Proposed diagnostic and prognostic markers of primary malignant hepatic vascular neoplasms.

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

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

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

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

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

Diagnostically Challenging Multifocal Penile Epithelioid Hemangioma Successfully Treated With Doxorubicin Hydrochloride.

ABSTRACT: Epithelioid hemangioma (EH), also known as angiolymphoid hyperplasia with eosinophilia, is an unusual vascular proliferation that tends to manifest in the head and neck region. Its occurrence on the penis is rare, with only scarce reported cases in the literature. The histopathological examination of this condition poses a challenge because it shares similarities with other entities, such as epithelioid hemangioendothelioma, epithelioid angiosarcoma, cutaneous epithelioid angiomatous nodule, or Kaposi sarcoma (KS). The infrequency of EH in penile locations underscores the need for accurate diagnostic differentiation and tailored treatment strategies for this atypical presentation. This case report highlights a rare instance of multifocal penile EH. The patient's lesions exhibited distinctive histopathologic features, with extensive eosinophilic infiltration, presence of necrosis, and infiltration to subcutaneous fat. The patient was treated with doxorubicin, a chemotherapy drug, with a very good response. This successful therapeutic outcome underscores the potential efficacy of doxorubicin in the management of multifocal penile EH. The comprehensive analysis of this case contributes to our understanding of the clinical presentation, histopathologic features, and treatment modalities for this rare penile tumor, providing valuable insights for future clinical considerations.

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.

Rapidly Progressive and Debilitating Epithelioid Hemangioendothelioma: An Atypical Presentation of a Rare Malignant Cutaneous Vascular Neoplasm.

ABSTRACT: Epithelioid hemangioendothelioma (EHE) is a rare vascular malignant tumor that comprises less than 1% of all vascular tumors. Cutaneous involvement in EHE can occur either by spreading from underlying bone or rarely could be limited to the skin and mostly presents as solitary well-circumscribed mass to an ill-defined infiltrative lesion. We present a case of rapidly progressive and debilitating EHE presenting multiple vascular papules and nodules. Histopathology showed an ill-circumscribed nodular proliferation of epithelioid and spindled cells in the dermis that extended into the subcutaneous tissue. The tumor cells had moderate eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. In addition, they showed evidence of lumen formation and intracytoplasmic vacuoles. Brisk mitosis was noted. On immunohistochemistry, the cells were strongly positive for CD31, CD34, and ERG (ETS [erythroblast transformation-specific]-related gene). MIB-1 labeling index was more than 75% in the highest proliferating areas. A high degree of clinical suspicion and immunopathological examination is recommended for early diagnosis of this rare condition before it becomes function or life-threatening.

Vascular tumors of intermediate malignancy: An update.

The term "hemangioendothelioma" is used for endothelial neoplasms of intermediate malignancy and describes a group of rare neoplasms having biologic behavior falling in between that of the benign hemangiomas and fully malignant angiosarcomas. The hemangioendotheliomas fall into several specific, clinicopathologically and genetically distinct entities, specifically epithelioid hemangioendothelioma, kaposiform hemangioendothelioma, papillary intralymphatic angioendothelioma and retiform hemangioendothelioma (hobnailed hemangioendothelioma), pseudomyogenic hemangioendothelioma, composite hemangioendothelioma, and YAP1::TFE3-fused hemangioendothelioma. The clinical, morphologic, immunohistochemical, and genetic features, and the differential diagnosis of each of these rare entities are discussed in this review.

Primary vascular tumors of bone: A comprehensive literature review on classification, diagnosis and treatment.

Primary vascular tumors of bone are a heterogeneous group of neoplasms, ranging from benign hemangiomas to frankly malignant epithelioid hemangioendotheliomas and angiosarcomas. Over the years, their classification has been a matter of discussion, due to morphologic similarities and uncertainty regarding biologic behavior. Over the past decade, with the development of next-generation sequencing, there has been a significant improvement in the molecular characterization of these lesions. The integration of their morphologic, immunohistochemical and molecular features has led to a better stratification, with important prognostic and therapeutic implications. Nevertheless, primary vascular bone tumors still represent a challenge for medical oncologists. Given their rarity and heterogeneity, in the last few years, there has been no significant progress in medical treatment options, so further research is needed. Here we present a review of the current knowledge regarding primary vascular tumors of the bone, correlating clinicopathologic features with tumor behavior and therapeutic approaches.

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 42 y). Twelve patients had solitary lesions, while 2 had multifocal polyostotic (pelvic bones) disease. Overall, 12 lesions were intra-osseous and 2 in soft tissue. By targeted RNA Fusion panels or FISH, there were 6 cases of EWSR1::NFATC1 , 4 EWSR1::NFATC2 , 2 FUS::NFATC2 , 1 EWSR1 rearrangement, and 1 with a novel FABP4::NFATC2 fusion. Follow-up was available in 4 patients. One patient experienced 2 local recurrences, 11 and 15 years postdiagnosis, and one patient experienced progressive disease despite multimodality treatment (curettings, embolization, radiation) over 3 years. In summary, our extended investigation confirms that NFATC -related fusions define a distinct group of vascular neoplasms with variable architecture, epithelioid phenotype, and cytologic atypia, commonly located in the bone, occasionally multifocal and with potential for local recurrence and aggressive behavior but no metastatic potential. Molecular analysis is recommended in diagnostically challenging cases with atypical histology to exclude malignancy.

Cervical Lymph Node Metastasis as the Initial Presentation of Femoral Epithelioid Hemangioendothelioma Revealed by 18 F-FDG PET/CT.

ABSTRACT: Femoral epithelioid hemangioendothelioma with cervical lymph node metastasis is rare. We report the FDG PET/CT findings of cervical lymph node metastasis from left femoral epithelioid hemangioendothelioma in a 50-year-old woman with painless enlargement of the left cervical lymph nodes as the initial presentation. Ultrasound and MRI revealed multiple enlarged lymph nodes in the left cervical sheath area. PET/CT showed strong radioactive uptake in the left cervical lymph nodes, and there was additional lesion with increased FDG uptake in the left femur, which was later confirmed as cervical lymph nodes metastasis from left femoral epithelioid hemangioendothelioma by pathological examination.

18 F-FDG PET/CT Imaging of Prostatic Epithelioid Hemangioendothelioma.

ABSTRACT: Epithelioid hemangioendothelioma of the prostate is a rare malignant vasogenic tumor. We report a case of epithelioid hemangioendothelioma of the prostate in a 65-year-old man with lymph nodes and lung metastases on 18 F-FDG PET/CT imaging. The patient presented with symptoms of frequent and urgent urination. On 18 F-FDG PET/CT, intense FDG uptake was observed in the prostate mass along with multiple FDG-avid lesions involving the lung and lymph nodes. Histopathological examination confirmed epithelioid hemangioendothelioma in both the prostate mass and lung nodule.

The oncogenic fusion protein TAZ::CAMTA1 promotes genomic instability and senescence through hypertranscription.

TAZ::CAMTA1 is a fusion protein found in over 90% of Epithelioid Hemangioendothelioma (EHE), a rare vascular sarcoma with an unpredictable disease course. To date, how TAZ::CAMTA1 initiates tumour formation remains unexplained. To study the oncogenic mechanism leading to EHE initiation, we developed a model system whereby TAZ::CAMTA1 expression is induced by doxycycline in primary endothelial cells. Using this model, we establish that upon TAZ::CAMTA1 expression endothelial cells rapidly enter a hypertranscription state, triggering considerable DNA damage. As a result, TC-expressing cells become trapped in S phase. Additionally, TAZ::CAMTA1-expressing endothelial cells have impaired homologous recombination, as shown by reduced BRCA1 and RAD51 foci formation. Consequently, the DNA damage remains unrepaired and TAZ::CAMTA1-expressing cells enter senescence. Knockout of Cdkn2a, the most common secondary mutation found in EHE, allows senescence bypass and uncontrolled growth. Together, this provides a mechanistic explanation for the clinical course of EHE and offers novel insight into therapeutic options.

An extremely rare case of pulmonary epithelioid hemangioendothelioma.

Epithelioid emangioendothelioma (EHE) is a rare tumor originating from vascular endothelial cells, which belongs to malignant vascular tumors with low to moderate differentiation and potential metastatic ability and its incidence rate is less than one in a million. We herein report a rare case of EHE of pulmonary origin and a review of the literature concerning the clinical and pathological features of this disease. The patient underwent left upper lobectomy to completely extirpate the lesion by video-assisted thoracic surgery. Our findings suggest the difficulty of making a diagnosis before surgery and that more cases need to be reported in order to facilitate the preoperative diagnosis of such a rare tumor.

[Diagnostic value of contrast-enhanced ultrasound in hepatic epithelioid hemangioendothelioma].

Objective: To investigate the features of contrast-enhanced ultrasound (CEUS) in hepatic epithelioid hemangioendothelioma (HEHE) in order to improve the preoperative diagnosis rate. Methods: CEUS images of 32 pathologically-proven cases of hepatic epithelioid hemangioendothelioma from January 2004 to August 2021 were collected. Lesions were analyzed to observe the features of enhancement mode, enhancement intensity, and distinct enhancement phases. Results: Among the 32 cases, one had a solitary lesion, 29 had multiple lesions, and two had diffuse-type lesions. Contrast-enhanced ultrasound revealed a total of 42 lesions in 32 cases. In terms of arterial phase enhancement, 18 lesions had overall enhancement, six lesions had uneven dendritic enhancement, 16 lesions had rim-like enhancement, and two lesions had just slight peripheral spot enhancement around the lesions. Among the three cases, there were multiple lesions that had overall enhancement and ring enhancement. In terms of the enhancement phase, 20 lesions showed "fast progression", 20 lesions showed "same progression", and two lesions showed "slow progression". During the late arterial or early portal venous phases with rapid washout, all lesions manifested as hypoechoic. With peaked enhanced intensity, 11 lesions had a lower enhancement intensity than the surrounding normal liver parenchyma; 11 lesions had the same enhancement degree as the surrounding normal liver parenchyma; and 20 lesions had a higher enhancement degree than the surrounding normal liver parenchyma. All 16 ring-enhancing lesions had marked hyperenhancement. In the typical enhancing lesions, four showed hyperenhancement, five showed low enhancement, and nine showed isoenhancement. In the dendrite-enhancing lesions, there were two isoenhancing and four hypoenhancing. Contrast-enhanced ultrasound delineated the boundaries of all lesions more clearly than two-dimensional ultrasound. Conclusion: Contrast-enhanced ultrasound has certain value in the diagnosis of hepatic epithelioid hemangioendothelioma.

Incidence, demographics, and survival of malignant hemangioendothelioma in the United States.

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

Primary epithelioid hemangioendotheliomas and angiosarcomas of the pleura: a clinicopathological and immunohistochemical analysis of 13 cases.

Thirteen cases of primary epithelioid hemangioendotheliomas (EHE) and epithelioid angiosarcomas (EA) of the pleura are presented. The patients were 7 men and 6 women between the ages of 34 and 65 years (mean: 47 years). The patients presented with non-specific symptoms of cough, dyspnea, and chest pain. Diagnostic imaging revealed the presence of either diffuse pleural thickening or pleural nodules involving the serosal surfaces. Open surgical biopsies were obtained in all cases. Histologically, eight tumors were characterized by the presence of a cellular proliferation composed of medium-sized epithelioid cells embedded in a myxohyaline stroma and a variable spindle cell component. Cellular atypia was mild to moderate and mitotic activity ranged from 1 to 2 per 2 mm2. Immunohistochemical stains for vascular markers, including CAMTA1 were positive, confirming a diagnosis of EHE. Five cases of epithelioid angiosarcomas were characterized by a neoplastic cellular proliferation admixed with areas of necrosis and hemorrhage and characterized by medium-sized epithelioid to spindle-shaped cells with eosinophilic cytoplasm, round to oval nuclei and prominent nucleoli. In addition, marked cytologic atypia and a mitotic activity ranging from 3 to 5 per 2 mm2 were identified. Immunohistochemical studies demonstrated positive staining for vascular markers; however, CAMTA1 was negative. Clinical follow-up obtained in eleven cases showed that all patients had died within 30 months post diagnosis. The current study highlights that even though it may be important to histologically separate EHE from EA for academic purposes, primary pleural origin of these tumors appears to portent an aggressive clinical behavior.

Epithelioid hemangioendothelioma of the retroperitoneal giant type treated with Toripalimab: A case report.

Epithelioid hemangioendotheliomas (EHEs), low-grade malignant tumors of vascular endothelial cell origin, are characterized by vascular endothelial proliferation. In 2002, the World Health Organization classified EHEs as locally aggressive tumors with the potential to metastasize. Currently, the diagnosis of EHE is based on pathology, histological and immunohistochemical examinations. There are no standard treatment guidelines. We here report a 69-year-old man who presented with left-sided chest and abdominal pain for more than 2 months. Enhanced computed tomography of the thorax and abdomen in another hospital suggested a mass in the left adrenal region that was considered malignant. Positron emission tomography- computed tomography in our hospital suggested a large multi-loculated, hypermetabolic, cystic mass in the left adrenal region that was considered malignant. Accordingly, a puncture biopsy of the mass was performed and the diagnosis of EHE confirmed by pathological examination, including immunohistochemical staining. This patient was treated with the programmed death 1 (PD-1) immune checkpoint inhibitor toripalimab with long-term success. The best response was stable disease (SD) with a progression-free survival (PFS) of more than 13 months. The patient is still alive now. Because the sample size of previous studies was small, further studies are needed to determine the safety and efficacy of toripalimab in the treatment of EHE.

[Epithelioid Hemangioendothelioma of the Upper Mediastinum:Report of a Case].

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

Clinicopathological study of pseudomyogenic hemangioendothelioma.

OBJECTIVES: Pseudomyogenic hemangioendothelioma (PHE) is a rare intermediate hemangioendothelioma. This article aims to study the clinicopathological features of PHE. METHODS: We collected the clinicopathological features of 10 new PHE, and examined their molecular pathological features by fluorescence in situ hybridization. In addition, we summarized and analyzed the pathological data of 189 reported cases. RESULTS: The case group consisted of six men and four women aged 12-83 years (median: 41 years). Five instances occurred in the limbs, three in the head and neck, and two in the trunk. Tumor tissues were composed of spindle cells and round or polygonal epithelioid cells, which were either arranged in sheets or interwoven, along with areas of transitional morphology. Scattered or patchy stromal neutrophil infiltration was observed. Tumor cells had abundant cytoplasm, and some contained vacuoles. The nuclei had mild to moderate atypia, with visible nucleoli, and mitosis was rare. PHE tissues diffusely expressed CD31 and ERG, but not CD34, Desmin, SOX-10, HHV8 or S100, while some samples expressed CKpan, FLI-1 and EMA. INI-1 stain is retained. The proliferation index of Ki-67 is 10-35%. Seven samples were detected by fluorescence in situ hybridization, six of which had breakages in FosB proto-oncogene (AP-1 transcription factor subunit). Two patients experienced recurrence; however, no metastasis or death occurred. CONCLUSIONS: PHE is a rare soft tissue vascular tumor, which has biologically borderline malignant potential, local recurrence, little metastasis, and good overall survival and prognosis. Immunomarkers and molecular detection are valuable for diagnosis.