Pazopanib for metastatic pulmonary epithelioid hemangioendothelioma—a suitable treatment option: case report and review of anti-angiogenic treatment options

According to a literature review, only 108 cases of this rare tumor involving the lungs have been published. The largest series of PEH published in 2006 contained 93 cases. The authors found an average age of 40.1 ± 17.3 years, with a female predominance of 73 %. Almost half the patients (49.5 %) were asymptomatic at diagnosis. Reported symptoms were dyspnea and cough (18.3 % each), chest pain (16 %), hemoptysis and weight loss (6.5 % each) [4].

Epithelioid hemangioendothelioma can be primary in the lung or pleura, or it may arise in liver, soft tissue or bone. The prognosis is very unpredictable, with life expectancy ranging from 1 to 15 years [5].

The poor prognostic factors of PEH include the presence of respiratory symptoms or pleural effusion at diagnosis, extensive intravascular, endobronchial or interstitial tumor spreading, hepatic metastases, peripheral lymphadenopathy, or the presence of spindle cells in the tumor [2]. However, the worst prognosis was for patients with pleural effusion or hemoptysis, with a median survival of less than 1 year [4]. The current patient had several poor prognostic factors (respiratory symptoms, hepatic metastases, and peripheral lymphadenopathy).

There is no established standard treatment for PEH, due to the rarity of the disease. Surgical resection should be performed if possible. In asymptomatic patients with diffuse lesions, watchful waiting is an acceptable option [1, 6]. Radiotherapy is not effective in certain patients due to the slow growth of the tumor cells, and chemotherapy appears to have little effect [7‐9]. A few cases reported response or stable disease following immunotherapy treatment with interferon alpha [10‐14].

Although its etiology remains unknown, immunohistochemical and electron microscopy studies have revealed that PEH is of endothelial origin [3]. Lymphatic dissemination is extremely rare, thus supporting the endothelial origin of the tumor. Vascular endothelial growth factor (VEGF) and the VEGF receptor were found on PEH tumor cells [15, 16], suggesting that VEGF inhibitors may be a potential treatment for PEH. In a review published a few years ago, anti-angiogenesis agents in angiosarcoma and EHE are discussed but, except for specific activating mutations in VEGFR2, which may be effectively targeted by VEGFR TKIs in some angiosarcomas, the biological mechanisms underlying the activity of these agents in angiosarcoma and EHE are poorly understood [17]. However two small phase II studies were performed with anti-angiogenic drugs in EHE. In a study by Agulnik et al., testing the effect of bevacizumab alone in angiosarcoma and EHE, seven patients with EHE were included; two had partial response (PR) and four had stable disease (SD) [18]. In a sub-group report of 15 patients with EHE who were included in the phase II study of the French Sarcoma group testing the effect of sorafenib in sarcoma patients, only two had PR and five had SD [19].

Pazopanib is a second-generation tyrosine kinase inhibitor with highly selective activity against VEGFR, PDGFR, and c-KIT, which has demonstrated significant clinical benefit in a variety of malignancies, especially for the treatment of metastatic renal cell carcinoma [20]. The PALETTE (Pazopanib Explored In Soft Tissue Sarcoma) study was the first randomized phase III trial demonstrating the efficacy of this anti-angiogenic agent in pretreated soft tissue sarcoma (STS) patients, and 10 % of the patients in the pazopanib group had low-grade sarcomas [21].

In the current case, the patient is still on treatment with pazopanib, with partial response after a few months and prolonged stable disease for up to 24 months based on follow-up with a CT-PET-FDG scan. Considering that chemotherapy is generally ineffective in epithelioid hemangioendothelioma, angiogenesis inhibition is a reasonable approach to manage patients with metastatic EHE.

In a literature review for PEH cases and different target anti-angiogenetic medication, only eight patients who received chemotherapy and bevacizumab were found [6, 9, 15, 16, 22‐24]. Those cases are summarized in Table 1. Partial response was reported in one case only, with the combination of paclitaxel and carboplatin [22]. Other reports of target therapy treatment in this entity were not found.

Although the mechanism of action of thalidomide and its analog, lenalidomide, is not fully understood, they are believed to have immunomodulatory as well as anti-angiogenic properties that logically can fit the treatment of this rare malignancy. A PubMed search using “thalidomide” and “hemangioendothelioma” identified five case reports [25‐29], while “lenalidomide” and “hemangioendothelioma” identified only two case reports [30, 31]. However, none of these had primary thoracic involvement. These cases are also summarized in Table 1, which shows that two cases had partial responses that lasted up to 9 years in one case and another two patients had stable disease lasting up to 7 years.