REVIEW Epithelioid hemangioendothelioma, an ultra-rare cancer: a consensus paper from the community of experts S. Stacchiotti1*, A. B. Miah2, A. M. Frezza1, C. Messiou3, C. Morosi4, A. Caraceni5, C. R. Antonescu6, J. Bajpai7, E. Baldini8, S. Bauer9, R. Biagini10, S. Bielack11, J. Y. Blay12, S. Bonvalot13, I. Boukovinas14, J. V. M. G. Bovee15, K. Boye16, T. Brodowicz17, D. Callegaro18, E. De Alava19,20, M. Deoras-Sutliff21, A. Dufresne12, M. Eriksson22, C. Errani23, A. Fedenko24, V. Ferraresi25, A. Ferrari26, C. D. M. Fletcher27, X. Garcia del Muro28, H. Gelderblom29, R. A. Gladdy30, F. Gouin31, G. Grignani32, J. Gutkovich21,33, R. Haas34,35, N. Hindi36, P. Hohenberger37, P. Huang38, H. Joensuu39, R. L. Jones40, C. Jungels41, B. Kasper42, A. Kawai43, A. Le Cesne44, F. Le Grange45, A. Leithner46, H. Leonard47, A. Lopez Pousa48, J. Martin Broto49, O. Merimsky50, P. Merriam51, R. Miceli52, O. Mir53, M. Molinari54, M. Montemurro55, G. Oldani56, E. Palmerini57, M. A. Pantaleo58, S. Patel59, S. Piperno-Neumann60, C. P. Raut61,62,63, V. Ravi59, A. R. A. Razak64, P. Reichardt65, B. P. Rubin66, P. Rutkowski67, A. A. Safwat68, C. Sangalli69, G. Sapisochin70, M. Sbaraglia71, S. Scheipl72, P. Schöffski73, D. Strauss74, S. J. Strauss75, K. Sundby Hall16, W. D. Tap76, A. Trama77, A. Tweddle78, W. T. A. van der Graaf79, M. A. J. Van De Sande80, W. Van Houdt81, G. van Oortmerssen82, A. J. Wagner51, M. Wartenberg83, J. Wood84, N. Zaffaroni85, C. Zimmermann86, P. G. Casali1, A. P. Dei Tos71 & A. Gronchi18 1 Adult Mesenchymal Tumor and Rare Cancer Unit, Cancer Medicine Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 2The Royal Marsden Hospital and The Institute of Cancer Research, London; 3Department of Radiology, The Royal Marsden Hospital and The Institute of Cancer Research, London, UK; 4 Radiology Department, Fondazione IRCCS Istituto Nazionale Tumori, Milan; 5Palliative Care Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 6 Department of Pathology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, USA; 7Medical Oncology Department, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India; 8Department of Radiation Oncology, Dana-Farber Cancer Center/Brigham and Women’s Hospital, Boston, USA; 9 Department of Medical Oncology, West German Cancer Center, Sarcoma Center, University of Duisburg-Essen, University Hospital, Essen, Germany; 10Orthopaedic Department, Regina Elena National Cancer Institute, Rome, Italy; 11Klinikum Stuttgart e Olgahospital, Zentrum für Kinder-, Jugend- und Frauenmedizin, Stuttgart Cancer Center, Pädiatrische Onkologie, Hämatologie, Immunologie, Stuttgart, Germany; 12Department of Medical Oncology, Centre Leon Berard, Université Claude Bernard Lyon, Unicancer, Lyon; 13Department of Surgical Oncology, Institut Curie, Université Paris Sciences et Lettres, Paris, France; 14Nordix, Athens, Greece; 15 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands; 16Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; 17Medical University Vienna & General Hospital Department of Internal Medicine 1/Oncology, Vienna, Austria; 18Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 19Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/ CIBERONC, Seville; 20Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Seville, Spain; 21The EHE Foundation, Wisconsin, USA; 22Department of Oncology, Skane University Hospital and Lund University, Lund, Sweden; 23Orthopaedic Service, Musculoskeletal Oncology Department, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; 24Medical Oncology Division, P.A. Herzen Cancer Research Institute, Moscow, Russian Federation; 25 Sarcomas and Rare Tumors Unit, IRCCS Regina Elena National Cancer Institute, Rome; 26Paediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 27Department of Pathology Brigham & Women’s Hospital, Boston, USA; 28University of Barcelona and Genitourinary Cancer and Sarcoma Unit Institut Català d’Oncologia, Hospitalet, Barcelona, Spain; 29Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands; 30University of Toronto and Lunenfeld-Tanenbaum Research Institute, Toronto, Canada; 31Department of Surgery, Centre Leon Berard, Lyon, France; 32Division of Medical Oncology, Candiolo Cancer Institute, FPO e IRCCS, Candiolo, Italy; 33NUY Langone Medical Center, New York, USA; 34Department of Radiotherapy, the Netherlands Cancer Institute, Amsterdam; 35Department of Radiotherapy, the Leiden University Medical Center, Leiden, the Netherlands; 36Group of Advanced Therapies and Biomarkers in Sarcoma, Institute of Biomedicine of Seville (IBIS, HUVR, CSIC, Universidad de Sevilla), Seville, Spain; 37Division of Surgical Oncology & Thoracic Surgery, Mannheim University Medical Center, University of Heidelberg, Heidelberg, Germany; 38Division of Molecular Pathology, The Institute of Cancer Research, London, UK; 39 Department of Oncology, Helsinki University Hospital & Helsinki University, Helsinki, Finland; 40Department of Cancer, The Royal Marsden Hospital and The Institute of Cancer Research, London, UK; 41Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; 42University of Heidelberg, Mannheim University Medical Center, Sarcoma Unit, Mannheim, Germany; 43Musculoskeletal Oncology and Rehabilitation Medicine, Rare Cancer Center National Cancer Center Hospital, Tokyo, Japan; 44International Department, Gustave Roussy, Villejuif, France; 45UCLH - University College London Hospitals NHS Foundation Trust, London, UK; 46Department of Orthopaedics and Trauma Medical University Graz, Graz, Austria; 47Chair of Trustees of the EHE Rare Cancer Charity (UK), Charity number 1162472; 48Medical Oncology Department, Hospital Universitario Santa Creu i Sant Pau, Barcelona; 49Hospital Universitario Fundación Jimenez Diaz, Madrid, Spain; 50Unit of Soft Tissue and Bone Oncology, Division of Oncology, Tel-Aviv Medical Center affiliated with Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 51Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 52Department of Clinical Epidemiology and Trial Organisation, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 53Sarcoma Group, Gustave Roussy, Villejuif, France; 54University of Pittsburgh Medical Center, Thomas Starzl Transplant Institute, Pittsburgh, USA; 55 Oncology, CHUV Lausanne, Lausanne; 56Division of Abdominal Surgery, University Hospitals of Geneva, Geneva, Switzerland; 57Chemotherapy Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna; 58Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; 59Sarcoma Center, The University of Texas M.D. Anderson Cancer Center, Houston, USA; 60Department of Medical Oncology, Institut Curie, Paris, France; 61Department of Surgery, Brigham and Women’s Hospital, Boston; 62Center for Sarcoma and Bone Oncology, Harvard Medical School, Boston; 63Dana Farber Cancer Center, Harvard Medical School, Boston, USA; 64Princess Margaret Cancer Centre and Sinai Healthcare System & Faculty of Medicine, University of Toronto, Toronto, Canada; 65Helios Klinikum Berlin-Buch, Department of Oncology and Palliative Care, Berlin, Germany; 66Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, USA; 67Maria Sklodowska- Curie National Research Institute of Oncology, Department of Soft Tissue/Bone Sarcoma and Melanoma, Warsaw, Poland; 68Aarhus University Hospital, Aarhus, Denmark; 69Department of Radiation Oncology, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 70Multi-Organ Transplant and HPB Surgical Oncology, Division *Correspondence to: Dr. Silvia Stacchiotti, Fondazione IRCCS Istituto Nazionale Tumori, via Venezian 1, Milan, Italy. Tel: þ39-0223902803 E-mail: silvia.stacchiotti@istitutotumori.mi.it (S. Stacchiotti). 2059-7029/© 2021 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 1 ESMO Open S. Stacchiotti et al. of General Surgery, Department of Surgery, University of Toronto, Toronto, Canada; 71Department of Pathology, Azienda Ospedaliera Università Padova, Padua, Italy; 72 Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria; 73Leuven Cancer Institute, Leuven, Belgium; 74Department of Surgery, The Royal Marsden Hospital and The Institute of Cancer Research, London; 75University College London Hospital, London, UK; 76Department of Medicine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, USA; 77Department of Research, Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 78Palliative Care, The Royal Marsden Hospital and The Institute of Cancer Research London; 79Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam; 80Department of Orthopedic Surgery Bone and Soft Tissue Tumor Unit, Leiden University Medical Center, Leiden; 81Sarcoma and Melanoma Unit, The Netherlands Cancer Institute, Amsterdam; 82Co-Chair of Sarcoma Patients EuroNet (SPAEN), Woelfersheim, Germany & Chairman of the Dutch organisation for sarcoma patients (Patiëntenplatform Sarcomen), Guest researcher at Leiden University (Leiden Institute for Advanced Computer Science), Leiden University, Leiden, The Netherlands; 83Chair of the Board of Directors of Sarcoma Patients EuroNet (SPAEN), Sarcoma Patients EuroNet (SPAEN), Woelfersheim, Germany; 84The Royal Marsden NHS Foundation Trust, London, UK; 85Molecular Pharmacology Unit, Department of Applied Research and Technological Development, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; 86Department of Supportive Care, Princess Margaret Cancer Centre and Division of Palliative Medicine, Department of Medicine, University of Toronto, Toronto, Canada Available online 2 June 2021 Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication. Key words: sarcoma, epithelioid hemangioendothelioma, diagnosis, treatment, management, guidelines INTRODUCTION only two prospective trials ongoing specifically dedicated to Epithelioid hemangioendothelioma (EHE) is an ultra-rare EHE on eribulin and trametinib (ClinicalTrials.gov Identifier: vascular sarcoma, usually behaving as a low-grade malig- NCT03331250 and NCT03148275). Current clinical practice nancy despite a high propensity for systemic involvement. is therefore based mostly on retrospective case series or The degree of uncertainty in selecting the most appropriate case reports (i.e. level IV-V evidence), in which the patho- treatment of EHE patients is high, treatment options vary logical diagnosis was often not confirmed by an experienced and the adoption of new treatments is inconsistent across STS pathologist and molecular testing was not available. the world, resulting in suboptimal outcomes for many pa- Many of these reports were published before the identifi- tients. Also, no active systemic agents are currently cation of characteristic WW domain-containing transcrip- approved specifically for EHE, which is typically refractory to tion regulator 1 (WWTR1)-calmodulin binding transcription the antitumor drugs used in soft tissue sarcomas (STS). activator 1 (CAMTA1) or Yes-associated protein 1 (YAP1)- In December 2020, the European Society for Medical transcription factor E3 (TFE3) gene fusions in EHE. Oncology (ESMO) convened a virtual consensus meeting to A degree of uncertainty needs to be accepted when update its clinical practice guidelines on sarcomas. Recog- facing regulatory matters and clinical decision making in nizing the special need for a global consensus on the ultra-rare cancers. In this consensus, however, we grade management of patients with EHE, ESMO hosted a parallel levels of evidence from I to V and use grades of meeting that included EHE experts from several disciplines recommendation from A to D adapted from the system from Europe, North America and Asia, with the contribution used by the Infectious Diseases Society of America-US of the EHE Group (composed by the EHE Rare Cancer Public Health Service Grading System 2 (Supplementary Charity, UK and the EHE Foundation), a global, disease- Table S1, Supplementary Material, available at https:// specific patient advocacy group and a patient representa- doi.org/10.1016/j.esmoop.2021.100170).1 tive from Sarcoma Patient EuroNet (SPAEN). QUALITY OF EXISTING EVIDENCE EPIDEMIOLOGY/CLINICAL PRESENTATION The quality of evidence available for common cancers is EHE has an incidence of 0.038/100 000/year and a preva- considerably stronger than for EHE. No phase II or III ran- lence of <1/1 000 000,2-4 showing a slight predominance in domized studies have ever been conducted and results from women. The incidence peaks in the fourth to fifth only two phase II trials are available. At present, there are decade.2,4-7 EHE is exceedingly rare in children. 2 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021 S. Stacchiotti et al. ESMO Open EHE can arise anywhere in the body and have various carefully investigated and recorded. A recent report indi- presentations, including unifocal lesion (i.e. localized dis- cated no impact of pregnancy and lactation on the course of ease characterized by a single tumor lesion), locoregional a multifocal EHE.22 metastases (i.e. a disease with multifocal single-organ As for hematological or biochemical markers, anemia is involvement or multiple lesions to a single anatomic the only reported negative prognostic factor.17 The prog- compartment), or systemic metastases (i.e. a disease with nostic relevance of inflammatory and hormonal circulating multi-organ involvement).2,7-9 The relative incidence of such biomarkers is currently under investigation. The identifica- presentations is currently unknown. When the onset occurs tion of reliable clinical and/or biological correlates of as a single lesion, this is usually a solitary mass in the soft outcome is indeed crucial to optimize the treatment strat- tissues.5,10,11 However, >50% of patients present with egy and design future clinical trials. metastatic disease, mostly involving lung, liver and bone.5-11 At present, many centers use sequential imaging to An origin from a blood vessel can be demonstrated in assess the growth dynamic as a measure of aggressiveness w50% cases.2,5 The monoclonal origin of multifocal EHE, at and potential hint for the further course of disease, least in liver, has also been established using WWTR1- although the disease burden may be underestimated with CAMTA1 breakpoint analysis, indicating that multiple le- conventional imaging techniques. sions arise from spread of a single primary malignant clone.12 GENERAL PRINCIPLES ON EHE MANAGEMENT The clinical presentation at the time of diagnosis is quite Due to the ultra-rare nature of EHE, patients should be variable. The initial diagnosis can be incidental in managed within sarcoma reference centers or reference completely asymptomatic patients. In symptomatic cases, networks, by a dedicated sarcoma multidisciplinary team the most common symptoms are pain (40%), a palpable including a pathologist, radiologist, surgical oncologist, or- mass (6%-24%) and weight loss (9%).2,6,9 Angiocentric EHE thopedic surgeon, radiation oncologist, medical oncologist may present with signs and symptoms of venous and palliative care specialist who are familiar with the nu- obstruction. ances of this disease23 [III, A]. Other specialists, such as liver transplant (LT) experts, should be involved on an individu- PROGNOSTIC FACTORS alized basis. Data available on prognostic factors in localized and PATHOLOGY AND MOLECULAR BIOLOGY advanced EHE are limited and only retrospective. In most EHE is a malignant vascular neoplasm, featuring an cases, the interpretation of these series is further hampered epithelioid endothelial cell population in a distinctive myx- by the unavailability of standard diagnostic criteria. ohyaline stroma, molecularly characterized by WWTR1- There are no clearly validated pathological/molecular CAMTA1 (90%) or YAP1-TFE3 (10%) gene fusions15,24 prognostic factors for EHE. Grading systems based on a (Figure 1). Rare WWTR1 translocations involving gene combination of mitotic activity and tumor size,13 or of his- partners other than CAMTA1 have been reported.25 The tologic atypia and tumor size have been proposed, but their immunohistochemical (IHC) or molecular assessment of prognostic value needs to be confirmed [level of evidence WWTR1-CAMTA1 and/or YAP1-TFE3 is highly recommended IV, C].14 Conflicting conclusions had been reported on the to confirm the diagnosis and rule out other mimics, like prognostic value of the gene rearrangement subtype,5,15,16 angiosarcoma and epithelioid hemangioma [V, A]. In while recently, the negative prognostic role of synapto- particular, CAMTA1 IHC is a good surrogate to detect physin expression has been proposed.14 translocation, whereas TFE3 IHC is less specific and there- The only prognostic factors are the extent of disease at fore, when suspected, molecular confirmation is suggested. presentation (tumor size or the evidence of metastatic At present, none of the translocations identified in EHE is disease) and the presence of systemic signs and symp- druggable. Their identification has currently no prognostic toms.2,5,14,16-21 In patients with serosal involvement with/ or predictive value, nor can it be used for treatment strat- without effusion, the expected survival ranges from 1 to 11 ification purposes. months. The prognostic impact of locoregional metastases Pathologic review is strongly recommended if the first versus systemic metastases is still controversial.2,20 diagnosis was made outside a sarcoma reference center The clinical behavior of metastatic EHE can be extremely [IV, A]. variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma. Reliable molecular and bio- logical features to stratify prognosis for advanced EHE are Morphology lacking. Macroscopically, the tumor size can vary from small nodules EHE can present with tumor-related systemic symptoms to large masses. The cut surface is white and firm. such as fever, weight loss and fatigue. Their presence seems Morphologically, EHE is most often composed of epithelioid to correlate with a worse quality of life (QoL) and sur- cells, organized in strands, cords or solid nests, showing vival.9,17,21 The same symptoms can also occur during sur- glassy eosinophilic cytoplasm often with cytoplasmatic veillance.21 The presence of serosal involvement/effusion, vacuoles, set in a distinctive myxohyaline stroma, occa- weight loss, fever, fatigue and tumor-related pain should be sionally associated with hemorrhagic foci. Rarely, neoplastic Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 3 ESMO Open S. Stacchiotti et al. Figure 1. Pathologic features of epithelioid hemangioendothelioma (EHE). (Panel A) Hematoxylineeosin staining in CAMTA1-rearranged EHE: epithelioid cells organized in strands and cords set in a collagenous stroma are typically observed. The neoplastic cells contain intracytoplasmic vacuoles. (Panel B) CAMTA1 immunostaining shows CAMTA1 nuclear expression in tumor cells. (Panel C) Hematoxylineeosin staining in TFE3-rearranged EHE: tumor cells tend to show larger eosinophilic cytoplasm. (Panel D) TFE3 immunostaining shows the nuclear expression of TFE3. CAMTA1, calmodulin binding transcription activator 1; TFE3, transcription factor E3. cells may organize in a cribriform pattern of growth that Molecular profile may mimic invasive carcinoma. Low mitotic activity and Up to 90% of EHEs harbor a t(1;3)(p36.3;q25) translocation, mild nuclear atypia are generally observed. EHE associated leading to the formation of WWTR1-CAMTA1 fusion with YAP1-TFE3 fusion is composed of epithelioid neoplastic gene,24,30 whereas a smaller subset shows an alternative cells with more copious bright eosinophilic cytoplasm, often genetic aberration represented by a t(X;11)(p11;q22) organized in a solid pattern of growth but featuring at least translocation, leading to a YAP1-TFE3 fusion.15 Patients with focally unequivocal vasoformative features, usually not seen YAP1-TFE3 fused EHE tend to be younger than those with a in WWTR1-CAMTA1 EHE.24 WWTR1-CAMTA1 fusion.15,16 Other rare fusions can be Approximately 10% of EHE cases feature marked nuclear seen.25 atypia with prominent nucleoli, focal solid growth pattern, The translocation is present irrespective of anatomical foci of necrosis and higher mitotic activity (>2 mitoses/10 site and clinical behavior. The WWTR1 (also call TAZ) protein high power field). These features are associated with more is one of two end effectors of the Hippo pathway.31 WWTR1 aggressive behavior. However, clear morphologic criteria to and YAP both exert a pro-oncogenic transcriptional func- distinguish EHE variants with a more or less favorable tion. Fusion of WWTR1 to CAMTA1 results in dysregulation prognosis are missing. of the Hippo pathway, such that WWTR1-CAMTA1 resides constitutively in the nucleus, driving oncogenic Immunophenotype transformation.32 Immunohistochemically, EHE consistently expresses endo- thelial differentiation markers such as CD31, ERG, CD34 and Differential diagnosis and diagnostic pitfalls FLI-1.26,27 Focal cytokeratin immunopositivity is observed in The main differential diagnosis is with primary or metastatic <30% of cases.13,28 Only occasionally, the expression of carcinomas. However, consistent expression of endothelial epithelial differentiation markers can be strong and diffuse. differentiation markers is a helpful diagnostic clue.26 Pan- As a consequence of both WWTR1-CAMTA1 and YAP1-TFE3 cytokeratin, however, may be expressed focally in EHE, fusions, nuclear expression of CAMTA29 and TFE3,15 further increasing diagnostic uncertainty.16,25 In pleural EHE, respectively, is consistently observed. However, TFE3 another differential diagnosis is malignant mesothelioma. expression is less specific than CAMTA1 to predict the Expression of calretinin and WT1, as well as negativity presence of the corresponding molecular alteration.7,29 for endothelial differentiation markers, generally allows 4 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021 S. Stacchiotti et al. ESMO Open accurate diagnosis. Epithelioid sarcoma (ES) may enter the contrast-enhanced CT, should raise the possibility of EHE46,47 differential diagnosis. In fact, in addition to epithelioid (Figure 3). The target appearance may also be seen on T2- morphology, ES may share with EHE the expression of weighted and dynamic contrast-enhanced MRI.38,39,46 The vascular markers such as CD34 and, less frequently, ERG. ‘lollipop’ sign (hepatic or portal vein tapering and termina- However, CD31 is consistently negative, and loss of nuclear tion at the periphery or just within a well-defined hypo- INI1 expression is almost invariably observed in ES.33 When enhancing lesion) may also be visible.46,48 However, a biopsy EHE exhibits greater cytologic atypia and cellularity, is required for definitive diagnosis, in particular to exclude epithelioid angiosarcoma needs to be excluded. The pres- mass-forming peripheral intrahepatic cholangiocarcinoma. ence of striking cytologic atypia, elevated mitotic count as Thoracic EHE can present with four main patterns: mul- well as the presence of a solid or sheet-like growth pattern tiple pulmonary nodules,2,19,38 reticulonodular opaci- is a valuable diagnostic clue. Importantly, expression of ties,36,49 diffuse pleural thickening and parenchymal CAMTA1 or TFE3 has never been observed in angio- nodule/mass with pleural invasion which simulates malig- sarcoma.34 Pseudomyogenic hemangioendothelioma (PE) is nant pleural mesothelioma50 (Figure 4). Sometimes pul- another differential diagnosis. By difference to EHE, PE monary nodules may exhibit a surrounding ground glass shows in most cases spindled cytomorphology, rather than halo similar in morphology to pulmonary metastatic epithelioid, and lacks cytoplasmic vacuoles.35 While sharing angiosarcoma. Patients with diffuse pleural thickening and expression of endothelial antigens with EHE, in contrast to effusion seem to have a poor prognosis.19,50 EHE, pseudomyogenic hemangioendothelioma typically ex- When EHE involves bones, the axial skeleton and lower presses FOSB due to FOSB-related fusion and is negative for limbs are the most common sites.51 Bone lesions are pre- CAMTA1 and TFE3.36 dominantly poorly demarcated and lytic, some with a sclerotic rim at initial presentation.5,7 Expansible mixed RADIOLOGY density lesions are also recognized. On MRI, lesions are hypointense on T1 and hyperintense on T2/STIR se- Baseline staging for EHE consists of whole-body imaging quences.37,40 Hemangiomas can be distinguished from EHE including the brain, by computed tomography (CT) or on CT as they appear as well-defined lucent lesions con- magnetic resonance imaging (MRI), or the combinations of both modalities (e.g. chest CT and abdominal/whole-body taining high-density rounded foci which correspond to thickened vertical trabeculae mixed with low attenuation MRI) [V, A]. A whole-body MRI, or whole-body [18F]-fluo- fat. On MRI, the majority of asymptomatic hemangiomas rodeoxyglucose (FDG)-PET/CT (including limbs) depending also have characteristic imaging features and exhibit high on locally available resources, is advisable to detect bone signal intensity on T1- and T2-weighted images owing to the and limb involvement. If whole-body MRI or PET/CT are presence of fat. However, extraspinal hemangiomas are less unavailable, a bone scan is recommended to exclude bone characteristic and can appear as non-specific, well-defined lesions [V, A]. As a general rule, to monitor the status of the osteolytic lesions without the web-like coarse trabecular disease, any relevant radiological study that is positive at baseline should be repeated while on treatment or pattern.40 The poorly marginated, lytic radiological appearance of angiosarcoma of bone is also non-specific surveillance. and it is not possible to differentiate angiosarcoma of Even in the absence of prospective studies on the bone from EHE on imaging alone.40 radiological assessment of EHE, CT of the chest, abdomen and pelvis is the imaging modality of choice [V, B], because of its wide coverage and optimal assessment of pulmonary Response assessment disease.37 Triple phase imaging of the liver is particularly The definition of radiological progression and the assess- helpful for hepatic involvement. ment of treatment response are a challenge in EHE. The MRI is recommended for the assessment of primary soft occurrence of serosal effusion and of slow-growing variants tissue disease [IV, C] (Figure 2) and should be considered for makes the use of RECIST 1.1 of limited value. Improvement the monitoring of liver and bone involvement and response of serosal effusion, reduction in size <30% and symptom assessments at these sites [IV, B].38-40 Where available, control should be valued in the treatment response whole-body MRI should be considered for detection, assessment. Symptomatic deterioration may not be re- monitoring and response assessment of bone disease flected by radiological changes, particularly for thoracic because of increased sensitivity and wide coverage [IV, B]. disease, therefore assessment of symptoms and QoL are an FDG uptake is usually mild-to-moderate.37,41-43 However, essential component of response assessment. Preliminary patients with higher standardized uptake value (SUV) le- data suggest that changes in SUV on FDG-PET/CT and signal/ sions seem to have significantly worse survival and higher apparent diffusion coefficient (ADC) on MRI can be of help progression rates.41,44 in response assessment. Imaging features and differential diagnosis DIAGNOSIS The presence of multifocal, coalescent hepatic nodules in a Percutaneous core-needle biopsy is recommended [V, A]. peripheral subcapsular location with capsular retrac- Biopsy should be carried out using 14-16-gauge needles tion39,40,45 and a target appearance at portal venous phase with preferred coaxial technique. The biopsy tract should be Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 5 ESMO Open S. Stacchiotti et al. Figure 2. Primary, soft tissue epithelioid hemangioendothelioma (EHE). Contrast-enhanced T1-weighted magnetic resonance imaging (MRI), axial view (A) and contrast-enhanced T1- Spectroscopie Dans le Proche Infrarouge (SPIR)-weighted MRI coronal view (B), showing a classic EHE with an infiltrative growth pattern in the vastus medialis (red circle). Surgical specimen cut along the longitudinal axis showing the macroscopic appearance of the tumor (black circle, C). Contrast-enhanced T1-SPIR-weighted MRI, axial view (D) and coronal view (E), showing a more aggressive EHE with infiltrative growth pattern and necrosis in the anterior aspect of the proximal forearm. Surgical specimen cut along the longitudinal axis showing the macroscopic appearance of the tumor (F). Contrast-enhanced T1-weighted MRI, axial view (G) and coronal view (H) showing a classic EHE with a nodular growth pattern in the medial aspect of the arm arising from the brachial vessels. Surgical specimen cut along the axial axis, showing the macroscopic appearance of the tumor (I, brachial artery is cannulated by the wire). placed in such a way to be safely removed at the time of procedures, or even isolated limb perfusion (ILP), depend- definitive surgery.52 ing on local/institutional expertise/policies [V, A]. Given the possible curative impact of local treatments and the risk of locoregional and/or systemic progression of TREATMENT EHE, at this state of knowledge, a prolonged watchful waiting policy for unifocal EHE is not suggested [V, A]. Active Surgery surveillance should be considered only for patients who are The treatment of choice for confirmed unifocal EHE (most not surgical candidates due to the presence of comorbid- often located in soft tissue) is surgery [II, A]. Resection ities or technical challenges.2,5,9,57 [V, A]. should be carried out in referral centers with experience in On the contrary, active surveillance is the initial recom- sarcoma surgery.53-56 mended option in cases presenting with asymptomatic The primary aim of surgery is the complete resection of locoregional or systemic metastases53 [V, A]. EHE with microscopic negative (R0) margins, with an ex- Prolonged disease stability and occasional regression pected cure rate of 70%-80%.5 However, the inherent have been reported.58 Although active surveillance has contribution of surgery to prognosis in this group is difficult never been formally studied, it is common practice in to determine, as the tendency to progress in the individual experienced centers to keep asymptomatic patients on case cannot be (reliably) predicted. Surgery can be com- active surveillance before engaging in treatment, including plemented with radiation therapy (RT) when R1 excisions surgery.2,5,9,53 occur [V, A]. When severe morbidity is anticipated or a macroscopic complete resection (R0/R1) is not possible, EHE of soft tissue and bone. Extent of resection should be surgery can be substituted by definitive RT, or ablative carried out according to the principles of sarcoma surgery. 6 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021 S. Stacchiotti et al. ESMO Open Figure 3. Thoracic epithelioid hemangioendothelioma (EHE). (A) Computed tomography (CT) scan of the chest, lung window, axial view, showing solid pulmonary nodules in both lungs (red arrows). (B) CT scan of the chest, lung window, axial view, showing multifocal areas of reticulonodular pattern in both lungs (red arrows). (C) Contrast enhanced CT scan of the chest, venous phase, soft tissue window, axial view, showing diffuse pleural involvement (red arrow) with mediastinal shift. (D) CT scan of the chest, lung window, axial view, showing pleural thickening (yellow arrow) and parenchymal lesions (red arrows). For soft tissue EHE, the mass should be resected en bloc. morbidity, patient symptoms and availability of alternative Resection should encompass the biopsy tract, and R0 local therapies, such as ILP, ablation procedures and/or margins should be obtained by leaving a cuff of normal RT.53,57 tissue all around the tumor surface, to minimize the risk of local recurrence (LR). For bony EHE, resection should aim at EHE of liver. Treatment of hepatic EHE should take into R0 margins with en bloc resection of the bone of origin and consideration the anatomical location within the liver, tu- of the involved soft tissues. Surgical curettage of the bone mor size, number of nodules, the presence of vascular in- with adjuvant or definitive RT in recurrent or metastasized vasion and the presence of extrahepatic disease. patients, or both, can be considered if surgical resection is After a short period of observation to assess the bio- not an option.34,52 logical behavior of EHE, surgical resection is considered the Amputation should be discouraged in patients who can treatment of choice for stable/slowly progressing unifocal be treated with a combination of surgical procedures, or limited locoregional disease that is technically resectable locoregional treatments and/or adjuvant RT, provided the [IV, B]. The goal is a complete resection of the tumor with limb remains functional after multimodality treatment. R0 margins. Based on the limited literature available, he- In angiocentric tumors, the vessel of origin should be patic resections provide cure in at least 50% of pa- resected en bloc with the mass. The need for vascular tients.44,59-63 However, none of the studies contained reconstruction depends on the vessel type (artery versus information of the pace of disease growth before surgery. vein), site and presence of collateral pathways. After venous In selected patients with unresectable hepatic EHE and resection, the vein is usually reconstructed if originally no extrahepatic disease, LT provides short- and long-term patent and in the absence of collateral pathways; other- outcomes comparable to patients with other indications. wise, ligation without reconstruction is acceptable. After Specifically, LT has been associated with a 5-year post-LT arterial resection, the artery is usually reconstructed. Pre- survival rate in excess of 50%.59,61 Similarly to the evi- operative RT is preferred to avoid irradiation of the vascular dence available for hepatic resections, none of the studies graft. Musculocutaneous flaps are frequently necessary to provided information on the pace of disease before LT. It is cover the defect and the vascular graft. well known that multifocal hepatic EHE can remain stable The role of surgery in metastatic EHE of bone is unknown, for many years without active treatment. On this basis, after but in the absence of alternative treatments, if feasible, full disclosure about the limitations of the current literature, surgery is an option. Such decisions should be individualized LT should be proposed as a treatment modality for patients and take into consideration the pattern of tumor progres- with unresectable EHE [IV, B]. LT is also an option for pa- sion, fracture risk, site and number of lesions, expected tients with liver-only EHE who develop liver failure due to Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 7 ESMO Open S. Stacchiotti et al. Figure 4. Hepatic epithelioid hemangioendothelioma (EHE). (A) T2-weighted magnetic resonance imaging of the abdomen, axial view, showing hepatic lesions with a target sign (red arrow). (B) Contrast enhanced computed tomography (CT) scan of the abdomen, portal phase, axial view, showing multiple peripheral low attenuation hepatic lesions. (C) Contrast enhanced CT scan of the abdomen, portal phase, axial view, showing multiple peripheral low attenuation hepatic lesions and capsular retraction (red arrow). the tumor, but who are in generally good condition, with an pleural involvement is associated with a worse expected good survival after LT. prognosis.2,5,21 The median survival in a study of 149 patients after LT Among four different thoracic involvement types, the was 7.6 years. It is unclear, however, to which extent this is lung multinodular pattern is associated with a longer sur- due to the natural history of stable EHE cases or, in part, to vival, whereas the shortest survival is observed in cases the impact of the complete removal of EHE by the with a nodule/mass with pleural involvement. There ap- replacement of the liver. Risk factors for post-LT recurrence pears to be no significant difference in survival between include tumor rupture, macrovascular invasion and the thoracic EHE and non-thoracic EHE.19 presence of hilar lymph node metastases.44,59-62 History of Surgical resection is the treatment of choice in cases with tumor rupture should be considered a major contraindica- proven unifocal disease or with reasonably limited locore- tion to LT. gional metastases that are technically resectable, after a The role of LT for unresectable locoregional EHE requires period of observation. Procedures such as pleural stripping further studies, as the current evidence is based only on and or pneumonectomy may be considered on an individ- retrospective cohorts with a high risk of selection and ualized basis, balancing the extent of disease and the ex- reporting biases. Therefore, LT is not universally supported pected benefit. Local ablative techniques can also be by all transplant centers. Nevertheless, LT should be considered when EHE involvement is isolated to the lungs considered and should be proposed to patients after full [V, B]. disclosure of the potential benefits and the risks associated with it. LT should not be proposed to patients with liver EHE RT and extrahepatic disease [V, A]. Future studies with a long follow-up should provide data General principles. There is limited evidence evaluating the about the patient population from which the subgroup of role of RT alone in EHE, although EHE is considered rela- transplanted patients has been drawn. tively radiosensitive. The potential role of radiation should Stereotactic body RT (SBRT), radiofrequency ablation be based upon individualized case considerations. This will (RFA) and microwave ablation (MWA) are therapeutic op- primarily depend on the resectability of the tumor and the tions for patients with unifocal disease who are not surgical risk of recurrence and/or the feasibility of further surgery in candidates and for patients with recurrent liver nodules the event of relapse. after liver resection/LT and/or as a bridge to LT (see below) Surgery remains the mainstay of treatment in primary [V, B]. localized, resectable cases. The risk of LR following complete surgical resection is in the range of 10%-15%.64 The role of EHE of the thorax. Thoracic EHEs are predominantly found RT in EHE is based on the principles and management of in association with liver and/or bone EHE.19 The presence of STS. Adjuvant RT to a total dose of 60 Gy in 30 fractions can 8 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021 S. Stacchiotti et al. ESMO Open be recommended in selected cases where margins are close small EHE with curative intent.71,72 Nevertheless, prospec- or positive and there is concern regarding the risk of LR [V, tive confirmatory data are necessary to make any definitive A]. There are no reported cases evaluating the role of pre- recommendations. operative RT for EHE, but following basic STS principles, Prospective data are needed to confirm that TACE is preoperative RT (50 Gy in 25 fractions) for cases of pre- superior to surgical modalities in advanced disease.73 In dicted close or positive surgical margins is reasonable to extrahepatic disease (lymph node, lung, bone) a trend to- consider. For inoperable cases, definitive RT to a total dose ward better survival and a lower morbidity was seen in four in the order of 60 Gy in conventional fractionation has been patients who received TACE compared with five patients recommended65 [V, A]. who underwent resection or LT,73 suggesting that TACE can Responses to RT have been described at a minimum dose be considered as a palliative option in most advanced cases. of 30 Gy in conventional fractionation.66 Depending on the The role of preoperative TACE as an adjunct to LT is not clinical presentation of multifocal or metastatic disease, established and warrants further investigation.71-76 symptoms, disease burden and involved anatomical site, Data on selective internal RT (radioembolization) (SIRT) appropriate radiation doses can range from 30 Gy (in con- are lacking. A single case report described significant ventional fractions) for palliation of symptoms, to a more remission of a multifocal, diffuse, non-resectable EHE 2 radical approach in the order of 60 Gy to obtain durable months after carrying out SIRT, with a single dose of 1.8 control. GBq yttrium-90 (48.6 mCi).77 EHE localized to the extremities can be treated by ILP EHE of bone. Post-operative RT with doses ranging from 40 with tumor necrosis factor (TNF) and melphalan. However, to 60 Gy has been shown to offer excellent local control at 2 while there is a uniform belief of high activity of this years in skeletal EHE.67 Albakr et al.67 summarized a series treatment in EHE, there are no published data reported to of 32 publications describing the management of spinal confirm this.57 It remains unclear whether surgery should EHE. RT intent for these series ranged from adjuvant RT, be carried out to resect residual disease post ILP, or primary RT for inoperable disease and palliation. Adjuvant whether patients should continue active surveillance, dosing of 60 Gy using conventional fractionation has been delaying further treatments to the time of progression. reported to provide effective disease control.68,69 Single- fraction high-dose intensity-modulated RT may be indi- cated in solitary bony lesions. Systemic treatment EHE of liver. Local ablative techniques including SBRT, RFA In patients with localized, resectable EHE there is no evi- and MWA, as described below, can be considered in unre- dence supporting the use of systemic therapies in the (neo) sectable unifocal disease or oligometastatic disease. The adjuvant setting [V, D]. most suitable ablative technique is best determined by a For patients with asymptomatic metastatic disease that is multimodality team and is based on such factors as size and not amenable to complete resection with acceptable anatomical location of the lesion (e.g. proximity to vessel or morbidity, active surveillance is the upfront preferred bowel). approach [V, B]. In this scenario, the risk of over-treatment SBRT delivers very high (ablative) radiation doses over a appears to outweigh the damage of a delayed treatment few fractions with high precision and using small margins. It start. can be considered in suitable cases at prescribed doses as Patients with serosal effusion and/or marked systemic for other STS when other treatment options are not symptoms tend to have a rapidly progressive course, indicated.70 therefore in this case, an early start of systemic therapy should be considered [IV, B]. EHE of the lung. Pulmonary EHE commonly manifests as Patients with metastatic disease and unequivocal evi- multifocal disease. In this case, RT is generally considered dence of disease progression and/or worsening of symp- only for palliation.62,63 SBRT can be considered in the toms and/or organ dysfunction are candidates for systemic setting of oligometastatic disease delivering doses treatment, even though a standard medical approach is employed for STS. currently not established. Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2021.100170 summa- rizes the data available on systemic agents in EHE, including Other locoregional treatments all reports published from 1999 to 2020 including at least Data on locoregional treatments as an alternative to surgery five patients. Conventional chemotherapy available for STS and/or RT in EHE are limited and only retrospective and do appears to have very limited activity [V, D] and should be not allow definitive conclusions on the specific role of any limited to more aggressive or rapidly progressive cases, of these approaches. They include percutaneous ablation, behaving as high-grade STS.78 Participation in clinical trials transarterial chemoembolization (TACE), radioembolization is encouraged. and ILP. No data are available on other local therapies such Antitumor activity has been seen retrospectively with as high-intensity focused ultrasound in EHE. interferon79,80 [V, C], thalidomide81 [V, C] multi-tyrosine ki- Retrospective data suggest that percutaneous ablation nase inhibitors [usually with a strong vascular endothelial (RFA/MWA) can be safe and useful to treat a single and growth factor receptor (VEGFR) inhibitory property]9,82-88 Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 9 ESMO Open S. Stacchiotti et al. [III, B] and mechanistic target of rapamycin (mTOR) in- nonsteroidal anti-inflammatory drugs (NSAIDs), neuropathic hibitors17,81,89-91 [IV, B]. Among them, the highest clinical pain medications such as gabapentin, when indicated95 and activity has been reported for mTOR inhibitors, with a opioids81 with consideration for opioid rotation in case of progression-free survival (PFS) and overall survival in the tolerance or adverse effects to escalating doses [V, B].96 range of 1 year and 2 years, respectively, and w10% of Pain related to EHE can be severe, with spontaneous patients having even longer PFS. The panel agrees that flares that are difficult to treat with opioids and electively these represent the preferred treatment options for pa- sensitive to NSAIDs.93 Anesthesiologists’ and pain special- tients with advanced and moderately progressive disease. ists’ expertise may be needed when interventional pro- No formal prospective comparison, however, has been cedures are considered. Localized surgical and RT can be carried out and selection of drugs should factor in comor- necessary for pain management of symptomatic lesions. bidities as well as patient preferences. New pharmacological strategies would be of great benefit. As with other ultra-rare cancers, as far as reimbursement is concerned, in many countries EHEs are merged with more FOLLOW-UP common sarcomas, even though most trials that led to There are no data to indicate the optimal length and fre- approval of drugs commonly used in sarcomas have never quency for follow-up of EHE patients treated with complete included patients with EHE.3 The use of off-label drugs may surgical resection. Currently, routine follow-up schedules be substantially limited. We strongly advocate treatments differ across institutions. An MRI of the primary tumor site for EHE based on the best available clinical evidence, even and a whole-body CT scan can be suggested every 6 months though the best evidence is limited to small trials and case for the first 4 to 5 years after diagnosis. Thereafter, if no series. disease progression is observed, MRI and whole-body CT EHE patients should be considered for clinical studies scans could be done yearly [V, B]. when available. Based on unpublished preclinical work suggesting the CAMTA1 fusion leads to overexpression of FUTURE PROSPECTIVE growth factors that may activate the methyl ethyl ketone There are several unmet needs that require clinical studies (MEK) signaling pathway, the MEK-inhibitor trametinib is in EHE. Given the rarity of the condition, it is almost inev- currently under investigation in the disease. In addition, itable that these trials have to be uncontrolled. The main also eribulin, that is a mitotic inhibitor, is under assessment challenge for uncontrolled studies is the unpredictable in patients with EHE within a clinical study currently behavior of EHE, characterized by stability for many years in ongoing in the US. Ongoing efforts are trying to clarify the a significant proportion of patients. For that reason, patient role of hormonal stimulation and inflammation in EHE registries should be encouraged, to generate external con- pathogenesis, with the aim of possibly identifying new trols for uncontrolled studies. Uncontrolled studies, case treatment targets. series analyses and even case reports with all the caveats mentioned above all contribute to the available evidence. Palliative care Global collaboration will be critical to advance our knowl- edge, including a better definition of QoL for EHE patients, Palliative care should be an integral part of the care of EHE collection of prospective data and understanding the role of patients.92 Early palliative care referral can be particularly LT in isolated multifocal liver EHE. useful for symptomatic patients and those with serosal effusion.9,93 Identifying clinical and psychosocial support ACKNOWLEDGEMENTS needs for patients and their family caregivers as early as We thank the European Society for Medical Oncology possible across the changing pattern of the disease is crucial (ESMO) for their invaluable support to the consensus and requires an interdisciplinary palliative care approach and research efforts.94 Systematic symptom screening and building process, without which this effort would not have been possible. We are also deeply grateful to the Epithelioid assessment should be formally present in clinical records Hemangioendothelioma (EHE) Group for inspiring and and registries. helping to spearhead this international consensus-building EHE pain pathophysiology is not well understood. effort. Constitutional symptoms may be related to cytokine release from the tumor, which may also be responsible for FUNDING increasing local nociceptive mechanisms and justifying relative opioid resistance.9,21 This observation requires None declared. specific research efforts. Some aspects of palliative care for EHE can be chal- DISCLOSURE lenging, such as predicting the response to analgesia.94 SS: Honoraria, consultancy or advisory role: Adaptimmune, General palliative care principles apply and criteria for Bayer, Daiichi Sankyo, Deciphera, Epizyme, Eli Lilly, Glaxo, referral to specialized palliative care should be personal- Immune Design, Karyopharm, MaxiVAX, Novartis, Pharma- ized92,94 (Supplementary Table S3, available at https://doi. Mar; Institutional financial interests: Advenchen, Amgen org/10.1016/j.esmoop.2021.100170). Pain management Dompè, Bayer, Epizyme, Eli Lilly, Daiichi Sankyo, Glaxo, should follow state-of-the-art multimodal approaches, using Hutchison MediPharma, Karyopharm, Novartis, Pfizer, 10 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021 S. Stacchiotti et al. ESMO Open PharmaMar, SpringWorks. AMF: Institutional financial in- Pharma and Sartar Therapeutics. RJ: Advisory board Adap- terests: Advenchen, Amgen Dompè, Bayer, Epizyme, Eli Lilly, timmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Daiichi Sankyo, Glaxo, Hutchison MediPharma, Karyopharm, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immune Design, Novartis, Pfizer, PharmaMar, SpringWorks. AC: Advisory Lilly, Merck, PharmaMar, SpringWorks, TRACON, UptoDate; board: Angelini Holding S.p.A, Shionogi B.V., L. Molteni & C., honoraria: BMS, MSD, Novartis, Pierre Fabre, Merck, Sanofi. Kyowa Kirin S.r.l.; invited speaker King Faisal Specialist CJ: Travel grants from PharmaMar, Ipsen. BK: Reports Hospital & Research Center. JB: Uncompensated advisory advisory board Bayer, Blueprint, Boehringer Ingelheim, GSK, board: Novartis; research funding (institutional) from Eli PharmaMar, SpringWorks; research funding (institutional) Lilly, Novartis, Roche, Samsung Bioepis Co. Ltd, Paxman PharmaMar, SpringWorks. AK: Advisory board Otsuka; Coolers Ltd, Sun Pharma. SB: Personal fees from Bayer, invited speaker for Daiichi Sankyo, Eisai, Eli Lilly, Novartis, Deciphera, Lilly, Daiichi Sankyo, Plexxikon, Exelixis, Phar- Taiho. ALC: Advisory boards with Lilly, PharmaMar, Deci- maMar, Lilly, Roche, GlaxoSmithKline (GSK); grants from phera, Blueprint. AL: Reports institutional financial interest, Incyte, grants and personal fees from Blueprint Medicines, and educational grant from Alphamed, ImplanTec, Johnson Novartis; research funding (institutional) Pfizer. SB: & Johnson, Medacta. JMB: Research grants from Pharma- Research support from Novartis, Incyte, Blueprint Medi- Mar, Eisai, Immix BioPharma and Novartis; honoraria from cines; honoraria or consultation fees from Novartis, Lilly, PharmaMar, Lilly, Bayer, Eisai, Daichii. Travel grants from Pfizer, PharmaMar, Bayer. JYB: Research support and hon- PharmaMar; advisory board: Roche, Lilly, PharmaMar; oraria from Bristol-Myers Squibb (BMS), Merck Sharp & research funding for clinical studies (institutional) from Dohme (MSD), Roche, Bayer, Novartis, GSK, Deciphera, OSE PharmaMar, Eli Lilly and Company, Adaptimmune Thera- Pharma, AstraZeneca. Member of the supervisory board: peutics, AROG, Bayer, Eisai, Lixte, Karyopharm, Deciphera, Innate Pharma. SB: Honoraria from PharmaMar. JVMGB: GSK, Novartis, Blueprint, Nektar, Forma, Amgen, Celgene, Research funding from TRACON Pharmaceuticals; Royalties Pfizer, BMS, and Daiichi Sankyo. OMe: Consultation fees from UptoDate and Wolters Kluwer. KB: Advisory: Bayer; from MSD, AstraZeneca, Takeda, Megapharm, Medison, expert testimony: Bayer; invited speaker: Lilly; institutional Progenetics; supported lecture: MSD, AstraZeneca, Roche, research funding: Lilly. TB: Advisory board from Bayer; BMS. OMi: Consultancy for Amgen, AstraZeneca, Bayer, honoraria: Novartis, PharmaMar, Eli Lilly. ME: Consultant for BMS, Eli Lilly, Ipsen, Lundbeck, MSD, Novartis, Pfizer, Roche, Blueprint Medicines; advisory boards for Clinigen and Bayer. Servier, Vifor Pharma; Speakers bureau: Eli Lilly, Roche, AF; Honoraria: Amgen, Lilly, Roche, MSD; research funding; Servier; Stock ownership: Amplitude Surgical, Ipsen, Trans- MSD, Roche, Clovis, AstraZeneca. BMS; Abbvie. VF: gene. EP: Advisory boards for Amgen, Daiichi Sankyo, Lilly, Consulting or advisory role: BMS, MSD, Novartis; speakers’ Deciphera, EUSA Pharma, and SynOx Therapeutics; research bureau: BMS, MSD, Novartis, Pierre Fabre. XGdM: Advisory support from BMS, Pfizer, PharmaMar, Daiichi Sankyo, boards for Ipsen, EUSA Pharma, BMS, Pfizer, Roche, Phar- Incyte; travel support from Lilly, PharmaMar and Takeda. maMar; honoraria from Lilly, Astellas Pharma, Eisai, Pfizer. MAP: Advisory board Lilly, Pfizer, Roche. SP: Consultant: HG: Reports institutional funding from Novartis, Deciphera. Deciphera, Daichi Sankyo, Dova, Epizyme, MaxiVAX; FG: Honoraria from Deciphera, Amgen; stock ownership Research/Grant Support: Blueprint Medicines, Hutchison from Atlanthera; royalties from Zimmer. GG: Grants/ MediPharma. SPN: Advisory board for Immunocore. AR: research supports: PharmaMar, Novartis, Bayer; honoraria Consulting role with Lilly, Merck, Boehringer Ingelheim; or consultation fees: PharmaMar, Bayer, Merck, Eisai, research funding from CASI Pharmaceuticals, Boehringer Novartis, Glaxo. NH: Research grants from PharmaMar, Ingelheim, Lilly, Novartis, Deciphera, Karyopharm Thera- Eisai, Immix BioPharma and Novartis; honoraria and travel peutics, Pfizer, Roche/Genentech, Boston Biomedical, BMS, grants from PharmaMar; and research funding for clinical MedImmune, Amgen, GSK, Blueprint Medicines, Merck, studies (institutional) from PharmaMar, Eli Lilly and Com- AbbVie, Adaptimmune. PRe: Advisory roles for Bayer, pany, Adaptimmune Therapeutics, AROG, Bayer, Eisai, Lixte, Clinigen, Roche, MSD, Deciphera, PharmaMar, Mundibio- Karyopharm, Deciphera, GSK, Novartis, Blueprint, Nektar, pharma, and speaker’s honoraria from Lilly, PharmaMar. Forma, Amgen and Daiichi Sankyo. PH: Honoraria for con- BPR: Reports advisory board from Deciphera. PRu: Advisory sultations and speaker’s fees from Roche, GSK, AstraZeneca, board MSD, BMS, Merck, Sanofi, Pierre Fabre, Blueprint Pfizer, PharmaMar, Lilly, Nanobiotix, Novartis, EISAI, Nektar, Medicines; honoraria from BMS, MSD, Novartis, Pierre Sirtex and Pekkip Oncology; research funding and educa- Fabre, Merck, Sanofi. MS: Travel grant from PharmaMar. tional grants from Novartis, Siemens, Boehringer, Merck, SJS: Advisory boards for Lilly and GSK. WDT: Reports fees BLUMedicine and Springer; trial support to my institution from Eli Lilly, EMD Serono, Eisai, Mundipharma, C4 Thera- by Novartis and Siemens. PH: Advisory roles for Sarcoma UK peutics, Daiichi Sankyo, Blueprint, GSK, Agios Pharmaceu- and National Leiomyosarcoma Foundation; research grants ticals, NanoCarrier, Deciphera; patent Companion from Sarcoma UK, Desmoid Tumor Research Foundation, Diagnostic for CDK4 inhibitors - 14/854 329 pending to Children’s Cancer and Leukemia Group and Cancer Research MSKCC/SKI, and patent Enigma and CDH18 as companion UK, funding from EHE Rare Cancer Charity (UK). HJ: Chair of Diagnostics for CDK4 inhibition e SKI2016-021-03 pending to the Orion Pharma Scientific Advisory Board, chair of MSKCC/SKI and Scientific Advisory Board - Certis Oncology Neutron Therapeutics Advisory Board; he has been Solutions, Stock Ownership Üo-Founder - Atropos Thera- employed by Orion Pharma, and owns stocks of Orion peutics; Stock Ownership/scientific advisory board Innova Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 11 ESMO Open S. Stacchiotti et al. Therapeutics. WTAWDG: Reports consultancy from Spring- a proposal of risk stratification and identification of a synaptophysin- Works to her institute; research grant support from Novartis positive aggressive subset. Am J Surg Pathol. 2021;45:616-626. 15. Antonescu CR, Le Loarer F, Mosquera JM, et al. Novel YAP1-TFE3 and Lilly to her institute; advisory for Bayer to her institute. fusion defines a distinct subset of epithelioid hemangioendothelioma. AJW: Consulting: Daiichi Sankyo, Deciphera, Epizyme, Mun- Genes Chromosomes Cancer. 2013;52:775-784. dipharma; research support to my Institution: Aadi Biosci- 16. Mentzel T, Beham A, Calonje E, Katenkamp D, Fletcher CD. Epithelioid ence, Daiichi Sankyo, Deciphera, Eli Lilly, Karyopharm, hemangioendothelioma of skin and soft tissues: clinicopathologic and Plexxikon. PGC: Honoraria, consultancy or advisory role: immunohistochemical study of 30 cases. Am J Surg Pathol. 1997;21: 363-374. Bayer, Deciphera, Eisai, Eli Lilly, Pfizer. Institutional financial 17. Bagan P, Hassan M, Le Pimpec Barthes F, et al. Prognostic factors interest: Advenchen Laboratories, Amgen Dompé, AROG and surgical indications of pulmonary epithelioid hemangioendo- Pharmaceuticals, Bayer, Blueprint Medicines, Daiichi Sankyo, thelioma: a review of the literature. Ann Thorac Surg. 2006;82: Deciphera, Eisai, Eli Lilly, Epizyme, Glaxo, Hutchinson Medi- 2010-2013. Pharma, Karyopharm, Novartis, Pfizer, PharmaMar. APDT: 18. Woo JH, Kim TJ, Lee KS, Kim TS, Kim BT. Epithelioid hemangioendo- thelioma in the thorax: clinicopathologic, CT, PET, and prognostic fea- Honoraria: Roche, Bayer, Pharmamar, MSD. AG: Compensa- tures. Medicine (Baltimore). 2016;95(30):e4348. tions for Advisory boards from Novartis, Pfizer, Bayer, Lilly, 19. Stacchiotti S, Simeone N, Lo Vullo S, et al. Activity of sirolimus in pa- PharmaMar, SpringWorks, Nanobiotix; honoraria from Lilly tients with progressive epithelioid hemangioendothelioma: a case- and PharmaMar; institutional research grants from Pharma- series analysis within the Italian rare cancer network. Cancer. Mar. All other authors have declared no conflicts of interest. 2021;127:569-576. 20. Amin RM, Hiroshima K, Kokubo T, et al. Risk factors and independent predictors of survival in patients with pulmonary epithelioid hae- REFERENCES mangioendothelioma. Review of the literature and a case report. 1. Dykewicz CA, Centers for Disease Control and Prevention (U.S.), In- Respirology. 2006;11:818-825. fectious Diseases Society of America, American Society of Blood and 21. Frezza AM, Napolitano A, Miceli R, et al. Clinical prognostic factors in Marrow Transplantation. Summary of the guidelines for preventing advanced epithelioid haemangioendothelioma: a retrospective series opportunistic infections among hematopoietic stem cell transplant within the Italian Rare Cancers Network. ESMO open. 2021;6:100083. recipients. Clin Infect Dis. 2001;33:139-144 (Adapted from: Gross PA, 22. Yazigi A, Lecointe-Artzner E, Cesne AL, Ray-Coquard I, Blay JY. Preg- Barrett TL, Dellinger EP, et al. Purpose of quality standards for infec- nancy in women with metastatic sarcomas. Oncologist. 2020;25:e2010- tious diseases. Clin Infect Dis.1994;18:421). e2012. 2. Lau K, Massad M, Pollak C, et al. Clinical patterns and outcome in 23. Blay JY, Soibinet P, Penel N, et al. Improved survival using specialized epithelioid hemangioendothelioma with or without pulmonary multidisciplinary board in sarcoma patients. Ann Oncol. 2017;28:2852- involvement: insights from an internet registry in the study of a rare 2859. cancer. Chest. 2011;140:1312-1318. 24. Errani C, Zhang L, Sung YS, et al. A novel WWTR1-CAMTA1 gene fusion 3. Stacchiotti S, Frezza AM, Blay JY, et al. Ultra-rare sarcomas: a consensus is a consistent abnormality in epithelioid hemangioendothelioma of paper from the Connective Tissue Oncology Society community of different anatomic sites. Genes Chromosomes Cancer. 2011;50:644- experts on the incidence threshold and the list of entities. Cancer. 653. 2021. https://doi.org/10.1002/cncr.33618. 25. Suurmeijer AJH, Dickson BC, Swanson D, et al. Variant WWTR1 gene 4. De Pinieux G, Karanian M, Le Loarer F, et al. Nationwide incidence of fusions in epithelioid hemangioendothelioma-A genetic subset asso- sarcomas and connective tissue tumors of intermediate malignancy ciated with cardiac involvement. Genes Chromosomes Cancer. 2020;59: over four years using an expert pathology review network. PLoS One. 389-395. 2021;16:e0246958. 26. Folpe AL, Chand EM, Goldblum JR, Weiss SW. Expression of Fli-1, a 5. Rosenbaum E, Jadeja B, Xu B, et al. Prognostic stratification of clinical nuclear transcription factor, distinguishes vascular neoplasms from and molecular epithelioid hemangioendothelioma subsets. Mod potential mimics. Am J Surg Pathol. 2001;25:1061-1066. Pathol. 2020;33:591-602. 27. Rossi S, Orvieto E, Furlanetto A, Laurino L, Ninfo V, Dei Tos AP. Utility of 6. Guo Q, Xue J, Xu L, Shi Z, Zhou B. The clinical features of epithelioid the immunohistochemical detection of FLI-1 expression in round cell hemangioendothelioma in a Han Chinese population: a retrospective and vascular neoplasm using a monoclonal antibody. Mod Pathol. analysis. Medicine (Baltimore). 2017;96(26):e7345. 2004;17:547-552. 7. Flucke U, Vogels RJ, de Saint Aubain Somerhausen N, et al. Epithelioid 28. Miettinen M, Fetsch JF. Distribution of keratins in normal endothelial hemangioendothelioma: clinicopathologic, immunhistochemical, and cells and a spectrum of vascular tumors: implications in tumor diag- molecular genetic analysis of 39 cases. Diagn Pathol. 2014;9:131. nosis. Hum Pathol. 2000;31:1062-1067. 8. Chavhan GB, Siddiqui I, Ingley KM, Gupta AA. Rare malignant liver 29. Doyle LA, Fletcher CD, Hornick JL. Nuclear expression of CAMTA1 tumors in children. Pediatr Radiol. 2019;49:1404-1421. distinguishes epithelioid hemangioendothelioma from histologic 9. Shiba S, Imaoka H, Shioji K, et al. Clinical characteristics of Japanese mimics. Am J Surg Pathol. 2016;40:94-102. patients with epithelioid hemangioendothelioma: a multicenter 30. Tanas MR, Sboner A, Oliveira AM, et al. Identification of a disease- retrospective study. BMC Cancer. 2018;18:993. defining gene fusion in epithelioid hemangioendothelioma. Sci Transl 10. Papke DJ Jr, Hornick JL. What is new in endothelial neoplasia? Virchows Med. 2011;3(98):98ra82. Arch. 2020;476:17-28. 31. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human 11. Wu X, Li B, Zheng C, Hong T, He X. Clinical characteristics of epithelioid cancer. Nat Rev Cancer. 2013;13:246-257. hemangioendothelioma: a single-center retrospective study. Eur J Med 32. Tanas MR, Ma S, Jadaan FO, et al. Mechanism of action of a Res. 2019;24(1):16. WWTR1(TAZ)-CAMTA1 fusion oncoprotein. Oncogene. 2016;35:929- 12. Errani C, Sung YS, Zhang L, Healey JH, Antonescu CR. Monoclonality of 938. multifocal epithelioid hemangioendothelioma of the liver by analysis 33. Hornick JL, Dal Cin P, Fletcher CD. Loss of INI1 expression is charac- of WWTR1-CAMTA1 breakpoints. Cancer Genet. 2012;205:12-17. teristic of both conventional and proximal-type epithelioid sarcoma. 13. Deyrup AT, Tighiouart M, Montag AG, Weiss SW. Epithelioid heman- Am J Surg Pathol. 2009;33:542-550. gioendothelioma of soft tissue: a proposal for risk stratification based 34. Righi A, Sbaraglia M, Gambarotti M, et al. Primary vascular tumors of on 49 cases. Am J Surg Pathol. 2008;32:924-927. bone: a monoinstitutional morphologic and molecular analysis of 427 14. Shibayama T, Makise N, Motoi T, et al. Clinicopathologic character- cases with emphasis on epithelioid variants. Am J Surg Pathol. ization of epithelioid hemangioendothelioma in a series of 62 cases: 2020;44:1192-1203. 12 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021 S. Stacchiotti et al. ESMO Open 35. Hornick JL, Fletcher CDM. Pseudomyogenic hemangioendothelioma: a future directions. A survey of experts and a review of literature. Cancer distinctive, often multicentric tumor with indolent behavior. Am J Surg Treat Rev. 2020;88:102058. Pathol. 2011;35:190-201. 58. Kitaichi M, Nagai S, Nishimura K, et al. Pulmonary epithelioid hae- 36. Hung YP, Fletcher CDM, Hornick JL. FOSB is a useful diagnostic marker mangioendothelioma in 21 patients, including three with partial for pseudomyogenic hemangioendothelioma. Am J Surg Pathol. spontaneous regression. Eur Respir J. 1998;12:89-96. 2017;41:596-606. 59. Brahmbhatt M, Prenner S, Bittermann T. Liver transplantation for he- 37. Epelboym Y, Engelkemier DR, Thomas-Chausse F, et al. Imaging findings patic epithelioid hemangioendothelioma is facilitated by exception in epithelioid hemangioendothelioma. Clin Imaging. 2019;58:59-65. points with acceptable long-term outcomes. Transplantation. 38. Paolantonio P, Laghi A, Vanzulli A, et al. MRI of hepatic epithelioid 2020;104:1187-1192. hemangioendothelioma (HEH). J Magn Reson Imaging. 2014;40:552- 60. Lai Q, Feys E, Karam V, et al. European Liver Intestine Transplant As- 558. sociation (ELITA). Hepatic epithelioid hemangioendothelioma and 39. Kim EH, Rha SE, Lee YJ, Yoo IeR, Jung ES, Byun JY. CT and MR imaging adult liver transplantation: proposal for a prognostic score based on findings of hepatic epithelioid hemangioendotheliomas: emphasis on the analysis of the ELTR-ELITA registry. Transplantation. 2017;101:555- single nodular type. Abdom Imaging. 2015;40:500-509. 564. 40. Errani C, Vanel D, Gambarotti M, Alberghini M, Picci P, Faldini C. 61. Rodriguez JA, Becker NS, O’Mahony CA, Goss JA, Aloia TA. Long-term Vascular bone tumors: a proposal of a classification based on clinico- outcomes following liver transplantation for hepatic hemangioendo- pathological, radiographic and genetic features. Skeletal Radiol. thelioma: the UNOS experience from 1987 to 2005. J Gastrointest Surg. 2012;41:1495-1507. 2008;12:110-116. 41. Wang W, Liu G, Hu P, et al. Imaging characteristics and prognostic 62. Lerut JP, Orlando G, Adam R, et al. The place of liver transplantation in values of hepatic epithelioid hemangioendothelioma on (18)F-FDG the treatment of hepatic epitheloid hemangioendothelioma: report of PET/CT. Clin Exp Med. 2020;20:557-567. the European liver transplant registry. Ann Surg. 2007;246:949-957. 42. Lin E, Agoff N. Recurrent hepatic epithelioid hemangioendothelioma: 63. Konstantinidis IT, Nota C, Jutric Z, et al. Primary liver sarcomas in the detection by FDG PET/CT. Clin Nucl Med. 2007;32:949-951. modern era: resection or transplantation? J Surg Oncol. 2018;117:886- 43. Dong A, Dong H, Wang Y, Gong J, Lu J, Zuo C. MRI and FDG PET/CT 891. findings of hepatic epithelioid hemangioendothelioma. Clin Nucl Med. 64. Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular 2013;38:e66-e73. tumor often mistaken for a carcinoma. Cancer. 1982;50:970-981. 44. Mehrabi A, Kashfi A, Fonouni H, et al. Primary malignant hepatic 65. Sardaro A, Bardoscia L, Petruzzelli MF, Portaluri M. Epithelioid epithelioid hemangioendothelioma: a comprehensive review of the hemangioendothelioma: an overview and update on a rare vascular literature with emphasis on the surgical therapy. Cancer. 2006;107: tumor. Oncol Rev. 2014;8:259. 2108-2121. 66. Sybert DR, Steffee AD, Keppler L, Biscup RS, Enker P. Seven-year follow- 45. Miller WJ, Dodd GD, Federle MP, Baron RL. Epithelioid hemangioen- up of vertebral excision and reconstruction for malignant heman- dothelioma of the liver: imaging findings with pathologic correlation. gioendothelioma of bone. Spine (Phila Pa 1976). 1995;20:841-844. AJR Am J Roentgenol. 1992;159:53-57. 67. Albakr A, Schell M, Drew B, Cenic A. Epithelioid hemangioendothe- 46. Ganeshan D, Pickhardt PJ, Morani AC, et al. Hepatic hemangioendo- lioma of the spine: case report and review of the literature. J Spine thelioma: CT, MR, and FDG-PET-CT in 67 patientsda bi-institutional Surg. 2017;3:250-259. comprehensive cancer center review. Eur Radiol. 2020;30:2435-2442. 68. Yim K-L, Sumathi VP, Spooner D. Radiotherapy as an effective primary 47. Lyburn ID, Torreggiani WC, Harris AC, et al. Hepatic epithelioid treatment for epithelioid haemangioendothelioma of the cervical hemangioendothelioma: sonographic, CT, and MR imaging appear- spine. Anticancer Res. 2012;32:4597-4600. ances. AJR Am J Roentgenol. 2003;180:1359-1364. 69. Themistocleous GS, Papagelopoulos PJ, Petraki KD, Stilianessi EV, 48. Alomari AI. The lollipop sign: a new cross-sectional sign of hepatic Partsinevelos AA, Sapkas GS. A 23-year-old woman with complete epithelioid hemangioendothelioma. Eur J Radiol. 2006;59:460-464. paraplegia and anesthesia below the T8 level. Clin Orthop Relat Res. 49. Kim EY, Kim TS, Han J, Choi JY, Kwon OJ, Kim J. Thoracic epithelioid 2005;430:258-265. hemangioendothelioma: imaging and pathologic features. Acta Radiol. 70. Hoyer M, Swaminath A, Bydder S, et al. Radiotherapy for liver me- 2011;52:161-166. tastases: a review of evidence. Int J Radiat Oncol Biol Phys. 2012;82: 50. Bahrami A, Allen TC, Cagle PT. Pulmonary epithelioid hemangioendo- 1047-1057. thelioma mimicking mesothelioma. Pathol Int. 2008;58:730-734. 71. Kamarajah SK, Robinson D, Littler P, White SA. Incidental hepatic 51. Ignacio EA, Palmer KM, Mathur SC, Schwartz AM, Olan WJ. Epithelioid epithelioid haemangioendothelioma the role of ablative therapy in hemangioendothelioma of the lower extremity. Radiographics. borderline patients. J Surg Case Rep. 2018;2018(8):rjy223. 1999;19:531-537. 72. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation for hepa- 52. Casali PG, Abecassis N, Aro HT, et al. Soft tissue and visceral sarcomas: tocellular carcinoma: 10-year outcome and prognostic factors. Am J ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment Gastroenterol. 2012;107:569-577. and follow-up. Ann Oncol. 2018;29:iv51-iv67. 73. Cardinal J, de Vera ME, Marsh JW, et al. Treatment of hepatic 53. Tong D, Constantinidou A, Engelmann B, et al. The role of local therapy epithelioid hemangioendothelioma. Arch Surg. 2009;144:1035-1039. in multi-focal epithelioid haemangioendothelioma. Anticancer Res. 74. Kou K, Chen YG, Zhou JP, et al. Hepatic epithelioid hemangioendo- 2019;39:4891-4896. thelioma: update on diagnosis and therapy. World J Clin Cases. 2020;8: 54. Lazarides AL, Kerr DL, Nussbaum DP, et al. Soft tissue sarcoma of the 3978-3987. extremities: what is the value of treating at high-volume centers? Clin 75. Weitz J, Klimstra DS, Cymes K, et al. Management of primary liver Orthop Relat Res. 2019;477:718-727. sarcomas. Cancer. 2007;109:1391-1396. 55. Gutierrez JC, Perez EA, Moffat FL, Livingstone AS, Franceschi D, 76. Thomas RM, Aloia TA, Truty MJ, et al. Treatment sequencing strategy Koniaris LG. Should soft tissue sarcomas be treated at high-volume for hepatic epithelioid haemangioendothelioma. HPB (Oxford). centers? An analysis of 4205 patients. Ann Surg. 2007;245:952-958. 2014;16:677-685. 56. Vos M, Blaauwgeers HGT, Ho VKY, et al. Dutch Sarcoma Study Group 77. Bostancı EB, Karaman K, Turhan N, et al. Selective internal radiotherapy (DSSG). Increased survival of non low-grade and deep-seated soft tis- for hepatic epithelioid hemangioendothelioma. Turk J Gastroenterol. sue sarcoma after surgical management in high-volume hospitals: a 2014;25(suppl 1):252-253. nationwide study from the Netherlands. Eur J Cancer. 2019;110:98- 78. Frezza AM, Ravi V, Lo Vullo S, et al. Systemic therapies in advanced 106. epithelioid haemangioendothelioma: a retrospective international case 57. Martin-Tellez KS, van Houdt WJ, van Coevorden F, Colombo C, Fiore M. series from the World Sarcoma Network and a review of literature. Isolated limb perfusion for soft tissue sarcoma: current practices and Cancer Med. 2021;10:2645-2659. Volume 6 - Issue 3 - 2021 https://doi.org/10.1016/j.esmoop.2021.100170 13 ESMO Open S. Stacchiotti et al. 79. Moon SB, Kwon HJ, Park KW, Yun WJ, Jung SE. Clinical experience with 88. Semenisty V, Naroditsky I, Keidar Z, Bar-Sela G. Pazopanib for meta- infantile hepatic hemangioendothelioma. World J Surg. 2009;33:597- static pulmonary epithelioid hemangioendothelioma, a suitable treat- 602. ment option: case report and review of anti-angiogenic treatment 80. Radzikowska E, Szczepulska-Wojcik E, Chabowski M, Oniszh K, options. BMC Cancer. 2015;15:402. Langfort R, Roszkowski K. Pulmonary epithelioid haemangioendothe- 89. Engel ER, Cournoyer E, Adams DM, Stapleton S. A retrospective review lioma, interferon 2-alpha treatment, case report. Pneumonol Alergol of the use of sirolimus for pediatric patients with epithelioid heman- Pol. 2008;76:281-285. gioendothelioma. J Pediatr Hematol Oncol. 2020;42:e826-e829. 81. Soape MP, Verma R, Payne JD, Wachtel M, Hardwicke F, Cobos E. 90. Riou S, Morelon E, Guibaud L, Chotel F, Chotel F, Marec-Berard P. Ef- Treatment of hepatic epithelioid hemangioendothelioma: finding uses ficacy of rapamycin for refractory hemangioendotheliomas in Maf- for thalidomide in a new era of medicine. Case Rep Gastrointest Med. fucci’s syndrome. J Clin Oncol. 2012;30:e213-e215. 2015;2015:326795. 91. Cohen EE, Wu K, Hartford C, et al. Phase I studies of sirolimus alone or 82. Saada E, Saint Paul MC, Gugenheim J, Follana P, François E. Metastatic in combination with pharmacokinetic modulators in advanced cancer hepatic epithelioid hemangio-endothelioma: long-term response to patients. Clin Cancer Res. 2012;18:4785-4793. sunitinib malate. Oncol Res Treat. 2014;37:124-126. 92. Ferrell BR, Temel JS, Temin S, et al. Integration of palliative care into 83. Kollár A, Jones RL, Stacchiotti S, et al. Pazopanib in advanced vascular standard oncology care: American Society of Clinical Oncology Clinical sarcomas: an EORTC Soft Tissue and Bone Sarcoma Group (STBSG) Practice guideline update. J Clin Oncol. 2017;35:96-112. retrospective analysis. Acta Oncol. 2017;56:88-92. 93. Cronin P, Arenberg D. Pulmonary epithelioid hemangioendothelioma: 84. Chevreau C, Le Cesne A, Ray-Coquard I, et al. Sorafenib in patients with an unusual case and a review of the literature. Chest. 2004;125:789- progressive epithelioid hemangioendothelioma: a phase 2 study by the 793. French Sarcoma Group (GSF/GETO). Cancer. 2013;119:2639-2644. 94. Zimmermann C, Ryan S, Hannon B, et al. Team-based outpatient early 85. Agulnik M, Yarber JL, Okuno SH, et al. An open-label, multicenter, palliative care: a complex cancer intervention. BMJ Support Palliat phase II study of bevacizumab for the treatment of angiosarcoma and Care. 2019. https://doi.org/10.1136/bmjspcare-2019-001903. epithelioid hemangioendotheliomas. Ann Oncol. 2013;24:257-263. 95. Wei SC, Yang PM, Chen CH, Chu JS, Chen DS. Case report: successful 86. Yousaf N, Maruzzo M, Judson I, Judson, Fisher C, Benson C. Systemic palliative treatment with intraperitoneal OK-432 injection for epithe- treatment options for epithelioid haemangioendothelioma: the Royal lioid haemangioendothelioma presenting with intractable ascites. Marsden Hospital experience. Anticancer Res. 2015;35:473-480. J Gastroenterol Hepatol. 1997;12:39-43. 87. Zheng Z, Wang H, Jiang H, Chen E, Zhang J, Xie X. Apatinib for the 96. Caraceni A, Hanks G, Kaasa S, et al. Use of opioid analgesics in the treatment of pulmonary epithelioid hemangioendothelioma: a case treatment of cancer pain: evidence-based recommendations from the report and literature review. Medicine (Baltimore). 2017;96:e8507. EAPC. Lancet Oncol. 2012;13:e58-e68. 14 https://doi.org/10.1016/j.esmoop.2021.100170 Volume 6 - Issue 3 - 2021