Identification of site-specific prognostic biomarkers in patients with oral squamous cell carcinoma.

The purpose of the present study was to identify site-specific prognostic biomarkers in patients with oral squamous cell carcinoma (OSCC). For this purpose, Epidermal growth factor receptor (EGFR), Stat3, H-ras, c-myc, p53, cyclin D1, p16, Rb and Bcl-2 were localized immunohistochemically in buccal mucosa carcinoma (n=74) and tongue carcinoma (n=61) patients. Expression of markers was compared between buccal mucosa and tongue carcinoma and assessed for their prognostic value in site-specific manner. On comparison, only cyclin D1 showed significant difference in expression with higher accumulation in tongue tumors (r=+0.177, p=0.039). Moreover, univariate survival analysis showed that in buccal mucosa patients, loss of p16 and overexpression of H-ras were significant prognosticators for relapse-free survival (RFS) and overall survival (OS), respectively. However, in Cox multivariate analysis, they lost their significance after adjusting for significant clinicopathological parameters. On the other hand, in tongue cancer patients, Cox multivariate analysis showed that for RFS, Stat3 and c-myc, and for OS, Stat3, Bcl-2 and p53 were significant prognosticators after adjusting for significant confounding factors. Our findings indicated that buccal mucosa and tongue carcinoma exhibit different biological behavior which is reflected in prognosis. Therefore, this approach might be helpful to precisely identify patients for more effectively tailored treatment strategy.

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.

Molecular alterations in oral carcinogenesis: significant risk predictors in malignant transformation and tumor progression.

In this study an attempt was made to establish the significance of a battery of molecular alterations and thereby identify risk predictors in oral carcinogenesis. For this purpose, EGFR, Stat3, H-ras, c-myc, p53, cyclin D1, p16, Rb, Ki-67 and Bcl-2 were localized immunohistochemically in normal mucosa (n=12), hyperplasia (n=35), dysplasia (n=25), early stage carcinoma (n=65) and advanced stage carcinoma (n=70). Deregulation occurred at an early stage and the number of alterations increased with disease progression. Using multivariate logistic regression analysis, the significant risk predictor for hyperplasia from normal mucosa was Ki-67 (OR=5.75, p=0.021); the significant risk predictors for dysplasia from hyperplasia were EGFR (OR=12.96, p=0.002), Stat3 (OR=17.16, p=0.0001), p16 (OR=5.50, p=0.039) and c-myc (OR=5.99, p=0.052); the significant risk predictors for early stage carcinoma from dysplasia were p53 (OR=6.63, p=0.0001) and Rb (OR=3.81, p=0.056); and the significant risk predictors for further progression were EGFR (OR=5.50, p=0.0001), Stat3 (OR=4.49, p=0.0001), H-ras (OR=4.05, p=0.001) and c-myc (OR=2.99, p=0.015). Cyclin D1 holds a key position linking upstream signaling pathways to cell cycle regulation. Gene products of the mitogenic signaling pathway play an equally significant role as cell cycle regulatory proteins in the hyperplasia-dysplasia-early-advanced-carcinoma sequence and together may provide a reference panel of markers for use in defining premalignant lesions and predicting the risk of malignant transformation and tumor progression.

Stat3 expression in oral squamous cell carcinoma: association with clinicopathological parameters and survival.

The present study sought to explore the occurrence of signal transducer and activator of transcription 3 (Stat3) in patients with oral squamous cell carcinoma (n=135) and its potential relationship with clinicopathological parameters and survival. Stat3 expression was studied by immunohistochemistry. Cytoplasmic or nuclear localization of Stat3 was observed in 62% of patients, whereas only nuclear Stat3 expression was found in 44%. Stat3 positivity in early-stage patients was 45% compared to 79% in advanced-stage patients. However, early-stage Stat3-positive patients showed a gradual increase in staining intensity, with intense staining seen in 52% of the tumors compared to 18% in Stat3-positive advanced-stage patients, where a gradual decrease in intensity expression was observed (p=0.001). Stat3 showed a significant positive correlation with disease stage (p=0.001), nodal status (p=0.033) and tumor size (p=0.001). Multivariate survival analysis using the Cox proportional hazard regression model showed that nuclear Stat3 was a significant independent prognosticator for both relapse-free survival (p=0.014) and overall survival (p=0.042) in early-stage patients. Our results indicated that Stat3 activation is an early event in oral squamous cell carcinoma and represents a potential risk factor for poor prognosis in early-stage patients.