Epidemiology and molecular mechanisms
EHE is a rare malignant vascular tumor that can occur in any site of the body with low incidence (1/1,000,000 per year). It accounts for less than 1% of all vascular tumors [6]. Soft tissue involvement is frequent, whereas spinal involvement is uncommon. EHE fatality rate was estimated to be 20%, and it involved multiple bones with poor prognosis [2]. Molecular mechanisms are not fully known. Tsuneyosh was the first to report EHE of the bone in 1986[7]. In 1999, the first diagnostic imaging of EHE and detailed description suggested affection of young males having osteolytic lesions involving the cortex and cancellous bone of the lower extremities[8]. Although the pathogenesis of EHE remains unclear, molecular genetics studies represented a breakthrough in recent years, elucidating the etiology and the pathology. The putative malignant progression was paralleled by altered expression levels of tumor protein P53 (TP53), murine double minute2 (MDM-2), Caveolin-1 (CAV-1), and vascular endothelial growth factor (VEGF)[9]. Recent studies have shown that Bartonella spp induce the expression of vascular endothelial growth factor, thereby causing the proliferation of vascular endothelial cells [10]. The WWTR1 promoter encoding a specific fusion transcription factor participates in the development of tumors—WWTR1/CAMTA1 gene fusion by chromosome translocation (1; 3) (p36. 3; q25)[11]. Studies have shown that FOSB (fused to ZNF36 or WWTR1) and FOS (with various fusion partners) were rearrangements accounting for 20% and 29% of the EHE cases, respectively [12].
Pathological Features
The final diagnosis of EHE is established based on the pathological perspective, which is the “gold standard.” CD34 and CD31 are recognized markers of endothelial cells. CD34 is non-specific and was estimated at 90% in malignant vascular tumors [13, 14]. Although the expression of CD31 is limited to endothelial cells, macrophages, and platelets, it is a relatively specific vascular tumor marker[15]. Ets-related gene (ERG) is a member of signal transducers and activators of the ETS transcription family, which is expressed by endothelial cells, and the ERG fusion gene can cause several types of tumors, such as prostate cancer, acute myeloid leukemia, and Ewing’s sarcoma[16]. Miettinen et al. (2011) reported 43 cases of EHE, among which 42 expressed ERG and TFE3, one of the known fusion proteins with high expression [17]. Fli-1 is a nuclear transcription factor involved in cell proliferation and tumorigenesis, which can be used to distinguish benign vascular tumors from malignant vascular tumors[17]. Fli-1 is more sensitive and specific than CD34 and CD31, and 38% of all cases of EHE CK were positive [17, 18]. EMA and smooth muscle antibody were negative in most cases or weakly focally positive in a few cases[15]. One study showed that the expression positive rate of the WWTR1-CAMTA1 protein was 94% and that of YAP1-TFE was 6% in EHE [19]. Several studies have also shown the nuclear expression of FOSB protein in the subsets of epithelioid hemangioma (EH), including lesions showing angiolymphoid hyperplasia with eosinophilia pattern[1]. Additionally, EHE needs to be differentiated from diseases such as EH, and epithelioid angiosarcoma (EA) should be differentiated from synovial sarcoma, malignant melanoma, and other malignant tumors with epithelioid morphology.
Treatment Status
We reviewed previous reports on spinal EHE and found no specific treatment plans or guidelines of prognostic value. Surgery for spinal EHE was the primary choice of treatment, and adjuvant chemotherapy was routine treatment [4]. Chemotherapy drugs to treat EHE including carboplatin, paclitaxel, carboplatin, etoposide, adriamycin, dacarbazine, and ifosfamide have been investigated [1, 4]. Angiogensis plays an important role in tumor growth and metastasis, and anti-angiogenic therapy is a promising treatment of cancer. Overexpression of VEGF, VEGFR2, and VEGFR3 has been observed in pulmonary EHE samples [20]. Currently, bevacizumab combined with carboplatin and paclitaxel is the first-line treatment for EHE, achieving partial remission depending on patient’s condition [4, 20]. Disease stabilization can be achieved with anti-angiogenic agents, such as interferon, thalidomide, and celecoxib, showing to help people with EHE to live at least 6 months longer when given with bevacizumab combined with nab-paclitaxel[4].Anlotinib is a new, small, orally administered multi-target tyrosine kinase inhibitor that strongly inhibits multiple targets, such as VEGFR, PDGFR, FGFR, and c-kit[21]. Anlotinib is in clinical trials for treatment of many human cancers, including non-small cell lung cancer (NSCLC), soft tissue sarcoma, gastric cancer, colorectal cancer, medullary thyroid cancer, differentiated thyroid cancer, and esophageal squamous cell carcinoma [5].
Recent ALTER0203 study showed that Antinib significantly prolonged progression-free survival (PFS), improved objective response rate (ORR) and disease control rate (DCR), and showed good safety in advanced soft tissue sarcoma(STS).A multicenter, single-arm, phase II study subsequently explored anlotinib activity in patients with advanced STS who had failed previous conventional treatments and a phase IIB study to demonstrate the role of anlotinib in advanced STS[22].Overall,233 patients who were treatment-in tolerant or progressed on anthracic line-based chemotherapy were enrolled. The ORR and DCR in the anlotinib group were significantly higher than those in the control group (ORR 10.13% vs 1.33%,P = 0.0145; DCR 55.7% vs 22.67%, P < 0.0001). Additionally, anlotinb treatment significantly improved the median PFS relative to the control (6.27 months, 95% CI 4.30–8.40vs1.47months, 95% CI 1.43–1.57,HR = 0.33,P < 0.0001). This trial further confirmed the efficacy and safety of anlotinib in advanced STS [23].
At present, there are no specific treatment plans and guidelines of prognostic value for treatment of EHE [24].
Anlotinib is a novel multitarget receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor (VEGFR), fibroblast growth factor receptor (FGFR), platelet-derived growth factor receptors (PDGFR), and c-kit. It can prevent tumor angiogenesis and proliferative signaling [23]. ALTER0203 trial demonstrated that anlotinib significantly prolonged the median PFS in patients with advanced soft tissue sarcoma (STS)In this case, histopathological examination was performed to definitively diagnose EHE, a rare malignant vascular tumor with an aggressive clinical course, with a high tendency for both local recurrence and distant metastasis. We recommend treatment with anlotinib after surgery and postoperative adjuvant chemotherapy. The PFS was 6 months, and OS was 16 months, which were good results. Adverse reactions such as hand-foot skin reaction and hypertension were observed.