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We describe a case with severely compromised edentulous ridge in the mandible, which previously received marginal resection and radiotherapy due to oral cancer at the mouth floor. Through careful evaluation, the patient had 30 dives of hyperbaric oxygen therapy (HBO) before implant surgery. The edentulous ridge was rehabilitated with 4 endosteal implant fixtures, and palatal mucosa grafting vestibulosulcoplasty. The case had been followed for 4 years with stability of bone and a satisfactory result of rehabilitation.

To identify molecular events involved in the pathogenesis of oral squamous cell carcinoma (OSCC), genes differentially expressed in OSCC and non-cancerous matched tissue (NCMT) samples were analysed using a subtractive hybridization strategy. NCMT-enriching clones that have been linked to suppressor pathway in previous studies were subjected to advanced analyses. Complete absence of insulin-like growth factor binding protein-5 (IGFBP-5) expression at both the mRNA and the protein level was identified in nearly all (5/6) OSCC cell lines with the exception of the SCC25 cell line, which exhibited high IGFBP-5 expression. However, this protein is consistently present in cultured normal human oral keratinocytes (NHOKs). Immunohistochemistry revealed moderate to strong cytoplasmic immunoreactivity of IGFBP-5 in the stratum spinosum and stratum granulosum in the vast majority of NCMT samples. A remarkable reduction in IGFBP-5 immunoreactivity was detected in 56% (26/46) of OSCC samples, compared with the corresponding NCMT (p < 0.0001). Induction of differentiation in both NHOKs and SCC25 up-regulated IGFBP-5 expression. Administration of a green tea compound with anti-cancer properties, (-)-epigallocatechin 3-gallate, at a concentration of 5-20 micro g/ml also up-regulated IGFBP-5 expression in NHOKs in a dose-dependent manner. The findings suggest that IGFBP-5 may be an important factor in the differentiation of oral keratinocytes and that down-regulation of IGFBP-5 may be involved in the neoplastic transformation of oral keratinocytes.

The importance of the CYP1A1 polymorphisms at exon 7 (Ile/Val) and 3'-untranslated region (3'-UTR) has been controversial in oral squamous cell carcinoma (OSCC) or head and neck SCC (HNSCC) denoting the value of exploring the correlation between these polymorphisms and risk of betel/smoking associated OSCC. It is also important to evaluate the association between CYP1A1 polymorphisms and susceptibility of oral precancerous lesion (OPL) to confirm the findings in OSCC cases.We examined polymorphic prevalence of CYP1A1 at exon 7 (Ile/Val) and 3'-UTR in 106 cases with OSCC, 60 cases with OPL, and 146 controls. DNA isolated from surgical specimens and whole blood was used for PCR-based genotyping.The prevalence of the CYP1A1 A/G genotype (Ile/Val) and G/G genotype (Val/Val) in exon 7 of cases with OSCC (79.2 and 7.6%) and OPL (68.3 and 10%) were significantly higher than in controls (53.4 and 1.4%) (P0.0001). The novelty of the present study is that we identified the onset age of OSCC in CYP1A1 A/G genotype to be significantly younger than that in A/A genotype (P0.01). No significant difference was seen between cases and controls regarding the polymorphisms at 3'-UTR.The findings indicate that the individuals with the CYP1A1 exon 7 containing G allele were at increased risk for OSCC and OPL.

Within the abundant retinoids nuclear receptors, abnormally low expression of the RAR-beta has been shown to contribute to neoplastic progression in oral epithelium in western countries. Distinctly different risk factors contributing to oral squamous cell carcinoma (OSCC) in epidemiologically different societies denote the value of exploring the role of RAR-beta expression in OSCC associated with betel quid (BQ) use in our society.We examined the cellular expression of RAR-beta using in situ hybridization (ISH) analysis on 38 pairs of surgical specimens of primary OSCC and non-cancerous matched tissues (NCMT) to correlate with their clinico-pathological features including age, sites of tumor, habit of BQ use, stage, size of primary tumor, lymph node metastasis, differentiation.Of all cases analyzed, BQ users were significantly younger than non-BQ users (51.2 +/- 2.1 vs. 60.2 +/- 2.6, P = 0.01). 52% OSCC of BQ users (13/25) and 23% OSCC of non-BQ users (3/13) exhibited the absence of RAR-beta expression. In 17 paired-samples from buccal mucosa (BM), most NCMT and less than half of OSCC exhibited RAR-beta expression (16/17, 94% vs. 8/17, 47%, P = 0.003). The RAR-beta expression was seen in the vast majority of the well-differentiated OSCC and in less than half of the moderately differentiated OSCC only (15/20, 75% vs. 7/18, 39%, P = 0.03).A correlation between the loss of RAR-beta expression and more advanced histopathological grade tumors was observed. This study also suggests that the loss of RAR-beta expression is significant in BM OSCC, which preferentially occurs in BQ users.

We report a rare case of papillary carcinoma in the tongue and floor of the mouth with metastasis in cervical lymph nodes. Treatment was by total thyroidectomy with right radical lymph node dissection of the neck, followed by 60 Gy of radiotherapy and 100 mCi (131)I. Pathological examination of the thyroid gland showed no primary cancer. We review publications about ectopic thyroid and the value of antithyroglobulin immunostaining for diagnosis and treatment of the tumour.

To investigate the chromosomal imbalances that occur in oral carcinoma associated primarily with betel use and their clinical implications, we performed chromosomal analysis using comparative genomic hybridization on 47 patients with this disease. The most common gains of chromosome arms were 8q, 9q and 11q, and the most frequent losses were of chromosomal arms 3p and 4q. The clinical parameters significantly associated with the numbers of chromosomal imbalances per tumor were the age of the patients and nodal metastasis. The preliminary findings of a lower incidence of loss of 4q and gain of 8q in betel-associated tumors compared to non-betel-associated tumors might provide insight into the carcinogenic effect of betel. Deletion of 3p and the gain of 11q alterations were more prevalent in carcinomas with lymph node metastasis than in node-negative tumors, indicating possible loci for metastasis suppressor or metastasis enhancing genes, respectively. Losses of 3p and 4q and gain of 9q were associated with poor outcome for the patients. These data demonstrated that the frequent aberrations in 4q and 9q sites can be used as novel prognostic predictors.

Oral squamous cell carcinoma (OSCC) is one of the most prevalent carcinomas worldwide. MicroRNAs (miRNAs) are short, non-coding RNAs that regulate gene expression and modulate physiological or pathological processes including OSCC carcinogenesis. miR-31 has been found to be up-regulated in OSCC and to act as an oncogenic miRNA. However, the molecular mechanism underlying miR-31 up-regulation in OSCC is still obscure. The activation of epidermal growth factor receptor (EGFR) signaling axis plays key roles in driving oral carcinogenesis. Our screening identified that there is up-regulation of miR-31, miR-181b and miR-222 in OSCC cells following EGF treatment. Subsequent analysis showed that EGF treatment led to AKT activation, which then resulted in miR-31 up-regulation. Moreover, EGF treatment and the AKT activation induced by exogenous expression up-regulated C/EBPβ expression. The miR-31 up-regulation induced by EGF was abrogated by AKT inhibition or by the knockdown of C/EBPβ expression. In OSCC cell subclones stably overexpressing the functional isoform of C/EBPβ, miR-31 expression was up-regulated. Curcumin is a natural ingredient exhibiting anti-cancer potential. It was found that curcumin attenuated AKT activation and the up-regulation of C/EBPβ and miR-31 caused by EGF stimulation in OSCC cells. Lastly, concordance across the expression of EGFR, the expression of C/EBPβ and the expression of miR-31 in OSCC tissues was found. This study describes a novel scenario where the up-regulation of miR-31 expression in OSCC is, at least in part, a consequence of EGFR oncogenic activation. Although the AKT activation and C/EBPβ expression after EGF treatment might not be directly linked, both events are the crucial mediators underlying miR-31 up-regulation in the EGFR signaling axis.

Oral melanomas are extremely rare, representing less than 2% of all reported melanomas. They are known to have a high potential for malignancy, invasiveness, and metastasis.1,2 Although melanoma in the oral cavity sometimes tends to be neglected more than similar lesions on the skin and other locations, pigmented melanoma is usually easy to diagnose clinically because of its red to black or brown color and its irregular outline.1 However, amelanotic melanoma (AM), with lack of pigmentation, often defies correct clinical diagnosis initially before confirmation by biopsy.3 We present a case of AM of the left maxilla.

MicroRNAs (miRNAs) play important roles in modulating the neoplastic process of cancers including head and neck squamous cell carcinoma (HNSCC). Purpose A genetic polymorphism (rs2292832, C > T) has been recently identified in the precursor of miR-149; nevertheless its clinicopathological implications remain obscure. Material and methods 273 HNSCC patients and 122 healthy controls were enrolled for genotyping analysis and HNSCC cell lines including SAS, OECM-1, FaDu were chosen for phenotypic assay regarding to miR-149 expression. Results We showed that miR-149 is down-regulated in HNSCC compared to normal mucosa and this is associated with a poorer patient survival. In addition, HNSCC patients with the T/T genotype have more advanced tumors and a worse prognosis. Multivariate analysis indicated that patients carried the T/T genotype have a 2.81-fold (95% CI: 1.58–4.97) increased risk of nodal metastasis and 1.66-fold (95% CI: 1.05–2.60) increased risk of mortality compared to other groups. T/T genotype also predicted the worse prognosis of buccal mucosa carcinoma subset of HNSCC. In vitro analysis indicated that exogenous miR-149 expression reduces the migration of HNSCC cells. Moreover, HNSCC cell subclones carrying the pri-mir-149 sequence containing the T variant show a low processing efficacy when converting the pre-mir-149 to mature miR-149. Conclusions These findings suggest that miR-149 suppresses tumor cell mobility, and that the pre-mir-149 polymorphism may affect the processing of miR-149, resulting in a change in the abundance of the mature form miRNA, which, in turn, modulates tumor progression and patient survival.

Mammalian target of rapamycin (mTOR) is an important regulator of protein translation, biosynthesis, cell growth and cell proliferation, is over-activated in various human malignancies, but very few studies have yet to explore the mTOR activity in oral squamous cell carcinoma (OSCC), which is the 7th leading death of malignancy in Taiwan. We collect tissue samples of 58 OSCC patients from Taipei veteran general hospital during along with their clinical parameters. Immunohistochemical (IHC) staining was performed on the tissues for investigating active mTOR (p-mTOR) expression level with the use of tissue microarray (TMA) technique. The results revealed p-mTOR expression level in OSCC tissues are significantly higher than in normal oral mucosal tissues ( p p = 0.0391) and higher tumor recurrence after adjuvant cisplantin treatment ( p = 0.0159). Although positive group shows a relatively rapid descent on survival curves, no significant difference between positive and negative group in over-all survival rate ( p = 0.1064), cancer specific survival rate ( p = 0.0914) and disease free survival rate ( p = 0.0509). p-mTOR expression level in OSCC correlates to tumor recurrence, possible poorer survival rate and may even associate with cisplantin resistance in our study. A scale-up study in the future may further elucidate the role of mTOR in OSCC.

We present a case of odontogenic carcinoma with ghost-cell keratinization of the right maxilla, with a history of 23 years after initial treatment. Within this period, multiple local recurrence, as well as metastasis to axilla, brain, and lung, was noted. Several attempts at resection of the primary lesion were unsuccessful at achieving local control, even when supplemented with chemotherapy and radiotherapy. Metastatic tumors were studied histologically, and their morphology coincided with that of the primary tumor. The medical history of the patient and pathologic findings of the tumor are reviewed.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer in the world, and is highly mortal due to tumor recurrence and metastasis. Invasion of tumor cells into lymph nodes is one of the characters of regional metastasis and DNA hypermethylation is characterized in all types of human cancers. We therefore assessed whether epigenetic modification of DNA methylation is correlated to HNSCC metastasis, and evaluated the potential clinical implications of DNA methylation-based biomarker. Methylation array (Illumina infinium beadsarray) was applied to profile aberrant methylated CpG loci in HNSCC with lymph node invasiveness. Fourteen HNSCC tumors and two normal oral tissues were included. ≤ value, the indicator of methylation status of each tested CpG locus, was derived with normalization. A cluster of 111 CpG loci was selected based on the difference between the mean ≤ value of HNSCC tumors with and without regional metastasis (Δβmetz minus non-metz ≥ 0.2 or ≤ −0.2). Hierarchical diagram revealed distinct methylation signature was observed between tumors with or without regional metastasis. Ingenuity pathway analysis showed that the major diseases associated were neurological disorder and endocrine system disorder; and the top canonical pathway was Huntington's disease signaling. Of the top aberrant hypermethylated alleles, p16 and brain-derived neurotrophic factor (BDNF) were selected for further investigation on clinical implication. The methylation status of p16 (n=107) and BDNF (n=88) in HNSCC tumors was assayed by methylation-specific PCR. The primer sequences of both alleles were adopted from published report. Statistic analysis (t-test, χ2 or Fisher's exact, logistic regress, Kaplan-Meier survival, and Cox regression) was performed using SPSS. Hypermethylation of p16 or BDNF were not associated with stage, metastasis at diagnosis, and differentiation. Hypermethylation of p16 was significantly associated with age (p=0.008, t-test) and lymph node invasion (p=0.021, χ2-test), in contrast to distant metastasis of follow-up (p=0.061, χ2-test). However, hypermethylation of BDNF was associated with distant metastasis of follow-up (odds ratio: 4.96, 95% CI: 1.28-18.87, p=0.002), and combination with p16 improved the prediction (odds ratio: 10.31, 95% CI: 1.68-62.5, p=0.012). Hypermethylation of BDNF was associated with poor survival of patients (odds ratio: 2.80, 95% CI: 1.17-6.71, p=0.021), and hypermethylation of both alleles increased the risk (odds ratio: 3.81, 95% CI: 1.71-8.49, p=0.001). Together, our data suggest hypermethylation of p16 and BDNF may be potential biomarker associate with poor prognosis of HNSCC. The results also show the association of p16 and BDNF in gain of metastatic properties, which warrants further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4038. doi:1538-7445.AM2012-4038

Background: Oral squamous cell carcinoma (OSCC) is the sixth common cancer and is highly mortal due to tumor recurrence and metastasis. Invasion of tumor cells into lymph nodes is one of the characters of regional metastasis. Here we assessed whether epigenetic modification of DNA methylation is correlated to OSCC regional metastasis and evaluated the potential clinical implications of DNA methylation-based biomarker. Methods: A case-control study of OSCC patients with lymph node invasion (N=8), OSCC patients without lymph node invasion (N=6), and normal oral tissues (N=2) was performed. To characterize aberrant DNA methylation in OSCC tumors with regional metastasis at diagnosis, Illumina infinium beadsarrays containing 27,578 CpG loci which cover 14,475 genes were applied. The genomic DNA of test samples was individually bisulfite-converted and subjected to beadsarray analysis. β value, the indicator of methylation status of each tested CpG locus, was derived with proper normalization. Results: Methylation β values allocated tested tissues into regional metastatic tumor, non-metastatic tumor, and control groups. A cluster of 111 CpG loci was selected based on the difference between the mean β value of OSCC tumors with and without regional metastasis. There were 69 loci and 42 loci that were hypermethylated (Δβ value ≫ 0.2) and hypomethylated (Δβ value ≪ −0.2), respectively, in OSCC with regional metastasis. Differentially methylated genes appeared to be mainly related to organ development, cell death, cell signaling, behavior, nucleic acid metabolism, and molecular transport. Several genes were further investigated for their methylation statuses by genomic bisulfite sequencing and DNA methyltransferase inhibitor reactivation in oral carcinoma cell lines with or without invasiveness. Characterization the association of hypermethylation of metastatic-associated genes and clinical pathological variables, we found combination of the hypermethylation status of a candidate gene and p16INK4A improved the prediction of lymph node invasiveness (p=0.003) and survival rate (p=0.010). Our results show the feasibility of this beadsarray analysis to identify aberrant methylation of metastatic-associated genes in OSCC as well as potential risk assessment application. The cohort for the risk assessment assay will be increased and the biological activities of candidate genes in carcinogenesis will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 103. doi:10.1158/1538-7445.AM2011-103