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Annals of Oncology : Official Journal... Oct 2013Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific...
BACKGROUND
Malignant tumours of the salivary glands (MSGT) are rare and pleomorphic entities. Patients with advanced disease may benefit from targeted therapy; however, specific targets for optimising and personalising treatments are yet to be identified.
DESIGN
Immunohistochemistry for C-KIT, EGFR, HER2, MUC1, phospho-mTOR, androgen/estrogens/progesterone receptors and Ki67 was carried out and evaluated in terms of progression-free and overall survival. High throughput molecular screening of key oncogenes was done in 107 patients using routine diagnostic methods and Sequenom technology.
RESULTS
Several therapy leads were identified, including high levels of HER2 and androgen receptors in salivary duct carcinomas, C-KIT in myoepithelial carcinomas and EGFR in mucoepidermoid carcinomas. Recurrent mutations involving downstream elements of the EGFR pathway were found in HRAS, notably in tumours with a myoepithelial component, and in other key oncogenes (KRAS/NRAS/PI3KCA/BRAF/MAP2K). On the other hand, <1% of samples had EGFR or HER2 mutations.
CONCLUSION
Several tumour subtypes overexpressed targets of directed therapies suggesting potential therapy leads. Genotyping results suggest activation downstream of EGFR in 18 of the 107 samples that could be associated with low efficacy of EGFR inhibitors. Other molecules, such as PI3K/MEK or mTOR inhibitors, may have anti-tumour activity in this subgroup. The high mutation rate in HRAS highlights a novel key oncogenic event in MSGT.
Topics: Androgen Receptor Antagonists; Biomarkers, Tumor; Carcinoma, Mucoepidermoid; Chemotherapy, Adjuvant; Disease-Free Survival; ErbB Receptors; Female; Genotype; High-Throughput Screening Assays; Humans; Male; Middle Aged; Molecular Targeted Therapy; Myoepithelioma; Oncogenes; Proto-Oncogene Proteins c-kit; Receptor, ErbB-2; Receptors, Androgen; Salivary Gland Neoplasms; Survival
PubMed: 23933559
DOI: 10.1093/annonc/mdt338 -
Molecular Pathology : MP Aug 2003Molecular genetic changes involved in tumorigenesis and malignant transformation of human tumours are novel targets of cancer diagnosis and treatment. This study aimed...
Analysis of the tumour suppressor genes, FHIT and WT-1, and the tumour rejection genes, BAGE, GAGE-1/2, HAGE, MAGE-1, and MAGE-3, in benign and malignant neoplasms of the salivary glands.
AIMS
Molecular genetic changes involved in tumorigenesis and malignant transformation of human tumours are novel targets of cancer diagnosis and treatment. This study aimed to analyse the expression of putative tumour suppressor genes, FHIT and WT-1, and tumour rejection genes, BAGE, GAGE-1/2, MAGE-1, MAGE-3, and HAGE (which are reported to be important in human cancers), in salivary gland neoplasms.
METHODS
Gene expression was analysed by reverse transcription polymerase chain reaction (RT-PCR) in normal salivary gland tissue and 44 benign and malignant salivary gland tumours.
RESULTS
Aberrant FHIT transcripts were found in one of 38 normal salivary glands, three of 28 adenomas, and two of 16 carcinomas. WT-1 mRNA was detectable in two adenomas and five carcinomas. Immunoblotting showed that WT-1 mRNA expression was associated with raised WT-1 protein concentrations. RT-PCR for detection of BAGE, GAGE, and MAGE gene expression was positive in two adenomas and nine carcinomas, but negative in normal salivary gland tissue. HAGE mRNA was found in two normal salivary glands, 11 benign, and eight malignant tumours.
CONCLUSIONS
FHIT mRNA splicing does not appear to be involved in the genesis of salivary gland neoplasms. The upregulation of WT-1 mRNA in tumours of epithelial/myoepithelial phenotype may imply a potential role of WT-1 in the genesis and/or cellular differentiation of these salivary gland tumours. The tumour rejection genes were more frequently, but not exclusively, expressed in malignant salivary gland tumours than in benign neoplasms, although none was suitable as a diagnostic marker of malignancy in salivary gland neoplasms.
Topics: Acid Anhydride Hydrolases; Adenocarcinoma; Adenoma, Pleomorphic; Antigens, Neoplasm; Carcinoma, Acinar Cell; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Carcinoma, Squamous Cell; Case-Control Studies; Cystadenoma; DEAD-box RNA Helicases; DNA Helicases; Gene Expression; Genes, Tumor Suppressor; Humans; Melanoma-Specific Antigens; Myoepithelioma; Neoplasm Proteins; Palatal Neoplasms; Parotid Neoplasms; Reverse Transcriptase Polymerase Chain Reaction; WT1 Proteins
PubMed: 12890744
DOI: 10.1136/mp.56.4.226 -
Journal of Thoracic Oncology : Official... Dec 2013Salivary gland-type cancers are rare lung neoplasms involving mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and epithelial-myoepithelial carcinoma...
INTRODUCTION
Salivary gland-type cancers are rare lung neoplasms involving mucoepidermoid carcinoma (MEC), adenoid cystic carcinoma (ACC), and epithelial-myoepithelial carcinoma (EMC). Their behavior and prognostic features are not clearly defined because of their low incidence. We retrospectively analyzed the clinicopathologic profiles of these tumors in a large series.
METHODS
Eighty-eight patients confirmed as having primary salivary gland-type lung cancer between May 2001 and January 2013 were included from the archives of two thoracic oncology center institutions in China and retrospectively evaluated.
RESULTS
Of the total 88 patients, 69 were MEC, 12 ACC, and seven EMC. Overall survival (OS) at 3, 5, and 10 years was 91.3%, 86%, and 80.6% in all cases, respectively, and disease-free survival (DFS) was 90.1%, 78.6%, and 55%, respectively. No significant difference was found among MEC, ACC, and EMC groups regarding OS (p = 0.518) and DFS (p = 0.082). Tumor-node-metastasis stage, lymph node involvement, intrathoracic invasion, and margin status were found to be related with OS (p = 0.000, 0.029, 0.000, 0.004) and DFS (p = 0.018, 0.042, 0.002, 0.002). Intrathoracic invasion was an independent predictor for OS (hazard ratio [HR], 1.129; p = 0.039) and DFS (HR, 1.071; p = 0.011). For patients with MEC, pathological grade also was an independent predictor of OS (HR, 0.045; p = 0.006) and DFS (HR, 0.067; p = 0.001).
CONCLUSIONS
Salivary gland-type lung cancers are a group of low-aggressive entities with higher tendency to recurrence/metastasis. Intensive clinical, radiological, and pathological examinations are essential to estimation of the risk stratification and management.
Topics: Adolescent; Adult; Aged; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Child; China; Combined Modality Therapy; Female; Follow-Up Studies; Humans; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Myoepithelioma; Neoplasm Recurrence, Local; Neoplasm Staging; Prognosis; Retrospective Studies; Salivary Gland Neoplasms; Survival Rate; Young Adult
PubMed: 24389442
DOI: 10.1097/JTO.0b013e3182a7d272 -
The American Journal of Surgical... Jan 2018We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and...
Epithelial-Myoepithelial Carcinoma: Frequent Morphologic and Molecular Evidence of Preexisting Pleomorphic Adenoma, Common HRAS Mutations in PLAG1-intact and HMGA2-intact Cases, and Occasional TP53, FBXW7, and SMARCB1 Alterations in High-grade Cases.
We hypothesized that there is a relationship between the preexisting pleomorphic adenoma [PA]), histologic grade of epithelial-myoepithelial carcinomas (EMCAs), and genetic alterations. EMCAs (n=39) were analyzed for morphologic and molecular evidence of preexisting PA (PLAG1, HMGA2 status by fluorescence in situ hybridization, FISH, and FGFR1-PLAG1 fusion by next-generation sequencing, NGS). Twenty-three EMCAs were further analyzed by NGS for mutations and copy number variation in 50 cancer-related genes. On the basis of combined morphologic and molecular evidence of PA, the following subsets of EMCA emerged: (a) EMCAs with morphologic evidence of preexisting PA, but intact PLAG1 and HMGA2 (12/39, 31%), (b) Carcinomas with PLAG1 alterations (9/39, 23%), or (c) HMGA2 alterations (10/39, 26%), and (d) de novo carcinomas, without morphologic or molecular evidence of PA (8/39, 21%). Twelve high-grade EMCAs (12/39, 31%) occurred across all subsets. The median disease-free survival was 80 months (95% confidence interval, 77-84 mo). Disease-free survival and other clinicopathologic parameters did not differ by the above defined subsets. HRAS mutations were more common in EMCAs with intact PLAG1 and HMGA2 (7/9 vs. 1/14, P<0.001). Other genetic abnormalities (TP53 [n=2], FBXW7 [n=1], SMARCB1 deletion [n=1]) were seen only in high-grade EMCAs with intact PLAG1 and HMGA2. We conclude that most EMCAs arose ex PA (31/39, 80%) and the genetic profile of EMCA varies with the absence or presence of preexisting PA and its cytogenetic signature. Progression to higher grade EMCA with intact PLAG1 and HMGA2 correlates with the presence of TP53, FBXW7 mutations, or SMARCB1 deletion.
Topics: Adenoma, Pleomorphic; Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; DNA-Binding Proteins; Disease-Free Survival; F-Box-WD Repeat-Containing Protein 7; Female; Follow-Up Studies; HMGA2 Protein; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Mutation; Myoepithelioma; Neoplasm Grading; Neoplasms, Glandular and Epithelial; Proto-Oncogene Proteins p21(ras); SMARCB1 Protein; Salivary Gland Neoplasms; Sequence Analysis, DNA; Tumor Suppressor Protein p53
PubMed: 29135520
DOI: 10.1097/PAS.0000000000000933 -
The Tohoku Journal of Experimental... Feb 2024Parotid tumors present a wide range of histological features, from benign to malignant. Periostin, an extracellular matrix protein specifically expressed in the...
Parotid tumors present a wide range of histological features, from benign to malignant. Periostin, an extracellular matrix protein specifically expressed in the periosteum and periodontal ligament, is isolated from osteoblast cell lines. It regulates fibrosis and collagen deposition and plays an important role in myocardial repair after myocardial infarction. It is also known to be involved in otorhinolaryngological-diseases. This study included 36 patients [38 specimens; 16 men and 20 women, mean age 59.2 (range 26-82) years] who underwent parotid tumor resection at the Division of Otorhinolaryngology, Tohoku Medical and Pharmaceutical University, between April 2017 and March 2022 and were clinically and pathologically diagnosed as having benign parotid tumors. Formalin-fixed, paraffin-embedded sections from the surgical specimens were autoclaved and immunostained with anti-periostin antibodies to evaluate the expression and distribution of periostin. Histologically, the tumors were diagnosed as pleomorphic adenomas in 15 cases (15 specimens), Warthin's tumors in 13 cases (15 specimens), basal cell adenomas in 2 cases (2 specimens), oncocytomas in 4 cases (4 specimens), and myoepitheliomas in 2 cases (2 specimens). An increased expression of periostin was found in 32 of 38 samples (84.2%) in the stroma of benign parotid tumors. Four distinct patterns of periostin expression were observed in benign parotid gland tumors: negative, superficial, infiltrative, and diffuse. Statistically significant differences were found between periostin expression patterns and histological classification of the tumors. Our results suggest that periostin may be involved in the pathogenesis of benign parotid tumors and could serve as a new biomarker for these tumors.
Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Male; Middle Aged; Adenoma; Adenoma, Pleomorphic; Parotid Neoplasms; Periostin; Salivary Gland Neoplasms
PubMed: 38092409
DOI: 10.1620/tjem.2023.J099 -
The American Journal of Surgical... Oct 2019Cutaneous syncytial myoepithelioma (CSM) is a rare but distinctive benign variant in the family of myoepithelial neoplasms of skin and soft tissue. CSM has unique...
Cutaneous syncytial myoepithelioma (CSM) is a rare but distinctive benign variant in the family of myoepithelial neoplasms of skin and soft tissue. CSM has unique morphologic and immunohistochemical features, characterized by intradermal syncytial growth of spindled, ovoid, and histiocytoid cells and consistent staining for S-100 protein and EMA, and differs from other myoepithelial tumors by showing only infrequent keratin staining. Rearrangement of the EWSR1 gene is now known to occur in up to half of all skin and soft tissue myoepithelial tumors, with a wide family of documented fusion partners. In 2013, we reported frequent (80%) EWSR1 rearrangements in CSM, but were unable to identify the fusion partner using available studies at that time. After recent identification of an index case of CSM harboring an EWSR1-PBX3 fusion, we used a combination of targeted RNA sequencing and fluorescence in situ hybridization (FISH) studies to investigate the genetic features of a cohort of CSM. An EWSR1-PBX3 fusion was identified in all 13 cases successfully tested. RNA sequencing was successful in 8/13 cases, all of which were found to have identical breakpoints fusing exon 8 of EWSR1 to exon 5 of PBX3. FISH confirmed both EWSR1 and PBX3 rearrangements in 9/9 cases tested, which included 4 confirmed to have EWSR1-PBX3 fusion by RNA-Seq, 3 cases that failed RNA-Seq, and 2 cases examined by FISH alone. Two cases failed RNA sequencing but had no additional tissue remaining for FISH studies. Our findings demonstrate that EWSR1-PBX3 fusions occur in most (and possibly all) cases of CSM.
Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Female; Gene Fusion; Gene Rearrangement; Genetic Predisposition to Disease; Homeodomain Proteins; Humans; In Situ Hybridization, Fluorescence; Male; Middle Aged; Myoepithelioma; Proto-Oncogene Proteins; RNA-Binding Protein EWS; Sequence Analysis, RNA; Skin Neoplasms; Young Adult
PubMed: 31135487
DOI: 10.1097/PAS.0000000000001286 -
The Oncologist Dec 2016Malignant myoepithelioma of the breast (MMB) is extremely rare and often presents as a diagnostic challenge. This article reports on a rare case of aggressive MMB in a...
Malignant myoepithelioma of the breast (MMB) is extremely rare and often presents as a diagnostic challenge. This article reports on a rare case of aggressive MMB in a 52-year-old woman who experienced a dramatic response to carboplatin, paclitaxel, and radiation.
Topics: Anorexia; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast; Breast Neoplasms; Carboplatin; Dose Fractionation, Radiation; Fatigue; Female; Humans; Immunohistochemistry; Lymphatic Metastasis; Middle Aged; Myoepithelioma; Paclitaxel; Radiotherapy, Adjuvant; Rare Diseases; Tomography, X-Ray Computed; Treatment Outcome; Weight Loss
PubMed: 27473043
DOI: 10.1634/theoncologist.2016-0092 -
The Journal of Cell Biology Oct 2018The mammary epithelium is composed of an inner luminal and surrounding myoepithelial cell layer. The presence of cancer cells beyond the myoepithelium defines invasive...
The mammary epithelium is composed of an inner luminal and surrounding myoepithelial cell layer. The presence of cancer cells beyond the myoepithelium defines invasive breast cancer, yet the role of the myoepithelium during invasion remains unclear. We developed a 3D organotypic culture assay to model this process through lineage-specific expression of the prometastatic transcription factor We sought to distinguish the functional role of the myoepithelium in regulating invasion and local dissemination. Myoepithelial-specific expression induced cell-autonomous myoepithelial cell escape. Remarkably, luminal-specific expression was rarely sufficient for escape. Time-lapse microscopy revealed that myoepithelial cells collectively restrain and reinternalize invading Twist1 luminal cells. Barrier function correlated with myoepithelial abundance and required the expression of α-smooth muscle actin and P-cadherin. We next demonstrated that myoepithelial cells can restrain and recapture invasive cancer cells. Our data establish the concept of the myoepithelium as a dynamic barrier to luminal dissemination and implicate both smooth muscle contractility and intercellular adhesion in barrier function.
Topics: Animals; Cadherins; Female; Mammary Glands, Animal; Mammary Neoplasms, Animal; Mice; Mice, Transgenic; Myoepithelioma; Neoplasm Invasiveness; Neoplasm Proteins; Nuclear Proteins; Twist-Related Protein 1
PubMed: 30061105
DOI: 10.1083/jcb.201802144 -
Genes, Chromosomes & Cancer Jan 2023The RREB1::MRTFB (former RREB1::MKL2) fusion characterizes ectomesenchymal chondromyxoid tumors (EMCMT) of the tongue. Only five molecularly confirmed extra-glossal...
RREB1::MRTFB fusion-positive extra-glossal mesenchymal neoplasms: A series of five cases expanding their anatomic distribution and highlighting significant morphological and phenotypic diversity.
The RREB1::MRTFB (former RREB1::MKL2) fusion characterizes ectomesenchymal chondromyxoid tumors (EMCMT) of the tongue. Only five molecularly confirmed extra-glossal EMCMT cases have been reported recently; all occurring at head and neck or mediastinal sites. We herein describe five new cases including the first two extracranial/extrathoracic cases. The tumors occurred in three male and two female patients with an age ranging from 18 to 61 years (median, 28). Three tumors were located in the head and neck (jaw, parapharyngeal space, and nasopharyngeal wall) and two in the soft tissue (inguinal and presacral). The tumor size ranged from 3.3 to 20 cm (median, 7). Treatment was surgical without adjuvant treatment in all cases. Two cases were disease-free at 5 and 17 months; other cases were lost to follow-up. Histologically, the soft tissue cases shared a predominant fibromyxoid appearance, but with variable cytoarchitectural pattern (cellular perineurioma-like whorls and storiform pattern in one case and large polygonal granular cells embedded within a chondromyxoid stroma in the other). Two tumors (inguinal and parapharyngeal) showed spindled to ovoid and round cells with a moderately to highly cellular nondescript pattern. One sinonasal tumor closely mimicked nasal chondromesenchymal hamartoma (NCMH). Mitotic activity was low (0-5 mitoses/10 hpfs). Immunohistochemical findings were heterogeneous with variable expression of S100 (2/5), EMA (2/3), CD34 (1/4), desmin (1/4), and GFAP (1/3). Targeted RNA sequencing revealed the same RREB1::MRTFB fusion in all cases, with exon 8 of RREB1 being fused to exon 11 of MRTFB. This study expands the topographic spectrum of RREB1::MRTFB fusion-positive mesenchymal neoplasms, highlighting a significant morphological and phenotypic diversity. Overall, RREB1::MRTFB-rearranged neoplasms seem to fall into two subcategories: tumors with lobulated, chondroid, or myxochondroid epithelioid morphology (Cases 2 and 3) and those with more undifferentiated hypercellular spindle cell phenotype (Cases 1, 4, and 5). Involvement of extracranial/extrathoracic sites and the NCMH-like pattern are novel. The biology of these likely indolent or benign tumors remains to be verified in the future.
Topics: Male; Female; Humans; Biomarkers, Tumor; Tongue Neoplasms; Gene Fusion; Myoepithelioma; Phenotype; Soft Tissue Neoplasms; DNA-Binding Proteins; Transcription Factors
PubMed: 35763541
DOI: 10.1002/gcc.23082 -
BMJ Case Reports Oct 2019Myoepithelioma is rare benign neoplasm, usually involves salivary glands and very less often seen in minor salivary glands of nose. Clinically it resembles like other...
Myoepithelioma is rare benign neoplasm, usually involves salivary glands and very less often seen in minor salivary glands of nose. Clinically it resembles like other tumour masses and thus posed challenge to clinician and pathologist. It becomes very difficult to diagnose due to its varied presentation and propensity for malignant transformation. We reported a case of a male patient with pink fleshy mass in the left nose with epistaxis and nasal obstruction. Preliminary biopsy and contrast-enhanced CT were done to delineate tumour size and type and then patient underwent endoscopic en-bloc resection. Histopathology and immunohistochemistry were found to be consistent for myoepithelioma. No recurrence was seen during a 6-month follow-up period. Its rarity should be a part of differential diagnosis among nasal tumours. Many of the tumour recurrences are associated with incomplete surgical resection so wide local excision with regular follow-up is essential for this rare entity.
Topics: Adult; Diagnosis, Differential; Endoscopy; Epistaxis; Humans; Male; Myoepithelioma; Nasal Obstruction; Nasal Septum; Nose Neoplasms; Salivary Gland Neoplasms; Salivary Glands, Minor
PubMed: 31653626
DOI: 10.1136/bcr-2019-230926