In the present study, we investigated the clinical features and treatments of 42 patients with EHEs at 13 Japanese tertiary hospitals. Few studies have conducted a multicenter evaluation of EHE, which is an exceedingly rare and unique sarcoma. To our knowledge, this is one of the largest published multi-institutional cohorts of patients with EHEs ever reported. Although our study is limited by its retrospective nature, novel data on EHE have been obtained. The clinical diagnosis and treatments for patients with such malignancy remains a challenge for clinicians. The patient characteristics, such as age, female-to-male ratio, involved organs, tumor features, symptoms at diagnosis, and prognosis, in Japanese patients with EHEs are similar to those in previous reports [
1,
6]. The survival rates from our study are generally same as those reported in Western countries [
1,
6,
4].
Twenty-two patients (52%) presented with various symptoms derived from the site of EHEs. The symptoms were not only local, such as pain, cough, and palpable mass, but also systemic, such as weight loss, fatigue, and pyrexia. These systematic symptoms seem to be induced by some cytokines released from the EHEs [
15]. Interestingly, the symptoms noted in the present study tended to be similar to those previously reported, with pain being the most common symptom. However, the proportion of symptomatic patients was higher in Western countries (72%) [
1] than that in Japan (52%, Table
1).
Various treatments were performed for the patients with EHE in this study. Sugical resection can be curative for EHE and it was performed in 11 patients (26%) as initial treatment. Debulking surgery (
n = 1), radiofrequency ablation (
n = 1), radiation (
n = 1), transcatheter arterial chemoembolization (
n = 1), and observation/watchful waiting (
n = 17) were also performed, which are not commonly done for EHE in Western countries (Table
4). Additionally, wathchful waiting is sometimes a reasonable strategy for patients with EHE because it was actually done in 17 patients in this study. Concerning systemic chemotherapy, paclitaxel was frequently used in both Japan and Western counties. Clinical trial of weekly paclitaxel for patients with angiosarcoma: the ANGIOTAX study [
16] reported a median time to progression of 4 months for metastatic angiosarcoma, a disease belonging to the same group of vascular sarcoma, and this might be a basis for deciding on the treatment regimen for patients with EHEs. Combination regimens are often used in Japan (Table
5), while monotherapy is mainly used in Western countries [
14]. Anti-angiogenic drugs, such as bevacizumab, pazopanib, sorafenib, sunitinib, and axitinib and the mammalian target of rapamycin (mTOR) inhibitor, such as sirolimus are used in Western countries [
14,
17‐
20]. Concerning the efficacy of systemic chemotherapy, our findings showed that the combination regimens of carboplatin, paclitaxel plus bevacizumab or carboplatin, and pemetrexed plus bevacizumab achieved PR as evaluated using the Response Evaluation Criteria In Solid Tumors version 1.1 (Table
5). In contrast to the findings of the present study, patients treated with systemic chemotherapy using single regimens such as interferon, celecoxib, bevacizumab, sorafenib, pazopanib, and thalidomide in previous studies were confirmed to have achieved PR [
14,
17‐
19,
21]. The combination of carboplatin and bevacizumab is interesting because the efficacy of those combination regimen for EHE have never been reported, and these regimens should be explored in clinical trials. Concurrently, role of systemic therapy and its efficacy for advanced EHEs need further investigation. Novel gene fusions with oncogene properties, namely,
WWTR1(TAZ)-CAMTA1 and
YAP1-TFE3, are expected to be directly used as treatment in the future because
TAZ and
YAP1 play major roles in the Hippo pathway, which regulates tissue homeostasis, organ size, cell regeneration, and tumorigenesis [
22,
23].
Most EHEs are considered to be indolent; however, our data and previous reports have shown 20–60% of tumors metastasize, and approximately 15% of patients die of EHE [
8,
14,
15]. Deyrup et al. reported that a combination of tumor size and mitotic activity has been useful to stratify tumors into low- and high-risk groups, that is, patients with tumors > 3 cm in diameter and > 3 mitoses per 50 HPF have a lower 5-year survival of 59% than the 100% survival rate in patients with tumors that lacked both features [
6]. The result of multivariate analysis in the present study demonstrated that tumor diameter > 3.0 cm was associated with poor outcome (Table
6), and that patients with Ki-67 index > 10% suggested worse survival than those with Ki-67 index ≤10% (Fig.
3). As mentioned by the previous report [
7], one of factors that corresponded with poor prognosis was high Ki-67 values (≥ 10%) in angiosarcoma which mimics EHE. This result implied that the Ki-67 index could be used to classify EHE into low- and high-risk groups. Moreover, the role of the Ki-67 index needs to be explored further because its value in 24 of the 42 patients in the present study was unknown. Our data support past reports proposing risk classification of EHE. The findings of the current study suggest that the presence of symptoms, most of which are caused by large tumors and may reflect performance status, is related to poor outcome (Fig.
2).