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
Epithelioid hemangioendothelioma (EHE) is a remarkably rare tumor arising from endothelial cells that is classified as a vascular tumor in the WHO classification. The tumor is predominantly characterized by the presence of fusion genes, such as WWTR1-CAMTA1 or YAP1-TFE3, with a minority of cases exhibiting other rare fusion genes. EHE exhibits a broad age of onset, typically presenting at ~50 years, but it is not uncommon in pediatric populations. It manifests in a variety of organs, including the liver, lung, soft tissue and bone. Initial multiple-organ involvement is also observed. The tumor's biological behavior and prognosis vary substantially based on the primary site of manifestation. From a therapeutic perspective, initial active surveillance might be considered in selected cases, although surgical intervention remains the mainstay of treatment, especially for localized single-organ involvement. Chemotherapy is administered to patients with progressive unresectable tumors. Recent advances in the biological analysis of EHE fusion genes have elucidated their diverse functions. Additionally, next-generation sequencing has facilitated the identification of other mutations beyond the fusion genes. These continuous efforts to understand the biology of the fusion genes themselves and/or the dysregulated signaling by fusion genes are expected to lead to the development of novel therapeutic strategies for EHE. This article aims to provide a comprehensive review of EHE, encompassing its historical context, clinical manifestations, molecular biology and the current state of treatment.
Assuntos
Hemangioendotelioma Epitelioide , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/terapia , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/tratamento farmacológico , Humanos , Proteínas de Fusão Oncogênica/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Fatores de Transcrição/genética , Prognóstico , Biologia Molecular , Transativadores/genética , Proteínas de Ligação ao CálcioRESUMO
ABSTRACT: Epithelioid hemangioma (EH) is a benign vascular tumor displaying diverse histomorphologies. Among these, one EH subtype comprises cellular sheets of atypical epithelioid cells, posing potential challenges in distinguishing it from malignant vascular lesions. In this case report, we present a cutaneous cellular EH that carries the rare GATA6::FOXO1 gene fusion, a recent discovery. Our aim is to provide an updated insight into the evolving knowledge of EHs while delving into the histologic and molecular characteristics of the primary differential diagnoses.
Assuntos
Hiperplasia Angiolinfoide com Eosinofilia , Hemangioendotelioma Epitelioide , Hemangioma , Neoplasias Vasculares , Humanos , Hiperplasia Angiolinfoide com Eosinofilia/patologia , Hemangioma/patologia , Fusão Gênica , Diagnóstico Diferencial , Hemangioendotelioma Epitelioide/genética , Proteína Forkhead Box O1/genética , Fator de Transcrição GATA6/genéticaRESUMO
The term "hemangioendothelioma" is used for endothelial neoplasms of intermediate malignancy and describes a group of rare neoplasms having biologic behavior falling in between that of the benign hemangiomas and fully malignant angiosarcomas. The hemangioendotheliomas fall into several specific, clinicopathologically and genetically distinct entities, specifically epithelioid hemangioendothelioma, kaposiform hemangioendothelioma, papillary intralymphatic angioendothelioma and retiform hemangioendothelioma (hobnailed hemangioendothelioma), pseudomyogenic hemangioendothelioma, composite hemangioendothelioma, and YAP1::TFE3-fused hemangioendothelioma. The clinical, morphologic, immunohistochemical, and genetic features, and the differential diagnosis of each of these rare entities are discussed in this review.
Assuntos
Biomarcadores Tumorais , Hemangioendotelioma , Humanos , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Hemangioendotelioma/patologia , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/genética , Diagnóstico Diferencial , Imuno-Histoquímica , Neoplasias Vasculares/patologia , Neoplasias Vasculares/genética , Predisposição Genética para Doença , Hemangioendotelioma Epitelioide/patologia , Hemangioendotelioma Epitelioide/genética , Proteínas de Sinalização YAPRESUMO
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 TranscricionalAssuntos
Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Humanos , Proteínas de Ligação ao Cálcio , Família de Proteínas EGF , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/genética , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fatores de TranscriçãoRESUMO
Composite hemangioendothelioma is a rare, locally aggressive, and rarely metastasizing vascular neoplasm which affects both children and adults. Recently, a number of gene fusions including YAP1::MAML2, PTBP1::MAML2, and EPC1::PHC2 have been detected in a small subset of cases with or without neuroendocrine expression. Herein, we present four additional cases with novel in-frame fusions. The cohort comprises two females and two males with a wide age range at diagnosis (24-80 years). Two tumors were deep involving the right brachial plexus and mediastinum, while the remaining were superficial (right plantar foot and abdominal wall). The size ranged from 1.5 to 4.8 cm in greatest dimension. Morphologically, all tumors had an admixture of at least two architectural patterns including retiform hemangioendothelioma, hemangioma, epithelioid hemangioendothelioma, or angiosarcoma. The tumors were positive for endothelial markers CD31 (3/3), ERG (4/4), and D2-40 (1/4, focal), while SMA was expressed in 2/3 highlighting the surrounding pericytes. Synaptophysin showed immunoreactivity in 2/3 cases. One patient had a local recurrence after 40 months, while two patients had no evidence of disease 4 months post-resection. Targeted RNA sequencing detected novel in-frame fusions in each of the cases: HSPG2::FGFR1, YAP1::FOXR1, ACTB::MAML2, and ARID1B::MAML2. The two cases with neuroendocrine expression occurred as superficial lesions and harbored YAP1::FOXR1 and ARID1B::MAML2 fusions. Our study expands on the molecular spectrum of this enigmatic tumor, further enhancing our current understanding of the disease.
Assuntos
Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Adulto , Masculino , Criança , Feminino , Humanos , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Hemangioendotelioma/patologia , Hemangioendotelioma Epitelioide/genética , Sequência de Bases , Diagnóstico Diferencial , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas , Proteína de Ligação a Regiões Ricas em PolipirimidinasRESUMO
TAZ::CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ::CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ::CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ::CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ::CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ::CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.
Assuntos
Hemangioendotelioma Epitelioide , Transativadores , Humanos , Transativadores/genética , Células Endoteliais/patologia , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Ligação ao Cálcio/genética , Fatores de Transcrição/genética , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Proteínas de Fusão Oncogênica/genética , Instabilidade GenômicaRESUMO
Epithelioid and spindle cell sarcomas with NR1D1::MAML1/2 gene fusions are rare and emerging entities. Only six cases of NR1D1-rearranged mesenchymal tumors have previously been reported in the literature; they are often characterized by an epithelioid morphology, at least focal pseudogland formation, prominent cytoplasmic vacuoles, and focal to diffuse immunohistochemical expression of keratin. We herein report the first case of an NR1D1::MAML1 epithelioid and spindle cell sarcoma with dual immunohistochemical expression of ERG and FOSB, mimicking a pseudomyogenic hemangioendothelioma (PHE) on core biopsy. The sarcoma arose in the left forearm of a 64-year-old man. Initial biopsy showed a mesenchymal neoplasm composed of epithelioid and spindle cells dispersed in myxoid stroma with scattered stromal neutrophils. The morphologic features, combined with the dual immunohistochemical expression of ERG and FOSB, initially mimicked PHE, representing an important potential diagnostic pitfall. The patient subsequently underwent a radical resection, which showed a much more diffuse epithelioid appearance with nested architecture and pseudogland formation. Next-generation sequencing was performed on the resection specimen, which revealed an NR1D1::MAML1 gene fusion, confirming the final diagnosis. Given the fully malignant potential of this tumor, knowledge and recognition of this rare entity are essential to ensure proper management, prevent misdiagnosis, and further characterize the clinical course of this emerging entity. Comprehensive molecular testing can help to identify these rare tumors and exclude the possibility of epithelioid mimics, including PHE.
Assuntos
Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Sarcoma , Masculino , Humanos , Pessoa de Meia-Idade , Hemangioendotelioma/genética , Biomarcadores Tumorais/genética , Biópsia , Sarcoma/diagnóstico , Sarcoma/genética , Sarcoma/patologia , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/cirurgia , Proteínas de Ligação a DNA/genética , Fatores de Transcrição , Membro 1 do Grupo D da Subfamília 1 de Receptores NuclearesRESUMO
OBJECTIVES: Pseudomyogenic hemangioendothelioma (PHE) is a rare intermediate hemangioendothelioma. This article aims to study the clinicopathological features of PHE. METHODS: We collected the clinicopathological features of 10 new PHE, and examined their molecular pathological features by fluorescence in situ hybridization. In addition, we summarized and analyzed the pathological data of 189 reported cases. RESULTS: The case group consisted of six men and four women aged 12-83 years (median: 41 years). Five instances occurred in the limbs, three in the head and neck, and two in the trunk. Tumor tissues were composed of spindle cells and round or polygonal epithelioid cells, which were either arranged in sheets or interwoven, along with areas of transitional morphology. Scattered or patchy stromal neutrophil infiltration was observed. Tumor cells had abundant cytoplasm, and some contained vacuoles. The nuclei had mild to moderate atypia, with visible nucleoli, and mitosis was rare. PHE tissues diffusely expressed CD31 and ERG, but not CD34, Desmin, SOX-10, HHV8 or S100, while some samples expressed CKpan, FLI-1 and EMA. INI-1 stain is retained. The proliferation index of Ki-67 is 10-35%. Seven samples were detected by fluorescence in situ hybridization, six of which had breakages in FosB proto-oncogene (AP-1 transcription factor subunit). Two patients experienced recurrence; however, no metastasis or death occurred. CONCLUSIONS: PHE is a rare soft tissue vascular tumor, which has biologically borderline malignant potential, local recurrence, little metastasis, and good overall survival and prognosis. Immunomarkers and molecular detection are valuable for diagnosis.
Assuntos
Hemangioendotelioma Epitelioide , Hemangioendotelioma , Hemangioma , Lesões Pré-Cancerosas , Neoplasias de Tecidos Moles , Feminino , Humanos , Masculino , Biomarcadores Tumorais/genética , Hemangioendotelioma/diagnóstico , Hemangioendotelioma/patologia , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Hibridização in Situ Fluorescente , Neoplasias de Tecidos Moles/patologia , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou maisRESUMO
PURPOSE: Epithelioid hemangioendothelioma (EHE) as a very rare malignant vascular tumor belongs to the heterogenous group of soft-tissue sarcomas. Depending on the clinical course of the disease, interdisciplinary treatment concepts are required, including surgery, radiotherapy and systemic cancer therapy. However, due to its uncommonness, standard treatment options are lacking so far, especially in advanced disease with distant metastases. METHODS AND RESULTS: Here we report on an unusual case of a patient with metastasized EHE showing long-term response to second line treatment with gemcitabine over almost 2 decades. Cancer genome sequencing of the patient's tumor tissue detected a NOTCH3 missense mutation which could provide an explanation for these clinical findings. NOTCH3 is known to be a mediator of resistance towards gemcitabine-based cancer treatment, at least in pancreatic cancer and non-small cell lung cancer. CONCLUSION: The observation that this missense mutation of NOTCH3 is associated with an increased response to treatment with gemcitabine in EHE can be used prospectively to assess NOTCH3 as potential biomarker for predicting therapy response to gemcitabine.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Hemangioendotelioma Epitelioide , Neoplasias Pulmonares , Humanos , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Gencitabina , Mutação de Sentido Incorreto , Receptor Notch3/genéticaRESUMO
PURPOSE: Epithelioid hemangioendothelioma (EHE) is a vascular sarcoma caused by the WWTR1(TAZ)-CAMTA1 (TC) gene fusion. This fusion gene has been observed in almost all reported EHE cases and functions as a constitutively activated TAZ. Sequencing of human tumors has, however, identified additional secondary mutations in approximately 50% of EHE, most commonly the loss of tumor suppressor CDKN2A. In this study, the effect of loss of CDKN2A in EHE tumorigenesis was evaluated. EXPERIMENTAL DESIGN: Mice bearing a conditional TC allele were paired with a conditional Cdkn2a knockout allele and an endothelial-specific Cre. Histologic characterization and single-cell RNA-seq of the resultant tumors were performed. EHE cell lines were established through ex vivo culture of tumor cells and evaluated for sensitivity to TEAD inhibition and trametinib. RESULTS: Loss of Cdkn2a within EHE was associated with more aggressive disease, as displayed by earlier tumor-related morbidity/mortality and enhanced tumor cell proliferation. As no previous EHE cell lines exist, we attempted, successfully, to expand EHE tumor cells ex vivo and produced the first EHE cell lines. These cell lines are "addicted" to the TC oncoprotein, replicate the EHE transcriptional profile, and generate EHE tumors when injected into immunodeficient mice. CONCLUSIONS: CDKN2A loss enhances the tumorigenicity of EHE in vivo and enabled the generation of the first cell lines of this disease. These cell lines replicate key facets of the human disease phenotype. Therefore, these cell lines and allograft tumors generated after implantation serve as robust model systems for therapeutic testing of compounds directed at either EHE or other TAZ-driven cancers.
Assuntos
Hemangioendotelioma Epitelioide , Animais , Humanos , Camundongos , Proteínas de Ligação ao Cálcio/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Fusão Gênica , Hemangioendotelioma Epitelioide/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transativadores/genética , Fatores de Transcrição/genética , Proteínas com Motivo de Ligação a PDZ com Coativador TranscricionalRESUMO
Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. The authors report the case of a young woman diagnosed with PEH. DNA and RNA analysis by next-generation sequencing was performed on the tumor tissue. A novel germline PALB2 mutation and classical WWTR1-CAMTA1 fusion were identified. She experienced a poor response to sintilimab (a PD-1 inhibitor) plus platinum-based chemotherapy as the first-line treatment. PEH patients harboring a germline PALB2 mutation and WWTR1-CAMTA1 gene fusion may respond poorly to treatment with PD-1 inhibitors plus chemotherapy.
Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumor with no established treatment protocol. Although PD-1 inhibitors have dramatically improved the prognosis of some tumors, the efficacy is unknown in PEH patients. The authors report an advanced PEH patient treated with sintilimab plus platinum-based chemotherapy, who died after two cycles of treatment. The authors inferred that PEH patients with a germline PALB2 mutation and WWTR1-CAMTA1 fusion may not benefit from PD-1 inhibitors plus chemotherapy.
Assuntos
Hemangioendotelioma Epitelioide , Neoplasias Pulmonares , Feminino , Humanos , Transativadores/genética , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangioendotelioma Epitelioide/genética , Proteínas de Ligação ao Cálcio/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Fatores de Transcrição , Peptídeos e Proteínas de Sinalização IntracelularRESUMO
PURPOSE: A consistent genetic alteration in vascular cancer epithelioid hemangioendothelioma (EHE) is the t(1;3)(p36;q25) chromosomal translocation, which generates a WWTR1(TAZ)-CAMTA1 (TC) fusion gene. TC is a transcriptional coactivator that drives EHE. Here, we aimed to identify the TC transcriptional targets and signaling mechanisms that underlie EHE tumorigenesis. EXPERIMENTAL DESIGN: We used NIH3T3 cells transformed with TC (NIH3T3/TC) as a model system to uncover TC-dependent oncogenic signaling. These cells proliferated in an anchorage-independent manner in suspension and soft agar. The findings of the cell-based studies were validated in a xenograft model. RESULTS: We identified connective tissue growth factor (CTGF) as a tumorigenic transcriptional target of TC. We show that CTGF binds to integrin αIIbß3, which is essential for sustaining the anchorage-independent proliferation of transformed NIH3T3/TC cells. NIH3T3/TC cells also have enhanced Ras and MAPK signaling, and the activity of these pathways is reduced upon CTGF knockdown, suggesting that CTGF signaling occurs via the Ras-MAPK cascade. Further, pharmacologic inhibition of MAPK signaling through PD 0325901 and trametinib abrogated TC-driven anchorage-independent growth. Likewise, for tumor growth in vivo, NIH3T3/TC cells require CTGF and MAPK signaling. NIH3T3/TC xenograft growth was profoundly reduced upon CTGF knockdown and after trametinib treatment. CONCLUSIONS: Collectively, our results demonstrated that CTGF and the Ras-MAPK signaling cascade are essential for TC-mediated tumorigenesis. These studies provided the preclinical rationale for SARC033 (NCI 10015-NCT03148275), a nonrandomized, open-label, phase II study of trametinib in patients with unresectable or metastatic EHE.
Assuntos
Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Animais , Proteínas de Ligação ao Cálcio/genética , Carcinogênese/genética , Criança , Fator de Crescimento do Tecido Conjuntivo/genética , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Hemangioendotelioma Epitelioide/tratamento farmacológico , Hemangioendotelioma Epitelioide/genética , Humanos , Camundongos , Células NIH 3T3 , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular tumor with indolent biology, characterized by reciprocal t(1;3)(p36.6;q25) with resultant WWTR1::CAMTA1 gene fusion in the vast majority of cases, regardless of anatomic location. Only a small subset, exhibiting well formed vasoformative features will contain YAP1::TFE3 gene fusion. Primary intranodal EHE is exquisitely rare. We report a case in a 54-year-old male with persistent left groin mass with discomfort for nine months. A CT of the abdomen and pelvis showed a minimally enlarged left inguinal lymph node measuring 2.8â cm with no other masses or lymphadenopathy. PET/CT and MRI imaging of the abdomen showed no evidence of disease elsewhere. Sections showed an epithelioid vasoformative neoplasm, centrally necrotic and involving a lymph node. The cells were arranged in anastomosing cords with intracytoplasmic lumens, resembling "signet ring cells". By immunohistochemistry, the tumor cells were positive for vimentin, CD31, CD34, ERG and CAMTA1; and negative for AE1/3, CAM 5.2, KRT7, KRT20, desmin, actin, HMB-45 and S-100. Ki-67 proliferation index was estimated at <1%. Molecular studies including next generation sequencing (NGS) revealed the presence of WWTR1::CAMTA1 gene fusion, and fluorescence in situ hybridization for CAMTA1 (1p36.23) and WWTR1 (3p25.1) showed fusion signals, diagnostic of EHE. We highlight a rare occurrence of EHE in a lymph node exhibiting morphologic mimicry with metastatic carcinoma.
Assuntos
Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Proteínas de Ligação ao Cálcio/genética , Criança , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/patologia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Transativadores/genética , Fatores de Transcrição/genéticaRESUMO
Vascular tumors of bone can be diagnostically challenging because of their rarity and histologic overlap with diverse mimics. Vascular tumors of bone can be categorized as benign (hemangioma), intermediate-locally aggressive (epithelioid hemangioma), intermediate-rarely metastasizing (pseudomyogenic hemangioendothelioma), and malignant (epithelioid hemangioendothelioma and angiosarcoma). Recurrent genetic alterations have been described, such as FOSB rearrangements in pseudomyogenic hemangioendothelioma and a subset of epithelioid hemangiomas; CAMTA1 or TFE3 rearrangements in epithelioid hemangioendothelioma. This review discusses the clinical, histologic, and molecular features of vascular tumors of bone, along with diagnostic pitfalls and strategies for avoidance.
Assuntos
Hemangioendotelioma Epitelioide , Hemangiossarcoma , Neoplasias de Tecido Vascular , Sarcoma , Neoplasias Vasculares , Adulto , Criança , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Humanos , Neoplasias Vasculares/diagnósticoRESUMO
Objective: To investigate the clinicopathological and molecular features, diagnosis and differential diagnosis of TFE3-rearranged epithelioid hemangioendothelioma (EHE). Methods Two cases of TFE3-rearranged EHE arising from soft tissues, diagnosed by the Pathology Department of the First Affiliated Hospital of Nanjing Medical University from 2013 to 2020 were observed. EnVision method was used for immunophenotyping, fluorescence in situ hybridization (FISH) was used to test TFE3 gene rearrangements and WWTR1-CAMTA1 fusion gene,and next-generation sequencing (NGS) was used to delineate the fusion transcripts. Results: Details of these two cases were as follows: case 1, male, 51 years old, with tumor in the right temporal region; case 2, female, 42 years old, with tumor in the right neck. The tumors showed progressive painless enlargement. Grossly, the tumor of case 1 was multinodular with unclear boundary and grayish red cut surface, while the tumor of case 2, originating from a vein, appeared as a firm, tan mass within vessel wall. Microscopically, both tumors showed moderate cellularity and were consisted of plump, epithelioid, or histiocytoid cells with eosinophilic cytoplasm and mild-to-moderate nuclear pleomorphism. Most of the tumor cells were arranged in solid or alveolar growth patterns, while some tumor cells showed intraluminal papillary growth pattern in case 1 and anastomosing vascular channels and extramedullary hematopoiesis in case 2. Immunohistochemically, the tumor cells showed diffuse positivity for CD31, CD34, ERG, and TFE3. FISH revealed TFE3 break-apart signals in two cases, but WWTR1-CAMTA1 gene fusion was not detected. NGS identified YAP1 (exon1)-TFE3 (exon6) fusion gene in case 2. Clinical follow-up information was available in both cases for a follow-up period of 15 and 59 months respectively. Patient 1 had a relapse 22 months after surgery, and was currently alive with the tumor. Patient 2 remained disease-free. Conclusions: TFE3-rearranged EHE is a rare molecular subtype of EHE, with accompanying characteristic morphologic features. However the morphologic spectrum remains under-recognized, and more experience is needed. Immunohistochemical and molecular examinations are helpful for the diagnosis and differential diagnosis of the disease.
Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Hemangioendotelioma Epitelioide , Neoplasias de Tecido Vascular , Adulto , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Proteínas de Ligação ao Cálcio , Feminino , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/genética , Hemangioendotelioma Epitelioide/cirurgia , Humanos , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-IdadeRESUMO
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 JovemRESUMO
Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular sarcoma with a very heterogeneous presentation and prognosis. We here present five cases of EHE emphasizing diversity in presentation, treatment, and prognosis. Furthermore, we present a review of the literature on EHE treatment options.