The expression of the cancer testis antigen MAGE A4: A favorable prognostic biomarker in salivary gland carcinomas related to low tumor grading.

BACKGROUND: Aim was to analyze the expression of different cancer testis antigens (CTA) and to assess its prognostic value in salivary gland carcinomas. METHODS: Patients with salivary gland carcinomas diagnosed 1994 to 2010 were included. Baseline characteristics, pathohistological, clinical, and outcome data were assessed. Tissue microarrays were constructed and immunohistochemistry for different CTA (NY-ESO1, NY-BR1, MAGE A1, MAGE A3, MAGE A4, MAGE C1/CT7, and MAGE C2/CT10) was performed. CTA expression was assessed and statistically correlated with pathological and outcome data. RESULTS: Expression rates of CTA in salivary gland tumors ranged from 0% to 40%. MAGE A4 expression was associated with a lower tumor grade tumor grading (P = .017), and a favorable recurrence-free (P = .003), disease-specific (P = .046) and overall survival (P = .028). CONCLUSIONS: MAGE A4 is a highly significant prognostic marker in salivary gland carcinoma; its expression is associated with low-grade histology, a low rate of distant metastasis and a favorable survival. LEVEL OF EVIDENCE: 4.

Computed tomography perfusion imaging of renal cell carcinoma: systematic comparison with histopathological angiogenic and prognostic markers.

PURPOSE: The aim of this study was to systematically analyze the correlation between computed tomography (CT) perfusion and histopathological angiogenic and prognostic markers in patients with renal cell carcinoma (RCC). MATERIAL AND METHODS: Fifteen patients (12 men; mean age, 64.5 ± 9.4 years) with RCC underwent contrast-enhanced CT perfusion imaging (scan range, 10 cm; scan time, 40 seconds; dual-source 128-section CT) 1 day before surgery. The procedure for surgical specimen processing was modified to obtain an exact match with CT images. Microvessel density (MVD) was quantified by CD34 staining, and lymphatic vessel density (LVD) was stained with D2-40 antibodies. The CT perfusion values blood flow (BF), blood volume (BV), and flow extraction product (K(Trans)) were calculated using the maximum-slope and a delay-corrected modified Patlak approach and were correlated to MVD and LVD. The relationship between CT perfusion and the prognostic markers pT stage, Fuhrman grade, and tumor necrosis was evaluated. RESULTS: Histopathology revealed varying high MVD but low or absent intratumoral LVD. The BF and BV of RCC, both including and excluding necrotic regions, showed significant correlations with MVD (r = 0.600-0.829, P < 0.05 each). Significant correlations between MVD and K(Trans) were found only in small tumor areas exhibiting no necrosis (r = 0.550, P < 0.05). No significant correlation was found between BF, BV, and K(Trans) with intratumoral LVD (P = 0.35-0.82). With higher pT stage and Fuhrman grade, BF, BV, and K(Trans) were lower, similar to the MVD, but without reaching statistical significance. Blood flow, BV, and K(Trans) were significantly higher in RCCs with less than 50% necrosis than in those with 50% or grater necrosis (P < 0.05 each). CONCLUSION: Our study indicates that BF and BV from CT perfusion reflect blood vessels of RCC. Computed tompgraphic perfusion parameters differ significantly depending upon the degree of tumor necrosis.

p53 suppresses type II endometrial carcinomas in mice and governs endometrial tumour aggressiveness in humans.

Type II endometrial carcinomas are a highly aggressive group of tumour subtypes that are frequently associated with inactivation of the TP53 tumour suppressor gene. We show that mice with endometrium-specific deletion of Trp53 initially exhibited histological changes that are identical to known precursor lesions of type II endometrial carcinomas in humans and later developed carcinomas representing all type II subtypes. The mTORC1 signalling pathway was frequently activated in these precursor lesions and tumours, suggesting a genetic cooperation between this pathway and Trp53 deficiency in tumour initiation. Consistent with this idea, analyses of 521 human endometrial carcinomas identified frequent mTORC1 pathway activation in type I as well as type II endometrial carcinoma subtypes. mTORC1 pathway activation and p53 expression or mutation status each independently predicted poor patient survival. We suggest that molecular alterations in p53 and the mTORC1 pathway play different roles in the initiation of the different endometrial cancer subtypes, but that combined p53 inactivation and mTORC1 pathway activation are unifying pathogenic features among histologically diverse subtypes of late stage aggressive endometrial tumours.

Down regulation of E-Cadherin (ECAD) - a predictor for occult metastatic disease in sentinel node biopsy of early squamous cell carcinomas of the oral cavity and oropharynx.

BACKGROUND: Prognostic factors in predicting occult lymph node metastasis in patients with head and neck squamous-cell carcinoma (HNSCC) are necessary to improve the results of the sentinel lymph node procedure in this tumour type. The E-Cadherin glycoprotein is an intercellular adhesion molecule in epithelial cells, which plays an important role in establishing and maintaining intercellular connections. OBJECTIVES: To determine the value of the molecular marker E-Cadherin in predicting regional metastatic disease. METHODS: E-Cadherin expression in tumour tissue of 120 patients with HNSCC of the oral cavity and oropharynx were evaluated using the tissue microarray technique. 110 tumours were located in the oral cavity (91.7%; mostly tongue), 10 tumours in the oropharynx (8.3%). Intensity of E-Cadherin expression was quantified by the Intensity Reactivity Score (IRS). These results were correlated with the lymph node status of biopsied sentinel lymph nodes. Univariate and multivariate analysis was used to determine statistical significance. RESULTS: pT-stage, gender, tumour side and location did not correlate with lymph node metastasis. Differentiation grade (p = 0.018) and down regulation of E-Cadherin expression significantly correlate with positive lymph node status (p = 0.005) in univariate and multivariate analysis. CONCLUSION: These data suggest that loss of E-cadherin expression is associated with increased lymhogeneous metastasis of HNSCC. E-cadherin immunohistochemistry may be used as a predictor for lymph node metastasis in squamous cell carcinoma of the oral cavity and oropharynx. LEVEL OF EVIDENCE: 2b.

Expression patterns of Bmi-1 and p16 significantly correlate with overall, disease-specific, and recurrence-free survival in oropharyngeal squamous cell carcinoma.

BACKGROUND: The objective of this study was to link expression patterns of B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) and p16 to patient outcome (recurrence and survival) in a cohort of 252 patients with oral and oropharyngeal squamous cell cancer (OSCC). METHODS: Expression levels of Bmi-1 and p16 in samples from 252 patients with OSCC were evaluated immunohistochemically using the tissue microarray method. Staining intensity was determined by calculating an intensity reactivity score (IRS). Staining intensity and the localization of expression within tumor cells (nuclear or cytoplasmic) were correlated with overall, disease-specific, and recurrence-free survival. RESULTS: The majority of cancers were localized in the oropharynx (61.1%). In univariate analysis, patients who had OSCC and strong Bmi-1 expression (IRS >10) had worse outcomes compared with patients who had low and moderate Bmi-1 expression (P = .008; hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.167-2.838); this correlation was also observed for atypical cytoplasmic Bmi-1 expression (P = .001; HR, 2.164; 95% CI, 1.389-3.371) and for negative p16 expression (P < .001; HR, 0.292; 95% CI, 0.178-0.477). The combination of both markers, as anticipated, had an even stronger correlation with overall survival (P < .001; HR, 8.485; 95% CI, 4.237-16.994). Multivariate analysis demonstrated significant results for patients with oropharyngeal cancers, but not for patients with oral cavity tumors: Tumor classification (P = .011; HR, 1.838; 95%CI, 1.146-2.947) and the combined marker expression patterns (P < .001; HR, 6.254; 95% CI, 2.869-13.635) were correlated with overall survival, disease-specific survival (tumor classification: P = .002; HR, 2.807; 95% CI, 1.477-5.334; combined markers: P = .002; HR, 5.386; 95% CI, 1.850-15.679), and the combined markers also were correlated with recurrence-free survival (P = .001; HR, 8.943; 95% CI, 2.562-31.220). CONCLUSIONS: Cytoplasmic Bmi-1 expression, an absence of p16 expression, and especially the combination of those 2 predictive markers were correlated negatively with disease-specific and recurrence-free survival in patients with oropharyngeal cancer. Therefore, the current results indicate that these may be applicable as predictive markers in combination with other factors to select patients for more aggressive treatment and follow-up.