Search

Purpose: Epithelioid hemangioendothelioma (EHE), an ultra-rare sarcoma, poses therapeutic challenges because of limited efficacy of conventional chemotherapy in advanced cases, necessitating exploration of new treatment avenues and identification of novel aggressive biomarkers. This study aimed at (i) utilizing a patient-derived xenograft model of EHE and its associated cell line to assess the efficacy of sirolimus and (ii) analyzing two distinct patient cohorts to pinpoint circulating biomarkers of EHE aggressiveness., Experimental Design: A patient-derived xenograft model and corresponding cell line were established from a patient with advanced EHE, demonstrating consistency with the original tumor in terms of histomorphology, WWTR1::CAMTA1 fusion presence, and genomic and transcriptomic profiles. Two independent patient series were employed to investigate the association between growth/differentiation factor 15 (GDF-15) serum levels and EHE aggressiveness., Results: ELISA analyses on EHE cell culture medium and blood from EHE-carrying mice revealed the release of GDF-15 by EHE cells. Sirolimus exhibited markedly higher antitumor activity compared with doxorubicin, concurrently reducing GDF-15 expression/release both in vivo and in vitro. This reduction was attributed to the drug-induced inhibition of phosphorylation/activation of 4E-BP1 and subsequent downregulation of the GDF-15 transcription factors ATF4 and ATF5. Blood sample analyses from two independent patient series showed a significant correlation between GDF-15 and EHE aggressiveness., Conclusions: This study identifies GDF-15 as a novel biomarker of EHE aggressiveness and underscores the superior efficacy of sirolimus compared with doxorubicin in our experimental models. The observed inhibition of GDF-15 release by sirolimus suggests its potential as a biomarker for monitoring the drug's activity in patients., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Epithelioid hemangioendothelioma (EHE), is an uncommon, intermediate-grade malignant vascular tumor that can manifest in diverse organs, including the liver, lungs, and bones. Given its unique malignancy profile and rarity, there lacks a consensus on a standardized treatment protocol for EHE, particularly for hepatic epithelioid hemangioendothelioma (HEHE). This study aims to elucidate factors influencing the clinical prognosis of EHE by analyzing data from the SEER database, complemented with insights from a departmental cohort of 9 HEHE cases. Through this, we hope to shed light on potential clinical outcomes and therapeutic strategies for HEHE., Methods: Using SEER data from 22 registries, we analyzed 313 liver cancer patients with ICD-O-3 9130 and 9133 histology. Twelve variables were examined using Cox regression and mlr3 machine learning. Significant variables were identified and compared. Clinical data, imaging characteristics, and treatment methods of nine patients from our cohort were also presented., Result: In univariate and multivariate Cox regression analyses, Age, Sex, Year of diagnosis, Surgery of primary site, Chemotherapy, and Median household income were closely related to survival outcomes. Among the ten survival-related machine learning models, CoxPH, Flexible, Mboost, and Gamboost stood out based on Area Under the Curve(AUC), Decision Curve Analysis(DCA), and Calibration Curve Metrics. In the feature importance analysis of these four selected models, Age and Surgery of primary site were consistently identified as the most critical factors influencing prognosis. Additionally, the clinical data of nine patients from our cohort not only demonstrated unique imaging characteristics of HEHE but also underscored the importance of surgical intervention., Conclusion: For patients with resectable HEHE, surgical treatment is currently a highly important therapeutic approach., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Chen, Li, Ai, Ye, Zhao, Zhang, Huang, Li, Bi, Zhao, Cao, Cai, Zhou and Yan.)

Background: Hepatic epithelioid hemangioendothelioma (EHE) is an extremely rare tumour. The aim of this study was to investigate the long-term prognosis and its relationship with treatment modalities., Methods: From March 2014 to June 2024, a total of 234 patients with histologically confirmed hepatic EHE were treated or followed up regularly by our team. The patients' clinical data at the time of diagnosis and initial treatment modalities were retrospectively collected. Kaplan-Meier curves were constructed to determine overall survival (OS). To explore prognostic factors and treatment outcomes, univariable and multivariable Cox proportional hazard models were developed., Results: A total of 228 patients were ultimately included. The median age of the cohort was 41 years. For all patients, the OS of 1-, 3- and 5-year were 96.2%, 87.9% and 84.9%, respectively. For patients who underwent liver transplantation (LT), the OS of 1- and 3-year were 62.5% and 25%, respectively. No difference was found in the OS between patients who received surgical therapy and those who did not (1-year: 100% vs. 96.9%; 3-year: 90.1% vs. 91.5%; 5-year: 87.2% vs. 88.2%; P = 0.891). In the multivariable analysis, age ≥ 60 years [HR (95% CI): 4.207 (1.266-13.973), P = 0.019], the size of the largest lesion > 10 cm [HR (95% CI): 12.140 (1.419-103.872), P = 0.023] and LT [HR (95% CI): 5.502 (1.343-22.536), P = 0.018] were poor prognostic factors., Conclusions: Compared with nonsurgical therapy, surgical therapy has no advantage in terms of long-term survival. The role of LT in the management of hepatic EHE should be reevaluated. Age ≥ 60 years and the size of the largest lesion > 10 cm are poor prognostic factors., (© 2024. The Author(s).)

Epithelioid hemangioendothelioma is an ultra-rare cancer driven by YAP-CAMTA1 fusion. Based on the link of the fusion to the MEK pathway, SARC33 was performed. It is a phase 2 trial examining trametinib that missed its primary objective by RECIST but demonstrated patient-reported outcome benefits in improved pain. See related article by Schuetze et al., p. 4584., (©2024 American Association for Cancer Research.)

Purpose: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 (calmodulinbinding transcription activator 1) operating as an oncogenic driver through activation of the MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE., Patients and Methods: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management before enrollment. The primary endpoint was objective response rate (ORR) as per RECIST1.1 in cases with TAZ- CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median progression-free survival (PFS), 2-year overall survival (OS) rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires., Results: 44 patients enrolled and 42 started trametinib. TAZ- CAMTA1 was detected in 27 tumor samples. TheORRwas 3.7%[95% confidence interval (CI), 0.094-19.0], median PFS was 10.4 months (95%CI, 7.1-NA), and 2-year OS rate was 33.3%(95%CI, 19.1-58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common adverse events related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia, and edema; one grade 5 ARDS/pneumonitis was related to trametinib., Conclusions: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months, providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal. See related commentary by Van Tine and Haarberg, p. 4552., (©2024 American Association for Cancer Research.)

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor arising from vascular endothelial cells. This study delves into the molecular mechanisms underlying EHE, with a specific focus on the Hippo-YAP/TAZ pathway. EHE is characterized molecularly by transcriptional co-activator with a PDZ-motif (TAZ)-calmodulin binding transcription activator 1 (CAMTA1) or Yes-associated protein (YAP)-transcription factor E3 (TFE3) fusions. YAP/TAZ, a transcription co-activator, binds to transcription factors and regulates gene expression. The YAP/TAZ and its upstream Hippo pathway are involved in cell proliferation and cell contact inhibition, regulating organ size and carcinogenesis. In addition to oncogenic effects, dysfunction or gene duplication of the Hippo pathway results in a poor prognosis due to epithelial-mesenchymal transformation of epithelial cells, stem cell transformation, and increased drug resistance. Notably, the TAZ-CAMTA1 fusion is specific to EHE, and genetic alterations in the Hippo pathway other than this fusion gene are absent in EHE. The TAZ-CAMTA1 fusion is a promising therapeutic target. This review summarizes recent advances in EHE, focusing on the role of the Hippo-YAP/TAZ pathway in EHE and its potential as a therapeutic target for drug development., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Competing Interests: The authors declare no conflicts of interest.

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., (© 2024 Japanese Society of Neuropathology.)

Purpose: There are no effective treatment options for patients with aggressive epithelioid hemangioendothelioma (EHE) driven by the TAZ-CAMTA1 (TC) fusion gene. Here, we aimed to understand the regulation of TC using pharmacologic tools and identify vulnerabilities that can potentially be exploited for the treatment of EHE., Experimental Design: TC is a transcriptional coregulator; we hypothesized that compounds that reduce TC nuclear levels, either through translocation of TC to the cytoplasm, or through degradation, would render TC less oncogenic. TC localization was monitored using immunofluorescence in an EHE tumor cell line. Two target-selective libraries were used to identify small molecules that reduce TC localization in the nucleus. The ability of the shortlisted hits to affect cell viability, apoptosis, and tumorigenesis was also evaluated., Results: Basal TC remained "immobile" in the nucleus; administration of cyclin-dependent kinase (CDK) inhibitors such as CGP60474 and dinaciclib (Dina) mobilized TC. "Mobile" TC shuttled between the nucleus and cytoplasm; however, it was eventually degraded through proteasomes. This dramatically suppressed the levels of TC-regulated transcripts and cell viability, promoted apoptosis, and reduced the area of metastatic lesions in the allograft model of EHE. We specifically identified that the inhibition of CDK9, a transcriptional CDK, destabilizes TC., Conclusions: The CDK inhibitor Dina exhibited antitumorigenic properties both in vitro and in vivo in EHE models. Dina has been rigorously tested in clinical trials and displayed an acceptable toxicity profile. Therefore, there is a potential therapeutic window for repurposing Dina for the treatment of EHE., (©2024 American Association for Cancer Research.)

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., (© 2024 John Wiley & Sons Ltd.)

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with metastatic potential. EHE can have single- or multiorgan involvement, with presentations ranging from asymptomatic disease to pain and systemic symptoms. The extremely heterogeneous clinical presentation and disease progression complicates EHE diagnosis and management. We present the case of a 24-year-old woman with two periauricular erythematous papules, leading to the discovery of metastatic EHE through routine biopsy, despite a noncontributory medical history. Histology revealed the dermal proliferation of epithelioid cells and vacuoles containing red blood cells. Immunohistochemistry markers consistent with EHE solidified the diagnosis. Although extremely rare, prompt diagnosis of EHE is essential for informed decision-making and favorable outcomes. Key clinical and histopathological findings are highlighted to aid dermatologists in diagnosing and managing this uncommon condition., (©Kayd Pulsipher, Samantha Mills, Blair Harris, Rene Bermudez, Muammar Arida, Jonathan Crane. Originally published in JMIR Dermatology (http://derma.jmir.org), 28.08.2024.)

Introduction: Epithelioid hemangioendothelioma (EHE) is an ultra-rare sarcoma, marked by distinctive molecular and pathological features and with a variable clinical behavior. Its natural history is still partially understood, reliable prognostic and predictive factors are lacking and many questions are still open on the optimal management. In the context of EURACAN, a prospective registry specifically dedicated to EHE was developed and launched with the aim of providing, through high-quality prospective data collection, a better understanding of this disease., Study Design: Registry-based cohort study including only new cases of patients with a pathological and molecularly confirmed diagnosis of EHE., Objectives: To improve the understanding of EHE natural history, validate and identify new prognostic and predictive factors, clarify the activity and efficacy of currently available treatment options, describe treatment pattern., Methods: Settings and participantsIt is an hospital-based registry established in centers with expertise in EHE including adult patients with a new pathological and molecularly confirmed diagnosis of EHE starting from the 1st December 2023. The characteristics of each patient in the facility who meets the above-mentioned inclusion criteria will be collected prospectively and longitudinally with follow-up at cancer progression and / or cancer relapse or patient death. It is a secondary use of data which will be collected from the clinical records. The data collected for the registry will not entail further examinations or admissions to the facility and/or additional appointments to those normally provided for routine patient follow-up. VariablesFull details on patients and disease features, treatment and outcome will be collected, according to common clinical practice guidelines developed and shared with all the contributing centers. In addition, data on potential confounders (e.g. comorbidity; functional status etc.) will also be collected. Statistical methodsThe data analyses will include descriptive statistics and analytical analyses. Multivariable Cox's proportional hazards model and Hazard ratios (HR) for all-cause or cause-specific mortality will be used to determine independent predictors of overall survival, recurrence and progression., Results: The registry has been joined by 21 sarcoma reference centers across EU and UK, covering 10 countries. Patients' recruitment started in December 2023. The estimated completion date is December 2033 upon agreement on the achievement of all the registry objectives. The already established collaboration and participation of EHE patient's associations involved in the project will help in promoting the registry and fostering accrual., Competing Interests: Anna Maria Frezza declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Alexia Bertuzzi declares support for attending meeting and/or travels from Pharmamar and Istituto Gentili; support for scientific activities from Istituto Gentili. Antonella Brunello declares consulting fees or serving on advisory boards for Eli Lilly, Roche, GSK, Eisai, Pharmamar, Boehringer Ingelheim, Deciphera; payment or honoraria for educational events by GSK and Pharmamar; travel grants by Pharmamar, Istituto Gentili. Giacomo G. Baldi declares consulting fees from Eli Lilly, Pharmamar, AboutEvents; honoraria from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai, IstitutoGentili; support for attending meetings and/or travels from Novartis, Pharmamar, Eli Lilly; participation on the advisory board from Pharmamar, Eli Lilly, Glaxo Smith Kline, Merck Sharp & Dome, Eisai. Paolo G. Casali declares institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Virginia Ferraresi declares consultancy fees or honoraria from PharmaMar, Boehringer Ingelheim, Gentili e Serb Pharmaceuticals. Matilde Ingrosso reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Laura Monteleone reports institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Johanna Szkandera reports participation in advisory boards or invited speaker fees for PharmaMar, Bayer, Roche, Lilly, Amgen; travel expenses coverage from PharmaMar, Roche, Lilly, Amgen, Bristol Myers Squibb; research funding from PharmaMar, Roche, Eisai. Bruno Vincenzi reports consulting fees from Eisai, Lilly, Bayer, Deciphera, PharmaMar, Blueprint, Pfizer, GSK, Accord, Abbott and research support from PharmaMar, Novartis, Lilly Silvia Stacchiotti declares advisory board roles with Bayer, Boehringer, Daiichi, Ikena, Nec Oncology, Pharma Essentia, Regeneron, Servier; invited speaker roles for Bayer, Boehringer, Gentili, Pharmamar; institutional research funding from Advenchen Laboratories, Amgen Dompé, AROG Pharmaceuticals, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Boehriger Ingelheim, Daiichi Sankyo, Deciphera, Eisai, Eli Lilly, Epizyme Inc, Foghorn Therapeutics Inc., Glaxo, Hutchison MediPharma Limited, Inhibrx, Inc., Karyopharm Pharmaceuticals, Novartis, Pfizer, PharmaMar, PTC Therapeutics, Rain Oncology, SpringWorks Therapeutics. Carlo Cicala, Lorenzo D’Ambrosio, Angelo Paolo Dei Tos, Alessandro Gronchi, Nadia Hindi, Robin Jones, Iwona Lugowska, Julia Ketzer, Anna Mariuk-Jarema, Andrea Napolitano, Andri Papakonstantinou, Sandro Pasquali, Marta Sbaraglia, Federico Scolari, Elisa Crotti, Irene Benzonelli, Jean-Yves Blay, Christophe Bouvier, Javier Martin Broto, Hugh Leonard, Ninna Aggerholm-Pedersen, Andri Papakonstantinou, Giuseppe Bianchi, Federica Zuccheri, Paolo Baili, Simone Bonfarnuzzo, Domenico Campanacci, Armelle Dufresne, Sebastian Bauer, Serena Bazzurri, Stefano Gabellini, Claudia Giani, Vincenzo Giannusa, Melissa Gil-Sanjines, Teresa Grassani, Paolo Lasalvia, Stefan Lindskog, Salvatore Vizzaccaro, Nils Dieckmann, Alessandro Mazzocca, Andrei Ivanescu, Giuseppe Badalamenti, Carlo Morosi, Stephanie Elston, Kyetil Boye, Francesca Nardozza, Elisabetta Neri, Maria Nilsson and Annalisa Trama declares no conflict of interest., (Copyright: © 2024 Frezza et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: To investigate the feasibility, safety, and clinical outcomes of image-guided thermal ablation in patients with hepatic epithelioid hemangioendothelioma (HEHE)., Materials and Methods: This was a multicenter retrospective investigation of 18 patients (43.9 years [SD ± 14.8]; 6 men) who underwent image-guided thermal ablation for HEHE between January 2013 and February 2023. A total of 31 ablation sessions (24 involving microwave ablation and 7 involving radiofrequency ablation) were evaluated. The rates of technical success, adverse events, and outcomes were assessed. The Kaplan‒Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) rates. The risk factors affecting PFS were investigated using Cox proportional hazard regression analysis., Results: The technical success rate was 93.5% (29/31). No major adverse events occurred. Local tumor progression occurred after 2 sessions (6.5%, 2/31), and intrahepatic distant metastasis occurred after 16 sessions (51.6%, 16/31). During the medium follow-up time of 37.2 months (range, 3-117 months), the OS and PFS rates were 87.6% and 62.2%, respectively, at 1 year; 75.5% and 37.4%, respectively, at 3 years; and 75.5% and 37.4%, respectively, at 5 years. The median OS and PFS were 90.5 months (95% CI: 68.1-112.8) and 23.8 months (95% CI: 15.4-32.2), respectively. According to the multivariate analysis, a larger tumor size (P = .026) was associated with shorter PFS., Conclusions: Image-guided thermal ablation is a feasible and safe treatment option for patients with HEHE that resulted in local tumor control and a favorable long-term prognosis., (Copyright © 2024 SIR. Published by Elsevier Inc. All rights reserved.)

Abstract: Pseudomyogenic hemangioendothelioma (PHE) is an uncommon mesenchymal neoplasm of intermediate malignant potential showing endothelial differentiation. Around 20 cases of primary osseous PHE have been reported to date. A 16-year-old boy presented with complaints of pain in his right leg. Imaging revealed multifocal intramedullary and cortical-based lytic lesions involving long and small bones. Microscopic examination revealed plump, spindled cells arranged in fascicles and admixed "epithelioid" and "rhabdoid" cells sans vasoformative areas. By immunohistochemistry, the lesional cells were reactive for AE1/AE3, CD31, Erg, Fli1, and SMA, while immunonegative for CD34, myogenin, and S100. Nuclear expression of the INI1/SMARCB1 protein was retained. PHE is a rare entity, more so as a primary osseous lesion; therefore, awareness of the presence of this entity in the bone is the key to making a diagnosis. We discuss its clinicopathological features, differential diagnosis, and an attempt a short review of the literature., (Copyright © 2023 Copyright: © 2023 Indian Journal of Pathology and Microbiology.)

Introduction: Primary malignant hepatic vascular tumors with various malignant potentials include epithelioid hemangioendothelioma (EHE) and angiosarcoma (AS), which may overlap pathologically. This study aimed to compare the pathological findings of hepatic EHE with those of AS, in association with patient outcomes., Methods: Fifty-nine histologically confirmed patients with 34 EHE and 25 AS were admitted to a tertiary hospital from 2003 to 2020. Their EHE and AS pathological features were compared. Immunohistochemistry for CD31, ERG, CAMTA-1, TFE3, P53, and Ki-67 labeling was performed on paraffin-embedded blocks. Markers, along with histological findings, were analyzed for the purposes of diagnostic and prognostic significance by multivariate analysis., Results: CAMTA-1 was 91.2% positive in EHE, but negative in AS (p = < 0.001). AS was significantly correlated to an aberrant p53 expression, high Ki-67 labeling, and high mitotic activity, compared to EHE (all, p = < 0.001). EHE can be classified as low grade (LG) and high grade (HG) using the prognostic values of mitotic activity and ki-67 labeling (sensitivity = 1, specificity = 1). Low grade-EHE showed significantly better overall survival than high grade-EHE (p = 0.020)., Conclusions: Immunohistochemistry for CAMTA-1, P53, and Ki-67 labeling may help distinguish EHE and AS in histologically ambiguous cases, especially small biopsied tissue. Moreover, the combination of mitotic activity and Ki-67 labeling can be a prognostic factor for EHE with various clinical features., (© 2024. The Author(s).)

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., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context: Recent molecular discoveries have led to improved understanding of tumor biology and the development of new diagnostic assays., Objective: To review primarily 3 examples of liver tumors and to briefly illustrate how recent molecular discoveries have altered clinical liver pathology practice., Data Sources: First, we will discuss fibrolamellar carcinoma, which will be the main focus of discussion, as an example for new diagnostic tests that have been developed as a result of molecular discoveries. Additional information on the role of molecular diagnostics in hepatocellular adenoma and hepatocellular carcinoma will be provided. Second, we will use the example of epithelioid hemangioendothelioma as an example of how new diagnostic tools, based on molecular discoveries, may support improved prognostication. Finally, we will use the example of intrahepatic cholangiocarcinoma as an example of a liver tumor where new molecular discoveries have identified tractable therapeutic targets and led to new effective therapies. This portion of the manuscript will also include a description of the anatomic and molecular differences between intrahepatic, hilar, and extrahepatic cholangiocarcinoma., Conclusions: Fueled by molecular discoveries, new and better diagnostic tests and therapeutic targets have improved clinical care in patients affected by liver tumors., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Abstract: Epithelioid hemangioma (EH), also known as angiolymphoid hyperplasia with eosinophilia, is an unusual vascular proliferation that tends to manifest in the head and neck region. Its occurrence on the penis is rare, with only scarce reported cases in the literature. The histopathological examination of this condition poses a challenge because it shares similarities with other entities, such as epithelioid hemangioendothelioma, epithelioid angiosarcoma, cutaneous epithelioid angiomatous nodule, or Kaposi sarcoma (KS). The infrequency of EH in penile locations underscores the need for accurate diagnostic differentiation and tailored treatment strategies for this atypical presentation. This case report highlights a rare instance of multifocal penile EH. The patient's lesions exhibited distinctive histopathologic features, with extensive eosinophilic infiltration, presence of necrosis, and infiltration to subcutaneous fat. The patient was treated with doxorubicin, a chemotherapy drug, with a very good response. This successful therapeutic outcome underscores the potential efficacy of doxorubicin in the management of multifocal penile EH. The comprehensive analysis of this case contributes to our understanding of the clinical presentation, histopathologic features, and treatment modalities for this rare penile tumor, providing valuable insights for future clinical considerations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Despite significant advances in their molecular pathogenesis, skeletal vascular tumors remain diagnostically challenging due to their aggressive radiologic appearance and significant morphologic overlap. Within the epithelioid category and at the benign end of the spectrum, recurrent FOS/FOSB fusions have defined most epithelioid hemangiomas, distinguishing them from epithelioid hemangioendothelioma and angiosarcoma. More recently, the presence of EWSR1/FUS :: NFATC1/2 fusions emerged as the genetic hallmark of a novel group of unusual vascular proliferations, often displaying epithelioid morphology, with alternating vasoformative and solid growth, variable atypia, reminiscent of composite hemangioendothelioma. In this study, we further our understanding and morphologic spectrum of NFATC -fusion positive vascular neoplasms by describing 9 new cases, including soft tissue locations and novel fusion partners. Combining with the initial cohort of 5 cases, a total of 14 patients were analyzed, showing slight female predilection and an age range of 10 to 66 (mean 42 y). Twelve patients had solitary lesions, while 2 had multifocal polyostotic (pelvic bones) disease. Overall, 12 lesions were intra-osseous and 2 in soft tissue. By targeted RNA Fusion panels or FISH, there were 6 cases of EWSR1::NFATC1 , 4 EWSR1::NFATC2 , 2 FUS::NFATC2 , 1 EWSR1 rearrangement, and 1 with a novel FABP4::NFATC2 fusion. Follow-up was available in 4 patients. One patient experienced 2 local recurrences, 11 and 15 years postdiagnosis, and one patient experienced progressive disease despite multimodality treatment (curettings, embolization, radiation) over 3 years. In summary, our extended investigation confirms that NFATC -related fusions define a distinct group of vascular neoplasms with variable architecture, epithelioid phenotype, and cytologic atypia, commonly located in the bone, occasionally multifocal and with potential for local recurrence and aggressive behavior but no metastatic potential. Molecular analysis is recommended in diagnostically challenging cases with atypical histology to exclude malignancy., Competing Interests: Conflicts of Interest and Source of Funding: The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Epithelioid hemangioendothelioma (EHE) is a rare vascular malignant tumor that comprises less than 1% of all vascular tumors. Cutaneous involvement in EHE can occur either by spreading from underlying bone or rarely could be limited to the skin and mostly presents as solitary well-circumscribed mass to an ill-defined infiltrative lesion. We present a case of rapidly progressive and debilitating EHE presenting multiple vascular papules and nodules. Histopathology showed an ill-circumscribed nodular proliferation of epithelioid and spindled cells in the dermis that extended into the subcutaneous tissue. The tumor cells had moderate eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. In addition, they showed evidence of lumen formation and intracytoplasmic vacuoles. Brisk mitosis was noted. On immunohistochemistry, the cells were strongly positive for CD31, CD34, and ERG (ETS [erythroblast transformation-specific]-related gene). MIB-1 labeling index was more than 75% in the highest proliferating areas. A high degree of clinical suspicion and immunopathological examination is recommended for early diagnosis of this rare condition before it becomes function or life-threatening., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Epithelioid hemangioendothelioma (EHE) is a rare malignancy of vascular origin which can be primarily be seen in various tissues. EHE originating from the pleura is an even more uncommon subtype which may mimic mesothelioma and pleural carcinomatosis. The prognosis of pleural EHE is poor and there is no consensus on the optimal therapeutic approach., Case Presentation: A 39-year-old middle-eastern female presented with progressive dyspnea and left shoulder discomfort. Chest computed tomography scan revealed a left side pleural effusion and pleural thickening. Pleuroscopy was done and biopsies were taken which were positive for CD31, CD34, CK, factor 8-R-antigen, and vimentin. Patient was diagnosed with pleural epithelioid hemangioendothelioma (PEHE) and chemotherapy was started and underwent extrapleural pneumonectomy 7 months later. Unfortunately, the patient passed away 10 months after diagnosis due to disease complications., Conclusions: Once PEHE is suspected in histology it can be confirmed with immunohistochemistry. Chemotherapy, surgery or a combination of both is currently used as the treatment but the standard treatment remains a question., (© 2024. The Author(s).)

Primary vascular tumors of bone are a heterogeneous group of neoplasms, ranging from benign hemangiomas to frankly malignant epithelioid hemangioendotheliomas and angiosarcomas. Over the years, their classification has been a matter of discussion, due to morphologic similarities and uncertainty regarding biologic behavior. Over the past decade, with the development of next-generation sequencing, there has been a significant improvement in the molecular characterization of these lesions. The integration of their morphologic, immunohistochemical and molecular features has led to a better stratification, with important prognostic and therapeutic implications. Nevertheless, primary vascular bone tumors still represent a challenge for medical oncologists. Given their rarity and heterogeneity, in the last few years, there has been no significant progress in medical treatment options, so further research is needed. Here we present a review of the current knowledge regarding primary vascular tumors of the bone, correlating clinicopathologic features with tumor behavior and therapeutic approaches., Competing Interests: Declaration of Competing Interest PR reports personal fees as Consultant for Exactech and Stryker. AB reports serving on advisory boards for Eli Lilly, Roche, GSK, Eisai, Pharmamar, Boehringer Ingelheim, Deciphera; personal fees or honoraria for educational events by GSK and Pharmamar; travel grants by Gentili and Pharmamar. All the authors, including PR and AB, declare no competing interests with respect to this research., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Abstract: Epithelioid hemangioendothelioma of the prostate is a rare malignant vasogenic tumor. We report a case of epithelioid hemangioendothelioma of the prostate in a 65-year-old man with lymph nodes and lung metastases on 18 F-FDG PET/CT imaging. The patient presented with symptoms of frequent and urgent urination. On 18 F-FDG PET/CT, intense FDG uptake was observed in the prostate mass along with multiple FDG-avid lesions involving the lung and lymph nodes. Histopathological examination confirmed epithelioid hemangioendothelioma in both the prostate mass and lung nodule., Competing Interests: Conflicts of interest and sources of funding: No competing financial interests exist. The study was funded by the Natural Science Foundation of Sichuan Province (grant no. 2023NSFSC0635)., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Femoral epithelioid hemangioendothelioma with cervical lymph node metastasis is rare. We report the FDG PET/CT findings of cervical lymph node metastasis from left femoral epithelioid hemangioendothelioma in a 50-year-old woman with painless enlargement of the left cervical lymph nodes as the initial presentation. Ultrasound and MRI revealed multiple enlarged lymph nodes in the left cervical sheath area. PET/CT showed strong radioactive uptake in the left cervical lymph nodes, and there was additional lesion with increased FDG uptake in the left femur, which was later confirmed as cervical lymph nodes metastasis from left femoral epithelioid hemangioendothelioma by pathological examination., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

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., (© 2024 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)

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., (© 2023. The Author(s).)

Competing Interests: Declaration of competing interest We have no disclosures and no competing interests. Funding was not received for this work.

Thirteen cases of primary epithelioid hemangioendotheliomas (EHE) and epithelioid angiosarcomas (EA) of the pleura are presented. The patients were 7 men and 6 women between the ages of 34 and 65 years (mean: 47 years). The patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Diagnostic imaging revealed the presence of either diffuse pleural thickening or pleural nodules involving the serosal surfaces. Open surgical biopsies were obtained in all cases. Histologically, eight tumors were characterized by the presence of a cellular proliferation composed of medium-sized epithelioid cells embedded in a myxohyaline stroma and a variable spindle cell component. Cellular atypia was mild to moderate and mitotic activity ranged from 1 to 2 per 2 mm 2 . Immunohistochemical stains for vascular markers, including CAMTA1 were positive, confirming a diagnosis of EHE. Five cases of epithelioid angiosarcomas were characterized by a neoplastic cellular proliferation admixed with areas of necrosis and hemorrhage and characterized by medium-sized epithelioid to spindle-shaped cells with eosinophilic cytoplasm, round to oval nuclei and prominent nucleoli. In addition, marked cytologic atypia and a mitotic activity ranging from 3 to 5 per 2 mm 2 were identified. Immunohistochemical studies demonstrated positive staining for vascular markers; however, CAMTA1 was negative. Clinical follow-up obtained in eleven cases showed that all patients had died within 30 months post diagnosis. The current study highlights that even though it may be important to histologically separate EHE from EA for academic purposes, primary pleural origin of these tumors appears to portent an aggressive clinical behavior., (Copyright © 2023 Elsevier Inc. All rights reserved.)

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., (© 2023. The Author(s).)

Background: Malignant hemangioendothelioma is an endothelial cancer with heterogeneous clinical behavior that can range from indolent to aggressive, of which the majority are epithelioid (EHE). Its incidence and demographics have not been previously well defined in a large cohort., Methods: This retrospective analysis used the US Cancer Statistics National Program of Cancer Registries - Surveillance Epidemiology End Results (SEER) combined database to identify patients in the US newly diagnosed with hemangioendothelioma between the years of 2001 and 2017 (n = 1986). Survival analyses were performed on a subset of patients within the SEER-18 database with survival information available (n = 417). Outcomes included incidence, demographics of patients newly diagnosed with hemangioendothelioma, extent of disease at presentation, and overall survival., Results: The incidence of hemangioendothelioma in the US is 0.4 cases per million person-years. Although cases rose to 122 newly diagnosed in the year 2017 (90 EHE, 32 other hemangioendothelioma), incidence rates were stable. Skin and connective tissues were the most common presenting sites (33.4%), followed by liver (24.5%), lung (17.6%), and bone (12.5%). Median age at diagnosis was 55 years; 27.2% of patients were pediatric, adolescent, or young adult (<40 years). At presentation, 36.4% of patients had localized disease; 21.6% presented with regional and 41.7% with distant metastases. Observed survival at 3 years was 79.7%, 70.7%, and 46.0% for patients presenting with local, regional, and distant disease and most deaths occurred within the first 2 years., Conclusions: Malignant hemangioendothelioma is ultra-rare but meaningfully impacts affected patients. These data may provide benchmarks for comparison of new approaches to hemangioendothelioma therapy and highlight poor survival outcomes., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

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.

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., (© 2023. The Author(s).)

A 81-year-old woman was referred to our hospital for neck discomfort. Chest computed tomography (CT) showed a tumor in the upper mediastinum. Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed the mild accumulation in the tumor. Percutaneous biopsy was performed and epithelioid hemangioendothelioma was suspected, and the surgical treatment was performed. The histological study showed polygonal and irregular cells with nuclear atypia in myxoma-like substrate compatible with epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma is a rare malignant vascular neoplasm caused by the proliferation of neoplastic endothelial cells. Epithelioid hemangioendothelioma may develop in any organ, but it is commonly observed in the extremities. The tongue is a very unusual location for epithelioid hemangioendothelioma. A 55-year-old male patient presented to the outpatient head and neck clinic with lumps in the tongue, pain, and limitation of motion. The polypoid mass detected in the anterior midline of the tongue was excised. Microscopically, the tumor cells included slightly pleomorphic oval or round vesicular nuclei with an eosinophilic cytoplasm that variably contained vacuoles. There were 4 mitoses per 10 high power fields and there was no necrosis. In immunohistochemical study, the tumor cells were positively stained with CD31 and CD34 whereas they were negatively stained with TFE3, SMA, S-100, HHV-8 and EMA. The patient was diagnosed with "epitheloid hemangioendothelioma". Only ten cases have been reported in the tongue in the literature. Our case was the eleventh case, and we aimed to report this case as a rare entity with an unusual location.

Aim: The purpose of this study was to analyze the features of conventional ultrasound (US) and contrast-enhanced ultrasound (CEUS) in hepatic epithelioid hemangioendothelioma (HEHE)., Material and Methods: We retrospectively analyzed the US images (grayscale, color Doppler and CEUS) of the patients with histopathologically confirmed HEHE in our hospital from March 2015 to August 2021 who had underwent a US investigation., Results: A total of 13 patients were reported during the study period (seven men, aged from 23 to 62 years, with an average age of 40 years). The unifocal, multifocal, and diffuse lesions were 2, 9, and 2, respectively. Five patients (5/13) had liver involvement of both lobes, and eight (8/13) patients had only right lobe involvement. The maximum diameter of the lesions ranged from 1.9 to 7.0 cm. The grayscale US of HEHE mainly showed multiple hypoechoic lesions (n=9) near the capsule of the right lobe of the liver, with well-defined margins (n=7), accompanied by a hypoechoic halo (n=3) or capsule retraction (n=4) and calcification (n=8). Color Doppler US can detect blood flow in the lesion (n=8). CEUS was performed in five patients (5/13). The enhancement pattern of CEUS varied in the arterial phase, mainly including rim-like hyper-enhancement (n=2) and inhomogeneous hypo-enhancement (n=2), but was approximately the same in the portal venous phase and the late venous phase, both showing varying degrees of regression., Conclusions: The grayscale US and CEUS seem to provide some reference value for diagnosing HEHE.

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., (© 2022 Wiley Periodicals LLC.)

Vascular neoplasms are rare tumors with a multitude of clinical presentations and behavior, which make accurate identification and subclassification challenging on limited small biopsies. Within the spectrum of these lesions, the ones with epithelioid morphology, such as epithelioid hemangioendothelioma and epithelioid angiosarcoma, are particularly challenging given the morphologic overlap with nonvascular lesions and the limited cells due to hemodilution on sampling. Herein, we review the differential diagnosis of epithelioid vascular neoplasms, with a focus on the cytomorphology, differential diagnoses, and ancillary studies that pathologists should be aware of when evaluating small biopsies and aspirates, including novel translocations, and associated monoclonal immunohistochemistry antibodies, that can help in the diagnosis of some of these tumors. Awareness of these morphologic and ancillary study findings in these rare tumors will hopefully allow pathologists to recognize and render-specific diagnoses on limited samples of these challenging lesions., Competing Interests: The authors have no fundings or conflicts of interest to disclose., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Epithelioid hemangioendothelioma is a low- to intermediate-grade malignant vascular tumor with a slowly progressive course and unpredictable prognosis. We report a case of epithelioid hemangioendothelioma with pleura and bone metastases on 68 Ga-FAPI-04 PET/CT in a 65-year-old woman who underwent surgery and chemotherapy., Competing Interests: Conflicts of interest and sources of funding: none declared. This work was supported by the National Natural Science Foundation of China (no. 81871391) and the Improvement Project for Theranostic Ability on Difficulty Miscellaneous Disease (no. ZLYNXM202007)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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 2.8 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.

Background and Objective: Hepatic epithelioid hemangioendothelioma (HEHE) is an uncommon vascular endothelial cell cancer involving the hepatic tissue with full malignant potential. HEHE diagnosis is challenging because blood tests and radiological findings are often non-pathognomonic. Therapeutic possibilities are manifold, ranging from a simple "wait and see" to surgical approaches, up to systemic therapies with vascular endothelial growth factor (VEGF) and mechanistic target of rapamycin (mTOR) inhibitors. The standardized adoption of the surgical approaches, namely resection or transplantation, still remains unclear. Aim of this review is to clarify the role of the surgical strategies for the management of HEHE., Methods: A review of the literature was done with the intent to focus on the relevant studies exploring the role of the different surgical therapies. A search of these studies was done using the electronic database MEDLINE-PubMed., Key Content and Findings: The surgical approaches, namely resection or transplantation, represent the best option in treating well-selected patients with HEHE. Resection is indicated in the case of single lesion or oligonodular monolobar disease. Liver transplantation is indicated in the case of multifocal bilobar disease, even in the presence of resectable extrahepatic disease. The potential role of a minimally invasive approach should represent a relevant field to explore., Conclusions: The impact of surgery for the treatment of HEHE requires further studies to further clarify its relevant role. Standardized approaches are required.