cyclin-d1 and Parotid-Neoplasms

Dedifferentiation of salivary gland neoplasms is a rare event, unlike bone and soft part sarcomas, which was first described by Stanley et al. in 1988. An additional case of dedifferentiated epithelial-myoepithelial carcinoma (EMC) is reported here. The patient was a 70-year-old Japanese man who requested examination of the rapid growth of a mass in the right parotid region, which he had first noticed 25 years previously. Clinical examination showed an ill-circumscribed, 6.8 x 4.7 x 7.0-cm lesion. Histologically, most parts of the lesion were high-grade carcinoma (HGC) with sheetlike and nestlike growth of markedly atypical cells and comedonecrosis, whereas the minor part consisted of typical EMC. The outer clear cells of EMC were positive for alpha-smooth muscle actin (ASMA), p63, cytokeratin (CK) 14, and vimentin, and the inner ductal cells of EMC were positive for CKs and epithelial membrane antigen. HGC was negative for ASMA, CK14, and vimentin, but diffusely positive for p53 protein and cyclin D1. The Ki-67 labeling index of EMC was 11.5%, whereas that of HGC was 67.1%. These findings and a review of literature indicate that HGC arose from preexisting EMC, and this phenomenon is the dedifferentiation of EMC. Dedifferentiated EMC is extremely rare.

Topics: Actins; Aged; Carcinoma; Cell Dedifferentiation; Cyclin D1; Humans; Immunohistochemistry; Keratin-14; Ki-67 Antigen; Male; Membrane Proteins; Parotid Neoplasms; Tumor Suppressor Protein p53; Vimentin

Malignant tumors of the salivary glands comprise about 3% to 5% of all head and neck carcinomas. The purpose of our study was to find possible predictive and/or prognostic markers for parotid cancer.. A total of 46 tissue samples of carcinomas of the parotid gland were immunohistochemically stained for ß-catenin, cyclin D1, and PIN1. The factors were analyzed regarding their prognostic value for disease-free and overall survival.. An overexpression of the cytoplasmatic ß-catenin was linked to a statistically significant worse outcome regarding disease-free (p = .0296) and overall survival (p = .0416). The 5-year overall survival was 83.9% in patients without and 0% in patients presenting with overexpression of cytoplasmatic ß-catenin. Additionally, Union Internationale Contre le Cancer (UICC) stage correlated with overall survival (p = .0306) and disease-free survival (DFS; p = .0473).. Multivariate analysis showed that overexpression of cytoplasmatic ß-catenin and the UICC stage are 2 independent prognostic markers for survival in patients with parotid cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; beta Catenin; Carcinoma; Cyclin D1; Disease-Free Survival; Female; Humans; Male; Middle Aged; NIMA-Interacting Peptidylprolyl Isomerase; Parotid Neoplasms; Peptidylprolyl Isomerase; Retrospective Studies; Survival Rate; Young Adult

Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and β-catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6-NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG-transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6-NTRK3 translocation may represent a therapeutic target in MASC.

Topics: Aged; beta Catenin; Biomarkers, Tumor; Biopsy; Carcinoma; Cell Transformation, Neoplastic; Cyclin D1; DNA Mutational Analysis; ErbB Receptors; Fatal Outcome; Humans; Immunohistochemistry; Male; Middle Aged; Mutation; Neoplasm Grading; Oncogene Proteins, Fusion; Parotid Neoplasms; Prognosis; Time Factors; Tumor Suppressor Protein p53

Transgenic mice expressing specific oncogenes usually develop tumors in a stochastic fashion suggesting that tumor progression is a multi-step process. To gain further understanding of the interactions between oncogenes and tumor suppressor genes during tumorigenesis, we have crossed a transgenic strain (TG.NK) carrying an activated c-neu oncogene driven by the MMTV enhancer/promoter with p53-deficient mice. c-neu transgenic mice have stochastic breast tumor formation and normal appearing salivary glands. However, c-neu mice heterozygous for a p53 deletion develop parotid gland tumors and loose their wild type p53 allele. c-neu mice with a homozygous p53 deletion have increased rates of parotid tumor onset suggesting that inactivation of p53 is required and sufficient for parotid gland transformation in the presence of activated c-neu. In contrast to the dramatic effect of p53 in parotid gland transformation, p53 loss has little effect on the rate or stochastic appearance of mammary tumors. In addition, p53 loss was accompanied by the down regulation of p21 in parotid gland tumors but not breast tumors. The parotid gland tumors were aneuploid and demonstrated increased levels of Cyclin D1 expression. These observations suggest that in c-neu transgenic mice, p53 alterations have differential tissue effects and may be influenced by the tissue specific expression of genes influencing p53 activity.

Topics: Aneuploidy; Animals; Cell Transformation, Neoplastic; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Female; Gene Expression Regulation, Neoplastic; Genes, erbB-2; Genes, p53; Loss of Heterozygosity; Male; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Parotid Neoplasms; Salivary Gland Neoplasms; Salivary Glands; Stochastic Processes; Tissue Distribution; Tumor Suppressor Protein p53

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a newly proposed clinicopathologic entity; a few cases of LCNEC have been reported in other sites, such as the uterine cervix and the thymus. In the salivary glands, LCNEC is extremely rare and is not recognized as a specific entity in the World Health Organization classification. We retrospectively reviewed from our files 1675 cases of surgically resected primary parotid gland tumors and found 2 cases of LCNEC that fulfilled the criteria of pulmonary LCNEC. These cases occurred in 72- and 73-year-old men who had short histories of enlarging parotid gland tumors. The tumors were composed of large cells that exhibited organoid, solid, trabecular, and rosette-like growth patterns with a high mitotic rate and a conspicuous tendency for necrosis. The tumor cells were polygonal and characterized by a moderate nuclear:cytoplasmic ratio, coarse chromatin, and conspicuous nucleoli. Immunohistochemical examination revealed that the tumor cells were positive for six general neuroendocrine markers, cytokeratin, p53, bcl-2, epidermal growth factor receptor, and cyclin D1. Markedly reduced expressions of p21Waf1 and p27Kip1 were also noticed. The Ki-67 labeling index was more than 50% in both cases. One case showed loss of heterozygosity at TP53 accompanied by a p53 gene point mutation. Loss of heterozygosity at chromosome 9p21 was detected in both cases; one was accompanied by a p16 gene silent point mutation. Both patients died of the disease, with recurrence 5 months and 4 years after surgery, respectively. These findings indicate that LCNEC is a rare but distinct salivary gland tumor with highly aggressive biologic behavior. Multiple alterations of cell cycle regulators and tumor suppressor genes may play an important role in presenting the biologic characteristics of this rare parotid gland tumor.

Topics: Aged; Base Sequence; Carcinoma, Large Cell; Carcinoma, Neuroendocrine; Carcinoma, Non-Small-Cell Lung; Cyclin D1; Diagnosis, Differential; DNA Mutational Analysis; DNA, Neoplasm; ErbB Receptors; Humans; Keratins; Ki-67 Antigen; Loss of Heterozygosity; Lung Neoplasms; Male; Microscopy, Electron; Parotid Neoplasms; Point Mutation; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53

Carcinoma arising in pleomorphic adenoma of the salivary gland is a rare tumor, and its molecular aspects are unknown. Recent studies have revealed that malignant transformation of various human cancers may involve two different genetic alterations: inactivation of the p16 gene, which is a putative tumor suppressor gene, and genetic instability represented by microsatellite instability (MSI). However, so far, molecular investigations including p16 gene alteration and MSI have not been performed on carcinoma arising in pleomorphic adenoma. Both inactivation of the p16 gene and MSI were studied using DNA extracted from paraffin-embedded sections of carcinoma arising in pleomorphic adenoma. Samples also were analyzed for cyclin D1 gene amplification, which is thought to have oncogenic effects similar to those with inactivation of the p16 gene. One case showed the homozygous deletion of the p16 gene in the carcinoma, although hypermethylation of the p16 gene and amplification of the cyclin D1 gene were not observed in any cases. In two of four cases, MSI was observed. One case in two showed MSI in both the pleomorphic adenoma and the carcinoma. Results of this study suggest that two different genetic alterations, the inactivation of the p16 gene and genetic instability, play roles in the malignant transformation of carcinoma in pleomorphic adenoma. The MSI observed in the adenoma suggests that genetic alterations occur in pleomorphic adenoma.

Topics: Adenocarcinoma; Adenoma, Pleomorphic; Aged; Cyclin D1; DNA Methylation; DNA Primers; DNA, Neoplasm; Female; Gene Deletion; Genes, p16; Humans; Male; Microsatellite Repeats; Middle Aged; Neoplasms, Multiple Primary; Parotid Neoplasms; Polymerase Chain Reaction