Epithelioid Hemangioendothelioma Research Articles

The Profuse Bleeding Potential of Orbital Epithelioid Hemangioendotheliomas

Epithelioid hemangioendothelioma is a rare vascular tumor originating from vascular endothelial or pre-endothelial cells. We present the case of a 4-month-old male with a rapidly enlarging left zygomatico-orbital tumor causing mass effect on the eye globe. Examination revealed a large, nontender, solid lesion. CT angiography showed no major feeder or intralesional vessels. Complete surgical excision was performed, which was complicated by life-threatening intraoperative bleeding and successfully controlled with electrocautery. Microscopically, tumor cells exhibited varying morphologies. Immunohistochemistry confirmed the diagnosis of epithelioid hemangioendothelioma (positive for CD31 and CD34, negative for CK AE1/AE3). We also highlight 2 similar case reports with life-threatening bleeding complications. Surgeons should be aware of this condition and optimize surgical preparation, including blood products, to manage potential bleeding complications.

Epithelioid hemangioma of the acromion causing shoulder pain: a case report.

Epithelioid hemangioma of bone is a rare benign vascular tumor. Because of the locally destructive clinical presentation and the presence of atypical histologic features with increased mitotic activity and necrosis, it is often misdiagnosed as low-grade malignant epithelioid hemangioendothelioma or high-grade malignant epithelioid angiosarcoma. Correct diagnosis through imaging studies and histopathological examination is mandatory to determine the appropriate course of treatment, as the prognosis differs from that of other malignant hemangioma tumors. A 69-year-old male who presented with intractable shoulder pain caused by epithelioid hemangioma in the acromion of the scapula was treated with tumor curettage. This paper reports a good result with a review of the relevant literature.

Epithelioid hemangioendothelioma-its history, clinical features, molecular biology and current therapy.

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 ~50years, 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.

A Single Arm Phase 2 Trial of Trametinib in Patients With Locally Advanced or Metastatic Epithelioid Hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 operating as an oncogenic driver through activation of 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. 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 prior to enrollment. The primary endpoint was objective response rate (ORR) per RECIST1.1 in cases with TAZ-CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median PFS, 2-year OS rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. 44 patients enrolled and 42 started trametinib. TAZ-CAMTA1 was detected in 27 tumor samples. The ORR was 3.7% (95% 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 AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia and edema; one Grade 5 ARDS/pneumonitis was related to trametinib. 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.

TFE3 rearranged epithelioid hemangioendothelioma of the lymph node: A rare primary presentation of vascular tumor.

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor that has been described in numerous sites such as soft tissue, liver, and lungs. However, primary lymph nodal presentation of hemangioendothelioma is extremely rare. We present a 49-year-old male patient who presented with an inguinal mass but was otherwise asymptomatic. Clinical and radiological workup failed to reveal any other primary lesion. The lymph node was excised and the histomorphological examination showed an epithelioid and spindle neoplasm with chondromyxoid stroma. The diagnosis of epithelioid hemangioendothelioma was suspected based on histomorphology and immunohistochemistry, which showed diffuse positivity for CD31, CD34, and TFE3 stains. This was further confirmed by the fluorescent in-situ hybridization (FISH) technique that showed TFE3 gene rearrangement.

Abstract 7280: Potential activity of TEAD inhibitor in Hippo-altered cancer including NF2 mutant solid cancer and TAZ-CAMTA1 fusion-driven epithelioid hemangioendothelioma (EHE)

Abstract The Hippo pathway, a conserved signaling, modulates diverse processes including cell proliferation, survival, differentiation, organ size, and tissue homeostasis. The core kinases, MST1/2 and LATS1/2 phosphorylate downstream effectors, YAP/TAZ, and sequestrate them in cytoplasm1). The upstream regulator, NF2 activates these kinases and its loss-of-function mutation leads to YAP nuclear translocation, which in turn promotes tumorigenesis2). Dysregulation of Hippo pathway triggers constitutive YAP/TAZ accumulation and binding to TEAD family that upregulate prosurvival target genes such as CTGF and CYR611), which are deeply associated with drug resistance and tumor microenvironment3). TEADs, a transcription activation complex with primary key partners of YAP/TAZ, function in response to the Hippo altered-pathway4). Although a number of reports in the area of small molecules targeting YAP/TAZ-TEAD complex is exponentially increased, there is a lack of understanding regarding how TEAD subtypes may contribute to cancer progression. Moreover, TAZ-CAMTA1 gene fusion is a driver oncogene expressed in more than 90% of epithelioid hemangioendothelioma (EHE), a vascular sarcoma5). Here, we explore the potential of anti-cancer efficacy on our established TAZ-CAMTA1 fusion-driven EHE model. Our TEAD inhibitor effectively suppressed TEAD reporter activity in MCF7-TEAD-luc cells and induced 10~100 nM range of growth inhibition in NF2 or LATS mutant mesothelioma by disrupting YAP-TEAD1/3 protein-protein interactions (PPI). We found that knockdown TEAD1 as well as TEAD3 downregulate growth ability of NF2 altered solid cancer cells such as LOU-NH-91 and YD8. Our TEAD inhibitor, showing TEAD1/3 isoform specificity, exhibited a superior anti-proliferative effect in broader range of Hippo-altered solid cancer cells than of selective TEAD1 inhibitor. This highlights the importance of targeting TEAD1 and suggest that TEAD3 inhibition can enhance anticancer effects. We established the TAZ-CAMTA1 fusion-expressing cells, demonstrating its oncogenic function through increased anchorage-independent growth and upregulation of TEAD target genes, CTGF and CYR61, compared to parental NIH3T3. Our TEAD inhibitor suppressed TAZ-CAMTA1 fusion-TEAD1 PPI in NanoBRET system. It also inhibited TAZ-CAMTA1 driven colony formation. Our inhibitor more greatly prevented the growth of TAZ-CAMTA1 expressing NIH3T3 cells than parental cells and exhibited mRNA expression inhibition of CTGF and CYR61 on qRT-PCR, showing superior effects compared to the selective TEAD1 inhibitor. In conclusion, we emphasize the importance of TEAD inhibition for the treatment of Hippo-altered cancers including NF2 mutant solid cancer and TAZ-CAMTA1 fusion-driven EHE, highlighting the advantages of our TEAD1/3 inhibitor over the selective TEAD1 inhibitor. Citation Format: Jooyun Byun, Seung Hyun Jung, Heesun Moon, Semi Lim, Soonki Park, Seungheon Baek, Yu-Yon Kim, Junghwa Park, Jisook Kim, Sang Hyun Lee, Young Gil Ahn. Potential activity of TEAD inhibitor in Hippo-altered cancer including NF2 mutant solid cancer and TAZ-CAMTA1 fusion-driven epithelioid hemangioendothelioma (EHE) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7280.

Pleural epithelioid hemangioendothelioma in a 39-Year-old female: a case report

BackgroundEpithelioid 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 presentationA 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.ConclusionsOnce 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.

Image-Guided Thermal Ablation for Hepatic Epithelioid Hemangioendothelioma: A Multicenter Experience

PurposeTo investigate the feasibility, safety, and clinical outcomes of image-guided thermal ablation in patients with hepatic epithelioid hemangioendothelioma (HEHE). Materials and MethodsThis 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. ResultsThe technical success rate was 93.5% (29/31). No major adverse events occurred after ablation. Local tumor progression occurred in 2 sessions (6.5%, 2/31) after ablation, and intrahepatic distant metastasis occurred in 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. ConclusionsImage-guided thermal ablation is a feasible and safe treatment option for patients with HEHE that results in good local tumor control and a favorable long-term prognosis.

The patient perspective on sirolimus for epithelioid hemangioendothelioma (EHE): results of a community survey highlighting the importance of equitable access to treatments.

Epithelioid hemangioendothelioma (EHE) is an ultra-rare, vascular sarcoma with clinical presentation ranging from an indolent to an aggressive form. Over 50% of patients present with metastatic disease, requiring systemic therapy, although no systemic therapies are specifically approved for EHE. Retrospective evidence supports the activity of mTOR inhibitors (e.g. sirolimus), although available only off-label. EHE patients and advocates are therefore working to support approval of effective treatments by collecting data on patient perspectives and experiences. In February 2023, the EHE Rare Cancer Charity (UK) and The EHE Foundation (US), with other advocates, conducted a survey of perspectives and experiences of EHE patients regarding the use and accessibility of sirolimus. The survey consisted of 20 questions designed for individuals undergoing treatment, those who had been treated, or had never been treated with the drug. Widely promoted within the patient community, the online survey categorized patients into three cohorts for the analysis: liver transplant patients, non-transplant patients who had ever taken sirolimus and sirolimus-naïve non-transplant patients. The survey evaluated data from 129 patient responses from 21 countries, mostly from USA, UK, Australia, and Canada (70%). The liver transplant, sirolimus and non-sirolimus cohorts were 16%, 25% and 59%, respectively. In the sirolimus group 66% reported treatment durations exceeding one year, with 16% exceeding five years, indicating the drug's efficacy. In the non-sirolimus group, the drug was not available for 42% and for 11% sirolimus was available but not selected for treatment because of its off-label status. Overall, 87% of all patients across all cohorts expressed the importance of the drug's availability as hugely or very important. The survey responses highlight the activity of sirolimus for EHE and the importance of securing a label extension for the drug delivering equitable access to this treatment for patients.

Evaluation of TRIM63 RNA in situ hybridization (RNA-ISH) as a potential biomarker for alveolar soft-part sarcoma (ASPS)

Alveolar soft-part sarcoma (ASPS) is a rare soft tissue tumor with a broad morphologic differential diagnosis. While histology and immunohistochemistry can be suggestive, diagnosis often requires exclusion of other entities followed by confirmatory molecular analysis for its characteristic ASPSCR1-TFE3 fusion. Current stain-based biomarkers (such as immunohistochemistry for cathepsin K and TFE3) show relatively high sensitivity but may lack specificity, often showing staining in multiple other entities under diagnostic consideration. Given the discovery of RNA in situ hybridization (RNA-ISH) for TRIM63 as a sensitive and specific marker of MiTF-family aberration renal cell carcinomas, we sought to evaluate its utility in the workup of ASPS. TRIM63 RNA-ISH demonstrated high levels (H-score greater than 200) of expression in 19/20 (95%) cases of ASPS (average H-score 330) and was weak or negative in cases of paraganglioma, clear cell sarcoma, rhabdomyosarcoma, malignant epithelioid hemangioendothelioma, as well as hepatocellular and adrenal cortical carcinomas. Staining was also identified in tumors with known subsets characterized by TFE3 alterations such as perivascular epithelioid cell neoplasm (PEComa, average H-score 228), while tumors known to exhibit overexpression of TFE3 protein without cytogenetic alterations, such as melanoma and granular cell tumor, generally showed less TRIM63 ISH staining (average H-scores 147 and 96, respectively). Quantitative assessment of TRIM63 staining by RNA-ISH is potentially a helpful biomarker for tumors with molecular TFE3 alterations such as ASPS.

Surgical treatment of intracranial epithelioid hemangioendothelioma: a case report

Epithelioid hemangioendothelioma (EHE) is an extremely rare vascular neoplasm with an intermediate pattern of malignancy between benign neoplasms and angiosarcomas. Only 46 cases of intracranial localization of primary EHE in adults have been published.Case report: A 47-year-old male patient developed pronounced speech disorder of sensory and amnestic aphasia type, right-sided pyramidal hemiparesis within 3–4 days. Magnetic resonance imaging revealed a delimited left sided brain islet neoplasm with signs of hemorrhage and small perifocal edema. Intraoperatively, the neoplasm was represented by a conglomerate of pathologic vessels, with involvement of the terminal branches of the M2 segment of the middle cerebral artery, which prevented radical resection of the neoplasm. Based on histopathological and immunohistochemistry analysis of the neoplasm (positive expression of CD31, CD34, proliferative activity index Ki-67 10%) the morphologic diagnosis of EHE was established. 3 months after surgery, continued growth of the residual part of the neoplasm was noted. Temozolomide chemotherapy was clinically ineffective. The patient died due to the development of dislocation syndrome after 9 months.Discussion. The malignant characteristics of EHE include invasive growth, recurrence, and metastasis, which is more common in intracranial localization of the neoplasm. If EHE is suspected, radical surgical removal of the neoplasm should be sought.

Molecularly Confirmed Pseudomyogenic Hemangioendothelioma with Unusual EGFL7::FOSB Fusion in the Head and Neck Region of an Older Patient

Pseudomyogenic hemangioendothelioma (PMHE), a rare vascular neoplasm, was first described in 1992 asa fibroma-like variant of epithelioid sarcoma, and would be termed as epithelioid sarcoma-like hemangioendothelioma a decade later due to its significant histologic overlap with epithelioid sarcoma and diffuse cytokeratin expression. PHME is currently defined as a distinct, potentially intermediate malignant, rarely metastasizing neoplasm with vascular/endothelial differentiation. It is characterized by young age (typically less than 40 years old), extremity location (approximately ~80%), and t(7:19) SERPINE1::FOSB fusion as the most common molecular alteration. Herein, we report a case of a 59-year-old male presenting with multifocal lesions, including in the right temporalis muscle, right frontoparietal calvarium, right pterygoid muscles, and right mandibular condyle. Histologic examination of the right temporal lesion revealed a multinodular biphasic lesion composed of sheets and fascicles of elongated spindle and epithelioid cells infiltrating into the adjacent skeletal muscle. Admixed abundant neutrophilic infiltration is noted; however, areas of necrosis, increased mitosis, nuclear atypia, or rhabdomyoblast-like cells are absent. Immunohistochemical (IHC) staining showed that the tumor cells were diffusely and strongly positive for FOSB, pan-cytokeratin (AE1/AE3), CD31, and ERG. Molecular testing demonstrated a t(9:19) EGFL7::FOSB fusion mRNA. This constellation of morphological, IHC and molecular findings was consistent with a diagnosis of PMHE. This is the first reported case of multifocal PMHE with EGFL7::FOSB fusion in the head and neck area of a patient aged more than 50 years old. Since the differential diagnoses for PMHE includes high-grade malignancies with aggressive clinical behavior, coupled with the rare reports of PMHE in the head and neck region, awareness of this tumor in the head and neck region will avoid the misdiagnosis and overtreatment of this entity.

Epithelioid hemangioendothelioma (EHE) with WWTR1::TFE3 gene fusion, a novel fusion variant.

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.

Imaging features and deep learning for prediction of pulmonary epithelioid hemangioendothelioma in CT images.

Pulmonary epithelioid hemangioendothelioma (PEH) is a rare vascular tumour, and its early diagnosis remains challenging. This study aims to comprehensively analyse the imaging features of PEH and develop a model for predicting PEH. Retrospective and pooled analyses of imaging findings were performed in PEH patients at our center (n=25) and in published cases (n=71), respectively. Relevant computed tomography (CT) images were extracted and used to build a deep learning model for PEH identification and differentiation from other diseases. In this study, bilateral multiple nodules/masses (n=19) appeared to be more common with most nodules less than 2 cm. In addition to the common types and features, the pattern of mixed type (n=4) and isolated nodules (n=4), punctate calcifications (5/25) and lymph node enlargement were also observed (10/25). The presence of pleural effusion is associated with a poor prognosis in PEH. The deep learning model, with an area under the receiver operating characteristic curve (AUC) of 0.71 [95% confidence interval (CI): 0.69-0.72], has a differentiation accuracy of 100% and 74% for the training and test sets respectively. This study confirmed the heterogeneity of the imaging findings in PEH and showed several previously undescribed types and features. The current deep learning model based on CT has potential for clinical application and needs to be further explored in the future.

Epitheloid hemangioendothelioma of the urinary bladder: A case report of a rare entity

Epithelioid hemangioendothelioma (EHE) is a rare, often multifocal, intermediate-grade vascular sarcoma arising from the endothelial cells. Their behavior is intermediate between hemangioma and conventional angiosarcoma. Their rarity and unpredictable clinical behavior result in our still limited understanding and treatment options for this variety of tumors. Molecular diagnostic tools like the presence of WWTR1-CAMTA1 fusion have been developed to aid this challenging diagnosis. There is no definitive consensus on the management of patients with this disease and no commonly accepted treatment strategies have been found to be effective, particularly in the metastatic setting. When possible, surgery with clear margins should be considered in case of localized disease. Here, we not only present such a rare case of EHE of the urinary bladder but also provide a comprehensive discussion on the present treatment modalities offered, as found through a thorough search of the published studies. Finally, more studies are required to establish a standard of care for this rare entity.  

Image-guided percutaneous ablation of hepatic epithelioid hemangioendothelioma.

Disease control and survival following percutaneous ablation of hepatic epithelioid hemangioendothelioma (EHE) was studied retrospectively. Six patients underwent 16 image-guided ablation procedures to treat 35 liver tumors from 2015 to 2022 (17 microwave ablation, 9 irreversible electroporation, 8 cryoablation, and 1 radiofrequency ablation). Technical success, local progression, intrahepatic progression, distant progression, overall survival, and adverse events were assessed. Four of six (67%) patients were treatment naïve prior to ablation. The mean length of imaging follow-up from first ablation procedure was 43.0 ± 31.2months. Thirty-three of 35 (94.3%) ablated tumors did not progress locally. Three of 6 patients (50%) had new intrahepatic progression and underwent repeat ablation or systemic treatment. No extrahepatic progression was observed. One patient died from EHE 2.7years after initial diagnosis. No severe adverse events occurred. Percutaneous ablation is feasible, often in a staged fashion, and may provide favorable intermediate to long-term disease control for patients with hepatic EHE.

Epithelioid Hemangioma Masquerading as Traumatic Lesion: A Rare Case Report with Diagnostic Workup

Abstract Wells and Whemser first identified epithelioid hemangioma (EH) as angiolymphoid hyperplasia in 1969. It is a rare type of vascular tumor that primarily affects men in their middle ages. Typically, it appears as a single or few reddish-to-brown nodules. EHs of the oral cavity have only seldom been reported up to this point. Histologically, it is distinguished by lobular vessel configuration, tombstone-like epithelioid cells lining the vessel wall, and a persistent inflammatory infiltration predominately made up of eosinophils. Although the terms EH and epithelioid hemangioendothelioma are sometimes confused, the two are distinct based on histopathology and a number of immunohistochemistry (IHC) markers, including high Ki67 index and ERG positivity observed later. Local trauma to a nearby vessel may be one of the etiopathogeneses for this entity. This is a rare case report of EH that was identified with the use of a panel of IHC markers and hematoxylin and eosin histology.

Vascular Neoplasms With NFATC1/C2 Gene Alterations : Expanding the Clinicopathologic and Molecular Characteristics of a Distinct Entity.

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 42y). 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.

А very rare cutaneous epithelioid hemangioendothelioma in the right auricle on a male adult

Introduction. Epithelioid hemangioendothelioma is an extremely rare tumor of vascular origin, which mainly affects soft tissues and, in rare cases, also affects the skin. Case outline. A 71-year-old man came for an examination due to a tumor localized on the antihelix of the right ear. A radical excision of the tumor and reconstruction of the defect with a preauricular transposition tunnelized Banner flap was performed. Conclusion. Epithelial hemangioendothelioma of the skin is an extremely rare, vascular tumor. It is characterized by local aggression, the appearance of local recurrences and metastatic hematogenous and lymphogenic spread. Standard dermoscopic examination of this tumor is not important. The appearance of the tumor itself has no clinical specificity, and most often resembles nodular basal cell carcinoma. An early visit to the doctor and removing the change early are the key to success in treating this tumor. So far, no case has been reported that is localized on the antihelix of the ear. Radical surgical excision is the therapy of choice.

Short-term outcomes of combined therapy with sirolimus and interferon-alpha 2b for advanced hepatic epithelioid hemangioendothelioma.

Hepatic epithelioid hemangioendothelioma (EHE) is an extremely rare tumor, and no standard therapy has been established yet. The aim of this study was to investigate the short-term results of combined therapy with sirolimus and interferon-alpha 2b (IFN-a 2b) (SI therapy). From January 2022 to April 2023, 40 patients histologically diagnosed with hepatic EHE and progressive disease received SI therapy. All patients were regularly evaluated for the safety and efficacy of the SI therapy. Patients who received SI therapy for <3 months without a tumor status evaluation after treatment were excluded. Twenty-nine patients with hepatic EHE were included in this study. The Eastern Cooperative Oncology Group (ECOG) performance status was 0 in 19 (65.5%) patients and 1 in 10 (34.5%) patients. The median duration of the SI therapy was 8 months (range, 3-15 months). Twenty-three (79.3%) patients showed a decrease in tumor size, including 11 (37.9%) patients who achieved a partial response and one (3.4%) who achieved a complete response; the objective response rate was 41.4%. Stable disease was observed in 13 (44.8%) patients, with a disease control rate of 86.2%. Adverse events (AES) were observed in 18 patients, including leukopenia (31.0%), oral ulcers (13.8%), and liver injury (10.3%). No severe (grade ⩾ 3) AEs were recorded, and SI therapy was not interrupted for any patient due to AEs. Sirolimus and IFN-a 2b may have synergistic effects in the treatment of hepatic EHE. SI therapy is a safe and effective treatment for hepatic EHE patients with good ECOG performance status.