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/genéticaRESUMO
Epithelioid hemangioendothelioma (EHE) is a poorly understood and devastating vascular cancer. Sequencing of EHE has revealed a unique gene fusion between the Hippo pathway nuclear effector TAZ (WWTR1) and the brain-enriched transcription factor CAMTA1 in â¼90% of cases. However, it remains unclear whether the TAZ-CAMTA1 gene fusion is a driver of EHE, and potential targeted therapies are unknown. Here, we show that TAZ-CAMTA1 expression in endothelial cells is sufficient to drive the formation of vascular tumors with the distinctive features of EHE, and inhibition of TAZ-CAMTA1 results in the regression of these vascular tumors. We further show that activated TAZ resembles TAZ-CAMTA1 in driving the formation of EHE-like vascular tumors, suggesting that constitutive activation of TAZ underlies the pathological features of EHE. We show that TAZ-CAMTA1 initiates an angiogenic and regenerative-like transcriptional program in endothelial cells, and disruption of the TAZ-CAMTA1-TEAD interaction or ectopic expression of a dominant negative TEAD in vivo inhibits TAZ-CAMTA1-mediated transformation. Our study provides the first genetic model of a TAZ fusion oncoprotein driving its associated human cancer, pinpointing TAZ-CAMTA1 as the key driver and a valid therapeutic target of EHE.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Carcinogênese/genética , Células Endoteliais/patologia , Regulação Neoplásica da Expressão Gênica , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Transativadores/metabolismo , Animais , Proteínas de Ligação ao Cálcio/genética , Linhagem Celular Tumoral , Fusão Gênica , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Camundongos , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
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 TranscricionalRESUMO
In this report, we describe a very rare case of metastatic epithelioid hemangio-endothelioma (EHE) originating from other organs such as the lung and requiring craniotomy due to subsequent hemorrhage. A 50-year-old man was diagnosed with EHE in the bilateral lungs, the mediastinum, and the right adrenal gland 8 years earlier. One year earlier, he had developed spinal metastasis. Six months earlier, a screening brain MRI had revealed multiple brain metastases of tumor. He developed subcortical hemorrhage from the tumor in the right parietal lobe and successfully underwent removal of hematoma and tumor. Histopathological examinations revealed EHE. Metastatic EHE is very rare but may be at high risk of intracranial hemorrhage. It is quite important to consider the possibility of brain metastasis and subsequent bleeding when treating patients with EHE.
RESUMO
Cases of epithelioid hemangioendothelioma with WWTR1::CAMTA1 fusion can show rhabdoid cytomorphology. Lack of intracytoplasmic luminal spaces, marked rhabdoid cytomorphology, and variability in the expression of vascular markers makes the diagnosis of EHE challenging. Therefore, a high level of suspicion and ancillary studies (immunohistochemistry and next generation sequencing) help reach a definitive diagnosis in these cases.
Assuntos
Hemangioendotelioma Epitelioide , Mutação , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Humanos , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/diagnóstico , Mutação/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/diagnóstico , Proteínas de Ligação ao Cálcio/genética , Linfonodos/patologia , Feminino , Pleura/patologia , Transativadores/genética , Masculino , Proteínas de Fusão Oncogênica/genética , Biomarcadores Tumorais/genética , Fatores de Transcrição/genética , Peptídeos e Proteínas de Sinalização Intracelular/genéticaRESUMO
Objective: To explore the MRI characteristics of the hepatic epithelioid hemangioendothelioma (HEHE) classification according to morphology and size. Methods: The clinical, pathological, and MRI imaging data of 40 cases with HEHE confirmed pathologically from December 2009 to September 2021 were retrospectively analyzed. A paired sample t-test was used for comparison between the two groups. Results: There were 40 cases (5 solitary, 24 multifocal, 9 local fusion, and 2 diffuse fusion) and 214 lesions (163 nodules, 31 masses, and 20 fusion foci). The most common features of lesions were subcapsular growth and capsular depression. The signal intensity of lesions ≤1cm was usually uniform with whole or ring enhancement. Nodules and mass-like lesions ≥1cm on a T1-weighted image had slightly reduced signal intensity or manifested as a halo sign. Target signs on a T2-weighted image were characterized by: target or centripetal enhancement; fusion-type lesions; irregular growth and hepatic capsular retraction, with ring or target-like enhancement in the early stage of fusion and patchy irregular enhancement in the late stage; blood vessels traversing or accompanied by malformed blood vessels; focal bleeding; an increasing proportion of extrahepatic metastases and abnormal liver function with the type of classified manifestation; primarily portal vein branches traversing; and reduced overall intralesional bleeding rate (17%). Lollipop signs were presented in 19 cases, with a high expression rate in mass-type lesions (42%). The fusion lesions were expressed, but the morphological manifestation was atypical. The diffusion-weighted imaging mostly showed high signal or target-like high signal. An average apparent diffusion coefficient of lesions was (1.56±0.36) ×10(-3)mm(2)/s, which was statistically significantly different compared with that of adjacent normal liver parenchyma (t=8.28, P<0.001). Conclusion: The MRI manifestations for the HEHE classification are closely related to the morphology and size of the lesions and have certain differences and characteristics that are helpful for the diagnosis of the disease when combined with clinical and laboratory examinations.
Assuntos
Hemangioendotelioma Epitelioide , Neoplasias Hepáticas , Imageamento por Ressonância Magnética , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/classificação , Neoplasias Hepáticas/patologia , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/classificação , Estudos Retrospectivos , Imageamento por Ressonância Magnética/métodos , Fígado/patologia , Fígado/diagnóstico por imagem , Feminino , Masculino , Pessoa de Meia-Idade , AdultoRESUMO
An 8-year-old boy initially thought to have a penile arteriovenous malformation was later diagnosed with a rare vascular sarcoma, epithelioid hemangioendothelioma (EHE). Despite challenges in diagnosis, he underwent supraselective angioembolization and partial penectomy for oncological clearance. EHE, a low-grade malignancy, requires prompt identification and treatment due to potential systemic involvement.
RESUMO
OPINION STATEMENT: Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated vascular sarcoma. EHE can have different clinical presentations from indolent to rapidly evolving cases, behaving as a high-grade sarcoma. Serosal effusion and systemic symptoms such as fever and severe pain are known as adverse prognostic factors; however, outcome prediction at disease onset remains a major challenge. In spite of its rarity, an international collaborative effort is in place with the support of patient advocates to increase the knowledge of EHE biology, develop new treatment options, and improve patient access to new active medications. Currently, systemic therapies are indicated only for patients suffering from progressive and/or symptomatic disease and in patients with a high risk of organ dysfunction. Standard systemic agents available so far for treatment of sarcomas, and in particular anthracycline-based chemotherapy, have marginal activity in EHE. On this background, EHE patients should be always considered for clinical study when available. The MEK inhibitor trametinib has been recently investigated prospectively in advanced EHE showing some activity, but the publication of the full dataset is still awaited to better interpret the results. Besides, there are data on response to antiangiogenics such as sorafenib and bevacizumab and, from retrospective studies, interferon, thalidomide, and sirolimus. Unfortunately, none of these agents is formally approved for EHE patients and access to treatments varies greatly between countries causing a huge disparity in patient care from one country to another.
Assuntos
Hemangioendotelioma Epitelioide , Sarcoma , Humanos , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangioendotelioma Epitelioide/etiologia , Estudos Retrospectivos , Sorafenibe/uso terapêutico , PrognósticoRESUMO
We report the case of a 28-year-old female patient who complained of extreme neck pain when giving birth to a child. Magnetic resonance imaging (MRI) of the cervical spine demonstrated an osteolytic lesion at the second cervical vertebral body (C2). In this presentation, we highlight a transoral surgical approach in order to prevent instability of this osteolytic lesion. To the best of our knowledge, this is the first time that such a route of access has been described for this tumor entity. A histopathologic examination led to the diagnosis of epithelioid hemangioendothelioma. During a follow-up period of 33 months, the patient had no complaints.
Assuntos
Hemangioendotelioma Epitelioide , Osteólise , Neoplasias da Coluna Vertebral , Gravidez , Feminino , Criança , Humanos , Adulto , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Hemangioendotelioma Epitelioide/cirurgia , Osteólise/diagnóstico por imagem , Osteólise/etiologia , Osteólise/cirurgia , Corpo Vertebral/patologia , Neoplasias da Coluna Vertebral/diagnóstico por imagem , Neoplasias da Coluna Vertebral/cirurgia , Vértebras Cervicais/diagnóstico por imagem , Vértebras Cervicais/cirurgia , Vértebras Cervicais/patologia , HormôniosRESUMO
Objective: To investigate the features of contrast-enhanced ultrasound (CEUS) in hepatic epithelioid hemangioendothelioma (HEHE) in order to improve the preoperative diagnosis rate. Methods: CEUS images of 32 pathologically-proven cases of hepatic epithelioid hemangioendothelioma from January 2004 to August 2021 were collected. Lesions were analyzed to observe the features of enhancement mode, enhancement intensity, and distinct enhancement phases. Results: Among the 32 cases, one had a solitary lesion, 29 had multiple lesions, and two had diffuse-type lesions. Contrast-enhanced ultrasound revealed a total of 42 lesions in 32 cases. In terms of arterial phase enhancement, 18 lesions had overall enhancement, six lesions had uneven dendritic enhancement, 16 lesions had rim-like enhancement, and two lesions had just slight peripheral spot enhancement around the lesions. Among the three cases, there were multiple lesions that had overall enhancement and ring enhancement. In terms of the enhancement phase, 20 lesions showed "fast progression", 20 lesions showed "same progression", and two lesions showed "slow progression". During the late arterial or early portal venous phases with rapid washout, all lesions manifested as hypoechoic. With peaked enhanced intensity, 11 lesions had a lower enhancement intensity than the surrounding normal liver parenchyma; 11 lesions had the same enhancement degree as the surrounding normal liver parenchyma; and 20 lesions had a higher enhancement degree than the surrounding normal liver parenchyma. All 16 ring-enhancing lesions had marked hyperenhancement. In the typical enhancing lesions, four showed hyperenhancement, five showed low enhancement, and nine showed isoenhancement. In the dendrite-enhancing lesions, there were two isoenhancing and four hypoenhancing. Contrast-enhanced ultrasound delineated the boundaries of all lesions more clearly than two-dimensional ultrasound. Conclusion: Contrast-enhanced ultrasound has certain value in the diagnosis of hepatic epithelioid hemangioendothelioma.
Assuntos
Hemangioendotelioma Epitelioide , Neoplasias Hepáticas , Humanos , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Hemangioendotelioma Epitelioide/patologia , Meios de Contraste , Estudos Retrospectivos , Neoplasias Hepáticas/patologia , Veia Porta/patologia , UltrassonografiaRESUMO
BACKGROUND: Hepatic epithelioid hemangioendothelioma (HEH) is a rare vascular tumor of unknown etiology and unpredictable natural history. To date, no large-scale studies have been published evaluating this disease due to its rare occurrence. METHODS: The National Cancer Database was reviewed between 2004 and 2016 to identify patients with HEH. Univariate analysis with overall survival (OS) was performed by Cox proportional hazards model. Kaplan-Meier method was used to create OS curves and compared using the log-rank test. RESULTS: We identified 229 patients with HEH. The majority of patients were female (61.1%), white (84.3%), and had a Charlson-Deyo score of 0 (75%). Chemotherapeutic intervention was seen in 26% of the patients while 33% received surgical intervention in the form of wedge/segmental liver resection (n = 27), hepatectomy lobectomy/extended lobectomy (n = 18), and liver transplant (n = 22). Five-year survival in surgical patients was 90.5%, 66.5% and 81%, respectively (p = 0.485). Age greater than 55 years (hazard ratio [HR], 2.78; p < 0.001), Asian ethnicity compared to white (HR, 2.84; p = 0.012), and a higher Charlson-Deyo score (score 1: HR, 2.28; p < 0.001 and score ≥2: HR, 2.76; p = 0.011) were associated with worse OS. CONCLUSION: Treatment for HEH remains variable with only a third of the patients undergoing surgery. International collaboration is necessary to determine the optimal treatment for this rare disease.
Assuntos
Hemangioendotelioma Epitelioide , Neoplasias Hepáticas , Transplante de Fígado , Humanos , Feminino , Masculino , Pessoa de Meia-Idade , Hemangioendotelioma Epitelioide/cirurgia , Hemangioendotelioma Epitelioide/patologia , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/patologia , Hepatectomia , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND AND AIMS: Epithelioid hemangioendothelioma is a rare malignant vascular tumor with limited literature. AIMS: We reported an innovative endovascular biopsy of the right innominate vein tumor. MATERIALS AND METHODS: Endovascular suction thrombectomy was performed with multipurpose catheter and constant negative pressure under fluoroscopic guidance. RESULTS: Epithelioid hemangioendothelioma was diagnosed preoperatively and a complete margin-free tumor resection with patch repair of the right innominate vein was achieved via sternotomy. DISCUSSION: Preoperatively diagnosis is usually not available due to lesions' location. Identifying malignant vascular tumors becomes valuable to guide the surgical treatment. CONCLUSIONS: In this case report, this innovative endovascular approach led to a rare preoperative diagnosis of EHE and subsequent margin-free resection.
Assuntos
Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Biópsia , Veias Braquiocefálicas/diagnóstico por imagem , Veias Braquiocefálicas/patologia , Veias Braquiocefálicas/cirurgia , Criança , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/cirurgia , Humanos , Sarcoma/patologia , TrombectomiaRESUMO
Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor, which is typically characterized by recurrent fusion genes. EHEs most commonly occur in the lung, liver, bone, and internal organs. EHE has rarely been reported to occur in the post-radiotherapeutic setting, the breast site or in association with breast cancer. The differential diagnosis for radiation-associated vascular lesions of the breast is classically limited to atypical vascular lesion and angiosarcoma and does not include EHE. We present the case of a woman with a history of breast cancer and post-surgical radiotherapy who went on to develop an EHE of the chest wall skin within 3 years of the completion of radiotherapy. Microscopically, the lesion was infiltrative and composed of anastomosing nests of epithelioid-to-spindled cells with eosinophilic and vacuolated cytoplasm. By immunohistochemistry, the cells were positive for ERG, D2-40, and CD31. The diagnosis was confirmed by identification of a characteristic WWTR1-CAMTA1 fusion gene using RNA sequencing. This case expands our understanding of radiation-associated tumors.
Assuntos
Neoplasias da Mama/radioterapia , Hemangioendotelioma Epitelioide/genética , Neoplasias Induzidas por Radiação/genética , Idoso , Proteínas de Ligação ao Cálcio/genética , Feminino , Hemangioendotelioma Epitelioide/etiologia , Hemangioendotelioma Epitelioide/patologia , Humanos , Neoplasias Induzidas por Radiação/patologia , Proteínas de Fusão Oncogênica/genética , Radioterapia/efeitos adversos , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/genéticaRESUMO
The article describes the clinical, radiological and pathological features of epithelioid hemangioendothelioma (EHE) in 27 adult patients, mainly female. In all cases, with the exception of one, there was a benign course of the disease over many years with a tendency to stabilize growth, the morphological sign of which was the development of widespread sclerotic changes. With the help of immunohistochemical method, the endothelial nature of EHE cells and its relatively low proliferative potential were confirmed. Clinical and morphological features of EHE raise the question of the essence of proliferation of endothelial cells with the formation of tumor-like nodes. There is every reason to consider EHE as a pseudotumor of the type of nodose hyperplasia in the nosological group of dyshormonal hyperplasia, similar to benign leiomyoma of the uterus with lung damage, as we have previously proposed.
Assuntos
Neoplasias Ósseas , Neoplasias da Mama , Hemangioendotelioma Epitelioide , Neoplasias Pulmonares , Neoplasias Cutâneas , Adulto , Neoplasias Ósseas/patologia , Neoplasias da Mama/patologia , Criança , Células Endoteliais/patologia , Feminino , Hemangioendotelioma Epitelioide/diagnóstico por imagem , Humanos , Hiperplasia/patologia , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Neoplasias Cutâneas/patologiaRESUMO
Pseudomyogenic hemangioendothelioma (PHE) is a rare angiogenic tumor. Histologically, the morphological characteristics of neoplastic vessels and endothelial differentiation are not obvious, and it is easy to be confused with epithelioid sarcoma, epithelioid hemangioendothelioma and myogenic tumor. PHE usually occurs in arms and legs in young people and has a significant male predominance. The tumor has a predilection for the distal extremities and its typical manifestation is multiple center invasion of a single limb, which can involve all layers of skin and subcutaneous tissues,and is often accompanied by abvious pain. Histologically, PHE is characterized by infiltrative growth of tumor. Most tumor lesions are composed of sheets and loose fascicles of plump spindle or epithelioid cells within a background of variably prominent inflammatory infiltration, which was commonly composed of neutrophils. Some cells may resemble rhabdomyoblasts, and nuclear atypia and mitosis were rare. The tumor cells generally expressed positive cytokeratin (CK), ETS-related gene (ERG), Friend leukemia virus integration 1 (FLI1) and integrase interactor 1(INI1). In some cases, the tumor cells expressed CD31. A case of a young woman was reported in this paper, who presented with a subcutaneous mass with severe pain and was chronologically misdiagnosed with herpes zoster, low-grade malignant fibrous histiocytoma and epithelioid hemangioendothelioma. In this study, the clinical and pathological features, differential diagnosis and the latest progress in therapy of PHE were analyzed based on relevant literature.
Assuntos
Hemangioendotelioma Epitelioide , Hemangioma , Histiocitoma Fibroso Maligno , Lesões Pré-Cancerosas , Adolescente , Adulto , Biomarcadores Tumorais , Criança , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/patologia , Histiocitoma Fibroso Maligno/diagnóstico , Humanos , Masculino , Dor , Lesões Pré-Cancerosas/diagnósticoRESUMO
BACKGROUND: The objective of this study was to report on a retrospective series of patients with epithelioid hemangioendothelioma (EHE) who received treatment with sirolimus within the Italian Rare Cancer Network. METHODS: From January 2005, 38 adult patients with advanced EHE received continuous-dosing sirolimus, 5 mg daily, until they developed either toxicity or disease progression. Disease progression in the 6 months before the start of treatment was required. Each pathologic diagnosis was reviewed. The daily dose of sirolimus was adjusted based on plasma levels. Response was retrospectively assessed by local investigators using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST). Survival was estimated using the Kaplan-Meier method. RESULTS: All 38 patients (WW Domain Containing Transcription Regulator 1 [WWTR1]-positive, n = 37; transcription factor E3 [TFE3]-positive, n = 1) had disease progression before starting sirolimus (at baseline, 13 of 38 patients had the presence of serosal effusions and systemic symptoms). Thirty-seven patients were evaluable for response (there was 1 early interruption). The best RECIST responses were a partial response in 4 patients (10.8%), stable disease in 28 patients (75.7%), and disease progression in 5 patients (13.5%). At a 41.5-month median follow-up (interquartile range [IQR], 23.9-56.8 months), the median PFS was 13 months (95% CI, 3.7 months to not estimated [NE]), and the median OS was 18.8 months (95% CI, 10.6 months to NE). In patients who had serosal effusions at baseline, the median PFS was 4.8 months (IQR, 3.5-11.7 months), and the median OS was 10.6 months (IQR, 5.1-13.0 months), compared with 47.8 months (IQR, 11.4 months to NE) and 47.8 months (IQR, 15.7 months to NE), respectively, in patients without serosal effusions. Overall, sirolimus was fairly well tolerated, with 10 patients reporting irregular menstruation/ovary disfunction. CONCLUSIONS: The current results confirm that sirolimus is active in EHE, leading to prolonged stabilization in most patients who present without serosal effusions. Serosal effusions are confirmed as an unfavorable prognostic sign associated with short survival, and sirolimus displays limited activity in this subgroup.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Hemangioendotelioma Epitelioide/tratamento farmacológico , Peptídeos e Proteínas de Sinalização Intracelular/genética , Sirolimo/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Criança , Progressão da Doença , Feminino , Hemangioendotelioma Epitelioide/epidemiologia , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Critérios de Avaliação de Resposta em Tumores Sólidos , Sirolimo/efeitos adversos , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
BACKGROUND: Hepatic angiosarcoma (AS) and hepatic epithelioid hemangioendothelioma (HEHE) are rare primary hepatic vascular malignancies (PHVM) that remain poorly understood. To guide management, we sought to identify factors and trends predicting survival after surgical intervention using a national database. MATERIALS AND METHODS: In a retrospective analysis of the National Cancer Database patients with a diagnosis of PHVM were identified. Clinicopathologic factors were extracted and compared. Overall survival (OS) was estimated and predictors of survival were identified. RESULTS: Three hundred ninty patients with AS and 216 with HEHE were identified. Only 16% of AS and 36% of HEHE patients underwent surgery. The median OS for patients who underwent surgical intervention was 97 months, with 5-year OS of 30% for AS versus 69% for HEHE patients (P< 0.001). Tumor biology strongly impacted OS, with AS histology (Hazard Ratio [HR] of 3.61 [1.55-8.42]), moderate/poor tumor differentiation (HR = 3.86 [1.03-14.46]) and tumor size (HR = 1.01 [1.00-1.01]) conferring worse prognosis. The presence of metastatic disease in the surgically managed cohort (HR = 5.22 [2.01-13.57]) and involved surgical margins (HR = 3.87 [1.59-9.42]), were independently associated with worse survival. CONCLUSIONS: In this national cohort of PHVM, tumor biology, in the form of angiosarcoma histology, tumor differentiation and tumor size, was strongly associated with worse survival after surgery. Additionally, residual tumor burden after resection, in the form of positive surgical margins or the presence of metastasis, was also negatively associated with survival. Long-term clinical outcomes remain poor for patients with the above high-risk features, emphasizing the need to develop effective forms of adjuvant systemic therapies for this group of malignancies.
Assuntos
Hemangioendotelioma Epitelioide/terapia , Hemangiopericitoma/terapia , Hemangiossarcoma/terapia , Hepatectomia/estatística & dados numéricos , Neoplasias Hepáticas/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante/estatística & dados numéricos , Feminino , Hemangioendotelioma Epitelioide/mortalidade , Hemangioendotelioma Epitelioide/patologia , Hemangiopericitoma/mortalidade , Hemangiopericitoma/patologia , Hemangiossarcoma/mortalidade , Hemangiossarcoma/patologia , Humanos , Fígado/irrigação sanguínea , Fígado/patologia , Fígado/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Neoplasia Residual , Radioterapia Adjuvante/estatística & dados numéricos , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Carga Tumoral , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Hepatic vascular malignancies (HVMs) are rare malignancies, with no standardized treatment regimens. The most common HVMs, angiosarcoma and malignant epithelioid hemangioendothelioma (EHE), are often grouped together in the literature complicating our ability to achieve reliable survival data and treatment strategies. OBJECTIVE: To compare the disease characteristics of HVMs, with a subanalysis on pediatric patients. METHODS: The 2016 National Cancer Database was queried for patients with HVMs using international classification of diseases-oncology-3 (ICD-O-3) codes yielding 699 patients. Descriptive statistics, chi-square, Kaplan-Meier, and log-rank analyses were performed. RESULTS: We found 478 patients (68%) with angiosarcoma and 221 (32%) with EHE. The median (Q1, Q3) age for angiosarcoma patients was 65 years (56, 75) versus 54 years (37, 65) in EHE patients (P < .001). The rate of resection was lower in patients with angiosarcoma than EHE (13% vs 32%, P < .001). The mean 1-, 3-, and 5-year overall survival for angiosarcoma patients was 17%, 8%, and 6%, respectively, versus 80%, 65%, and 62% in EHE patients (P < .0001). A subgroup analysis was performed on pediatric patients demonstrating six with angiosarcoma and 10 with EHE. The mean 1-, 3-, and 5-year overall survival for pediatric angiosarcoma patients was 67%, 50%, and 50%, respectively, and 90%, 90%, and 90% for pediatric EHE patients. CONCLUSION: In the largest study of HVMs to date, we found angiosarcoma has significantly worse overall survival than EHE. Pediatric patients appear to have improved survival and higher rates of resection. Larger studies of HVMs are needed to clearly differentiate tumor types, standardize care, and improve survivorship.
Assuntos
Hemangioendotelioma Epitelioide/patologia , Hemangiossarcoma/patologia , Neoplasias Hepáticas/patologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Hemangioendotelioma Epitelioide/mortalidade , Hemangioendotelioma Epitelioide/cirurgia , Hemangiossarcoma/mortalidade , Hemangiossarcoma/cirurgia , Humanos , Lactente , Recém-Nascido , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/cirurgia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor, affecting the liver, the lungs and the bones most frequently. It has a heterogenous clinical presentation and there is no consensus on optimal treatment. This report aims to present a rare case of a retroperitoneal EHE and to discuss on proper management.
Assuntos
Hemangioendotelioma Epitelioide , Sarcoma , Neoplasias Vasculares , Adulto , Criança , Humanos , Fígado , PulmãoRESUMO
The genetic hallmark of epithelioid hemangioendothelioma (EHE) is a recurrent WWTR1-CAMTA1 fusion, which is present in most cases bearing a conventional histology. A subset of cases is characterized by a distinct morphology and harbors instead of YAP1-TFE3 fusion. Nevertheless, isolated cases lack these canonical fusions and remain difficult to classify. Triggered by an index case of a left atrial mass in a 76-year-old female with morphologic features typical of EHE, but which showed a WWTR1-MAML2 fusion by targeted RNA sequencing, we searched our files for similar cases displaying alternative WWTR1 fusions. A total of 6 EHE cases were identified with variant WWTR1 fusions, four of them presenting within the heart. There were three females and three males, with a wide age range at diagnosis (21-76 years, mean 62, median 69). The four cardiac cases occurred in older adults (mean age of 72, equal gender distribution); three involved the left atrium and one the right ventricle. One case presented in the vertebral bone and one in pelvic soft tissue. Microscopically, all tumors had morphologic features within the spectrum of classic EHE; two of the cases appeared overtly malignant. All cases were tested by FISH and four were investigated by targeted RNA sequencing. Two tumors harbored WWTR1-MAML2 fusions, one WWTR1-ACTL6A, and in three cases, no WWTR1 partner was identified. Of the four patients with follow-up, two died of disease, one was alive with lung metastases, and the only patient free of disease was s/p resection of a T11 vertebral mass. Our findings report on additional genetic variants involving WWTR1 rearrangements, with WWTR1-MAML2 being a recurrent event, in a small subset of EHE, which appears to have predilection for the heart.