Predictive value of cyclooxygenase 2 and Bcl-2 for cervical lymph node metastasis in mucoepidermoid carcinoma

The expression of cyclooxygenase 2 (COX-2) is induced by growth factors, tumor promoters, and cytokines. It is correlated with carcinogenesis and apoptosis inhibition. This study was designed to investigate the expression of COX-2 and BCl-2 and to correlate their expressions with the clinicopathologic features in the mucoepidermoid carcinoma (MEC). The expression of COX-2 and BCl-2 proteins was investigated in 16 archival tumor tissues of MEC using the streptavidin-biotin complex technique. Clinical information was obtained through the computerized retrospective database from the tumor registry between 2001 and 2007. It revealed that grading system of MEC did not correlate with the presence or absence of node metastasis. The expression of COX-2 and BCl-2 was variably expressed in all the examined specimens. COX-2 and BCl-2 immunoreactivity was observed mainly in the cytoplasm of neoplastic cells. As regard the clinicopathologic parameters, there was no significant difference in expression rates of COX-2 in patients among age, sex, and MEC grades (P > .05). However, the expression of COX-2 in node-positive tumors was significantly higher than that of node-negative tumors (P = .001). For BCL-2 expression, there was no significant difference in expression rates of BCl-2 in patients among age, sex, site, clinical stage, and lymph node metastasis (P > .05), whereas a high significant difference was observed between BCl-2 staining index and MEC grades (P = .027). Moreover, there is a positive correlation between COX-2 expression and BCL-2 staining index (P = .000). COX-2 is a good predictor for lymph node metastasis as well as ideal therapeutic target for the prevention or treatment of MEC. BCl-2 and COX-2 are potentially useful prognostic markers for MEC.     

Multiple expression of tissue markers in mucoepidermoid carcinomas and acinic cell carcinomas of the salivary glands

Summary The distribution of various tissue antigens was studied in mucoepidermoid carcinomas (n=74) and acinic cell carcinomas (n=38) by means of immunocytochemistry. Mucoepidermoid carcinomas were generally positive for cytokeratin and showed double expression for cytokeratin and vimentin in 31.1% and triple expression for cytokeratin, vimentin and GFAP in 24.1%. CEA was studied using new monoclonal antibodies which distinguish between epitopes that are present on CEA alone and those which are present on nonspecific cross reacting antigens as well. The monospecific CEA antibody was completely negative in mucoepidermoid carcinomas, while nonspecific cross reacting antigens (NCAs) were positive in mucoepidermoid carcinomas to a varying degree. Alpha 1-antichymotrypsin, a marker formerly thought to be specific for tissues for histiocytic origin, was positive in 85.1% of mucoepidermoid carcinomas. Twenty three percent of mucoepidermoid carcinomas showed focal infiltration by S-100 positive dendritic stromal cells, tumour cell being negative. Leu-M 1 antigen was positive in 58.1% of mucoepidermoid carcinomas. Acinic cell carcinomas were generally positive for cytokeratin and in single cases showed double expression for cytokeratin and vimentin and triple expression for cytokeratin, vimentin and GFAP. Monospecific CEA antibody positivity could be demonstrated in 24.2% of acinic cell carcinoma, while nonspecific cross reacting antigens (NCAs) were positive in acinic cell carcinomas to a varying degree. Alpha 1-antichymotrypsin was positive in 97.4% of acinic cell carcinomas. 2.5% of acinic cell carcinomas showed focal infiltration by S-100 positive dendritic stromal cells, 2.5% of acinic cell carcinomas were positive for S-100 protein with no dendritic stromal cells present. Leu-M 1 antigen was positive in 86.8% of acinic cell carcinomas. For S-100 protein and Leu-M 1, no correlation with the clinical course, as reported previously for other tumours, could be observed.Supported by the Deutsche Forschungsgemeinschaft (DFG), the Hamburger Landesverband für Krebsbekämpfung und Krebsforschung, and the Hamburger Stiftung zur Förderung der KrebsbekämpfungProf. Dr. Dres. h.c. W. Doerr on the occasion of his 75th birthday     

Sclerosing mucoepidermoid carcinoma of the salivary glands

Mucoepidermoid carcinoma (MEC) comprises approximately 30% of all salivary gland malignancies, making it the most common malignant tumor of the salivary glands. Multiple histologic variants with a wide range of differentiation have been described. Sclerosing MEC (SMEC) is a rare subtype that may be misdiagnosed as a benign reactive condition or low-grade non-SMEC malignancy. We report 4 cases of SMEC and evaluated them with Her-2/neu and MIB-1 to determine whether an association exists between the histologic grade and immunohistochemical findings. In 3 cases, histologic examination demonstrated relatively well-circumscribed, nonencapsulated tumors composed of extensive central sclerosis with keloid-like stroma and scattered epithelial islands of low-grade MEC. In the fourth case, the tumor showed similar sclerotic stroma; but the epithelial component was of intermediate grade. In all 4 cases, eosinophils and neutrophils were part of the inflammatory infiltrate; and the edges were surrounded by lymphoid tissue, with germinal center formation and residual epithelial islands. A Mayer mucicarmine stain revealed abundant intracytoplasmic mucin. We found MIB-1 labeling indices of 5% or less in cases 1, 2, and 3 and 12% in case 4, suggesting an association between MIB-1 index and tumor grade. The tumors were negative for Her-2/neu in all 4 cases. The latter seems to bear no relationship to tumor grade.     

Mucoepidermoid carcinoma of upper aerodigestive tract: clinicopathologic study of 78 cases with immunohistochemical analysis of dicer expression

MicroRNAs (miR) are small noncoding RNAs that are predicted to regulate up to 30% of protein-encoding genes. miR maturation requires functional microRNA machinery, including the Dicer protein. We review our experience with mucoepidermoid carcinoma (MEC) and characterize the prognostic value of Dicer expression. Expression of Dicer was assessed in 78 MEC by immunohistochemistry. Dicer expression was scored semiquantitatively and relative to the internal controls: large excretory/striated ducts or basal/parabasal layers of normal squamous epithelium (mucosa). Dicer scores were then correlated with clinical and pathologic parameters. Dicer over- and/or under-expression were more commonly seen in high-grade MEC (83%) than in low/intermediate grade MEC (35%; p = 0.002) and in stage III/IV MEC (80%) than in stage I/II MEC (41%; p = 0.04). Abnormal Dicer expression correlates with high-grade and advanced stage, acting as a univariate predictor of poor disease-specific survival (DSS) in MEC. Age and stage were independent predictors of poor DSS on multivariate analysis. Abnormal immunoexpression of Dicer in aggressive MEC suggests a role for miR and miR machinery in tumor progression.     

An intracapsular carcinoma ex pleomorphic adenoma with lung metastases composed exclusively of benign elements: Histological evidence of a continuum between metastasizing pleomorphic adenoma and carcinoma ex pleomorphic adenoma

Malignant mixed tumors of the salivary glands, encompassing carcinoma ex pleomorphic adenoma (ca ex PA), carcinosarcoma and metastasizing pleomorphic adenoma (mPA), are rare neoplasms. Ca ex PA arises in a pre-existing pleomorphic adenoma (PA). When the malignant component does not breach the capsule of the parent PA, the lesion is termed intracapsular ca ex PA, a neoplasm which is thought to have no metastatic potential. Metastatic deposits of ca ex PA are composed exclusively of malignant elements or mixed benign and malignant components. We describe the case of a 62-year-old female with an intracapsular ca ex PA of the buccal mucosa with subsequent metastases to the lung. The metastatic deposits resembled benign PA with no histological evidence of malignancy. This pattern of spread is described with mPA, an entity that caused controversy in the past regarding its exact classification as a benign or malignant tumor. The possibility that ca ex PA originates from a mPA, with intracapsular ca ex PA representing an intermediate lesion in a histological continuum, is discussed.     

Sclerosing mucoepidermoid carcinoma with eosinophilia of the salivary glands

We encountered two cases of low malignant mucoepidermoid carcinoma with scanty cellular atypism which originated in the parotid or submandibular gland and was characterized by marked fibrosis and eosinophilic infiltration within tumor tissue despite the predominance of the squamous component. Here we report these two cases and provide a review of the literature. We believe that clinically these two tumors with stromal fibrosis and eosinophilic infiltration have a low malignant potential, although histological examination revealed a scanty mucus-producing epithelial component. Therefore, we consider this type of tumor as a new subtype of mucoepidermoid carcinoma. A low-malignant mucoepidermoid carcinoma with stromal fibrosis and eosinophilic infiltration, as described in these two cases, may be misdiagnosed as a highly malignant mucoepidermoid carcinoma or squamous cell carcinoma because of its histologically scanty mucus-producing epithelial component. The objective of this study was to clarify their differences and to discuss the rendering of an accurate histological diagnosis, the degree of malignancy in relation to prognosis prediction, and the choice of therapy. In addition, we propose regarding this type of tumor as a new subtype of mucoepidermoid carcinoma.     

Combined salivary duct carcinoma and squamous cell carcinoma suspected of carcinoma ex pleomorphic adenoma

A 76‐year‐old Japanese woman had noticed an asymptomatic and palpable mass in her left parotid gland region for 20 years. The tumor had showed rapid growth during the last two months. Therefore, the tumor was clinically suspected of being a malignant tumor and was surgically resected. A histopathological examination revealed that the tumor consisted of two different histopathological neoplastic components accompanied by hyalinized fibrosis at the center of the tumor. The two‐neoplastic components were squamous cell carcinoma and salivary duct carcinoma. The tumor was suspected to be a carcinoma ex pleomorphic adenoma after considering the clinical course and the histopathological findings, such as hyalinized fibrosis at the center of the tumor. There was no evidence of recurrence at 30 months after the surgical resection.     

A case of mucoepidermoid carcinoma with melanin pigmentation manifested in the palate

This paper describes the first documented case of mucoepidermoid carcinoma (MEC) with melanin pigmentation manifested in the palate. Histopathological sections showed a neoplasm composed of epidermoid, mucous-producing and intermediate cells. Numerous large cells contained dark pigmented materials. Fontana Masson staining revealed dendritic melanocytes and melanin granules. HMB-45, Melan A and S-100 protein were all positive for melanocytes. Histopathological examination was not typical for malignant melanoma; the lesion was diagnosed as a low-grade MEC with melanin pigmentation.M. Vieth received a research grant from the Japanese Society of Pathology at the Institute of Pathology, Shiga University of Medical Science, Ohtsu, Japan     

Ultrastructural similarities of adenoid cystic carcinoma and pleomorphic adenoma

Ultrastructural examination of five adenoid cystic carcinomas, three breast and two salivary gland, reveals identical patterns of tumour cell differentiation, organization and distribution of cellular products (Zaloudek, Oertel & Orenstein 1984). In both sites, there is proliferation of two populations of cells, one with characteristics and organization of duct-type luminal epithelial cells and a second that forms the principal proliferating component and has the overall organization and appearance that would suggest that they represent modified myoepithelial cells. Recent ultrastructural studies also indicate that tumour cell types and histological organization similar to those described for adenoid cystic carcinoma occur during histodifferentiation of salivary gland pleomorphic adenoma (Dardick et al. 1983a, b). The characteristic histological pattern of adenoid cystic carcinoma is dependent on the formation of pseudolumina containing proteoglycans and reduplicated basal lamina. Similar, but smaller, lumina of like organization and contents are evident in some cases of pleomorphic adenoma. Both the ultrastructural similarities of the tumour cell types and their organization, in adenoid cystic carcinoma and pleomorphic adenoma, suggest that these tumours have a similar histogenetic basis. The fact that one lesion is malignant and the other benign does not preclude common types of tumour cells and developmental processes.     

Light-electron microscopic and cytochemical studies on the morphogenesis of familial medullary thyroid carcinoma

Summary Six cases of familial medullary thyroid carcinoma (MTC) were investigated by light and electron microscopy as well as by ultracytochemical methods. Light microscopic examination revealed multifocal C-cell proliferation in 5 subjects. These cells were mostly limited to thyroid follicles, but occasionally extended across the follicular capsule forming microscopic MTC. Electron microscopic examination showed that, in some follicles, the proliferating C-cells were still covered by a continuous layer of follicular cells, whereas in others the proliferation extended to the follicular center. C-cells were in direct contact with the colloid, and ultramicroinvasion of the follicular capsule was detected. These observations are consistent with the hypothesis that familial MTC seems to begin as multifocal C-cell proliferation, limited at first to thyroid follicles, between the capsule and the follicular epithelium. Later, the proliferation extends to the follicular center, and C-cells come in contact with the colloid, at which time an in situ carcinoma stage is reached. Some neoplastic cells invade the follicular capsule and, finally, multiple MTC appear and eventually conglomerate.Generally, there were no constant morphologic criteria for a dysplasia or neoplasia among the proliferating C-cells limited to thyroid follicles, when compared with normal or even malignant C-cells. For these reasons, a hyperplastic or dysplastic process preceding MTC cannot be clearly distinguished from a neoplastic process. Our study, however, shows that a light microscopic, apparently hyperplastic process may be a malignant one.Amyloid was present in the more voluminous MTC, associated with tumor cell necrosis, but it was not evident in small MTC and within the foci of C-cell proliferation.Ultracytochemical techniques revealed that the secretory granules of normal, proliferating and neoplastic C-cells contained polysaccharides and/or glycoproteins.This investigation was supported by the MacDonald-Stewart Foundation of Montreal, and the Medical Research Council of Canada     

Mucoepidermoid carcinoma of the breast

Five cases of mucoepidermoid carcinoma (MEC) of the breast are reported. All patients were women ranging in age from 29 years to 80 years. As histological grading is one of the most important prognostic factors in breast invasive carcinomas, MEC was graded using the Auclair et al. [1] grading system specific for MEC of salivary glands and the Elston and Ellis [4] grading method, a widely employed grading system in breast cancer. It was found that the two different grading systems appear to be interchangeable in assessing the grade of MEC of the breast. Accordingly, three cases were regarded low grade (G. 1), one intermediate (G. 2) and one high grade (G. 3). The cases were studied with immunohistochemistry and were found to have the same keratin pattern shown by their salivary gland counterpart. It was found that there are more similarities than differences between MEC of the breast and of salivary glands.     

Cyclin D1 and p16 expression in pleomorphic adenoma and carcinoma ex pleomorphic adenoma of the parotid gland

AIMS: To compare cyclin D1 and p16(ink4) (p16) expression in normal tissue, pleomorphic adenoma (PA) and carcinoma ex pleomorphic adenoma (CXPA) of the parotid gland. METHODS AND RESULTS: Immunohistochemistry was used to examine cyclin D1 and p16 expression in 43 parotid tumours (29 PAs and 14 CXPAs). Cyclin D1 and p16 were both significantly more likely to be expressed in the neoplastic than in the normal epithelial and stromal components of PA and CXPA (P < 0.001 and P < 0.005, respectively). Cyclin D1 was more likely to be expressed in the malignant components of CXPA than in the benign components of PA (50% versus 31% and 31%, respectively), but the trend was not statistically significant. There was no evidence of this association for p16 (corresponding positivity rates 69% versus 81% and 52%). CONCLUSIONS: Our findings provide preliminary evidence of roles for cyclin D1 and p16 in the development of PA and for cyclin D1 in the progression of PA to CXPA.     

Oncocytic myoepithelioma and pleomorphic adenoma of the salivary glands

 Twenty oncocytic myoepitheliomas (MEs) and pleomorphic adenomas (PAs) were composed of interlacing fascicles of swollen spindle-shaped or/and epithelioid oncocytic myoepithelial cells showing intense finely granular immunoreactivity with anti-mitochondrial antibody. Focal vacuolation of the cytoplasm of oncocytic myoepithelial cells and their gradual transition into sebaceous metaplasia were observed in 3 cases. Another unusual feature found in 5 cases was the presence of slit-like adenomatoid spaces lined with double-layered oncocytic myoepithelium closely resembling Warthin’s tumour. The nuclei of oncocytic cells were characterized by enlargement, hyperchromasia and polymorphism, which should not be confused with malignancy. Oncocytic change in myoepithelial cells in MEs and PAs can cause pitfalls in the differential diagnosis of salivary gland tumours. We describe some unusual histological features associated with onococytic metaplasia in benign myoepithelial cell-derived salivary gland tumours, hoping to help to avoid the overdiagnosis of malignancy. Received: 24 September 1998 / Accepted: 31 January 1999     

Intraductal carcinoma is the precursor of carcinoma ex pleomorphic adenoma and is often associated with dysfunctional p53

AIMS: Although intraductal carcinoma has been demonstrated in intracapsular carcinoma ex pleomorphic adenoma (CEPA), the morphological and genetic stages of transformation of pleomorphic adenoma (PA) to CEPA are not fully understood. The aim of this study was to investigate the morphology of intracapsular CEPA. METHODS AND RESULTS: The largest series of intracapsular CEPA studied was subject to immunohistochemical double-staining to detect p53 protein and cellular proliferation in different types of cell combined with mutational analysis of the p53 gene in laser-microdissected material. Intraductal carcinoma with high-grade cellular atypia and frequent accumulation of p53 protein was found in 15/19 cases. Purely intraductal carcinoma was found in eight cases. Mutation of p53 was found in 7/19 cases, of which it was found in intraductal carcinoma in 5/15 cases. CONCLUSIONS: The frequent demonstration of intraductal carcinoma indicates that this preinvasive lesion is likely to be a constant feature in the malignant transformation of PA to CEPA. It appears to be a feature of CEPA developing from both primary and recurrent PA. The combined immunohistochemical and genetic data show that 14/19 cases of CEPA and 11/15 cases with intraductal carcinoma showed genetic or morphological evidence of dysfunctional p53, indicating that this is an early event in malignant transformation.     

Ultrastructural observations on luminal structures of pleomorphic adenoma of parotid and submandibular salivary glands of man

Summary Luminal structures found in salivary pleomorphic adenomas consisted of lumina surrounded by epithelial cells that varied from being packed together to being widely separated except at the luminal margin. Communication between lumina and the surrounding stroma was occasionally seen. Secretory material and cellular debris were seen in lumina, invaginations of the luminal surfaces of periluminal cells, associated vesicles, and vacuoles. Secretory granules, lysosomes and lipofuscin were seen in periluminal cells. Secretory material and debris from necrotic periluminal cells appear to accumulate in lumina, and to be endocytosed and degraded lysosomally by periluminal cells. The finding of communications between lumina and the surrounding stroma suggests that the stromalization of the epithelium includes the luminal structures. The present investigation supports the hypothesis that many of the cellular features of the pleomorphic adenoma relate to the microenvironment.     

Salivary duct carcinoma: report of a case and review of the literature

Summary Salivary duct carcinoma is a rare primary tumour of the salivary glands arising most frequently in the parotid gland. It has a male preponderance and occurs most often in patients over the age of 50 years. Its distinctive histological features include dilated ducts containing cells arranged in cribriform, papillary or solid patterns often with central necrosis and reminiscent of intraduct carcinoma of the breast. These features are associated with an obvious invasive component. It is an aggressive neoplasm and may metastasize widely, causing death in a high proportion of cases.     

Cyclin A expression and its diagnostic value in pleomorphic adenoma and carcinoma expleomorphic adenoma of the parotid gland

AIMS: To investigate cyclin A expression in pleomorphic adenoma (PA) and carcinoma expleomorphic adenoma (CXPA) of the parotid gland with a view to assessing its potential value as a diagnostic marker for CXPA. METHODS AND RESULTS: Cyclin A expression in PA and CXPA was studied using semiquantitative immunohistochemistry. The epithelial component of the tumours expressed cyclin A in a statistically significantly (P < 0.005) higher number of CXPA cases (86%) compared with the PA cases (39%). Cyclin A was not expressed in normal salivary tissues of PA and CXPA. CONCLUSIONS: High cyclin A expression is a useful marker for the pathological diagnosis of CXPA.     

Pigmented pleomorphic adenoma,a novel melanin-pigmented benign salivary gland tumor

This paper reports a pleomorphic adenoma with grossly visible pigmentation resulting in the macroscopic appearance of melanotic lesion in a 33-year-old Japanese male. In addition to the characteristic histopathological features of a benign pleomorphic adenoma, variously formed and -sized cells, many of which were considered to be melanocytes, containing melanin pigment in their cytoplasm, were distributed in the epithelial component. In addition, melanin pigment was deposited in tumor cells of duct structures. Furthermore, condensed secretory substances with marked pigmentation were frequently seen in the tubular lumina. Perusal of the English language literature revealed only two cases of parenchymal pigmentation of salivary gland tumors: both were mucoepidermoid carcinoma. The possible histogenesis of melanocytes in the salivary gland lesions is discussed, though no firm conclusion could be drawn.     

Pleomorphic adenoma and carcinoma ex pleomorphic adenoma: immunohistochemical demonstration of the association between tenascin expression and malignancy

AIMS: To investigate tenascin expression in salivary gland tumours. Tenascin is a matricellular protein that has been studied in several tumour types. Its expression has been correlated with tumour morphogenesis as well as with local invasiveness and tumour metastatic behaviour. METHODS AND RESULTS: The distribution pattern of tenascin in a series of 63 pleomorphic adenomas (PA) and 20 carcinomas ex- pleomorphic adenoma (Ca ex PA) was studied immunohistochemically. Ten normal adult salivary glands were used as controls. Tenascin surrounded the excretory ducts of normal adult salivary gland tissue. It was absent in the basement membrane compartment of both benign and malignant mixed tumours. In the interstitial compartment of the extracellular matrix, the fibro-hyaline type expressed tenascin in a statistically significantly (P < 0.001) lower number of PA cases (25%) in comparison with both malignant and benign areas of Ca ex PA (75% and 90%, respectively). In the Ca ex PA group, a statistically significantly difference (P < 0.001) was found in the frequency of tenascin deposits around aggregates of neoplastic cells between metastasizing (73%) and non-metastasizing neoplasms (0%). CONCLUSIONS: These findings strongly support the hypothesis that tenascin deposition is involved in the mechanisms of malignant transformation of pleomorphic adenomas into carcinomas as well as being associated with clinical disease progression.