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1.
Cell ; 179(6): 1330-1341.e13, 2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31761532

RESUMO

Non-coding regions amplified beyond oncogene borders have largely been ignored. Using a computational approach, we find signatures of significant co-amplification of non-coding DNA beyond the boundaries of amplified oncogenes across five cancer types. In glioblastoma, EGFR is preferentially co-amplified with its two endogenous enhancer elements active in the cell type of origin. These regulatory elements, their contacts, and their contribution to cell fitness are preserved on high-level circular extrachromosomal DNA amplifications. Interrogating the locus with a CRISPR interference screening approach reveals a diversity of additional elements that impact cell fitness. The pattern of fitness dependencies mirrors the rearrangement of regulatory elements and accompanying rewiring of the chromatin topology on the extrachromosomal amplicon. Our studies indicate that oncogene amplifications are shaped by regulatory dependencies in the non-coding genome.


Assuntos
Cromossomos Humanos/genética , Elementos Facilitadores Genéticos , Amplificação de Genes , Oncogenes , Acetilação , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Cromatina/metabolismo , DNA de Neoplasias/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Genes Neoplásicos , Loci Gênicos , Glioblastoma/genética , Glioblastoma/patologia , Histonas/metabolismo , Humanos , Neuroglia/metabolismo
2.
Genes Dev ; 35(7-8): 512-527, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33766982

RESUMO

Epithelioid hemangioendothelioma (EHE) is a genetically homogenous vascular sarcoma that is a paradigm for TAZ dysregulation in cancer. EHE harbors a WWTR1(TAZ)-CAMTA1 gene fusion in >90% of cases, 45% of which have no other genetic alterations. In this study, we used a first of its kind approach to target the Wwtr1-Camta1 gene fusion to the Wwtr1 locus, to develop a conditional EHE mouse model whereby Wwtr1-Camta1 is controlled by the endogenous transcriptional regulators upon Cre activation. These mice develop EHE tumors that are indistinguishable from human EHE clinically, histologically, immunohistochemically, and genetically. Overall, these results demonstrate unequivocally that TAZ-CAMTA1 is sufficient to drive EHE formation with exquisite specificity, as no other tumor types were observed. Furthermore, we fully credential this unique EHE mouse model as a valid preclinical model for understanding the role of TAZ dysregulation in cancer formation and for testing therapies directed at TAZ-CAMTA1, TAZ, and YAP/TAZ signaling.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Carcinogênese/genética , Modelos Animais de Doenças , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Transativadores/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Proteínas de Ligação ao Cálcio/genética , Humanos , Camundongos , Transdução de Sinais/genética , Transativadores/genética
3.
Trends Biochem Sci ; 48(5): 450-462, 2023 05.
Artigo em Inglês | MEDLINE | ID: mdl-36709077

RESUMO

The Hippo signaling pathway inhibits the activity of the oncogenic YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif)-TEAD (TEA/ATTS domain) transcriptional complex. In cancers, inactivating mutations in upstream Hippo components and/or enhanced activity of YAP/TAZ and TEAD have been observed. The activity of this transcriptional complex can be effectively inhibited by targeting the TEAD family of transcription factors. The development of TEAD inhibitors has been driven by the discovery that TEAD has druggable hydrophobic pockets, and is currently at the clinical development stage. Three small molecule TEAD inhibitors are currently being tested in Phase I clinical trials. In this review, we highlight the role of TEADs in cancer, discuss various avenues through which TEAD activity can be inhibited, and outline the opportunities for the administration of TEAD inhibitors.


Assuntos
Neoplasias , Fatores de Transcrição de Domínio TEA , Humanos , Fatores de Transcrição/metabolismo , Neoplasias/tratamento farmacológico , Via de Sinalização Hippo
4.
Genes Chromosomes Cancer ; 63(2): e23226, 2024 02.
Artigo em Inglês | MEDLINE | ID: mdl-38380774

RESUMO

Epithelioid hemangioendothelioma (EHE) is a rare endothelial sarcoma associated with a high incidence of metastases and for which there are no standard treatment options. Based on disease-defining mutations, most EHEs are classified into two subtypes: WWTR1::CAMTA1-fused EHE or YAP1::TFE3-fused EHE. However, rare non-canonical fusions have been identified in clinical samples of EHE cases and are challenging to classify. In this study, we report the identification of a novel WWTR1::TFE3 fusion variant in an EHE patient using targeted RNA sequencing. Histologically, the tumor exhibited hybrid morphological characteristics between WWTR1::CAMTA1-fused EHE and YAP1::TFE3-fused EHE. In addition to the driver fusion, there were six additional secondary mutations identified, including a loss-of-function FANCA mutation. Furthermore, in vitro studies were conducted to investigate the tumorigenic function of the WWTR1::TFE3 fusion protein in NIH3T3 cells and demonstrated that WWTR1::TFE3 promotes colony formation in soft agar. Finally, as the wild-type WWTR1 protein relies on binding the TEAD family of transcription factors to affect gene transcription, mutation of the WWTR1 domain of the fusion protein to inhibit such binding abrogates the transformative effect of WWTR1::TFE3. Overall, we describe a novel gene fusion in EHE with a hybrid histological appearance between the two major genetic subtypes of EHE. Further cases of this very rare subtype of EHE will need to be identified to fully elucidate the clinical and pathological characteristics of this unusual subtype of EHE.


Assuntos
Hemangioendotelioma Epitelioide , Transativadores , Humanos , Camundongos , Animais , Transativadores/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Células NIH 3T3 , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fusão Gênica , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional
5.
Genes Chromosomes Cancer ; 63(1): e23203, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37724942

RESUMO

Spindle cell mesenchymal neoplasms are a diverse and often challenging diagnostic group. While morphological impression is sufficient for some diagnoses, increasingly immunohistochemical and even molecular data is required to render an accurate diagnosis, which can lead to the characterization of new entities. We describe five cases of novel mesenchymal neoplasms with rearrangements in the NCOA2 and NCOA3 genes partnered with either CTCF or CRTC1. Three tumors occurred in the head and neck (palate, auditory canal), while the other two were in visceral organs (lung, urinary bladder). All cases occurred in adults (range 33-86) with a median age of 42 and fairly even sex distribution = (male-to-female = 3:2). Morphologically, they had similar features consisting of monotonous, bland spindle to ovoid cells with fascicular and reticular arrangements in a myxohyaline to collagenous stroma. However, immunophenotypically they had essentially a null phenotype, with only two tumors staining partially for CD34 and smooth muscle actin. Targeted RNA sequencing detected in-frame CTCF::NCOA2 (one case), CRTC1::NCOA2 (two cases), and CTCF::NCOA3 (two cases) fusions. Treatment was surgical resection in all cases. Local recurrence and/or distant metastases were not observed in any case (median follow-up, 7.5 months; range, 2-19 months). Given their morphologic, immunohistochemical, and molecular similarities, we believe that these cases may represent an emerging family of low-grade NCOA2/3-rearranged fibroblastic spindle cell neoplasms.


Assuntos
Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias de Tecidos Moles , Adulto , Humanos , Masculino , Feminino , Fibroblastos/patologia , Sequência de Bases , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Fenótipo , Biomarcadores Tumorais/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Coativador 2 de Receptor Nuclear/genética
6.
J Pathol ; 260(5): 637-648, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37345731

RESUMO

Bone and soft tissue tumors are generally classified into complex karyotype sarcomas versus those with recurrent genetic alterations, often in the form of gene fusions. In this review, we provide an overview of important co-occurring genomic alterations, organized by biological mechanisms and covering a spectrum of genomic alteration types: mutations (single-nucleotide variations or indels) in oncogenes or tumor suppressor genes, copy number alterations, transcriptomic signatures, genomic complexity indices (e.g. CINSARC), and complex genomic structural variants. We discuss the biological and prognostic roles of these so-called secondary or co-occurring alterations, arguing that recognition and detection of these alterations may be significant for our understanding and management of mesenchymal tumors. On a related note, we also discuss major recurrent alterations in so-called complex karyotype sarcomas. These secondary alterations are essential to sarcomagenesis via a variety of mechanisms, such as inactivation of tumor suppressors, activation of proliferative signal transduction, telomere maintenance, and aberrant regulation of epigenomic/chromatin remodeling players. The use of comprehensive genomic profiling, including targeted next-generation sequencing panels or whole-exome sequencing, may be incorporated into clinical workflows to offer more comprehensive, potentially clinically actionable information. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Assuntos
Sarcoma , Neoplasias de Tecidos Moles , Humanos , Sarcoma/genética , Sarcoma/patologia , Mutação , Oncogenes/genética , Transcriptoma , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia
7.
J Infect Dis ; 227(3): 344-352, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36214810

RESUMO

BACKGROUND: Four severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants predominated in the United States since 2021. Understanding disease severity related to different SARS-CoV-2 variants remains limited. METHOD: Viral genome analysis was performed on SARS-CoV-2 clinical isolates circulating March 2021 through March 2022 in Cleveland, Ohio. Major variants were correlated with disease severity and patient outcomes. RESULTS: In total 2779 patients identified with either Alpha (n 1153), Gamma (n 122), Delta (n 808), or Omicron variants (n 696) were selected for analysis. No difference in frequency of hospitalization, intensive care unit (ICU) admission, and death were found among Alpha, Gamma, and Delta variants. However, patients with Omicron infection were significantly less likely to be admitted to the hospital, require oxygen, or admission to the ICU (2 12.8, P .001; 2 21.6, P .002; 2 9.6, P .01, respectively). In patients whose vaccination status was known, a substantial number had breakthrough infections with Delta or Omicron variants (218/808 [26.9] and 513/696 [73.7], respectively). In breakthrough infections, hospitalization rate was similar regardless of variant by multivariate analysis. No difference in disease severity was identified between Omicron subvariants BA.1 and BA.2. CONCLUSIONS: Disease severity associated with Alpha, Gamma, and Delta variants is comparable while Omicron infections are significantly less severe. Breakthrough disease is significantly more common in patients with Omicron infection.


Assuntos
COVID-19 , Humanos , SARS-CoV-2/genética , Gravidade do Paciente , Infecções Irruptivas
8.
Histopathology ; 82(3): 376-384, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36073677

RESUMO

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are among the most frequent sarcomas. Accurate diagnosis, classification, and reporting are critical for prognostication and patient management, including selection of appropriate targeted therapy. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of GIST. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major international pathology and cancer organizations. An international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialized soft tissue tumour experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain its clinical relevance and the rationale for selection as a core or noncore element. Following international public consultation, the datasets, which include synoptic reporting guides, were finalized and ratified, and published on the ICCR website. These first international datasets for GIST are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will ultimately help to improve the management of patients with GIST. All the ICCR datasets, including these on GIST, are freely available worldwide on the ICCR website (www.iccr-cancer.org/datasets).


Assuntos
Carcinoma , Tumores do Estroma Gastrointestinal , Patologia Clínica , Humanos , Carcinoma/patologia , Biópsia
9.
Virus Genes ; 59(5): 653-661, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37310519

RESUMO

SARS-CoV-2 mutation is minimized through a proofreading function encoded by NSP-14. Most estimates of the SARS-CoV-2 mutation rate are derived from population based sequence data. Our understanding of SARS-CoV-2 evolution might be enhanced through analysis of intra-host viral mutation rates in specific populations. Viral genome analysis was performed between paired samples and mutations quantified at allele frequencies (AF) ≥ 0.25, ≥ 0.5 and ≥ 0.75. Mutation rate was determined employing F81 and JC69 evolution models and compared between isolates with (ΔNSP-14) and without (wtNSP-14) non-synonymous mutations in NSP-14 and by patient comorbidity. Forty paired samples with median interval of 13 days [IQR 8.5-20] were analyzed. The estimated mutation rate by F81 modeling was 93.6 (95%CI 90.8-96.4], 40.7 (95%CI 38.9-42.6) and 34.7 (95%CI 33.0-36.4) substitutions/genome/year at AF ≥ 0.25, ≥ 0.5, ≥ 0.75 respectively. Mutation rate in ΔNSP-14 were significantly elevated at AF ≥ 0.25 vs wtNSP-14. Patients with immune comorbidities had higher mutation rate at all allele frequencies. Intra-host SARS-CoV-2 mutation rates are substantially higher than those reported through population analysis. Virus strains with altered NSP-14 have accelerated mutation rate at low AF. Immunosuppressed patients have elevated mutation rate at all AF. Understanding intra-host virus evolution will aid in current and future pandemic modeling.


Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , Taxa de Mutação , SARS-CoV-2/genética , Pandemias , Mutação , Genoma Viral/genética
10.
J Cutan Pathol ; 50(2): 140-146, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36107728

RESUMO

AIM: Post-radiation angiosarcoma is an iatrogenic event seen in the setting of breast cancer treatment. Histopathologically, there are morphologic variants of angiosarcoma that mimic benign entities, including the capillary lobule variant of post-radiation angiosarcoma. We present the largest case series to date of this histopathologic variant of post-radiation angiosarcoma. METHODS AND RESULTS: Cases of the capillary lobule variant of post-radiation angiosarcoma from institutional/consultation archives from 2008 to June 2022 were reviewed. For inclusion, tumors had to occur in irradiated skin and exhibit a multi-lobular proliferation of tightly packed capillary-like vessels, as previously described in this variant. Prior ancillary studies were also reviewed. Eight cases met the criteria. All occurred in women treated with radiation for breast cancer (median age 75 years). All cases had similar findings, including a multi-lobular proliferation of tightly packed vessels, infiltrative cords, and atypical single endothelial cells. A conventional angiosarcoma pattern was also seen in five cases. All cases tested were positive for vascular markers (CD31, CD34, and/or ERG) and MYC. MYC amplification was shown by FISH in all cases tested. Smooth muscle actin (SMA) was positive in pericytes in the capillary lobules in all five cases tested and areas of conventional angiosarcoma in two of three cases. CONCLUSIONS: The capillary lobule variant of angiosarcoma is a rare and therefore potentially under-recognized variant of post-radiation angiosarcoma. The lobular architecture and SMA positivity may mimic benign vascular proliferations. Careful attention to histopathologic features and ancillary tests may facilitate accurate diagnosis.


Assuntos
Neoplasias da Mama , Hemangiossarcoma , Neoplasias Cutâneas , Doenças Vasculares , Feminino , Humanos , Hemangiossarcoma/etiologia , Hemangiossarcoma/patologia , Células Endoteliais/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/patologia , Pele/patologia , Doenças Vasculares/patologia , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/patologia
11.
J Cutan Pathol ; 50(2): 147-154, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36074249

RESUMO

BACKGROUND: Low-grade fibromyxoid sarcoma (LGFMS) typically involves deep soft tissue (beneath the fascia) of the proximal extremities and trunk. Long-term follow-up has shown a high rate of local recurrence, metastasis, and death. To the best of our knowledge, there is only one previous large series focusing on superficial LGFMS suggesting superficial tumors are disproportionately more common in children and may have a better prognosis. Our study's primary goals are to confirm these findings and increase general awareness that LGFMS may arise in superficial soft tissue. METHODS: We retrieved our cases of superficial LGFMS diagnosed between 2008 and 2020. Available slides were reviewed, and clinical data and follow-up information were obtained. RESULTS: The patients included nine males and 14 females with a median age of 29 years; eight (35%) were children (<18 years) and five (22%) were young adults (18-30 years). The majority involved the lower extremities (65%). The tumors were primarily centered in the subcutis (91%) and dermis (9%). Microscopically, they had typical features of LGFMS with alternating fibrous and myxoid zones composed of bland, slightly hyperchromatic spindled cells. All were positive for MUC4 by immunohistochemistry and/or FUS rearrangement by FISH. Follow-up on 14 cases ranged from 11 to 148 months (median 61 months) with no evidence of recurrences or distant metastases. CONCLUSIONS: Compared to conventional deep-seated counterparts, superficial LGFMS is more likely to occur in the extremities of children and young adults and may have a better clinical outcome. Further studies with longer follow-up will likely help support these findings.


Assuntos
Fibrossarcoma , Neoplasias de Tecidos Moles , Masculino , Feminino , Humanos , Neoplasias de Tecidos Moles/patologia , Fibrossarcoma/patologia , Imuno-Histoquímica
12.
Mod Pathol ; 35(9): 1193-1203, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35449398

RESUMO

Correctly diagnosing a rare childhood cancer such as sarcoma can be critical to assigning the correct treatment regimen. With a finite number of pathologists worldwide specializing in pediatric/young adult sarcoma histopathology, access to expert differential diagnosis early in case assessment is limited for many global regions. The lack of highly-trained sarcoma pathologists is especially pronounced in low to middle-income countries, where pathology expertise may be limited despite a similar rate of sarcoma incidence. To address this issue in part, we developed a deep learning convolutional neural network (CNN)-based differential diagnosis system to act as a pre-pathologist screening tool that quantifies diagnosis likelihood amongst trained soft-tissue sarcoma subtypes based on whole histopathology tissue slides. The CNN model is trained on a cohort of 424 centrally-reviewed histopathology tissue slides of alveolar rhabdomyosarcoma, embryonal rhabdomyosarcoma and clear-cell sarcoma tumors, all initially diagnosed at the originating institution and subsequently validated by central review. This CNN model was able to accurately classify the withheld testing cohort with resulting receiver operating characteristic (ROC) area under curve (AUC) values above 0.889 for all tested sarcoma subtypes. We subsequently used the CNN model to classify an externally-sourced cohort of human alveolar and embryonal rhabdomyosarcoma samples and a cohort of 318 histopathology tissue sections from genetically engineered mouse models of rhabdomyosarcoma. Finally, we investigated the overall robustness of the trained CNN model with respect to histopathological variations such as anaplasia, and classification outcomes on histopathology slides from untrained disease models. Overall positive results from our validation studies coupled with the limited worldwide availability of sarcoma pathology expertise suggests the potential of machine learning to assist local pathologists in quickly narrowing the differential diagnosis of sarcoma subtype in children, adolescents, and young adults.


Assuntos
Rabdomiossarcoma Embrionário , Rabdomiossarcoma , Adolescente , Animais , Criança , Humanos , Aprendizado de Máquina , Camundongos , Redes Neurais de Computação , Patologistas , Rabdomiossarcoma/diagnóstico , Rabdomiossarcoma Embrionário/patologia , Adulto Jovem
13.
J Vasc Surg ; 76(6): 1432-1439.e2, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-35944733

RESUMO

In 2011, the Society for Vascular Surgery (SVS) prepared a set of clinical research priorities through a survey of its membership. These priorities were developed with the goal of enhancing clinical research to improve care for vascular patients. In the subsequent decade, several of these priorities served as the focus of clinical trials and significant research efforts. It was understood from the outset that this list of priorities represented a starting point with the intention that they be reevaluated at suitable intervals. In 2021, the SVS Research Council set out to update the research priorities by surveying the SVS membership and engaged a panel of subject matter experts. This process resulted in an updated set of vascular research priorities that more clearly align with current areas of emphasis. Our priorities remain focused on basic areas including aortic disease, carotid disease, lower extremity arterial disease, venous disease, dialysis access, and medical management of vascular disease, along with the topic of health care disparities. The 10 updated priorities reported herein reflect our increasing awareness of the need to understand vascular disease pathogenesis and prevention in the context of a diverse patient population. Importantly, patient-centered outcomes and personalized vascular care are at the core of these updated priorities. Similar to the aims of the original 2011 clinical research priorities, our hope is that this updated list will help to drive large-scale investigations that will improve how we care for our vascular patients.


Assuntos
Especialidades Cirúrgicas , Doenças Vasculares , Humanos , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Extremidade Inferior/irrigação sanguínea , Doenças Vasculares/diagnóstico , Doenças Vasculares/cirurgia , Avaliação de Resultados em Cuidados de Saúde
14.
Genes Dev ; 28(14): 1578-91, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-25030697

RESUMO

Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.


Assuntos
Antineoplásicos/farmacologia , Benzamidas/farmacologia , Piridinas/farmacologia , Rabdomiossarcoma Alveolar/patologia , Animais , Linhagem Celular Tumoral , Linhagem da Célula , Modelos Animais de Doenças , Epigênese Genética/efeitos dos fármacos , Proteína Forkhead Box O1 , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados/metabolismo , Proteína Supressora de Tumor p53/metabolismo
15.
Mod Pathol ; 34(9): 1710-1718, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34088997

RESUMO

Gene rearrangements involving the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase gene have been identified in various neoplasms, including inflammatory myofibroblastic tumor and epithelioid fibrous histiocytoma. We present an ALK-rearranged cutaneous soft tissue tumor with unique morphologic and immunophenotypic features that are not shared by other entities with ALK rearrangements. The six cases involved two females and four males, aged 18-84 (mean 51) years old. Three tumors were on the back and three on the lower extremities (thigh, knee, shin); ranging from 0.5 to 5.6 (mean 2.1) cm. Four were confined to the dermis; two involved the subcutis. All six cases were characterized by the presence of spindled to ovoid cells arranged in concentric whorls and cords against a myxoid to myxohyaline stroma and relatively cellular aggregates of plump ovoid to epithelioid cells. Four cases showed distinct hyalinized blood vessels. Both cases that involved the subcutis showed peripheral lipofibromatosis-like areas. Tumor-infiltrating lymphocytes were absent to moderate. Severe cytologic atypia or conspicuous mitotic activity was not identified. Immunohistochemically, all tumors diffusely expressed ALK (D5F3) and CD34. All but one tumor was diffusely positive for S100 protein. All tumors were negative for EMA, AE1/AE3, SMA, and SOX10. Next-generation sequencing revealed ALK fusions with FLNA (3 cases), MYH10 (2 cases), and HMBOX1 (1 case) as the partner genes. In all six cases, the breakpoints involved exon 20 of ALK, which preserves the receptor tyrosine kinase domains of ALK in the fusion product. Of the four cases with limited follow-up information (2-18 months), none recurred. In conclusion, we report an ALK-rearranged cutaneous soft tissue tumor characterized by the presence of myxoid spindle cell whorls and cords, and co-expression of ALK, CD34, and frequently S100 protein, we term "superficial ALK-rearranged myxoid spindle cell neoplasm".


Assuntos
Quinase do Linfoma Anaplásico/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Rearranjo Gênico , Humanos , Imunofenotipagem , Masculino , Pessoa de Meia-Idade , Fusão Oncogênica
16.
Mod Pathol ; 34(12): 2211-2221, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34381186

RESUMO

YAP1-TFE3-fused hemangioendothelioma is an extremely rare malignant vascular tumor. We present the largest multi-institutional clinicopathologic study of YAP1-TFE3-fused hemangioendothelioma to date. The 24 cases of YAP1-TFE3-fused hemangioendothelioma showed a female predominance (17 female, 7 male) across a wide age range (20-78 years old, median 44). Tumors were most commonly located in soft tissue (50%), followed by bone (29%), lung (13%), and liver (8%), ranging from 3 to 115 mm in size (median 40 mm). About two-thirds presented with multifocal disease, including 7 cases with distant organ metastasis. Histopathologically, we describe three dominant architectural patterns: solid sheets of coalescing nests, pseudoalveolar and (pseudo)vasoformative pattern, and discohesive strands and clusters of cells set in a myxoid to myxohyaline stroma. These patterns were present in variable proportions across different tumors and often coexisted within the same tumor. The dominant cytomorphology (88%) was large epithelioid cells with abundant, glassy eosinophilic to vacuolated cytoplasm, prominent nucleoli and well-demarcated cell borders. Multinucleated or binucleated cells, prominent admixed erythrocytic and lymphocytic infiltrates, and intratumoral fat were frequently present. Immunohistochemically, ERG, CD31, and TFE3 were consistently expressed, while expression of CD34 (83%) and cytokeratin AE1/AE3 (20%) was variable. CAMTA1 was negative in all but one case. All cases were confirmed by molecular testing to harbor YAP1-TFE3 gene fusions: majority with YAP1 exon 1 fused to TFE3 exon 4 (88%), or less commonly, TFE3 exon 6 (12%). Most patients (88%) were treated with primary surgical resection. Over a follow-up period of 4-360 months (median 36 months) in 17 cases, 35% of patients remained alive without disease, and 47% survived many years with stable, albeit multifocal and/or metastatic disease. Five-year progression-free survival probability was 88%. We propose categorizing YAP1-TFE3-fused hemangioendothelioma as a distinct disease entity given its unique clinical and histopathologic characteristics in comparison to conventional epithelioid hemangioendothelioma.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Biomarcadores Tumorais/genética , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma/genética , Proteínas de Sinalização YAP/genética , Adulto , Idoso , Ásia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/análise , Biomarcadores Tumorais/análise , Europa (Continente) , Éxons , Feminino , Predisposição Genética para Doença , Hemangioendotelioma/química , Hemangioendotelioma/patologia , Hemangioendotelioma/cirurgia , Hemangioendotelioma Epitelioide/química , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , Intervalo Livre de Progressão , Fatores de Tempo , Adulto Jovem
17.
Mod Pathol ; 34(4): 770-785, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33012788

RESUMO

The knowledge of clinical features and, particularly, histopathological spectrum of EWSR1-PATZ1-rearranged spindle and round cell sarcomas (EPS) remains limited. For this reason, we report the largest clinicopathological study of EPS to date. Nine cases were collected, consisting of four males and five females ranging in age from 10 to 81 years (average: 49 years). Five tumors occurred in abdominal wall soft tissues, three in the thorax, and one in the back of the neck. Tumor sizes ranged from 2.5 to 18 cm (average 6.6 cm). Five patients had follow-up with an average of 38 months (range: 18-60 months). Two patients had no recurrence or metastasis 19 months after diagnosis. Four patients developed multifocal pleural or pulmonary metastasis and were treated variably by surgery, radiotherapy, and chemotherapy. The latter seemed to have little to no clinical benefit. One of the four patients was free of disease 60 months after diagnosis, two patients were alive with disease at 18 and 60 months, respectively. Morphologically, low, intermediate, and high-grade sarcomas composed of a variable mixture of spindled, ovoid, epithelioid, and round cells were seen. The architectural and stromal features also varied, resulting in a broad morphologic spectrum. Immunohistochemically, the following markers were most consistently expressed: S100-protein (7/9 cases), GFAP (7/8), MyoD1 (8/9), Pax-7 (4/5), desmin (7/9), and AE1/3 (4/9). By next-generation sequencing, all cases revealed EWSR1-PATZ1 gene fusion. In addition, 3/6 cases tested harbored CDKN2A deletion, while CDKN2B deletion and TP53 mutation were detected in one case each. Our findings confirm that EPS is a clinicopathologic entity, albeit with a broad morphologic spectrum. The uneventful outcome in some of our cases indicates that a subset of EPS might follow a more indolent clinical course than previously appreciated. Additional studies are needed to validate whether any morphological and/or molecular attributes have a prognostic impact.


Assuntos
Biomarcadores Tumorais/genética , Fatores de Transcrição Kruppel-Like/genética , Proteína EWS de Ligação a RNA/genética , Proteínas Repressoras/genética , Sarcoma/genética , Neoplasias de Tecidos Moles/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Criança , Europa (Continente) , Feminino , Fusão Gênica , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Sarcoma/química , Sarcoma/patologia , Sarcoma/cirurgia , Neoplasias de Tecidos Moles/química , Neoplasias de Tecidos Moles/patologia , Neoplasias de Tecidos Moles/cirurgia , Resultado do Tratamento , Estados Unidos
18.
Histopathology ; 79(6): 940-946, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34156713

RESUMO

AIMS: Clear cell (haemangioblastoma-like) stromal tumour of the lung is a newly described, rare pulmonary neoplasm. Recurrent YAP1-TFE3 gene fusions have recently been reported in three cases. We describe two additional cases and confirm the characteristic YAP1-TFE3 gene fusion. METHODS AND RESULTS: Two mesenchymal tumours of lung were identified from our soft tissue pathology consultation services and RNA sequencing was performed. Both cases were in male patients, aged 35 and 77 years. Both presented as solitary lung nodules measuring 3.9 and 7.5 cm in greatest dimension. Histopathologically, the tumours were composed of epithelioid to plump spindle cells arranged in packets and solid sheets. The cells showed fusiform to ovoid nuclei with open chromatin, variably prominent nucleoli and scant to moderate, clear to eosinophilic cytoplasm. Cytological atypia and significant mitotic activity were minimal. None of the tumours expressed lineage-specific immunophenotypical markers. Both cases were diffusely positive for nuclear TFE3. Unlike YAP1-TFE3-fused epithelioid haemangioendothelioma, for which the fusion breakpoint occurs in YAP1 exon 1 and TFE3 exons 4 or 6, the fusion breakpoints of these tumours were located in YAP1 exon 4 and TFE3 exon 7. Following complete surgical resection, neither of the tumours has recurred or metastasised (follow-up period 6-7 months). CONCLUSIONS: We validate the presence of YAP1-TFE3 gene fusion in a unique primary mesenchymal tumour of lung, adding additional support for clear cell stromal tumour of the lung as a distinct entity.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Neoplasias Pulmonares/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Sinalização YAP/genética , Adulto , Idoso , Humanos , Neoplasias Pulmonares/patologia , Masculino , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia
19.
Histopathology ; 79(6): 997-1003, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34272753

RESUMO

AIMS: PRRX1-NCOA1-rearranged fibroblastic tumour is a recently described, rare mesenchymal tumour. Only four cases have been previously reported. The aim of this article is to report six additional cases of this unusual mesenchymal neoplasm, with an emphasis on its differential diagnosis. METHODS AND RESULTS: The six cases were from three females and three males (age, 20-49 years; median, 42 years). Three tumours were located on the abdominal wall; two from the shoulder/axillary areas, and one on the lateral hip. All presented as slow-growing subcutaneous nodules, ranging from 26 to 55 mm (median, 40 mm). The tumours consisted of circumscribed, variably cellular nodules composed of relatively bland plump spindled to epithelioid cells arranged singly, in cords, and occasionally in nests, embedded in hyalinised and collagenous stroma. Small hypocellular myxoid zones with ropey collagen fibres were present, as were irregularly dilated, gaping, crescent-shaped or staghorn-like thin-walled vessels, best appreciated at the periphery. Immunohistochemistry for CD34, S100, MUC4 and STAT6 was consistently negative. RNA-sequencing revealed PRRX1-NCOA1 fusions in all cases. Of the four cases with limited follow-up (1.5-4 months), none recurred following local surgical excision. CONCLUSIONS: The morphological features of PRRX1-NCOA1-rearranged fibroblastic tumour overlap with those of RB1-deficient soft-tissue tumours, solitary fibrous tumour, and low-grade fibromyxoid sarcoma/sclerosing epithelioid fibrosarcoma. This differential diagnosis can be resolved with a combination of careful morphological study and the application of a panel of immunostains, although molecular genetic study is most definitive. The natural history of PRRX1-NCOA1-rearranged fibroblastic tumour appears to be quite favourable, although longer-term study of a larger number of cases is warranted.


Assuntos
Proteínas de Homeodomínio/genética , Coativador 1 de Receptor Nuclear/genética , Neoplasias de Tecidos Moles/genética , Neoplasias de Tecidos Moles/patologia , Adulto , Feminino , Rearranjo Gênico , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/genética
20.
J Pathol ; 252(4): 441-450, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32944951

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gut. GISTs are thought to arise solely from interstitial cells of Cajal (ICC), a KIT-positive population that controls gut motility. Activating gain-of-function mutations in KIT and PDGFRA are the most frequent driver events, and most of these tumors are responsive to the tyrosine kinase inhibitor imatinib. Less common drivers include mutant BRAFV600E and these tumors are resistant to imatinib. A mouse model of GIST was recently reported using Etv1, the master transcriptional regulator of ICC-intramuscular (IM) and ICC-myenteric (MY), to induce mutant Braf expression. ICC hyperplasia was observed in Etv1CreERT2 ;BrafLSL-V600E/+ mice but loss of Trp53 was required for development of GIST. We identified previously expression of the pan-ErbB negative regulator, LRIG1, in two distinct subclasses of ICC [ICC-deep muscular plexus (DMP) in small intestine and ICC-submucosal plexus (SMP) in colon] and that LRIG1 regulated their development from smooth muscle cell progenitors. Using Lrig1CreERT2 to induce BrafV600E , we observed ICC hyperplasia beyond the confines of ICC-DMP and ICC-SMP expression, suggesting smooth muscle cells as the cell-of-origin. To examine this possibility, we selectively activated BrafV600E in smooth muscle cells. Myh11CreERT2 ;BrafLSL-V600E/+ mice developed not only ICC hyperplasia but also GIST and in the absence of Trp53 disruption. In addition to providing a simpler model for mutant Braf GIST, these results provide conclusive evidence for smooth muscle cells as an alternative cell-of-origin for GIST. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Neoplasias Gastrointestinais/genética , Tumores do Estroma Gastrointestinal/genética , Músculo Liso/metabolismo , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Modelos Animais de Doenças , Neoplasias Gastrointestinais/metabolismo , Neoplasias Gastrointestinais/patologia , Tumores do Estroma Gastrointestinal/metabolismo , Tumores do Estroma Gastrointestinal/patologia , Camundongos , Músculo Liso/patologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas c-kit/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética
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