Epithelioid Hemangioendothelioma: Symptoms, Types, Causes and Treatment

Epithelioid hemangioendothelioma (EHE) is an ultra-rare vascular tumor that challenges patients and clinicians alike. Its unpredictable behavior, diverse presentation, and lack of standardized guidelines can make diagnosis and management especially complex. In this article, we’ll break down the symptoms, types, causes, and treatments of EHE, using the latest research to help you understand this enigmatic cancer.

Symptoms of Epithelioid Hemangioendothelioma

EHE presents a wide spectrum of symptoms, often making it difficult to recognize. Symptoms can be mild or severe, and sometimes the disease is discovered incidentally during imaging for unrelated problems. Understanding the typical and atypical symptoms can empower patients and prompt timely evaluation.

Symptom	Frequency/Pattern	Impact	Sources
Pain	Common initial symptom	Can be persistent or episodic, often in affected bones or organs	2 3 4 9
Mass/Swelling	Frequently palpable	May be noticed in soft tissues or extremities	2 9
Fatigue	Often reported, variable	Reduces quality of life, especially in high-burden patients	3
Dyspnea/Chest pain	Typical with lung/pleura involvement	Causes respiratory distress, especially in older men	1 2 7
Insomnia	Reported in highly symptomatic patients	Worsens quality of life and psychological distress	3
Systemic symptoms	Variable; includes fever, weight loss	Associated with advanced or aggressive disease	4 7

Table 1: Key Symptoms of Epithelioid Hemangioendothelioma

Symptom Variation and Burden

EHE’s presentation is famously variable. Some patients have minimal symptoms for years, while others experience rapid progression. Studies show that:

• Pain is the most common first complaint, especially when bone is involved. In the liver or lungs, pain may be dull or absent until the disease is advanced. Soft tissue EHE can also cause a palpable mass or swelling, sometimes mistaken for benign lesions 2 4 9.
• Fatigue and insomnia are significant for a subset of patients, leading to reduced daily functioning and increased psychological distress. In a large patient-driven survey, about one-third experienced a high symptom burden, mainly pain, fatigue, and insomnia, correlating with decreased quality of life 3.
• Respiratory symptoms such as dyspnea (shortness of breath), cough, chest pain, and occasionally hemoptysis (coughing blood) are seen when the lungs or pleura are affected. Unilateral pleural effusion and nodular thickening can mimic other cancers like mesothelioma 1 2 7.
• Systemic symptoms like fever and weight loss are less common but may signal aggressive or advanced disease 4 7.

Quality of Life and Psychological Impact

The unpredictable course of EHE can lead to significant psychological distress. High symptom burden—particularly pain, insomnia, and fatigue—has been linked to reduced health-related quality of life and increased anxiety or depression. Notably, even among patients with milder symptoms, the emotional impact should not be underestimated, and supportive care is important 3.

Types of Epithelioid Hemangioendothelioma

EHE is not a single disease but a family of related tumors that can manifest in various organs, each with distinct features and challenges. Recognizing the main types is essential for diagnosis and management.

Type	Primary Site(s)	Key Features	Sources
Hepatic EHE (HEHE)	Liver	Solitary, multifocal, or diffuse; often in females; may show peripheral nodules and "lollipop" sign on imaging	2 13 15 17
Pulmonary EHE	Lungs, Pleura	Multiple nodules, pleural thickening, effusion; often mimics carcinomatosis or mesothelioma	1 2 7
Osseous EHE	Bone	Lytic lesions, often axial skeleton; may be multifocal	2 4 10
Soft Tissue EHE	Extremities, trunk, superficial/deep tissues	Palpable mass, often subcutaneous or deep; variable behavior	5 9 10
Multicentric EHE	Multiple organs/tissues	Simultaneous involvement of liver, lung, bone, and/or soft tissue	2 4 7 12

Table 2: Main Types of Epithelioid Hemangioendothelioma

Hepatic EHE (HEHE)

• Epidemiology & Presentation: More common in females; can be solitary, multifocal, or diffuse. Imaging often shows multiple peripheral nodules, sometimes with unique features like the "lollipop" sign (a vessel tapering into a tumor nodule) 2 13 15 17.
• Course: May be indolent or aggressive; extrahepatic spread does not always preclude curative treatment like transplantation 13 15.

Pulmonary EHE

• Features: Usually presents with multiple lung nodules, sometimes with pleural thickening or effusion. Can be mistaken for metastatic carcinoma or mesothelioma 1 2 7.
• Symptoms: Dyspnea, chest pain, cough, and—less commonly—hemoptysis. Older men are more frequently affected in pleural cases 1.

Osseous EHE

• Features: Lytic (bone-destroying) lesions, often in the axial skeleton (spine, pelvis). May be painful and multifocal 2 4 10.
• Differential Diagnosis: Must be distinguished from more aggressive sarcomas and other bone lesions 10.

Soft Tissue EHE

• Sites: Can arise in superficial (dermal) or deep soft tissues; commonly affects extremities, trunk, or head/neck 5 9.
• Behavior: Variable; although sometimes considered "borderline," more recent studies support its classification as a fully malignant vascular tumor 9 10.

Multicentric and Multifocal Disease

• Many patients present with EHE in more than one organ or tissue at diagnosis. The classic triad is liver, lung, and bone, but combinations vary widely 2 4 7 12. Multifocality is associated with a worse prognosis 10.

Causes of Epithelioid Hemangioendothelioma

While the exact triggers for EHE are still being unraveled, advances in molecular genetics have illuminated the main drivers—unique gene fusions that set EHE apart from other vascular tumors.

Cause/Driver	Description	Clinical Relevance	Sources
WWTR1-CAMTA1 fusion	Chromosomal translocation (t(1;3)(p36;q25)); results in constitutive activation of TAZ/WWTR1 signaling	Present in ~90% of cases; diagnostic marker	8 10 11 12
YAP1-TFE3 fusion	Alternative gene fusion in ~10% of cases; activates YAP-driven transcription	Distinct morphology; possibly better prognosis	8 10 11 12
Other rare gene fusions	Less common, not fully characterized	Under investigation	12
Unknown environmental/host factors	No clear environmental or lifestyle risk factors identified	Research ongoing	4 12 16

Table 3: Causes and Molecular Drivers of EHE

Molecular Genetics: The Heart of EHE

• WWTR1-CAMTA1 Fusion:

  • Found in about 90% of EHE tumors, this fusion gene results from a translocation between chromosomes 1 and 3.
  • The fusion protein leads to unchecked activation of TAZ-driven gene expression, which promotes tumor development and growth 8 10 11 12.
  • Immunohistochemical detection of CAMTA1 in the nucleus is a powerful diagnostic tool for differentiating EHE from similar tumors 8.

• YAP1-TFE3 Fusion:

  • Seen in approximately 10% of EHE cases, this alternate fusion also drives tumorigenesis through the Hippo pathway but may be associated with distinct histology and a more favorable prognosis 10 11 12.
  • Tumors with this fusion often lack CAMTA1 expression but express TFE3 8.

• Other Fusions/Mutations:

  • Ongoing research is uncovering additional rare fusions or secondary genetic alterations, which may contribute to disease heterogeneity and aggressiveness 10 12.

The Hippo Pathway and Cancer

The Hippo signaling pathway, which normally restrains cell growth, is bypassed in EHE due to fusion proteins that keep TAZ or YAP activated. This molecular insight not only explains the tumor’s behavior but may also pave the way for targeted therapies 11.

Environmental and Host Factors

• No clear environmental, lifestyle, or occupational exposures have been definitively linked to EHE.
• The disease affects a wide age range, from children to older adults, with a slight female predominance in some subtypes 4 12 16.

Treatment of Epithelioid Hemangioendothelioma

Treatment strategies for EHE are as variable as the disease itself. Decisions depend on tumor location, extent, symptoms, molecular subtype, and patient factors. A multidisciplinary and personalized approach is essential.

Treatment	Indication	Notes/Outcomes	Sources
Surgical resection	Localized, resectable tumors	Preferred for single-organ disease; may be curative	12 14 15 17
Liver transplantation	Unresectable hepatic EHE	5-year survival 43–55%; extrahepatic spread not an absolute contraindication	13 15 17
Radiation therapy	Symptom/pain control, brain mets	Used for palliation or local control	4 14
Chemotherapy	Progressive, unresectable, or metastatic disease	No standard regimen; doxorubicin, ifosfamide, and others tried with variable success	4 12 14 16
Targeted therapy	Advanced disease, clinical trials	Anti-angiogenic agents, emerging molecular therapies	14 16
Immunotherapy	Investigational	Potential role; ongoing research	14 16
Observation	Indolent, asymptomatic cases	“Watch and wait” may be appropriate in select patients	12 14 16
Supportive care	All patients as needed	Pain management, psychological support, symptom relief	3 14

Table 4: Treatment Options for Epithelioid Hemangioendothelioma

Surgical Approaches

• Surgical resection is the treatment of choice for localized EHE, especially in soft tissue, bone, or liver when technically feasible. Complete excision can be curative in many cases 12 14 15 17.
• Liver transplantation is an important option for unresectable hepatic EHE. Large registry studies confirm good long-term survival, even for some patients with limited extrahepatic disease, with 5-year disease-free survival up to 93.9% in low-risk patients 13 15 17.
• Hepatectomy (partial liver resection) is possible for selected patients with solitary or localized hepatic lesions 15.

Systemic Therapy

• Chemotherapy is reserved for patients with progressive, unresectable, or metastatic disease. Responses are variable, and no single regimen is standard. Agents like doxorubicin and ifosfamide have been used, but EHE is often refractory to conventional sarcoma drugs 4 12 14 16.
• Targeted therapies (such as anti-angiogenic drugs) are under active investigation, as EHE is a vascular tumor driven by specific molecular changes 14 16.
• Immunotherapy is an emerging area, with some early data suggesting potential efficacy, but more research is needed 14 16.

Observation (“Watch and Wait”)

• In select patients with indolent, asymptomatic, or slow-growing disease, careful observation may be appropriate, delaying treatment until progression or symptom development 12 14 16.

Palliative and Supportive Care

• Symptom management—including pain control, respiratory support, and psychological care—is crucial to improve quality of life, especially for patients with high symptom burden or advanced disease 3 14.

Prognostic Factors

• Outcomes vary widely. Factors linked to worse prognosis include:
  • Male gender, older age (≥55 years)
  • Pattern B disease (uncontained growth, pleural effusion, hemoptysis, >2 bone lesions)
  • Multifocality, pleural involvement, lymph node or distant metastases 7 10
• Molecular subtype may also affect prognosis (WWTR1-CAMTA1–positive tumors generally have worse outcomes than YAP1-TFE3–positive tumors) 10.

Conclusion

Epithelioid hemangioendothelioma is a rare and complex vascular cancer with diverse presentations, unpredictable behavior, and evolving management strategies. Here’s what to remember:

• Symptoms range from pain and mass/swelling to respiratory distress and systemic effects, with significant impact on quality of life in some patients [1–4,7,9].
• Types are defined by the primary site—liver, lung, bone, soft tissue—or by multicentric involvement, each with unique features and challenges 1 2 4 9 10 13 15 17.
• Causes are rooted in unique gene fusions (WWTR1-CAMTA1, YAP1-TFE3), which drive tumor growth by dysregulating the Hippo pathway; environmental or lifestyle triggers remain unidentified [8,10–12].
• Treatment is personalized: surgery or transplantation for localized disease, systemic therapy or observation for multifocal or advanced cases, and a strong emphasis on supportive care. Research into targeted and immune therapies is ongoing and vital [12–17].

Key takeaways:

• EHE requires expert, multidisciplinary care and patient-centered decision-making.
• Molecular diagnosis is essential for accurate classification and may guide future therapies.
• Clinical trials and international collaboration are crucial to improving outcomes for this ultra-rare sarcoma.

With continued research and global collaboration, there is hope for more effective, tailored treatments for EHE in the years ahead.