Prognostic and Clinicopathological Significance of the Aberrant Expression of ß-Catenin in Oral Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aims to evaluate the prognostic and clinicopathological significance of the aberrant expression of ß-catenin (assessed through the immunohistochemical loss of membrane expression, cytoplasmic and nuclear expression) in oral squamous cell carcinoma (OSCC). We searched for primary-level studies published before October-2021 through PubMed, Embase, Web of Science, Scopus, and Google Scholar, with no limitation in regard to their publication date or language. We evaluated the methodological quality and risk of bias of the studies included using the QUIPS tool, carried out meta-analyses, explored heterogeneity and their sources across subgroups and meta-regression, and conducted sensitivity and small-study effects analyses. Forty-one studies (2746 patients) met inclusion criteria. The aberrant immunohistochemical expression of ß-catenin was statistically associated with poor overall survival (HR = 1.77, 95% CI = 1.20-2.60, p = 0.004), disease-free survival (HR = 2.44, 95% CI = 1.10-5.50, p = 0.03), N+ status (OR = 2.39, 95% CI = 1.68-3.40, p < 0.001), higher clinical stage (OR = 2.40, 95% CI = 1.58-3.63, p < 0.001), higher tumour size (OR = 1.76, 95% CI = 1.23-2.53, p = 0.004), and moderately-poorly differentiated OSCC (OR = 1.57, 95% CI = 1.09-2.25, p = 0.02). The loss of ß-catenin in the cell membrane showed the largest effect size in most of meta-analyses (singularly for poor overall survival [HR = 2.37, 95% CI = 1.55-3.62, p < 0.001], N+ status [OR = 3.44, 95% CI = 2.40-4.93, p < 0.001] and higher clinical stage [OR = 2.51, 95% CI = 1.17-5.35, p = 0.02]). In conclusion, our findings indicate that immunohistochemical assessment of the aberrant expression of ß-catenin could be incorporated as an additional and complementary routine prognostic biomarker for the assessment of patients with OSCC.

Immunoexpression of Apoptosis and Cell-cycle Arrest Markers in Oral Lichen Planus.

The expression pattern of a panel of 5 molecular markers (p53, cyclin D1, Ki-67, BCL-2, and BAX) was studied in samples from patients with oral lichen planus (OLP) and normal oral mucosa (NOM) of healthy controls to investigate the implications of cell cycle and apoptosis in OLP. The 59 OLP and 16 NOM biopsies were stained by an inmunoperoxidase technique for p53, cyclin D1, Ki-67, BCL-2, and BAX and assessed microscopically for semiquantitative analysis. Positivity for BCL-2 and Ki-67 was significantly more frequent in NOM than in OLP (P<0.05). p53 levels were upregulated in atrophic/erosive clinical presentations when compared with reticular presentations and in cases with discontinued inflammatory infiltrate. Multivariate analysis through logistic regression showed that BCL-2 in OLP versus NOM was the only significantly altered marker in the present cohort (adjusted odds ratio=12.42; 95% confidence interval: 2.5-61.65; P=0.002). The cell patterns in OLP and NOM are distinct according to the present molecular markers panel. The presence of BCL-2 altered expression may be related to various molecular pathways that connect/link this condition to other autoimmune disorders and also may be involved in complex roles that evoke malignant transformation of OLP.

Epidemiological study of oral cancer patients in Alava province, Spain.

The authors conducted a retrospective study of oral squamous cell carcinoma (OSSC) patients in the province of Alava, Spain, to investigate the various epidemiological factors involved. The study included data on 30 patients referred to the Otolaryngology Department of our hospital. The authors identified epidemiological data, including age, symptoms, localization, tumor size, risk factors, tumor stage, treatment and outcome. An elevated percentage of risk factors was found, underlining the importance of early diagnosis. The highest prevalence was in the sixth decade of life. The most frequent symptom was pain, and the localization was in the tongue in 70% of cases. Tumor size ranged from 2 to 3 cm, and 85% of patients underwent surgical resection. Risk factors of smoking and drinking affected 50% of the patients.

Substance P and NK-1R expression in oral precancerous epithelium.

The objectives of this study were to investigate the presence and distribution of substance P and neurokinin 1 receptor in oral premalignant epithelium and their relation with the presence of dysplasia, and to analyze whether the expression of substance P can be considered an early oncogenic event in oral carcinogenesis. substance P and neurokinin 1 receptor expression was immunohistochemically studied in 83 oral carcinomas and adjacent non-tumor epithelia. The presence and degree of epithelial dysplasia was assessed according to WHO criteria. The nuclear, cytoplasmic, and membrane expression of substance P and the cytoplasmic and membrane expression of neurokinin 1 receptor were assessed in tumor and adjacent non-tumor epithelium. Nuclear and cytoplasmic expression of substance P in non-tumor epithelium was significantly associated with the presence of epithelial dysplasia (p<0.001) and carcinoma in situ (p=0.021). Nuclear, cytoplasmic, and membrane expressions of substance P in non-tumor epithelium were significantly (p<0.001) associated with its expression in the corresponding tumor. These findings suggest that substance P plays a role in early oral carcinogenesis by promoting the proliferation and growth of premalignant fields.

NK-1 receptor antagonists induce apoptosis and counteract substance P-related mitogenesis in human laryngeal cancer cell line HEp-2.

It has been demonstrated that substance P (SP) induces cell proliferation and neurokinin-1 (NK-1) receptor antagonists inhibit growth in several human cancer cell lines, but it is currently unknown whether such actions are exerted on human laryngeal carcinoma cell line HEp-2. In addition, the presence of NK-1 receptor has not been demonstrated in this cell line. We carried out an in vitro study of the growth inhibitory capacity of the NK-1 receptor antagonists L-733,060 and L-732,138 against human laryngeal carcinoma cell line HEp-2. Coulter counter was used to determine viable cell numbers followed by application of the tetrazolium compound MTS. Furthermore, an immunoblot analysis was used to determine the NK-1 receptor, and the 4',6-diamidino-2-phenylindole (DAPI) method was applied to demonstrate apoptosis of the laryngeal carcinoma cells. We observed the presence of several NK-1 receptors isoforms (34, 46, 58 and 75 kDa). Nanomolar concentrations of SP increased the growth rate of the cell line and micromolar concentrations of L-733,060 and L-732,138 inhibited the growth of the HEp-2 cells in a dose-dependent manner, with and without previous administration of SP. The 50% inhibition concentration values were 21.34 microM and 37.97 (48 h) respectively for HEp-2. NK-1 receptor presence on HEp-2 cells was confirmed by western blotting. DAPI staining revealed the presence of apoptosis following NK-1 receptor antagonists treatment. We demonstrated that NK-1 receptors were present in this laryngeal cancer cell line; these findings demonstrate that SP acts as a mitogen on the human laryngeal carcinoma cell line HEp-2 through the NK-1 receptor, and also indicate that both NK-1 receptors antagonists induced apoptosis of the tumour cells. This new action, reported here for the first time, suggests that the NK-1 receptor is a new and promising target in the treatment of human laryngeal carcinoma.

Expression of the antiapoptotic proteins clusterin and bcl-2 in laryngeal squamous cell carcinomas.

Bcl-2 and clusterin genes have been related to the inhibition of apoptosis, an event that plays a key role in malignant transformation and in invasive disease. In this work, we determine the significance of clusterin and bcl-2 expression in a large series of laryngeal carcinomas. We used immunohistochemical methods and in situ hybridization to examine the expression of these proteins. Nontumoral epithelial laryngeal tissues did not express clusterin and bcl-2 proteins. However, 9% (14 out of 154) and 25% of these tumors (39 of 154) had positive clusterin and bcl-2 staining, respectively. Clusterin expression was significantly related to the degree of local invasion and higher bcl-2 expression was found in these clusterin-positive tumors (p < 0.05). Bcl-2 expression was significantly correlated with supraglottic localization, nodal metastases, invasion in depth, and poorly differentiated tumors. However, by multivariate analysis, bcl-2 was shown to be an independent predictor of good prognosis in these tumors (OR = 0.12, 95% CI = 0.02-0.91). These findings indicate that clusterin and bcl-2 are upregulated in laryngeal carcinomas and their expression is related to the invasiveness of these tumors.

Analysis of p53 protein by PAb240, Ki-67 expression and human papillomavirus DNA detection in different types of odontogenic keratocyst.

OBJECTIVE: To investigate the possible association between alterations in the p53 system and human papillomavirus (HPV) infection in the etiology of odontogenic keratocysts (OKCs) and to study proliferation and epithelial maturation patterns by topographic analysis of Ki-67 expression. MATERIALS AND METHODS: Eighty-three OKC samples (29 cases associated with nevoid basal cell carcinoma syndrome, 29 solitary non-recurrent cases 20 solitary recurrent cases, and 5 chondroid keratocysts) were studied by immunohistochemistry to detect p53 protein (PAb 244) and Ki-67 (MIB-1) expression, and by PCR to detect HPV DNA. RESULTS: Twelve cases (14.6%) expressed p53 protein; no case showed the presence of HPV DNA; 9 cases (11%) presented with mild epithelial dysplasia. The suprabasal expression of Ki-67 was significantly more frequent than its basal expression (p < 0.001). p53 protein expression was significantly associated with the presence of epithelial dysplasia (p = 0.023). Ki-67 expression was not associated with OKC type, the presence of dysplasia, or p53 expression. CONCLUSION: HPVs do not participate in the etiology of OKC, and it appears unlikely that a p53 gene mutation mechanism plays a major role in the genesis of OKC. OKCs show proliferation and genuine maturation behavior reminiscent of benign neoplasms with local destructive capacity.