Mucoepidermoid carcinoma metastatic to the skin. An histologic mimic of a primary sweat gland carcinoma.

Mucoepidermoid carcinomas are tumors that usually arise from salivary glands and have a characteristic histologic pattern of atypical squamous cells showing focal mucin production. Mucoepidermoid carcinomas are uncommon neoplasms that metastasize most commonly via lymphatic and hematogenous channels. We report what we believe to be the first case of a mucoepidermoid carcinoma arising from a sublingual salivary gland with metastasis to a distant site on the skin. The patient is a 58-year-old black woman who was initially diagnosed with a high grade mucoepidermoid carcinoma of the salivary glands of the tongue. Approximately 18 months after presentation, and 6 months following surgery, chemotherapy, and radiation therapy, the patient noted a firm nodule on her flank. Biopsy showed malignant squamous epithelium. Periodic acid-Schiff and alcian blue stains revealed focal mucin production. The histologic differential diagnosis included an eccrine carcinoma, mucin-producing adenocarcinoma with squamous differentiation, a primary cutaneous adenosquamous (mucoepidermoid) carcinoma and a malignant mixed tumor of the skin. Clinical correlation was essential in making the correct diagnosis. While mucoepidermoid carcinomas only uncommonly show distant metastasis, and even less frequently involve the skin, this entity should be included in the differential diagnosis of mucin-producing neoplasms in the skin.     

Carcinoma of the salivary gland: a clinicopathologic study of 405 cases

Four hundred five cases with carcinoma of salivary glands were analyzed clinicopathologically; 181 tumors were located in parotid, 52 were in submandibular, 21 were in sublingual, and 151 were in minor salivary glands. Mucoepidermoid carcinoma and adenoid cystic carcinoma were the most common histologic types. The overall 3-, 5-, 10-, and 15-year survival rates were 77.8%, 69.6%, 55.8%, and 36.7%, respectively. The difference between survival and recurrence-free survival rate was 9%. The prognosis of acinic cell carcinoma and mucoepidermoid carcinoma was much better than that of squamous cell carcinoma, adenocarcinoma, and undifferentiated carcinoma. The survival rates of minor salivary gland tumors was the highest, and those of submandibular gland tumors were the lowest. Postoperative radiotherapy improved the prognosis of adenoid cystic carcinoma. The overall recurrence rate was 40.2%; the cervical lymph node metastases rate was 15.3%, and the distant metastases rate was 11.1%.     

CRTC1-MAML2 gene fusion in mucoepidermoid carcinoma of the lacrimal gland

Epithelial tumors of the lacrimal gland are histologically similar to salivary gland tumors. Here we report on a rare case of mucoepidermoid carcinoma (MEC) in a 73?year-old man with a swelling of the left lacrimal gland. The tumor had a microscopic appearance consistent with a classical low-grade MEC of the lacrimal gland. There were no signs of recurrence or metastases during a five-year follow-up. Using RT-PCR and FISH we demonstrated that the tumor was positive for the CRTC1-MAML2 gene fusion previously shown to be associated with in particular low-grade salivary MECs with favorable prognosis. By immunohistochemistry we showed that the majority of tumor cells, including epidermoid, intermediate and mucous producing cells, expressed the CRTC1-MAML2 fusion protein. In contrast, 15 non-MEC lacrimal neoplasm were fusion-negative. Our findings show that lacrimal MEC is not only clinically and morphologically but also genetically identical to MECs originating from other exocrine glands, including those of the lung, thyroid, cervix and salivary glands. Taken together, the present and previous studies further emphasize the fundamental biologic and genetic similarities among MECs developing from different anatomical sites and organs. Moreover, our findings indicate that the CRTC1-MAML2 fusion may be a useful diagnostic and prognostic biomarker for lacrimal MEC.     

116例腮腺粘液表皮样癌患者的预后因素分析

背景与目的:粘液表皮样癌是涎腺中最常见的恶性肿瘤,有关腮腺的粘液表皮样癌的大宗病例报道较少.本研究旨在探讨影响腮腺粘液表皮样癌患者预后的临床病理因素.方法:回顾性分析中山大学肿瘤防治中心1980年5月至2000年12月收治的116例腮腺粘液表皮样癌患者的临床资料,对其预后进行单因素和多因素分析.结果:116例腮腺粘液表皮样癌患者的5、10和15年生存率分别为75.64%、64.55%和60.39%.单因素生存分析显示年龄、饮酒及T分期等12项因素是腮腺粘液表皮样癌预后的影响因素.多因素分析表明T分期(P=0.006,OR＞1)、病理分级(P=0.000,OR＞1)、远处转移(P=0.000,OR＞1)是影响腮腺粘液表皮样癌患者预后的独立因素.结论:T分期、病理分级和远处转移是影响腮腺粘液表皮样癌患者预后的独立危险因素.     

Silencing of CXCR4 inhibits the proliferation, adhesion, chemotaxis and invasion of salivary gland mucoepidermoid carcinoma Mc3 cells in vitro

Mucoepidermoid carcinoma is the most common malignant tumor in salivary glands and high-grade mucoepidermoid carcinoma is often accompanied with poor prognosis. Many recent research works demonstrated that stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor-4 (CXCR4) interaction was critical for metastasis of various cancers. In this study, the immunoexpression of CXCR4 in human salivary gland mucoepidermoid carcinoma in different grades was detected by immunohistochemical analysis and the expression of CXCR4 and its ligand SDF-1 in mucoepidermoid carcinoma MEC-1 cell line and its highly metastatic clone Mc3 was examined by RT-PCR, flow cytometry and immunocytochemical analysis. It was found that CXCR4 was over-expressed in Mc3 cell line and SDF-1 was expressed in both cell lines at a nearly equal level. We further constructed CXCR4-shRNA expression vector to stably transfect Mc3 cells. We found that silencing of endogenous CXCR4 gene expression in Mc3 cells resulted in inhibition of the proliferation, adhesion, chemotaxis and invasion of Mc3 cells in vitro. This study implies that CXCR4 molecule is a potential factor controlling the proliferation and metastasis of Mc3 cells.     

Salivary gland tumors of the tongue. Analysis of 55 new cases and review of the literature

Fifty-five cases of primary salivary gland tumors of the tongue from the files of the Armed Forces Institute of Pathology are reported and analyzed and the results compared with the information in the literature. Five tumors were benign and 50 were malignant. The average age at presentation was 47 years for the benign tumors and 54.3 years for the malignant ones. Although the overall benign/malignant ratio was 1:10, women were more likely to have a malignant tumor than were men. The site of 80% of the benign tumors was the middle to anterior portion of the tongue, whereas over 85% of malignant tumors involved the base. Clinical signs and/or symptoms related to the site aroused suspicion in some cases but often were of short duration and in over 60% of cases did not occur. The most common benign tumor type was the myoepithelial variant of the benign mixed tumor. The most common malignant tumor type was the low-grade mucoepidermoid carcinoma (38%) followed by adenocarcinoma (20%), high-grade mucoepidermoid carcinoma (14%), adenoid cystic carcinoma (10%), and clear cell carcinoma (8%), with occasional basaloid, papillary cystadenocarcinoma, acinic cell and mucus-producing adenocarcinoma. Treatment was similar to that of other accessory salivary gland neoplasms of similar histologic type and clinical stage. Prognosis worsened with high histologic grade, old age, and advanced clinical disease at presentation.     

The range and demographics of salivary gland tumours diagnosed in a UK population

Salivary gland tumours are relatively rare and comprise a diverse range of neoplasms. The aim of this study was to determine the range and demographics of all histologically diagnosed salivary tumours in a European population. All entries for salivary gland tumours from 1974 to 2005 inclusive were retrieved and analysed for each diagnosis including number of specimens, male:female ratio and age range. These data were then analysed for the distribution of benign and malignant salivary tumours in major and minor salivary glands. 58,880 specimens were received; of these, 741 cases (1.3% of all specimens) were diagnosed as salivary gland tumours with a male to female ratio of 0.7:1. There were 481 (64.9%) benign and 260 (35.1%) malignant neoplasms, with the most common tumours being pleomorphic adenoma and mucoepidermoid carcinoma, respectively. Our study provides demographic data on a large series of salivary gland tumours in a European population. Accurate diagnosis is essential as salivary lesions have diverse clinical and prognostic outcomes. This study has confirmed that some tumours have a predilection for certain sites and that the risk of malignant disease is also greater at specific sites within the oral cavity.     

Benign, malignant salivary gland tumors: comparison of immunohistochemical expression of e-cadherin

The aim of the present study was to assess any variation in the immunohistochemical expression of E-cadherin in benign and malignant salivary gland tumors. A total of 60 cases of benign and malignant salivary gland tumors were evaluated immunohistochemically for E-cadherin expression. These included 10 cases of pleomorphic adenoma (PA), 2 cases of canalicular adenoma (CA), 2 cases of myoepithelioma (MY), 24 cases of adenoid cystic carcinoma (ACC), 12 cases of mucoepidermoid carcinoma (MEC), 9 cases of adenocarcinoma (AC) and 1 case of carcinoma ex pleomorphic adenoma (Ca Ex PA). 48 cases (80%) showed positive expression, in which benign tumors exhibited relatively increased reactivity (85.7%) as compared to the malignant tumors (78.3%). 10 PA, 2 MY, 20 ACC, 9 MEC, 6 AC and 1 Ca Ex PA expressed E-cadherin. Negative expression was evident in CA, ACC, MEC and AC. Statistically significant reduction in reactivity was evident in mucoepidermoid carcinoma and adenocarcinoma, when compared to pleomorphic adenoma.     

黏膜表皮样癌31例临床病理分析

目的 探讨黏膜表皮样癌的临床和病理特征.方法 通过对31例黏膜表皮样癌临床病理进行回顾性分析,结合文献进行讨论.结果 显示不同性别肿瘤发病部位有差异,发生于大涎腺者及颌骨者男多于女,而发生于小涎腺者反之.大、小涎腺病变平均年龄分别为37.1和35.4岁.组织学特征,高分化(76.7%),以黏液细胞、透明细胞和分化好的表皮样细胞为主,细胞呈大片状、囊腔状或腺管状.异型性不明显,核分裂少见.低分化以分化差的表皮样细胞和中间型细胞为主,癌细胞呈小团块状或条索状排列.腺管样和囊腔样结构少见,癌巢中心常坏死,异型性明显,核分裂多见,呈浸润性生长.结论 黏膜表皮样癌的病理分型对治疗方式有重要指导意义.     

Immuno-histochemical evaluation of Cathepsin D in malignant salivary gland carcinomas

Objective: Cathepsin D is a lysosomal acid protease secreted in increased levels in several malignancies. However, its role in salivary gland tumors has not been studied extensively. The present study aims to assess the expression of Cathepsin D in malignant salivary gland tumors and to compare its expression in these tumors. Study design: A total of 30 cases of malignant salivary gland carcinomas which included 16 cases of adenoid cystic carcinoma (ACC), 9 cases of mucoepidermoid carcinoma (MEC), and 5 cases of polymorphous low grade adenocarcinoma (PLGA) were evaluated immunohistochemically using anti-Cathepsin D antibody. Result: All the cases showed positivity (100%) for Cathepsin D with intense expression noted in ACC and MEC as compared to PLGA. Comparison of these tumors revealed statistical significant difference in expression between ACC and PLGA. Conclusion: Intense expression of Cathepsin D in high grade carcinomas may be a marker for invasive potential and aggressive behavior. Key words: Cathepsin D, Adenoid cystic carcinoma, Mucoepidermoid carcinoma, Polymorphous low grade adenocarcinoma.     

H-ras gene mutations in salivary gland mucoepidermoid carcinomas

BACKGROUND: The authors' recent investigation of salivary gland tumors in ras gene alteration has suggested that K-ras activation may not play a role in their oncogenesis but H-ras may, especially in mucoepidermoid carcinomas. A study was undertaken to assess the overall incidence of mutated H-ras genes in mucoepidermoid carcinomas and to discover its potential correlation with clinicopathologic parameters. METHODS: Fifty samples from patients with salivary gland mucoepidermoid carcinoma were analyzed for point mutations at codons 12, 13, and 61 of the H-ras gene using the polymerase chain reaction followed by automated direct sequencing methodology. RESULTS: Mutated H-ras genes were detected in 9 patients, for an overall incidence of 18% (9 of 50 patients). All but 1 of the mutations occurred at codon 12: a GGC-to-GTC transversion in 8 patients and a GGC-to-GAC transition in 1 patient, resulting in the amino acid substitution of valine and aspartic acid, respectively, for glycine. One of the samples showed concurrent mutations at codons 12 (GGC-to-GTC) and 13 (GGT-to-GGA). None of the samples demonstrated mutations involving codon 61. The H-ras mutations were observed in 5% (1of 21), 17% (2 of 12), and 35% (6 of 17) of low, intermediate, and high grade lesions, respectively. CONCLUSIONS: These data suggest involvement of H-ras activation in conjunction with other yet-unknown events in the development and/or progression of mucoepidermoid carcinomas. It is noteworthy that a stepwise increase in the frequency of H-ras mutations strongly correlates with tumor grade (P = 0.017). Molecular analysis of this gene alteration may provide assistance in the determination of tumor grade and differentiation.     

Mucoepidermoid carcinoma of the bronchus: an electron microscopic study of the low grade and the high grade variants.

Two cases of mucoepidermoid carcinoma of the bronchus--one a low grade tumor and the other a high grade tumor--are presented with findings by light and electron microscopy. This represents the first report of the ultrastructure of mucoepidermoid carcinoma of the bronchus and demonstrates the ultrastructural similarities between the low grade exophytic tumor confined to the bronchus and the high grade infiltrating tumor with lymph node and pulmonary metastases. The ultrastructural features are similar to those described for mucoepidermoid carcinoma of the salivary gland and are consistent with the proposed origin of the tumor from the submucosal bronchial gland duct. These two cases and a review of previously reported cases indicate that, analogous to mucoepidermoid carcinoma of the salivary glands, mucoepidermoid carcinoma of the bronchus may occur as either a low grade or high grade variant which can be identified on the basis of growth characteristics and histologic features.     

Application of laser capture microdissection to cytologic specimens for the detection of immunoglobulin heavy chain gene rearrangement in patients with malignant lymphoma

BACKGROUND: The demonstration of the monoclonality of immunoglobulin heavy chain (IgH) gene rearrangement is an indispensable method for the diagnosis of B-cell lymphoma as well as histocytochemical analysis. For the detection of IgH gene rearrangement, the extraction of DNA from a homogenous cell population is necessary. Recently, the laser capture microdissection (LCM) technique was shown to isolate specific cells from histopathologic specimens for molecular analysis. However, to the authors' knowledge the applicability of LCM to cytologic specimens has not yet been well established. METHODS: Using LCM, a homogenous population of B-cell lymphoma cells as both histologic sections and cytologic specimens was captured, and genomic DNA was extracted from the captured cells. IgH gene rearrangement was analyzed by the polymerase chain reaction (PCR)-based single-strand conformational polymorphism (SSCP) method. RESULTS: Genomic DNAs were extracted successfully from ethanol-fixed cytologic specimens, but cells were not captured from air-dried specimens. Using PCR-SSCP analysis, the monoclonality of the IgH gene rearrangement was detected in five cases of tissue sections among nine analyzed cases of malignant lymphoma diagnosed immunohistochemically. However, analysis of the cytologic specimens with LCM demonstrated the monoclonality of the IgH gene rearrangement in seven cases of lymphoma. CONCLUSIONS: The results of the current study suggest that the novel application of LCM to cytologic specimens occasionally exhibits high sensitivity for the detection of IgH gene rearrangement monoclonality compared with the use of histologic sections.     

SalvGlandDx – a comprehensive salivary gland neoplasm specific next generation sequencing panel to facilitate diagnosis and identify therapeutic targets

Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the “SalvGlandDx” panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.     

涎腺黏液表皮样癌中p16、p15的表达及相关性研究

[目的]研究p16、p15在正常涎腺组织和黏液表皮样癌中的表达,探讨其在黏液表皮样癌发生、发展中的作用及临床意义.[方法]应用免疫组化S-P法检测10例正常涎腺组织、45例黏液表皮样癌中p16、p15蛋白的表达.[结果]黏液表皮样癌中p16、p15的阳性表达率分别为62.2%、73.3%,显著低于其在正常涎腺组织中的表达(100%)(P＜0.05),且随肿瘤分化程度的降低而递减并具有显著性差异,其中p16的阳性率与淋巴结转移有关.p16、p15两基因在黏液表皮样癌的表达中呈显著相关性(P＜0.05).[结论]p16、p15的失表达与黏液表皮样癌的发生和发展关系密切,p16基因的异常可能是更为直接的因素.     

多药耐药基因在涎腺粘液表皮样癌中的表达及意义

目的探讨涎腺粘液表皮样癌多药耐药基因MDR1/P-gp的表达情况及其临床意义。方法应用免疫组织化学技术(EnVision法)检测36例涎腺粘液表皮样癌(其中高分化组21例、低分化组各15例)以及15例正常涎腺组织中MDR1/P-gp的表达。结果MDR1/P-gp在粘液表皮样癌及正常涎腺组织中均有不同程度表达,阳性部位主要见于细胞膜。高分化粘液表皮样癌、低分化粘液表皮样癌和正常涎腺组织MDR1/P-gp表达阳性率分别为81.0%(17/21)、73.3%(11/15)和26.7%(4/15),组间两两比较均具有显著性差异(P<0.01)。结论MDR1/P-gp是涎腺粘液表皮样癌多药耐药产生的重要细胞机制,检测MDR1/P-gp可为临床拟定化疗方案提供依据,也可作为判断涎腺粘液表皮样癌组织分化程度及预后的参考指标。