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1.
Biol Open ; 11(10)2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-36214254

RESUMO

While the typical role of receptor tyrosine kinases is to receive and transmit signals at the cell surface, in some cellular contexts (particularly transformed cells) they may also act as nuclear proteins. Aberrant nuclear localization of receptor tyrosine kinases associated with transformation often enhances the transformed phenotype (i.e. nuclear ErbBs promote tumor progression in breast cancer). Rhabdomyosarcoma (RMS), the most common soft tissue tumor in children, develops to resemble immature skeletal muscle and has been proposed to derive from muscle stem/progenitor cells (satellite cells). It is an aggressive cancer with a 5-year survival rate of 33% if it has metastasized. Eph receptor tyrosine kinases have been implicated in the development and progression of many other tumor types, but there are only two published studies of Ephs localizing to the nucleus of any cell type and to date no nuclear RTKs have been identified in RMS. In a screen for protein expression of Ephs in canine RMS primary tumors as well as mouse and human RMS cell lines, we noted strong expression of EphA1 in the nucleus of interphase cells in tumors from all three species. This localization pattern changes in dividing cells, with EphA1 localizing to the nucleus or the cytoplasm depending on the phase of the cell cycle. These data represent the first case of a nuclear RTK in RMS, and the first time that EphA1 has been detected in the nucleus of any cell type.


Assuntos
Receptor EphA1 , Rabdomiossarcoma , Animais , Criança , Cães , Humanos , Camundongos , Músculo Esquelético , Proteínas Nucleares , Receptor EphA1/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Tirosina
2.
Medicina (B Aires) ; 82(5): 784-786, 2022.
Artigo em Espanhol | MEDLINE | ID: mdl-36220040

RESUMO

Rhabdomyosarcoma is a malignant neoplasm of mesenchymal origin with skeletal striated muscular differentiation. It is the most common sarcoma of childhood and has four subtypes: embryonal, alveolar, pleomorphic and spindle cell/sclerosing. Of all of them, the embryonal one is the most prevalent and presents a variant, botryoid, which usually involves hollow organs in the form of a multilobed polypoid mass. We present the case of a 27-year-old woman who consulted for vaginal bleeding and in whom colposcopy revealed a whitish polypoid lesion that was externalized through the external cervical os. Histological examination revealed cellular sectors alternated by lax, myxoid areas, together with typical isthmic-endometrial glands. The atypical spindle cell proliferation was arranged in nests, made up of ce lls with large eosinophilic cytoplasm with transverse cytoplasmic striations and eccentric nuclei with homogeneous chromatin. Areas of densely packed cells were exhibited immediately, but separated from, the intact epithelial lining by a thin layer of loose stroma (cambium layer). The immunostaining profile was positive for desmin, muscle-specific actin and myogenin, and negative for smooth muscle actin. A diagnosis of embryonal botryoid rhabdomyosarcoma of the uterine corpus was made.


El rabdomiosarcoma es una neoplasia maligna de origen mesenquimal con diferenciación muscular estriada esquelética. Es el sarcoma más común de la infancia y presenta cuatro subtipos: embrionario, alveolar, pleomórfico y de células ahusadas/esclerosante. De todos ellos el embrionario es el de mayor prevalencia y presenta una variante, botrioide, que suele comprometer órganos huecos en forma de una masa polipoide multilobulada. Presentamos el caso de una mujer de 27 años que consultó por sangrado vaginal y en quien se evidenció en la colposcopia, una lesión polipoide blanquecina que se exteriorizaba a través del orificio cervical externo. El estudio histológico reveló sectores celulares alternados por áreas laxas, mixoides, junto a glándulas ístmico-endometriales típicas. La proliferación fusocelular atípica, se disponía en nidos, constituidos por células de amplio citoplasma eosinófilo con estriaciones citoplasmáticas transversales y núcleos excéntricos con cromatina homogénea. Se exhibían áreas de células densamente condensadas inmediatas y próximas al revestimiento epitelial intacto, pero separadas de él, por una fina capa de estroma laxo (capa cambial). El perfil de inmunomarcación resultó positivo para desmina, actina músculo específico y miogenina, y negativo para actina músculo liso. Se realizó diagnóstico de rabdomiosarcoma embrionario botroide de cuerpo uterino.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Actinas , Adulto , Cromatina , Desmina , Feminino , Humanos , Miogenina , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia , Rabdomiossarcoma Embrionário/diagnóstico , Rabdomiossarcoma Embrionário/patologia , Útero/patologia
3.
Surg Clin North Am ; 102(5): 715-737, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36209742

RESUMO

Pediatric cancer patients have improved outcomes over the past several decades leading to a greater number of survivors living well into adulthood. Owing to their increased longevity, adult care providers are encountering childhood cancer survivors with greater frequency in their clinics and hospitals. Childhood cancer treatments are associated with varied and significant systemic complications that either persist or develop well into adulthood, including secondary malignancies, cardiomyopathies, and adhesive disease that can complicate even the simplest operation. This article reviews four of the most common solid abdominal tumors in the pediatric population and the long-term sequelae of their respective treatment regimens.


Assuntos
Neoplasias Abdominais , Hepatoblastoma , Neoplasias Renais , Neoplasias Hepáticas , Neuroblastoma , Rabdomiossarcoma , Tumor de Wilms , Neoplasias Abdominais/terapia , Adulto , Criança , Hepatoblastoma/diagnóstico , Hepatoblastoma/patologia , Hepatoblastoma/terapia , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Neuroblastoma/epidemiologia , Neuroblastoma/patologia , Neuroblastoma/terapia , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Tumor de Wilms/patologia , Tumor de Wilms/terapia
4.
Sci Rep ; 12(1): 17149, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229514

RESUMO

Rhabdomyosarcoma is a soft tissue cancer that arises in skeletal muscle due to mutations in myogenic progenitors that lead to ineffective differentiation and malignant transformation. The transcription factors Pax3 and Pax7 and their downstream target genes are tightly linked with the fusion positive alveolar subtype, whereas the RAS pathway is usually involved in the embryonal, fusion negative variant. Here, we analyse the role of Pax3 in a fusion negative context, by linking alterations in gene expression in pax3a/pax3b double mutant zebrafish with tumour progression in kRAS-induced rhabdomyosarcoma tumours. Several genes in the RAS/MAPK signalling pathway were significantly down-regulated in pax3a/pax3b double mutant zebrafish. Progression of rhabdomyosarcoma tumours was also delayed in the pax3a/pax3b double mutant zebrafish indicating that Pax3 transcription factors have an unappreciated role in mediating malignancy in fusion negative rhabdomyosarcoma.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Animais , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição PAX3/genética , Fator de Transcrição PAX3/metabolismo , Fator de Transcrição PAX7/genética , Fator de Transcrição PAX7/metabolismo , Fatores de Transcrição Box Pareados/genética , Fatores de Transcrição Box Pareados/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma Embrionário/genética , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismo
5.
J Pak Med Assoc ; 72(9): 1880-1881, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36281001

RESUMO

Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sarcoma, making 50% of all diagnosed cases. It is a complex disease that has the potential to arise from any tissue of the body except the bones. There are four types of rhabdomyosarcoma; embryonal, botryoidal, alveolar and pleomorphic. [18F]-FDG PET-CT plays a vital role in staging, response evaluation and follow-up of the disease. Due to significant morbidity and mortality with high-risk disease, proper staging is of paramount importance.  Staging of rhabdomyosarcoma depends on tumour localization, infiltration of local structures by the primary tumour, nodal involvement, and presence of visceral metastases. Without timely intervention, rhabdomyosarcoma progresses at an exponential speed.


Assuntos
Fluordesoxiglucose F18 , Rabdomiossarcoma , Criança , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia Computadorizada por Raios X , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Rabdomiossarcoma/diagnóstico por imagem , Rabdomiossarcoma/patologia , Compostos Radiofarmacêuticos
6.
Indian J Pathol Microbiol ; 65(4): 864-868, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36308195

RESUMO

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Anaplasia is a rare phenomenon seen in childhood RMS. The most common histologic subtype was Embryonal followed by Alveolar and spindle subtype. Design: A total of 11 cases of pediatric RMS were selected from January 2017 to June 2019 presenting at various sites. Out of 11 cases, 2 were further diagnosed as Embryonal, 2 as Alveolar, 2 as Pleomorphic, 1 as Spindle subtype and rest 4 as RMS-NOS based on morphology. All cases were positive for Desmin. The presence of cells with lobated, hyperchromatic nuclei at least three times larger than the tumor cell (anaplastic cells) was selected as the main criterion to diagnose Anaplasia. Results: Out of the total 11 cases, anaplasia was seen in 7 cases. Out of these seven, five cases showed Focal Anaplasia (FA) (71.4%) and 2 cases showed Diffuse Anaplasia (DA) (28.6%). Out of 2 cases of Embryonal RMS one exhibited focal anaplasia (50%). One case of Spindle RMS showed diffuse anaplasia, 2 cases of pleomorphic RMS showed focal anaplasia. Out of 3 cases of RMS- NOS, 2 exhibited focal anaplaisa and one displayed Diffuse anaplasia. Both Alveolar RMS had no features of anaplasia. Conclusion: Presence of Anaplasia is a frequent observation in pediatric RMS. Anaplasia is often under reported in pediatric RMS. Pathologist should be more aware of this rare phenomenon.


Assuntos
Rabdomiossarcoma Alveolar , Rabdomiossarcoma , Sarcoma , Neoplasias de Tecidos Moles , Criança , Humanos , Anaplasia , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia , Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Rabdomiossarcoma Alveolar/diagnóstico , Rabdomiossarcoma Alveolar/patologia
7.
In Vivo ; 36(6): 2965-2972, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36309350

RESUMO

BACKGROUND/AIM: Sinonasal rhabdomyosarcoma (RMS) is a rare soft tissue malignancy. Due to the limited cases, the clinicopathological features and prognostic factors are still not well understood. PATIENTS AND METHODS: This retrospective review included eight patients with sinonasal RMS at our institution between 2004 and 2020. Patient demographics, tumor features, Intergroup Rhabdomyosarcoma Study Group (IRSG) stage and clinical group, treatment strategy, and survival rates were evaluated. Kaplan-Meier analysis and log-rank tests were performed to analyze the possible prognostic factors. RESULTS: We observed a predominance of male sex and alveolar-type tumor in sinonasal RMS. Nasal obstructions and neck masses were the most common symptoms. Patients with pretreatment lactate dehydrogenase (LDH) levels >400 U/l and negative immunohistochemical staining for desmin or MyoD1 had lower survival rates. CONCLUSION: In patients with sinonasal RMS, pretreatment LDH levels >400 U/l and negative immunohistochemical staining for desmin or MyoD1 may suggest a poor prognosis. These factors can not only contribute to the prediction of prognosis in patients with sinonasal RMS but also facilitate the design of more appropriate treatment strategies.


Assuntos
Neoplasias dos Seios Paranasais , Rabdomiossarcoma , Sarcoma , Humanos , Masculino , Feminino , Prognóstico , Desmina , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/terapia , Rabdomiossarcoma/patologia , Neoplasias dos Seios Paranasais/diagnóstico , Neoplasias dos Seios Paranasais/terapia , Sarcoma/patologia
8.
Pediatr Blood Cancer ; 69(12): e29967, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36094298

RESUMO

BACKGROUND: Rhabdomyosarcoma (RMS) is an aggressive malignancy, and 20% of children present with metastases at diagnosis. Patients presenting with disseminated disease very occasionally have no clear evidence of a primary tumor mass. As these patients have rarely been investigated, we report on a series of patients with RMS and unknown primary tumor site registered in the Metastatic (MTS) RMS 2008 protocol (October 2008 to December 2016) coordinated by the European pediatric Soft tissue sarcoma Study Group. METHODS: Patients were administered nine cycles of induction chemotherapy, and 48 weeks of maintenance chemotherapy. Surgery and/or radiotherapy were planned after the first assessment of tumor response, and implemented after six cycles of chemotherapy. If feasible, radiotherapy to all sites of metastasis was recommended. RESULTS: We identified 10 patients with RMS and unknown primary site, most of them adolescents (median age 15.8 years, range: 4.6-20.4). Nine had fusion-positive alveolar RMS. Multiple organ involvement was identified in seven patients, two only had bone marrow disease, and one only had leptomeningeal dissemination. All patients were given chemotherapy, four were irradiated, and none had surgery. Three patients underwent allogeneic bone marrow transplantation. At the time of this analysis, only two patients are alive in complete remission: one had received radiotherapy; and one had a bone marrow transplant. CONCLUSIONS: RMS with unknown primary tumor occurs mainly in adolescents and is typically fusion-positive alveolar. Radiotherapy may be important, but survival is poor and patients should be offered enrollment in investigational trials.


Assuntos
Neoplasias Primárias Desconhecidas , Rabdomiossarcoma Alveolar , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Criança , Adolescente , Humanos , Neoplasias Primárias Desconhecidas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Rabdomiossarcoma/patologia , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma Alveolar/patologia
9.
Commun Biol ; 5(1): 992, 2022 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-36127469

RESUMO

Rhabdomyosarcoma, the most common pediatric sarcoma, has no effective treatment for the pleomorphic subtype. Still, what triggers transformation into this aggressive phenotype remains poorly understood. Here we used Ptch1+/-/ETV7TG/+/- mice with enhanced incidence of rhabdomyosarcoma to generate a model of pleomorphic rhabdomyosarcoma driven by haploinsufficiency of the lysosomal sialidase neuraminidase 1. These tumors share mostly features of embryonal and some of alveolar rhabdomyosarcoma. Mechanistically, we show that the transforming pathway is increased lysosomal exocytosis downstream of reduced neuraminidase 1, exemplified by the redistribution of the lysosomal associated membrane protein 1 at the plasma membrane of tumor and stromal cells. Here we exploit this unique feature for single cell analysis and define heterogeneous populations of exocytic, only partially differentiated cells that force tumors to pleomorphism and promote a fibrotic microenvironment. These data together with the identification of an adipogenic signature shared by human rhabdomyosarcoma, and likely fueling the tumor's metabolism, make this model of pleomorphic rhabdomyosarcoma ideal for diagnostic and therapeutic studies.


Assuntos
Neuraminidase , Rabdomiossarcoma , Animais , Haploinsuficiência , Humanos , Proteína 1 de Membrana Associada ao Lisossomo , Lisossomos/metabolismo , Camundongos , Neuraminidase/genética , Neuraminidase/metabolismo , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Microambiente Tumoral
10.
BMJ Case Rep ; 15(8)2022 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-36038153

RESUMO

In this report, we describe the case of an adolescent male with an unusual case of fusion-negative, paratesticular alveolar rhabdomyosarcoma who presented with spontaneous tumour lysis syndrome and diffuse bony metastases throughout the axial and appendicular skeleton with additional significant bone marrow involvement. Both spontaneous tumour lysis syndrome and diffuse bony metastases are extremely unusual for rhabdomyosarcoma. On the backbone of standard vincristine, dactinomycin and cyclophosphamide (VAC) chemotherapy, the only local control was orchiectomy at 15 weeks, with no radiation administered due to the initially diffuse nature of the disease and rapid response to chemotherapy. Following 43 weeks of VAC, a year-long maintenance phase with pazopanib was given which was well tolerated. The patient remains in remission now 4 years after completion of therapy.


Assuntos
Doenças da Medula Óssea , Neoplasias Ósseas , Neoplasias dos Genitais Masculinos , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Síndrome de Lise Tumoral , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Doenças da Medula Óssea/induzido quimicamente , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/secundário , Ciclofosfamida , Dactinomicina/uso terapêutico , Neoplasias dos Genitais Masculinos/tratamento farmacológico , Humanos , Masculino , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia , Rabdomiossarcoma Embrionário/tratamento farmacológico , Síndrome de Lise Tumoral/etiologia , Vincristina
11.
EMBO Mol Med ; 14(10): e16001, 2022 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-35916583

RESUMO

Rhabdomyosarcomas (RMS) are mesenchyme-derived tumors and the most common childhood soft tissue sarcomas. Treatment is intense, with a nevertheless poor prognosis for high-risk patients. Discovery of new therapies would benefit from additional preclinical models. Here, we describe the generation of a collection of 19 pediatric RMS tumor organoid (tumoroid) models (success rate of 41%) comprising all major subtypes. For aggressive tumors, tumoroid models can often be established within 4-8 weeks, indicating the feasibility of personalized drug screening. Molecular, genetic, and histological characterization show that the models closely resemble the original tumors, with genetic stability over extended culture periods of up to 6 months. Importantly, drug screening reflects established sensitivities and the models can be modified by CRISPR/Cas9 with TP53 knockout in an embryonal RMS model resulting in replicative stress drug sensitivity. Tumors of mesenchymal origin can therefore be used to generate organoid models, relevant for a variety of preclinical and clinical research questions.


Assuntos
Organoides , Rabdomiossarcoma , Criança , Humanos , Organoides/patologia , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia
12.
Diagn Cytopathol ; 50(12): E367-E372, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35929754

RESUMO

Spindle cell/sclerosing rhabdomyosarcoma (RMS), characterized by MYOD1 (L122R) mutation in a subset of cases is a newly described subtype of RMS. Presently, there is no documentation of cytomorphological features, especially of sclerosing RMS. Case 1: A 24-year-old male presented with pain and swelling in his wrist for a one-year duration. MRI revealed a well-defined soft tissue lesion measuring 5.3 cm, encasing the lower end of the ulna. Fine-needle aspiration cytology (FNAC) smears revealed clusters of tumor cells with round to oval to spindle-shaped nuclei, scant to moderate amount of cytoplasm with the wisps of the metachromatic stroma. Histopathological examination revealed a malignant tumor comprising cells with polygonal to spindle-shaped nuclei, arranged in a sclerotic stroma. Immunohistochemically, the tumor cells were positive for desmin, myogenin, and MYOD1. A diagnosis of sclerosing RMS was offered. Furthermore, the tumor revealed MYOD1 (L122R) mutation. Case 2: A 43-year-old male presented with a 4-month history of "nasal stuffiness" and pressure. Imaging revealed a poorly defined infiltrative lesion in his nasal cavity. FNAC smears revealed loose and tightly cohesive clusters of malignant cells with oval to spindle-shaped nuclei, a moderate amount of ill-defined bluish to finely vacuolated cytoplasm, and focal streak artifact with interspersed stromal fragments. Histopathological examination revealed a malignant tumor composed of oval to spindle-shaped nuclei, embedded in a variably hyalinized stroma. Immunohistochemically, the tumor cells were positive for desmin, and myogenin. Diagnosis of spindle cell/sclerosing RMS was offered. The present study constitutes one of the first documentation of cytomorphological features of two rare cases of spindle cell/sclerosing RMS. The differential diagnoses and treatment-related implications are presented.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Masculino , Adulto , Criança , Humanos , Adulto Jovem , Miogenina/genética , Proteína MyoD/genética , Desmina/genética , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Mutação , Biomarcadores Tumorais
13.
Mol Oncol ; 16(20): 3587-3605, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36037042

RESUMO

Rhabdomyosarcoma (RMS), a cancer characterized by features of skeletal muscle, is the most common soft-tissue sarcoma of childhood. With 5-year survival rates among high-risk groups at < 30%, new therapeutics are desperately needed. Previously, using a myoblast-based model of fusion-negative RMS (FN-RMS), we found that expression of the Hippo pathway effector transcriptional coactivator YAP1 (YAP1) permitted senescence bypass and subsequent transformation to malignant cells, mimicking FN-RMS. We also found that YAP1 engages in a positive feedback loop with Notch signaling to promote FN-RMS tumorigenesis. However, we could not identify an immediate downstream impact of this Hippo-Notch relationship. Here, we identify a HES1-YAP1-CDKN1C functional interaction, and show that knockdown of the Notch effector HES1 (Hes family BHLH transcription factor 1) impairs growth of multiple FN-RMS cell lines, with knockdown resulting in decreased YAP1 and increased CDKN1C expression. In silico mining of published proteomic and transcriptomic profiles of human RMS patient-derived xenografts revealed the same pattern of HES1-YAP1-CDKN1C expression. Treatment of FN-RMS cells in vitro with the recently described HES1 small-molecule inhibitor, JI130, limited FN-RMS cell growth. Inhibition of HES1 in vivo via conditional expression of a HES1-directed shRNA or JI130 dosing impaired FN-RMS tumor xenograft growth. Lastly, targeted transcriptomic profiling of FN-RMS xenografts in the context of HES1 suppression identified associations between HES1 and RAS-MAPK signaling. In summary, these in vitro and in vivo preclinical studies support the further investigation of HES1 as a therapeutic target in FN-RMS.


Assuntos
Proteômica , Rabdomiossarcoma , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/genética , Inibidor de Quinase Dependente de Ciclina p57/genética , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Regulação Neoplásica da Expressão Gênica , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , RNA Interferente Pequeno , Fatores de Transcrição HES-1/genética , Fatores de Transcrição HES-1/metabolismo , Animais
14.
Medicina (Kaunas) ; 58(7)2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35888670

RESUMO

Epithelioid rhabdomyosarcoma is a rare condition, which may be clinically misinterpreted as melanoma due to its morphological appearance. Careful morphological and immunohistochemical analysis play an important role in its diagnosis. This case report describes the clinicopathological features of an epithelioid RMS diagnosed at the high parietal area of the head. A 71-year-old male patient presented a red-brown pigmented ulcerative nodule in the high parietal region of the head. Previous biopsy and computer tomography imaging revealed a malignant melanoma in stage I (pT2, sN0, Mx). After tumor operation, histological and immunohistochemical analysis of the tumor were conducted. Histological analysis showed an erosive lesion with a monomorphic cell population containing small cells with prominent nucleoli. A positivity was confirmed for CD10, Vimentin, and Desmin. MyoD1 was detected, as well as a fluctuating signal for p53. Molecular analysis revealed a negativity for Sox-10, and a weak positivity for CK8/18 by absence of p40. Based on the morphological and immunohistochemical findings, the tumor was diagnosed as epithelioid RMS.


Assuntos
Melanoma , Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Neoplasias Cutâneas , Idoso , Biomarcadores Tumorais/análise , Humanos , Masculino , Rabdomiossarcoma/química , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma/patologia , Neoplasias Cutâneas/patologia
15.
Int J Oncol ; 61(3)2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35796028

RESUMO

Rhabdomyosarcoma (RMS) is a highly aggressive soft tissue malignancy that predominantly affects children. The main subtypes are alveolar RMS (ARMS) and embryonal RMS (ERMS) and the two show an impaired muscle differentiation phenotype. One pathway involved in muscle differentiation is WNT signaling. However, the role of this pathway in RMS is far from clear. Our recent data showed that the canonical WNT/ß­Catenin pathway serves a subordinate role in RMS, whereas non­canonical WNT signaling probably is more important for this tumor entity. The present study investigated the role of WNT5A, which is the major ligand of non­canonical WNT signaling, in ERMS and ARMS. Gene expression analysis showed that WNT5A was expressed in human RMS samples and that its expression is more pronounced in ERMS. When stably overexpressed in RMS cell lines, WNT5A decreased proliferation and migration of the cells as demonstrated by BrdU incorporation and Transwell migration or scratch assay, respectively. WNT5A also decreased the self­renewal capacity and the expression of stem cell markers and modulates the levels of muscle differentiation markers as shown by sphere assay and western blot analysis, respectively. Finally, overexpression of WNT5A can destabilize active ß­Catenin of RMS cells. A WNT5A knockdown has opposite effects. Together, the results suggest that WNT5A has tumor suppressive functions in RMS, which accompanies downregulation of ß­Catenin.


Assuntos
Rabdomiossarcoma , beta Catenina , Diferenciação Celular/genética , Linhagem Celular , Humanos , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Via de Sinalização Wnt/genética , Proteína Wnt-5a/genética , Proteína Wnt-5a/metabolismo , beta Catenina/metabolismo
16.
Eur J Cancer ; 172: 367-386, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35839732

RESUMO

Rhabdomyosarcomas (RMSs) are the most common soft tissue sarcomas in children/adolescents less than 18 years of age with an annual incidence of 1-2/million. Inter/intra-tumour heterogeneity raise challenges in clinical, pathological and biological research studies. Risk stratification in European and North American clinical trials previously relied on clinico-pathological features, but now, incorporates PAX3/7-FOXO1-fusion gene status in the place of alveolar histology. International working groups propose a coordinated approach through the INternational Soft Tissue SaRcoma ConsorTium to evaluate the specific genetic abnormalities and generate and integrate molecular and clinical data related to patients with RMS across different trial settings. We review relevant data and present a consensus view on what molecular features should be assessed. In particular, we recommend the assessment of the MYOD1-LR122R mutation for risk escalation, as it has been associated with poor outcomes in spindle/sclerosing RMS and rare RMS with classic embryonal histopathology. The prospective analyses of rare fusion genes beyond PAX3/7-FOXO1 will generate new data linked to outcomes and assessment of TP53 mutations and CDK4 amplification may confirm their prognostic value. Pathogenic/likely pathogenic germline variants in TP53 and other cancer predisposition genes should also be assessed. DNA/RNA profiling of tumours at diagnosis/relapse and serial analyses of plasma samples is recommended where possible to validate potential molecular biomarkers, identify new biomarkers and assess how liquid biopsy analyses can have the greatest benefit. Together with the development of new molecularly-derived therapeutic strategies that we review, a synchronised international approach is expected to enhance progress towards improved treatment assignment, management and outcomes for patients with RMS.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Neoplasias de Tecidos Moles , Adolescente , Criança , Consenso , Humanos , Técnicas de Diagnóstico Molecular , Recidiva Local de Neoplasia , Estudos Prospectivos , Rabdomiossarcoma/genética , Rabdomiossarcoma/patologia , Rabdomiossarcoma/terapia , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/terapia , Medição de Risco , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia
17.
Zhonghua Yi Xue Za Zhi ; 102(20): 1500-1505, 2022 May 31.
Artigo em Chinês | MEDLINE | ID: mdl-35692064

RESUMO

Objective: To analyze the efficacy and prognostic factors in children with parameningeal rhabdomyosarcoma (PMRMS) treated by 125I brachytherapy combined with chemotherapy. Methods: A retrospective analysis of the clinical data of 33 pediatric patients treated with 125I brachytherapy combined with chemotherapy in Peking University Stomatological Hospital from July 2013 to October 2018 was carried out to analyze the efficacy and prognostic factors. Results: Among the 33 patients, 19 were males and 14 were females; the median age was 4 years old (1-12 years old). There were 17 cases with embryonic type, 9 cases with alveolar type, and 7 with undifferentiated type; 26 cases with original PMRMS, and 7 cases with recurrent PMRMS. The tumors occurred in subtemporal-mastoid area in 15 patients, while nasopalatine-paranasal area in 6 cases, and parapharyngeal-submandibular area in 12 cases. There were 28 patients in IRS Ⅲ, and 5 patients in IRS Ⅳ. As for the risk level, 28 cases were in the middle-risk group and 5 cases in the high-risk group. The median follow-up time was 52 months. The 1, 3, and 5-year local control rates were 87.9%, 58.6%, and 49.9%, and the 1, 3, and 5-year survival rates were 93.8%, 60.5%, and 47.5%, respectively. The 5-year local control rate and 5-year survival rate of 12 patients with the tumor in the parapharyngeal-submandibular area were 91.7% and 100%, respectively. The 5-year local control rate and 5-year survival rate of the 6 patients with tumor in the nasopalatine-paranasal area were both 83.3%. The 3-year local control rate and 3-year survival rate of the 15 patients with tumor in the subtemporal-mastoid area were 17.5% and 21.4%. The multivariate survival analysis using Cox proportional risk regression model showed that the tumor located in the subtemporal-mastoid area was an independent risk factor affecting the 5-year overall survival rate (HR=38.40, 95%CI: 4.87-302.52, P=0.001). Within 3 months after 125I seed implantation, the incidence of acute radiotherapy adverse reactions in all patients was 84.8% (28/33). Twenty-one patients (63.6%) had a grade 1 acute radiotherapy reaction, and 7 cases (21.2%) had a grade 2 acute radiotherapy reaction. No acute radiotherapy adverse reactions of grade 3 or 4 occurred. Three months after 125I seed implantation, the adverse reactions were significantly alleviated, and no adverse reactions of grade 3 or above such as skin ulcer or salivary gland fibrosis occurred, and no serious cranio-maxillofacial deformities occurred. Conclusions: 125I seed brachytherapy combined with chemotherapy has a definite clinical effect in the treatment of children with parameningeal rhabdomyosarcoma. The prognosis of rhabdomyosarcoma in the parapharyngeal-submandibular area and nasopalatine-paranasal area is better than that in the subtemporal-mastoid area.


Assuntos
Recidiva Local de Neoplasia , Rabdomiossarcoma , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Pré-Escolar , Terapia Combinada , Feminino , Humanos , Lactente , Radioisótopos do Iodo , Masculino , Prognóstico , Estudos Retrospectivos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia
18.
J Clin Oncol ; 40(32): 3730-3740, 2022 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-35709412

RESUMO

PURPOSE: Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study. PATIENTS AND METHODS: In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible. RESULTS: MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% (P < .0001) and 3-year OS 60.0% versus 26.0% (P < .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance. CONCLUSION: Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.


Assuntos
Segunda Neoplasia Primária , Rabdomiossarcoma , Sarcoma , Criança , Humanos , Intervalo Livre de Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Rabdomiossarcoma/tratamento farmacológico , Rabdomiossarcoma/patologia , Sarcoma/tratamento farmacológico , Ifosfamida , Vincristina , Ciclofosfamida , Dactinomicina , Doxorrubicina , Segunda Neoplasia Primária/etiologia
19.
Eur J Cancer ; 170: 179-193, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35660252

RESUMO

BACKGROUND: The clinical development of immune checkpoint-targeted immunotherapies has been disappointing so far in paediatric solid tumours. However, as opposed to adults, very little is known about the immune contexture of paediatric malignancies. METHODS: We investigated by gene expression and immunohistochemistry (IHC) the immune microenvironment of five major paediatric cancers: Ewing sarcoma (ES), osteosarcoma (OS), rhabdomyosarcoma (RMS), medulloblastoma (MB) and neuroblastoma (NB; 20 cases each; n = 100 samples total), and correlated them with overall survival. RESULTS: NB and RMS tumours had high immune cell gene expression values and high T-cell counts but were low for antigen processing cell (APC) genes. OS and ES tumours showed low levels of T-cells but the highest levels of APC genes. OS had the highest levels of macrophages (CSF1R, CD163 and CD68), whereas ES had the lowest. MB appeared as immune deserts. Tregs (FOXP3 staining) were higher in both RMS and OS. Most tumours scored negative for PD-L1 in tumour and immune cells, with only 11 of 100 samples positive for PD-L1 staining. PD-L1 and OX40 levels were generally low across all five indications. Interestingly, NB had comparable levels of CD8 by IHC and by gene expression to adult tumours. However, by gene expression, these tumours were low for T-cell cytotoxic molecules GZMB, GZMA and PRF1. Surprisingly, the lower the level of tumour infiltrative CD8 T-cells, the better the prognosis was in NB, RMS and ES. Gene expression analyses showed that MYCN-amplified NB have higher amounts of immune suppressive cells such as macrophages, myeloid-derived suppressor cells and Tregs, whereas the non-MYCN-amplified tumours were more infiltrated and had higher expression levels of Teff. CONCLUSIONS: Our results describe the quality and quantity of immune cells across five major paediatric cancers and provide some key features differentiating these tumours from adult tumour types. These findings explain why anti-PD(L)1 might not have had single agent success in paediatric cancers. These results provides the rationale for the development of biologically stratified and personalised immunotherapy strategies in children with relapsing/refractory cancers.


Assuntos
Neoplasias Ósseas , Neuroblastoma , Osteossarcoma , Rabdomiossarcoma , Sarcoma de Ewing , Antígeno B7-H1/metabolismo , Criança , Humanos , Imunoterapia , Linfócitos do Interstício Tumoral , Neuroblastoma/genética , Prognóstico , Rabdomiossarcoma/patologia , Microambiente Tumoral
20.
Genes Chromosomes Cancer ; 61(12): 701-709, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35766997

RESUMO

The mammalian Vestigial-like (VGLL) transcriptional cofactor family of proteins VGLL1-4 has recently emerged as an important player in the tumorigenesis of diverse neoplasms. The role of VGLL3 in soft tissue tumors is exemplified by its amplification in myxoinflammatory fibroblastic sarcoma and its rearrangement (fused to CHD7, CHD9, or MAMLD1) in hybrid schwannoma-perineurioma. This study characterizes a distinctive low-grade myogenic neoplasm with a striking predilection for the head and neck, characterized by VGLL3 fusions. The study includes five males and one female patient, aged 30-71 years (median, 56). Three tumors originated in the tongue, with one case each in the nasopharynx, oral cavity, and oropharynx. The VGLL3 fusion partners included TCF12 (n = 3), EP300 (n = 2), and PPARGC1A (n = 1). The tumor size range was 0.8-1.6 cm (all, but one, was <1 cm). Histologically, all tumors displayed bland spindle to ovoid cells arranged into vague fascicular and diffuse patterns. Mitotic activity ranged from 1 to 7 per 10 HPFs. Five tumors were muscle-centered and infiltrative, and one was centered beneath nasopharyngeal mucosa. Immunohistochemistry revealed consistent expression of desmin (diffuse in four and patchy in two cases) associated with patchy smooth muscle actin expression (4/6), and focal reactivity for myogenin (5/6) and myoD1 (1/3). All patients were managed surgically; one patient each received adjuvant radio- or chemotherapy. Three patients with follow-up were without disease at 8, 19, and 60 months and one was alive with unknown disease status at 24 months. All VGLL3 fusions were in-frame and involved exon 2, fused with either TCF12 exon 16, EP300 exon 31, or PPARGC1A exon 5, respectively. This series characterizes a distinctive subset of spindle cell rhabdomyosarcoma (RMS) with a predilection for the head and neck in adults, defined by VGLL3 fusions, likely indolent behavior and limited rhabdomyoblastic differentiation. Further delineation of this entity and differentiation from more aggressive molecular subtypes of spindle cell RMS is mandatory to define the most appropriate therapeutic strategy and avoid overtreatment.


Assuntos
Rabdomiossarcoma , Neoplasias de Tecidos Moles , Fatores de Transcrição , Actinas , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Ligação a DNA , Desmina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miogenina/genética , Rabdomiossarcoma/química , Rabdomiossarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética
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