Primary cardiac neoplasms are rare, with an incidence of ~0.2%. Primary cardiac angiosarcoma (PCA) comprises 2% of all primary cardiac neoplasms (including benign tumors) and is the most common primary malignant cardiac tumor (1,2). PCA typically presents between the third and fifth decades of life, most often arising in the right atrium (RA) and infiltrating the pericardium, which may cause right-sided heart failure or tamponade, usually with superimposed systemic signs, such as fever, night sweats, chills, fatigue and weight loss. Pericardiocentesis yields bloody fluid that often does not contain malignant cells, even when the tumor cells have invaded the pericardium (3). Diagnostic assessment includes tissue biopsy followed by histological confirmation, transthoracic echocardiography (TTE) to determine the tumor dimensions, pericardial status and cardiac function, computed tomography (CT) imaging to exclude metastatic disease, magnetic resonance imaging (MRI) to depict the extracardiac extent of the disease and delineate the extent of the primary lesion; positron emission tomography (PET) imaging may also be useful for detecting metastases when radical surgery is planned (2,4). However, even radical surgery often yields unsatisfactory results, as >90% of the patients succumb to the disease within 1 year (5). Comprehensive treatment includes neoadjuvant or adjuvant chemotherapy, radiotherapy or targeted therapy with complete surgical resection; even orthotopic heart transplantation may prove beneficial for the patients (6). We herein report a case of unresectable PCA originating in the RA. The patient received first-line chemotherapy with weekly paclitaxel, and second-line therapy with vinorelbine and bevacizumab when the disease progressed. The relevant literature was also reviewed, to compare and summarize the treatment of unresectable locally advanced or metastatic PCA.

In June 2015, a healthy 41-year-old Chinese woman complained of a 2-month progressive shortness of breath and chest discomfort for no apparent reason, which was relieved by rest. There was no precordialgia, no radiating back pain, no headache or dizziness, and no edema in the lower extremities. The previous medical history revealed that the patient had presented with unexplained pericardial effusion and underwent pericardiocentesis; however, analysis of the pericardial fluid failed to determine the etiology. On auscultation, there were no heart murmurs or lung rales, with the exception of a pericadial rub. The results of the laboratory tests were as follows: Carbohydrate antigen (CA)125 435.70 U/ml (normal, <35.00 U/ml), CA199 12.70 U/ml (normal, <35.00 U/ml), carcinoembryonic antigen (CEA)1.69 ng/ml (normal, <5.00 ng/ml) and neuron-specific enolase 32.51 ng/ml (normal, <17.00 ng/ml). TTE revealed a large mass (6.7×3.7 cm), originating from the free wall of the RA, of which the lower part entered the right ventricle (RV) during diastole (Fig. 1A), accompanied by a massive pericardial effusion. Chest X-ray revealed expansion of the heart shadow (cardiothoracic ratio, 70%) and bilateral pleural effusion (blunting of the bilateral costophrenic angle; Fig. 1B). A CT scan confirmed the presence of a heterogeneous irregularly shaped mass infiltrating the RA, and also detected bilateral pulmonary nodules (Fig. 1C and D). On MRI, the mass exhibited heterogeneous signal intensity enhancement on T1-weighted images, and flow void on T2-weighted images (Fig. 1E and F). The ¹⁸F-fluorodeoxyglucose uptake in the tumor reached a standardized uptake value of 13.6 (Fig. 2B). PET-CT also revealed tumor metastasis to multiple organs, including the lungs and bones (Fig. 2A and C-G). CT-guided percutaneous biopsy of a left ilium metastasis revealed poorly differentiated spindle-shaped tumor cells with slit-like or irregular vascular channels containing red blood cells (RBCs; hematoxylin and eosin staining; magnification, ×400). Immunohistochemically, the tumor cells were positive for CD31 and CD34 (magnification, ×400; Fig. 3). Taken together, these findings confirmed the diagnosis of metastatic PCA (T2N1M1).

Although the patient's performance status score was 1 on the Eastern Cooperative Oncology Group scale, the tumor had metastasized to other internal organs and total excision of the cardiac tumor was anatomically impossible. Therefore, 90 mg/m² paclitaxel was administered intravenously on days 1, 8 and 15 of a 28-day cycle. Prior to the administration of paclitaxel, the patient received intravenous premedications, including dexamethasone 5 mg, cimetidine 400 mg and phenergan 25 mg. Standard antiemetics (mainly palonosetron 0.25 mg) were prescribed by the treating physician when clinically indicated. Cycles could not be initiated unless the granulocyte count was >1500/μl and the platelets were >100,000/μl. The treatment was well-tolerated by the patient, except for grade II neutropenia (white blood cells 2.41×10⁹/l, neutrophils 1.06×10⁹/l) and prophylactic granulocyte colony-stimulating factor was administered at 150 μg. In December 2015, TTE revealed a shrinkage in the cardiac tumor size (1.5×1.1 cm) and absorption of the pericardial effusion. A CT scan, however, revealed that the volume of the pulmonary nodules had increased and identified new foci in the liver (Fig. 4). On laboratory tests the CA125 level was 19.00 U/ml, the CA199 level was 37.60 U/ml and the CEA level was 8.13 ng/ml. Therefore, vinorelbine was selected as second-line treatment, with 25 mg/m² vinorelbine administered intravenously on days 1 and 8 of a 21-day cycle. In December 24, bevacizumab was added to the therapy scheme (vinorelbine 25 mg/m² on days 1 and 8 of a 21-day cycle following administration of bevacizumab 10 mg/kg on day 1). The patient complained of abdominal pain; thus, Oxycontin was administered at 30 mg/12 h to control the symptom. On January 8, 2016, the patient displayed anemia and respiratory failure (hemoglobin 56 g/l, RBC count 2.16×10¹², PaO₂ 9.18 kPa, PaCO₂ 4.63 kPa, SpO₂ 91.5%, actual base excess 18.9 mmol/l, standard base excess 19.4 mmol/l, D-dimer 40.00 mg/l, and fibrin degradation products 128.1 mg/l) and was unable to tolerate the chemotherapy; thus, a blood transfusion was performed, with oxygen inhalation and diprophylline injection. The patient succumbed to respiratory failure 7 months after diagnosis.

Due to the rapid local relapse and high incidence of systemic metastasis, PCA has a dismal prognosis, with a mean life expectancy of only a few months. The literature focusing on the treatment of unresectable PCA was reviewed. Although the relevant studies were scarce, several case reports and results from phase II trials expanded our knowledge of this rare disease. A summary of most common locations, treatment modalities and outcome is presented in Table I. The cases included in the Table I were almost inoperable, which was undoubtedly among the key factors determining the patients' prognosis. Although there are currently no established guidelines for the treatment of angiosarcoma, no further subgroups have been identified by which adjuvant therapy could be recommended; as previously reported, chemotherapy, radiotherapy and targeted therapy are the most common choices for the treatment of unresectable PCA. In the present case, addition of radiotherapy to the second-line treatment was initially attempted, as several cases of PCA exhibited high sensitivity to radiotherapy (14–16); however, due to the patient's poor physical condition, radiotherapy had to be abandoned. Weekly paclitaxel has been reported to be effective in the treatment of unresectable angiosarcomas (including PCA), with a median progression-free survival (PFS) of 4 months and a median overall survival of 8 months (17). Vinorelbine has demonstrated antitumor activity in angiosarcoma, as monotherapy or combined with gemcitabine (18,19). Bevacizumab is a recombinant humanized monoclonal IgG1 antibody that blocks the activity of vascular endothelial growth factor (VEGF)-A. A phase II trial concluded that bevacizumab is an effective and well-tolerated single-agent treatment for metastatic or locally advanced angiosarcoma (20). Several case reports demonstrated that combination therapy with bevacizumab and chemotherapy or radiotherapy may improve quality of life and survival in patients with metastatic angiosarcoma (21–25). In addition, another VEGF inhibitor, pazopanib, may prolong the PFS of metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy (26), particularly when used as maintenance therapy for PCA (16).

In conclusion, unresectable cardiac angiosarcomas are rare but lethal. In such cases, a multimodality approach including image-guided radiotherapy and targeted therapy may be considered, as the overall prognosis of these patients is poor. Further clinical trials focusing on the treatment of unresectable PCA are warranted.