Potential role for inhibition of protein phosphatase 2A tumor suppressor in salivary gland malignancies.

The aetiology and pathogenesis of salivary gland malignancies remain unknown. To reveal novel molecular factors behind the development of salivary gland cancer, we performed gene expression analyses from Smgb-Tag mouse salivary gland samples. The overall purpose was to apply these results for clinical use to find new approaches for both possible therapeutic targets and more accurate diagnostic tools. Smgb-Tag mouse strain, in which salivary neoplasms arise through a dysplastic phase in submandibular glands, was investigated using genome-wide microarray expression analysis, ingenuity pathway analysis, RT-PCR, and immunohistochemistry. Thirty-eight human salivary gland adenoid cystic carcinoma samples were investigated using immunohistochemistry for validation purposes. Our genome-wide study showed that Ppp2r1b, a PP2A subunit encoding tumor suppressor gene, is underexpressed in submandibular gland tumors of Smgb-Tag mice. mTOR signaling pathway was significantly enriched and mTOR linked PP2A subunit gene B55 gamma was significantly underexpressed in the analyses. Furthermore, parallel immunohistochemical analysis of three PP2A inhibitors demonstrated that two PP2A inhibitors, CIP2A and SET, are highly expressed in both dysplastic and adenocarcinomatous tumors of the Smgb-Tag mice. In addition, all 38 investigated human salivary adenoid cystic carcinoma samples stained positively for CIP2A and most for SET. Finally, p-S6 staining showed activation of mTOR pathway in human adenoid cystic carcinoma samples. Our results suggest that PP2A inhibition either via PP2A subunit underexpression or PP2A inhibitor overexpression play an important role in the formation of salivary gland malignancy, potentially due to mTOR signaling activation.

Matrix metalloproteinase (MMP)-7 in salivary gland cancer.

INTRODUCTION: High levels of certain matrix metalloproteinases (MMPs) have been detected in various human cancers. The purpose of this study was to analyze the expression of MMP-7 in salivary gland cancer (SGC) by immunohistochemistry and to associate the results with the clinical data and the 10-year survival of the SGC patients. MATERIAL AND METHODS: Immunohistochemistry for MMP-7 was performed in a series of 107 paraffin-embedded sections of SGC. The samples represent the entire SGC population in Finland from 1991-1996. Mortality follow-up ended December 31, 2006. RESULTS: The study population of 107 patients consisted of 47 male and 60 female subjects, ranging in age at the time of diagnosis between 23 and 90 years. The minimum follow-up time was 10.6 years and the maximum 15.9 years. By age-adjusted analysis lower staining intensity was associated with worse overall survival of patients with acinic cell carcinoma (p = 0.047, HR 6.5, 95% Cl 1.0-41.7) and in mucoepidermoid carcinoma (p = 0.010, HR 9.3, 95% CI 1.7-50.0). Low staining intensity was also associated with worse disease-specific survival of patients with acinic cell carcinoma (0-1 vs. 2-3; p = 0.047, HR 13.7, 1.0-200.0). VCI Ki-67 was an important prognostic factor for survival of the entire data set (p < 0.0001, HR 4.7, 95% Cl 2.3-9.8). CONCLUSIONS: MMP-7 is associated with the prognosis of patients with acinic cell and mucoepidermoid carcinoma.

Expression of matrix metalloproteinase-1, -7, -9, -13, Ki-67, and HER-2 in epithelial-myoepithelial salivary gland cancer.

BACKGROUND: The expression of matrix metalloproteinases (MMPs) in epithelial-myoepithelial salivary gland carcinoma has not been studied previously. METHODS: Immunohistochemistry for MMP-1, -7, -9, -13, Ki-67, and HER-2, as well as HER-2 gene amplification by silver enhanced in situ hybridization was performed in a series of 12 paraffin-embedded histopathologic samples of patients from Canada and Finland. RESULTS: A positive MMP-13 (p = .0022), higher MMP-13 (p = .0274), and higher MMP-9 (p = .0274) index (multiplication of staining intensity by percentage of the positive cells) predicted better overall survival. In disease-specific analysis, higher MMP-9 index (p = .0327) predicted better survival. A higher volume corrected index (VCI) of Ki-67 (p = .0339) predicted worse disease-specific survival. In 1 patient, HER-2 oncogene amplification was observed. CONCLUSION: MMPs and Ki-67 may have prognostic impact in epithelial-myoepithelial carcinoma.

Matrix metalloproteinase (MMP)-1, -9 and -13 as prognostic factors in salivary gland cancer.

CONCLUSIONS: In the current study matrix metalloproteinases (MMPs)-9 and -13 were associated with the prognosis in salivary gland cancer (SGC), indicating that they contribute to the progression and invasion of these malignant tumours. OBJECTIVES: Elevated levels of certain MMPs have been detected in various advanced human cancer types. The purpose of the study was to analyse the expression of MMP-1, -9 and -13 in SGC by immunohistochemistry and correlate the results to the clinical data and 10-year survival of SGC patients in a nationwide material. MATERIALS AND METHODS: Immunohistochemistry for MMP-1, -9 and -13 was performed in series of 103 paraffin-embedded sections of SGC. RESULTS: High MMP-13 staining intensity predicted poor survival (3 vs 1; p=0.08) in the whole material studied. High MMP-13 intensity (2+3 vs 1; p=0.05), percentage (2 vs 1; p=0.03) and index (3 vs 1; p=0.02) were associated with poor survival in acinic cell carcinoma. However, high MMP-9 index in adenoid cystic carcinoma (p=0.06) and the percentage of positively staining cells in salivary duct carcinoma patients (p=0.05) was associated with poor survival. High MMP-1 staining intensity (2 vs 0; p=0.06) and index (% x intensity); (2 vs 1, p=0.04) were associated with better overall survival in the whole material.

Morphometric analysis using automated image analysis of CD34-positive vessels in salivary gland acinic cell carcinoma.

CONCLUSIONS: In computer-assisted analysis of acinic cell cancer (ACC) morphological characteristics of CD34 immunoreactivity were detected. Bigger vessel size, vessel irregularity, and lower intensity of CD34-positive vessel staining may indicate unfavorable prognosis. OBJECTIVES: Salivary gland cancer (SGC) is a morphologically diverse group of malignancies, the most common histological types being mucoepidermoid, adenoid cystic and ACC, which has the most favorable prognosis of the three. The aim of this research was to study the applicability of automated image analysis as prognostic criteria in ACC. PATIENTS AND METHODS: In a nationwide study covering SGC patients in Finland during 1991-1996, 34 patients with ACC (15 males, 19 females, aged 19-95 years, mean 55 years) were included. Parameters were measured from CD34-stained samples. RESULTS: In all, 10 385 vessels were measured, of which 9873 were from specimens from patients who were alive 5 years after treatment (n=32, group I) and 512 were from patients who died of disease (n=2, group II). The following results were found in group II versus group I: mean vessel size 469 microm vs 272 microm (p=0.024); vessel irregularity 28.3 microm vs 22.3 microm (p<0.001); CD34 staining intensity 0.555 microm vs 0.584 microm (p=0.024).

Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: an evaluation of 212 cases.

The proliferative capacity of a tumor as measured by Ki-67 nuclear antigen is one of the most powerful indicators of tumor behavior. Ki-67 is considered a useful tool in determining the aggressiveness of malignant neoplasms. p53 tumor suppressor gene mutations have been linked with the development and progression of a number of various cancer types. p53 tumor suppressor protein and the volume corrected index of Ki-67 corresponding to Ki-67 /mm2 of tumor tissue (VCI Ki-67) in salivary gland tumors were evaluated by immunohistochemistry from paraffin embedded sections in a series of 212 patients. The follow-up time in this nationwide full population-based study was up to five years. The association of clinicopathological features and the results of present study with survival were examined. In multivariate analysis high VCI Ki-67 was associated with worse survival of SGC patients (p = 0.0114). Supplementary information was brought by age (p = 0.0002), lymph node status (p = 0.0014), gender (p = 0.0017) and stage (p = 0.0191). p53 expression did not have additional value in prediction of survival (p = 0.1433) compared to the commonly clinical used parameters. In this material consisting of various salivary gland carcinomas VCI Ki-67 was a good prognostic factor for survival.

Salivary gland cancer in Finland 1991--96: an evaluation of 237 cases.

CONCLUSION: In this material consisting of various salivary gland carcinomas, stage I, male gender and age were the most powerful predictors of patient outcome. OBJECTIVES: To retrieve the records of all salivary gland cancer (SGC) patients diagnosed in Finland between 1991 and 1996 and to evaluate the incidence, histological type and location of SGC, the treatment given and the outcome. MATERIAL AND METHODS: The records for all SGCs (n =286) diagnosed in Finland between 1991 and 1996 and reported to the Finnish Cancer Registry were retrieved. The histological re-evaluation and retrospective study involved 237 SGC patients. RESULTS: The study population consisted of 125 males and 112 females. The mean age was 59 years (males 61 years, females 58 years). Follow-up was at least 5 years. The commonest tumor location was the parotid gland (n = 152; 64%), followed by the minor salivary glands (n =46; 19%), the submandibular gland (n =38; 16%) and the sublingual gland (n = 1; 0.4%). The most frequent histological types of SGC were adenoid cystic carcinoma (n =65; 27%), mucoepidermoid carcinoma (n =45; 19%) and acinic cell carcinoma (n =41; 17%). Surgery, either alone or in combination with other treatment modalities, was used in 209 cases (88%). Radiotherapy was given to 136 patients (57%), 13 of whom (5%) did not undergo surgery. The 5-year overall survival rate was 56.5%, and for stages I-IV it was 78%, 25%, 21% and 23%, respectively (p <0.001; log-rank test). Of the commonest tumor types, the best 5-year relative survival rate was for patients with acinic cell carcinoma (96%), followed by those with mucoepidermoid (79%) and adenoid cystic carcinoma (74%).