RESUMEN
BACKGROUND: Rhabdomyosarcomas are aggressive tumors that comprise a group of morphologically similar but biologically diverse lesions. Owing to its rarity, Mixed pattern RMS (ARMS and ERMS) constitutes a diagnostic and therapeutic dilemma. CASE: Herein is presented a very rare case of mixed alveolar & embryonal rhabdomyosarcoma in the uterus of a 68-year-old woman. The wall of the uterine corpus & cervix was replaced by multiple whitish-yellow, firm nodules, measuring up to 12 cm. Microscopically, the tumor was predominantly composed of round to polygonal cells arranged in nests with alveolar pattern intermingled with hypo- & hypercellular areas of more primitive cells with scattered multinucleated giant cells seen as well. Extensive sampling failed to show epithelial elements. Immunohistochemical staining showed positive staining for vimentin, desmin, myogenin, CD56 & WT-1. However, no staining was detected for CK, LCA, CD10, ER, SMA, CD99, S100, Cyclin-D1 & Olig-2. Metastatic deposits were found in the peritoneum. The patient received postoperative chemotherapy and radiotherapy but died of systemic metastases 3 months after surgery. CONCLUSION: The rarity of this histological tumor entity and its aggressive behavior and poor prognosis grab attention to improving recognition and treatment modalities in adults.
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Biomarcadores de Tumor , Inmunohistoquímica , Neoplasias Uterinas , Humanos , Femenino , Anciano , Neoplasias Uterinas/patología , Biomarcadores de Tumor/análisis , Resultado Fatal , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/terapia , Rabdomiosarcoma Embrionario/diagnóstico , Rabdomiosarcoma/patología , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma Alveolar/patología , Rabdomiosarcoma Alveolar/terapiaRESUMEN
Rhabdomyosarcomas are the most common soft-tissue sarcomas, found usually in the younger age group. Histologically, they are subdivided into embryonal, alveolar, pleomorphic and not otherwise specified. They have a heterogenous appearance on imaging with few additional characteristic features based on the subtype. Botryoid variant of embryonal rhabdomyosarcoma commonly involves the genitourinary and the biliary system. They can be multifocal. Most of these lesions have a heterogenous appearance on imaging with areas of necrosis and haemorrhage. On ultrasound, they are polypoidal with cystic areas and are vascular. The lesions are hyperintense on T2 sequences, isointense to the skeletal muscle on T1 sequences and show heterogenous enhancement. Surgery is the mainstay of treatment along with radiotherapy or chemotherapy depending on the site and the stage of the tumour. We report a case of botryoid variant of rhabdomyosarcoma involving the vagina and the urinary bladder.
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Rabdomiosarcoma Embrionario , Neoplasias de la Vejiga Urinaria , Neoplasias Vaginales , Femenino , Humanos , Imagen por Resonancia Magnética , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/diagnóstico , Rabdomiosarcoma Embrionario/diagnóstico por imagen , Rabdomiosarcoma Embrionario/cirugía , Ultrasonografía , Neoplasias de la Vejiga Urinaria/diagnóstico por imagen , Neoplasias de la Vejiga Urinaria/patología , Neoplasias Vaginales/patología , Neoplasias Vaginales/diagnóstico por imagen , Neoplasias Vaginales/cirugía , Neoplasias Vaginales/diagnóstico , PreescolarAsunto(s)
Quinasa de Linfoma Anaplásico , Crizotinib , Proteínas de Fusión Oncogénica , Rabdomiosarcoma Embrionario , Humanos , Crizotinib/uso terapéutico , Rabdomiosarcoma Embrionario/tratamiento farmacológico , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/patología , Quinasa de Linfoma Anaplásico/genética , Proteínas de Fusión Oncogénica/genética , Masculino , Inhibidores de Proteínas Quinasas/uso terapéutico , Femenino , Recién Nacido , Proteínas Tirosina Quinasas Receptoras/genéticaRESUMEN
Cervical embryonal rhabdomyosarcoma(ERMS) is a rare malignancy. To date, no cases of ERMS diagnosed by cervical cytology have been reported. In this study, we report a case of cervical ERMS identified by a liquid-based cytology test and cell blocks in a 46-year-old postmenopausal woman. We describe the cytological features of ERMS, with the aim of helping cytopathologists recognize this rare cervical tumor.
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Rabdomiosarcoma Embrionario , Neoplasias del Cuello Uterino , Humanos , Femenino , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/diagnóstico , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/diagnóstico , Persona de Mediana Edad , Cuello del Útero/patología , Citodiagnóstico/métodosRESUMEN
Rhabdomyosarcoma (RMS) is a solid tumor whose metastatic progression can be accelerated through interleukin-4 receptor alpha (Il4ra) mediated interaction with normal muscle stem cells (satellite cells). To understand the function of Il4ra in this tumor initiation phase of RMS, we conditionally deleted Il4ra in genetically-engineered RMS mouse models. Nullizygosity of Il4ra altered the latency, site and/or stage distribution of RMS tumors compared to IL4RA intact models. Primary tumor cell cultures taken from the genetically-engineered models then used in orthotopic allografts further defined the interaction of satellite cells and RMS tumor cells in the context of tumor initiation: in alveolar rhabdomyosarcoma (ARMS), satellite cell co-injection was necessary for Il4ra null tumor cells engraftment, whereas in embryonal rhabdomyosarcoma (ERMS), satellite cell co-injection decreased latency of engraftment of Il4ra wildtype tumor cells but not Il4ra null tumor cells. When refocusing on Il4ra wildtype tumors by single cell sequencing and cytokine studies, we have uncovered a putative signaling interplay of Il4 from T-lymphocytes being received by Il4ra + rhabdomyosarcoma tumor cells, which in turn express Ccl2, the ligand for Ccr2 and Ccr5. Taken together, these results suggest that mutations imposed during tumor initiation have different effects than genetic or therapeutic intervention imposed once tumors are already formed. We also propose that CCL2 and its cognate receptors CCR2 and/or CCR5 are potential therapeutic targets in Il4ra mediated RMS progression.
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Subunidad alfa del Receptor de Interleucina-4 , Animales , Ratones , Subunidad alfa del Receptor de Interleucina-4/genética , Subunidad alfa del Receptor de Interleucina-4/metabolismo , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Rabdomiosarcoma/metabolismo , Humanos , Células Satélite del Músculo Esquelético/metabolismo , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/patología , Rabdomiosarcoma Alveolar/metabolismo , Modelos Animales de Enfermedad , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/metabolismo , Transducción de Señal , Receptores de Superficie CelularRESUMEN
BACKGROUND Sinonasal rhabdomyosarcoma (RMS) is a rare malignancy in children and adolescents. It is aggressive and locally invasive, and can require local postoperative radiotherapy. This report presents the case of a 16-year-old girl with a sinonasal-cutaneous fistula following excision and radiotherapy for rhabdomyosarcoma, which required reconstructive surgery using an expanded forehead flap. CASE REPORT We report the case of a16-year-old girl who was referred to our clinic with sinonasal-cutaneous fistula. Prior to presentation at our department, she presented with bilateral intermittent nasal congestion 3 years ago. At a local hospital, orbital computed tomography and nasal endoscopic biopsy revealed an embryonal rhabdomyosarcoma (ERMS). One month later, skull base tumor resection, nasal cavity and sinus tumor resection, and low-temperature plasma ablation were performed at a local hospital. Two weeks after the operation, the patient received intensity-modulated radiation therapy for a total of 50 Gy. Chemotherapy started 15 days after radiotherapy, using a vincristine, dactinomycin, and cyclophosphamide (VAC) regimen. Approximately 1 month later, an ulcer appeared at the nasal root and the lesion gradually expanded. The patient was referred to our hospital due to the defect. Firstly, a tissue expander was implanted at the forehead for 7 months. Then, the skin around the defect was trimmed and forehead flap was separated to repair the lining and external skin. The flap survived well 1-year after the operation. CONCLUSIONS This report highlights the challenges of post-radiation reconstructive surgery and describes how an expanded forehead flap can achieve an acceptable cosmetic outcome in a patient with a sinonasal-cutaneous fistula.
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Fístula Cutánea , Frente , Colgajos Quirúrgicos , Humanos , Femenino , Adolescente , Fístula Cutánea/etiología , Fístula Cutánea/cirugía , Procedimientos de Cirugía Plástica/métodos , Neoplasias de los Senos Paranasales/cirugía , Neoplasias de los Senos Paranasales/radioterapia , Rabdomiosarcoma/cirugía , Rabdomiosarcoma/radioterapia , Rabdomiosarcoma Embrionario/cirugía , Rabdomiosarcoma Embrionario/radioterapia , Neoplasias Nasales/cirugía , Neoplasias Nasales/radioterapia , Complicaciones PosoperatoriasRESUMEN
Pleomorphic rhabdomyosarcoma (PRMS) is a rare and highly aggressive sarcoma, occurring mostly in the deep soft tissues of middle-aged adults and showing a variable degree of skeletal muscle differentiation. The diagnosis is challenging as pathologic features overlap with embryonal rhabdomyosarcoma (ERMS), malignant Triton tumor, and other pleomorphic sarcomas. As recurrent genetic alterations underlying PRMS have not been described to date, ancillary molecular diagnostic testing is not useful in subclassification. Herein, we perform genomic profiling of a well-characterized cohort of 14 PRMS, compared to a control group of 23 ERMS and other pleomorphic sarcomas (undifferentiated pleomorphic sarcoma and pleomorphic liposarcoma) using clinically validated DNA-targeted Next generation sequencing (NGS) panels (MSK-IMPACT). The PRMS cohort included eight males and six females, with a median age of 53 years (range 31-76 years). Despite similar tumor mutation burdens, the genomic landscape of PRMS, with a high frequency of TP53 (79%) and RB1 (43%) alterations, stood in stark contrast to ERMS, with 4% and 0%, respectively. CDKN2A deletions were more common in PRMS (43%), compared to ERMS (13%). In contrast, ERMS harbored somatic driver mutations in the RAS pathway and loss of function mutations in BCOR, which were absent in PRMS. Copy number variations in PRMS showed multiple chromosomal arm-level changes, most commonly gains of chr17p and chr22q and loss of chr6q. Notably, gain of chr8, commonly seen in ERMS (61%) was conspicuously absent in PRMS. The genomic profiles of other pleomorphic sarcomas were overall analogous to PRMS, showing shared alterations in TP53, RB1, and CDKN2A. Overall survival and progression-free survival of PRMS were significantly worse (p < 0.0005) than that of ERMS. Our findings revealed that the molecular landscape of PRMS aligns with other adult pleomorphic sarcomas and is distinct from that of ERMS. Thus, NGS assays may be applied in select challenging cases toward a refined classification. Finally, our data corroborate the inclusion of PRMS in the therapeutic bracket of pleomorphic sarcomas, given that their clinical outcomes are comparable.
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Rabdomiosarcoma Embrionario , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Anciano , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Rabdomiosarcoma/clasificación , Mutación , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Genómica/métodos , Biomarcadores de Tumor/genética , Proteínas de Unión a Retinoblastoma/genética , Ubiquitina-Proteína LigasasRESUMEN
The wide application of RNA sequencing in clinical practice has allowed the discovery of novel fusion genes, which have contributed to a refined molecular classification of rhabdomyosarcoma (RMS). Most fusions in RMS result in aberrant transcription factors, such as PAX3/7::FOXO1 in alveolar RMS (ARMS) and fusions involving VGLL2 or NCOA2 in infantile spindle cell RMS. However, recurrent fusions driving oncogenic kinase activation have not been reported in RMS. Triggered by an index case of an unclassified RMS (overlapping features between ARMS and sclerosing RMS) with a novel FGFR1::ANK1 fusion, we reviewed our molecular files for cases harboring FGFR1-related fusions. One additional case with an FGFR1::TACC1 fusion was identified in a tumor resembling embryonal RMS (ERMS) with anaplasia, but with no pathogenic variants in TP53 or DICER1 on germline testing. Both cases occurred in males, aged 7 and 24, and in the pelvis. The 2nd case also harbored additional alterations, including somatic TP53 and TET2 mutations. Two additional RMS cases (one unclassified, one ERMS) with FGFR1 overexpression but lacking FGFR1 fusions were identified by RNA sequencing. These two cases and the FGFR1::TACC1-positive case clustered together with the ERMS group by RNAseq. This is the first report of RMS harboring recurrent FGFR1 fusions. However, it remains unclear if FGFR1 fusions define a novel subset of RMS or alternatively, whether this alteration can sporadically drive the pathogenesis of known RMS subtypes, such as ERMS. Additional larger series with integrated genomic and epigenetic datasets are needed for better subclassification, as the resulting oncogenic kinase activation underscores the potential for targeted therapy.
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Rabdomiosarcoma Alveolar , Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Masculino , Humanos , Adulto , Niño , Rabdomiosarcoma/genética , Rabdomiosarcoma Embrionario/genética , Epigenómica , Genómica , Ribonucleasa III , ARN Helicasas DEAD-box , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genéticaRESUMEN
BACKGROUND: The clinical characteristics, outcomes, and prognostic factors of adult embryonal rhabdomyosarcomas (ERMS) and alveolar rhabdomyosarcomas (ARMS), particularly the differences among adolescents/young adults (AYA), adults, and older adults, remain unclear. We assessed the clinicopathological features and survival outcomes of adult patients with ERMS and ARMS in Japan and to compare these features among AYA, adult, and older adult patients. METHODS: We retrospectively analyzed data from the Bone and Soft Tissue Tumor Registry of Japan and enrolled patients aged ≥15 years with ERMS and ARMS. Disease-specific overall survival (DOS) was estimated using the Kaplan-Meier method, and a Cox regression model was used to identify prognostic factors. RESULTS: Among 184 patients with ERMS and ARMS (median age, 27 years; interquartile range, 18-49 years), a high rate of distant and regional nodal metastases was initially observed in 65 (35%) and 66 (36%) cases, respectively. Older age and distant metastasis at first presentation were statistically poor prognostic factors, and histological subtype and site of tumor origin were not associated with DOS. In patients with localized ERMS and ARMS, older age and nodal metastasis were poor prognostic factors; the 5-year DOS rates of patients with and without nodal metastasis were 23% and 72%, respectively. CONCLUSIONS: Older patients with rhabdomyosarcoma had a dismal prognosis, and distant metastasis was a poor prognostic factor. The prognostic factors differed between adult and pediatric patients with rhabdomyosarcoma; biological analyses, such as genome analysis of adult rhabdomyosarcoma and clinical trials with pediatric oncologists, are needed to improve the prognosis of adult rhabdomyosarcoma.
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Rabdomiosarcoma Alveolar , Rabdomiosarcoma Embrionario , Humanos , Masculino , Rabdomiosarcoma Alveolar/patología , Rabdomiosarcoma Alveolar/mortalidad , Femenino , Adulto , Adolescente , Rabdomiosarcoma Embrionario/patología , Rabdomiosarcoma Embrionario/mortalidad , Rabdomiosarcoma Embrionario/terapia , Persona de Mediana Edad , Adulto Joven , Estudios Retrospectivos , Pronóstico , Japón/epidemiología , Factores de Edad , Anciano , Tasa de Supervivencia , Estudios de CohortesRESUMEN
BACKGROUND: Primary brain rhabdomyosarcoma is a rare primary brain malignancy with few case reports. The vast majority of cases of primary brain rhabdomyosarcoma occur in pediatric patients, and immunohistochemistry can distinguish it from embryonal subtypes; however, few cases of primary brain rhabdomyosarcoma in adults have been reported in the literature. CASE PRESENTATION: We report the case of a 26-year-old White male patient who was found to have primary brain alveolar rhabdomyosarcoma after developing headaches for several months. A brain MRI revealed a mixed cystic and solid tumor along the vermis of the cerebellum. The patient underwent a gross total surgical resection, which confirmed the diagnosis of alveolar rhabdomyosarcoma. Further staging workup for another primary focus or disseminated disease yielded negative results, confirming the diagnosis of primary alveolar rhabdomyosarcoma of the brain. CONCLUSION: The standard of care for managing this rare type of brain tumor involves surgery with adjuvant chemoradiotherapy. Further studies should be conducted for a better diagnostic and therapeutic understanding.
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Neoplasias Encefálicas , Rabdomiosarcoma Alveolar , Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Adulto , Humanos , Masculino , Encéfalo/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/cirugía , Imagen por Resonancia Magnética , Rabdomiosarcoma Alveolar/diagnóstico por imagen , Rabdomiosarcoma Alveolar/terapia , Rabdomiosarcoma Embrionario/diagnósticoRESUMEN
Rhabdomyosarcoma of the prostate is a rare mesenchymal tumor that originates from undifferentiated mesenchymal cells. Spindle cell rhabdomyosarcoma is a variant of embryonal rhabdomyosarcoma. The vast majority of these two pathological types occur in children, with only a few adult cases reported to date, and both are associated with poor clinical outcomes. We herein report a case involving a man in his early 40s with spindle cell embryonal rhabdomyosarcoma of the prostate. His chief complaint was difficult urination. The diagnosis was confirmed by puncture biopsy of the prostate, and pelvic lymph node metastasis was already present at the time of diagnosis. The patient underwent three courses of chemotherapy. However, his response to the treatment was very poor, and he died of the disease 4 months after diagnosis.
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Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Adulto , Humanos , Masculino , Embrión de Mamíferos , Pelvis , Próstata/diagnóstico por imagen , Próstata/cirugía , Rabdomiosarcoma Embrionario/diagnósticoRESUMEN
INTRODUCTION: The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population. METHODS: This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model. RESULTS: Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs. CONCLUSION: AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.
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Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Neoplasias de los Tejidos Blandos , Niño , Humanos , Adolescente , Adulto Joven , Adulto , Estudios Retrospectivos , Rabdomiosarcoma/patología , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: According to previous research, 2.8% of lesions clinically identified as endodontic pathosis were ultimately diagnosed as non-endodontic periapical lesions via histopathology, and 3.7% of these non-endodontic periapical lesions were malignant neoplasms. Rhabdomyosarcoma, a malignant tumor most commonly observed in children, is uncommon in the oral cavity. CASE PRESENTATION: This is a report of a rare case of embryonal rhabdomyosarcoma in a 41-year-old female, in which the lesion was in the maxillary gingiva. The biopsy reports confirmed the diagnosis of embryonal rhabdomyosarcoma. The wide excision of the tumor, free flap reconstruction, chemotherapy, and radiotherapy were performed. Clinical, radiological, and histopathological and management aspects of the neoplasm were also discussed. CONCLUSIONS: This case report aimed to create awareness that rhabdomyosarcoma is one of the differential diagnoses of periapical lesions.
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Rabdomiosarcoma Embrionario , Rabdomiosarcoma , Adulto , Niño , Femenino , Humanos , Rabdomiosarcoma Embrionario/patología , Encía/patologíaRESUMEN
The landscape of uterine sarcomas is becoming more complex with the description of new entities associated with recurrent driver molecular alterations. Uterine sarcomas, in analogy with soft tissue sarcomas, are distinguished into complex genomic and simple genomic sarcomas. Leiomyosarcomas and undifferentiated uterine sarcomas belong to complex genomic sarcomas group. Low-grade and high-grade endometrial stromal sarcomas, other rare tumors associated with fusion transcripts (such as NTRK, PDGFB, ALK, RET ROS1) and SMARCA4-deficient uterine sarcoma are considered simple genomic sarcomas. The most common uterine sarcoma are first leiomyosarcoma and secondly endometrial stromal sarcomas. Three different histological subtypes of leiomyosarcoma (fusiform, myxoid, epithelioid) are identified, myxoid and epithelioid leiomyosarcoma being more aggressive than fusiform leiomyosarcoma. The distinction between low-grade and high-grade endometrial stromal sarcoma is primarily morphological and immunohistochemical and the detection of fusion transcripts can help the diagnosis. Uterine PEComa is a rare tumor, which is distinguished into borderline and malignant, according to a risk assessment algorithm. Embryonal rhabdomyosarcoma of the uterine cervix is more common in children but can also occur in adult women. Embryonal rhabdomyosarcoma of the uterine cervix is almost always DICER1 mutated, unlike that of the vagina which is wild-type DICER1, and adenosarcoma which can be DICER1 mutated but with less frequency. Among the emerging entities, sarcomas associated with fusion transcripts involving the NTRK, ALK, PDGFB genes benefit from targeted therapy. The integration of molecular data with histology and clinical data allows better identification of uterine sarcomas in order to better treat them.
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ARN Helicasas DEAD-box , Neoplasias Endometriales , Neoplasias de los Genitales Femeninos , Leiomiosarcoma , Rabdomiosarcoma Embrionario , Ribonucleasa III , Sarcoma Estromático Endometrial , Neoplasias de los Tejidos Blandos , Neoplasias del Cuello Uterino , Neoplasias Uterinas , Adulto , Niño , Femenino , Humanos , Leiomiosarcoma/diagnóstico , Leiomiosarcoma/genética , Leiomiosarcoma/terapia , Rabdomiosarcoma Embrionario/diagnóstico , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/terapia , Sarcoma Estromático Endometrial/diagnóstico , Sarcoma Estromático Endometrial/genética , Sarcoma Estromático Endometrial/terapia , Proteínas Tirosina Quinasas , Proteínas Proto-Oncogénicas , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/genética , Neoplasias Uterinas/terapia , Proteínas Tirosina Quinasas Receptoras , ADN Helicasas , Proteínas Nucleares , Factores de TranscripciónRESUMEN
BACKGROUND: Noonan syndrome (NS) due to the RRAS2 gene, the pathogenic variant is an extremely rare RASopathies. Our objective was to identify the potential site of RRAS2, combined with the literature review, to find the correlation between clinical phenotype and genotype. De novo missense mutations affect different aspects of the RRAS2 function, leading to hyperactivation of the RAS-MAPK signaling cascade. METHODS: Conventional G-banding was used to analyze the chromosome karyotype of the patient. Copy number variation sequencing (CNV-seq) was used to detect the chromosomal gene microstructure of the patient and her parents. The exomes of the patient and her parents were sequenced using trio-based whole exome sequencing (trio-WES) technology. The candidate variant was verified by Sanger sequencing. The pathogenicity of the variant was predicted with a variety of bioinformatics tools. RESULTS: Chromosome analysis of the proband revealed 46, XX, and no abnormality was found by CNV-seq. After sequencing and bioinformatics filtering, the variant of RRAS2(c.67G>T; p. Gly23Cys) was found in the proband, while the mutation was absent in her parents. To the best of our knowledge, our patient was with the typical Noonan syndrome, such as short stature, facial dysmorphism, and developmental delay. Furthermore, our study is the first case of NS with embryonal rhabdomyosarcoma (ERMS) caused by the RRAS2 gene mutation reported in China. CONCLUSIONS: Our investigations suggested that the heterozygous missense of RRAS2 may be a potential causal variant in a rare cause of Noonan syndrome, expanding our understanding of the causally relevant mutations for this disorder.
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Proteínas de Unión al GTP Monoméricas , Síndrome de Noonan , Rabdomiosarcoma Embrionario , Humanos , Femenino , Síndrome de Noonan/patología , Rabdomiosarcoma Embrionario/genética , Rabdomiosarcoma Embrionario/complicaciones , Variaciones en el Número de Copia de ADN , Mutación , Genotipo , Proteínas de la Membrana/genética , Proteínas de Unión al GTP Monoméricas/genéticaRESUMEN
Accurate diagnosis of neuroblastoma may be challenging, especially with limited or inadequate specimen and at the metastatic sites due to overlapping imaging, histopathologic, and immunohistochemical (immunohistochemistry [IHC]; infidelity among various lineage-associated transcription factors eg FLI1, transducin-like enhancer 1, etc) features. GATA3 and ISL1 have recently been described as markers of neuroblastic differentiation. This study aims at determining the diagnostic utility of GATA3 and ISL1 in differentiating neuroblastoma from other pediatric malignant small round blue cell tumors.We evaluated GATA3 and ISL1 expression in 74 pediatric small round blue cell tumors that included 23 NMYC-amplified neuroblastomas, 11 EWSR1-rearranged round cell sarcomas, 7 SYT::SSX1-rearranged synovial sarcomas, 5 embryonal rhabdomyosarcomas, 10 Wilms tumors (nephroblastomas), 7 lymphoblastic lymphoma, 7 medulloblastoma, and 4 desmoplastic small round cell tumor.All 23 neuroblastomas (moderate to strong staining in >50% of the tumor cells), 5â T-lymphoblastic lymphomas (moderate to strong staining in 40%-90% of the tumor cells), and 2 desmoplastic small round cell tumors (weak to moderate staining in 20%-30% of the tumor cells) expressed GATA3, while other tumors were negative. ISL1 immunoreactivity was observed in 22 (96%) neuroblastomas (strong staining in in >50% of the tumor cells, n = 17; moderate to strong staining in 26%-50% of the tumor cells, n = 5), 3 embryonal rhabdomyosarcoma (moderate to strong staining in 30%-85% of the tumor cells), 1 synovial sarcoma (weak staining in 20% of the tumor cells), and 7 medulloblastoma (strong staining in 60%-90% of the tumor cells). Other tumors were negative. Overall, GATA3 showed 86% specificity, 100% sensitivity, and 90% accuracy for neuroblastoma, with a positive predictive value (PPV) and negative predictive value (NPV) of 77% and 100%, respectively. ISLI showed 72% specificity, 96% sensitivity, and 81% accuracy for neuroblastoma, with a PPV and NPV of 67% and 97%, respectively. After the exclusion of T-lymphoblastic lymphoma and desmoplastic small round cell tumors, GATA3 had 100% specificity, sensitivity, accuracy, and PPV and NPV for neuroblastoma. Similarly, in pediatric small round blue cell tumors, ISL1 had 100% specificity, sensitivity, accuracy, PPV, and NPV for neuroblastoma, after embryonal rhabdomyosarcoma, synovial sarcoma, and medulloblastoma were excluded. CONCLUSIONS: GATA3 and ISL1 may be valuable in the diagnostic work-up of neuroblastoma and may reliably be used to support the neuroblastic lineage of pediatric small round blue cell tumors. Furthermore, dual positivity helps in challenging scenarios, when there is equivocal imaging, overlapping IHC features, limited specimen, and the lack of facility for a molecular work up.