Open Access

Diagnostic and therapeutic understanding of multiple foci hepatic epithelioid haemangioendothelioma: A case report

  • Authors:
    • Jiang-Wei Mou
    • Ze-Liang Zhang
    • Bo Peng
    • Sheng Wu
    • Ye Zheng
    • Ke-Xiang Zhu
  • View Affiliations

  • Published online on: June 3, 2025     https://doi.org/10.3892/ol.2025.15129
  • Article Number: 383
  • Copyright: © Mou et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, low‑grade malignant liver tumour. Due to the small number of reported cases and available literature, the understanding of this condition has remained limited. Surgical resection is an important treatment option that substantially prolongs patient survival. This case report discusses a 23‑year‑old male patient diagnosed with HEHE who presented with multiple tumours, including nine lesions distributed across six different segments of the liver. Prior to surgery, the anatomical locations of the lesions in relation to the liver vasculature were mapped using three‑dimensional liver reconstruction. Intraoperative ultrasound (IOUS) was performed to ensure the complete excision of all lesions. At three months post‑surgery, follow‑up imaging revealed abnormally enhanced nodules in the S4 segment of the liver, which were considered new lesions. After consultation with a multidisciplinary team, the new liver lesions were treated with microwave ablation (MWA) following a puncture biopsy. Given the lack of standardised treatment guidelines for HEHE, this case illustrates the clinical manifestations, laboratory test results and imaging features of multifocal HEHE. Furthermore, it underscores the application of techniques including three‑dimensional reconstruction, IOUS and MWA in building diagnostic and therapeutic experiences for HEHE, providing a clinical basis and reference for standardised management in the future.

Introduction

Epithelioid hemangioendothelioma is a rare vascular tumour that can occur in any part of the body, including the bones, lungs and liver. The liver is the most common site (1). Hepatic epithelioid hemangioendothelioma (HEHE) is a rare, low-grade malignant tumour (2). Its global prevalence is <1 in 10 million and the average age of onset is 41.7 years (3). Women are more likely to experience HEHE, with a male-to-female ratio of 3:2. It affects the right lobe of the liver more than the left lobe (4). Compared with other forms of liver cancer, HEHE progresses at a relatively slow rate and generally has a favourable prognosis (5,6). Since HEHE is usually multifocal at the time of initial diagnosis, with indolent or even aggressive progression of the disease and a tendency to recur and metastasise, therapeutic intervention is typically required (7). There is currently no standard treatment for this condition. Surgical resection is a crucial treatment modality that facilitates long-term survival (5). This study presents the case of a young patient with multiple intrahepatic HEHE lesions with the aim of enhancing the current understanding of the diagnosis and management of multiple HEHE foci. The importance of liver resection in the treatment of this condition was emphasised. In addition, the study recommends the integration of preoperative three-dimensional reconstruction with intraoperative ultrasonography (IOUS) during radical resection. This combination may enhance the accuracy of localising multifocal lesions and improve the thoroughness of the procedure. Ultimately, the objective of this approach was to provide a more effective surgical strategy for patients with multifocal HEHE and improve their prognosis.

Case report

Case presentation

In July 2024, a 23-year-old male patient was admitted to the First Hospital of Lanzhou University (Lanzhou, China) after having had a liver mass for over a month. Upon examination and laboratory tests conducted after hospitalisation, the following results were noted: All vital signs of the patient were in the normal ranges and physical examination revealed no obvious abnormalities. Laboratory tests revealed some abnormal results: Gamma-glutamyl transferase, 96.3 U/l (normal range: 10–60 U/l); direct bilirubin, 4.1 µmol/l (normal range: 0–4 µmol/l) and abnormal plasminogen, 13.2 mAU/ml (normal range: 13.62–40.38 mAU/ml). Other laboratory results, including total bilirubin, albumin, prothrombin time, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, alpha-fetoprotein, carcinoembryonic antigen and glycoconjugate antigen 19-9, were within normal limits. The patient had a Child-Pugh liver function score of 5, corresponding to grade A (Table I). Furthermore, the patient had no medical or family history of hepatitis or alcohol consumption.

Table I.

The patient had a Child-Pugh liver function score of 5, corresponding to grade A.

Table I.

The patient had a Child-Pugh liver function score of 5, corresponding to grade A.

Child-Pugh Grading IndicatorResultChild-Pugh grading score
Total bilirubin<34μmol/L1
Albumin>35g/L1
Prothrombin time prologation<4 seconds1
HydroperitoneumNo1
Hepatic encephalopathyNo1

A contrast-enhanced computed tomography (CT) scan of the upper abdomen, enhanced using the contrast agent iopromide, along with a three-dimensional reconstruction of the hepatic vessels, revealed multiple rounded areas of abnormal enhancement beneath the hepatic capsule (Fig. 1A). There was also evidence of hepatic capsular retraction (Fig. 1B) and a partial manifestation of the ‘lollipop’ (Fig. 1C) and ‘fried egg’ signs. Three-dimensional reconstruction of the liver was performed based on CT scans to clarify the relationship between the lesions and the surrounding tissues (Fig. 1D-H). Furthermore, liver-specific magnetic resonance imaging (MRI), enhanced with the contrast agent gadoxetic acid disodium, identified multiple round shadows with long T1 and T2 signals at the periphery of the liver adjacent to the capsule. A heightened T2 signal was evident at the centre, accompanied by halo signs at the periphery (Fig. 2A and B). Enhancement revealed an increase in the arterial phase at the periphery (Fig. 2C), whereas progressive enhancement was observed in the portal vein phase (Fig. 2D).

After a discussion with a multidisciplinary team (MDT), a diagnosis of HEHE with multiple foci was established. At eight days after admission, open hepatic resection was performed under general anaesthesia to excise masses located in segments S2, S3, S4, S5, S6 and S7 (Fig. 3A-E). The postoperative pathological diagnosis confirmed the presence of HEHE (Fig. 4A). The results of the immunohistochemical analysis were as follows: Epithelial membrane antigen (EMA) (Fig. 4B) (−), platelet endothelial cell adhesion molecule-1 (CD31) (+) (Fig. 4C), hematopoietic progenitor cell antigen (CD34) (+) (Fig. 4D), Ets related gene (ERG) (+) (Fig. 4E), friend leukemia virus integration-1 (FLI-1) (+) (Fig. 4F), Kiel-67 antigen (Ki-67) (10%) (Fig. 4G), cytokeratin pan [CK (Pan)] (focal+) (Fig. 4H), cytokeratin 8&18 (CK8&18) (partially+) and transcription factor E3 (TFE3) (±). The patient was discharged on postoperative day 6 with satisfactory recovery.

The patient returned to the medical facility for a follow-up examination three months post-surgery. An iodixanol-enhanced CT scan of the upper abdomen revealed a rounded, slightly hypodense shadow in the S4 segment of the liver. This shadow exhibited mild circular enhancement and was ~11 mm in diameter (Fig. 5A). Following an MDT discussion, this was identified as a new HEHE lesion. Percutaneous hepatic mass aspiration biopsy and microwave ablation (MWA) were performed under ultrasound guidance (Fig. 5B and D). The procedure was completed without complications and postoperative ultrasonography revealed complete tumour inactivation (Fig. 5E). Biopsy results indicated the absence of HEHE tumour cells (Fig. 5C). The patient recovered after surgery and was discharged from the hospital. Regular follow-up visits will be scheduled to assess the prognosis.

Haematoxylin-eosin staining and immunohistochemistry

After tissue sampling, the specimens were fixed in a 10% neutral formalin solution at room temperature for 6 to 24 h. This was followed by dehydration using alcohol solutions and clearing using xylene at room temperature. The samples were then placed in melted paraffin wax at a temperature of 60 to 65°C, dipped 2 to 3 times for 1 to 2 h each time. After embedding, the wax block was cut into 3-µm sections, which were then subjected to xylene dewaxing and alcohol hydration at room temperature. Finally, staining was performed using hematoxylin and eosin at room temperature. The hematoxylin staining lasted for 5 to 10 min, followed by eosin staining for 1 to 3 min.

Standard procedures were followed for immunohistochemistry. The primary antibodies used were as follows: EMA (ready-to-use; cat. no. Kit-0011; Fuzhou Maixin Biotechnology Development Co., Ltd), CK(Pan) (ready-to-use; cat. no. MAB-0671; Fuzhou Maixin Biotechnology Development Co., Ltd), CK8&18 (ready-to-use; cat. no. CCM-1012; CELNOVTE), CD31 (ready-to-use; cat. no. PA007; ABCARTA), CD34 (ready-to-use; catalog no. Kit-0004; Fuzhou Maixin Biotechnology Development Co., Ltd), ERG (ready-to-use; cat. no. RMA-0748; Fuzhou Maixin Biotechnology Development Co., Ltd), FLI-1 (ready-to-use; cat. no. MAB-0649; Fuzhou Maixin Biotechnology Development Co., Ltd), TFE3 (ready-to-use; cat. no. RMA-0663; Fuzhou Maixin Biotechnology Development Co., Ltd), Ki-67 (ready-to-use; cat. no. 790-4286; Roche Diagnostics). The secondary antibody was a horseradish peroxidase-labeled antibody multimer (ready-to-use; cat. no. 760-500; Roche Diagnostics). All images above were obtained using an upright microscope (BX43; Olympus Corp.).

Discussion

The aetiology of HEHE, a rare malignant tumour derived from endothelial cells (8), remains poorly understood. However, factors such as viral hepatitis, liver trauma and exposure to certain chemicals (including oral contraceptives, polyvinyl chloride, asbestos and contrast agents) have been implicated as possible contributors to the development of HEHE (9). A common genetic abnormality associated with HEHE is a reciprocal translocation involving chromosome t(1;3)(p36.3;q25), which leads to the fusion of the WW domain-containing transcription coactivator 1 (WWTR1) gene with the calmodulin-binding transcription activator 1 (CAMTA1) gene (10). A small proportion of patients may also exhibit t(11;X)(q13;p11) translocation, resulting in the fusion of the Yes-associated protein 1 (YAP1) gene with the TFE3 (11). YAP1 and Transcriptional co-activator with PDZ-binding motif (TAZ) (the product of WWTR1) act as co-transcription factors and are key components of the Hippo signalling pathway, suggesting that this pathway plays a significant role in the development of HEHE (12,13). Furthermore, mutations in the KMT2A, SMARCA4, BAP1, MTOR and NOTCH1 genes have been identified in HEHE, which could serve as potential therapeutic targets (14). HEHE is frequently characterised by the lack of conventional clinical symptoms and specific diagnostic indicators, and ~68% of patients are asymptomatic at diagnosis (15). Certain patients may present with Budd-Chiari syndrome and exhibit clinical signs related to portal hypertension, such as epigastric pain, abdominal distension, loss of appetite, fatigue, splenomegaly, jaundice and ascites. These symptoms are typically associated with tumour invasion of the hepatic vascular system (16,17).

Enhanced CT scans may reveal the distinctive ‘lollipop’ sign, which is characterised by low-density lesions (resembling the candy of a lollipop) and occluded blood vessels (comparable to the lollipop stick). This distinctive finding is uncommon in other benign and malignant liver tumours (4). MRI revealed that HEHE exhibits low-signal intensity on T1-weighted images and high signal intensity on T2-weighted images (9). Additionally, peripheral enhancement was observed in the hepatic artery phase, with progressive enhancement noted in the portal vein phase (3). Reportedly, the ‘core pattern’ of low-signal centres in the hepatocellular phase can also serve as a distinctive imaging marker of HEHE on MRI (18).

The definitive diagnosis of HEHE relies on histopathological results. Tumour cells exhibit invasive growth patterns and comprise epithelioid, dendritic and intermediate cells, as evidenced by haematoxylin-eosin staining (6). Immunohistochemistry indicates that most patients are positive for CAMTA1, factor VIII related antigen, vimentin, CD31, CD34 and D2-40, with a minority showing TFE3 positivity (3,17). CD31 has high specificity for HEHE diagnosis, while CD34 has high sensitivity. Notably, CAMTA1 is a critical marker for HEHE diagnosis, exhibiting both high specificity and sensitivity (6). By contrast, hepatocellular carcinomas, metastatic carcinomas and intrahepatic cholangiocarcinomas commonly express cytokeratin, whereas CD31 and CD34 are less frequently detected (19). Distinguishing HEHE from haemangiosarcomas, both of which may express CD31 and CD34, poses additional challenges (20). Haemangiosarcoma, a high-grade malignant tumour, typically exhibits considerable nuclear pleomorphism, heterogeneity and substantial mitotic activity (15). CAMTA1 was present in the cytosolic nucleus in ~85% of HEHE cases, providing high sensitivity and specificity for effectively differentiating HEHE from angiosarcoma (6,20). Unfortunately, CAMTA1 immunohistochemistry could not be performed for the patient in this study due to unavailability of the CAMTA1 antibody at our hospital. However, other positive indicators in the immunohistochemistry programme, such as CD31, CD34, ERG and FLI-1, and the imaging and pathological findings, fully supported the diagnosis of HEHE. Classical HEHE is frequently associated with a WWTR1-CAMTA1 fusion, accounting for ~90% of cases, whereas subtypes with a YAP1-TFE3 fusion are uncommon. In such cases, immunohistochemistry is usually positive for TFE3 (11,21). Therefore, TFE3 immunostaining has been suggested as an effective method to differentiate classical HEHE from its subtypes (22). Although positive TFE3 immunostaining does not directly imply a YAP1-TFE3 fusion phenotype, it highly correlates with the phenotype (23).

The scarcity of literature and the rarity of HEHE have restricted our understanding of this disease. Currently, the most commonly used therapeutic modality for HEHE encompasses hepatectomy, liver transplantation, chemotherapy and follow-up monitoring. These modalities have been associated with 5-year survival rates of 75, 54.5, 30.0 and 4.5%, respectively (16). Furthermore, patients who received therapeutic interventions experienced prolonged survival compared with those who did not (17).

Surgical intervention, primarily involving partial hepatectomy and liver transplantation, is currently the only effective treatment for HEHE. For single or multiple lesions that can be excised, liver resection is the preferred treatment for HEHE, given that it not only achieves radical tumour resection but is also strongly associated with optimal prognosis (6). Conversely, liver transplantation is an appropriate treatment option for diffuse multifocal disease that cannot be effectively managed surgically (3). Specifically, hepatectomy should be preferred in patients with tumour diameter ≤10 cm and ≤10 lesions, whereas liver transplantation is a more appropriate treatment strategy in the presence of >10 lesions (24). Zhao and Yin (17) reported that radical hepatectomy with negative margins was the optimal treatment option for HEHE. The average survival time of patients who underwent hepatectomy was 158.6 months, which was markedly longer than that of patients who underwent liver transplantation (147.3 months). However, owing to the insidious nature of HEHE, its clinical diagnosis is typically established in the mid-to-late stages. Furthermore, 66.6–87% of cases exhibit a multinodular or diffuse distribution, making it difficult to achieve radical hepatic resection (6). Therefore, liver transplantation is considered the treatment of choice for patients with inoperable or diffuse HEHE (17). In clinical practice, a minimum standard of 50% survival after liver transplantation is universally achievable (15). Even with extrahepatic metastases, patients have been shown to achieve survival rates of 80 and 70% at three and five years after liver transplantation, respectively (25). However, there are numerous limitations to the application of liver transplantation, including high cost, donor shortage, unpredictable biological behaviour of tumours and risk of postoperative recurrence (5,9). Liver transplantation was found to be associated with a longer operative time and hospital stay, more intraoperative blood loss, a higher risk of postoperative infection and substantially higher mortality rates of 1–5% in the early stage (≤3 months) and 22% in the late stage (>3 months) than after hepatectomy (0–3 %) (26). Considering the clinical features of the current patient, including normal liver function, <10 lesions and the largest lesion diameter <10 cm, all lesions were completely resected, and the decision to perform a hepatectomy was reached. Patients with HEHE who are non-candidates for surgery can be treated with chemotherapeutic drugs such as adriamycin, 5-fluorouracil, platinum and cyclophosphamide (17). However, no specific chemotherapeutic agents have been identified to treat HEHE. Furthermore, combining anti-vascular endothelial growth factor drugs with cell cycle inhibitors, such as bevacizumab, capecitabine, cyclophosphamide and doxorubicin, was found to be an effective treatment for HEHE (9).

Image-guided MWA and radiofrequency ablation (RFA) are safe and effective in treating HEHE, achieving a technical success rate of 93.5%. The overall survival rates for patients treated with ablation at 1, 3 and 5 years were 87.6, 75.5 and 75.5%, respectively, comparable to the prognosis following liver resection or liver transplantation (7). While both RFA and MWA induce tumour necrosis through thermal effects, their heat-generating mechanisms differ. RFA primarily relies on ion excitation and energetic collisions, whereas MWA utilises dielectric heating to convert electromagnetic energy into thermal energy (27). MWA operates at higher frequencies and shorter wavelengths than RFA, which allows it to reduce ablation time and increase the ablation area. Additionally, the ablation effect in MWA is not influenced by tissue impedance, making it suitable for solid organs and dry tissues while minimising temperature drops at the margins that could occur due to the heat sink effect (28). The main complications associated with MWA stem from insufficient control of the microwave radiation field and may include vascular, biliary, mechanical and infectious complications. However, developing new technologies, such as temperature-controlled microwave irradiation systems, is anticipated to reduce these risks. Therefore, MWA remains a safe and effective method for liver tumour ablation, particularly for lesions smaller than 3 cm in diameter. It has a high complete ablation rate and a low incidence of complications (29). In the current case, ultrasound-guided MWA was used to successfully treat a suspected neoplastic lesion in the S4 segment, resulting in complete tumour ablation without any complications.

Despite multiple lesions, preoperative CT, MRI and three-dimensional reconstruction may indicate that radical resection of HEHE with multiple lesions could be achieved. Preoperative three-dimensional reconstruction can accurately assess the number and location of lesions while considering their spatial relationship with the hepatic vasculature, thereby facilitating the development of an optimal resection plan. This approach also helps preserve postoperative arterial blood supply and venous drainage (30). In addition, IOUS enables precise lesion localisation during excision. IOUS uses a high-frequency ultrasound probe positioned directly on the liver surface to localise lesions and evaluate surgical margins (31). Imaging plays a pivotal role in HEHE management. Enhanced CT and MRI techniques serve as the foundation for accurate diagnosis and evaluation of surgical feasibility. Combining preoperative three-dimensional reconstruction and IOUS allows for complete and accurate resection of all multiple HEHE lesions during the intraoperative period.

Although a tumour number ≥4 was unrelated to tumour recurrence, a tumour diameter ≥4 cm was associated with a higher risk of tumour recurrence (1). Given the unpredictable biological behaviour of tumours, regular postoperative follow-up is essential for the timely detection of recurrent lesions. Na et al (1) suggested that patients with junctional tumours who have undergone hepatectomy should be followed up every 3–4 months for the first year after surgery and every 4–8 months thereafter. Furthermore, monitoring patients with HEHE every 3 months for the first 2 years after hepatectomy has been recommended, followed by every 6 months thereafter (32). Based on these recommendations, a follow-up schedule was established: Every 3 months for the first year post-surgery and every 6 months thereafter. A review three months after surgery revealed an abnormal enhancement in the S4 segment of the liver. The lesion was identified as a new HEHE owing to its considerable distance from the initial surgical resection site. However, the biopsy did not provide conclusive evidence of HEHE tumour cells. Nevertheless, owing to the inherent limitations of puncture biopsy and the inability to completely rule out tumour recurrence, the team elected to treat the patient of the present study with MWA to avoid delays. Patients aged ≥65 years, those with a tumour diameter exceeding 10 cm, those with hepatic dysfunction and those with intrahepatic metastases (diffuse) were associated with a poor prognosis (6,17). In the present study, the patient was a 23-year-old male with normal liver function but with multiple intrahepatic lesions involving six liver segments, including tumours with a maximum diameter of ≥4 cm. The patient's prognosis warrants further follow-up.

Although HEHE is a rare, low-grade malignant tumour of the liver, CT and MRI examinations reveal distinctive features that distinguish it from other liver tumours. These imaging techniques are crucial for preoperative diagnosis and help determine the appropriate diagnostic and treatment options. When considering surgical resection for multifocal HEHE, three-dimensional reconstruction and IOUS can enhance the accuracy of resection of all lesions. Patients with HEHE who undergo hepatectomy should be regularly monitored to detect recurrent or new lesions. MWA is a safe and effective treatment option that yields favourable results for solitary HEHE lesions <3 cm in diameter.

Acknowledgements

Not applicable.

Funding

The present study was funded by the Natural Science Foundation of Gansu Province (grant no. 22JR11RA023).

Availability of data and materials

The data generated in the present study are included in the figures and table of this article.

Authors' contributions

JWM performed literature review and drafted and edited the manuscript. KXZ and ZLZ advised on patient treatment and performed the surgery. BP and SW collected and analyzed medical images (e.g. ultrasound, CT, MRI and three-dimensional reconstruction). YZ collected and analyzed pathological images (e.g. haematoxylin-eosin staining and Immunohistochemistry). JWM, ZLZ and KXZ contributed to data analysis and interpretation. All authors have read and approved the final version of the manuscript. JWM and KXZ confirm the authenticity of all the raw data.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Ethics Committee of the First Hospital of Lanzhou University (approval no. LDYYLL-2025-21; Lanzhou, China).

Patient consent for publication

The patient provided written informed consent for publication, authorizing the use of their imaging, pathological and clinical data for publication.

Competing interests

The authors declare that they have no competing interests.

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Spandidos Publications style
Mou J, Zhang Z, Peng B, Wu S, Zheng Y and Zhu K: Diagnostic and therapeutic understanding of multiple foci hepatic epithelioid haemangioendothelioma: A case report. Oncol Lett 30: 383, 2025.
APA
Mou, J., Zhang, Z., Peng, B., Wu, S., Zheng, Y., & Zhu, K. (2025). Diagnostic and therapeutic understanding of multiple foci hepatic epithelioid haemangioendothelioma: A case report. Oncology Letters, 30, 383. https://doi.org/10.3892/ol.2025.15129
MLA
Mou, J., Zhang, Z., Peng, B., Wu, S., Zheng, Y., Zhu, K."Diagnostic and therapeutic understanding of multiple foci hepatic epithelioid haemangioendothelioma: A case report". Oncology Letters 30.2 (2025): 383.
Chicago
Mou, J., Zhang, Z., Peng, B., Wu, S., Zheng, Y., Zhu, K."Diagnostic and therapeutic understanding of multiple foci hepatic epithelioid haemangioendothelioma: A case report". Oncology Letters 30, no. 2 (2025): 383. https://doi.org/10.3892/ol.2025.15129