Epithelioid hemangioendothelioma (EHE) is a rare tumor of the vascular endothelium first described in 1975 by Dail and Liebow (1). The most common original sites of development are liver, lung and bone (2). Approximately one-third of reported cases are also known to occur in other sites, such as the skin or large vessels. Although there is no established standard treatment, surgical resection, including an adequate surgical margin with appropriate adjuvant therapy depending on the risk factors, seems to be suitable treatment method for resectable EHE. On the other hand, there is no consensus on the treatment of unresectable EHE. Here, we report the case of multiple cutaneous EHE on both feet in an 81-year-old woman treated by definitive radiotherapy (RT).
Past history and clinical presentation of patient
An 81-year-old female patient presented with a 2-month history of multiple painful purple-colored patches and papules on both soles and toes (Figure 1). She had no preexisting medical illness or medication history except for hypertension.
Biopsy was performed from the cutaneous papules and nodules. On haematoxylin and eosin staining, round cells with prominent cytoplasmic vacuolization and erythrocytes within the cytoplasmic vacuoles were observed (Figure 2) (3). In the immunohistochemical analysis, CD31 was weakly positive and CD34 was positive. The Ki-67 index was 5–7%. An experienced pathologist examined the biopsy specimens, and the histological diagnosis of EHE was histopathologically confirmed. The patient visited other institution for additional diagnostic consultation, and the diagnosis of EHE was reconfirmed. Systemic staging work-up procedures were conducted, including chest, abdomen and pelvis computed tomography (CT) scans. Imaging indicated no evidence of distant metastasis.
Treatment and clinical outcome
A non-steroid anti-inflammatory drug was prescribed for conservative purposes. Initial symptoms, such as pain and swelling, were improved. However, disease progression was notably observed after 2 months. The size of previously known lesions was enlarged and new lesions were found on the soles and dorsum of both feet.
In the multidisciplinary discussion, we decided to treat the patient with curative RT to control tumors rather than surgical resection because multiple lesions were widely and superficially spread. She underwent CT simulation using an immobilization vac-lock bag to improve the reproducibility of daily treatment. A volumetric modulated arc therapy (VMAT) (4) planning using 6 megavoltage energy was designed with a 0.5 cm bolus to entirely cover involved lesions (Figure 3).
A total dose of 40 Gy over 20 daily fractions at 2 Gy per fraction was delivered. EHE lesions were widely spread on both soles and an area of the right foot dorsum; thus, the RT field included nearly whole soles and involved part of the foot dorsum to eradicate all lesions. There was a break of 2 months after delivering 40 Gy due to dermatitis and edema. RT was continued for residual disease thereafter with an additional 20 Gy. Four months after the completion of RT, lesions on both soles were completely resolved and there were a few remaining lesions on the foot dorsum (Figure 4). There was grade 1 foot edema, swelling and skin erythema. At the 7-month follow-up, the lesions were almost completely resolved. Foot edema was much improved but remained in a mild state. The patient’s last visit was 20 months after the completion of RT. There was no evidence of disease recurrence.
EHE is a rare vascular tumor, classified as a locally aggressive tumor with metastatic potential by World Health Organization (WHO) 2002 (5).
EHE was initially thought to be an aggressive form of bronchioalveolar cell carcinoma and was thus called intravascular bronchioalveolar tumor (1). However, in 1982, Weiss and Enzinger named it EHE, a vascular tumor of bone and soft tissue that presented features between those of hemangioma and angiosarcoma (6). Although its incidence is not clear, the majority of EHE develops in middle-aged adults (7). However, cases in children and elderly people also have been reported (8,9). No gender preference has been reported (5).
As the name suggests, EHE originates from vascular endothelial or pre-endothelial cells. Although approximately two-thirds of reported cases were observed in the liver, lung or bone, it can arise from any organ that has vascular tissue. It may be difficult to determine whether the tumor is multicentric or if it is a primary lesion with metastases in other tissues, as EHE can originate in either organ and metastasize to the other sites or it may have more than one primary site. The disease location in most reports was solitary. However, multifocal disease locations were also reported (10). There are no definitely determined predisposing factors in the development of EHEs, but possible associations with trauma and hormonal factors have been postulated (11). A new hypothesis of the pathogenesis refers to a causal relationship between the development of EHE and chronic Bartonella infection (2). Skin manifestations caused by Bartonella species are well described in the study by Chian et al. (12).
So far, complete surgical resection with adequate margins has been the treatment of choice in EHE. Deyrup et al. reported a retrospective survival analysis of patients with EHE of soft tissue who received surgical resection with or without adjuvant therapy (7). According to this analysis of 49 cases, the 5-year disease-specific survival in patients with EHE of soft tissue was 81%. In univariate analysis, patients with tumors larger than 3 cm or more than 3 mitoses per 50 high power field showed poor prognosis. They reported a 59% 5-year survival rate of the patients who had disease with any of these features, and patients who had disease without these features showed a 100% 5-year disease-specific survival rate. Other factors, such as age, sex, tumor site, cytologic atypia or adjuvant therapy, were not shown to be prognostic.
The usefulness of RT for several cutaneous malignancies was well reported (13-15). In EHE, RT is usually used for postoperative adjuvant therapy; thus, the results of definitive RT have been rarely reported. Wedmid et al. (16) performed induction chemotherapy followed by RT to multiple penile skin lesions. The lesions were completely resolved after treatment and no recurrence developed by 18 months.
Several case reports have described the treatment outcomes of palliative RT for EHE without surgical resection. Suga et al. (17) reported treatment results following palliative RT on multiple liver lesions. They delivered 60 Gy in 10 fractions of RT and achieved a complete metabolic response in positron emission tomography CT (PET-CT) after 7 months of follow-up. Saste et al. (18) performed conventional RT and radiosurgery on bone EHE lesions and achieved metabolic complete response at 2 years of follow-up. Sardaro et al. (2) treated a spine lesion compressing the spinal cord with 30 Gy in 10 fractions of RT and achieved complete symptom resolution. On the other hand, there were also discouraging reports on the use of RT. Van Kasteren et al. (9) treated spinal cord compressing lesions with 40 Gy of RT and chemotherapy, but the disease continued to grow and the patient developed a quadriparesis. Despite the use of doxorubicin chemotherapy, the tumor was disseminated and progressive, and the patient eventually died of respiratory insufficiency. Bahrami et al. (19) also reported disease progression after palliative RT on a thoracic lesion. The patient had a large hilar mass involving the large vessels and bronchus, resulting in atelectasis, pericardial and pleural effusion. In both cases, the patients had metastatic lesions in multiple organs such as the lung, liver or bones, resulting in poor general condition and organ failure.
Ma et al. (20) reported the results of neoadjuvant RT followed by surgical resection. The patient had a huge EHE lesion in the right iliac bone; thus, complete resection was impossible. They performed neoadjuvant RT using intensity-modulated radiation therapy and observed partial regression of the tumor. Complete surgical resection was attempted after RT, and no evidence of disease was observed after 1 year of follow-up. The results of RT in previous studies are summarized in Table 1.
Although RT could not provide satisfactory results in cases of aggressive progression, it achieved complete resolution in cases of small but inoperable lesions, such as our case or that of Wedmid et al. (16). Furthermore, as a neoadjuvant therapy, RT could help local control after complete surgical resection with an adequate margin (20).
In conclusion, this report described a case of EHE developing on both feet of an 81-year-old woman. Surgical resection was rejected due to the multiplicity of the lesions and the advantageousness of RT in terms of organ preservation; thus, 60 Gy of definitive RT was administered. All of the lesions were nearly completely resolved after our treatment, while the patient suffered foot edema and skin dermatitis for several periods. Our study suggests that primary RT can be a good treatment option for patients who have multiple and inoperable cutaneous EHE that is not amenable to complete resection.
Conflicts of Interest: The authors have no conflicts of interest to declare.
Informed Consent: Written informed consent was obtained from the patient for publication of this case report and any accompanying images.
- Dail DH, Liebow AA. Intravascular bronchioloalveolar tumor. Am J Pathol 1975;78:6a.
- Sardaro A, Bardoscia L, Petruzzelli MF, et al. Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor. Oncol Rev 2014;8:259. [Crossref] [PubMed]
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- Fletcher CD, Unni KK, Mertens F. editors. World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of Soft Tissue and Bone. Lyon: IRAC Press, 2002.
- Weiss SW, Enzinger FM. Epithelioid hemangioendothelioma: a vascular tumor often mistaken for a carcinoma. Cancer 1982;50:970-81. [Crossref] [PubMed]
- Deyrup AT, Tighiouart M, Montag AG, et al. Epithelioid hemangioendothelioma of soft tissue: a proposal for risk stratification based on 49 cases. Am J Surg Pathol 2008;32:924-7. [Crossref] [PubMed]
- Carranza-Romero C, Molina-Ruiz AM, Perna Monroy C, et al. Cutaneous epithelioid hemangioendothelioma on the sole of a child. Pediatr Dermatol 2015;32:e64-9. [Crossref] [PubMed]
- van Kasteren ME, van der Wurff AA, Palmen FM, et al. Epithelioid haemangioendothelioma of the lung: clinical and pathological pitfalls. Eur Respir J 1995;8:1616-9. [PubMed]
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- Chian CA, Arrese JE, Piérard GE. Skin manifestations of Bartonella infections. Int J Dermatol 2002;41:461-6. [Crossref] [PubMed]
- Joseph D, Irukulla MM, Ahmed SF, et al. Radiotherapy in aggressive cutaneous pseudolymphoma: a case report and review of literature. Radiat Oncol J 2016;34:76-80. [Crossref] [PubMed]
- Olofsson Bagge R, Ny L. Adjuvant therapies for malignant melanoma. Br J Surg 2016;103:1095-6. [Crossref] [PubMed]
- Rong Y, Zuo L, Shang L, et al. Radiotherapy treatment for nonmelanoma skin cancer. Expert Rev Anticancer Ther 2015;15:765-76. [Crossref] [PubMed]
- Wedmid A, Masterson TA, Maki RG, et al. A case of high-risk penile epithelioid hemangioendothelioma. Nat Rev Urol 2009;6:223-7. [Crossref] [PubMed]
- Suga K, Kawakami Y, Hiyama A, et al. F-18 FDG PET/CT monitoring of radiation therapeutic effect in hepatic epithelioid hemangioendothelioma. Clin Nucl Med 2009;34:199-202. [Crossref] [PubMed]
- Saste A, Cabrera Fernandez DF, Gulati R, et al. A trimodality approach in the management of metastatic low-grade epithelioid hemangioendothelioma of the bone. BMJ Case Rep 2015.2015.
- Bahrami A, Allen TC, Cagle PT. Pulmonary epithelioid hemangioendothelioma mimicking mesothelioma. Pathol Int 2008;58:730-4. [Crossref] [PubMed]
- Ma JK, Barr J, Vijayakumar S. A multidisciplinary approach to the management of atypical osseous epithelioid hemangioendothelioma. Case Rep Oncol Med 2014;2014:917425.