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Epithelioid haemangioendothelioma (EHE) is an ultra-rare malignant vascular tumour with a prevalence of 1 per 1,000,000. It develops from endothelial cells, which are the cells that line all blood vessels in the body. Therefore, it typically expresses endothelial cell markers. It can also be identified through analysis of the genes. Two genes, WWTR1 and CAMTA1, are broken and fused together in 90% of cases. Alternatively, in approximately 10% of cases, the genes that are broken and fused together are YAP1 and TFE3.
- epithelioid haemangioendothelioma
- rare cancer
- malignant vascular tumour
1. Introduction
Epithelioid haemangioendothelioma (EHE) is a rare, low-to-intermediate grade malignant tumour of vascular origin that may develop in the extremities, soft tissue, lung, bone, and liver. The name was first coined in 1982 by Weiss and Enzinger due to its overlapping features between a haemangioma and angiosarcoma. It is a very rare tumour with a prevalence of 1 per 1,000,000 in the general population [1].
The World Health Organisation (WHO) has recommended that EHE be grouped with malignant tumours [2]. It has an unpredictable clinical behaviour ranging from indolent to aggressively malignant, with a mean survival of 4.6 years, ranging from 6 months to 24 years [2]. Risk stratification models have been proposed to identify lesions at high risk for tumour progression, with tumour cellularity, tumour size, high mitotic figures, and a Ki67 score greater than 10% being the most significant indicators for poor prognosis [3,4].
EHE has no standard treatment regimen, and very few therapeutic options are available. Historically, liver resection and transplantation has been the only curative option for patients with hepatic EHE because of tumour multifocality, but is associated with variable outcomes [5]. However, an expanding oncology therapeutic landscape and advances in genomic tumour analysis may help direct the choice of potentially active treatments, such as those targeting vascular endothelial growth factor (VEGF) or immunotherapy.
2. Epithelioid Haemangioendothelioma
2.1. Radiological Characterisation
Radiologic findings are often nonspecific and vary according to the site. Two characteristic computed tomography (CT) and magnetic resonance imaging (MRI) findings in hepatic EHE include the “lollipop sign”, in larger lesions (>5 cm) due to bridging vein thrombosis with a rounded “head” and a tapering “tail” [6], and the “target sign”, which is a lesion with a low intensity central area surrounded by a hyperintense rim, and is more likely to be found in smaller lesions (2–5 cm) [7]. Of note, benign-looking pulmonary calcification and hepatic capsular retractions are common findings in positron-emission topography (PET)/CT scans of pleural and hepatic EHE, respectively [8].
2.2. Histopathological Features
Morphologically, EHE is most often composed of epithelioid cells, organised in nests or cords, with eosinophilic to vacuolated cytoplasm, set in a distinctive myxohyaline stroma, and occasionally associated with haemorrhagic foci [9]. Blister cells with intraluminal erythrocytes, mild-to-moderate atypia, and a low rate of mitosis may also be present [10]. Immunohistochemical (IHC) stains show EHE consistently expresses endothelial cell markers (CD31, CD34 and ERG), and up to 40% of cases may be positive for cytokeratins [11]. EHE with a YAP1::TFE3 fusion has several distinct morphologic features, including voluminous cytoplasm, well-formed vascular lumens, solid growth, and minimal or no stroma [10]. A minority of cases show atypical or malignant features, such as increased cytological atypia and increased mitotic activity with or without necrosis, and may have morphologic overlap with epithelioid angiosarcoma [12].
2.3. Molecular Characterisation
The WHO classification of sarcomas and the European Society of Medical Oncology (ESMO) consensus have set two gene translocations, both involving the Hippo pathway, as disease-defining fusion genes for EHE [13,14]. The Hippo pathway is involved in normal development, cell growth and homeostasis, hence its dysfunction can lead to the development and progression of multiple cancers [15,16]. The pathognomonic WWTR1::CAMTA1 fusion, which results from a t(1;3)(p36.3;q25) translocation, and the less common YAP1::TFE3 fusion are considered diagnostic fusion genes [13,14,17]. Most cases of EHE are characterised by WWTR1::CAMTA1 (90%) or YAP1::TFE3 (10%) gene fusions [14].
Transcriptional co-activator with PDZ-binding motif (TAZ), encoded by the WWTR1 gene, regulates the activity of various transcription factors, including the Transcriptional enhancer associated domain (TEAD) transcription factors, which play roles in cell proliferation and apoptosis [18]. Nuclear translocation of TAZ is inhibited by upstream proteins in the Hippo pathway [18]. The fusion between TAZ and CAMTA1 results in constitutive activation of TAZ, hyperactivation of TEAD-based transcriptional programs, and upregulated cellular proliferation [19,20] which may be inhibited with drugs that modulate TEAD activity [21].
YAP1 is a transcriptional coactivator, also controlled by the Hippo signalling pathway, which also interacts with transcription factors, such as TEADs, to promote growth and inhibit apoptosis [18]. TFE3 belongs to the MiTF/TFE family of basic helix-loop-helix (bHLH) transcription factors and regulates lysosomal biogenesis and energy homeostasis [22]. The YAP1::TFE3 fusion protein also drives hyperactivation of TEAD-based transcription programs [19].
These different fusion genes give rise to diverse biologic behaviour. Some propose that YAP1-TFE3 fusion tumours should be classified as a distinct entity given their unique clinical and histopathologic characteristics in comparison to conventional EHE [9,23]. In addition, YAP1::TFE3 fused EHE tends to arise in younger patients and has a more favourable outcome than EHE characterised by TAZ::CAMTA1 fusions, with the 5-year overall survival being 86% versus 59%, respectively [23,24].
Next-generation DNA sequencing (IMPACT) and targeted RNA sequencing (Archer FusionPlex Custom Solid Panel) on cohorts of 18 and 49 patients have uncovered additional drivers; at least 22% of cases had alterations in cell cycle and epigenetic pathways, and/or loss-of-function alterations in the DNA damage response pathways. These included pathogenic variants in XRCC1/2, ERCC1, RB1, APC, FANCA, CDKN2A and CKDN2B and ATRX loss [25]. More than 50% of EHE tumours have secondary genomic variants, the presence of which may indicate more aggressive disease [24].
2.4. Clinical Behaviour
Notably, EHE has a variable clinical behaviour: patients with either solitary soft tissue or multifocal lung/liver disease may follow a relatively indolent course, whereas those with either pleural or lymph node involvement, regardless of their primary site or pathologic grade, follow a highly aggressive clinical course similar to a high-grade sarcoma [24]. In general, Mehrabi et al. found that the 1-, 3-, and 5-year survival rates for hepatic EHE, regardless of treatment, were 83.4%, 55.7% and 41.1%, respectively [5].
Several sets of predictors of clinical outcomes have been proposed. Clinical factors associated with shorter survival include: clinical baseline tumour-related pain (TRP), development of TRP during follow-up, baseline temperature, and development of fatigue during follow-up [26]; multifocality, nodal involvement, lung primary, and distant metastasis [24,27]. A proposed three-tiered risk assessment system using tumour size and histologic atypia (defined as high mitotic rate, tumour grade and coagulative necrosis) to stratify patients into low-risk, intermediate-risk, and high-risk groups has shown 5-year overall survival rates of 100%, 81.8%, and 16.9%, respectively [28]. Most recently, Li et al. have established and internally validated the first EHE nomogram prognostic model [29]. Based on the Surveillance, Epidemiology, and End Results (SEER) database, they recruited 512 EHE patients and calculated overall survival (OS) at 1, 5, and 10 years for all patients as 76.5%, 57.4%, and 48.2%, respectively. The age, tumour stage, degree of tissue differentiation, surgical treatment, chemotherapy, and radiotherapy were independent factors predicting prognosis [29].
2.5. Treatment and Management Principles
There is no universally agreed treatment strategy for EHE due to its rarity and lack of comprehensive molecular characterisation. However, a recent consensus strategy by experts and consumers has been published.
Treatment strategies include liver transplantation (44.8%), surgical resection for isolated tumours (9.4%) [14,30,31,32], and chemotherapy [5]. Although active surveillance has never been formally studied, it is also a common practice in experienced centres, particularly for a favourable prognostic subgroup [24]. Indeed, active surveillance is the preferred upfront approach in asymptomatic patients (level of evidence V, B) by the ESMO and SPAEN (Sarcoma Patient EuroNet) [14,33].
Based on analysis of the World Sarcoma Network database, all systemic treatments for sarcoma have limited activity in EHE. Seventy-three patients (33 treated with anthracycline-based regimens, 11 with weekly paclitaxel, 12 with pazopanib, 15 with IFN-α 2b and 27 with other agents) were included, and none showed meaningful activity [34]. Systemic therapy should be reserved for patients with unresectable disease which is symptomatic and progressive. By contrast the experience with targeted therapies (Table 1), especially with VEGF(R) inhibitors and mTOR inhibitors, is slightly more encouraging, with the potential advantage of a more favourable toxicity profile. In particular, VEGF inhibition with bevacizumab is a promising therapy that exploits the vascular nature of EHE and is well tolerated [35,36].
There are currently no reported cases of delivering genomically guided therapies against any of the identified molecular targets. However, novel small molecules targeting the Hippo pathway are in early-phase trials (NCT04665206) [37]. The fusions identified in EHE are also thought to lead to activation of the MEK signalling pathway. Based on this, trametinib is under investigation in an ongoing phase II clinical trial (NCT03148275) [38].
Table 1. Targeted Therapies in EHE.
| Treatment [Reference] |
Study Design and Patient Nos. | Study Outcome [CR, PR, SD, PD] |
|---|---|---|
| Sirolimus [39] |
A case-series analysis within the Italian Rare Cancer Network for 38 EHE patients |
|
| Pazopanib [40] |
A retrospective analysis; an EORTC of Soft tissue and Bone Sarcoma group of 10 EHE patients |
|
| Bevacizumab [35] |
A multicentre, phase II study with 7 EHE patients |
|
| [36] | Case series of 4 EHE patients |
|
| [41] | Case report of one EHE patient | 1 PR to capecitabine and bevacizumb for 6 months. |
| Sorafenib [42] |
Phase II study by the French Sarcoma Group of 15 EHE patients |
|
| Lenalidomide [43] |
A case report of one EHE patient |
|
| Anlotinib [44] |
A case report of one EHE patient | SD for more than 2 years |
| Lenvatinib [45] |
A case report of one EHE patient | PR for 6 months bridging liver transplant |
This entry is adapted from the peer-reviewed paper 10.3390/cancers15174378
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