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Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature
CRVASA-389; No. of Pages 6 cor et vasa xxx (2016) e1–e6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.elsevier.com/locate/crvasa
Case report
Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature Jan Přeček a, Zbyněk Tüdös b,*, Martin Hutyra a, František Kováčik a, David Vindiš a, Zuzana Prouzová c, Miloš Táborský a a
Department of Internal Medicine I – Cardiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, Olomouc, Czech Republic b Department of Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, Olomouc, Czech Republic c Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, I. P. Pavlova 6, Olomouc, Czech Republic
article info
abstract
Article history:
Primary cardiac tumors are very rare diseases, wherein the most frequent primary malig-
Received 29 February 2016
nant cardiac tumor is angiosarcoma. Despite the advances in diagnostics and therapy,
Accepted 1 April 2016
prognosis of primary cardiac angiosarcoma is still poor. Timely diagnosis is a key require-
Available online xxx
ment for the patients' survival. Multimodality imaging could contribute to brief differential diagnosis of cardiac masses. Our paper presents a fatal case of cardiac angiosarcoma in a
Keywords:
young man with special focus to multimodality imaging possibilities, including, next to
Cardiac angiosarcoma
echocardiography, also MRI and PET–CT. Review of literature describes a clinical character-
Imaging
istics of the cardiac angiosarcoma and also diagnostics and therapeutics modalities.
Echocardiography
# 2016 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights
MRI
reserved.
PET–CT
Introduction Primary cardiac tumors are very rare diseases; their incidence in autopsy studies is 0.0001–0.030% [1,2]. Secondary tumors of the heart developed as metastases of other tumors are much more frequent. Cardiac metastases are found at autopsies in up to 10% of cancer patients. Only 25% of primary cardiac tumors are malignant [3]. Myxoma is the
most frequent benign cardiac tumor while various kinds of sarcomas are the most common malignant tumors, out of which angiosarcoma is the most frequent one. The prognosis of angiosarcoma patients has been quite poor until now; their average survival is several months. The prognosis depends mainly on the tumor extent and possibility of its surgical removal. Unfortunately, late diagnosis is common because early signs of the tumor presence are missing or are not specific [3,4].
* Corresponding author at: Department of Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic. Tel.: +420 588 443 480. E-mail address: [email protected] (Z. Tüdös). http://dx.doi.org/10.1016/j.crvasa.2016.04.001 0010-8650/# 2016 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
CRVASA-389; No. of Pages 6
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Case report A 36-year-old man was examined repeatedly in an outpatient clinic for 6-week lasting protracted pain of epigastrium and right hypochondrium, loss of appetite, and cough. No more severe diseases or surgeries were found in the patient's history. There were no cardiac and malignant diseases in his family history. The patient was treated three times by using antibiotics for suspected respiration infection based on the presence of cough, C-reactive protein (CRP) elevation and findings of unclear shadows on the chest X-ray. However, the treatment did not improve the patient's complaints. Precollapse and collapse conditions developed gradually. A syncope with convulsions and short unconsciousness occurred during one of the outpatient examinations when the patient was placed on the bed. The patient underwent neurologic examination and brain CT – both with negative findings. The patient was then admitted to a department of internal medicine of a district hospital for additional examinations. An ultrasound abdomen examination found thickened gallbladder walls assessed like suspected cholecystitis at first. Loose fluid in abdominal cavity, hepatopathy and hepatomegaly were also found. Laboratory tests showed an increase of inflammation indicators (CRP 99.6 mg/L), progressing elevation of liver transaminases (AST 4.42 mkat/L, ALT 9.02 mkat/L), mild normocytic anemia (hemoglobin 116 g/L), increase of high-sensitivity troponin T (0.074 ng/mL), and coagulopathy (INR 1.87). ECG recorded anterolateral repolarization changes. The echocardiographic examination showed an irregular mass in the right atrium that did not obturate the tricuspid valve opening, and pericardial effusion. The patient was sent to our department for additional diagnostics. The control echocardiography (Fig. 1) confirmed the presence of a lobulated mass in the right atrium 42 mm 37 mm in size, coming out from the lateral wall of the right atrium. Pericardial fluid with numerous hyperdense areas was present. No signs of cardiac tamponade were found. Both systolic and diastolic functions of the left ventricle were normal. No valve defects were found. MRI of the heart (Fig. 2) was then performed. It confirmed the presence of tumorous mass coming out from the right atrial free wall, expanding into the right atrial cavity and right ventricle wall, then going along the pericardium and large vessels in a diffuse infiltrative way.
The tumor contained numerous hemorrhagic and necrotic areas. The nature of the tumor was heterogeneous in all sequences and predominantly isosignal and hypersignal. The saturation was not homogeneous. PET–CT (Fig. 3) was also performed and proved glucose hypermetabolism (18F-FDG) in pericardial cavity, upper mediastinal lymph node and multiple foci in both lungs. The focus protruding into the right atrium did not show an increased 18F-FDG accumulation. Out of the laboratory serum tumor markers, CA 15-3, CA 125, neuron-specific enolase, and protein S100 were positive. CEA, CA 19-9, CA 72-4, CYFRA 21-1, alpha-fetoprotein, and beta-2-microglobulin were negative. Cardiac surgery was planned. However, the patient's clinical condition worsened very quickly; right-sided heart failure signs prevailed. Despite all therapy and quick diagnostics, the patient died of multiple organ failure 7 days after a cardiac tumor diagnosing. Due to the quick disease progression, histologic nature of the tumor was not determined before the patient's death and, therefore, no specific oncological therapy could have been started. The autopsy (Fig. 4) proved a right atrium tumor metastasizing to the lung. The primary focus was in the right atrial free wall. The tumor grew through the myocardium to the pericardial sac where hematoma and necrotic mass were mostly found. In the histological analyses, the tumor was identified as an angiosarcoma (Fig. 5). Tumor cells were highly pleomorphic, with high mitotic activity and large amount of necrosis. From the immunohistochemical point of view, the tumor cells were CD31-, CD34- and fVIII-positive, focally vimentin-positive, variably Ki-67-positive (up to 90% at some sites). Desmin, sarcomeric actin, myoD1, calretinin, and MelanA were negative. This histochemical profile can be considered highly specific for angiosarcoma. Tumor metastasizing to the lung was proved. In addition to metastases, quite significant tumor angiopathy was also found in the lungs.
Literature review and discussion Angiosarcoma is the most common histological subtype of primary malignant cardiac tumors and forms 30% of the primary cardiac malignities. In spite of this, it is a very rare disease. The primary cardiac angiosarcoma belongs to very aggressive neoplasms with high potential of local recurrence
Fig. 1 – Transthoracic echocardiography: (a) apical 4-chember view – tumorous mass in the right atrium, rising above the lateral wall of the right atrium and (b) parasternal long axis view – pericardial effusion around both ventricles. Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
CRVASA-389; No. of Pages 6 cor et vasa xxx (2016) e1–e6
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Fig. 2 – Magnetic resonance imaging showed tumorous mass in right artrium – 4-chamber view in T1-weighed ‘‘dark blood’’ turbo spin echo (TSE) image (a) and balanced steady-state free precession (b). Also fluid and soft tissue filling the pericardial cavity around both ventricles was confirmed – short axis view in contrast-enhanced T1-weighed ‘‘dark blood’’ TSE image (c) and contrast-enhanced T1-weighed ‘‘dark blood’’ TSE image with fat saturation (d).
Fig. 3 – Contrast-enhanced CT (a, d) and fusion of CT with PET (b, c) showed accumulation of 18F-FDG in the pericardial cavity, right atrial wall and in focal lesions in the lungs. The focus protruding into the right atrium did not show an increased FDG accumulation – reason, later revealed in the autopsy, was an extensive necrosis. Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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Fig. 4 – Autopsy confirmed tumor protruding to the right atrium (a), also hemorrhagic sponge-like tissue was revealed in the pericardial cavity (b).
and formation of systemic metastases. From the histological point of view, it is an endothelial cell tumor which originates from mesenchymal tissue and endothelial subepicardium. The most common place of angiosarcoma origination is the right atrium where it is found in up to 90% of cases. Involvement of surrounding masses, especially the pericardium and in addition the tricuspid valve and venae cavae, is very common. The right atrium can be fully filled with the tumor and the tricuspid valve opening can be obstructed, which leads to the signs of the right heart failure. Pericardium involvement can lead to hemopericardium and cardiac tamponade.
Fig. 5 – Histology analysis identified tumor as angiosarcoma. Hematoxylin-eosin staining showed pleomorphy, mostly spindle-shaped cells with high mitotic activity and large amount of necrosis (a). Immunohistochemistry staining with positivity for CD34 (b).
Necrotic impairment of the heart wall can even result in myocardial rupture. The left atrium or the heart ventricles are the primary sites of angiosarcoma development in less than 5% of cases [5]. Metastases use to be developed in up to 80% patients at the time of diagnosis [6]. Most commonly, metastases are formed in the lungs; they can also appear in the liver, lymph nodes, bone, adrenal glands, lien, and brain [7]. Men are usually affected more often than women, in the ratio 2–3:1 [8]. The greatest prevalence of the disease is between 30 and 60 years of age [9,10]. Several cases of familial occurrence of angiosarcoma have been reported [11]. The initial manifestation of angiosarcoma is usually quite nonspecific, which is the basic problem disallowing an early diagnosis. The cardiac-specific manifestations appear no sooner than in the later disease stages. Dyspnea is usually the most common sign. Chest pain can appear in up to one half of patients [7]. Weight loss, fatigue, weakness, malaise, and loss of appetite belong to other signs as well as cardiac arrhythmias (AV blocks, supraventricular arrhythmias), manifestations of heart failure, signs caused by peripheral embolization of the tumor mass or thrombi, and manifestations of distant metastases. The patient prognosis is unfavorable, even in comparison with other primary cardiac malignities. The prognosis depends on the extent of the disease, occurrence of metastases, anatomic site (and related influence on the hemodynamic situation), and especially on the possibility of full surgical extraction. Literature reports the probability of survival from several weeks to several months. Pigott reports an average survival of 9–12 months in patients in whom surgical resection was not possible [12]. The longest survival of an angiosarcoma patient reported in available literature was 81 months [10]. The clinical case of the patient in our case report can be assessed as quite typical. The patient was a man of age corresponding to the most common angiosarcoma occurrence. The tumor site was quite typical as well. The first signs of the disease were not cardiac-specific. The chest X-ray performed in the early phase of the disease corresponded probably to a metastatic disease. The collapses and pre-collapses were apparently the consequence of a temporary dynamic obstruction of the tricuspid valve opening by the tumor.
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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In addition to the general procedures such as history, physical examination and ECG, imaging methods – echocardiography, CT and MRI – are used. Histological verification is required for the definitive determination of the cardiac tumor type and accurate therapy planning. Echocardiography is usually the first imaging method used. Transthoracic echocardiography is quite highly sensitive in the diagnostics of intracardiac pathological masses; it can also assess the hemodynamic consequences (cardiac tamponade, obstructions in the individual heart chambers). However, its contribution to the differentiation of the individual intracardiac pathologies is quite inaccurate; morphology and localization of the mass can only be used for assessment. Transesophageal echocardiography can bring better imaging and assessment of the relation to the surrounding masses. Magnetic resonance is another imaging method. Its undisputable advantages include the possibility to assess the characteristics of the soft tissues, vascularization of intracardiac tumors and other masses, and also the mass surroundings. By means of magnetic resonance imaging, the tumor type can be assessed more accurately and pseudotumors (like thrombi, vegetations, etc.) can be differentiated. The diagnostics is based, in addition to the mass localization, mainly on T1- and T2-weighted images without and with fat signal suppression, and also on the assessment of saturation by contrast. The intermediate density of signal in T1-weighted images is characteristic for angiosarcoma, while T2-weighted images show heterogeneity. This heterogeneous appearance in T2-weighted imaging may be due to the presence of hemorrhagic and necrotic material. Furthermore, areas of increased signal intensity have also been described on T1 images and may be secondary to the presence of blood products. Tumor can be differentiated from thrombus by means of contrast. Due to increased vascularization, cardiac tumors are saturated well by contrast contrary to thrombi. Magnetic resonance of the heart is considered more specific and more sensitive method than CT in the diagnostics of cardiac tumors [13]. The use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET–CT) is the most suitable imaging method for assessment of the malignant tumor potential as well as for the distant metastases diagnostics. There is positive correlation between 18F-FDG accumulation and the degree of malignity in most tumors. However, high uptake of 18F-FDG in myocardium does not mean necessarily a malignity. The level and extent of activity of 18F-FDG in the myocardium can be heterogeneous and variable. The increased focal activity of 18F-FDG in the myocardium can be caused by myocardial ischemia, coronary disease, etc. [14]. The respiratory movements can also lead to nonhomogeneity of 18F-FDG uptake in the myocardium – increase in the lateral and anterior areas and decrease in the septum area [14,15]. The standardized uptake value (SUV) is a semi-quantitative indicator of 18F-FDG (and other radiopharmaceuticals) utilization. It is a ratio between the local volume activity of the radiopharmaceutical and the average volume activity of the radiopharmaceutical in the body. SUV values above 1 correspond to an increased accumulation of the radiopharmaceutical in tissues. To determine SUV decision limits between a benign and malignant process, detailed
e5
studies must be performed at each given worksite to take the influence of all factors into account [16]. The study of Rahbar et al. performed at 24 patients with cardiac tumor, including 6 angiosarcoma patients, determined SUV cut-off value to be 3.5. With the use of this value, malignant tumors could be diagnosed with 100% sensitivity and 86% specificity (accuracy 96%) [17]. In our case report, the first cardiac imaging method was echocardiography like in most other cases. The localization of a pathological mass in the right atrium and presence of pericardial effusion raised great suspicion of malignant etiology. Benign cardiac tumors are localized typically in the left heart chambers. Malignant tumors can be found both in the right and left heart chambers quite evenly. The tissue characteristics of the tumor obtained by magnetic resonance made us think of sarcoma. Lymphoma was also considered in differential diagnostics. The PET–CT examination confirmed the suspected malignant nature of the tumor due to the high uptake of 18F-FDG. However, the absence of 18F-FDG accumulation in the mass in the right atrium was quite surprising. It was probably caused by an extensive necrosis proved by autopsy. Sample taking during a cardiosurgical intervention is the optimum method for getting the tumor sample for histological verification. Other possibilities of histological samples taking are related with much less recovery. Cytology of the pericardial puncture sample should not be used because even if the pericardium is affected by the tumor extensively, the presence of tumor cells in the puncture sample is very low [18]. Endomyocardial biopsy is diagnostic in one half of cases only; a bit better results can be achieved by means of the use of transesophageal echocardiography guiding. However, endomyocardial biopsy is related to a high risk of bleeding from the amply vascularized tumor and also to the possibility of metastasis spreading induction [19]. Therapy-related opinions are still controversial; the small rate of this diagnosis does not allow any standardization of therapeutic procedures. Radical surgical removal of the tumor is the most efficient method of therapy. However, complete radical removal is mostly not possible whether due to the extent of the primary tumor, or due to the presence of metastases. In practice, therefore, multimodality approach combining surgery with radiotherapy and chemotherapy is used most often. In case of a locally advanced disease, preoperative chemotherapy and radiotherapy can reduce the tumor extent and allow more radical resection, and can also eliminate the micrometastases. Postoperative adjuvant therapy is also used in most patients. Doxorubicin-based regimens are the gold standard of chemotherapy although the clinical benefit is modest only (progression-free survival of about 5 months). Moreover, the known anthracycline cardiotoxicity is also limiting. The use of taxanes, either alone or in combination with gemcitabine, is another therapeutic option. Radiotherapy is usually limited by the heart and lung sensitivity to radiation injury. Combination of radiotherapy and taxanes that act as radiosensitizer agents and reduce thus the required radiation dose appears to be advantageous. Immunotherapy and use of multikinase inhibitors on the basis of the immunohistochemical tumor analysis constitute another hopeful option [20,21].
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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Conclusion [6]
Primary angiosarcoma is a rare and aggressive malignant disease. Timely diagnosis is a key requirement for the patients' survival. However, the diagnosis is often complicated by nonspecific symptoms and rarity of the disease occurrence. Quick infiltration growth of the tumor and early metastatic spreading also contribute to poor prognosis. However, the multimodality approach in both the diagnostics and therapy is hopeful and can lead to clinical effect in some cases.
[7]
[8]
[9]
Conflict of interest [10]
None declared.
Ethical statement
[11]
Authors state that the research was conducted according to ethical standards.
[12]
Informed consent
[13]
I declare, that patient provided informed consent with all diagnostics and therapeutics procedures. Specific informed consent with this publication of the case was not obtained due to severity and rapid progression of the disease. However, patient provided general informed consent with the use of results of examination methods for the purposes of research and publications, which is included as a part of informed consent for hospitalization in our department.
[14]
[15]
[16]
Funding body [17]
None.
references
[1] K. Reynen, Frequency of primary tumors of the heart, The American Journal of Cardiology 77 (1) (1996) 107. [2] A.B. Barnes, D.C. Beaver, A.M. Snell, Primary sarcoma of the heart: report of a case with electrocardiographic and pathological studies, American Heart Journal 9 (2003) 480–491. [3] A. Hoffmeier, J.R. Sindermann, H.H. Scheld, S. Martens, Cardiac tumors – diagnosis and surgical treatment, Deutsches Ärzteblatt International 111 (12) (2014) 205–211. [4] R. Bellitti, M. Buonocore, N. De Rosa, et al., Primary cardiac angiosarcoma in a 25-year-old man: excision, adjuvant chemotherapy, and multikinase inhibitor therapy, Texas Heart Institute Journal 40 (2) (2013) 186–188. [5] S.D. Patel, A. Peterson, A. Bartczak, et al., Primary cardiac angiosarcoma – a review, Medical Science Monitor 20
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(January) (2014) 103–109. , http://dx.doi.org/10.12659/ MSM.889875. H.E. El-Osta, Y.S. Yammine, B.M. Chehab, et al., Unexplained hemopericardium as a presenting feature of primary cardiac angiosarcoma: a case report and a review of the diagnostic dilemma, Journal of Thoracic Oncology 3 (2008) 800–802. J. Butany, W. Yu, Cardiac angiosarcoma: two cases and a review of the literature, The Canadian Journal of Cardiology 16 (2000) 197–205. L. Antonuzzo, V. Rotella, F. Mazzoni, et al., Primary cardiac angiosarcoma: a fatal disease, Case Reports in Medicine (2009) 591512. M. Hamidi, J.S. Moody, T.L. Weigel, K.R. Kozak, Primary cardiac sarcoma, The Annals of Thoracic Surgery 90 (2010) 176–181. N.J. Look Hong, P.K. Pandalai, J.L. Hornick, et al., Cardiac angiosarcoma management and outcomes: 20-year singleinstitution experience, Annals of Surgical Oncology 19 (2012) 2707–2715. I.P. Keeling, F. Ploner, B. Rigler, Familial cardiac angiosarcoma, The Annals of Thoracic Surgery 82 (2006) 1570–1576. C. Pigott, M. Welker, P. Khosla, R.S. Higgins, Improved outcome with multimodality therapy in primary cardiac angiosarcoma, Nature Clinical Practice: Oncology 5 (2) (2008) 112–115. C. Chrysohoou, O. Lalude, A. Stillman, S. Lerakis, A rare case of angiosarcoma of the left ventricle detected by cardiac magnetic resonance imaging, Hellenic Journal of Cardiology 56 (September–October (5)) (2015) 444–445. V.S. Dhull, P. Sharma, A. Mukherjee, et al., 18F-FDG PET–CT for evaluation of cardiac angiosarcoma: a case report and review of literature, Molecular Imaging and Radionuclide Therapy 24 (1) (2015) 32–36. , http://dx.doi.org/10.4274/ mirt.02486. L. Le Meunier, R. Maass-Moreno, J.A. Carrasquillo, et al., PET/CT imaging: effect on respiratory motion on apparent myocardial uptake, Journal of Nuclear Cardiology 13 (2006) 821–830. J.A. Thie, Understanding the standardized uptake value, its methods, and implications for usage, Journal of Nuclear Medicine 45 (9) (2004) 1431–1434. K. Rahbar, H. Seifarth, M. Schafers, et al., Differentiation of malignant and benign cardiac tumors using 18F-FDG PET/ CT, Journal of Nuclear Medicine 53 (2012) 1–8. E.G. Riles, S. Gupta, D.D. Wang, K. Tobin, Primary cardiac angiosarcoma: a diagnostic challenge in a young man with recurrent pericardial effusions, Experimental & Clinical Cardiology 17 (2012) 39–42. Y. Hosokawa, E. Kodani, Y. Kusama, et al., Cardiac angiosarcoma diagnosed by transvenous endomyocardial biopsy with the aid of transesophageal echocardiography and intra-procedural consultation, International Heart Journal 51 (2010) 367–369. S. Minichillo, M.A. Pantaleo, M. Nannini, et al., Efficacy of weekly docetaxel in locally advanced cardiac angiosarcoma, BMC Research Notes 8 (July) (2015) 325, http://dx.doi.org/10.1186/s13104-015-1296-4. K. Elsayad, P. Lehrich, H. Yppaerilae-Wolters, et al., Primary cardiac angiosarcoma treated with positron emission tomography/magnetic resonance imaging-guided adaptive radiotherapy, The Canadian Journal of Cardiology (July) (2015), http://dx.doi.org/10.1016/j.cjca.2015.07.010, pii: S0828-282X(15)00538-3 (Epub ahead of print).
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
Available online at www.sciencedirect.com
ScienceDirect journal homepage: http://www.elsevier.com/locate/crvasa
Case report
Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature Jan Přeček a, Zbyněk Tüdös b,*, Martin Hutyra a, František Kováčik a, David Vindiš a, Zuzana Prouzová c, Miloš Táborský a a
Department of Internal Medicine I – Cardiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, Olomouc, Czech Republic b Department of Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, Olomouc, Czech Republic c Department of Clinical and Molecular Pathology, Faculty of Medicine and Dentistry, Palacky University and University Hospital, I. P. Pavlova 6, Olomouc, Czech Republic
article info
abstract
Article history:
Primary cardiac tumors are very rare diseases, wherein the most frequent primary malig-
Received 29 February 2016
nant cardiac tumor is angiosarcoma. Despite the advances in diagnostics and therapy,
Accepted 1 April 2016
prognosis of primary cardiac angiosarcoma is still poor. Timely diagnosis is a key require-
Available online xxx
ment for the patients' survival. Multimodality imaging could contribute to brief differential diagnosis of cardiac masses. Our paper presents a fatal case of cardiac angiosarcoma in a
Keywords:
young man with special focus to multimodality imaging possibilities, including, next to
Cardiac angiosarcoma
echocardiography, also MRI and PET–CT. Review of literature describes a clinical character-
Imaging
istics of the cardiac angiosarcoma and also diagnostics and therapeutics modalities.
Echocardiography
# 2016 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights
MRI
reserved.
PET–CT
Introduction Primary cardiac tumors are very rare diseases; their incidence in autopsy studies is 0.0001–0.030% [1,2]. Secondary tumors of the heart developed as metastases of other tumors are much more frequent. Cardiac metastases are found at autopsies in up to 10% of cancer patients. Only 25% of primary cardiac tumors are malignant [3]. Myxoma is the
most frequent benign cardiac tumor while various kinds of sarcomas are the most common malignant tumors, out of which angiosarcoma is the most frequent one. The prognosis of angiosarcoma patients has been quite poor until now; their average survival is several months. The prognosis depends mainly on the tumor extent and possibility of its surgical removal. Unfortunately, late diagnosis is common because early signs of the tumor presence are missing or are not specific [3,4].
* Corresponding author at: Department of Radiology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, I. P. Pavlova 6, 775 20 Olomouc, Czech Republic. Tel.: +420 588 443 480. E-mail address: [email protected] (Z. Tüdös). http://dx.doi.org/10.1016/j.crvasa.2016.04.001 0010-8650/# 2016 The Czech Society of Cardiology. Published by Elsevier Sp. z o.o. All rights reserved.
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
CRVASA-389; No. of Pages 6
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Case report A 36-year-old man was examined repeatedly in an outpatient clinic for 6-week lasting protracted pain of epigastrium and right hypochondrium, loss of appetite, and cough. No more severe diseases or surgeries were found in the patient's history. There were no cardiac and malignant diseases in his family history. The patient was treated three times by using antibiotics for suspected respiration infection based on the presence of cough, C-reactive protein (CRP) elevation and findings of unclear shadows on the chest X-ray. However, the treatment did not improve the patient's complaints. Precollapse and collapse conditions developed gradually. A syncope with convulsions and short unconsciousness occurred during one of the outpatient examinations when the patient was placed on the bed. The patient underwent neurologic examination and brain CT – both with negative findings. The patient was then admitted to a department of internal medicine of a district hospital for additional examinations. An ultrasound abdomen examination found thickened gallbladder walls assessed like suspected cholecystitis at first. Loose fluid in abdominal cavity, hepatopathy and hepatomegaly were also found. Laboratory tests showed an increase of inflammation indicators (CRP 99.6 mg/L), progressing elevation of liver transaminases (AST 4.42 mkat/L, ALT 9.02 mkat/L), mild normocytic anemia (hemoglobin 116 g/L), increase of high-sensitivity troponin T (0.074 ng/mL), and coagulopathy (INR 1.87). ECG recorded anterolateral repolarization changes. The echocardiographic examination showed an irregular mass in the right atrium that did not obturate the tricuspid valve opening, and pericardial effusion. The patient was sent to our department for additional diagnostics. The control echocardiography (Fig. 1) confirmed the presence of a lobulated mass in the right atrium 42 mm 37 mm in size, coming out from the lateral wall of the right atrium. Pericardial fluid with numerous hyperdense areas was present. No signs of cardiac tamponade were found. Both systolic and diastolic functions of the left ventricle were normal. No valve defects were found. MRI of the heart (Fig. 2) was then performed. It confirmed the presence of tumorous mass coming out from the right atrial free wall, expanding into the right atrial cavity and right ventricle wall, then going along the pericardium and large vessels in a diffuse infiltrative way.
The tumor contained numerous hemorrhagic and necrotic areas. The nature of the tumor was heterogeneous in all sequences and predominantly isosignal and hypersignal. The saturation was not homogeneous. PET–CT (Fig. 3) was also performed and proved glucose hypermetabolism (18F-FDG) in pericardial cavity, upper mediastinal lymph node and multiple foci in both lungs. The focus protruding into the right atrium did not show an increased 18F-FDG accumulation. Out of the laboratory serum tumor markers, CA 15-3, CA 125, neuron-specific enolase, and protein S100 were positive. CEA, CA 19-9, CA 72-4, CYFRA 21-1, alpha-fetoprotein, and beta-2-microglobulin were negative. Cardiac surgery was planned. However, the patient's clinical condition worsened very quickly; right-sided heart failure signs prevailed. Despite all therapy and quick diagnostics, the patient died of multiple organ failure 7 days after a cardiac tumor diagnosing. Due to the quick disease progression, histologic nature of the tumor was not determined before the patient's death and, therefore, no specific oncological therapy could have been started. The autopsy (Fig. 4) proved a right atrium tumor metastasizing to the lung. The primary focus was in the right atrial free wall. The tumor grew through the myocardium to the pericardial sac where hematoma and necrotic mass were mostly found. In the histological analyses, the tumor was identified as an angiosarcoma (Fig. 5). Tumor cells were highly pleomorphic, with high mitotic activity and large amount of necrosis. From the immunohistochemical point of view, the tumor cells were CD31-, CD34- and fVIII-positive, focally vimentin-positive, variably Ki-67-positive (up to 90% at some sites). Desmin, sarcomeric actin, myoD1, calretinin, and MelanA were negative. This histochemical profile can be considered highly specific for angiosarcoma. Tumor metastasizing to the lung was proved. In addition to metastases, quite significant tumor angiopathy was also found in the lungs.
Literature review and discussion Angiosarcoma is the most common histological subtype of primary malignant cardiac tumors and forms 30% of the primary cardiac malignities. In spite of this, it is a very rare disease. The primary cardiac angiosarcoma belongs to very aggressive neoplasms with high potential of local recurrence
Fig. 1 – Transthoracic echocardiography: (a) apical 4-chember view – tumorous mass in the right atrium, rising above the lateral wall of the right atrium and (b) parasternal long axis view – pericardial effusion around both ventricles. Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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Fig. 2 – Magnetic resonance imaging showed tumorous mass in right artrium – 4-chamber view in T1-weighed ‘‘dark blood’’ turbo spin echo (TSE) image (a) and balanced steady-state free precession (b). Also fluid and soft tissue filling the pericardial cavity around both ventricles was confirmed – short axis view in contrast-enhanced T1-weighed ‘‘dark blood’’ TSE image (c) and contrast-enhanced T1-weighed ‘‘dark blood’’ TSE image with fat saturation (d).
Fig. 3 – Contrast-enhanced CT (a, d) and fusion of CT with PET (b, c) showed accumulation of 18F-FDG in the pericardial cavity, right atrial wall and in focal lesions in the lungs. The focus protruding into the right atrium did not show an increased FDG accumulation – reason, later revealed in the autopsy, was an extensive necrosis. Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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Fig. 4 – Autopsy confirmed tumor protruding to the right atrium (a), also hemorrhagic sponge-like tissue was revealed in the pericardial cavity (b).
and formation of systemic metastases. From the histological point of view, it is an endothelial cell tumor which originates from mesenchymal tissue and endothelial subepicardium. The most common place of angiosarcoma origination is the right atrium where it is found in up to 90% of cases. Involvement of surrounding masses, especially the pericardium and in addition the tricuspid valve and venae cavae, is very common. The right atrium can be fully filled with the tumor and the tricuspid valve opening can be obstructed, which leads to the signs of the right heart failure. Pericardium involvement can lead to hemopericardium and cardiac tamponade.
Fig. 5 – Histology analysis identified tumor as angiosarcoma. Hematoxylin-eosin staining showed pleomorphy, mostly spindle-shaped cells with high mitotic activity and large amount of necrosis (a). Immunohistochemistry staining with positivity for CD34 (b).
Necrotic impairment of the heart wall can even result in myocardial rupture. The left atrium or the heart ventricles are the primary sites of angiosarcoma development in less than 5% of cases [5]. Metastases use to be developed in up to 80% patients at the time of diagnosis [6]. Most commonly, metastases are formed in the lungs; they can also appear in the liver, lymph nodes, bone, adrenal glands, lien, and brain [7]. Men are usually affected more often than women, in the ratio 2–3:1 [8]. The greatest prevalence of the disease is between 30 and 60 years of age [9,10]. Several cases of familial occurrence of angiosarcoma have been reported [11]. The initial manifestation of angiosarcoma is usually quite nonspecific, which is the basic problem disallowing an early diagnosis. The cardiac-specific manifestations appear no sooner than in the later disease stages. Dyspnea is usually the most common sign. Chest pain can appear in up to one half of patients [7]. Weight loss, fatigue, weakness, malaise, and loss of appetite belong to other signs as well as cardiac arrhythmias (AV blocks, supraventricular arrhythmias), manifestations of heart failure, signs caused by peripheral embolization of the tumor mass or thrombi, and manifestations of distant metastases. The patient prognosis is unfavorable, even in comparison with other primary cardiac malignities. The prognosis depends on the extent of the disease, occurrence of metastases, anatomic site (and related influence on the hemodynamic situation), and especially on the possibility of full surgical extraction. Literature reports the probability of survival from several weeks to several months. Pigott reports an average survival of 9–12 months in patients in whom surgical resection was not possible [12]. The longest survival of an angiosarcoma patient reported in available literature was 81 months [10]. The clinical case of the patient in our case report can be assessed as quite typical. The patient was a man of age corresponding to the most common angiosarcoma occurrence. The tumor site was quite typical as well. The first signs of the disease were not cardiac-specific. The chest X-ray performed in the early phase of the disease corresponded probably to a metastatic disease. The collapses and pre-collapses were apparently the consequence of a temporary dynamic obstruction of the tricuspid valve opening by the tumor.
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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In addition to the general procedures such as history, physical examination and ECG, imaging methods – echocardiography, CT and MRI – are used. Histological verification is required for the definitive determination of the cardiac tumor type and accurate therapy planning. Echocardiography is usually the first imaging method used. Transthoracic echocardiography is quite highly sensitive in the diagnostics of intracardiac pathological masses; it can also assess the hemodynamic consequences (cardiac tamponade, obstructions in the individual heart chambers). However, its contribution to the differentiation of the individual intracardiac pathologies is quite inaccurate; morphology and localization of the mass can only be used for assessment. Transesophageal echocardiography can bring better imaging and assessment of the relation to the surrounding masses. Magnetic resonance is another imaging method. Its undisputable advantages include the possibility to assess the characteristics of the soft tissues, vascularization of intracardiac tumors and other masses, and also the mass surroundings. By means of magnetic resonance imaging, the tumor type can be assessed more accurately and pseudotumors (like thrombi, vegetations, etc.) can be differentiated. The diagnostics is based, in addition to the mass localization, mainly on T1- and T2-weighted images without and with fat signal suppression, and also on the assessment of saturation by contrast. The intermediate density of signal in T1-weighted images is characteristic for angiosarcoma, while T2-weighted images show heterogeneity. This heterogeneous appearance in T2-weighted imaging may be due to the presence of hemorrhagic and necrotic material. Furthermore, areas of increased signal intensity have also been described on T1 images and may be secondary to the presence of blood products. Tumor can be differentiated from thrombus by means of contrast. Due to increased vascularization, cardiac tumors are saturated well by contrast contrary to thrombi. Magnetic resonance of the heart is considered more specific and more sensitive method than CT in the diagnostics of cardiac tumors [13]. The use of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography–computed tomography (PET–CT) is the most suitable imaging method for assessment of the malignant tumor potential as well as for the distant metastases diagnostics. There is positive correlation between 18F-FDG accumulation and the degree of malignity in most tumors. However, high uptake of 18F-FDG in myocardium does not mean necessarily a malignity. The level and extent of activity of 18F-FDG in the myocardium can be heterogeneous and variable. The increased focal activity of 18F-FDG in the myocardium can be caused by myocardial ischemia, coronary disease, etc. [14]. The respiratory movements can also lead to nonhomogeneity of 18F-FDG uptake in the myocardium – increase in the lateral and anterior areas and decrease in the septum area [14,15]. The standardized uptake value (SUV) is a semi-quantitative indicator of 18F-FDG (and other radiopharmaceuticals) utilization. It is a ratio between the local volume activity of the radiopharmaceutical and the average volume activity of the radiopharmaceutical in the body. SUV values above 1 correspond to an increased accumulation of the radiopharmaceutical in tissues. To determine SUV decision limits between a benign and malignant process, detailed
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studies must be performed at each given worksite to take the influence of all factors into account [16]. The study of Rahbar et al. performed at 24 patients with cardiac tumor, including 6 angiosarcoma patients, determined SUV cut-off value to be 3.5. With the use of this value, malignant tumors could be diagnosed with 100% sensitivity and 86% specificity (accuracy 96%) [17]. In our case report, the first cardiac imaging method was echocardiography like in most other cases. The localization of a pathological mass in the right atrium and presence of pericardial effusion raised great suspicion of malignant etiology. Benign cardiac tumors are localized typically in the left heart chambers. Malignant tumors can be found both in the right and left heart chambers quite evenly. The tissue characteristics of the tumor obtained by magnetic resonance made us think of sarcoma. Lymphoma was also considered in differential diagnostics. The PET–CT examination confirmed the suspected malignant nature of the tumor due to the high uptake of 18F-FDG. However, the absence of 18F-FDG accumulation in the mass in the right atrium was quite surprising. It was probably caused by an extensive necrosis proved by autopsy. Sample taking during a cardiosurgical intervention is the optimum method for getting the tumor sample for histological verification. Other possibilities of histological samples taking are related with much less recovery. Cytology of the pericardial puncture sample should not be used because even if the pericardium is affected by the tumor extensively, the presence of tumor cells in the puncture sample is very low [18]. Endomyocardial biopsy is diagnostic in one half of cases only; a bit better results can be achieved by means of the use of transesophageal echocardiography guiding. However, endomyocardial biopsy is related to a high risk of bleeding from the amply vascularized tumor and also to the possibility of metastasis spreading induction [19]. Therapy-related opinions are still controversial; the small rate of this diagnosis does not allow any standardization of therapeutic procedures. Radical surgical removal of the tumor is the most efficient method of therapy. However, complete radical removal is mostly not possible whether due to the extent of the primary tumor, or due to the presence of metastases. In practice, therefore, multimodality approach combining surgery with radiotherapy and chemotherapy is used most often. In case of a locally advanced disease, preoperative chemotherapy and radiotherapy can reduce the tumor extent and allow more radical resection, and can also eliminate the micrometastases. Postoperative adjuvant therapy is also used in most patients. Doxorubicin-based regimens are the gold standard of chemotherapy although the clinical benefit is modest only (progression-free survival of about 5 months). Moreover, the known anthracycline cardiotoxicity is also limiting. The use of taxanes, either alone or in combination with gemcitabine, is another therapeutic option. Radiotherapy is usually limited by the heart and lung sensitivity to radiation injury. Combination of radiotherapy and taxanes that act as radiosensitizer agents and reduce thus the required radiation dose appears to be advantageous. Immunotherapy and use of multikinase inhibitors on the basis of the immunohistochemical tumor analysis constitute another hopeful option [20,21].
Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001
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Conclusion [6]
Primary angiosarcoma is a rare and aggressive malignant disease. Timely diagnosis is a key requirement for the patients' survival. However, the diagnosis is often complicated by nonspecific symptoms and rarity of the disease occurrence. Quick infiltration growth of the tumor and early metastatic spreading also contribute to poor prognosis. However, the multimodality approach in both the diagnostics and therapy is hopeful and can lead to clinical effect in some cases.
[7]
[8]
[9]
Conflict of interest [10]
None declared.
Ethical statement
[11]
Authors state that the research was conducted according to ethical standards.
[12]
Informed consent
[13]
I declare, that patient provided informed consent with all diagnostics and therapeutics procedures. Specific informed consent with this publication of the case was not obtained due to severity and rapid progression of the disease. However, patient provided general informed consent with the use of results of examination methods for the purposes of research and publications, which is included as a part of informed consent for hospitalization in our department.
[14]
[15]
[16]
Funding body [17]
None.
references
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Please cite this article in press as: J. Přeček et al., Primary cardiac angiosarcoma in multimodality imaging – Case report and review of literature, Cor et Vasa (2016), http://dx.doi.org/10.1016/j.crvasa.2016.04.001