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Detection of squamous cell cancer and pre-cancerous lesions by imaging of tissue autofluorescence in the hamster cheek pouch model.

Early detection of invasive and pre-invasive neoplasms of the aerodigestive tract will ultimately improve the management of patients with these lesions. This paper describes the use of quantitative fluorescence imaging of early squamous cell carcinomas in an animal model. Dysplasia, carcinoma in situ and invasive cancers were imaged exploiting tumour autofluorescence. Mapped biopsies were obtained from areas imaged determining a sensitivity of 100% and specificity of 80%. Autofluorescence imaging is an excellent method of detecting neoplasms of the aerodigestive tract.

9,10-Dimethyl-1,2-benzanthracene↗

Oral cancer inhibition by micronutrients. The experimental basis for clinical trials.

Extensive research has been carried out in experimental animals to demonstrate the anticancer activity of retinoids, carotenoids and tocopherol on oral cancer and oral precancerous leukoplakia. The anticancer properties of these micronutrients have been studied in experiments dealing with inhibition of carcinogenesis, prevention of oral cancer development and regression of established oral carcinoma. Synergism has been demonstrated in the anticancer activity of beta carotene and alpha tocopherol. Synergism has also been demonstrated between beta carotene and anticancer alkylating agents such as melphalan and cyclophosphamide. Micronutrients such as beta carotene have been found to inhibit both major phases of carcinogenesis--initiation and promotion. Animal studies of oral cancer inhibition, prevention and regression have been substantiated by tissue culture studies, using animal and human derived oral cancer cell lines and normal epithelial cells. Mechanisms of the anticancer activity of the micronutrients on experimental oral cancer have been explored. They include stimulation of elements of the immune system to kill cancer cells, and enhanced expression of heat-shock proteins and repressor genes such as P 53.

Animals↗

A clinicopathological and immunohistochemical analysis of primary oral mucosal melanoma.

Nine cases of primary oral mucosal melanoma in Caucasian patients were reviewed and the tumours analysed for expression of S100, HMB45, NKI/C3, HLA-DR, PCNA, cytokeratin and von Willebrand factor. The clinical, histopathological and immunohistochemical features were quite distinctive and our findings support previous suggestions that oral melanoma should be classified as a separate entity rather than as a sub-type of cutaneous melanoma.

Adult↗

Expression of human cytokeratin 14 in normal, premalignant and malignant oral tissue following isolation by plaque differential hybridisation.

Differences in gene transcription between RNA samples extracted from oral normal and squamous cell carcinoma (SCC) tissue were examined using the technique of cDNA library differential plaque screening. A differentially expressed transcript was selected on the basis of it being under-expressed in the cancer tissue and was identified, using DNA sequencing, as cytokeratin 14. The level of cytokeratin 14 transcription in RNA samples extracted from a range of oral SCC and normal tissue, as well as "white patch" lesions, was then investigated. Cytokeratin 14 appeared to be significantly under-expressed in oral cancer specimens studied compared to normal and white-patch tissue (P < 0.01). The trend for higher levels of cytokeratin 14 transcription in the dysplastic "white patch" samples compared to that observed for the malignant tissue (P < 0.05) suggests that the decrease in cytokeratin 14 transcription is a late event in the carcinogenic pathway.

Adolescent↗

Prognosis in mouth cancer: tumour factors.

524 patients with histologically proven squamous cell carcinoma of the oral cavity who were previously untreated are studied for prognostic factors. There were various associations between T stage and site; T2 being more common in buccal cancer, T1 in tongue cancer, T4 in floor of mouth tumours and T2 in the roof of the mouth. Floor of mouth cancer tended to be more frequently associated with positive cervical lymph nodes than were other sites (45%). Well-differentiated tumours tended not to be associated with nodal disease (66%). Small tumours tended not to be associated with nodal metastases whereas large ones were. Univariate analysis of observed survival showed that well differentiated tumours had a slightly better survival than poorly-differentiated tumours (a difference of 8%). Survival fell with increasing T stage and with increasing pT stage. Positive resection margins and advanced pT stage in particular had a dismal prognosis. Survival also fell with increasing N stage and with increasing pathological N stage and extranodal rupture adversely affected prognosis. When the data were analysed by Cox's multivariate regression only two factors were found to be significant. These were T stage and N stage. Both were highly significant predictors of survival; survival falling with increasing stage.

Aged↗

Intermediate filaments in oral neoplasia. I. Oral cancer and epithelial dysplasia.

The major value of intermediate filaments (IFs) in biological and applied research lies in their high order of cell and tissue specificity. This is particularly well illustrated in keratin (K) expression in various oral epithelia. Although the original class of IF is usually conserved in tissues after neoplastic transformation, epithelia show a tendency to shift their pattern of keratin expression in a manner which, while not predictable with precision, may sometimes be of diagnostic or prognostic significance. This review compares the keratins in normal oral epithelia, which show a mainly site-dependent expression, with those in squamous cell carcinoma. Key changes in the latter are the presence of simple epithelial keratins, K8 and K18 (occasional K7), reduced expression of differentiation-linked keratins (K1, K10, K4 and K13) and a tendency for down-regulation of primary keratins, K5 and K14. Moderate and severe dysplasias also tend to exhibit K8 and K18 with concomitant disordered expression of differentiation-linked keratins. There are reports of similar changes after neoplastic transformation in other mucosal sites and skin. Before this information can be applied diagnostically in immunocytochemical studies, the anti-keratin antibodies must be fully characterised and their interaction with the relevant tissue, both frozen and conventionally processed, should be evaluated.

Carcinoma, Squamous Cell↗

PCNA and p53.

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Humans↗

Alcohol and oral cancer.

Alcohol, particularly when associated with tobacco use, has been recognized as an important risk factor for mouth cancer for almost 50 years. Together, they are associated with approximately 75% of upper aerodigestive tract cancers. However, intake of alcohol remains high in many countries. The rising incidence of oral cancer has prompted a revaluation of the role of alcohol (both alone and in partnership with other etiologic agents). In this article, the potential role of alcohol in the development of oral cancer is reviewed. In particular, the effect of alcohol on cellular structure and function is considered by reference to histologic and exfoliative cytologic studies of the oral epithelia. Alcohol may influence the proliferative cells by both intracellular (e.g., endocytosis) and intercellular (permeability) pathways. The carcinogenic exposure of the proliferating stem cells in the basal layer may be regulated through these pathways. Individual variation might help explain why oral cancer arises in some, but not in most, people who smoke and consume excess alcohol. Despite this finding, alcohol is strongly associated with the development of oral cancer and other upper aerodigestive tract cancers. Efforts to reduce this burden on the individual and society must be directed toward patient and professional education and research regarding (genetic) susceptibility.

Alcohol Drinking↗

Aromatase expression in normal human oral keratinocytes and oral squamous cell carcinoma.

UNLABELLED: Aromatase is the enzyme that catalyzes the conversion of androgen to oestrogen. Aromatase expression in extra-gonadal sites and local oestrogen synthesis play an important role in the physiological conditions and in the growth of certain neoplasms. OBJECTIVE: The purpose of this study was to investigate aromatase expression in oral keratinocytes and oral squamous cell carcinoma (SCC). DESIGN: Immunocytochemistry and RT-nested PCR were used to detect aromatase protein and mRNA expression in primary human oral epithelial cell culture and in an oral SCC cell line. Immunohistochemistry was used to detect aromatase protein expression in frozen and archival human tissue sections of normal oral epithelium and oral SCC. RESULTS: Cytoplasmic immunostaining was found in normal oral keratinocytes and SCC cells in culture. The common coding region of aromatase mRNA was detected in the oral keratinocytes derived from five different normal individuals and in the SCC cell line. However, there were variations in aromatase exon 1 expression among normal oral keratinocyte samples. Cytoplasmic staining was found in normal oral epithelium and well-differentiated oral SCC but not in poorly differentiated oral SCC by immunohistochemistry. CONCLUSION: Aromatase was expressed in normal oral keratinocytes and oral SCC both in cell culture and in tissues, indicating local oestrogen synthesis in normal and neoplastic conditions of oral epithelium.

Aged↗

Homogeneous boron targeting of heterogeneous tumors for boron neutron capture therapy (BNCT): chemical analyses in the hamster cheek pouch oral cancer model.

OBJECTIVE: BNCT is a tumour cell targeted radiation therapy. Uniform targeting of heterogeneous tumours with therapeutically effective boron carriers would contribute to a therapeutic effect on all tumour cell populations and avoid radioresistant fractions. This remains an unresolved challenge. The aim of the present study was to evaluate the degree of variation in boron content delivered by boronophenylalanine (BPA), GB-10 (Na(2)(10)B(10)H(10)) and the combined administration of (BPA+GB-10) in different portions of tumour, precancerous tissue around tumour and normal pouch tissue in the hamster cheek pouch oral cancer model. MATERIALS AND METHODS: Samples of different areas of tumour, precancerous tissue and normal pouch tissue were taken from tumour-bearing hamsters, 3h post-administration of i.p. BPA (15.5mg B/kg b.w.), or i.v. GB-10 (50mg B/kg b.w.), or 3h and 1.5h post-administration respectively of i.v. GB-10 (34.5mg B/b.w.) and sequential i.p. injections of BPA (total dose 31mg B/kg b.w.) given jointly. Boron content was evaluated by inductively coupled plasma optical emission spectroscopy (ICP-OES). The degree of homogeneity in boron targeting was assessed in terms of the coefficient of variation (V: [S.D./mean]x100) of boron values. Statistical analysis of the results was performed by one-way ANOVA and the least significant difference test. RESULTS: GB-10 and GB-10 plus BPA achieved respectively a statistically significant 1.8- and 3.3-fold increase in targeting homogeneity over BPA. CONCLUSIONS: The combined boron compound administration protocol contributes to homogeneous targeting of heterogeneous tumours and would be expected to increase therapeutic efficacy of BNCT.

9,10-Dimethyl-1,2-benzanthracene↗

Solitary mucosal neuroma of the hard palate: a case report.

Mucosal neuroma is rare neurogenic tumour that arises in the oral cavity as a component of multiple endocrine neoplasia type 2b (MEN 2b). We present the case of a histologically confirmed solitary mucosal neuroma of the hard palate in a 49-year-old woman with no other components of MEN 2b.

Female↗

Extraction of RNA from archival tissues and measurement of thrombospondin-1 mRNA in normal, dysplastic, and malignant oral tissues.

Thrombospondin-1 (TSP-1) is an extracellular matrix glycoprotein implicated in the regulation of angiogenesis and tumour development. Our objectives were to ascertain the quantity and quality of RNA extracted from archival, formalin-fixed, paraffin embedded, oral tissues and their application in measuring the concentrations of TSP-1 mRNA in these tissues. We compared three techniques of isolation of RNA as well as related experimental variables. TSP-1 mRNA was measured in specimens of normal, dysplastic, and malignant oral tissues by real-time reverse transcriptase polymerase chain reaction (RT-PCR). RNA suitable for analysis by real-time RT-PCR was obtained by the three techniques tested, although the yield varied depending on the protocol used (range 0.2-3.6 microg/mm(3)). The mean (S.D.) concentrations of TSP-1 mRNA relative to 18S were 21.1 (7.2) in normal oral tissues (n=9), 11.0 (8.2) in dysplastic tissue (n=8) and 7.3 (5.3) in carcinomatous tissue (n=17). The difference between normal and carcinomatous specimens was significant (p=0.01). This reduction in expression of TSP-1 mRNA from normal to dysplasia to carcinoma may favour the angiogenic drive that accompanies the development of oral tumours.

Carcinoma, Squamous Cell↗

The matrix metalloproteinase system in oral squamous cell carcinoma.

BACKGROUND: The matrix metalloproteinase (MMP) system is responsible for degradation of tissue in both normal and pathological processes, including tumour invasion and metastasis. AIM: To compare tissue concentrations of components of the MMP system between tumour tissue and normal tissue in patients with oral squamous cell carcinoma, and to correlate concentrations with pathological grade of tumour. METHODS: Thirty-eight paired tissue samples from tumours and normal tissue were analysed by three laboratory techniques: firstly, enzyme linked immunosorbent assays (ELISA) in ng/mg protein for MMP-1, MMP-3, and tissue inhibitors of metalloproteinases (TIMPs) -1 and -2. Secondly, gelatinase activity assays to measure concentrations of total and endogenous active gelatinases, MMP-2 and MMP-9 (ng/mg protein). And thirdly to use quenched fluorescent substrate hydrolysis to measure total MMP activity (pM/min). RESULTS: The concentration of all MMPs was significantly higher in tumour than in normal oral tissue (p < 0.05, Mann-Whitney U-test). Tissue concentrations of some of these factors correlated with clinical and pathological indices of aggressiveness of tumours, including T-stage, N-stage, tumour differentiation, and anatomical level of involved nodes. However, the study was not powered to show statistical significance. CONCLUSION: It is the balance between proteinases and their inhibitors that controls tissue degradation at each stage of tumour invasion and metastasis. Measurement of MMPs in oral mucosal biopsy samples may establish the invasive potential of tumours at their initial presentation.

Adolescent↗

Reconstruction of intraoral defects using facial artery musculomucosal flap.

The facial artery musculomucosal flap, technically a combination of the nasolabial flap and the buccal mucosal flap, has been a reliable, versatile flap, either superiorly or inferiorly based for reconstruction of a wide variety of postcancer excision intraoral mucosal defects including defects of the palate, alveolus, lips and floor of mouth. We have used it 17 times in 16 patients with no failures and one flap with terminal necrosis. Almost all flaps developed venous congestion which settled on its own by conservative management.

Adolescent↗

Frequent allelic imbalances at 8p and 11q22 in oral and oropharyngeal epithelial dysplastic lesions.

Allelic imbalance is characteristic of oral squamous cell carcinoma (SCC) and contributes to the tumorigenesis of this disease. Our previous studies suggest that chromosome regions 8p and 11q22.2 approximately q22.3 are frequent sites of loss of heterozygosity (LOH) in head and neck SCC. Here, we explored the allelic imbalance pattern of these regions in 27 cases of oral epithelial dysplastic lesions. A previously reported frequent LOH (9p21) in head and neck dysplasia was also examined. Laser capture microdissection (LCM) technology was utilized to harvest homogenous cell populations from archived clinical tissues and thus greatly enhancing the sensitivity, accuracy and reliability of genetic assessment. The allelic imbalance (LOH and microsatellite instability) on 8p, 11q22.2 approximately q22.3, and 9p21 were observed at one or more loci in 66.7%, 63.0%, and 63.0% of cases, respectively. Our results demonstrate that 8p, 11q22.2 approximately q22.3, and 9p21 are frequent allelic imbalance regions in oral premalignant dysplasia and suggest the presence of tumor suppressor genes in these regions.

Adult↗

Laser assisted topical 'biofilm' chemoprevention of oral cancer.

This study examines whether a combination of laser microvascular targeting, mucosal adhesive film (MAF) and retinoic acid (RA) techniques would improve the efficacy for oral cancer chemoprevention. The cheek pouches of 48 hamsters were painted with 7,12-dimethlbenz[a]nthrancene to produce premalignant lesions. There were four groups of 12 each: (1) control; (2) pulsed dye laser (PDL) treatment; (3) topical MAF/RA patch treatment; and (4) combined treatment of PDL and MAF/RA. The treatments were conducted for 27 days. Our findings indicate that this new combined treatment is safe and effective for oral cancer chemoprevention, and warrants further study.

9,10-Dimethyl-1,2-benzanthracene↗

The repressive effect of green tea ingredients on amyloid precursor protein (APP) expression in oral carcinoma cells in vitro and in vivo.

In a hamster model of N-methyl-N-benzylnitrosamine (MBN)-induced oral carcinogenesis, the incidence of buccal pouch (HBP) carcinomas in MBN-treated hamsters (17.8+/-7.5) was significantly higher than MBN-treated hamsters given tea (10.8+/-3.9) (P<0.05). Amyloid precursor protein (APP) expression was also significantly increased in MBN-induced HBP carcinomas but was significantly reduced by tea intake (P<0.0001). Furthermore, APP expression and secretion by OECM-1 oral squamous cell carcinoma cells was inhibited by a major polyphenolic ingredient of green tea, (-)-epigallocatechin gallate, in a dose-dependent manner. Thus, APP might promote oral carcinogenesis, whereas green tea ingredients might diminish it by down-regulating APP.

Amyloid beta-Protein Precursor↗