RESUMEN
Mucoepidermoid carcinoma is a malignant neoplasm of exocrine glands that arises predominantly in salivary glands. It is seldom encountered as a primary cutaneous neoplasm, and in those patients, it often involves the external auditory canal. Given their rarity, they can pose a diagnostic challenge and prompt extensive workup. In salivary glands, mucoepidermoid carcinomas commonly harbor CRTC1/3::MAML2 fusions; however, genetic alterations of primary cutaneous neoplasms are less characterized, with previous studies reporting CRTC1 rearrangements in the absence of MAML2 aberrations. Herein, we report a case of a primary cutaneous mucoepidermoid carcinoma of the external auditory canal with a CRTC1::MAML2 rearrangement. We also review the clinical, morphologic, and molecular features of this neoplasm and compare them to those reported in the literature and to histopathologic mimics.
Asunto(s)
Carcinoma Mucoepidermoide , Neoplasias de las Glándulas Salivales , Neoplasias Cutáneas , Humanos , Proteínas de Unión al ADN/genética , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Transactivadores/genética , Conducto Auditivo Externo/patología , Proteínas Nucleares/genética , Factores de Transcripción/genética , Neoplasias Cutáneas/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de las Glándulas Salivales/genéticaRESUMEN
Salivary gland neoplasms comprise a heterogeneous group of lesions with multiple histological subtypes, each with distinct growth patterns, resulting in a spectrum of tumor-specific prognoses; pleomorphic adenoma (PA) and mucoepidermoid carcinoma (MEC) are the most common representatives of these neoplasms. Many studies have associated specific profiles of membrane and adhesion molecules in salivary gland tissues; these profiles appear to be relevant in tumor biology as well as be interpreted as fingerprints for tumor classification, diagnostic prognostic and therapeutic targets. One of these membrane molecule complexes are the tight junctions, composed by various proteins, in which claudins are protagonists. The aim of this study was to evaluate the expressions of genes that encode tight junction proteins (CLDN-1, -3, -4, -5, -7, and -11, occludin [OCLN], zonula occludens [TJP1, TJP2, and TJP3] and junctional adhesion molecule A [F11R]) in MEC and PA using real time RT-PCR. We observed high expression of CLDN-1 and -7 and low expression of CLDN-3, -11 and TJP2 in MEC compared to PA. PA samples demonstrated high OCLN expression when compared to MEC. CRTC1::MAML2 fusion was detected in 12 of 20 (60.0%) MEC samples and was associated with CLDN7 expression, while the absence of fusion was associated with high histological grade. Increased CLDN5 expression was associated with submandibular gland tumors. This study demonstrated differential expressions of genes encoding tight junction constituent proteins and their associations with tumor characteristics, suggesting their potential future role as diagnostic and prognostic markers.
RESUMEN
Objective: Mucoepidermoid carcinoma (MEC) is the most common malignancy of the parotid gland, but the outcome depends on the histological grade. Therefore, the aim of this study was to evaluate MEC on the basis of histological grade. Study Design: Retrospective analysis. Methods: We performed a retrospective analysis of data from patients whose initial treatment for MEC of the parotid gland was performed at our department between 1999 and 2021. We examined the association between the Armed Forces Institute of Pathology (AFIP) grade and outcome. Results: The AFIP grades were as follows: low, 26 cases; intermediate, 9 cases; and high, 31 cases. About 50% of cases were correctly diagnosed as malignant, and both grade and histology were accurately determined by fine-needle aspiration cytology in 20% of cases. The 5-year disease-free survival rate was 95.5% and 53.8% in the low-/intermediate- and high-grade cases, respectively. In the high-grade group, cases with recurrence were found to have a higher rate of lymph nodes metastasis than cases without recurrence. Furthermore, in this high-grade group, total sacrifice of the facial nerve did not reduce local recurrence. However, radical resection in the cases without tumor invasion to the nerve has decreased the local recurrence rate. The CRTC1-MAML2 fusion gene was expressed in 42.3% of low-/intermediate- and 14.3% of high-grade cases. Conclusions: The survival rate in MEC was quite different between the low-/intermediate- and high-grade cases. However, the rate of correct assessment of the grade by fine-needle aspiration cytology was poor. In high-grade cases, total sacrifice of the facial nerve may improve the rate of local recurrence in cases without invasion of the main trunk of the nerve. Expression of the CRTC1-MAML2 fusion gene could be helpful in not only the assessment of grade but the prediction of recurrence. Level of Evidence: 4.
RESUMEN
Non-sebaceous lymphadenoma is a rare benign salivary gland tumor comprised of non-sebaceous epithelial cells and lymphoid tissue. Although its clinicopathological features have been described, its histogenesis and genetic background have not yet been elucidated. MAML2 rearrangement and the resultant CRTC1/3-MAML2 fusion gene are well-known specific genetic changes in mucoepidermoid carcinoma. Here, we present a case of lymphoepithelial tumor characterized by histomorphology of the non-sebaceous lymphadenoma and CRTC1-MAML2 fusion gene. The patient was an 83-year-old woman with an 8-year history of a solid, well-circumscribed tumor in the parotid gland. Histologically, the tumor was surrounded by thin fibrous connective tissue and was composed of tubular-cystic and solid nests of epithelial cells equally distributed in the lymphoid tissue. The histological features were suggestive of non-sebaceous lymphadenoma. Although the histomorphology was not consistent with mucoepidermoid carcinoma, a diagnosis of non-sebaceous lymphadenoma-like mucoepidermoid carcinoma was made based on the presence of the CRTC1-MAML2 fusion gene. The histological features alone could not establish the diagnosis, and ancillary molecular analysis was required.
Asunto(s)
Carcinoma Mucoepidermoide , Neoplasias de las Glándulas Salivales , Anciano de 80 o más Años , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Proteínas de Unión al ADN/genética , Femenino , Humanos , Proteínas Nucleares/genética , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Transactivadores/genéticaRESUMEN
Primary pulmonary mucoepidermoid carcinoma (PMEC) is a very rare form of lung carcinoma. Due to the low incidence, little is known about its inherent genetic variation characteristics. The uniform treatment for PMEC has not been determined. In this case, we present a 45-year-old male with stage IA PMEC. The surgical specimens contained changes from low- to intermediate-to-high grade. We performed integrative analysis of whole-exome sequencing (WES-seq) and messenger ribonucleic acid sequencing (RNA-seq) to compare the molecular changes in the different lesions. Molecular testing exhibits the specimens harboring CRTC3-MAML2 fusion. The copy number gain of PDPK1 is only present in high-grade regional specimens. We also explored the level of immune infiltration by CIBERSORT. To our knowledge, this is the first report to describe a case of PMEC in the low- to intermediate-high-grade transition with multiomics analysis.
RESUMEN
Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the major and minor salivary glands. Surgical resection is the only curative treatment and there is no effective post-operative therapy for MEC. The present study reports an Institutional Review Board-approved case of a 45-year-old Japanese female diagnosed with low-grade MEC in the hard palate. Radical resection, supraomohyoid neck dissection and antero-lateral thigh flap reconstruction was performed. A MEC cell line was then established from the resected tumor tissue. Short tandem repeat profiling confirmed the origin and authenticity of the cell line, that harbors a CRTC1-MAML2 translocation, which is frequently observed in MEC. Amphiregulin (AREG), identified as one of the targets of the CRTC1-MAML2 fusion gene, was expressed in the cell line. The AREG receptor, epidermal growth factor receptor (EGFR) was also highly phosphorylated. The results predicted that AREG-EGFR signaling, which is required for tumor growth and survival, might be activated in the cell line in a cell-autonomous manner. As AREG expression is associated with EGFR-targeted drug resistance, this cell line might assist with the identification of novel strategies for MEC treatment.
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Mucoepidermoid carcinoma (MEC) of the lacrimal gland (LG) is a rare entity. A 47-year-old woman was aware of periorbital swelling for 3 months. At presentation, the patient showed periorbital swelling in the right eye. CT scan showed an isodense mass in the anterior superolateral part of the orbit. MRI delineated the mass as enhancing, extra-conal tumor appearing isointense on T1-weighted sequences, and to be of mixed intensity on T2-weighted sequences. The tumor was totally resected. Microscopically, the tumor tissue was comprised of squamous, epithelioid cells, and cells with plump and clear cytoplasm. Necrosis, neural invasion, or mitotic figures were not observed. Immunohistochemical examination revealed intense staining for cytokeratin 7. A subset of the cells was positively stained with periodic acid-Schiff and mucicarmine stains. Genetic analysis revealed the presence of the CRTC1-MAML2 fusion. The CRTC1-MAML2 fusion may be a useful indicator for the prognosis and planning of adjuvant therapy.
RESUMEN
Mucoepidermoid carcinoma (MEC) is the most common carcinoma of the salivary glands. Here, we have used two large patient cohorts with MECs comprising 551 tumors to study clinical, histological, and molecular predictors of survival. One cohort (n = 167), with known CRCT1/3-MAML2 fusion status, was derived from the Hamburg Reference Centre (HRC; graded with the AFIP and Brandwein systems) and the other (n = 384) was derived from the population-based Cancer Registry of North Rhine-Westphalia (LKR-NRW; graded with the AFIP system). The reliability of both the AFIP and Brandwein grading systems was excellent (n = 155). The weighted kappa for inter-rater agreement was 0.81 (95% CI 0.65-0.97) and 0.83 (95% CI 0.71-0.96) for the AFIP and Brandwein systems, respectively. The 5-year relative survival was 79.7% (95% CI 73.2-86.2%). Although the Brandwein system resulted in a higher rate of G3-MECs, survival in G3-tumors (AFIP or Brandwein grading) was markedly worse than in G1/G2-tumors. Survival in > T2 tumors was markedly worse than in those with lower T-stage. Also, fusion-negative MECs had a worse 5-year progression-free survival. The frequency of fusion-positive MECs in the HRC cohort was 78.4%, of which the majority (86.7%) was G1/G2-tumors. In conclusion, the AFIP and Brandwein systems are useful in estimating prognosis and to guide therapy for G3-MECs. However, their significance regarding young age (≤ 30 years) and location-dependent heterogeneity of in particular G2-tumors is more questionable. We conclude that CRTC1/3-MAML2 testing is a useful adjunct to histologic scoring of MECs and for pinpointing tumors with poor prognosis with higher precision, thus avoiding overtreatment.
Asunto(s)
Biomarcadores de Tumor/genética , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Fusión Génica , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Transactivadores/genética , Factores de Transcripción/genética , Adolescente , Adulto , Carcinoma Mucoepidermoide/mortalidad , Carcinoma Mucoepidermoide/terapia , Femenino , Alemania , Humanos , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Supervivencia sin Progresión , Sistema de Registros , Neoplasias de las Glándulas Salivales/mortalidad , Neoplasias de las Glándulas Salivales/terapia , Factores de Tiempo , Adulto JovenRESUMEN
Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma Mucoepidermoide/tratamiento farmacológico , Factor I del Crecimiento Similar a la Insulina/metabolismo , PPAR gamma/antagonistas & inhibidores , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Comunicación Autocrina , Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Regulación Neoplásica de la Expresión Génica , Fusión Génica , Humanos , Factor I del Crecimiento Similar a la Insulina/genética , Masculino , Ratones Desnudos , Persona de Mediana Edad , Terapia Molecular Dirigida , PPAR gamma/genética , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Isoformas de Proteínas , Receptor IGF Tipo 1/antagonistas & inhibidores , Receptor IGF Tipo 1/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Neoplasias de las Glándulas Salivales/patología , Transducción de Señal , Transactivadores/genética , Factores de Transcripción/genética , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The presence of the CRTC1-MAML2 translocation has been described in mucoepidermoid carcinoma (MEC) as a predictor of better survival rates. However, the real prognostic value of the translocation has been debated due to recent controversial findings. The aim of this study was to perform a systematic review to understand the prognostic potential of the CRTC1-MAML2 translocation in MEC. An electronic search was carried out using the MEDLINE/PubMed, EMBASE and Scopus databases. Articles that assessed the association between the CRTC1-MAML2 translocation and survival of MEC patients were selected for the systematic review. Ten published articles were included in the qualitative synthesis. The prevalence of the translocation varied from 33.7% to 69.7%. Seven studies observed a significant association between the presence of the CRTC1-MAML2 translocation and a favourable clinical outcome, which could improve disease-free, disease-specific or overall survival. Five studies were included in the quantitative synthesis. Fixed-effects model confirmed that translocation-positive patients have a decreased risk of death (combined odds ratio 0.08, 95% confidence interval - 0.03-0.23, P < .00001). The detection of the CRTC1-MAML2 translocation appears to be useful as a prognostic factor in MEC. However, the level of evidence is not as high as it could be once important limitations were found in the published studies.
Asunto(s)
Carcinoma Mucoepidermoide/genética , Neoplasias de las Glándulas Salivales/genética , Transactivadores/genética , Factores de Transcripción/genética , Translocación Genética , Humanos , PronósticoRESUMEN
BACKGROUND: Gefitinib is well-known as a tyrosine kinase inhibitor targeting non-smalllung- cancer (NSCLC) containing EGFR mutations. However, its effectiveness in treating mucoepidermoid carcinoma (MEC) without such EGFR mutations suggests additional targets. OBJECTIVE: The CRTC1-MAML2 (C1-M2) fusion typical for MEC has been proposed to be a gefitinib target. METHODS: To test this hypothesis, we developed a set of siRNAs to down-regulate C1-M2 expression. RNA-seq and Western blot techniques were applied to analyze the effects of gefitinib and siC1-M2 on the transcriptome of and the phosphorylation of tyrosine kinases in a MEC cell line H292. RESULTS: Deep-sequencing transcriptome analysis revealed that gefitinib extensively inhibited transcription of genes in JAK-STAT and MAPK/ERK pathways. Both siC1-M2 and gefitinib inhibited the phosphorylation of multiple signaling kinases in these signaling pathways, indicating that gefitinib inhibited JAK-STAT and MAPK/ERK pathways activated by C1-M2 fusion. Moreover, gefitinib inhibition of EGFR and MAPK/ERK was more effective than that of AKT, JAK2 and STATs, and their dependence on C1-M2 could be uncoupled. Taken together, our results suggest that gefitinib simultaneously represses phosphorylation of multiple key signaling proteins which are activated in MEC, in part by C1-M2 fusion. Gefitinib-repressed kinase phosphorylation explains the transcriptional repression of genes in JAK-STAT and MAPK/ERK pathways. CONCLUSION: These findings provide new insights into the efficacy of gefitinib in treating mucoepidermoid carcinoma, and suggest that a combination of gefitinib and other inhibitors specifically against C1-M2 fusion could be more effective.
Asunto(s)
Carcinoma Mucoepidermoide/tratamiento farmacológico , Gefitinib/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Quinasas Janus/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Factor de Transcripción STAT1/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Carcinoma Mucoepidermoide/patología , Línea Celular Tumoral , Humanos , Proteínas de Fusión Oncogénica/metabolismo , Transducción de Señal , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
AIMS: Mucoepidermoid carcinomas (MEC) are the most common malignant neoplasms of salivary glands, but are uncommon in other sites. Salivary gland MEC are most frequently associated with CRTC1-MAML2 translocations. Exceedingly rare MEC of the breast demonstrate a basal-like and often triple (oestrogen and progesterone receptor, HER2)-negative immunophenotype, with a single case previously reported to show MAML2 rearrangement, although the fusion partner was not known. Comprehensive genomic studies of breast MEC are lacking. In this study, we analysed the immunophenotype and molecular landscape of two breast MEC to elucidate the pathogenesis of these rare tumours. METHODS AND RESULTS: Two breast MEC were subjected to capture-based next-generation DNA sequencing of 479 cancer-related genes. The presence of the CRTC1-MAML2 fusion transcript was interrogated by reverse transcriptase-polymerase chain reaction. In addition, the immunoprofiles of breast MEC were compared to salivary gland MEC. Both breast MEC harboured CRTC1-MAML2 fusions. In contrast to most triple-negative breast carcinomas of no special type, the mutational burden of MEC was very low, with one case demonstrating only an inactivating SETD2 mutation, and the other harbouring no somatic variants in genes on the panel. No copy number alterations were identified. The immunoprofiles of breast and salivary gland MEC were overlapping, but not identical. CONCLUSIONS: The findings highlight MEC as a breast cancer subtype more closely related to its salivary gland counterpart than to basal-like/triple-negative breast cancers of no special type.
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Neoplasias de la Mama/genética , Carcinoma Mucoepidermoide/genética , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Factores de Transcripción/genética , Femenino , Humanos , Persona de Mediana Edad , Proteínas de Fusión Oncogénica , TransactivadoresRESUMEN
In this article, we report a case of sclerosing mucoepidermoid carcinoma (MEC) arising in the parotid gland, with CRTC1-MAML2 gene fusion. A 73-year-old woman with a mass in the right parotid region was referred to our hospital. Radiological imaging tests revealed a well-defined mass, measuring 25 mm in diameter, with foci of calcification in the deep lobe of the parotid gland, extending to the parapharyngeal space. Microscopically, the tumor was composed of a proliferation of atypical glandular epithelial cells having intracytoplasmic mucin, squamoid cells, and intermediate cells arranged in nests embedded in a fibrosclerotic stroma, associated with a dense chronic inflammatory infiltrate containing immunoglobulin G4-immunoreactive plasma cells. Reverse transcription-polymerase chain reaction analysis using a formalin-fixed, paraffin-embedded tumor tissue specimen revealed the CRTC1-MAML2 fusion gene transcript. This is the first report of sclerosing MEC with the detection of the MEC-associated fusion gene, reinforcing a common genetic association between MEC and sclerosing MEC.
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Carcinoma Mucoepidermoide/patología , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Neoplasias de la Parótida/patología , Factores de Transcripción/genética , Anciano , Carcinoma Mucoepidermoide/genética , Femenino , Humanos , Neoplasias de la Parótida/genética , Esclerosis/patología , TransactivadoresRESUMEN
Mucoepidermoid carcinoma (MEC) shows a wide morphologic spectrum, including epithelium with oncocytic or squamous metaplastic changes overlying a prominent cystic architecture, as well as tumor-associated lymphoid tissue. We illustrate a case of MEC of the parotid in a 17-year-old female, in which all these features occurred extensively, such that they accounted for almost the entire neoplasm, and closely mimicked Warthin tumor histologically. This highlights the need for diagnostic awareness of this particular morphologic variant of MEC, as patients could potentially be inappropriately discharged from follow-up if diagnosed with a benign neoplasm.
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Carcinoma Mucoepidermoide/patología , Neoplasias de la Parótida/patología , Adenolinfoma/diagnóstico , Adenolinfoma/patología , Adolescente , Carcinoma Mucoepidermoide/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Neoplasias de la Parótida/diagnósticoRESUMEN
BACKGROUND: Our previous study suggested NR4A2, a subfamily member of orphan nuclear receptors, is essential for survival of human cancer cells such as mucoepidermoid carcinoma (MEC). METHODS: We conducted high throughput drug screening for NR4A2 inhibitors as a novel therapeutic modality. Positive screening was performed using a luciferase reporter vector containing NR4A2 binding sequence, and a CRE-reporter control vector was used to eliminate false positives. In vitro assays for positive hits were conducted. RESULTS: A total of 23 Food and Drug Administration (FDA) and 43 Life Science Library compounds were identified, including several epidermal growth factor inhibitors and Src inhibitors. Subsequent in vitro assays confirmed that identified compounds were preferentially active in NR4A2+ cancer cells. Several candidate compounds appeared to suppress NR4A2 via inhibition of p-ERK, whereas a novel compound KU0171309 may act as a more direct inhibitor. CONCLUSIONS: Further research should focus on homologue selectivity, in vivo activity, and definitively deciphering the mechanism of action of KU0171309.
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Mucoepidermoid carcinoma (MEC) with a predominant spindle cell composition occurring in the palatine tonsil is exceedingly rare. We present a case of a 17-year-old boy with an uncommon spindle cell variant of MEC arising in the palatine tonsil. Histologically, the tumor showed a solid, noncystic architecture and was composed of a predominant population of bland spindle to fusiform cells arranged in organoid nests with interspersed goblet cells and focal areas of ductular structures. Reverse transcriptase polymerase chain reaction and fluorescence in situ hybridization (FISH) revealed the presence of a t(11;19) CRTC1-MAML2 gene fusion in this rare variant of MEC. This is the first case report of a spindle cell MEC of the palatine tonsil, with molecular genetic confirmation. It illustrates the importance of awareness and recognition of this uncommon histological variant of MEC, which will help establish appropriate treatment and prognostication.
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Carcinoma Mucoepidermoide/genética , Carcinoma Mucoepidermoide/patología , Proteínas de Unión al ADN/genética , Proteínas Nucleares/genética , Neoplasias Tonsilares/genética , Neoplasias Tonsilares/patología , Factores de Transcripción/genética , Adolescente , Humanos , Masculino , Proteínas de Fusión Oncogénica/genética , Tonsila Palatina/patología , TransactivadoresRESUMEN
OBJECTIVE: Mucoepidermoid carcinoma (MEC) is the most common malignant tumor of the salivary glands. Tumor stage and grade have historically been important predictors of survival. An oncogenic CRTC1- or CRTC3-MAML2 gene fusion has been identified in a number of MECs. Historically, these gene fusions have been associated with lower grade tumors and better survival. However, reported gene fusion rates and prognosis varies widely across studies, and have not controlled for tumor grade. We sought to identify gene fusion rates and outcomes in our cohort of MEC patients. MATERIALS AND METHODS: An IRB-approved retrospective cohort of patients with MEC was identified at the University of Michigan. Clinical, histologic, and outcome data was collected from medical records. RNA was isolated from formalin fixed paraffin-embedded tumor sections, and qRT-PCR was performed to identify CRTC1/3-MAML2 gene fusions. Sanger sequencing of qRT-PCR products was used to confirm gene fusions. RESULTS: Overall, 90 patient MEC tumors were collected (58 low-grade, 25 intermediate-grade, and 7 high-grade). Gene fusions were identified in 59% (53/90) of tumors. On univariate and bivariate analysis, fusion status did not significantly associate with grade or survival. CONCLUSION: We have identified a high rate of CRTC1/3-MAML2 gene fusions in a large cohort of MEC. We do not identify any correlation between fusion status with tumor grade or survival. These findings suggest further characterization of MECs is needed before considering the CRTC1/3-MAML2 gene fusion as a prognostic biomarker. Additional genetic drivers may account for survival and grade in MECs.
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Carcinoma Mucoepidermoide/patología , Proteínas de Unión al ADN/genética , Fusión Génica , Proteínas Nucleares/genética , Factores de Transcripción/genética , Carcinoma Mucoepidermoide/genética , Estudios de Cohortes , Femenino , Humanos , Masculino , Mutación , Estudios Retrospectivos , Análisis de Supervivencia , TransactivadoresRESUMEN
BACKGROUND: Pediatric salivary gland carcinomas (SGCs) are very rare. They differ from the adult SGCs in terms of epidemiologic and clinical behavior, being generally limited only to selected histotypes (e.g. low-grade mucoepidermoid [LG-MEC] and acinic cell cancer [AcCC]) and characterized by very good outcome. Our aim was to investigate therapeutic targets on a series of pediatric SGCs by immunohistochemical and molecular analysis. METHODS: A retrospective analysis was performed to search for cases of pediatric SGCs in the database of the Pediatric Oncology Unit at the Istituto Nazionale Tumori and in the Pathology database at the Gerhard-Seifert-Reference-Centre. The expressions of the most common tyrosine-kinase receptors (TKRs) reported in adult SGCs as EGFR, HER2, KIT and hormonal receptors (HRs) (estrogen α and ß, progesterone as well as androgen receptors) were investigated. CRTC1/MAML2 and MYB/NFIB were also analyzed in MEC and adenoid cystic carcinoma cases, respectively. RESULTS: Twenty-nine cases were identified: 22 MECs, 4 AcCCs, 1 adenoid cystic carcinoma (ACC), 1 adenocarcinoma not otherwise specified and 1 sialoblastoma. EGFR was the most expressed TKR, whilst HRs were negative in all cases except for ER-ß in four cases of MEC. CRTC1/MAML2 was present in 15 out of 17 evaluable MEC cases and MYB/NFIB was identified in the ACC case. CONCLUSIONS: The immunohistochemical and molecular profiles of pediatric SGCs analyzed in our series are similar to that observed in adults, especially for MEC, supporting a common biological background.
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Biomarcadores de Tumor/análisis , Carcinoma/genética , Carcinoma/metabolismo , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/metabolismo , Adolescente , Niño , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Masculino , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
BACKGROUND AND AIMS: Pulmonary Mucoepidermoid carcinoma (MEC) accounts for 0.1-0.2% of all lung cancer. It occurred in the 3-78 years old, and 50% patients younger than 30. MEC has no standard treatment, but recently reports indicated MEC without epidermal growth factor receptor (EGFR) mutations sensitive to gefitinib. OBJECTIVES: To explore a new standard treatment strategy for MEC, after reviewed literature related to MEC, we used Gefitinib to treatment a patient with EGFR-negative MEC, and observe its effects. METHODS: 10-year-old boy was diagnosed with low-grade MEC by bronchial lung biopsy, EGFR gene mutation test was negative. Gefitinib was administered as neoadjuvant therapy at 125 mg daily. RESULTS: The patient underwent right middle lobe, lower lobe resection and mediastinal lymph node dissection. After surgery, the patient had gained weight (5 kg) after 18 days of gefitinib therapy. A CT scan of the chest 1 month after surgical resection showed no recurrence, and followed for 22 months after treatment without tumour recurrence, suggesting that the patient was completely cured. CONCLUSION: Gefitinib has potential to become a standard treatment for pulmonary MEC patients, including pediatric patients. However, the mechanisms need further investigation.
Asunto(s)
Carcinoma Mucoepidermoide/tratamiento farmacológico , Carcinoma Mucoepidermoide/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamiento farmacológico , Quinazolinas/farmacología , Carcinoma Mucoepidermoide/diagnóstico por imagen , Carcinoma Mucoepidermoide/cirugía , Niño , Proteínas de Unión al ADN/genética , Receptores ErbB/antagonistas & inhibidores , Gefitinib , Humanos , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/cirugía , Masculino , Mutación , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/administración & dosificación , Tomografía Computarizada por Rayos X/métodos , Factores de Transcripción , Resultado del TratamientoRESUMEN
The predominance of clear cells in mucoepidermoid carcinomas (MEC) is rare, and cases in which this occurs are termed clear cell variants of MEC. We present a case of a 70-year-old woman complaining of a right buccal mucosal mass, which had increased in size over 1 year. Histological examination revealed the mass to be composed predominantly of clear tumor cells, with mucin-containing cells and intermediate cell-like cells. Immunohistochemistry indicated that the tumor was positive for CK5/6 and p63, but negative for myoepithelial markers such as S-100 protein, αSMA, and calponin. These findings ruled out the possibility of a clear cell myoepithelial carcinoma, which is the most frequently observed type of salivary carcinoma composed predominantly of clear cells. However, it is difficult to distinguish between clear cell variants of MEC and hyalinizing clear cell carcinoma. Therefore, we performed fluorescence in situ hybridization to determine whether MAML2 rearrangement had occurred in this mass. Direct sequencing of the RT-PCR product demonstrated CRTC1-MAML2 fusion between exon 1 of CRTC1 and exon 2 of MAML2. Thus, the diagnosis of clear cell variant of MEC was confirmed. This is the first report of CRTC1-MAML2 fusion gene detection in a clear cell variant of MEC.