Posttransplant outcomes after liver transplantation (LT) have improved significantly over the past few decades, which is largely attributable to advances in surgical techniques, immunosuppression and the management of underlying pathologies [1]. Indications for LT are gradually expanding due to the usage of these outcomes which can serve as benchmarks for the efficacy of newer indications [2]. Non-resectable liver malignancies have emerged as eligible indications for LT that pose unique technical, immunological and oncological challenges [3,4]. This review intendd to summarize the current evidence in LT for hepatic epithelioid hemangioendothelioma (HEHE).

Epithelioid hemangioendothelioma, which was first described by Weiss and Enzinger [5] in 1982, is a rare vascular neoplasm with an estimated incidence of less than one per million [6]. The first report of HEHE was in a case series published in 1984 [7]. Patients often present with multifocal disease, and they frequently present with extrahepatic spread, typically to the lungs or bone [8]. Radiologically, there are two distinct identifiable patterns that correspond with tumor progression. Early-stage diseases are typically characterized by a peripheral pattern showing multiple nodular and usually subcapsular lesions. In later-stage diseases, these lesions coalesce and form large confluent masses in a diffuse pattern, often with vascular invasion and parenchymal distortion [8].

Although long-term survival and even spontaneous regression has been reported [9,10], a literature review showed that, in the absence of treatment, the 5-year survival rate is only 4.5% [8]. Standard chemotherapy and radiotherapy are not effective for HEHE, so surgical resection is the only curative option [11]. However, because of frequent multifocal pattern of the disease, the majority of HEHE cases are not suitable candidates for surgical resection [12]. In patients with limited disease in which complete resection is possible, a 5-year survival rate of 75% has been reported [8].

LT is regarded as the mainstay curative option for the majority of cases for which liver resection is not appropriate [13]. Despite the limited worldwide experience with LT due to the rarity of HEHE, the reported outcomes have generally been favorable. Results from large case series and database studies from Europe and North America in addition to a comprehensive literature review have demonstrated 5-year overall survival rates ranging between 55% and 83% even in the presence of lymph node or vascular involvement or extrahepatic disease [8,14-16]. However, the incidence of posttransplant tumor recurrence is relatively high, as it occurs in up to 1 in 4 patients. Recurrence is often within the liver graft, and it may occur late after LT. Like the primary lesions, the early clinical features can be subtle and the course can be unpredictable, so routine posttransplant surveillance with cross-sectional imaging is recommended [17].

A European collaborative study presented the results of the second HEHE-European Liver Transplant Registry (ELTR) study, in 2017, which built on information obtained from an initial study in 2007 [14,18]. The more recent study included data on 149 LT recipients for HEHE, and it represented the largest published LT series for HEHE to date. The study revealed an overall posttransplant recurrence rate of 24.8% and a 5-year disease-free survival rate of 79.4% [18]. This study identified three risk factors for disease recurrence: short pretransplant waiting time of less than 120 days, macrovascular invasion, and hilar lymph node involvement. This study also confirmed previously reported data indicating that pretransplant extrahepatic disease was not a significant risk factor for recurrence. That study proposed a scoring system (HEHE-LT Score) based on these risk factors to stratify patients according to recurrence risk. Patients with low, intermediate, and high scores had disease-free survival rates of 93.9%, 76.9% and 38.5% respectively. The group that published that study proposed a therapeutic algorithm for the treatment of HEHE, advocating for the adoption of a mandatory 120-day waiting time prior to LT to monitor tumor behavior arguing that such an approach would prevent the futile LT of aggressive angiosarcomas masquerading as HEHE. The study group also recommended the use of tailored immunosuppression and targeted therapy post-transplantation for patients in the high-risk bracket. A marked improvement in disease-free survival was noted in patients transplanted after 1999 compared to the previous period wherein the study group used to a growing approach of early LT for HEHE.

A Korean single-center study presented the outcomes of patients with HEHE who underwent living donor liver transplantation (LDLT) from 2007 to 2016 [19]. During the 10-year study period, four patients, one man and three women, with a mean age of 41.3±11.1 years, underwent LDLT for HEHE. Based on imaging modalities, these patients were preoperatively diagnosed with HEHE or hepatocellular carcinoma, with percutaneous liver biopsy confirming that all four had HEHE. The tumors were multiple and scattered over entire liver, precluding liver resection. The blood tumor markers were not elevated, aside from the fact that CA19-9 and des-γ-carboxy prothrombin was slightly elevated in one patient. The mean model for end-stage liver disease score was 10.8±5.7. All patients underwent LDLT using modified right liver grafts, with a graft-to-recipient weight ratio of 1.11±0.19, and they all recovered uneventfully after LDLT. One patient died due to tumor recurrence at 9 months, while the other three have done well without tumor recurrence, resulting in 5-year disease-free and overall patient survival rates of 75% each. The patient with tumor recurrence was classified as a high-risk patient based on both the original and modified HEHE-LT scoring systems. This study concluded that LDLT can be an effective treatment for patients with unresectable HEHE that are confined within the liver and who have an absence of macrovascular invasion and lymph node metastasis [19].

The recent identification of the pathognomonic fusion protein WWTR1-CAMTA1 in epithelioid hemangioendothelioma is considered to be a breakthrough in understanding the biology of this tumor. This fusion protein results from the translocation of chromosomes 1 and 3 and is present in the majority of cases of epithelioid hemangioendothelioma, this giving great diagnostic potential [20]. The analysis of variant fusion transcripts has demonstrated the monoclonal nature of multifocal HEHE, confirming these as metastatic implants of the same clone rather than synchronous tumors [21]. This finding is likely to facilitate the delivery of effective adjuvant therapies for multifocal epithelioid hemangioendothelioma in the future.

Treatments for HEHE include hepatic resection, LT, chemotherapy, radiotherapy, hormone therapy, radiofrequency ablation, and surveillance alone. A previous study found that the 5-year patient survival rates were 75% in 22 patients who underwent hepatic resection, 20% in 60 patients who were treated with chemotherapy/radiotherapy, and 4.5% in 70 patients who underwent surveillance alone [8]. Another study found that the 5-year patient survival rates were 86% in 11 patients who underwent hepatic resection and 73% in 11 LT recipients [22]. In a different study, the 3-year patient survival rates were reported to be 74.1% in 17 patients who underwent hepatic resection patients and 81.6% in 12 patients who underwent transarterial chemoembolization (TACE) [23]. Although these studies reported similar survival rates in patients who underwent hepatic resection, LT and TACE, the indications for each treatment modality are different. Hepatic resection is indicated for resectable intrahepatic lesions, whereas LT and TACE are indicated for unresectable lesions. Extrahepatic involvement, including lymph node and distant metastasis, is a contraindication for surgical treatment. The roles of non-surgical therapies, including systemic/regional chemotherapy, radiotherapy, hormone therapy, and immunotherapy, have only been investigated in a few small case series [24-26].

The ELTR reported a 5-year survival rate of 83% in 59 LT recipients with HEHE, while the United Network for Organ Sharing (UNOS) registry reported a 5-year survival rate of 64% in 110 LT recipients [14,16]. LT is regarded as primary or salvage therapy for patients with multiple unresectable tumors that are not responsive to other nonsurgical treatments. However, LT in patients with HEHE is limited by various factors, including donor shortage, high medical costs, the need for lifelong immunosuppressant therapy, patient willingness, and the risk of tumor recurrence. The indications of LT for HEHE have not been well-defined. A prognostic score based on an analysis of the ELTR-ELITA (European Liver Intestine Transplant Association) registry suggested that macrovascular invasion, short waiting time (≤120 days), and lymph node involvement were risk factors for posttransplant tumor recurrence, while extrahepatic disease was not found to be a formal contraindication to LT [18], as abovementioned. On the other hand, extrahepatic disease was not a significant risk factor for tumor recurrence in the ELTR-ELITA registry study [18], but another collective review study revealed that extrahepatic disease was significantly associated with higher tumor recurrence rates [27]. A Korean study suggested that extrahepatic disease, including regional lymph node metastasis, may not be an eligible indication for LT, especially LDLT [19].

HEHE is currently a formally recognized indication for model for end-stage liver disease (MELD) score exception point priority in the United States under the new National Liver Review Board. One study investigated the role of LT and exception point waitlist priority by using the UNOS database, in which exception point applications were submitted for 91.6% (120/131) of patients [28]. The 88 patients who received transplants had a median MELD score at LT of 7 and had waited 78.5 days. The unadjusted 1-, 3-, and 5-year posttransplant survival rates of HEHE recipients were found to be 88.6%, 78.9%, and 77.2%, respectively. The unadjusted posttransplant patient and graft survival rates of HEHE patients did not differ significantly from those rates in patients with hepatocellular carcinoma within the Milan criteria receiving exception point priority. This study concluded that most HEHE recipients receive exception points at a universal approval rate, thus allowing them to promptly undergo LT. Patients with HEHE may not have priority for liver allocation in countries with limited numbers of deceased donors. In Korea, an exception point priority is only given to patients with hepatocellular carcinoma within the Milan criteria [29].

In conclusion, LT should be considered as an effective treatment for patients with unresectable HEHE that are confined within the liver and with acceptable risk factors.

There was no funding related to this study.

All authors have no conflicts of interest to declare.

Conceptualization: JIP. Data curation: All. Formal analysis: JIP. Investigation: All. Methodology: All. Supervision: JIP. Writing - original draft: All. Writing - review &editing: All.