Common benign and malignant oral mucosal disease.

BACKGROUND: Mucosal diseases of the oral cavity are relatively common, and patients often seek initial assessment from their general practitioner. OBJECTIVE: The aim of this article is to provide an overview of common oral mucosal diseases to help with formulating a differential diagnosis and stratifying the urgency of referral. DISCUSSION: Pathological mucosal conditions of the oral cavity and jaws commonly present as a mucosal ulcer or a white, red or pigmented lesion. In this review, the authors outline the most common conditions organised according to their clinical presentation and describe their typical appearance and management.

Matrix metalloproteinases MMP1, MMP2, MMP9 and their tissue inhibitors TIMP1, TIMP2, TIMP3 in head and neck cancer: an immunohistochemical study.

INTRODUCTION: Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes implicated in the invasion and metastasis of many kinds of cancer because of their ability to degrade components of extracellular matrix. Specific tissue inhibitors of matrix metalloproteinases (TIMPs) regulate their activity. MMPs and TIMPs were identified in many neoplasm, including cancers of head and neck, lung, breast and colon cancer. In most researches a strong relation between MMPs and TIMPs expression and a clinical course of disease was observed, although there were many discrepancies between the authors. The aim of this research was to evaluate the expression of MMP1, MMP2, MMP9 and TIMP1, TIMP2, TIMP3 in head and neck cancer and to investigate the prognostic impact of these factors in patients with these tumors. MATERIAL AND METHODS: 210 patients with head and neck cancer that underwent surgical treatment with at least a 5-year follow-up were included in the study. Immunohistochemical studies were performed on formalin fixed, paraffin embedded sections by using monoclonal antibodies against MMP1, MMP2, MMP9 and TIMP1, TIMP2, TIMP3 antigens and Dako EnVision detection system. RESULTS: For all of the markers diffusion, cytoplasmatic staining of tumor cells and some surrounding stromal cells was observed. There was a correlation between TIMP2 and TIMP3 overexpression and tumors staged as III/IV (p=0,037 and p=0,022, respectively). Also, we observed a strong association between MMP2 expression and the presence of nodal metastases (p=0,013). It was found that the TIMP2 overexpression was significantly more frequent in the tumors of patients facing nodal recurrences during the follow-up period (p=0,05). Positive immunostainings of MMP1, MMP2, MMP9 and TIMP1, TIMP2 were significantly related to the higher tumor grade (G3). Specially strong correlation was seen between high TIMP2 expression and low histological differentiation (G3) (p<0,001). In univariate analysis the overall survival rate was shorter in cases with positive MMP2 and/or MMP9 expression. Patients with TIMP2 positive expression diminished both overall and disease-free survival (p=0,049). In multivariate analysis positive TIMP2 and MMP2 expressions were independent prognostic factors for overall survival. Only advanced nodal metastatic tumors (N3) were related to disease free survival. CONCLUSIONS: Our data suggest the conclusion that imbalance between matrix metalloproteinases and their inhibitors play the important role in progression of head and neck cancer and patients' prognosis.

Predictive Effects of Lung function test on Postoperative Pneumonia in Squamous Esophageal Cancer.

Pulmonary function tests had prospective implications for postoperative pneumonia, which occurred frequently after esophagectomy. Understanding factors that were associated with pulmonary infection may help in patient selection and postoperative management. We performed a retrospective review of 2 independent cohorts including 216 patients who underwent esophagectomy between November 2011 and May 2014, aiming at identifying predictors of primary pneumonia. Univariate analysis was used to identify potential covariates for the development of primary pneumonia. Adjustments for multiple comparisons were made using False Discovery Rate (FDR) (Holm-Bonferroni method). Multivariable logistic regression analysis was used to identify independent predictors and construct a regression model based on a training cohort (n = 166) and then the regression model was validated using an independent cohort (n = 50). It showed that low PEF (hazard ratio 0.97, P = 0.009) was independent risk factors for the development of primary pneumonia in multivariate analyses and had a predictive effect for primary pneumonia (AUC = 0.691 and 0.851 for training and validation data set, respectively). Therefore, PEF has clinical value in predicting postoperative pneumonia after esophagectomy and it may serve as an indicator of preoperative lung function training.

A novel polysaccharide from Lentinus edodes Mycelia exhibits potential antitumor activity on laryngeal squamous cancer cell line Hep-2.

A novel polysaccharide [Lentinus edodes mycelia polysaccharide 2 (LMP2)] with a molecular weight of 2.27 × 10(4) Da was isolated from the Lentinus edodes mycelia and purified by Sephadex G-200 and diethylaminoethyl-32 column chromatography. HPLC results indicated that LMP2 contained mannose, arabinose, galactose, xylose, and rhamnose with a relative molar ratio of 1:0.74:3.23:1.18:10.98. Its antitumor activity was evaluated in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, and transwell assay. LMP2 showed a remarkable inhibitory effect on the proliferation of Hep-2 cells, and at the concentration of 200 mg/ml, the inhibition ratio was 37.2 % after 72 h. Furthermore, colony formation of Hep-2 cells was reduced significantly after treatment with LMP2. Invasion of Hep-2 cells was inhibited significantly by LMP2. These results suggested that LMP2 could be explored as a potential antitumor material for laryngeal carcinoma.

Receptor tyrosine kinase alterations and therapeutic opportunities in squamous cell carcinoma of the lung.

PURPOSE: Targeted therapy has greatly improved the treatment for adenocarcinoma of the lung, but not squamous cell carcinoma (SCC) of the lung. The current paper describes the abnormalities of receptor tyrosine kinases (RTK) in lung SCC in a hope to stimulate the development of therapeutics that can have clinical impact. METHODS: We reviewed both clinical and preclinical studies published in English regarding RTK abnormalities and/ or RTK-targeting treatment for SCC of the lung. RESULTS: RTK alterations have been demonstrated as biological signature for SCC of the lung. A number of clinical trials of RTK-targeting therapy have been carried out or are ongoing, with encouraging results. CONCLUSIONS: SCC of the lung should be treated as an independent disease with unique treatment options based on molecular changes, particularly RTK.

Monitoring microcirculatory alterations in oral squamous cell carcinoma following photodynamic therapy.

BACKGROUND: One of the mechanisms through which photodynamic therapy (PDT) is thought to elicit tumour destruction is by producing microvascular damage and obstruction of nutritive blood flow. The aim of this study was to directly monitor and quantify microcirculatory changes following tissue illumination by PDT for oral squamous cell carcinoma. METHODS: Ten consecutive patients receiving PDT for a carcinoma in situ, a T1 or T2 tumour in the oral cavity without evidence of lymph node metastasis were selected for this study. Tumour and marginal healthy mucosa total capillary density (TCD) and functional capillary density (FCD) inside the field of illumination were measured and compared using sidestream dark-field (SDF) imaging prior to tissue illumination, immediately after PDT, and again after 15min. RESULTS: Baseline mean tumour TCD was 21.2±5capillaries per square millimetres (cpll/mm²) and 24.9±19cpll/mm² in the surrounding marginal healthy tissue; there were no significant differences between tumour and healthy tissue or time points. Comparisons between baseline and post-illumination time points revealed significant differences in both tumour and healthy tissue FCD (P<0.05). No significant differences in FCD were observed between the two tissues. CONCLUSIONS: Our findings using SDF imaging demonstrate that PDT significantly attenuates tumour and marginal healthy tissue perfusion by directly disrupting the functionality of the microcirculation.

Cutaneous malignancy in adolescents.

There is compelling epidemiologic evidence that cutaneous malignancies, most notably malignant melanoma and cutaneous T-cell lymphoma, are increasing in incidence. The adolescent population is also affected by this rise in incidence, but can represent both a unique diagnostic and therapeutic challenge. Herein we present up-to-date epidemiology, clinical presentation, risk factors for development, and management options for malignant melanoma, basal cell carcinoma, squamous cell carcinoma, and cutaneous T-cell lymphoma as each pertains to the adolescent population. Prevention in this age group is particularly addressed. One unifying theme that emerges is that a high degree of clinical suspicion and vigilance must be maintained to recognize these entities early on in their presentations.

Nutrition management of patients with malignancies of the head and neck.

The importance of nutrition and the prognostic impact of malnutrition in patients with head and neck cancer are not fully appreciated in the surgical world where a pervasive attitude exists that weight loss during treatment is inevitable and nutritional expertise or intervention may be dismissed out of ignorance. In this article, the authors explore the nutritional requirements of these patients and the impact of a multidisciplinary therapeutic approach to head, neck, and skull base cancer care.

Prevalence and pattern of nodal metastasis in pT4 gingivobuccal cancers and its implications for treatment.

CONTEXT: The pattern of nodal spread in oral cancers is largely predictable and treatment of neck can be tailored with this knowledge. Most studies available on the pattern are from the western world and for early cancers of the tongue and floor of the mouth. AIMS: The present study was aimed to evaluate the prevalence and pattern of nodal metastasis in patients with pathologic T4 (pT4) buccal/alveolar cancers. SETTINGS AND DESIGN: Medical records of the patients with pT4 primary buccal and alveolar squamous cell carcinomas treated by single-stage resection of primary tumor and neck dissection at Gujarat Cancer and Research Institute (GCRI), Ahmedabad, a regional cancer center in India, during September 2004 to August 2006, were analyzed for nodal involvement. MATERIALS AND METHODS: The study included 127 patients with pT4 buccal/alveolar cancer. Data pertaining to clinical nodal status, histologic grade, pT and pN status (TNM classification of malignant tumors, UICC, 6th edition, 2002), total number of nodes removed, and those involved by tumor, and levels of nodal involvement were recorded. Statistical analysis was performed using the Chi-square test. RESULTS: Fifty percent of the patients did not have nodal metastasis on final histopathology. Occult metastasis rate was 23%. All of these occurred in levels I to III. Among those with clinically palpable nodes, level V involvement was seen only in 4% of the patients with pT4 buccal cancer and 3% of the patients with alveolar cancer. CONCLUSIONS: Elective treatment of the neck in the form of selective neck dissection of levels I to III is needed for T4 cancers of gingivobuccal complex due to a high rate of occult metastasis. Selected patients with clinically involved nodes could be well served by a selective neck dissection incorporating levels I to III or IV.

Progressive 3q amplification consistently targets SOX2 in preinvasive squamous lung cancer.

RATIONALE: Amplification of distal 3q is the most common genomic aberration in squamous lung cancer (SQC). SQC develops in a multistage progression from normal bronchial epithelium through dysplasia to invasive disease. Identifying the key driver events in the early pathogenesis of SQC will facilitate the search for predictive molecular biomarkers and the identification of novel molecular targets for chemoprevention and therapeutic strategies. For technical reasons, previous attempts to analyze 3q amplification in preinvasive lesions have focused on small numbers of predetermined candidate loci rather than an unbiased survey of copy-number variation. OBJECTIVES: To perform a detailed analysis of the 3q amplicon in bronchial dysplasia of different histological grades. METHODS: We use molecular copy-number counting (MCC) to analyze the structure of chromosome 3 in 19 preinvasive bronchial biopsy specimens from 15 patients and sequential biopsy specimens from 3 individuals. MEASUREMENTS AND MAIN RESULTS: We demonstrate that no low-grade lesions, but all high-grade lesions, have 3q amplification. None of seven low-grade lesions progressed clinically, whereas 8 of 10 patients with high-grade disease progressed to cancer. We identify a minimum commonly amplified region on chromosome 3 consisting of 17 genes, including 2 known oncogenes, SOX2 and PIK3CA. We confirm that both genes are amplified in all high-grade dysplastic lesions tested. We further demonstrate, in three individuals, that the clinical progression of high-grade preinvasive disease is associated with incremental amplification of SOX2, suggesting this promotes malignant progression. CONCLUSIONS: These findings demonstrate progressive 3q amplification in the evolution of preinvasive SQC and implicate SOX2 as a key target of this dynamic process.

CD151 dynamics in carcinoma-stroma interaction: integrin expression, adhesion strength and proteolytic activity.

A member of tetraspanin CD151 is a scaffold protein of laminin-binding integrins and it plays an important role in stable interaction between cells and basement membrane. Although the upregulation of CD151 in tumor cells is thought to accelerate tumor invasion and metastasis, detailed pathological investigation on CD151 and its association with integrins has not been well documented, yet. In the present study, we showed that the expression levels of CD151 and its associated integrin subunits in epidermal carcinoma cell HSC5 were higher than those in immortalized epidermal cell HaCaT. By the stimulation of epidermal growth factor, CD151 was dissociated from cell surface and dispersed in the cytoplasm, and alpha3beta1 integrin was concomitantly internalized. To understand the significance of CD151 in tumor cell dynamics, CD151 in HSC5 was knocked down (HSC5(CD151-)), and the expression of integrin subunits and matrix metalloproteinases (MMPs) were investigated. In HSC5(CD151-), striking morphological alteration on Matrigel and laminin, and cytoskeletal rearrangements were demonstrated. alpha3beta1 integrin was internalized in part, and alpha6beta4 integrin was re-distributed from basal site to cell periphery. Quantitative RT-PCR, Western blot and zymography revealed that the expression levels of MMP2, MMP7 and MMP9 were markedly downregulated in HSC5(CD151-). Immunoprecipitation assay demonstrated that MMP7 was co-immunoprecipitated with CD151. In double stainings, MMP7 was colocalized with CD151 at the leading edge of lamellipodia under migratory status. These results elucidated the importance of CD151 as one of the key molecules for integrin-dependent carcinoma-stroma interaction. It is indicated that CD151 might contribute not only to cell stabilization by associating with adhesion complexes but also to cell migration by inducing integrins re-localization and MMPs production.

Professional delay in head and neck cancer patients: analysis of the diagnostic pathway.

The aim of this study was to identify which factors are related to specialist delay and to determine the length of the diagnostic pathway in head and neck cancer patients. Three hundred and six patients with a carcinoma of the larynx, pharynx or oral cavity were included in the study. Logistic regression analysis was used to identify risk factors for specialist delay. Large (T3-T4) tumors showed significantly less specialist delay than small (T1-T2) tumors (p=0.045, odds ratio [OR]=0.6). Pharyngeal (p=0.00, OR=0.2) and oral carcinomas (p=0.00, OR=0.2) had less specialist delay than glottic carcinomas. Hoarseness was associated with prolonged specialist delay (p=0.00, OR=5.9). Heavy drinking in combination with smoking (p=0.005, OR=0.3), a sore throat (p=0.02, OR=0.4) or having a lesion (p=0.03, OR=0.2) showed a shorter diagnostic period. The duration of the diagnostic process in a general hospital ranged from 0 to 570 days, with a median of 14 days. Only a small group of patients met the ideal management standards in our head and neck clinic. Although prolonged delay was associated with small (glottic) tumors, the diagnostic process takes a fairly long time. The results indicate that continued educational programs for professionals are warranted.

The extracellular matrix in oral squamous cell carcinoma: friend or foe?

Oral squamous cell carcinoma is a disfiguring, highly invasive and metastatic cancer. Despite advances in detection and therapy, many patients will continue to face a poor prognosis. It is well established that the predominate factor determining overall survival in patients with oral squamous cell carcinoma is lymph node involvement. Tumor growth and progression to invasive cancer requires tumor cell interactions with the extracellular matrix. An understanding of how the extracellular matrix influences tumor development and invasion is fundamental in the development of new prognostic indicators and treatment strategies for oral squamous cell carcinoma. In this review, we summarize how changes in the extracellular matrix contribute to oral cancer development.

Head and neck squamous cell carcinoma (HNSCC) 5 year study at BSMMU.

Head and Neck Squamous Cell Carcinoma (HNSCC) are generally similar in their clinical features, epidemiology and etiology although their natural and clinical history and treatment differ. Despite lot of improvement in diagnostic and management technique, there is little improvement in survival rate over the last few decades. This study was carried-out in a multidisciplinary tertiary level hospital (BSMMU), with a country-wide catchment area to see the burden of HNSCC existing in our country and their clinical pattern. The overall incidence rate of HNSCC in this study was (0.15%) i.e. 150 person in 1,00,000 population. Male incidence (0.19%) was higher than female (0.12%). This study revealed that carcinoma of the larynx (25.22%) and pyriform fossae (20.57%) were the main culprit, whereas buccal carcinoma was the main component (37.70%) in the female series. Highest incidence was found in the 6th decade in both sexes. As the treatment of HNSCC may be time consuming, requires multidisciplinary approach, demands lot of clinical, social and financial consideration, therefore, the best treatment can be offered through a combined board consisting of Surgical, Radiation, Medical oncologists, Histopathologist and Speech therapist as required.

Loss of cyclin E requirement in cell growth of an oral squamous cell carcinoma cell line implies deregulation of its downstream pathway.

Cyclin E and Cdk2 have been shown to play an important role in G1/S transition of the cell cycle. Two E-type cyclins (E1 and E2) have been identified to date and share functionally similarities. Upregulation of these cyclins has been observed frequently in human cancers. We examined the expression profile of cyclin E1 and E2 in cell lines derived from human oral squamous cell carcinoma (SCC), and found that the expression of cyclin E1 protein was hardly detected in HSC-2 cells. Although cyclin E2 was abundantly expressed, histone H1 kinase activities of both E-type cyclins were virtually undetectable in this cell line. Inhibition of cyclin E1, but not that of E2, by using vectors expressing antisense-oriented their cDNAs induced drastic growth suppression on HOC313 cells that express both E-type cyclins. Inhibition of neither cyclin E1 nor E2 suppressed the growth of HSC-2 cells, and compensatory elevation of cyclin E1 was not evident in cyclin E2-inhibited HSC-2 cells. In contrast, HSC-2 cells expressed cyclin D1 and hyperphosphorylated forms of Rb family proteins, and were arrested in G1 by overexpression of p16(INK4), a specific inhibitor against D-type cyclin activity. These results indicate that HSC-2 cells lost proper growth control specifically mediated by cyclin E and suggest that deregulation of its downstream pathway may contribute to tumorigenesis of oral SCC.

Organ preservation in patients with squamous cancers of the head and neck.

Treatment strategies that have the potential to improve functional organ preservation in patients who have head and neck cancer are emerging. Clinical research in this field, however, has been limited by the lack of standardized, objective criteria of organ function post treatment and by lack of prospective assessment of organ function in treatment trials [56]. Advances in surgical techniques, radiation techniques, radiation protectants, and combined-modality therapies are promising, but well-planned and executed clinical trials are necessary to determine how best to apply these techniques to patient care.

Viral load of high-risk human papillomavirus in cervical squamous intraepithelial lesions.

OBJECTIVES: This case-control study was conducted to investigate the role of viral load of high-risk human papillomaviruses (HPVs) in the development of cervical squamous intraepithelial lesions (SILs) and invasive cancers. METHODS: A total of 30 female cases who had histological evidence of low-grade SIL (n=10) or high-grade SIL and above (n=20) were identified as the case group at the Tri-Service General Hospital, Taipei between September 1998 and March 1999. In addition, 80 female controls who had normal cervical cytology were enrolled and individually matched on age (+/-5 years) and date of recruitment to each case. Cervical swabs collected from study subjects were tested for the positivity and viral load of high-risk HPVs by Hybrid Capture II assay. Additionally, subjects completed a risk factor questionnaire. RESULTS: Among sex behavioral factors studied, younger age at first intercourse was associated with a significantly elevated risk of cervical SIL and invasive cancers. With respect to HPV infection, high-risk HPV DNA was present in 70% (21/30) of case and 21% (17/80) of control subjects, resulting in an odds ratio (OR) of 6.6 [95% confidence interval (C.I.)=2.6-17.0]. Moreover, women who had a high viral load were at significantly greater risk for cervical SIL and invasive cancers than those who were infected with a low viral load (OR=18.0, 95% C.I.=3.0-108.5). CONCLUSIONS: Among the variables tested, infection with a high viral load of high-risk HPVs is the strongest determinant for cervical SIL and cervical cancers in Taiwan.