Epithelioid haemangioendothelioma
EHE; "low-grade angiosarcoma" (older, inaccurate); intravascular bronchoalveolar tumour (IVBAT — historic pulmonary form)
Epithelioid haemangioendothelioma is a rare, intermediate-grade endothelial-cell tumour now defined molecularly by the recurrent WWTR1-CAMTA1 gene fusion (~90% of cases) on translocation t(1;3)(p36;q25), or less commonly by YAP1-TFE3 fusion (a clinically distinct subgroup with younger patients and better prognosis). It can arise in essentially any organ — liver, lung, bone and soft tissue/skin are the most common — and frequently presents as multifocal disease at diagnosis. Cutaneous and subcutaneous EHE typically presents as a slow-growing, sometimes painful, dermal or subcutaneous nodule on the limbs of young to middle-aged adults. Behaviour is intermediate between haemangioma and angiosarcoma, with metastatic potential of ~25% (regional nodes, lung, liver, bone). Surgery is curative for solitary disease; sirolimus is the most active systemic agent for unresectable / metastatic EHE.
Clinical features
- Solitary or multifocal slow-growing dermal / subcutaneous nodule, often associated with a small or medium-sized vessel.
- Usually painless; sometimes mildly painful or pruritic.
- Limbs (~50%), trunk (~25%), head/neck (~15%); also internal sites (liver, lung, bone, mediastinum) — multifocal disease at presentation in 20–30%.
- Median age 30–50; F>M slightly.
- Often misdiagnosed as haemangioma, ganglion, lipoma, fibroma or vascular malformation; diagnostic delay common.
Histology & molecular
- Cords, nests and small clusters of plump epithelioid endothelial cells in a chondromyxoid / hyaline stroma — characteristic appearance.
- Intracytoplasmic vacuoles ("blister cells") containing single erythrocytes — primitive vascular lumina.
- Mild to moderate cytological atypia; mitoses typically low; tumour necrosis variable.
- Endothelial markers positive: CD31, CD34, ERG, FLI-1.
- Cytokeratins focally positive in ~30% (mimicking carcinoma).
- WWTR1-CAMTA1 fusion in ~90% (most cases); CAMTA1 immunohistochemistry strongly nuclear positive — a useful diagnostic surrogate.
- YAP1-TFE3 fusion in a smaller distinct subgroup (younger patients, often vasoformative morphology, better prognosis).
- Differential: epithelioid angiosarcoma (more atypia, mitoses, necrosis; aggressive behaviour); epithelioid haemangioma (benign); metastatic carcinoma (especially RCC, melanoma).
Management
- Sarcoma MDT involvement essential.
- Solitary localised disease: wide local excision with the largest feasible margins; nodal assessment if clinically suspicious.
- Imaging — MRI of affected region; CT chest/abdomen/pelvis to exclude multifocal / metastatic disease.
- Multifocal / metastatic disease:
- Active surveillance for indolent disease.
- Sirolimus (mTOR inhibitor) — the most active systemic agent in metastatic EHE; partial response and prolonged disease stabilisation.
- Pazopanib, sunitinib (multikinase inhibitors).
- Conventional sarcoma chemotherapy (doxorubicin) — modest activity.
- Bevacizumab in some series.
- Refer to specialist sarcoma centre with EHE experience (in the UK: Royal Marsden, University College London Hospitals, Birmingham Sarcoma Service).
Prognosis
Variable. Most localised cutaneous EHEs follow an indolent course with 5-year overall survival 70–90% after complete excision. Multifocal or metastatic disease has a wide range of outcomes — some patients achieve prolonged disease stabilisation on sirolimus; others progress to aggressive disease similar to angiosarcoma. Adverse factors include large tumour size (>3 cm), high mitotic count and YAP1-TFE3-negative WWTR1-CAMTA1-positive disease (with adverse histology). Long-term surveillance for at least 10 years is appropriate.
References
- Errani C et al. A novel WWTR1-CAMTA1 gene fusion is a consistent abnormality in epithelioid hemangioendothelioma. Genes Chromosomes Cancer; 2011.
- Stacchiotti S et al. Epithelioid haemangioendothelioma — international consensus. Lancet Oncol; 2021.
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