Do Myoepithelial Cells Hold the Key for Breast Tumor Progression?

Mammary myoepithelial cells have been a neglected facet of breast cancer biology, largely ignored since they have been considered to be less important for tumorigenesis than luminal epithelial cells from which most of breast carcinomas are thought to arise. In recent years as our knowledge of stem cell biology and the cellular microenvironment has been increasing, myoepithelial cells are slowly starting to gain more attention. Emerging data raise the hypothesis whether myoepithelial cells play a key role in breast tumor progression by regulating the in situ to invasive carcinoma transition and that myoepithelial cells are part of the mammary stem cell niche. Paracrine interactions between myoepithelial and luminal epithelial cells are known to be important for regulation of cell cycle progression, establishing epithelial cell polarity, and inhibiting cell migration and invasion. Based on these functions, normal mammary myoepithelial cells have been called “natural tumor suppressors.” However, during tumor progression myoepithelial cells seem to loose these properties, and eventually this cell population diminishes as tumors become invasive. Better understanding of myoepithelial cell function and their role in tumor progression may lead to their exploitation for cancer therapeutic and preventative measures.     

The pathology of head and neck tumors: the myoepithelial cell and its participation in salivary gland neoplasia, Part 17

Sharing a common ectodermal origin with salivary duct epithelium, the myoepithelial cell is two-sided in several respects. It lies between the epithelial cells and the basal lamina, with one side facing the duct or acinar cells and the other facing the stroma. It has a fine structure not unlike that of smooth muscle, and one of its functions is to contract. Despite its electron-optic similarity to smooth muscle, the myoepithelial cell's principal filamentous protein is cytokeratin, which is found only in epithelial cells. Myoepithelial cells do not have a demonstrable secretory capability, but they can store glycogen in abundance. In some tumors of the salivary glands, myoepithelial cells do not participate in histogenesis. These tumors arise from portions of the salivary duct system in which myoepithelial cells are not normally found. In tumors originating from intercalated ducts, myoepithelial cells may assume one of two roles; a passive presence or an active and integral formation of the tumors. Mixed tumors, clear cell tumors, plasmacytoid (hyaline cell) and fibroblastic myoepitheliomas, and terminal duct adenocarcinomas are examples of tumors in which the myoepithelial cell is prominent or dominant.     

Dual-color imaging of angiogenesis and its inhibition in bone and soft tissue sarcoma

BACKGROUND: Angiogenesis is a critical step in tumor growth, progression, and metastasis. Soft tissue and bone sarcoma are resistant to most therapeutic approaches. Angiogenesis of these tumors may be an effective target. We hypothesized that we could inhibit tumor growth by targeting angiogenesis in a mouse model of sarcoma. We demonstrate in this report, using powerful color-coded fluorescent imageable tumor-host models, the onset of angiogenesis of these sarcomas and its inhibition. MATERIALS AND METHODS: Transgenic mice were used as the host in which green fluorescent protein (GFP) is driven by a regulatory element of the stem cell marker nestin (ND-GFP). Nascent blood vessels express ND-GFP in this model. We visualized, by dual-color fluorescence imaging, angiogenesis of sarcoma formed by the HT-1080 human fibrosarcoma cell line expressing red fluorescent protein (RFP) in the ND-GFP mice. Tumor cells were injected into either the muscle or the bone. RESULTS: Nestin was highly expressed in proliferating endothelial cells and nascent blood vessels in the growing tumors, including the surrounding tissues. Immunohistochemical staining showed that CD31 colocalized in ND-GFP-expressing nascent blood vessels. The density of nascent blood vessels in the tumor was readily quantitated. The mice were given daily i.p. injections of 5 mg/kg of doxorubicin after implantation of tumor cells. Doxorubicin significantly decreased the mean nascent blood vessel density in the tumors as well as decreased tumor volume. CONCLUSION: The dual-color model of the ND-GFP nude mouse and RFP sarcoma cells is useful for the visualization and quantitation of bone and soft tissue tumor angiogenesis and evaluation of angiogenic inhibitors for such tumors. These data suggest targeting angiogenesis of sarcomas as a promising clinical approach.     

Cell adhesion and regulatory molecules involved in tumor formation,hemostasis, and wound healing

Background. Dynamic changes in cell adhesion and migration are fundamental properties of the cells that are important in hemostasis, vascularization, and wound repair. Changes in cell adhesion and migration are very important in the formation of tumors, and invasion and metastasis by neoplasms. Methods. Using immunolocalization and immunopurification techniques, expression of integrin molecules involved in cell adhesion has been characterized during tumor development and wound healing. The ability of cytokines to regulate expression and antibody and peptide inhibitors to inhibit function of integrins has been explored to better understand the role of integrins in pathogenesis. Results. Increased suprabasilar expression of the integrins α6β4, α2β1, and α3β1 accompanies development of squamous cell neoplasms of the head and neck. Integrin αllβ3 is an integrin receptor which is important in platelet aggregation in hemostasis and formation of tumor metastases. Increased expression of integrin αvβ3 has been identified in angiogenesis in response to growth factors and tumor angiogenic factors. Cytokine TGF-β and arachadonic acid metabolite 12(S)-HETE are important signals in regulation of integrins and affect cell aggregation and migration in these processes. Ligands and inhibitors for some of these receptors have been identified which will be useful in determining their role during tumor development and progression. Conclusions. Recent advances in understanding the functions of the integrin cell adhesion molecules may soon add new diagnostic methods and therapies to the armamentarium of the head and neck oncologic, microvascular, plastic, and reconstructive surgeon. Therapies directed at controlling integrin cell-adhesion molecule expression and function are being explored to improve scar formation, bone synthesis, inhibition of vascular occlusion, and inhibition of tumor invasion and metastasis. © 1995 Jons Wiley & Sons, Inc.     

Regulation of prostatic growth and function by peptide growth factors

Polypeptide growth factors are positive and negative regulators of prostatic growth and function. Expression and biological effects of epidermal growth factor (EGF), transforming growth factors (TGFs) α and β, fibroblast growth factors (FGFs), and insulin-like growth factors (IGFs) in the prostate have been extensively studied. EGF and TGFα, which share the same receptor, are strong mitogens for prostatic epithelial and stromal cells. Their paracrine mode of action in normal tissue and early-stage tumors is apparently altered towards an autocrine stimulation in hormone-independent tumors, which gain the ability to produce TGFα by themselves. TGFβ has a dual role in the regulation of prostatic growth. It inhibits growth of prostatic epithelial cells in culture and mediates programmed cell death after androgen withdrawal. However, advanced prostatic carcinomas become insensitive to the inhibitory effect of TGFβ. Several members of the FGF family have been identified in the prostate. They are mainly or exclusively expressed in the stromal cells, and stimulate the epithelial cells. In the rat Dunning tumor model, progression is accompanied by distinct changes in the expression of FGFs and their receptors. In the hyperplastic tissue, basic FGF (bFGF) is accumulated. This growth factor is also a potent angiogenic inducer, expression of which may determine the metastatic capability of a tumor. IGFs are paracrine growth stimulators in the normal and hyperplastic prostate. It is still under consideration whether prostatic cancer cells gain the ability to produce IGF-I by themselves and thus shift to an autocrine mode of IGF-I stimulation. Growth factors also interact with the androgen-signaling pathway. IGF-I in particular, other growth factors as well, can activate the androgen receptor. © 1996 Wiley-Liss, Inc.     

Use of Myoepithelial Cell Markers in the Differential Diagnosis of Benign,In situ,and Invasive Lesions of the Breast

Immunohistochemical markers for myoepithelial cells are commonly used to distinguish invasive from noninvasive lesions in the breast. The approach takes advantage of the fact that conventional invasive carcinomas lack surrounding myoepithelial cells, whereas nearly all benign lesions and in situ carcinomas retain their myoepithelial cell layer. Although conceptually straightforward, the interpretation of myoepithelial cell markers can be complicated by misleading patterns of reactivity (such as stromal or tumor cell staining) or lack of reactivity (due to reduced numbers of myoepithelial cells or variable antigenicity). In this article, we discuss the advantages and disadvantages of commonly used myoepithelial cell markers, their general utility in distinguishing invasive from noninvasive processes, and pitfalls in their interpretation. We also examine whether the detection of myoepithelial cells is helpful in the evaluation of papillary lesions, another common application. Myoepithelial cell markers can be diagnostically useful in the distinction of many benign, in situ, and invasive lesions, but they must be interpreted in conjunction with careful morphologic analysis.     

Role of nerve growth factor-like protein in the paracrine regulation of prostate growth.

Prostate cancer is the most commonly diagnosed form of malignant neoplasia in men. Considerable evidence has accumulated suggesting that paracrine interactions between stromal cells and epithelial cells mediate, in part, the growth and development of the prostate. A nerve growth factor-like protein secreted by stromal cells has been implicated in the paracrine regulation of prostate epithelial tumor cell growth in vitro. This prostate-derived nerve growth factor-like protein differs from the known members of the neurotrophin family of proteins, and may represent a prostate-specific form of this family of gene products. Furthermore, corresponding nerve growth factor receptors have been localized to the epithelial cells of the human prostate in vivo, consistent with a role of the receptors and the adjacent nerve growth factor-like protein secreted by stromal cells, in the paracrine regulation of prostate growth and neoplasia.     

Antiangiogenic therapy for liver metastasis of gastrointestinal malignancies

In about half of the patients with gastrointestinal carcinomas, surgical excision of the primary tumor is not curative because metastasis has already occurred. Recent investigations of metastasis have shown that angiogenesis plays an important role in this process. In solid tumors angiogenesis occurs continuously to provide a blood supply for the proliferating cancer cells. As a new and potent method to control metastasis, antiangiogenic therapy has attracted considerable interest. This therapy inhibits angiogenesis, inducing a dormant state in which tumors cannot grow; the prognosis may thus be remarkably improved. Antiangiogenic agents show a characteristic antitumor effect which is different from that of chemotherapy. Based on our experimental in-vivo data, we conclude that antiangiogenic agents should not be used only for achieving tumor shrinkage, like chemotherapy. These agents should be used to control micrometastases, as the therapeutic effect on such metastasis is excellent. In addition, antiangiogenic agents may be valuable for long-term administration to maintain tumor dormancy, because drug resistance does not develop and these agents have a sustained effect. Combinations with conventional anti-cancer treatments such as chemotherapy, radiotherapy, immunotherapy, or surgery may also be valuable. Received for publication on Aug. 30, 1998; accepted on Nov. 2, 1998     

Myoepithelial Cells: Their Origin and Function in Breast Morphogenesis and Neoplasia

The human breast epithelium is a branching ductal system composed of an inner layer of polarized luminal epithelial cells and an outer layer of myoepithelial cells that terminate in distally located terminal duct lobular units (TDLUs). While the luminal epithelial cell has received the most attention as the functionally active milk-producing cell and as the most likely target cell for carcinogenesis, attention on myoepithelial cells has begun to evolve with the recognition that these cells play an active part in branching morphogenesis and tumor suppression. A major question that has been the subject of investigation pertains to how the luminal epithelial and myoepithelial lineages are related and precisely how they arise from a common putative stem cell population within the breast. Equally important is the question of how heterotypic signaling occurs between luminal epithelial and surrounding myoepithelial cells in normal breast morphogenesis and neoplasia. In this review we discuss data from our laboratories and from others regarding the cellular origin of human myoepithelial cells, their function in maintaining tissue polarity in the normal breast, and their role during neoplasia.     

Pigment epithelium-derived factor targets endothelial and epithelial cells in Wilms' tumor

Purpose

Loss of pigment epithelium-derived factor (PEDF), a potent inhibitor of angiogenesis, has been linked to progression of angiogenesis-dependent diseases. We postulated that decreased levels of endogenous PEDF in the kidney creates a tumor permissive environment for Wilms' tumor.

Methods

Fresh and frozen Wilms' tumor (n = 28), adjacent (n = 3), and normal kidney (n = 8) were immunostained and graded. The Wilms' tumor cells (SK-NEP-1), renal epithelial cells (NRK-52), and fresh tumor samples were grown in culture. Condition media were collected and analyzed by an in vitro angiogenesis assay and Western blot. The SK-NEP-1 cells were treated with PEDF and cell viability assessed.

Results

Wilms' tumors expressed less PEDF than normal and adjacent kidney. Pigment epithelium-derived factor protein secretion was abundant in NRK-52 cells but significantly decreased in Wilms' tumor. Pigment epithelium-derived factor acted as blockade to angiogenesis and it had a dose-dependent cytotoxic effect on Wilms' tumor epithelial cells.

Conclusion

Renal tubular epithelial cells are a rich source of PEDF in the normal kidney. Reduced levels of PEDF in Wilms' tumor remove a critical endogenous renal barrier to angiogenesis and tumor cell survival. Therapeutic replacement of PEDF may prove to be an effective strategy to combat Wilms' tumor progression.     

Blood vessels are regulators of growth, diagnostic markers and therapeutic targets in prostate cancer

The vasculature plays an important role in the normal and malignant prostate. Under basal conditions both glandular epithelial and stromal prostate cells produce an abundance of blood flow and angiogenesis regulating substances and the expression of these is generally increased in prostate tumors. The proportion of proliferating endothelial cells is high in the normal prostate compared to other tissues in the body. After castration effects on the vasculature, such as decreased blood flow and vascular regression, precede effects on the glandular compartment. Correspondingly, hormone induced prostate growth is characterized by early effects on the vasculature such as increased blood flow and endothelial cell proliferation, thus indicating that the vasculature may be involved in the androgenic regulation of the prostate. Prostatic intraepithelial neoplasia (PIN) and prostate cancer are associated with increased vascular density and in experimental models prostate cancer growth is apparently angiogenesis-dependent since tumor growth and progression can be inhibited by antiangiogenic treatment. Moreover, vascular density has been related to prognosis in prostate cancer patients. A better understanding of the pathways regulating angiogenesis in the normal prostate and how these pathways change during malignant transformation can hopefully lead to better prognostic markers and therapies for the large group of patients with prostate cancer. The purpose of this review is therefore to summarize the current knowledge on the role and regulation of the vasculature in the prostate and its potential clinical applications.     

Is it ductal carcinoma in situ with microinvasion or “Ductogenesis”? The role of myoepithelial cell markers

Mammary myoepithelial cells have been under‐recognized for many years since they were considered less important in breast cancer tumorigenesis compared to luminal epithelial cells. However, in recent years with advances in genomics, cell biology, and research in breast cancer microenvironment, more emphasis has been placed on better understanding of the role that myoepithelial cells play in breast cancer progression. As the result, it has been recognized that the presence or absence of myoepithelial cells play a critical role in the assessment of tumor invasion in diagnostic breast pathology. In addition, advances in screening mammography and breast imaging has resulted in increased detection of ductal carcinoma in situ and consequently more diagnosis of ductal carcinoma in situ with microinvasion. In the present review, we discuss the characteristics of myoepithelial cells, their genomic markers and their role in the accurate diagnosis of ductal carcinoma in situ with microinvasion. We also share our experience with reporting of various morphologic features of ductal carcinoma in situ that may mimic microinvasion and introduce the term of ductogenesis.     

Biology of vascular endothelial growth factor and its receptors in head and neck cancer: beyond angiogenesis

Angiogenesis is a necessary process for tumor progression and is driven through molecular interactions between cancer cells and neighboring vascular endothelial cells. The primary mediators of angiogenesis are the vascular endothelial growth factors and their respective receptors on endothelial cells. There are several U.S. Food and Drug Administration-approved anti-angiogenic agents in clinical use. In head and neck cancer there are clinical trials assessing the efficacy of anti-angiogenic agents in combination with chemoradiation therapy. Although the aforementioned growth factors and receptors have been traditionally viewed as anti-angiogenic targets, there are concomitant efforts to understand the role these molecules play within the tumor cells. In this review, we first discuss the biology of angiogenic proteins and the targeting of angiogenic molecules for cancer treatment. We summarize the current clinical trials of anti-angiogenic therapies in head and neck squamous cell carcinoma. Finally, the additional role these molecules play in tumor progression independent of angiogenesis is discussed.     

Myoepithelial Tumors of Salivary Gland: A Clinicopathologic and Immunohistochemical Study of 15 Patients with MIB-1 Correlation

Myoepithelial neoplasms are rare tumors of the salivary glands with predominant myoepithelial differentiation and a broad histologic spectrum. Their histological features, immunohistochemical profile and biological behavior are not well characterized and pose a diagnostic challenge. A total of 15 myoepithelial tumors, diagnosed during 2012 and 2019 were subcategorized and correlated with MIB-1 labeling index (LI) and various histological parameters. Immunohistochemical stains for MIB-1 and other antibodies were performed. Statistical analysis was done by chi-square test, Fisher’s exact test and Kaplan Meier curve. Nine patients were male and six were female with the median age of 44 years (range 21–83 years). Of the 15 patients, 6 cases were classified as myoepithelioma (ME) and 9 cases as myoepithelial carcinoma (MECA). Parotid gland was the most common site (46.7%) followed by the palate. MEs showed well circumscribed tumor borders whereas MECAs exhibited focal capsular to extensive invasion into adjacent tissues. Epithelioid cell morphology was most common followed by mixed cell morphology. MIB-1 LI was significantly associated with invasive tumor borders, necrosis and high mitosis. Increased frequency of recurrence was noted with high MIB-1 LI, though it was not statistically significant. MIB-1 LI was high in nearly all MECAs with focal capsular to extensive invasion while low in MEs. Myoepithelial tumor with multinodular growth pattern and focal capsular invasion may have an indolent behavior if mitotic activity and MIB-1 LI is low. Early diagnosis and treatment of MECAs significantly improves the patient''s survival and prognosis.     

Myoepithelial Carcinoma Ex Pleomorphic Adenoma of the Maxillary Sinus: A Case Report and Review of Literature

Myoepithelial carcinoma ex pleomorphic adenoma is defined as a malignant epithelial neoplasm arising from a primary or recurrent benign pleomorphic adenoma. This type of tumor comprises 3.6% of all salivary gland tumors and 12% of malignant ones. Clinically, it most commonly presents as a firm mass in the parotid gland. The development of this neoplasm in the sinonasal and nasopharyngeal regions is extremely rare and only few cases are reported in the literature. The prognosis of myoepithelial carcinoma is variable. Marked cellular pleomorphism, high mitotic rate, and high proliferative activity correspond to a poor prognosis. In this article, the authors report the histopathological features of a clinical case of a 64-years-old patient with a large median maxillary neoplasm diagnosed as myoepithelial carcinoma/ex-pleomorphic adenoma. The tumor was resected and subjected to secondary reconstruction using a revascularized free fibula flap. The myoepithelial derivation of neoplastic cells was demonstrated by immunohistochemical positivity for S-100 protein (strong and diffuse), cytokeratin 14 (strong and diffuse), and GFAP (focal).     

Treatment of Human Pancreatic Cancer in Mice with Angiogenic Inhibitors

Tumor growth is dependent on the balance of positive and negative regulators of angiogenesis. Antiangiogenic compounds inhibit endothelial cell biology in vitro and angiogenesis in vivo. Therefore antiangiogenic therapy presumes to be an effective treatment for pancreatic cancer. We wanted to determine the effect of antiangiogenic therapy on the growth of human pancreatic cancer in a mouse model. The angiogenesis inhibitors TNP-470 and antiangiogenic antithrombin III (aaATIII) were tested in vitro for their ability to inhibit endothelial cell proliferation. These inhibitors, along with the known antiangiogenic molecule endostatin, were then employed to treat two different primary human pancreatic cancers implanted subcutaneously into the dorsa of immunodeficient (SCID) mice. Treated tumors were examined histologically for microvessel density, apoptosis, and proliferation. All three inhibitors suppressed the growth of pancreatic tumors in vivo. Immunohistochemical analysis revealed increased degrees of apoptosis and reduced microvessel density in treated tumors compared to untreated tumors, although tumor cell proliferation was the same in both groups. None of the inhibitors tested significantly inhibited proliferation of human pancreatic cancer cells, although both TNP-470 and aaATIII were able to inhibit the proliferation of endothelial cells. The observed tumor suppression may be due to increased tumor cell apoptosis as a result of capillary dropout. These studies show that after the angiogenic switch in a human tumor, there is residual production of angiogenesis inhibitors.     

Histogenesis of benign pleomorphic adenoma (mixed tumor) of the major salivary glands. An ultrastructural and immunohistochemical study

Twenty-two benign pleomorphic adenomas of the major salivary glands were studied by transmission electron microscopy and immunohistochemical techniques (three cases) in order to characterize the cell types comprising the epithelial and so-called mesenchymal regions of the tumors. Light- and electron-microscopic studies showed the tumors to consist of variable mixtures of neoplastic ductular epithelial cells, rare acinar cells, and metaplastic myoepithelial cells. Many of the loosely organized "stromal cells" contained structures indicative of their myoepithelial origin, e.g., perinuclear tonofilaments, ectoplasmic actin microfilaments, and remnants of basement membrane. Polyclonal antikeratin antisera strongly stained ductular epithelial and myoepithelial cells, squamoid cell nests, and periductular myoepithelial cells, whereas myxoid and chondroid cells were less intensely stained. Monoclonal cytokeratin antibody AE1 stained only the ductular epithelial cells in both the normal glands and tumors. In contrast, S-100 protein, which is present only in scattered acinar cells and myoepithelial cells in the normal parotid gland, was found in the ductular and periductular myoepithelial cells, isolated myxoid cells, and chondroid and cartilagenous cells in the tumors. Actin was found in all the cell types of the tumor but staining was strongest in the ducts. Double immunofluorescence staining for cytokeratin and vimentin revealed coexpression of both types of intermediate filaments in occasional normal acinar and intercalated duct myoepithelial cells, and in some cells in the myxoid and chondroid regions of the tumors. In the tumors, vimentin was present in occasional periductular myoepithelial cells, stellate myxoid cells, and especially in chondroid cells and chondrocytes. Our findings indicate that benign pleomorphic adenomas of the major salivary glands are pure epithelial cell tumors. The histologic complexity of these neoplasms is due to the ability of the neoplastic ductular myoepithelial cell to modulate its morphologic appearance and intermediate filament composition, and to produce large amounts of matrix substances. We further postulate that these tumors arise from neoplastically transformed intercalated ducts.     

Angiogenesis and breast cancer

The importance of angiogenesis in tumour progression and metastasis is well-recognized and has led to many developments; those with particular relevance to breast cancer are reviewed. There is now a clear understanding of the angiogenic switch, occurring as a discrete component of the tumour phenotype and depending on an alteration in the balance of angiogenic stimulators and inhibitors. The relationship between angiogenesis and oestrogen, which demonstrates an angiogenic effect, is examined. Clinical applications of breast tumour angiogenesis include its role as a prognostic indicator and potentially as a marker of treatment response. Therapeutic applications are under development, involving several different aspects of the angiogenic process and results of ongoing clinical trials are awaited with interest.     

Anti-angiogenesis in prostate cancer： knocked down but not out

Angiogenesis is a very complex physiological process, which involves multiple pathways that are dependent on the homeostatic balance between the growth factors （stimulators and inhibitors）. This tightly controlled process is stimulated by angiogenic factors, which are present within the tumor and surrounding tumor-associated stromal cells. The dependence of tumor propagation, invasion and metastasis on angiogenesis makes the inhibitors of new blood vessel formation attractive drugs for treating the malignancies. Angiogenesis can be disrupted by several distinct mechanisms： by inhibiting endothelial cells, by interrupting the signaling pathways or by inhibiting other activators of angiogenesis. This strategy has shown therapeutic benefit in several types of solid tumors, leading to Food and Drug Administration （FDA） approval of anti-angiogenic agents in the treatment of kidney, non-small cell lung, colon and brain cancers. Although no angiogenesis inhibitors have been approved for patients with metastatic prostate cancer, therapies that target new blood vessel formation are still an emerging and Dromising area of prostate cancer research.     

Myoepithelial Neoplasms of Soft Tissue: An Updated Review of the Clinicopathologic,Immunophenotypic, and Genetic Features

Myoepithelial tumors in skin and soft tissue are uncommon but have been increasingly characterized over the past decade. Men and women are equally affected across all age groups and lesions arise most frequently on the extremities and limb girdles. Approximately 20 % of cases occur in pediatric patients, in whom they are frequently malignant. Similar to their salivary gland counterparts, myoepithelial tumors of soft tissue demonstrate heterogeneous morphologic and immunophenotypic features. Tumors are classified as mixed tumor/chondroid syringoma, myoepithelioma, and myoepithelial carcinoma; in soft tissue, tumors having at least moderate cytologic atypia are classified as malignant. Mixed tumor and myoepithelioma show a benign clinical course, with recurrence in up to 20 % (typically secondary to incomplete excision), and do not metastasize. In contrast, myoepithelial carcinoma shows more aggressive behavior with recurrence and metastasis in up to 40–50 % of cases. The majority of myoepithelial neoplasms typically coexpress epithelial antigens (cytokeratin and/or EMA) and S-100 protein; GFAP and p63 are frequently positive and a subset of malignant neoplasms lose INI1 expression. Up to 45 % of myoepitheliomas and myoepithelial carcinomas harbor EWSR1 gene rearrangements, unlike mixed tumor/chondroid syringoma which is characterized by PLAG1 gene rearrangement. While mixed tumor/chondroid syringoma are likely related to primary salivary myoepithelial tumors, soft tissue myoepithelioma and myoepithelial carcinoma appear to be pathologically distinct neoplasms.