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1.
Anticancer Res ; 40(3): 1239-1245, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132020

RESUMO

BACKGROUND/AIM: Since the first description of five pericytomas with the t(7;12)/ACTB-GLI1 fusion gene, only three new tumors were studied by both cytogenetics and molecular techniques. We report here genetic data on another case of this rare tumor. MATERIALS AND METHODS: Cytogenetic, fluorescence in situ hybridization (FISH), reverse transcription polymerase chain reaction (RT-PCR), and Sanger sequencing analyses were performed. RESULTS: The pericytoma carried two structurally rearranged chromosomes: der(7)t(7;12)(p22;q13) and der(12)t(1;12)(q12;q13). In FISH experiments with a break-apart probe for GLI1, the distal part of the probe hybridized to der(7) whereas the proximal part to der(12). RT-PCR and Sanger sequencing detected an ACTB-GLI1 fragment in which exon 2 of ACTB was fused to exon 6 of GLI1. CONCLUSION: The ACTB-GLI1 fusion gene was mapped at der(7)t(7;12)(p22;q13) and coded for a putative ACTB-GLI1 protein in which the first 41 amino acid (aa) of ACTB replaced the first 177 aa of GLI1.


Assuntos
Actinas/genética , Proteínas de Fusão Oncogênica/genética , Pericitos/patologia , Neoplasias de Tecidos Moles/genética , Proteína GLI1 em Dedos de Zinco/genética , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 12 , Cromossomos Humanos Par 7 , Feminino , Humanos , Neoplasias de Tecidos Moles/patologia , Coxa da Perna/patologia , Translocação Genética
2.
Cancer Treat Rev ; 85: 101987, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32092619

RESUMO

AIMS: To make recommendations on the indications for molecular testing regarding the diagnosis, prediction of prognosis, and treatment selection in adult patients with s oft tissue sarcomas (STS) excluding gastrointestinal stromal tumour. MATERIALS AND METHODS: This guideline was developed by the Cancer Care Ontario's Program in Evidence-Based Care (PEBC) and the Sarcoma Disease Site Group (DSG). The medline, embase, and Cochrane Library databases, main guideline websites, abstracts of relevant annual meetings, and PROSPERO databases were searched (January 2005 to October 2016). Internal and external reviews were conducted, with final approval by the PEBC and the Sarcoma DSG. RESULTS: Based on the available evidence, we made three S trong Recommendations, 14 Recommendations, 9 Qualified Statements, and seven No Recommendations. The three Strong Recommendations include: i) MDM2 amplification by fluorescence in situ hybridization (FISH) is recommended as a sensitive and specific test to differentiate patients with atypical lipomatous tumour/well-differentiated liposarcoma, or dedifferentiated liposarcoma from lipoma or other STS in the differential diagnosis; ii) SS18 (SYT) break-apart by FISH or SS18-SSX (SYT-SSX) fusion by reverse transcription-polymerase chain reaction is recommended as a sensitive and specific test to differentiate patients with synovial sarcoma from other sarcomas; iii) CTNNB1 S45F mutation by polymerase chain reaction is recommended as a prognostic factor for poor recurrence-free survival in patients with desmoid tumours. CONCLUSION: This guideline may serve as a framework for the thoughtful implementation of molecular studies at cancer centres and other jurisdictions. Some of the recommendations may need to be updated when new evidence appears in the future.


Assuntos
Biomarcadores Tumorais/genética , Proteínas de Fusão Oncogênica/genética , Guias de Prática Clínica como Assunto , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Medicina Baseada em Evidências , Feminino , Tumores do Estroma Gastrointestinal/diagnóstico , Tumores do Estroma Gastrointestinal/genética , Testes Genéticos , Humanos , Masculino , Ontário , Prognóstico , Sarcoma/diagnóstico , Sarcoma/terapia , Sensibilidade e Especificidade , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/terapia
3.
Virchows Arch ; 476(1): 3-15, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701221

RESUMO

Although traditional morphological evaluation remains the cornerstone for the diagnosis of soft tissue tumors, ancillary diagnostic modalities such as immunohistochemistry and molecular genetic analysis are of ever-increasing importance in this field. New insights into the molecular pathogenesis of soft tissue tumors, often obtained from high-throughput sequencing technologies, has enabled significant progress in the characterization and biologic stratification of mesenchymal neoplasms, expanding the spectrum of immunohistochemical tests (often aimed towards recently discovered genetic events) and molecular genetic assays (most often fluorescence in situ hybridization and reverse transcription-polymerase chain reaction). This review discusses selected novel molecular and immunohistochemical assays with diagnostic applicability in mesenchymal neoplasms, with emphasis on diagnosis, refinement of tumor classification, and treatment stratification.


Assuntos
Neoplasias de Tecidos Moles/diagnóstico , DNA Helicases/análise , Fusão Gênica , Humanos , Imuno-Histoquímica , Proteínas Nucleares/análise , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-fos/genética , Proteína EWS de Ligação a RNA/genética , Receptor trkA/genética , Proteínas Repressoras/genética , Proteína SMARCB1/análise , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/análise
4.
Virchows Arch ; 476(1): 121-134, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31701222

RESUMO

Soft tissue tumors encompass a wide variety of mesenchymal neoplasms exhibiting diverse clinical, pathologic, and molecular features. Among these, osteoid and/or chondroid matrix deposition in some soft tissue tumors represents a noticeable characteristic. Unlike matrices present in bone tumors where they likely reveal the respective cells of origin (i.e., osteoblastic or chondroblastic precursors), those existing in soft tissue tumors more often denote a metaplastic phenomenon and reflect the diversity of differentiation these tumors can display. While many soft tissue tumor types can occasionally harbor metaplastic bone or cartilage as an incidental component or heterologous differentiation, in some other tumor types, the production of these matrices is a frequent and distinctive, if not diagnostic, feature. This review focuses on the latter tumor types where emerging immunohistochemical and molecular evidence has significantly improved our understanding of their respective pathogenesis and histopathological spectra. These tumor types include ossifying fibromyxoid tumor, phosphaturic mesenchymal tumor, synovial chondromatosis, soft tissue chondroma, calcifying aponeurotic fibroma, giant cell tumor of soft tissue, myositis ossificans and related diseases, mesenchymal chondrosarcoma, and extraskeletal osteosarcoma.


Assuntos
Neoplasias de Tecidos Moles/genética , Condromatose Sinovial/genética , Tumores de Células Gigantes/genética , Tumores de Células Gigantes/patologia , Humanos , Imuno-Histoquímica , Miosite Ossificante/genética , Miosite Ossificante/patologia , Osteossarcoma/genética , Osteossarcoma/patologia , Proteínas Proto-Oncogênicas c-mdm2/genética , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/etiologia , Neoplasias de Tecidos Moles/patologia
5.
Virchows Arch ; 476(1): 41-55, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31828431

RESUMO

Over the last 10 years, a number of advances have been made in our understanding of fibroblastic and myofibroblastic tumors. The rapidly evolving field of molecular diagnostics has resulted in the recognition of new entities and better understanding of tumor pathogenesis, while careful clinicopathologic correlative analyses have led to improvements in modeling tumor behavior. This review will discuss new and emerging entities in fibroblastic neoplasia and provide updates on the pathogenesis, diagnosis, and prognostication of these diverse and challenging tumors.


Assuntos
Fibroblastos/patologia , Neoplasias de Tecido Fibroso/patologia , Antígenos CD34/análise , Rearranjo Gênico , Humanos , Neoplasias de Tecido Fibroso/etiologia , Neoplasias de Tecido Fibroso/genética , Prognóstico , Proteína EWS de Ligação a RNA/genética , Sarcoma/patologia , Proteína Smad3/genética , Neoplasias de Tecidos Moles/etiologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
6.
Medicine (Baltimore) ; 98(45): e17872, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31702654

RESUMO

RATIONALE: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) is a rare type of soft tissue sarcomas (STS), especially in infants, with poor prognosis. It is a so-called "small round cell" sarcoma, and has many features of Ewing sarcoma, but lacks rearrangements in EWSR1. The diagnosis and treatment of this kind of STS remains challenging. BCOR genetic abnormalities have been found in some Ewing-like sarcomas. PATIENT CONCERNS: This report presents an ELS case of a female infant, who was 2 months old when initially diagnosed, with the clinical stage of IIIA (G2T2N0M0). Histologic findings revealed an undifferentiated neoplasm composed of small round tumor cells with round, open chromatic nuclei, and scant cytoplasm in a sheet growth pattern. Fluorescence in situ hybridization (FISH) analysis showed absence of EWSR1 and ETV6 gene rearrangement. Molecular genetic testing found no established variants of clinical significance but variants of unknown significance in APC, KMT2D, and MSH6 were detected. Immunostaining revealed that the tumor cells were positive for TLE1 and BCOR, and negative for cytokeratin (AE1/AE3), Desmin, CD45, S100, CD31, HMB45, and SATB2. INI-1 was retained. DIAGNOSIS: Ewing-like sarcoma (ELS)/undifferentiated round cell sarcoma (URCS) INTERVENTIONS:: After initial diagnosis, the patient received 4 cycles of combination chemotherapy for 2 months. Radical amputation of left upper extremity was performed 3 months after diagnosis. Postoperative chemotherapy was continued for 6 cycles. OUTCOMES: The patient died of intracranial metastasis with hemorrhage in 13 months after initial diagnosis, 5 months after the last cycle of chemotherapy. LESSONS: ELS in infancy is extremely rare and has a poorer prognosis than Ewing sarcoma or infantile fibrosarcoma. APC and MSH6 variation might be related with the disease progression and predict a poorer prognosis. This rare case promotes better understanding of the disease and suggests a promising role for the combination chemotherapy regimen in treating infantile ELS. Importantly, it brings to light the possibility of intracranial metastasis, which requires proactive screening for timely detection.


Assuntos
Sarcoma/patologia , Neoplasias de Tecidos Moles/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Dactinomicina/uso terapêutico , Evolução Fatal , Feminino , Antebraço/diagnóstico por imagem , Humanos , Lactente , Sarcoma/diagnóstico por imagem , Sarcoma/tratamento farmacológico , Sarcoma/genética , Neoplasias de Tecidos Moles/diagnóstico por imagem , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/genética , Ultrassonografia Doppler em Cores , Vincristina/uso terapêutico
7.
Semin Diagn Pathol ; 36(4): 260-268, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31301876

RESUMO

Perhaps the rarest cause of osteomalacia is that caused by a neoplasm, so-called "tumor-induced osteomalacia" (TIO). Although very rare cases of TIO have been associated with carcinomas and syndromes such as neurofibromatosis type-1 and McCune-Albright syndrome, the overwhelming majority of TIO is caused by tumors of mesenchymal origin. Although it was historically felt that almost any mesenchymal tumor type could occasionally result in TIO, it has become increasingly clear over the past several decades that almost all cases of mesenchymal tumor-associated TIO are caused by a single entity, known as "phosphaturic mesenchymal tumor" (PMT). This article will review historical aspects of this tumor, as well as its clinical, morphological, immunohistochemical and molecular genetic features. The distinction of PMT from its many potential morphological mimics is discussed in detail.


Assuntos
Mesenquimoma/complicações , Mesenquimoma/genética , Mesenquimoma/patologia , Neoplasias Ósseas/complicações , Neoplasias Ósseas/genética , Neoplasias Ósseas/patologia , Humanos , Neoplasias de Tecido Conjuntivo/etiologia , Neoplasias de Tecidos Moles/complicações , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
8.
J Clin Pathol ; 72(12): 810-816, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31300531

RESUMO

AIMS: Leiomyosarcomas (LMSs) occur in various tissues and harbour potential for metastases. The genomic landscape of LMS is poorly understood. In an effort to improve understanding of the LMS genome, we analysed 11 LMSs of somatic soft tissue including matching tissue of normal phenotype. METHODS: DNA derived from microdissected tumour domains and matching normal tissue underwent amplicon sequencing of 409 tumour suppressors and oncogenes using the Ion Torrent Comprehensive Cancer Panel. RESULTS: Genomic changes were heterogeneous with few recurrent abnormalities detected. Coding variants were identified in genes involved in signal transduction, transcriptional regulation and DNA repair. There were variants in several genes related to angiogenesis and GPR124 variants (TEM5) were confirmed by immunohistochemical analysis of a LMS tissue microarray. Surprisingly, there were shared coding variants in tumour and corresponding normal tissue. CONCLUSIONS: LMSs are a very heterogeneous population lacking recurrent somatic abnormalities. The presence of damaging mutations in normal tissue may reflect either a germline predisposition or field effect rather than tissue contamination. Hopeful therapeutic targets appear to be those related to AKT/MTOR pathway.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Dosagem de Genes , Leiomiossarcoma/genética , Reação em Cadeia da Polimerase Multiplex , Mutação , Neoplasias de Tecidos Moles/genética , Biomarcadores Tumorais/análise , Variações do Número de Cópias de DNA , Predisposição Genética para Doença , Humanos , Imuno-Histoquímica , Leiomiossarcoma/química , Leiomiossarcoma/patologia , Leiomiossarcoma/terapia , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/terapia
9.
Pediatr Blood Cancer ; 66(11): e27935, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31339226

RESUMO

Spindle cell and sclerosing rhabdomyosarcoma (ssRMS) is a rare variant of rhabdomyosarcoma, which includes three distinct subtypes. In infants, these tumors are commonly associated with recurring fusions involving VGLL2 or NCOA2 and have a favorable prognosis. We present four cases of ssRMS and 16 additional cases from the literature, which show that these patients present with localized disease and have an excellent prognosis regardless of surgical margin or lack of radiation therapy. Molecularly defined spindle cell rhabdomyosarcoma in infants is likely a biologically distinct entity which may not require the aggressive multimodal treatment used for other subtypes of rhabdomyosarcoma.


Assuntos
Rabdomiossarcoma Embrionário/congênito , Neoplasias de Tecidos Moles/congênito , Amputação , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Terapia Combinada , Ciclofosfamida/administração & dosagem , Dactinomicina/administração & dosagem , Extremidades/patologia , Feminino , Doenças do Pé/congênito , Doenças do Pé/tratamento farmacológico , Doenças do Pé/genética , Doenças do Pé/cirurgia , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/tratamento farmacológico , Doenças do Prematuro/genética , Doenças do Prematuro/cirurgia , Masculino , Proteínas de Fusão Oncogênica/genética , Indução de Remissão , Rabdomiossarcoma Embrionário/tratamento farmacológico , Rabdomiossarcoma Embrionário/genética , Rabdomiossarcoma Embrionário/cirurgia , Neoplasias de Tecidos Moles/tratamento farmacológico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/cirurgia , Coxa da Perna , Neoplasias Torácicas/congênito , Neoplasias Torácicas/tratamento farmacológico , Neoplasias Torácicas/genética , Neoplasias Torácicas/cirurgia , Parede Torácica/patologia , Vincristina/administração & dosagem
10.
Tohoku J Exp Med ; 248(2): 87-97, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31189751

RESUMO

Bone and soft tissue tumors are derived from mesenchymal cells, and they are hard to treat. Receptor-activator of nuclear factor-kappa B ligand (RANKL) is an essential cytokine for osteoclast differentiation and activation and is expressed on the surface of osteoblasts or stromal cells. In this study, to explore the potential of denosumab treatment for soft tissue tumors, we analyzed the expression profiles of RANKL mRNA in 425 tumor specimens of 33 histological types by real-time RT-PCR. Denosumab is a monoclonal antibody that prevents the binding of RANKL to receptor-activator of nuclear factor-kappa B (RANK). For comparison, the relative expression levels of RANK and osteoprotegerin (OPG) mRNAs were also measured. OPG functions as a soluble decoy receptor for RANKL. Higher expression levels of RANKL mRNA were detected in calcifying aponeurotic fibroma, fibrosarcoma, calcifying epithelioma, myositis ossificans, heterotopic calcification, giant cell tumor of the tendon sheath (GCTTS), and pigmented villonodular synovitis (PVNS), compared with the levels of other tumor types. Moreover, the expression levels of RANK mRNA were highest in GCTTS, followed by myositis ossificans and PVNS, whereas the expression levels of OPG mRNA were greatly varied among these histological types. We then analyzed RANKL protein expression by immunohistochemistry in 57 tumor specimens with higher expression levels of RANKL mRNA. RANKL-positive cells were detected in GCTTS, PVNS, myositis ossificans, heterotopic calcification, and calcifying aponeurotic fibroma. In conclusion, RANKL is expressed in subsets of soft tissue tumors with calcification, and denosumab is a potential therapeutic option for soft tissue tumors expressing RANKL.


Assuntos
Ligante RANK/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligante RANK/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/genética , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
11.
Pathologe ; 40(4): 339-352, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31240452

RESUMO

More than 20% of soft-tissue tumors belong to the group of adipocytic neoplasms. Difficulties may occur in the differential diagnosis of lipomas versus atypical lipomatous tumors/well-differentiated liposarcomas, in the distinction of dedifferentiated liposarcomas from other soft-tissue sarcoma entities and in the detailed subtyping of liposarcomas. Especially in biopsies, the correct diagnosis and grading may be hampered due to limited tissue. Because of the ever-increasing molecular-pathological knowledge of soft-tissue tumors and the rising distribution of molecular diagnostic assays in institutes of pathology, differential diagnosis has been facilitated, as more than 90% of adipocytic tumors carry more or less specific genomic alterations. In the following, the most important subtypes of adipocytic tumors are described morphologically and genomically.


Assuntos
Lipoma , Lipossarcoma , Neoplasias Lipomatosas , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Lipoma/diagnóstico , Lipoma/patologia , Lipossarcoma/diagnóstico , Lipossarcoma/patologia , Neoplasias Lipomatosas/diagnóstico , Neoplasias Lipomatosas/patologia , Sarcoma/diagnóstico , Sarcoma/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
12.
Medicine (Baltimore) ; 98(25): e16031, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31232935

RESUMO

Accurate diagnoses of sarcoma are sometimes challenging on conventional histomorphology and immunophenotype. Many specific genetic aberrations including chromosomal translocations have been identified in various sarcomas, which can be detected by fluorescence in situ hybridization and polymerase chain reaction analysis. Next-generation sequencing-based RNA sequencing can screen multiple sarcoma-specific chromosome translocations/fusion genes in 1 test, which is especially useful for sarcoma without obvious differentiation. In this report, we utilized RNA sequencing on formalin-fixed paraffin-embedded (FFPE) specimens to investigate the possibility of diagnosing sarcomas by identifying disease-specific fusion genes. Targeted RNA sequencing was performed on 6 sarcoma cases. The expected genetic alterations (clear cell sarcoma/EWSR1-ATF1, Ewing sarcoma/EWSR1-FLI1, myxoid liposarcoma/DDIT3-FUS) in four cases were detected and confirmed by secondary tests. Interestingly, three SS18 fusion genes (SS18-SSX2B, SS18-SSX2, and SS18-SSX4) were identified in a synovial sarcoma case. A rare fusion gene (EWSR1-PATZ1) was identified in a morphologically challenging case; which enabled us to establish the diagnosis of low grade glioneural tumor. In conclusion, RNA sequencing on FFPE specimen is a reliable method in establishing the diagnosis of sarcoma in daily practice.


Assuntos
Biomarcadores Tumorais/genética , Proteínas Proto-Oncogênicas/genética , Proteína EWS de Ligação a RNA/genética , Sarcoma/diagnóstico , Neoplasias de Tecidos Moles/diagnóstico , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inclusão em Parafina , Reação em Cadeia da Polimerase , Sarcoma/genética , Análise de Sequência de RNA , Neoplasias de Tecidos Moles/genética
13.
Curr Opin Pediatr ; 31(3): 368-377, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31090579

RESUMO

PURPOSE OF REVIEW: Nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) is a rare subgroup of malignancy in childhood that is composed of a variety of soft tissue and bony tumors. Prognosis for resectable localized disease is usually good and improved with systemic treatment. However, survival from locally advanced and metastatic disease remains poor. There have been numerous preclinical and clinical studies to define histopathology, biology, and genetic alteration of sarcomas. The purpose of this review is to clarify the progress in the management of NRSTS. RECENT FINDINGS: Genomic analysis, including the use of next-generation sequencing, has revealed fusion transcripts or specific genetic alterations which provide diagnostic biomarkers and potential targets for novel therapies. SUMMARY: Most cases are sporadic, but some are associated with genetic predispositions. Most present as a painless mass and diagnosis is frequently delayed because of a low index of suspicion. There is a wide array of histopathological subtypes. Investigations usually involve core, incisional or excisional biopsy for tissue diagnosis, and cross-sectional and nuclear imaging for staging. Management of pediatric sarcoma is largely dependent on the patient's histopathological diagnosis, age, disease stage, and co-morbidities but usually involves a combination of systemic and local therapies. Preclinical studies and phase I/II trials of newer targeted therapies are ongoing.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Criança , Estudos Transversais , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Prognóstico , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/terapia , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/terapia
14.
J Nippon Med Sch ; 86(2): 126-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31130564

RESUMO

Pseudomyogenic hemangioendothelioma (PMHE) is a new entity. It is an intermediate soft tissue tumor clinically and/or histopathologically mimicking some other high-grade malignant tumors and some inflammatory diseases. We report a case of PMHE on the left plantar surface of a 28-year-old woman. Histopathological examination of the resected specimen revealed spindle and epithelioid cells with plump and atypical nuclei proliferated in the dermis and subcutaneous fat tissue with marked fibroplasia. Both spindle and epithelioid cells had abundant eosinophilic cytoplasm. Neoplastic cells were diffusely positive for AE1/AE3, CK7, vimentin, CD31, FLI-1, ERG, and INI-1. From those findings, we made the diagnosis of PMHE. We describe the main points of differentiation between PMHE and diseases that have similar clinical and/or histopathological findings, including cellular dermatofibroma, spindle cell squamous cell carcinoma, epithelioid sarcoma, epithelioid hemangioendothelioma, epithelioid angiosarcoma, nodular or proliferative fasciitis, and granulomatous fibrosing granulation tissue due to a ruptured epidermal cyst.


Assuntos
Hemangioendotelioma Epitelioide/patologia , Neoplasias de Tecidos Moles/patologia , Adulto , Antiporters/metabolismo , Diagnóstico Diferencial , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Humanos , Queratinas/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Proteína Proto-Oncogênica c-fli-1/metabolismo , Proteína SMARCB1/metabolismo , Neoplasias de Tecidos Moles/diagnóstico , Neoplasias de Tecidos Moles/genética , Regulador Transcricional ERG/metabolismo , Vimentina/metabolismo
15.
Genes Chromosomes Cancer ; 58(11): 739-746, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31112350

RESUMO

NTRK3-rearranged tumors other than infantile fibrosarcomas (IFSs) harboring the canonical ETV6-NTRK3 fusions are uncommon, and include mainly inflammatory myofibroblastic tumors and gastrointestinal stromal tumors. Herein, we describe an additional subset of seven tumors sharing NTRK3 gene rearrangements. The cohort included five females and two males (age range 1-67 years). Tumors were located in extremities, trunk, retroperitoneum, or intra-abdominal. In all tumors, fluorescence in situ hybridization (FISH) revealed rearrangements in NTRK3 accompanied by NTRK3 amplification in two cases. In three cases, RNA sequencing identified a fusion transcript composed of NTRK3 exon 14 fused to ETV6, TFG, and TPM4, respectively, retaining the NTRK3 kinase domain. All tumors were positive for pan-TRK by immunohistochemistry (IHC). Two cases showed low- to intermediate-grade histology composed of monomorphic spindle cells arranged in a patternless architecture, stromal bands, and perivascular rings of hyalinized collagen and coexpression of S100 and CD34. The remaining five cases were high-grade fascicular monomorphic spindle cell sarcomas, morphologically somewhat reminiscent of either malignant peripheral nerve sheath tumors (MPNSTs) or fibrosarcomas (FSs). Two high-grade NTRK3 sarcomas showed aggressive clinical behavior with development of lung metastases. Identification of high-grade NTRK3-rearranged sarcomas is clinically important, since the development of selective NTRK inhibitors has opened new avenues for targeted therapy. Although IHC for pan-TRK can be applied as a screening tool, molecular studies are recommended for a conclusive diagnosis of NTRK-rearranged neoplasms.


Assuntos
Receptor trkC/genética , Sarcoma/genética , Sarcoma/patologia , Adolescente , Adulto , Idoso , Biomarcadores Tumorais/genética , Criança , Pré-Escolar , Feminino , Fusão Gênica/genética , Rearranjo Gênico/genética , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente/métodos , Lactente , Masculino , Pessoa de Meia-Idade , Receptor trkC/metabolismo , Neoplasias de Tecidos Moles/genética , Sequenciamento Completo do Exoma
16.
Histopathology ; 75(4): 508-516, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31136005

RESUMO

AIM: To characterise unclassifiable sarcomas by use of a combined histological and molecular approach. METHODS AND RESULTS: Using RNA sequencing, we identified in-frame fusions involving KMT2A (MLL) in two cases. Case 1 was a 20-year-old woman with a deep soft tissue mass in the thigh. The tumour consisted of monomorphic round, epithelioid and spindle cells in a highly sclerotic background that were focally immunopositive for CD34, CD31, and ERG. Case 2 was a 30-year-old woman with a tumour that affected the femur and surrounding soft tissue. The tumour consisted of monomorphic round to spindle cells that were immunopositive for BCOR, Wilms tumour 1, and NKX2-2. Both tumours were aggressive and had metastasised to the lung; both patients died within a few years. RNA sequencing identified a YAP1 (exon 5)-KMT2A (exon 4) fusion in case 1 and a VIM (exon 4)-KMT2A (exon 2) fusion in case 2, both of which were confirmed by reverse transcription polymerase chain reaction, Sanger sequencing, and fluorescence in-situ hybridisation. The fusion protein structure was different from that in acute leukaemia, suggesting a novel oncogenic mechanism. CONCLUSIONS: KMT2A fusions account for a subset of aggressive unclassifiable sarcomas in young adults. Although it is presently unclear whether these sarcomas belong to a single group, the well-established role of KMT2A fusions as drivers of acute leukaemia and a recent publication regarding identification of YAP1-KMT2A in one unclassifiable sarcoma support the significance of these fusions. Further studies on additional cases are necessary to fully understand the clinicopathological and molecular aspects of KMT2A-rearranged sarcomas.


Assuntos
Neoplasias Ósseas/genética , Histona-Lisina N-Metiltransferase/genética , Proteína de Leucina Linfoide-Mieloide/genética , Fusão Oncogênica/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Neoplasias Ósseas/patologia , Feminino , Humanos , Proteínas de Fusão Oncogênica/genética , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/patologia , Fatores de Transcrição/genética , Vimentina/genética , Adulto Jovem
17.
Ann Diagn Pathol ; 41: 1-7, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31108450

RESUMO

We present clinicopathological and molecular cytogenetic features of five rare cases of Ewing sarcomas, occurring in the female genital tract. A 40 year-old lady presented with a 5.4 cm-sized vaginal mass of 3 months duration, which was histopathologically diagnosed as ES. She defaulted chemotherapy and 8 months later, presented with a recurrence. She underwent chemotherapy and radiotherapy. A 45 year-old lady presented with recurrent vaginal bleeding, for which she underwent total abdominal hysterectomy (TAH) and unilateral salpingo-oophorectomy (USO), 2 and 1/2 years back. Subsequent vaginal biopsy was reported inconclusively, elsewhere. Thereafter, a 5 cm-sized, residual cervicovaginal mass was reported as ES. She completed induction chemotherapy with a significant response. A 35 year-old-lady was referred with a 4 cm-sized cervical mass, for which she underwent TAH-USO with pelvic and para-aortic lymphadenectomy. A 39 year-old-lady presented with a right labial lesion, which recurred. She underwent initial excision, chemotherapy, wide excision and brachytherapy. A year later, she developed multiple metastases; received palliative radiotherapy and died-of-disease. A 16 year-old girl presented with perineal swelling of 4 months duration. She underwent surgical excision of a recurrent right-sided labial cyst, followed by chemotherapy. On histopathological review, all 5 cases were malignant round cell tumors. Immunohistochemically, tumor cells displayed MIC2/CD99 and Fli1 positivity, along with focal positivity for pan cytokeratin (AE1/AE3) (cases 1 and 2) and p63 (case 2). Furthermore, tumor cells in the 1st, 2nd, 3rd and 5th cases displayed EWSR1 rearrangement. Five uncommon cases of ES involving the female genital tract are presented with diagnostic challenges and therapeutic implications.


Assuntos
Neoplasias dos Genitais Femininos/genética , Neoplasias dos Genitais Femininos/patologia , Proteína EWS de Ligação a RNA/genética , Sarcoma de Ewing/genética , Sarcoma de Ewing/patologia , Adolescente , Adulto , Feminino , Rearranjo Gênico , Humanos , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
18.
Genes Chromosomes Cancer ; 58(9): 680-685, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30938880

RESUMO

We report a case of a 35-year old male patient with a tumor located in the deep dermis on his forearm. The lesion was completely excised but recurred 4 years later. The patient showed no signs of neurofibromatosis type 1. The morphology and immunophenotype of the tumor corresponded to the recently characterized group of soft tissue spindle cell lesions defined by a relatively uniform cytomorphology, patternless architecture, conspicuous stromal and perivascular hyalinization, S100 and CD34 coexpression and recurrent fusions involving RAF1, BRAF, and NTRK1/2 genes. Using a 592-gene panel and massively parallel next-generation sequencing platform, we initially detected only NF1 gene mutation in our case. However, further molecular testing with Archer fusion assay revealed a novel NCOA4-RET gene fusion, adding it to the list of multiple kinase fusions originally reported in these tumors. Although break-apart FISH showed false negative result due to the presence of intrachromosomal rearrangement, RT-PCR confirmed the fusion transcript. Knowing the exact fusion is of great clinical importance especially for patients within the aggressive subset of these neoplasms that could be treated with selective kinase inhibitors. The presented case underscores the benefits of massively parallel sequencing as the types and number of gene fusions these tumors can potentially harbor render single-gene assays such as FISH impractical, and in this particular case, also insensitive.


Assuntos
Antígenos CD34/genética , Coativadores de Receptor Nuclear/genética , Fusão Oncogênica , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas S100/genética , Neoplasias de Tecidos Moles/genética , Adulto , Antígenos CD34/metabolismo , Derme/metabolismo , Derme/patologia , Humanos , Hialina/metabolismo , Masculino , Mutação , Neurofibromina 1/genética , Coativadores de Receptor Nuclear/metabolismo , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas S100/metabolismo , Neoplasias de Tecidos Moles/patologia
19.
Genes Chromosomes Cancer ; 58(10): 705-712, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31008539

RESUMO

Fibroblastic/myofibroblastic neoplasms represent a broad, and occasionally diagnostically challenging, category of soft tissue neoplasms. A subset of these tumors defy conventional classification. However, with the advent of next-generation sequencing, the identification of disease-defining molecular alterations is gradually improving their subclassification. Following identification of two index cases of a distinctive fibroblastic neoplasm with a fusion gene involving PRRX1 and NCOA1, we performed a retrospective review to further characterize this entity. We identified two additional cases, including one with a fusion between PRRX1 and NCOA2. The average patient age was 38 years, and three patients were female. Two tumors occurred on the neck, and the others involved the groin and thigh. Tumors were centered in the subcutis and ranged from 2.3 to 14.0 cm (average 5.8 cm). Morphologically, they were predominantly hypocellular, with focal hypercellularity. They were composed of monomorphic spindle-stellate cells with a vague fascicular pattern. The nuclei were bland with only rare mitotic activity, and occasional multinucleation. The intervening stroma was typically abundant and ranged from myxoid to collagenous, with frequent rope-like collagen bundles. Three of the cases had a prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn-like vessels. Immunohistochemistry was negative for desmin, smooth muscle actin, S100, CD34, keratin, and epithelial membrane antigen. Each of the patients was treated by simple excision and none of the tumors were associated with local recurrence or metastasis. Based on their unique morphological and molecular attributes, we believe this represents a novel fibroblastic tumor for which we have tentatively proposed the name "PRRX-NCOAx-rearranged fibroblastic tumor."


Assuntos
Proteínas de Homeodomínio/genética , Coativador 1 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/genética , Fusão Oncogênica , Neoplasias de Tecidos Moles/genética , Adulto , Núcleo Celular/metabolismo , Núcleo Celular/patologia , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Tecidos Moles/patologia
20.
Cancer Immunol Immunother ; 68(6): 927-936, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30879106

RESUMO

BACKGROUND: Immune cells can regulate disease progression and response to treatment in multiple tumor types, but their activities in human soft tissue sarcoma are poorly characterized. METHODS: Marker-defined immune cell subsets were characterized from a tumor microenvironmental perspective in two independent cohorts of human soft tissue sarcoma by multiplex IHC, quantitative PCR and/or bioinformatics. RESULTS: B cell profiling revealed a prognostic role for CD20 protein (cohort 1, 33 patients) and MS4A1 gene expression (cohort 2, 265 patients). Multiplex IHC and gene correlation analysis supported a role in antigen presentation, immune cell differentiation and T cell activation. The prognostic role of MS4A1 expressing B cells was only observed in an IL10low, PTGS2low or CD163low tumor microenvironment according to the transcriptomic data. IL10 levels consistently correlated with the M2-like macrophage marker CD163, which also defined the majority of macrophages. A polarization of these cells toward a pro-tumoral phenotype was further supported by lack of correlation between CD163 and M1 markers like NOS2, as well as by low abundance of CD80 positive cells in tissue. CONCLUSIONS: Analysis of CD20/MS4A1 expression in soft tissue sarcoma merits further attention as a promising candidate prognostic tool for survival, but not in patients with a pronounced immunosuppressive tumor microenvironment. Macrophages are ubiquitous and polarized toward a protumoral phenotype. This provides a rationale for further studies on B cell function and immunotherapy targeting M2-polarized macrophages.


Assuntos
Antígenos CD20/imunologia , Linfócitos B/imunologia , Macrófagos/imunologia , Sarcoma/imunologia , Neoplasias de Tecidos Moles/imunologia , Transcriptoma/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD20/genética , Antígenos CD20/metabolismo , Linfócitos B/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Sarcoma/genética , Sarcoma/metabolismo , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Adulto Jovem
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