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Indazoles , Factores de Transcripción de Tipo Kruppel , Mioepitelioma , Proteínas de Fusión Oncogénica , Pirimidinas , Proteína EWS de Unión a ARN , Sulfonamidas , Humanos , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Proteína EWS de Unión a ARN/genética , Indazoles/uso terapéutico , Factores de Transcripción de Tipo Kruppel/genética , Mioepitelioma/tratamiento farmacológico , Mioepitelioma/patología , Mioepitelioma/genética , Proteínas de Fusión Oncogénica/genética , Inducción de Remisión , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Femenino , MasculinoRESUMEN
The EWSR1::PBX3 fusion gene, commonly associated with cutaneous syncytial myoepitheliomas, is also found in myoepithelial tumors (METs) of bone and soft tissue. These tumors typically demonstrate benign histology and favorable outcomes. This study examines 6 previously unreported intraosseous METs harboring the EWSR1::PBX3 fusion, focusing on their histopathologic characteristics, immunophenotype, clinical and radiographic profiles, and patient outcomes. The cohort comprised 5 men and 1 woman, aged 25 to 65 years (median age: 31 years), with tumors located in the proximal tibia (3 cases), distal radius (2 cases), and ilium (1 case) and sizes between 3.2 and 12.2 cm (median size: 3.9 cm). Imaging showed osteolytic lesions with varying degrees of cortical involvement and soft tissue extension in 3 cases. Histologically, 4 tumors showed mainly uniform oval-to-spindled cells in syncytial or fascicular arrangements within a collagenous matrix, displaying either bland nuclear features or mild atypia, and low to slightly elevated mitotic activity (≤1 per 10 high-power fields in 3 cases and 6 per 10 high-power fields in 1), classifying them as benign or atypical METs. In contrast, 2 tumors exhibited pronounced nuclear atypia with ovoid, spindled, epithelioid and round cells, hyperchromatic nuclei, inconspicuous nucleoli, increased N/C ratios, high mitotic rates (17 and 19 per 10 high-power fields), and extensive necrosis. Both tumors behaved aggressively-one patient underwent amputation after neoadjuvant chemotherapy and radiation, and the other died within 7 months with the disease still present. Immunohistochemically, the tumors consistently expressed epithelial membrane antigen and S100 but lacked keratin (AE1/AE3) expression. Our study demonstrated that bone METs with EWSR1::PBX3 fusions encompass a histologic continuum from benign to malignant, with benign/atypical METs mirroring their cutaneous analogs in morphology, and malignant variants distinguished by heterogeneous cytologic and architectural features, pronounced nuclear atypia, and high mitotic rates.
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Neoplasias Óseas , Mioepitelioma , Proteína EWS de Unión a ARN , Humanos , Persona de Mediana Edad , Masculino , Femenino , Mioepitelioma/genética , Mioepitelioma/patología , Anciano , Adulto , Neoplasias Óseas/genética , Neoplasias Óseas/patología , Proteína EWS de Unión a ARN/genética , Proteínas de Homeodominio/genética , Proteínas de Fusión Oncogénica/genética , Biomarcadores de Tumor/genética , Proteínas Proto-OncogénicasRESUMEN
We describe a case of a pleomorphic adenoma (PA) arising from the para-tracheal accessory salivary gland in a 44-year-old male harboring a novel WWTR1::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in salivary gland tumors. The patient presented with hoarseness of voice. The radiological exam revealed a mass in the upper third of the trachea involving the larynx. Histologically, the tumor consisted of bland-looking monocellular eosinophilic epithelial cells arranged in cords and sheets separated by thin fibrous stroma, focally forming a pseudo-tubular pattern. In immunohistochemistry, the tumor cells demonstrated positivity for CK7, PS100, SOX10, and HMGA2; and negativity for CK5/6, p40 p63, and PLAG1. In addition, the clustering analysis clearly demonstrates a clustering of tumors within the PA group. In addition to reporting this novel fusion in the PA spectrum, we discuss the relevant differential diagnoses and briefly review of NCOA2 and WWTR1 gene functions in normal and neoplastic contexts.
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Proteína HMGA2 , Coactivador 2 del Receptor Nuclear , Transactivadores , Humanos , Masculino , Coactivador 2 del Receptor Nuclear/genética , Coactivador 2 del Receptor Nuclear/metabolismo , Adulto , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Transactivadores/genética , Proteínas Coactivadoras Transcripcionales con Motivo de Unión a PDZ , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de Fusión Oncogénica/genética , Mioepitelioma/genética , Mioepitelioma/patología , Mioepitelioma/metabolismoRESUMEN
Myoepithelial tumors of the soft tissue and bone occurring in patients 21 years of age and younger are rare, and their clinicopathologic features remain incompletely understood. We studied a well-characterized series of 40 such tumors. Cases were retrieved from our archives for the period 2009-2022 and re-reviewed. Available immunohistochemical and molecular genetic data was collected. Clinical information including available follow-up was obtained. The tumors occurred in 18 males and 22 females, ranging from 3 months to 21 years of age (median 11.5 years), and involved a wide variety of soft tissue (n = 36) and bone (n = 4) locations. Histologically benign myoepithelial tumors tended to occur in adolescents (median age 14.5 years; range 5-21 years), whereas myoepithelial carcinomas occurred in younger patients (median age 8.5 years; range 3 months-20 years). Microscopically, the tumors showed a complex admixture of epithelioid, plasmacytoid and spindled cells in a variably hyalinized, myxoid, chondroid or chondromyxoid background. Small subsets of histologically malignant tumors had rhabdoid or "round cell" features. Immunohistochemistry showed 35/40 (88%) cases to be positive with at least one keratin antibody. The 5 keratin-negative tumors were uniformly positive for S100 protein and/or SOX10 and expressed EMA (4 cases) and/or p63 (3 cases). EMA, SMA and GFAP were positive in 21/25 (84%), 13/21 (62%), and 8/21 (38%) tumors, respectively. SMARCB1 and SMARCA4 expression was retained in 29/31 (94%) and 22/22 (100%) of cases, respectively. FISH for EWSR1 gene rearrangement was positive in 6/18 (33%) tested cases. Two EWSR1-negative tumors were also FUS-negative. NGS identified EWSR1::POU5F1, FUS::KLF17, and BRD4::CITED1 gene fusions in 3 tested cases. Clinical follow-up (22 patients; median 23 months; range 1-119 months) showed 3 patients with local recurrences and 5 with distant metastases (lymph nodes, lung, and brain). Three patients died of disease, 3 were alive with recurrent or unresectable disease, and 16 were disease-free. Adverse clinical outcomes were seen only in patients with malignant tumors. We conclude that myoepithelial neoplasms of soft tissue and bone are over-repesented in patients ≤21 years of age, more often histologically malignant, and potentially lethal. Histologic evaluation appears to reliably predict the behavior of these rare tumors.
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Biomarcadores de Tumor , Neoplasias Óseas , Inmunohistoquímica , Mioepitelioma , Neoplasias de los Tejidos Blandos , Humanos , Masculino , Adolescente , Femenino , Niño , Adulto Joven , Mioepitelioma/patología , Mioepitelioma/genética , Preescolar , Neoplasias de los Tejidos Blandos/patología , Neoplasias de los Tejidos Blandos/genética , Neoplasias Óseas/patología , Neoplasias Óseas/genética , Lactante , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Reordenamiento Génico , Factores de Transcripción/genética , Factores de Transcripción/análisisRESUMEN
BACKGROUND: Cutaneous syncytial myoepithelioma (CSM) is an uncommon and distinct variant of cutaneous myoepithelioma. We aim to present a case of CSM to enhance the recognition of this unique variant, encompassing its clinical characteristics, histopathological features, immunohistochemical staining, and therapeutic approaches. CASE PRESENTATION: A 10-year-old girl presented with a dome-shaped nodule located on the skin of her left medial distal arm. Microscopic examination of the skin biopsy revealed a well-defined dermal nodular lesion, surrounded by an epidermal collarette. Tumor cells were composed of epithelioid to spindle-shaped cells with round-to-oval nuclei, small nucleoli, and abundant eosinophilic cytoplasm with a syncytial-like growth pattern. A moderate degree of nuclear pleomorphism was noted. Mitotic activity was not prominent. Immunohistochemical staining revealed positive staining for epithelial membrane antigen, GLUT1, collagen IV, and S100. Smooth muscle actin, CD10, and CD68 showed patchy positivity. CD31, CD34, p63, SOX10, anaplastic lymphoma kinase (ALK), glial fibrillary acidic protein, pankeratin (AE1/AE3/PCK26), Melan-A, and CD1a were negative. Fluorescence in situ hybridization targeting TFE3 and ALK genes was negative. The differential diagnosis included ALK-negative epithelioid cell histiocytoma, epithelioid perineurioma, and CSM. Based on the above findings, a diagnosis of CSM was rendered. DISCUSSION: CSM is a benign cutaneous neoplasm composed of sheets of histiocytoid or short spindle cells with pale eosinophilic cytoplasm with a syncytial-like growth pattern. Clinically, CSM often presents as a painless, slow-growing nodule or plaque in a broad anatomical distribution with a preference for the distal extremities. CSM is characteristically positive for epithelial membrane antigen (EMA) and S100 protein and negative for keratins. In challenging cases, molecular testing for EWSR1 gene rearrangement and EWSR1-PBX3 gene fusion aid in confirming the diagnosis. CONCLUSIONS: The histologic features of CSM present a unique set of challenges posing a diagnostic dilemma, as they can bear resemblance to a range of benign and malignant cutaneous neoplasms including ALK-negative epithelioid cell histiocytoma, epithelioid perineurioma, malignant or nevoid melanoma, and epithelioid sarcoma. An accurate diagnosis is crucial for guiding proper clinical management considering that this entity typically demonstrates an excellent prognosis following a complete surgical excision.
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Biomarcadores de Tumor , Mioepitelioma , Neoplasias Cutáneas , Humanos , Femenino , Neoplasias Cutáneas/patología , Neoplasias Cutáneas/genética , Niño , Mioepitelioma/patología , Mioepitelioma/genética , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Inmunohistoquímica , Células Epitelioides/patologíaRESUMEN
Recurrent gene fusions are common in salivary gland tumors including benign tumors, such as pleomorphic adenoma (PA) and myoepithelioma (ME). In cases where chromosomal rearrangement is identified in the pleomorphic adenoma gene 1 (PLAG1) gene, different gene partners are found. Oncocytic metaplasia, characterized by oncocytes with abundant eosinophilic granular cytoplasm and hyperchromatic nuclei, is a well-known phenomenon in salivary gland neoplasms. However, the pure oncocytic variant of PA/ME showed PLAG1 gene rearrangements involving various gene partners at the molecular level, without any recurrent fusion being found. Our study includes 20 cases of PA/ME, with 11 females and 9 males. The age of patients ranged from 37 to 96 years, with a median age of 62.8 years. Most tumors originate from the parotid gland. The median size of the tumor was 26.5 mm (range: 13 to 60 mm). Among the 20 cases, 14 were a pure oncocytic variant of PA/ME, whereas 6 cases showed focal oncocytic or oncocytic-like aspects. Molecular studies on 20 cases of PA/ME were conducted. A novel recurrent ZBTB47-AS1::PLAG1 fusion was identified in 6 of 12 cases with pure oncocytic metaplasia, whereas the other cases had PLAG1 gene fusion with different gene partners. The transcriptomic analysis of the cases harboring ZBTB47-AS1::PLAG1 fusion demonstrated that these tumors have a distinct molecular profile from conventional PA/ME. This study reveals a unique subset in the oncocytic PA/ME spectrum characterized by pure oncocytic morphology with larger oncocytic cells and recurrent ZBTB47-AS1::PLAG1 fusion. It also highlights the transcriptomic distinctness of salivary gland adenomas with pure oncocytic metaplasia in the spectrum of salivary gland neoplasms. Further studies are needed to better understand the oncocytic variant of PA/ME and to determine the true nature of oncocytic cells in PA/ME.
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Adenoma Oxifílico , Adenoma Pleomórfico , Mioepitelioma , Neoplasias de las Glándulas Salivales , Masculino , Femenino , Humanos , Persona de Mediana Edad , Adulto , Anciano , Anciano de 80 o más Años , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/patología , Mioepitelioma/genética , Mioepitelioma/patología , Proteínas de Unión al ADN/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Fusión Génica , MetaplasiaRESUMEN
Cutaneous mixed tumors exhibit a wide morphologic diversity and are currently classified into apocrine and eccrine types based on their morphologic differentiation. Some cases of apocrine-type cutaneous mixed tumors (ACMT), namely, hyaline cell-rich apocrine cutaneous mixed tumors (HCR-ACMT) show a prominent or exclusive plasmacytoid myoepithelial component. Although recurrent fusions of PLAG1 have been observed in ACMT, the oncogenic driver of eccrine-type cutaneous mixed tumors (ECMT) is still unknown. The aim of the study was to provide a comprehensive morphologic, immunohistochemical, and molecular characterization of these tumors. Forty-one cases were included in this study: 28 cases of ACMT/HCR-ACMT and 13 cases of ECMT. After morphologic and immunohistochemical characterization, all specimens were analyzed by RNA sequencing. By immunohistochemistry, all cases showed expression of SOX10, but only ACMT/HCR-ACMT showed expression of PLAG1 and HMGA2. RNA sequencing confirmed the presence of recurrent fusion of PLAG1 or HMGA2 in all cases of ACMT/HCR-ACMT, with a perfect correlation with PLAG1/HMGA2 immunohistochemical status, and revealed internal tandem duplications of SOX10 (SOX10-ITD) in all cases of ECMT. Although TRPS1::PLAG1 was the most frequent fusion, HMGA2::WIF1 and HMGA2::NFIB were detected in ACMT cases. Clustering analysis based on gene expression profiling of 110 tumors, including numerous histotypes, showed that ECMT formed a distinct group compared with all other tumors. ACMT, HCR-ACMT, and salivary gland pleomorphic adenoma clustered together, whereas myoepithelioma with fusions of EWSR1, FUS, PBX1, PBX3, POU5F1, and KLF17 formed another cluster. Follow-up showed no evidence of disease in 23 cases across all 3 tumor types. In conclusion, our study demonstrated for the first time SOX10-ITD in ECMT and HMGA2 fusions in ACMT and further refined the prevalence of PLAG1 fusions in ACMT. Clustering analyses revealed the transcriptomic distance between these different tumors, especially in the heterogenous group of myoepitheliomas.
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Adenoma Pleomórfico , Mioepitelioma , Neoplasias de las Glándulas Salivales , Neoplasias Cutáneas , Neoplasias de las Glándulas Sudoríparas , Humanos , Adenoma Pleomórfico/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Mioepitelioma/genética , Mioepitelioma/patología , Proteínas Represoras , Neoplasias de las Glándulas Salivales/genética , Neoplasias Cutáneas/genética , Factores de Transcripción SOXE , Neoplasias de las Glándulas Sudoríparas/genética , Factores de TranscripciónAsunto(s)
Carcinoma , Mioepitelioma , Humanos , Carcinoma/patología , Mioepitelioma/genética , Mioepitelioma/patología , Biología MolecularRESUMEN
Herein we report a case of an intraosseous myoepithelial carcinoma harboring a EWSR1::PBX3 fusion gene. The patient was a 64-year-old male found to have a 7 cm destructive lesion in the distal ulna with an extraosseous soft tissue component. Microscopic examination of the resected tumor showed a spindle-cell lesion within a sclerotic stroma and intravascular tumor emboli. At higher power the tumor cells showed moderate nuclear atypia with a high mitotic count (20 per mm2 ). Immunohistochemistry revealed diffuse EMA positivity and focal pancytokeratin (AE1/AE3) and S100 expression, consistent with myoepithelial differentiation. NGS using the Oncomine Childhood Cancer Assay (Thermo Fisher Scientific, Inc.) revealed a EWSR1-PBX3 fusion and ABL amplification. The patient subsequently developed local recurrence as well as distant lymph node, lung and vertebral metastases; he is currently awaiting systemic treatment in the context of a clinical trial. In this report, we present a rare case of a skeletal myoepithelial tumor harboring a EWSR1::PBX3 fusion with demonstrated histological and clinical features of malignancy.
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Neoplasias Óseas , Carcinoma , Mioepitelioma , Neoplasias de los Tejidos Conjuntivo y Blando , Humanos , Masculino , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Neoplasias Óseas/patología , Fusión Génica , Mioepitelioma/genética , Mioepitelioma/diagnóstico , Proteína EWS de Unión a ARN/genéticaRESUMEN
AIMS: Extraskeletal myxoid chondrosarcoma (EMC) is a rare form of adult sarcoma with distinct histology and NR4A3 gene fusion. Immunohistochemically, EMCs are variably positive for S100 protein and neuroendocrine markers. Unlike histologically similar soft-tissue myoepithelial tumours, keratin expression is rare. Prompted by two recent EMC cases with diffuse keratin expression, we investigated the expression of epithelial markers in a molecularly confirmed cohort of EMC and identified two additional similar cases. METHODS AND RESULTS: Four keratin-positive EMCs occurred in one man and three women aged 46-59 years. All tumours displayed nonclassic histology with prominent stromal fibrosis, and keratin AE1/AE3 was expressed either diffusely (N = 2) or focally (N = 2). In one tumour, keratin expression was limited to the sclerotic area. All tumours coexpressed epithelial membrane antigen and two additionally expressed S100 protein or glial fibrillary acidic protein. All tumours harboured NR4A3 fusions, including TAF15::NR4A3 (N = 1) and EWSR1::NR4A3 (N = 3). Two cases were initially considered as most consistent with myoepithelial tumours based on widespread stromal fibrosis and keratin expression. DNA methylation analysis classified two tumours tested as EMCs. CONCLUSIONS: We identified a small subset of EMCs characterised by keratin expression and prominent stromal fibrosis. This histological pattern must be recognised in the differential diagnosis of myoepithelial tumours because misclassification may lead to the erroneous prediction of tumour behaviour and may alter patient management. NR4A3 genetic analysis should be considered even in the face of keratin expression and prominent stromal fibrosis.
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Condrosarcoma , Mioepitelioma , Neoplasias de los Tejidos Blandos , Adulto , Masculino , Humanos , Femenino , Mioepitelioma/diagnóstico , Mioepitelioma/genética , Mioepitelioma/patología , Queratinas/metabolismo , Proteínas de Unión a Calmodulina , Proteínas de Unión al ARN/genética , Condrosarcoma/diagnóstico , Condrosarcoma/genética , Condrosarcoma/metabolismo , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/genética , Proteínas S100 , FibrosisRESUMEN
BACKGROUND: Secretory myoepithelial carcinomas (SMCA) are rare, mucinous, signet ring predominant tumors with primitive myoepithelial features. While many mucinous salivary gland tumors have now been molecularly characterized, key drivers in SMCA have yet to be elucidated. Recently, NKX3.1, a homeodomain transcription factor implicated in salivary mucous acinar development was also shown in a subset of salivary mucinous neoplasms, salivary intraductal papillary mucinous neoplasms (SG-IPMN). To date, NKX3.1 expression has not been characterized in other mucinous salivary lesions. Here, we report molecular and extended immunophenotypic findings in SMCA and NKX3.1 expression in the context of other head and neck lesions. METHODS: We retrieved 4 previously reported SMCA, performed additional immunohistochemical and targeted next-generation sequencing (NGS). We also investigated the use of NKX3.1 as a marker for SMCA in the context of its prevalence and extent (using H-score) in a mixed cohort of retrospectively and prospectively tested head and neck lesions (n = 223) and non-neoplastic tissues (n = 66). RESULTS: NKX3.1 positivity was confirmed in normal mucous acini as well as in mucous acinar class of lesions (5/6, mean H-score: 136.7), including mucinous adenocarcinomas (3/4), SG-IPMN (1/1), and microsecretory adenocarcinoma (MSA) (1/1). All SMCA were positive. Fluorescence in situ hybridization for SS18 rearrangements were negative in all successfully tested cases (0/3). NGS was successful in two cases (cases 3 and 4). Case 3 demonstrated a PTEN c.655C>T p.Q219* mutation and a SEC16A::NOTCH1 fusion while case 4 (clinically aggressive) showed a PTEN c.1026+1G>A p.K342 splice site variant, aTP53 c.524G>A p.R175H mutation and a higher tumor mutation burden (29 per Mb). PTEN immunohistochemical loss was confirmed in both cases and a subset of tumor cells showed strong (extreme) staining for P53 in Case 4. CONCLUSION: Despite a partial myoepithelial phenotype, SMCA, along with mucinous adenocarcinomas/SG-IPMN and MSA, provisionally constitute a mucous acinar class of tumors based on morphology and NKX3.1 expression. Like salivary mucinous adenocarcinomas/SG-IPMN, SMCA also show alterations of the PTEN/PI3K/AKT pathway and may show progressive molecular alterations. We document the first extramammary tumor with a SEC16A::NOTCH1 fusion.
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Adenocarcinoma Mucinoso , Adenocarcinoma , Mioepitelioma , Neoplasias Intraductales Pancreáticas , Neoplasias de las Glándulas Salivales , Humanos , Adenocarcinoma/patología , Adenocarcinoma Mucinoso/genética , Biomarcadores de Tumor/genética , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , Hibridación Fluorescente in Situ , Mioepitelioma/genética , Mioepitelioma/patología , Fenotipo , Fosfatidilinositol 3-Quinasas/genética , Estudios Retrospectivos , Neoplasias de las Glándulas Salivales/patología , Factores de Transcripción/genética , Proteínas de Transporte Vesicular/genéticaRESUMEN
Soft tissue myoepitheliomas (STM) are benign myoepithelial neoplasms (of nonsalivary gland origin) arising, most commonly within subcutaneous and deep soft tissues of the extremities and rarely within bones. To the best of our knowledge, the intravascular location of STM as well as the identification of a novel IRF2BP2::CDX2 fusion have not been previously reported. Herein, we report a case of spindle cell myoepithelioma arising within the intravascular space of the right index finger in a 52-year-old male of more than 20 years duration. Histopathology demonstrated an intravascular tumefactive lesion composed of predominantly plump banal spindle cells in a fascicular arrangement within a mixed collagenous and chondromyxoid stroma colliding with papillary endothelial hyperplasia (Masson tumor). By immunohistochemistry, the lesional cells were positive for keratin-AE1/3, epithelial membrane antigen, S100, SOX10, glial fibrillary acid protein, calponin and negative for CD34, smooth muscle actin, desmin, p63, and ERG. Fluorescence in situ hybridization for EWSR1 gene rearrangement was negative. Next-generation sequencing detected a novel IRF2BP2::CDX2 fusion involving Exon 1 of the IRF2BP2 gene and Exon 2 of the CDX2 gene confirmed by reverse transcriptase polymerase chain reaction and Sanger sequencing. Further, clinical evaluation for a salivary gland mass in the head and neck region and magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis was performed with no evidence of tumor elsewhere. Taken together, the overall features were considered diagnostic of STM. Our current case underscores the novelty of the IRF2BP2::CDX2 gene fusion in STM and its exceptionally rare intravascular location.
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Mioepitelioma , Neoplasias de los Tejidos Blandos , Masculino , Humanos , Persona de Mediana Edad , Mioepitelioma/genética , Mioepitelioma/diagnóstico , Hibridación Fluorescente in Situ , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Inmunohistoquímica , Fusión Génica , Neoplasias de los Tejidos Blandos/patología , Proteínas de Unión al ADN/genética , Factores de Transcripción/genética , Factor de Transcripción CDX2/genéticaRESUMEN
We describe a case of a myoepithelial carcinoma of the superficial parotid gland in a 46-year-old male harboring a novel CTCF::NCOA2 gene fusion. To our knowledge, this novel gene fusion has not been described previously in myoepithelial carcinoma. A 46-year-old male patient presented with a mass involving the superficial left parotid gland with extension into the external auditory canal (EAC) and erosion of the conchal cartilage. Histologically, the neoplasm was composed of uniform spindled, epithelioid/ovoid cells arranged in cords and nests within hyalinized to myxoid stroma. On immunohistochemistry (IHC), the tumor cells demonstrated patchy and variable staining for low molecular weight cytokeratin (CAM5.2), pan-cytokeratin (OSCAR), and S-100. Overall, the morphological and immunohistochemical attributes supported a locally aggressive tumor of myoepithelial differentiation consistent with myoepithelial carcinoma. Molecular analysis using a custom 115-gene gene panel by targeted RNA sequencing, showed an in-frame CTCF::NCOA2 fusion. In addition to reporting this novel fusion in myoepithelial carcinoma, we also discuss relevant differential diagnosis, and provide a brief review of NCOA2 gene function in both normal and neoplastic contexts.
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Carcinoma , Mioepitelioma , Neoplasias de la Parótida , Masculino , Humanos , Persona de Mediana Edad , Glándula Parótida/patología , Neoplasias de la Parótida/genética , Neoplasias de la Parótida/química , Neoplasias de la Parótida/diagnóstico , Carcinoma/genética , Mioepitelioma/genética , Mioepitelioma/patología , Queratinas/genética , Coactivador 2 del Receptor Nuclear/genéticaRESUMEN
Myoepithelial carcinomas (MECs) of soft tissue are rare and aggressive tumors affecting young adults and children, but their molecular landscape has not been comprehensively explored through genome sequencing. Here, we present the whole-exome sequencing (WES), whole-genome sequencing (WGS), and RNA sequencing findings of two MECs. Patients 1 and 2 (P1, P2), both male, were diagnosed at 27 and 37 yr of age, respectively, with shoulder (P1) and inguinal (P2) soft tissue tumors. Both patients developed metastatic disease, and P2 died of disease. P1 tumor showed a rhabdoid cytomorphology and a complete loss of INI1 (SMARCB1) expression, associated with a homozygous SMARCB1 deletion. The tumor from P2 showed a clear cell/small cell morphology, retained INI1 expression and strong S100 positivity. By WES and WGS, tumors from both patients displayed low tumor mutation burdens, and no targetable alterations in cancer genes were detected. P2's tumor harbored an EWSR1::KLF15 rearrangement, whereas the tumor from P1 showed a novel ASCC2::GGNBP2 fusion. WGS evidenced a complex genomic event involving mainly Chromosomes 17 and 22 in the tumor from P1, which was consistent with chromoplexy. These findings are consistent with previous reports of EWSR1 rearrangements (50% of cases) in MECs and provide a genetic basis for the loss of SMARCB1 protein expression observed through immunohistochemistry in 10% of 40% of MEC cases. The lack of additional driver mutations in these tumors supports the hypothesis that these alterations are the key molecular events in MEC evolution. Furthermore, the presence of complex structural variant patterns, invisible to WES, highlights the novel biological insights that can be gained through the application of WGS to rare cancers.
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Carcinoma , Mioepitelioma , Neoplasias de los Tejidos Blandos , Niño , Adulto Joven , Humanos , Masculino , Mioepitelioma/genética , Mioepitelioma/diagnóstico , Mioepitelioma/patología , Neoplasias de los Tejidos Blandos/genética , Carcinoma/genética , Biomarcadores de Tumor/genéticaRESUMEN
Myoepithelial tumors (MET) constitute a group of neoplasms with a variety of morphologic, immunophenotypic, and molecular features. Approximately half of MET of soft tissue harbor EWSR1 gene rearrangements with a subset showing EWSR1-POU5F1 fusions and demonstrating distinctive tendency towards aggressive behavior in children. Histologically, EWSR1-POU5F1-positive MET typically show clear-cell morphology with malignant features including marked pleomorphism and atypical mitotic figures. The cytomorphology of these tumors has not been well characterized. Reported here are the cytomorphologic features of two cases of EWSR1-POUF1-positive MET with histology correlation.
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Mioepitelioma , Neoplasias de los Tejidos Blandos , Biomarcadores de Tumor/genética , Niño , Humanos , Inmunofenotipificación , Mioepitelioma/genética , Mioepitelioma/patología , Factor 3 de Transcripción de Unión a Octámeros/genética , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Cutaneous syncytial myoepithelioma (CSM) is a recently recognized variant of myoepithelioma characterized by an intradermal syncytial proliferation of spindled, ovoid, and histiocytoid cells. Immunohistochemically, tumor cells usually show strong expression of S-100 protein and epithelial membrane antigen (EMA). Here we report a case of CSM in the thigh of a 51-year-old Japanese woman. Histopathological findings showed a sheet-like growth of ovoid cells and histiocytoid cells with an eosinophilic syncytial cytoplasm, and adipocytic metaplasia was widely observed in the tumor. Immunohistochemical staining revealed a diffuse, strong pattern for EMA, smooth muscle actin (SMA), and HHF35, and variable expression of S-100 protein and p63 in ovoid and histiocytoid cells without significant mitotic figures or pleomorphism. In addition, EWSR1-PBX3 gene fusion, which is characteristic of CSM, was observed in the tumor. Based on these findings, we diagnosed the patient as having CSM. Our case shows that CSM can exhibit extensive adipocytic metaplasia, which could make its histopathological diagnosis challenging.
Asunto(s)
Adipocitos/patología , Mioepitelioma , Neoplasias Cutáneas , Femenino , Fusión Génica , Proteínas de Homeodominio/genética , Humanos , Metaplasia , Persona de Mediana Edad , Mioepitelioma/genética , Mioepitelioma/patología , Proteínas Proto-Oncogénicas/genética , Proteína EWS de Unión a ARN/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patologíaRESUMEN
BACKGROUND: Soft tissue myoepithelial carcinomas (STMC) are a rare, malignant subgroup of myoepithelial tumors that arise typically in glandular or ductal tissues, but also in the bone and soft and cutaneous tissues. Due to its rarity, there is no consensus regarding the treatment of STMC, including chemotherapy or other systemic agents for metastatic STMC. CASE REPORT: A chemotherapy- and regorafenib-refractory STMC, harboring an AGK-BRAF fusion, was successfully treated using MEK-inhibition with cobimetinib in monotherapy. MEK-inhibition with cobimetinib effectively silenced paradoxical MAP kinase/ERK-signaling pathway activation after regorafenib monotherapy, and resulted in a significant and durable clinical response. CONCLUSION: This effect of MEK-inhibition in STMC harboring an AGK-BRAF fusion has not been previously reported and contributes to the existing, yet limited, knowledge on the treatment of BRAF fusion-driven tumors. Also, our case highlights the importance of next generation sequencing in driving further rational therapeutic choices to provide disease control and palliation.
Asunto(s)
Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Mioepitelioma/tratamiento farmacológico , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Carcinoma/tratamiento farmacológico , Carcinoma/genética , Carcinoma/patología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Mutación , Mioepitelioma/genética , Mioepitelioma/patología , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Myoepithelial carcinoma (MECA) is a rare salivary gland (SG) neoplasm (0.1-0.45% of all SG tumors) that often presents with bland cytomorphology and can be misclassified as cellular pleomorphic adenoma (PA) or myoepithelioma. This is particularly challenging in MECA ex-PA cases, especially if tumor shows minimal to no capsular invasion. We report a rare case of a 76-year-old female; history of left superficial parotidectomy with diagnosis (outside hospital) of cellular PA, who re-presented 9 months post surgery with enlarging left parotid mass, neck lymphadenopathy and facial nerve deficits. FNAB of parotid and neck lymph node revealed cellular aspirates with loosely cohesive clusters of myoepithelial cells with occasional chondromyxoid stroma. Prior resection slides were reviewed, and diagnosis of MECA ex-PA was made. Patient underwent left radical parotidectomy, selective neck dissection, with facial nerve sacrifice (due to extensive encasing by tumor). Histology showed a multinodular tumor with pushing borders, zonal arrangement comprising of a hypocellular, necrotic/myxoid center, and a peripheral rim of myoepithelial cells, confirmed by positive S100, and p63. Tumor extensively infiltrated peri parotid soft tissues with multiple foci of lymphovascular and perineural invasion; and metastatic neck lymph nodes. Next generation sequencing revealed a novel TERT promoter mutation (c.-124C > T), not usually described in SG neoplasms. Further, PD-L1 immunohistochemistry showed positive expression, making patient eligible for anti-PDL-1 immunotherapy. This case highlights importance of recognizing the subtle malignant features of MECA in distinguishing it from benign mimics like PA. In addition, presence of TERT mutation opens a new arena for future research to explore potential treatment targets.
Asunto(s)
Adenocarcinoma , Adenoma Pleomórfico , Carcinoma , Mioepitelioma , Neoplasias de la Parótida , Neoplasias de las Glándulas Salivales , Telomerasa , Adenoma Pleomórfico/diagnóstico , Adenoma Pleomórfico/genética , Adenoma Pleomórfico/patología , Anciano , Antígeno B7-H1 , Carcinoma/patología , Errores Diagnósticos , Femenino , Humanos , Mutación , Mioepitelioma/diagnóstico , Mioepitelioma/genética , Mioepitelioma/patología , Neoplasias de la Parótida/diagnóstico , Neoplasias de la Parótida/genética , Neoplasias de la Parótida/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Telomerasa/genéticaRESUMEN
Myoepithelial tumors arising in soft tissue are uncommon and mostly manifest a benign clinical course, although a malignant form does exist. An EWSR1 gene rearrangement is a common event in these tumors. Ossifying fibromyxoid tumor, a rare soft tissue neoplasm of uncertain differentiation, may have overlapping histologic and immunophenotypic features with myoepithelial tumors, but frequently harbors a PHF1 gene rearrangement. Interestingly, a PHF1-TFE3 fusion has been recently reported in both entities. Here we report a case of a malignant soft tissue tumor demonstrating myoepithelial differentiation and harboring a PHF1-TFE3 fusion. Despite being slow-growing and lacking significant cytologic atypia at initial presentation, the patient deteriorated rapidly with local recurrence and distant metastases. A discussion of the potential clinicopathologic implications of a PHF1-TFE3 fusion in these entities is also developed.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Proteínas de Unión al ADN/genética , Fibroma Osificante/genética , Mioepitelioma/genética , Fusión de Oncogenes , Proteínas del Grupo Polycomb/genética , Neoplasias de los Tejidos Blandos/genética , Femenino , Fibroma Osificante/patología , Reordenamiento Génico , Humanos , Persona de Mediana Edad , Mioepitelioma/patología , Neoplasias de los Tejidos Blandos/patologíaRESUMEN
Myoepithelial tumors of soft tissue are rare mesenchymal neoplasms that overlap with their salivary gland and skin counterparts at both the histopathologic and molecular levels. EWSR1 gene rearrangements with various fusion partners represent a common genetic event in myoepithelial tumors of soft tissue, whether benign or malignant, and may prove useful as a diagnostic tool in difficult cases. However, the number of diagnostic entities with EWSR1 gene rearrangements has grown considerably in recent years, and there is significant morphologic and immunophenotypic overlap amongst this group, underscoring the importance of fusion testing to detect fusion partners that are characteristic of discrete diagnostic entities. Herein, we report a malignant myoepithelial tumor of soft tissue/myoepithelial carcinoma with an undifferentiated round cell morphology arising in a pediatric patient with a EWSR1-ATF1 gene fusion.