Tumori, 94: 892-897, 2008 Primary cardiac angiosarcoma: a case report Ozge Petek Erpolat1, Fikri Icli2, Orhan Veli Dogan3, Gokhan Gokaslan3, Muge Akmansu4, Selim Erekul5, and Ertan Yucel3 1 Kutahya Evliya Celebi Government Hospital, Department of Radiation Oncology, Kutahya; Ankara University Medical School, Department of Medical Oncology, Ankara; 3Ankara Dıskapı Yildirim Beyazit Training and Research Hospital, Department of Cardiovascular Surgery, Ankara; 4 Gazi University Medical School, Department of Radiation Oncology, Ankara; 5Ankara University Medical School, Department of Pathology, Ankara, Turkey 2 ABSTRACT Primary tumors of the heart are rarely seen. Cardiac angiosarcomas are malignant tumors that almost always have a poor prognosis. We describe a 29-year-old man with primary cardiac angiosarcoma with multiple site metastases. The therapeutic approach includes surgery, chemotherapy and radiotherapy alone or in combination. New techniques of radiotherapy and combined chemotherapeutic agents may relieve symptoms and prolong a patient’s life. We discuss the diagnosis and treatment of cardiac angiosarcoma in the light of a case report. Introduction Primary tumors of the heart are rarely observed. Whereas 75% of them are benign, 25% are malignant1. The most common type of primary cardiac malignancies is lymphomas and angiosarcomas, which mostly originates in the right atrium and pericardium2-4. These patients carry a poor prognosis due to delayed diagnosis until tumors become untreatable and there is a high incidence of systemic metastasis at presentation5. The rareness of this disease limits gaining experience for optimal approach to treatment. Although the prognosis after surgery is usually excellent in the case of benign tumors, it is unfortunately still limited in localized malignant disease. Patients with sarcomas live for a mean of 3 months to 1 year6. This fact led us to review the literature in the light of a case report. Case report A 29-year-old man with an one-month history of chest pain, fatigue, and dyspnea occurring with exercise was admitted to the hospital. No fever, weight loss or syncope was reported. There was no remarkable medical or surgical history except a varicosal operation 2 years before. Upon physical examination, the patient (who had a normal appearance) had a 120/85 mmHg blood pressure and 85 beats/min heart rate. Electrocardiography showed normal sinus rhythm. Routine blood tests were regular. Transthoracic echocardiography showed a round, smooth margin and capsulated mass measuring 30k17 mm and originating from right atrium. The mass extended to the inner part of the vena cava superior and tricuspid valve. Moreover, minimal pleural effusion was seen. No thorax computerized tomography (CT) or magnetic resonance imaging (MRI) was performed. A few days later, surgery was scheduled. After median sternotomy, a sample of serohemorrhagic fluid in the pericardium was taken to exclude infectious agents. Minimal pleural effusion was established as seen at transthoracic echocardiography. The right atrium was adhesive to the pericardium. In spite of the non-existence of a malignant mass externally, a soft mass was palpated at the right atrium wall. After right atriotomy, a mass with a malignant appearance and filling the right atrial cavity was established macroscopically. The tu- Key words: cardiac angiosarcoma, chemotherapy, radiotherapy. Correspondence to: O Petek Erpolat, MD, Konutkent 2 A8 Blok 62, Cayyolu Ankara, Turkey. Tel +90-533-348-5950; e-mail petektater@yahoo.com Received November 7, 2006; accepted April 24, 2007 CARDIAC ANGIOSARCOMA mor and related right atrial wall were then removed with an adequate margin. Upon gross examination, the pathologist defined the resected material as measuring 10k10k5 cm, enclosing a dark colored, hemorrhagic and necrotic tumor with indistinct boundaries, and appearing only partly encapsulated (Figure 1). Histologically, the tumor consisted of irregular, anastomosing vascular structures lined by oval-irregularshaped atypical mesenchymal cells. Frequent mitotic figures and large necrotic areas were noted (Figure 2A). Immunohistochemically, the tumor cells displayed strong positive cytoplasmic staining for CD 31, CD 34 and factor VIII-related antigen (Figure 2B). These fea- 893 tures were found to be typical for angiosarcoma (No of pathology report: 502342/28.02.2005). After histopathologic evaluation, a thorax CT was performed which showed a few suspicious nodules in the lung measuring less than 1 cm. Abdominal and cranial CT scans were normal. Upon physical examination in our clinic he was a well-built young male patient. Other than a pulse rate around 50/min and a sternotomy scar, he had no other pathologic finding. Subsequently, the patient received 4 cycles of chemotherapy consisting of ifosfamide (1.8 g/m2 x 5 days), doxorubicin (60 mg/m2 day 1), mesna (1.8 g/m2 x 5 days) and granulocyte colony-stimulating factor scheduled for once in 3 weeks. A repeat CT scan of the A B Figure 1 - A) In gross examination, pathologist defined a 10k10k5 cm sized resection material, enclosing a dark colored, hemorrhagic and necrotic tumor with indistinct boundaries, appearing only partly encapsulated. B) Multi-slice sections of the material. A B Figure 2 - A) Anastomosing irregular vascular structures lined by atipical oval mesenchymal cells; H&E, x200. B) Strong cytoplasmic positivity of the tumor cells with antibody to CD31 antigen; H&E, x200. 894 OP ERPOLAT, F ICLI, OV DOGAN ET AL thorax at this stage failed to show any lung nodules, and while waiting for radiotherapy to the right atrium, two additional cycles of chemotherapy without doxorubicin were given. A positron emission tomography (PET) following the last cycle of chemotherapy was reported as within normal limits. However, two months after completion of the sixth cycle of chemotherapy, multiple nodules in the lungs were observed at thorax CT (Figure 3A). A combination of ifosfamide (1.3 g/m2 x 3 days), vepesid (100 mg/m2 x 3 days), and cisplatin (20 mg/m2 x 3 days) was started. Two weeks following the first cycle of this combination chemotherapy, the patient was admitted to the emergency room for nausea, vomiting, abdominal pain and cramps. Clinical and radiologic evaluation indicated invagination of the small bowel. Metastatic angiosarcoma in the jejunum was determined after partial intestinal resection (No of pathology report: 13857/23.09.2005). Ten days later, symptoms of hemiplegia of right upper and lower extremities occurred. Cranial MRI detected three metastatic lesions, the largest of which (2 cm) was in the cerebrum. The patient received gamma-knife treatment for brain metastasis and right hemiplegia improved. Following the gamma-knife treatment, the patient was given 6 cycles of gemcitabine (800 mg/m2, on days 1 and 8) and taxotere (80 mg/m2, on day 8) every 3 weeks. A thorax CT after the 6th cycle showed significant regression of the metastatic lesions in the lung (Figure 3B). While receiving the 6th cycle, a new lesion in the left atri- um was identified. He was experiencing dyspnea on exertion and was having mild bradycardia (around 50/min). Palliative radiotherapy was scheduled. The distance between the jugular notch and the L2 vertebra was measured for using thoracic MRI scanning at the simulator, which was preferred due to its advantages in diagnosing soft tissue tumors and demonstrating their margins related to adjacent organs (Figure 4). For treatment planning, some reference markers like fish oil (which had tissue intensity like soft tissue) was used. The fish oil capsule was placed on the patient’s midline as a reference that could be established by MRI. Slices were loaded into our three-dimensional (3D) planning system (Eclipse, Varian, Switzerland). A tumor in the left atrium near the interatrial septum was detected and marked. Planning target volume encompassed gross tumor volume with a margin of 2 cm. One anterior open, one left-anterior oblique open, and two posterior oblique wedge portals were used to provide homogenous dose distribution at a 100% reference dose. Dose-volume histograms for some critical organs such as the medulla spinalis, esophagus, lung, and heart showed that they received tolerable doses. A radiation dose of 46 Gy at 2 Gy daily fractions was applied to the patient. The 7th cycle of chemotherapy was given during the radiotherapy. Grade 2 esophagitis occurred. However, no grade 3 acute side effects were seen during radiotherapy. Following radiation to the left atrium, the patient received another gamma-knife treatment to the A B Figure 3 - A) Two months later from completion of chemotherapy, multiple nodules in lung were seen at thorax CT. B) After the 6th cycle of gemcitabine and taxotere, metastatic lesions showed a significant regression. CARDIAC ANGIOSARCOMA Figure 4 - A new lesion in the left atrium on thoracic MRI. brain because of progressive brain metastasis. Brain CT following the treatment showed significant improvement in edema and a decrease in size of the metastatic lesions. The patient was doing well other than some dysphagia related to left atrial radiation combined with chemotherapy. However, he died 2 months after the last gamma-knife treatment at home following sudden onset of severe headache and loss of consciousness in a couple of hours. He survived for 18 months from the diagnosis of left atrial angiosarcoma. Discussion Primary tumors of the heart are rare. In autopsy series, the incidence was reported to range from 0.001% to 0.030%7. The incidence of benign tumors is 75% of primary cardiac tumors1. Most of them are myxomas, usually located within the left atrium8. Angiosarcoma is the most common histologic type of malignant cardiac tumors. Contrary to benign tumors, it mainly originates in the right atrium, interatrial septum and may involve the pericardium2,4,9. In our case, however, the tumor originated in the right atrium, and a new lesion appeared in the left atrium after surgery. Morphologically, it is a welldefined, large mass which usually shows hemorrhagic and necrotic areas. The pericardium may be infiltrated by the tumor10,11. Angiosarcoma is usually asymptomatic until it becomes untreatable and metastatic. Patterns of clinical presentation are signs of pulmonary hypertension, vena 895 cava obstruction, and pulmonary emboli. Left-sided tumors may cause rapidly progressive congestive heart failure or mitral valve disease1,9. Arrhythmia is usually seen12. Dyspnea is the most common symptom and is reported in 59% to 88% of patients1. Chest pain, tamponade, hemopericardium caused by a pericardial involvement or constitutional symptoms such as fever, weight loss and anemia may occur9,10. For the early diagnosis of malignant cardiac tumor, echocardiography, either transesophageal or transthoracic, is the most useful tool for describing the size and origin of a mass13. Tumor appearance may be interpreted as benign or malignant by echocardiography8,13. In addition, MRI and CT are used for diagnosis and systematic evaluation of disease4. Despite these techniques, histopathology is the most accurate way to diagnose a malignant cardiac tumor5. Some authors have suggested that CT does not show a clear image due to moving artifacts, and the angiosarcoma contained too much blood in the right atrial cavity by both plain and enhanced CT. However, MRI can demonstrate clear distinctions between the tumor and the blood. MRI has more advantages to diagnose a cardiac tumor by tissue characterization14. Our case was admitted due to his chest pain, dyspnea, and general fatigue. A right atrial mass was detected by using transthoracic echocardiography, which was performed initially. According to the literature, a tumor located in the right side of the heart or in the pericardium is usually interpreted as malignant13. Additionally, early diagnosis of a tumor may improve survival significantly by allowing tumor resection15. For this reason, in order to make a definite diagnosis and improve survival, resection was scheduled before systemic evaluation. One of the main problems of these patients is a delayed diagnosis, because cardiac angiosarcomas are usually asymptomatic until they become large and infiltrate vital structures, which carries the disease to a later stage and deems it unresectable. The other problem is systemic metastases, which were shown in 66-89% of patients at first presentation3,5. The most common site of distant failure is the lung, the other sites being brain, bone and colon6. The cause of death is usually as result of postoperative complications, obstructive cardiac lesion or progressive metastatic sites5. In our patient, at first evaluation by using thorax CT, nodules measuring <1 cm were detected in the lung and were accepted with uncertainty as metastasis. After 6 months from the initial diagnosis, lung, jejunum and brain metastases developed respectively in time with short intervals. The therapeutic approach for primary cardiac angiosarcoma is surgery, chemotherapy and radiotherapy, alone or in combination. The initial treatment is surgery. Complete resection is required to improve survival, but it is rarely achieved due to tumor aggressiveness5. After complete resection, local relapse is commonly seen and is the cause of nearly one-third of the 896 deaths3. Most patients receive incomplete resection to relieve symptoms or to prevent progression of disease. The other surgical approach is heart transplantation. It is an attractive option in unresectable tumors after excluding the presence of systemic metastasis. Different results of the latter method are reported in the literature and necessitate further studies. However, it can be applied to selected patients1. The treatment principles for cardiac angiosarcoma should be similar to sarcomas arising from other areas of the body6. Adjuvant radiotherapy and chemotherapy are usually recommended after incomplete or complete resection to improve control of local and distant disease1,3. The radiotherapy dose ranges from 45 to 50 Gy at 1.8-2 Gy fractions after complete resection. This scheme is based on experience with soft tissue sarcomas6. If possible, a 10-20 Gy boost dose should be given to residual disease, but risks of serious cardiac and pericardiac toxicity and technical difficulties limit the safe application of an effective radiation dose1,6. Novel radiotherapy techniques such as 3D conformal planning or intensitymodulated radiation therapy may provide a more homogeneous dose distribution and limit normal tissue damage. 3D conformal radiotherapy planning using MRI images was adapted in our patient. He received 46 Gy at 2 Gy per fraction daily. The aim of radiotherapy for the patient was palliation and preventing progression of disease. Multiple lung metastases and logic of the therapy led us to limit the dose. In radiotherapy, 3D planning is preferred to protect surrounding structures such as the lungs and medulla spinalis while providing high-dose delivery to the gross tumor volume. Our case tolerated radiotherapy well, in accordance with the results of one series in the literature that reported radiotherapy is well tolerated and is effective in controlling cardiac tamponade in nearly 60% of patients1. The other treatment approach is chemotherapy, which can be used as neoadjuvant, adjuvant and also for metastatic disease. Today, for patients with metastatic sarcomas, most first-line chemotherapy regimens includes anthracyclines and/or ifosfomide16. Unfortunately, most soft tissue sarcomas are resistant to agents such as doxorubicin and ifosfomide. Owing to the rarity of the disease and the limited experience reported in the literature, the role of adjuvant and neoadjuvant chemotherapy is not clear. Chemotherapy was given to our patient after surgery for residual disease and lung nodules suggesting metastasis observed on thorax CT. After 4 cycles of a combined regimen, adriablastine was excluded because radiotherapy to the right atrium was planned. Unfortunately, radiotherapy was delayed and systemic metastases occurred 2 months after the last dose of chemotherapy. The rapid development of disseminated lung metastasis shortly after a normal CT and PET scan may be due to the aggressive behavior of the tumor. It OP ERPOLAT, F ICLI, OV DOGAN ET AL may also be related to development of resistance to ifosfamide. Therefore, the chemotherapy was changed to a docetaxel-gemcitabine combination. The combination of gemcitabine and docetaxel is being applied for treatment of metastatic or unresectable sarcomas. In a various number of phase II trials carried out for patients with advanced or metastatic disease, gemcitabine alone17-22 or docetaxel alone23 was evaluated. According to the results of phase II trials, the response rate was between 3 and 20.5% for gemcitabine and 0 to 18% for docetaxel. However, these studies included either heterogeneous histologic subtypes of sarcomas or drug dosages and schemes. The combination of gemcitabine and docetaxel has been evaluated in a variety of malignancies such as breast cancer, non-small cell lung cancer and esophageal cancer24,25. Hensley et al.26 evaluated the effect of gemcitabine plus docetaxel in a phase II trial in unresectable leiomyosarcomas, with an overall response rate of 53%. Moreover, Leu et al.27 confirmed the synergistic anti-tumor activity biologically for a combination of these drugs27. In our case, the combination of gemcitabine and docetaxel was applied in the light of recent published trials. A good response of pulmonary metastasis and 8 months of survival from the first cycle of this combination chemotherapy was observed despite disseminated metastasis. According to this favorable outcome, it can be stated that gemcitabine plus docetaxel may be an option for treatment of patients with metastatic angiosarcoma who have failed first-line chemotherapeutic agents. The prognosis of angiosarcoma is extremely poor, with a life expectancy ranging from 6-12 months after the initial diagnosis15. There are only a few long-term survivors who received combined therapy in the literature4. In some series, complete resection of gross tumor of a left atrial side origin, with a low mitotic count, no necrotic or hemorrhagic areas and no systemic disease at presentation predicted long-term survival3,5. The low incidence in achievement of complete resection results in recurrence of cardiac sarcomas. Hence, systemic metastases are common so that adjuvant radiotherapy and chemotherapy are strongly recommended3,6. Burke et al.3 reported a significantly improved median survival of 12 months for patients who received radiotherapy, chemotherapy, or both. Median survival time was reported as 3 months for patients who did not receive adjuvant therapy3. Our patient’s survival of 18 months with combined treatment for metastatic disease including chemotherapy, palliative radiotherapy and surgery is in favor of this approach even for disseminated metastatic disease. Altogether, the prognosis is still poor. In spite of combined treatment modalities, the patients still have a dismal prognosis, and optimal therapeutic strategies need to be defined. CARDIAC ANGIOSARCOMA References 1. Chidel MA, Macklis RM: Tumors of the heart and great vessels. In: Principles and practice of radiation oncology, Perez C, Brady LW, Halperin EC, Schmidit-Ullrich RK (Eds), pp 1305-1314, Lippincott Williams and Wilkins, Philadelphia, 2004. 2. Ormerod OJM, Spratt PM, Lewis NP, Wallwork J: Primary angiosarcoma of the heart mimicking a left atrial myxoma. Thorax, 39: 798-799, 1984. 3. Burke AP, Cowan D, Virmani R: Primary sarcomas of the heart. Cancer, 69: 387-395, 1992. 4. Deetjen AG, Conradi G, Möllmann S, Hamm CW, Dill T: Cardiac angiosarcoma diagnosed and characterized by cardiac magnetic resonance imaging. Cardiol Rev, 14: 101103, 2006. 5. Putnam JB, Sweeny MS, Colon R, Lanza LA, Frazier OH, Cooley DA: Primary cardiac sarcomas. Ann Thorac Surg, 51: 906-910, 1991. 6. Butany J, Nair V, Naseemuddin A, Nair GM, Catton C, Yau T: Cardiac tumors: diagnosis and management. Lancet Oncol, 6: 219-228, 2005. 7. Centofanti P, Di Rosa E, Deorsola L, Dato GM, Patane F, La Torre M, Barbato L, Verzini A, Fortunato G, Di Summa M: Primary cardiac neoplasms: early and late results of surgical treatment in 91 patients. Ann Thorac Surg, 68: 12361241, 1999. 8. Grebenc ML, Rosado de Christenson ML, Burke AP: Primary cardiac and pericardial neoplasms: radiologicpathologic correlation. Radiographics, 20: 1073-1103, 2000. 9. Fortmann T: Hemorrhagic nonspecific pericardial effusion as an initial symptom of angiosarcoma of the right heart. Z Kardiol, 93: 807-812, 2004. 10. Loffler H, Grille W: Classification of malignant cardiac tumors with respect to oncological treatment. Thorac Cardiovasc Surg, 38: 173-175, 1990. 11. Engelen M, Bruch C, Hoffmeier A, Kersting C, Stypmann J: Primary left atrial angiosarcoma mimicking severe mitral valve stenosis. Heart, 91: 27-30, 2005. 12. Thomas CR Jr, Johnson GW Jr, Stoddard MF, Cliford S: Primary malignant cardiac tumors: update 1992. Med Pediatr Oncol, 20: 519-531, 1992. 13. Meng Q, Lai H, Lima J, Tong W, Qian Y, Lai S: Echocardiographic and pathologic characteristics of primary cardiac tumors: a study of 149 patients. Int J Cardiol, 84: 69-75, 2002. 14. Inoko M, Iga K, Kyo K, Kondo H, Tamura T, Izumi C, Kitagichi S, Hirozane T, Himura Y, Gen H, Konishi T: Primary cardiac angiosarcoma detected by magnetic resonance imaging but not by computed tomography. Intern Med, 40: 391-395, 2001. 15. Hoffmeier A, Scheld HH, Tjan TD, Schneider M, Kerber S, Schmidt T, Schmid C: Ex situ resection of primary cardiac tumors. Thorac Cardiovasc Surg, 51: 99-101, 2003. 16. Silvestris N, Piscitelli D, Crucitta E, Fiore M, De Lena M, Lorusso V: Unusual response to second-line single-agent gemcitabine in locally advanced primary leiomyosarcoma of the lung: a case report. J Chemother, 15: 507-509, 2003. 897 17. Patel SR, Gandhi V, Jenkins J, Papadopolous N, Burgess MA, Plager C, Punkett W, Benjamin RS: Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol, 19: 3483-3489, 2001. 18. Look KY, Sandler A, Blessing JA, Lucci JA, III. Rose PG: Phase II of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) study. Gynecol Oncol, 92: 644-647, 2004. 19. Hartmann JT, Oechsle K, Huober J, Jakob A, Azemar M, Horger M, Kanz L, Bokemeyer C: An open label, non-comparative phase II study of gemcitabine as salvage treatment for patients with pretreated adult type soft tissue sarcoma. Invest New Drugs, 24; 249-253, 2006. 20. Okuno S, Ryan LM, Edmonson JH, Priebat DA, Blum RH: Phase II trial of gemcitabine in patients with advanced sarcomas (E1797): a trial of Eastern Cooperative Oncology Group. Cancer, 97: 1969-1973, 2003. 21. Spath-Schwalbe E, Genvresse I, Koschuth A, Dietzmann A, Grunewald R, Possinger K: Phase II trial of gemcitabine in patients with pretreated advanced soft tissue sarcomas. Anticancer Drugs, 11: 325-329, 2000. 22. Svancarova L, Blay JY, Judson IR, van Hosel QG, van Oosterom AT, le Cesne A, Keizer HJ, Hermans C, van Glabbeke M, Verweij J, Hogendoorn PC, Nielsen OS: Gemcitabine in advanced adult soft-tissue sacomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer, 38: 556-559, 2002. 23. van Hoesel QG, Verweij J, Catimel G, Clavel M, Kerbrat P, van Oosterom AT, Kerger J, Tursz T, van Glabbeke M, van Pottelsberghe C : Phase II study with docetaxel (Taxotere) in advanced soft tissue sarcoma of the adult. EORTC Soft Tissue and Bone Sarcoma Group. Ann Oncol, 5: 539-542, 1994. 24. Spiridonidis CH, Laufman LR, Jones J, Rhodes VA, Wallace K, Nicol S. Phase I study of docetaxel dose escalation in combination with fixed weekly gemcitabine in patients with advanced malignancies. J Clin Oncol, 16: 3866-3873, 1998. 25. Georgoulias V, Kouroussis C, Androulakis N, Kakolyris S, Dimopoulos MA, Papadakis E, Bouros D, Apostolopoulou F, Papadimitriou C, Aqelidou K, Hatzakis K, Kalbakis K, Kotsakis A, Vardakis N, Vlachonicolist J: Front-line treatment of advanced non-small cell lung cancer with docetaxel and gemcitabine: a multicenter phase II trial. J Clin Oncol, 17: 914-920, 1999. 26. Hensley ML, Maki R, Venkatraman E, Geller G, Lovegren M, Aghajanian C, Sabbatini P, Tong W, Barakat R, Spriggs DR: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol, 20: 2824-2831, 2002. 27. Leu KM, Ostruszka LJ, Shewach D, Zalupski M, Sondak V, Biermann JS, Lee JSJ, Couwlier C, Palazzolo K, Baker LH: Laboratory and clinical evidence of synergistic cytotoxicity of sequential treatment with gemcitabine followed by docetaxel in the treatment of sarcoma. J Clin Oncol, 22: 17061712, 2004.