benign. The integumentary, haemolymphatic, digestive and endocrine systems were common sites for tumours. The most common tumours were mammary gland adenocarcinoma, lymphosarcoma and oral squamous cell carcinoma.

The majority of genes in the HLA region are directly or indirectly involved in immunological functions. They comprise HLA, HLA-related and non-HLA-related genes. Aberrant HLA expression patterns, including heterogeneous and negative HLA expression, are observed in specimens from head and neck squamous cell carcinoma (HNSCC). To explore the possible role of genes in the HLA region other than the classical HLA genes, susceptibility regions within the HLA region for HNSCC were defined in this study. Microsatellite analysis for 49 microsatellites dispersed throughout the HLA region, in combination with the DNA pooling approach of respectively one control DNA pool and three patient DNA pools, based upon the tumour location, offered an efficient method to define susceptibility regions. In the oral cavity three significant susceptibility regions were localized, one in the class I region (330 kb), and two in the class II region (170 and 210 kb). Eighteen genes from these regions were tested for their RNA expression in oral cavity tumour tissue and compared to expression in the surrounding healthy tissue. A significant increased MICA RNA expression in tumour tissues compared to healthy surrounding tissue and a significant decreased HSD17B8 RNA in tumour tissues compared to surrounding healthy tissue, particular in those tumours without lymph node metastasis, were observed. A trend for decreased RXR␤ and NOTCH4 RNA expression was observed in tumour tissue. In addition to the classical HLA genes, other genes within the HLA region define susceptibility for oral squamous cell carcinoma of the head and neck.

Expression Pattern of Epstein-Barr Virus Latent Genes in Cell ... Lines Derived from Oral Squamous Cell Carcinoma ... Abu Mohammad Eahsan Rasul1,2, Ieyoshi Kobayashi2, Tamotsu Kiyoshima2, Kou Matsuo2, Masamichi Ohishi1 and Hidetaka Sakai2 1Department of Oral ...

To analyze the impact of resection margin status and histologic prognosticators on local recurrence (LR) and overall survival (OS) for patients with oral squamous cell carcinoma (OSCC). This study was both retrospective and prospective in design. Cohort 1 refers to the entire group of 292 patients with OSCC. The slides from the earliest resection specimens from Cohort 1 were examined in an exploratory manner for multiple parameters. Cohort 2 refers to a subset of 203 patients, who did not receive any neoadjuvant therapy and had outcome data. Cohort 3 represents a subset of Cohort 2 (n = 168) wherein the histologic resection margin status could be reconfirmed. Cohort 4 refers a subset of 85 patients with tongue/floor of mouth tumors. Margin status was designated as follows: group 1, clearance of $5 mm with intraoperative analysis, no need for supplemental margins (n = 46); group 2, initial margins were measured as ,5 mm during intraoperative frozen section; supplemental resection margins were negative on final pathology (n = 73); group 3, the final pathology revealed resection margins ,5 mm (n = 30); group 4, the final pathology revealed frankly positive resection margins (n = 19). The endpoints of LR and OS were queried with respect to T stage, tumor site, margin status, and numerous histologic variables, by Cox regression and Kaplan-Meier survival analyses. Tumor stage (T) was significantly associated with LR (P = 0.028). Kaplan-Meier analysis for stage and for intraoral site was significantly associated with LR for T4 tumors. The increased likelihood of LR was higher for T4 OSCC of the buccal mucosa (75%), sinopalate (50%), and gingiva (100%) compared with mobile tongue (27%), and oropharynx (13%) (P = 0.013). Margin status was not associated with LR or OS (Cohort 3). This was so when all tumors were grouped together and when separate analyses were performed by tumor stage and oral subsite. No significance was demonstrated when margin status was examined for patients with similar treatment (surgery alone or surgery with adjuvant RT). However, the administration of adjuvant RT did significantly increase local disease-free survival (P = 0.0027 and P = 0.001 for T1 and T2 SCC, respectively). On exploratory analyses of histologic parameters, worst pattern of invasion was significantly associated with LR (P = 0.015) and OS (P , 0.001). Perineural invasion involving large nerves (.1 mm) was associated with LR (P = 0.005) and OS (P = 0.039). Limited lymphocytic response was also significantly associated with LR (P = 0.005) and OS (P = 0.001). When used as covariates in a multivariate Cox regression model, worst pattern of invasion, perineural invasion, and lymphocytic response were significant and independent predictors of both LR and OS, even when adjusting for margin status. Thus, these factors were used to generate our risk assessment. Our risk assessment classified patients into low-, intermediate-, or high-risk groups, with respect to LR (P = 0.0004) and OS (P , 0.0001). This classification retained significance when examining patients with uniform treatment. In separate analyses for each risk group, we found that administration of adjuvant radiation therapy is associated with increased local disease-free survival for high-risk patients only (P = 0.0296) but not low-risk or intermediate-risk patients. Resection margin status alone is not an independent predictor of LR and cannot be the sole variable in the decision-making process regarding adjuvant radiation therapy. We suggest that the recommendation for adjuvant radiation therapy be based on, not only traditional factors (inadequate margin, perineural invasion, bone invasion) but also histologic risk assessment. If clinicians want to avoid the debilitation of adjuvant radiation therapy, then a 5-mm margin standard may not be effective in the presence of high-risk score.

Previous investigations in our laboratory and others have shown that the levels of certain inflammatory, proangiogenic cytokines in saliva and tissue specimens of patients with oral premalignant lesions (OPML) are elevated. We have also shown that these cytokines are elevated in tissue culture of oral squamous cell carcinoma (OSCC) cell lines. The purpose of this pilot study was to determine the level of several inflammatory, NF-kB-dependent cytokines in whole unstimulated saliva (WUS), in subjects with OPML as compared to those with diagnosed OSCC. Subjects (n = 13) with OMPL, OSCC (n = 13), and age-sex matched controls without oral lesions (C) (n = 13) were enrolled. The mean age was 58.7 years. WUS was collected by standard techniques for 5 min (Navazesh, 1993). WUS samples were centrifuged and the cytokine analysis was performed on the supernatants by ELISA as previously described by Ondrey et al. (1991). The cytokines analyzed were: TNF-alpha, interleukin-1, interleukin-6, and interleukin-8 (TNF-a, IL-1, IL-6, and IL-8). The results as analyzed by Pairwise t-tests revealed significant differences in the salivary levels of: (1) TNF-a: (mean AE S.E.M.: TNF-a-OSSC = 28.9 AE 14.6 * pcg/ml versus OPML = 10.5 AE 7.4 * pcg/ml versus controls = 3.0 AE 1.0 pcg/ml; * p < 0.01); (2) IL-1: (IL-1-OSSC = 454.4 AE 215.8 * pcg/ml versus OPML = 255.1 AE 124.8 * pcg/ml versus controls = 173.2 AE 66.9 pcg/ml; * p < 0.01); (3) IL-6: (mean AE S.E.M.: IL-6-OSSC = 88.2 AE 43.2 * pcg/ml versus OPML = 70.8 AE 24.3 * pcg/ml versus controls = 1.4 AE 1.0 pcg/ml; * p < 0.001) and (4) IL-8 in saliva: (mean AE S.E.M.: IL-8-OSSC = 3154.1 AE 1023.2 * pcg/ml versus OPML = 1918.2 AE 899.1 * pcg/ml versus controls = 1580.7 AE 789.0 pcg/ml; * p < 0.001). There was a significant increase in the levels of all cytokines in the saliva of the OPML as compared to controls, and a significant difference in the cytokines of OSSC saliva compared to the OPML and controls. These results suggest that these proangiogenic, proinflammatory cytokines are elevated in the saliva of patients with OSSC and OPML as compared to controls, which may have diagnostic and/or prognostic significance. #

We evaluated promoter hypermethylation of a panel of tumor suppressor genes as a means to detect epigenetic alterations in oral squamous cell carcinomas (OSCC) of Indian-origin and compare with North-American head and neck squamous cell carcinomas (HNSCC). Quantitative-methylationspecific PCR was used to investigate the promoter methylation status of DCC, EDNRB, p16 INK4a and KIF1A in 92 OSCC, and compared to 48 paired normal tissues and 30 saliva and sera samples from healthy control subjects. Aberrant methylation of at-least one of these genes was detected in 74/92 (80.4%) OSCC; 72.8% at EDNRB, 71.7% at KIF1A, 47.8% at p16 INK4a and 58.7% at DCC; and in 5 of 48 (10.4%) normal oral tissues. None of the saliva and sera samples from controls exhibited DNA methylation in these four target genes. Thirty-two of 72 node positive cases harbored p16 INK4a and DCC hypermethylation (p = 0.005). Thus, promoter hypermethylation in genes analyzed herein is a common event in Indian OSCC and may represent promising markers for the molecular staging of OSCC patients. We found higher frequency of p16 INK4a methylation (47.8%) in this Indian cohort in comparison with a North-American cohort (37.5%). In conclusion, aberrant methylation of EDNRB, KIF1A, DCC and p16 INK4a genes is a common event in Indian OSCC,

The importance of early diagnosis in improving mortality and morbidity rates of oral squamous cell carcinoma (SCC) has long been recognized. However, a major challenge for early diagnosis is our limited ability to differentiate oral premalignant lesions (OPL) at high risk of progressing into invasive SCC from those at low risk. We investigated the potential of quantitative tissue phenotype (QTP), measured by highresolution image analysis, to identify severe dysplasia/ carcinoma in situ (CIS; known to have an increased risk of progression) and to predict progression to cancer within hyperplasia or mild/moderate dysplasia. We generated a nuclear phenotype score (NPS), a combination of five nuclear morphometric features that best discriminate 4,027 ''normal'' nuclei (selected from 29 normal oral biopsies) from 4,298 ''abnormal'' nuclei (selected from 30 SCC biopsies). This NPS was then determined for a set of 69 OPLs. Severe dysplasia/CIS showed a significant increase in NPS compared with hyperplasia or mild/moderate dysplasia. However, within the latter group, elevated NPS was strongly associated with the presence of high-risk loss of heterozygosity (LOH) patterns. There was a statistical difference between NPS of hyperplasia or mild/ moderate dysplasia that progressed to cancer and those that did not. Individuals with a high NPS had a 10-fold increase in relative risk of progression. In the multivariate Cox model, LOH and NPS together were the strongest predictors for cancer development. These data suggest that QTP could be used to identify lesions that require molecular evaluation and should be integrated with such approaches to facilitate the identification of hyperplasia or mild/moderate dysplasia OPLs at high risk of progression. [Cancer Res 2008;68(9):3099-107] Requests for reprints:

Objectives: Oral Squamous cell carcinoma (OSCC) is primarily a disease that mainly occurs in males in their sixth and seventh decades of life and is rare in young adults. Study Design: In this retrospective study, records of patients under the age of 40, with the diagnosis of OSCC in the Oral Medicine Department of Mashhad Dental Faculty during the past 13 years were analyzed. Their socioeconomic data, demographic, clinical and histopathological characteristics, risk factors, familial history were assessed and applicable studies and case reports in the literatures were reviewed. PCR (Polymerase chain reaction) analysis was also done for detection of human papilloma virus (HPV). Results: From 158 cases of OSCC diagnosed in our centre, 21 patients were younger than 40 years. Most of them were young men (12 cases). There was no significant risk factor in this group. The most common site of involvement was the tongue. The most common clinical presentation was exophytic lesion with ulcer. No HPV DNA was detected in these patients. Conclusion: Characteristics of OSCC in young patients are different from older age group. Major risk factors (smoking and alcohol consumption and HPV) were not etiologic factors for OSCC in young patients in our province.

Background. Oral cancer is the fourth most common cancer in males and the seventh most common cancer in females in Thailand. The survival rates and quality of life of oral cancer patients will significantly be improved if they receive treatment for lesions that are less advanced or premalignant. Early diagnosis is therefore of paramount importance. A number of techniques have been developed to supplement clinical examination for oral malignancy. One interesting screening method is the application of 3% to 5% acetic acid, which has been used for cervical cancer screening.

Clinical proteomics using a large archive of formalin-fixed paraffinembedded (FFPE) tissue blocks has long been a challenge. Recently, a method for extracting proteins from FFPE tissue in the form of tryptic peptides was developed. Here we report the application of a highly sensitive mass spectrometry (MS)-based quantitative proteome method to a small amount of samples obtained by laser microdissection from FFPE tissues. Cancerous and adjacent normal epithelia were microdissected from FFPE tissue blocks of 10 squamous cell carcinomas of the tongue. Proteins were extracted in the form of tryptic peptides and analyzed by 2-dimensional image-converted analysis of liquid chromatography and mass spectrometry (2DICAL), a label-free quantitative proteomics method developed in our laboratory. From a total of 25 018 peaks we selected 72 mass peaks whose expression differed significantly between cancer and normal tissues (P < 0.001, paired ttest). The expression of transglutaminase 3 (TGM3) was significantly down-regulated in cancer and correlated with loss of histological differentiation. Hypermethylation of TGM3 gene CpG islands was observed in 12 oral squamous cell carcinoma (OSCC) cell lines with reduced TGM3 expression. These results suggest that epigenetic silencing of TGM3 plays certain roles in the process of oral carcinogenesis. The method for quantitative proteomic analysis of FFPE tissue described here offers new opportunities to identify disease-specific biomarkers and therapeutic targets using widely available archival samples with corresponding detailed pathological and clinical records. (Cancer Sci 2009; 100: 1605-1611)

Background: Oral squamous cell carcinoma (OSCC) is one of the most frequent malignant worldwide. Early diagnosis can mean adequate treatment and increase survival. Methods: This study uses ClinProt technique to identify salivary biomarkers for early diagnosis of OSCC. A total of 71 salivary samples from both OSCC patients (n=41) and healthy donors (n=30) were analyzed with MALDI-TOF MS technology. Results: Salivary peptides from OSCC patients were separated, using C8-functionalized magnetic beads. Three signals (2918.57 Da, 5592.64 Da, and 4372.66 Da) distinguished OSCC patients from controls. Among them, unique peptide 2918.57 Da, identified as a 24-mer peptide of zinc finger protein 510 (ZNF510), was found in 0% of saliva from healthy individuals, versus 25.0% and 44.4% from OSCC patients with T1+T2 and T3+T4 stages, respectively (P < 0.001). ELISA analysis with rabbit anti-ZNF510 peptide sera shows a starkly higher 24-mer ZNF510 peptide level in saliva from OSCC patients than that in controls (P < 0.001). Also, immunohistochemical analysis of oral tissues, a significantly higher level of ZNF510 was observed in OSCC tissues than the OSCC free control tissues. Analysis of areas under Receiver-Operating Characteristic (ROC) curves in OSCC early (T1+T2) and late stages (T3+T4) show greater than 0.85. Conclusions: Identifying 24-mer ZNF510 peptide as OSCC-related salivary biomarkers via proteomic approach proved useful in adjunct diagnosis for early detection rather than specific diagnosis marker for progression of OSCC patients.

A case of Donovanosis is observed. While observing this case,
initially it was suspected with verrucous type. Clinically identified
as ulcer over right labium majus with pain and itching over the
lesions.  On  examination  by  Obstetrician,  single  granulomatous
ulcer without induration identified. No observation of leukoplakia
and tissue smear for the demonstration of CBG showed negative.
The treatment started with 100mg doxycycline twice a day for 10
days, where the ulcer is not healed but the morphology of the
lesion  changed.  After  referring  to  Surgery  department,  it  was
suspected to squamous cell carcinoma where the excisional biopsy
also  confirmed  the  same.  Later  right  radical  hemivulvuctomy
done.

Oral cancer is one of the most disfiguring types of cancer, since the surgical removal of the tumor may result in facial distortion. Oral cancer is also known to exhibit "field cancerization", resulting in the development of a second primary tumor. Furthermore, the five-year survival rate of this disease has remained approximately 50% during the past 30 years. Prevention and early detection/ treatment of oral cancer could significantly improve the quality of life for individuals at risk. Recently, the targeted elimination of oral squamous cell carcinoma cells by inducing apoptosis has emerged as a valued strategy to combat oral cancer. Studies utilizing a variety of chemical or biological interventions demonstrated promising results for induction of apoptosis in oral malignant cells. This review summarizes the results of a number of investigations focused specifically on induction of apoptosis in oral cancer cells by synthetic compounds and naturally occurring chemopreventive agents with apoptotic potential.

The aims of this study were to assess the expression levels of three proteins involved in apoptosis—Bcl-2, Bcl-X, and Bax—and evaluate their relationship with clinicopathologic features and survival in oral squamous cell carcinoma (OSCC). Immunohistochemistry was used ...

Methylation of specific lysine residues in histone tails has been proposed to function as a stable epigenetic marker that directs biological functions altering chromatin structure. Recent findings have implicated alteration in heterochromatin formation as a contributing factor in cancer development. In order to verify whether changes in the overall level of H3K4 histone methylation could be involved in oral squamous carcinoma, the levels of H3K4me1, me2 and me3 were measured in oral squamous carcinoma, leukoplakias and normal tissues. The levels of H3K4me2 and me3 were significantly different in oral squamous cell carcinoma in comparison with normal tissue: the level of H3K4me2 was increased while that of H3K4me3 decreased. No significant differences could be found between the two types of tissues in the level of H3K4me1. A similar trend was found in the leukoplakias that appeared more like the pathological than normal tissue. These results support the idea that alteration of chromatin structure could contribute to oncogenic potential.

Human papillomavirus (HPV) infects the squamous epithelial cells of oral cavity and cervix leading to formation of warts that develops into the cancer. Human papillomavirus (HPV)-16 and 18 encode E6 oncoprotein, which binds to and induces degradation of the tumour suppressor protein p53. A common polymorphism of p53, encoding either proline (Pro) or arginine (Arg) at position 72, affects the susceptibility of p53 to E6 mediated degradation in vivo. Oral cancer is a pressing problem in India due to the widespread habit of chewing betel quid, which plays an important role in etiology of this disease. In the present study an attempt has been made to analyze the genetic predisposition of the Indian population to HPV infection and oral carcinogenesis. In our study a total of 110 cases of Oral Cancer highly addicted to betel quid and tobacco chewing are analyzed for HPV 16/18 infection and its association with polymorphism at p53 codon 72. Of these a total number of 37 patients (33.6%) have shown the presence of HPV, among which the presence of HPV-16, 18 and 16/18 coinfection is 22.7%, 14.5% and 10%, respectively. Our results also indicate that the p53 codon 72 genotype frequencies in Indian Oral Cancer patients are 0.55 (Arg) and 0.45 (Pro) as per Hardy-Weinberg equilibrium. In our study, striking reduction in Pro/Pro allele frequency has been found in HPV positive cases, indicating Arg/Arg genotype to be more susceptible to HPV infection and oral carcinogenesis. © 2001 Wiley-Liss, Inc.

The N stage and number of patients was N0-44, N1-13 and N2-27. Sixty-two patients had a normal OGD, 21 patients had a suspicious lesion and one patient had a probable malignant lesion on OGD. Of the 23 biopsies of patients with an abnormal OGD, 19 were benign or inflamed, one showed moderate dysplasia, one showed severe dysplasia and two showed carcinoma. Both dysplastic lesions were excised with an endoscopic submucosal dissection, while one malignant lesion was treated with radiotherapy and the other with an oesophagectomy. No patient with an early primary lesion or with none or a single regional lymph node metastasis had a synchronous oesophageal lesion. The overall rate of a synchronous primary tumour in the oesophagus of patients with an oral cavity carcinoma in the study population was 2.38%.

To investigate the mechanisms of areca quid (AQ)-induced carcinogenesis, expression of c-fos and c-jun protooncogenes was examined in human oral mucosal ®broblasts after exposure to areca nut extracts (ANE) or arecoline. We found that treatment of cells with 200 mg/ml ANE or 10 mg/ml arecoline for 1 h induced about three-fold increase in c-jun mRNA levels. This increase was transient and the level of c-jun mRNAs returned rapidly to control levels thereafter. However, ANE and arecoline did not induce cfos mRNA expression at detectable levels. During AQ chewing, oral mucosal cells are continuously stimulated by ANE and arecoline. Persistent induction of the c-jun protooncogene by ANE and arecoline may be one of the mechanisms in the carcinogenesis of oral squamous cell carcinoma in Taiwan. Furthermore, we observed that pre-incubation of cells with either N-acetyl-cysteine [a glutathione (GSH) precursor] or l-buthionine-S,R-sulfoximine (a speci®c inhibitor of GSH biosynthesis) had a minimal eect on arecoline-induced c-jun expression. Therefore, arecoline-induced c-jun expression is independent of GSH depletion. #

Verification of oral cancer relies on histo-pathological diagnosis of suspect or malignant lesions. There is evidence for further pre-surgical screening procedures to localize tumor borders and define other malignant lesions. Important methods are: visual examination, including pan-endoscopy, fluorescence imaging, and brush biopsy, as well as radiologic techniques such as conventional radiography, computed tomography, magnetic resonance imaging, scintigraphy, and ultrasonography, which may reduce the mortality rate associated with oral cancer. In addition, toluidine blue staining is a simple, inexpensive, and excellent diagnostic tool. Herein we show that the clinical use of in vivo staining is effective to define the superficial tumor borders and to detect malignant or pre-malignant cells in the surrounding area of the tumor following detection of a malignancy of the oral cavity. In our reported case, the main tumor mass was surrounded by layers of an intact mucosa, yet in a distance of more than 1 cm a group of malignant or pre-malignant cells in the surrounding area required a resection of the tumor in a size that would have been unaddressed during visual examination alone followed by clinical routine program of presurgical examinations after the detection of a malignancy of the oral cavity.

To analyze the impact of resection margin status and histologic prognosticators on local recurrence (LR) and overall survival (OS) for patients with oral squamous cell carcinoma (OSCC). This study was both retrospective and prospective in design. Cohort 1 refers to the entire group of 292 patients with OSCC. The slides from the earliest resection specimens from Cohort 1 were examined in an exploratory manner for multiple parameters. Cohort 2 refers to a subset of 203 patients, who did not receive any neoadjuvant therapy and had outcome data. Cohort 3 represents a subset of Cohort 2 (n = 168) wherein the histologic resection margin status could be reconfirmed. Cohort 4 refers a subset of 85 patients with tongue/floor of mouth tumors. Margin status was designated as follows: group 1, clearance of $5 mm with intraoperative analysis, no need for supplemental margins (n = 46); group 2, initial margins were measured as ,5 mm during intraoperative frozen section; supplemental resection margins were negative on final pathology (n = 73); group 3, the final pathology revealed resection margins ,5 mm (n = 30); group 4, the final pathology revealed frankly positive resection margins (n = 19). The endpoints of LR and OS were queried with respect to T stage, tumor site, margin status, and numerous histologic variables, by Cox regression and Kaplan-Meier survival analyses. Tumor stage (T) was significantly associated with LR (P = 0.028). Kaplan-Meier analysis for stage and for intraoral site was significantly associated with LR for T4 tumors. The increased likelihood of LR was higher for T4 OSCC of the buccal mucosa (75%), sinopalate (50%), and gingiva (100%) compared with mobile tongue (27%), and oropharynx (13%) (P = 0.013). Margin status was not associated with LR or OS (Cohort 3). This was so when all tumors were grouped together and when separate analyses were performed by tumor stage and oral subsite. No significance was demonstrated when margin status was examined for patients with similar treatment (surgery alone or surgery with adjuvant RT). However, the administration of adjuvant RT did significantly increase local disease-free survival (P = 0.0027 and P = 0.001 for T1 and T2 SCC, respectively). On exploratory analyses of histologic parameters, worst pattern of invasion was significantly associated with LR (P = 0.015) and OS (P , 0.001). Perineural invasion involving large nerves (.1 mm) was associated with LR (P = 0.005) and OS (P = 0.039). Limited lymphocytic response was also significantly associated with LR (P = 0.005) and OS (P = 0.001). When used as covariates in a multivariate Cox regression model, worst pattern of invasion, perineural invasion, and lymphocytic response were significant and independent predictors of both LR and OS, even when adjusting for margin status. Thus, these factors were used to generate our risk assessment. Our risk assessment classified patients into low-, intermediate-, or high-risk groups, with respect to LR (P = 0.0004) and OS (P , 0.0001). This classification retained significance when examining patients with uniform treatment. In separate analyses for each risk group, we found that administration of adjuvant radiation therapy is associated with increased local disease-free survival for high-risk patients only (P = 0.0296) but not low-risk or intermediate-risk patients. Resection margin status alone is not an independent predictor of LR and cannot be the sole variable in the decision-making process regarding adjuvant radiation therapy. We suggest that the recommendation for adjuvant radiation therapy be based on, not only traditional factors (inadequate margin, perineural invasion, bone invasion) but also histologic risk assessment. If clinicians want to avoid the debilitation of adjuvant radiation therapy, then a 5-mm margin standard may not be effective in the presence of high-risk score.

Background: Head and neck cancer including oral cancer is considered to develop by accumulated genetic alterations and the major pathway is cancerization from lesions such as intraepithelial dysplasia in oral leukoplakia and erythroplakia. The relationship of proliferation markers with the grading of dysplasia is uncertain. The involvement of EBV in oral carcinogenesis is not fully understood.

Oral squamous cell carcinoma (OSCC) is a common cancer characterised by low survival rate and poor prognosis. The multistep process of oral carcinogenesis is affected by multiple genetic events such as alterations of oncogenes and tumour suppressor genes. The use of appropriate experimental animal models that accurately represent the cellular and molecular changes which are associated with the initiation and progression of human oral cancer is of crucial importance. The Syrian golden hamster cheek pouch oral carcinogenesis model is the best known animal system that closely correlates events involved in the development of premalignant and malignant human oral cancers. Therefore, we established an experimental system of chemically induced oral carcinogenesis in hamsters, in order to study different stages of tumour formation: normal mucosa, hyperkeratosis, hyperplasia, dysplasia, early invasion, well differentiated OSCC and moderately differentiated OSCC. We investigated the expression of oncogenes EGFR, erbB2, erbB3, FGFR-2, FGFR-3, c-myc, N-ras, ets-1, H-ras, c-fos and c-jun, apoptosis markers Bax and Bcl-2, tumour suppressor genes p53 and p16, and cell proliferation marker Ki-67 in the sequential stages of hamster oral oncogenesis. Here, we describe the findings of the experimental model in regard to the involvement of signal transduction pathways in every stage of cancer development. Increased apoptosis and cell proliferation were observed in early stages of oral oncogenesis. Furthermore, the increased expression of transmembrane 1368-8375/$ -see front matter ª

Oral squamous cell carcinoma (SCC) represents more than 90% of all head and neck cancers as reported by Hermans (Cancer Imaging, 5(Spec No A), S52–S57, 2005), which draws attention of investigative research for novel predictive metabolic biomarkers to understand the malignancy induced biochemical perturbations occurring at molecular level. In the present work, proton HR-MAS NMR spectroscopic studies have been performed on resected human oral SCC tumor tissues, its neighboring margins and bed tissues (n = 159), obtained from 36 patients (n = 27 training set; n = 9 unknown test set), for the identification of metabolic fingerprints. The proton NMR spectra were then subjected to chemometric unsupervised PCA and supervised OSC-filtered PCA and PLS-DA multivariate analysis. Application of PLS-DA on orthogonally signal corrected training data-set (n = 120 tissue specimens; 27 patients) allowed >95% correct classification of malignant tissues from benign samples with >98% specificity and sensitivity. The OSC-PLS-DA model thus constructed was used to predict the class membership of unknown tissue specimens (n = 39) obtained from nine patients. These tissue samples were correctly predicted in its respective histological categories with 97.4% diagnostic accuracy. The regression coefficients obtained from OSC-filtered PLS-DA model indicated that malignant tissues had higher levels of glutamate, choline, phosphocholine, lactate, acetate, taurine, glycine, leucine, lysine, isoleucine and alanine, and lower levels of creatine and PUFA, representing altered metabolic processes (lipidogenesis, protein synthesis, and volume regulation) during tumor progression. Thus proton HR-MAS MR spectroscopy could efficiently identify the metabolic perturbations of malignant tumor from non-malignant bed and margins tissue specimens, which may be helpful in understanding the extent of tumor penetration in neighboring tissues.

The ability to diagnose oral cancer depends in part on the knowledge, attitudes, and practices of the health professional. On the other hand, the patients' choice of health professional depends on their perceptions of the ability of such professionals to diagnose and treat what they believe their health problem is. In this study, we investigated the clinical profiles of patients with oral cancer (n=354) when first seen by dentists (n=129) or physicians (n=225) in a teaching hospital. The charts of patients with oral squamous cell carcinoma were analyzed for the following variables: age, sex, race, signs and symptoms by the time of presentation to the health professional, size and site of the tumor since first manifestation, and clinical stage of the disease. Our results demonstrate that dentists and physicians assessed patients comparably regarding age, sex, and race. Patients complaining of dysphagia and odynophagia were seen more often by physicians than dentists (45/225 vs 9/129 [20.0% vs 7.0%] and 30/225 vs 4/129 [13.3% vs 3.1%], respectively), whereas those with local pain and burning preferentially sought dentists (77/129 vs 56/225 [59.7% vs 24.9%] and 4/129 [3.1%] vs 0/225, respectively). Physicians diagnosed oropharyngeal (45/208 vs 9/116 [21.6% vs 7.8%]) and lip lesions (71/208 vs 7/116 [34.1% vs 6.0%]) more often, whereas dentists saw more cases of cancer of the alveolar ridge (42/116 vs 7/208 [36.2% vs 3.4%]) and floor of the mouth (19/116 vs 10/208 [16.4% vs 4.8%]). Our findings suggest that patients have different perceptions of the roles of dentists and physicians regarding the ability to diagnose and treat oral lesions. Signs, symptoms, and location of the cancer lesions appear to be the most important variables associated with the choice of health professional.

Head & Neck Cancer (HNC) represents the sixth most common malignancy worldwide and it is historically linked to well-known behavioural risk factors, i.e., tobacco smoking and/or the alcohol consumption. Recently, substantial evidence has been mounting that Human Papillomavirus (HPV) infection is playing an increasing important role in oral cancer. Because of the attention and clamor surrounding oral HPV infection and related cancers, as well as the use of HPV prophylactic vaccines, in this invited perspective the authors raise some questions and review some controversial issues on HPV infection and its role in HNC, with a particular focus on oral squamous cell carcinoma.

Oral lichen planus (OLP) carries a very small probability of becoming malignant. Our Finnish series comprised eight patients suering from OLP and concurrent or subsequent oral squamous cell carcinoma over a 10-year period. The mean interval between the histologically suggested initial diagnosis of OLP and carcinoma was 3.4 years. An oral ulcer as a clinical manifestation of malignant change appeared in seven of these eight patients; ®ve of the eight died of carcinoma on average 13 months (range 7±20) after the ®nal squamous cell carcinoma diagnosis. These eight patients were compared to eight control OLP patients without malignant transformation matched as to follow-up time, age, gender, sites of the lesions, etc. We could discover no histological features leading to malignant development. However, the clinically unilateral atrophic/erosive type of OLP more often preceded the malignant change, compared to the situation for control patients, in whom the most prevalent type was the bilateral reticular OLP. However, the probability seems to be very small. #

This study investigated if tumor-associated tissue eosinophilia (TATE) could be associated with the process of tissue invasion in oral squamous cell carcinomas (OSCCs) and its influence on patient's prognosis. Forty-three patients treated for OSCCs with or without lymph nodes involvement, at A. C. Camargo Cancer Hospital, Brazil, were selected for TATE analysis. Two degrees of tissue eosinophilia were established in OSCC: absent⁄mild and intense. The TATE was evaluated in relation to the clinicopathological features and prognostic value using χ 2 test and the Kaplan-Meier method. Most of the patients with OSCC in advanced clinical stage presented muscular infiltration and significantly intense TATE whereas those with tumors in early stage frequently showed absent/mild eosinophilia (P = .009). The TATE showed no prognostic value for 5-year and 10-year survival rates of the OSCC. These findings suggest that intense TATE seems to reflect the stromal invasion of the OSCCs that occur in advanced clinical stage.

The most important complication of oral lichen planus (OLP) is the development of oral squamous cell carcinoma (OSCC) but this is a very controversial matter. The aim of the study was to estimate in a Northern Italian cohort of OLP patients the risk for OSCC. Four hundred and two patients with histologically confirmed OLP diagnosed from January 1988 to July 1999, were followed-up to the end of February 2001. The standardized incidence ratio (SIR) of OSCC was calculated for the entire cohort and specific for gender, type of OLP, therapy for OLP and hepatitis C virus (HCV) infection. The relative risk (RR) of OSCC according to HCV infection was also estimated in the cohort. During the follow-up period, two men (1.3%) and seven women (2.9%) developed an OSCC. The SIR was 44.9 (95% CI: 20.5-85.2), being higher among women, but statistically significant in both genders. The RR of OSCC for patients with HCV as compared with those without HCV infection was 3.16 (0.8-12.5). Patients with OLP had a significantly increased risk of OSCC, irrespective of the clinical type of OLP and therapy. HCV infection apparently increased the risk for OSCC although this result could reflect the role of confounders, such as liver cirrhosis. #

Tumorigenesis of oral squamous cell carcinoma (OSCC) has been postulated to represent a multistep process driven by the accumulation of carcinogen-induced genetic changes. Alterations of the 3p14 fragile site containing the fragile histidine triade gene and of the 9p21 tumor suppressor locus containing methylthioadenosine phosphorylase, p16 and p15 characteristically occur in oral leukoplakia, a known precursor of OSCC, and are at present considered to indicate the transition from simple keratosis (hyperplasia) to dysplasia. The aim of the study was to evaluate the occurrence of losses of 3p14 and 9p21 and to evaluate polysomies 3 and 9 in leukoplakias using highly sensitive fluorescence in situ hybridization (FISH) probes. Examining 67 leukoplakias (24 hyperplasias, 33 dysplasias, 10 in situ carcinomas), control tissues of oral mucosa from infants and adults as well as invasive carcinomas and normal epithelia of tumor patients with locus specific FISH probes targeting 3p14 and 9p21, and centromeric probes for chromosomes 3 and 9 we could demonstrate that losses of these sites appeared very early in the tumorigenesis of OSCC and were already present in the great majority of simple keratoses. Polysomy 3 occurring more frequently than polysomy 9 was characteristic of dysplasia and in situ carcinomas and thus seems to follow losses of 3p14 and 9p21 during oral squamous cell carcinogenesis. ' 2007 International

Background and Aim: Oral cancer is a major public health issue worldwide; it remains a highly lethal and disfiguring disease, it is primarily a disease of epithelial origin, it has various clinicopathological pictures. is to demonstrate various clinical and pathological presentations of oral squamous cell carcinoma in Iraqi population. Materials and Methods: A total of 80 cases of histologically diagnosed squamous cell carcinoma collected from the main centers of Sulaymaniyah teaching hospital/Hiwa cancer center Hospital/Sulaymaniyah/Iraq were analyzed according to age, sex, site, clinical, and pathological presentation of oral squamous cell carcinoma at the time of presentation, and histological grading. Results: Patients in their sixth decade of life were the most commonly affected with a male-tofemale ratio of 1.4:1. The tongue was the most frequently affected site, followed by the floor of the mouth. The most common clinical presentation is ulceration and swelling. More than 40% of the cases were well-differentiated squamous cell carcinoma. Conclusion: Oral cancer is increasingly seen as a major health problem, in line with the general trend in the region, the need for inter-professional health care delivery approaches for reducing oral cancer mortality and improving patients' quality of life.

Objective. The aim of this report was to examine the oral cancer incidence by sex, race/ethnicity, and anatomical subsite. Study design. Data from the California Cancer Registry (CCR) were used to calculate the age-adjusted incidence rates of invasive oral squamous cell carcinoma (OSCC) by sex, race/ethnicity, and anatomical subsite among residents in California during 1988 to 2001. Results. Although non-Hispanic (NH) black men have the highest overall incidence rate for OSCC, NH whites and NH blacks have similar incidence patterns by subsite, but the male-to-female (M:F) rate ratio is higher among NH blacks. The OSCC incidence rates for Hispanics are much lower than those for NH whites and NH blacks and similar to those of Asians. The Asian ethnic groups display dramatic variations in terms of the subsite-specific incidence rates and M:F rate ratios.

Objective: It has been the aim of the present study to introduce a novel automatic technique for the objective and quantitative assessment of speech intelligibility to the evaluation of postoperative outcome. Patients and Methods: Forty-six patients with oral carcinomas, mean age 59.8 8 10.1 years, and an age-matched control group of 40 subjects without oral diseases. Recordings of a standard text read by the patients and the control group were analyzed by an automatic speech recognition system. Results: For the patients, automatic speech recognition yielded word recognition rates between 8 and 82% (mean 49 8 19%), for the control group between 60 and 91% (76 8 7%). Automatic evaluation closely correlated with the experts' perceptual evaluation of intelligibility (r = -0.93; p ! 0.01). The multirater kappa of the experts alone (0.55) differed only slightly from the multi-rater kappa of the experts and the speech recognition system (0.58). Conclusion: For adults with speech disorders, automatic speech recognition may serve as a valuable tool to assess global speech outcome after treatment of oral squamous cell carcinoma objectively and quantitatively for clinical and research purposes.

Amplification of chromosomal band 11q13 is a common event in human cancer. It has been reported in about 45% of head and neck carcinomas and in other cancers including esophageal, breast, liver, lung, and bladder cancer. To understand the mechanism of 11q13 amplification and to identify the potential oncogene(s) driving it, we have fine-mapped the structure of the amplicon in oral squamous cell carcinoma cell lines and localized the proximal and distal breakpoints. A 5-Mb physical map of the region has been prepared from which sequence is available. We quantified copy number of sequence-tagged site markers at 42-550 kb intervals along the length of the amplicon and defined the amplicon core and breakpoints by using TaqMan-based quantitative microsatellite analysis. The core of the amplicon maps to a 1.5-Mb region. The proximal breakpoint localizes to two intervals between sequence-tagged site markers, 550 kb and 160 kb in size, and the distal breakpoint maps to a 250 kb interval. The cyclin D1 gene maps to the amplicon core, as do two new expressed sequence tag clusters. We have analyzed one of these expressed sequence tag clusters and now report that it contains a previously uncharacterized gene, TAOS1 (tumor amplified and overexpressed sequence 1), which is both amplified and overexpressed in oral cancer cells. The data suggest that TAOS1 may be an amplification-dependent candidate oncogene with a role in the development and͞or progression of human tumors, including oral squamous cell carcinomas. The approach described here should be useful for characterizing amplified genomic regions in a wide variety of tumors.

Hydroxyurea (HU) is commonly used for the treatment of chronic myelogenous leukaemia, polycythemia vera and essential thrombocythaemia. Patients receiving HU present a number of side-effects including skin/mucosa changes and tumours. Mucocutaneous abnormalities include xerosis, ichthyosiform lesions, dark brown pigmentation of skin folds and nails, malleolar ulcers, oral mucositis and oral ulcers. Cutaneous squamous/basal cell carcinomas have also often been reported following long-term administration of HU. HU-induced carcinogenesis is due to both the mutagenic potential of this agent and to an impairment of DNA repair mechanisms after damage by external factors such as ultraviolet radiation. Oral cancer following long-term treatment with HU has been reported only once, in a patient with concomitant multiple skin tumours. We present the unique case of a patient with polycythemia vera who developed oral cancer after 15 years of HU therapy.

Circulating matrix metalloproteinase-9 (MMP-9) is a prognostic factor for gastric cancer and vascular diseases, and has been associated with head and neck cancers. The -1562 C-to-T polymorphism in MMP-9 promoter (abbreviated MMP-9 -1562 C&amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T polymorphism) leads to differential transcription, and is associated with increased susceptibility to neoplastic and vascular diseases. Thus, our aim was to determine whether a functional MMP-9 polymorphism might also influence the risk or affect the progression of areca-associated oral cancers. Genomic DNAs were obtained from peripheral blood cells of male subjects with areca-associated oral squamous cell carcinoma (OSCC) (n = 192), oral submucosal fibrosis (OSF) (n = 73), and non-diseased areca users (n = 191). The PCR-based restriction fragment length polymorphism analysis was performed for MMP-9 genotyping. MMP-9 -1562 C&amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T polymorphism was not associated with the risk of OSCC or OSF. However, when subjects were stratified by the median age, an association with the risk of OSCC was found in younger patients (P = 0.029). The T allele frequency was significantly higher in the subset of older patients with buccal mucosa OSCC than older patients with OSCC in counterpart locations. The joint MMP-9 -1562 C&amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T and MMP-3 -1171 5A&amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;6A functional polymorphisms were not associated with OSCC risk or patient survival. Aberrant MMP-9 expression is closely related to tumor invasiveness and the prognosis of head and neck cancers. However, functional MMP-9 -1562 C&amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;T polymorphism is associated with OSCC risk only in younger areca chewers. The impact of aging or areca-related effect on this functional polymorphism should be elucidated.

The location of oral leukoplakia correlates strongly with the probability of finding dysplastic or malignant alterations at biopsy. It is well established that early detection can dramatically improve the 5-year survival rates for oral squamous cell carcinomas. Since aneuploidy is predictive of future conversion to malignancy, we hypothesized that dysplastic lesions from high-risk sites (floor of mouth, tongue and lips)

Aims: In light of recently found contribution of angiogenic and inflammation-related factors to malignancies, this study investigated the possible association of interleukin-8 gene (IL-8) to increased risk of oral cancer. Methods: The IL-8 (À251A/T) polymorphism, which influences IL-8 gene expression, was evaluated by restriction fragment length polymorphism analysis in DNA samples of 158 German and Greek patients with oral squamous cell carcinoma and 156 healthy controls of equivalent sex, ethnicity and age. Results: Significant increase of mutant (A-251) allele, which results in higher IL-8 gene expression, was observed in all patients in comparison to normal controls (P < 0.001). The A/T heterozygotes had a two-fold greater risk (odds ratio 1.76, CI 1.11e2.79) for developing oral cancer compared to normal TT homozygotes. Furthermore, significantly increased values of mutant allele frequencies compared to controls were observed in all patients as well as in subgroups of patients with or without positive history of cancer (P < 0.05 and P < 0.001, respectively) and with or without positive history of thrombophilia (P < 0.05 and P < 0.001, respectively). Conclusions: In light to known observations of elevated plasma levels of IL-8 in several types of cancer including oral squamous cell carcinoma, the findings of this study suggest that the mutant allele of the (À251A/T) polymorphism may be a major contributing genetic factor to risk for oral cancer.

Oral submucous fibrosis (OSF) is a precancerous condition of the oral cavity and oropharynx and a significant number of such cases transform into oral squamous cell carcinoma (OSCC). Presently, diagnosis of OSF is done mainly through qualitative histopathological techniques and in the level of diagnostic molecular biology no specific genetic marker is evident. Keeping these facts in mind this study evaluates histopathological changes in the epithelium and subepithelial connective tissue of OSF through quantitative digital image analysis in respect to specific candidate features and analyses null mutations in the GSTM1 and GSTT1 by PCR amplification. The analysis revealed that there are subtle quantitative differences in the histological images of OSF compared to NOM. The thickness of the epithelium and cell population in its different zones, radius of curvature of rete-ridges and connective tissue papillae were decreased but length of rete-ridges and connective tissue papillae, fibrocity and the number of cellular components (predominantly inflammatory cells) in the subepithelial connective tissue were increased in OSF. The PCR study revealed that there is no significant difference in the allelic variants in GSTM1 between OSF and normal, while GSTT1 null gene showed significantly higher frequencies in this precancerous condition. This study establishes a distinct quantitative difference between normal oral mucosa (NOM) and OSF in respect to their histological features and GST null gene frequencies.

Oral squamous cell carcinoma (OSCC) is common in many Asian countries. The immunopathogenesis of OSCC is unclear. The authors analyzed the lymphocyte subtypes and surface activation markers in healthy Taiwanese people (n = 130) and patients with OSCC (n = 97)/oral leukoplakia (OL, n = 28) using flow cytometry. Univariate analysis found an elevation in the percentage of CD56+ NK cells, CD4+/CD69+ T cells, CD19+/CD69+ B cells and CD56+/CD69+ NK cells in OSCC patients relative to healthy people. The CD19+ and CD19+/CD25+ lymphocyte subtypes decreased in OSCC patients. CD56+ NK cells increased in OL patients. CD56+/CD69+ NK cells were elevated in recurrent and advanced OSCC. Multivariate analysis revealed an increase in CD56+ NK and CD19+/CD69+ cells in OL patients relative to controls. CD19+ B cells declined during progression from OL to OSCC. Betel quid chewing, alcohol, smoking, tumour location and staging showed little effect on lymphocyte subtypes. These results suggest that alterations and activation of NK cells, T and B cells are important and associated with disease status in oral carcinogenesis.