- Email: [email protected]
Primary Cardiac Synovial Sarcoma
Primary Cardiac Synovial Sarcoma Ji-Gang Wang, MS, and Ning-Ning Li, MD Departments of Pathology and Internal Medicine, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China
Primary cardiac synovial sarcoma is an extremely rare entity. The clinical and pathologic characteristics are still poorly understood, and prognostic factors influencing overall survival are still unknown. In the present study, all characteristics of reported patients, including sex, age, clinical presentations, laboratory tests, electrocardiogram, imaging findings, pathology, location, therapy, and
follow-up were carefully reviewed and survival analysis was performed. The present study has summarized some key features and may provide an effective consultation for the diagnosis and treatment of the tumor.
S
sarcomas. In previous case reports with literature reviews, researchers have described some clinical features, although, the characterizations, especially adjunctive diagnostic devices and treatment, remain poorly acknowledged. To the best of our knowledge, there are few large population studies of cardiac sarcomas and no accumulated knowledge of PCSS to date. We present an analysis of 60 patients with PCSS derived from 54 isolated articles in an effort to establish definite clinical, pathologic, treatment and outcome patterns of PCSS and to develop a rationale for prognostication in this disease.
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ynovial sarcoma (SS) represents only a small proportion of the soft-tissue sarcomas. In the World Health Organization classifications of cardiac tumors, SS was defined as a biphasic tumor composed of spindled and epithelioid areas, characterized by X;18 chromosomal translocations [1]. More than 80% arise in the deep soft tissue of extremities, especially around the knee, and the tumor frequently arises adjacent to joints or tendon sheaths. Histologically, SS is biphasic (BSS), characterized by epithelial and spindle cell components, or monophasic (MSS), characterized by the spindle cell component. Up to 50% of SS recur, usually within 2 years, but sometimes up to 30 years after diagnosis [2]. Quite a few large-population prognostic factor studies of SS have been published, but results have varied from report to report. Cardiac sarcomas often manifest clinical features, such as dyspnea and palpitation, that are similar to myxomas [3, 4]. Some patients may experience a long term before onset of symptoms, especially when they arise from the pericardium [3]. Therefore, these sarcomas are usually larger than their superficial counterparts. Owing to the poor understanding and indefinite conclusions for them, the correct preoperative diagnoses are always difficult to make, although varieties of examinations are performed to identify the lesion. Moreover, most cardiac sarcomas can seldom be completely removed, and are thus susceptible to recur. Despite the publication of numerous case reports and several series of cardiac sarcomas with long-term follow-up, prognostic factors are still being debated [5–7]. Primary cardiac SS (PCSS) is an extremely rare entity, which was first described in 1978 by McAllister and Fenoglio [8] in a 30-year-old woman. Since then, a series of isolated case reports have been published. An analysis of reviews shows that PCSS is calculated to account for approximately 4.2% (1 of 117 [8, 9], 2 of 75 [10], 1 of 24 [6], 1 of 14 [11], 3 of 24 [7], 2 of 17 [5], 2 of 14 [12], and 1 of 2 [13], respectively; mean, 4.2%) of the primary cardiac
Address correspondence to Mr Wang, Department of Pathology, the Affiliated Hospital of Medical College, Qingdao University, 16 Jiangsu Rd, Qingdao 266003, China; e-mail: [email protected].
© 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2013;95:2202–9) © 2013 by The Society of Thoracic Surgeons
Material and Methods We searched PubMed using the terms “cardiac” and “synovial sarcoma,” “heart” and “synovial sarcoma.” The cases meeting the following criteria were included in the study: (1) originated from the heart chambers, myocardium, or pericardium; (2) excluded metastasis, with no history of PCSS, no SS in other location at diagnosis, or the extracardiac tumor was firmly demonstrated to be metastatic [14]; (3) article written in English, or if not, at least with an English abstract; (4) case without any descriptions was excluded [12, 13]. To expand the population size as large as possible, we also evaluated the references cited by these reports to identify any patients that might have been missed, including patients reported in previously published books. Three reports published in books [8, 15, 16] could not be accessed fully so that only available information described in literature reviewing works [17–19] was collected. A total of 60 unique patients reported in 54 isolated articles, as case reports or as original research, were selected and included in the study. All patient data, including sex, age, clinical presentations, laboratory tests, electrocardiogram, imaging findings, pathology, location, therapy, and follow-up, were collected and entered in Excel software (Microsoft Corp, Redmond, WA). Survival curves were calculated using the Kaplan-Meier method and compared with the logrank test. Data were analyzed using Prism 5.0 software 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.01.030
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Fig 1. Age and sex distribution (light bars, female; dark bars, male) is shown of patients with reported primary cardiac synovial sarcoma.
Results Study Population PCSS appeared to have a striking male predominance. The cohort consisted of 45 male and 15 female patients (male/female ratio was approximately 3:1). At presentation, patients were a mean age of 37.1 years (range, 13 to 70 years). The exact age was available in 58 patients (44 males and 14 females, excluding Burke and colleagues [10]), and the detailed age distribution is described in Figure 1. The medical history review appeared to be nonspecific. Amongst the 60 patients studied, only 2 had been exposed to asbestos [20, 21]. Other positive history records included 1 patient each with mediastinal teratoma [22], 3-vessel coronary artery bypass grafting [23], illicit drug and alcohol abuse [24], smoking [14], and hypertension [25]. A previous healthy or unremarkable medical history was definitely stated in 11 patients [26 –36].
Clinical Presentations Presenting complaints were provided in 50 patients. All available descriptions were carefully re-reviewed and divided mainly into three categories: cardiorespiratory symptoms (44 patients), extra-cardiorespiratory symptoms (11 patients), and nonspecific systemic symptoms (14 patients; Table 1). Dyspnea, at 68%, was by far the most common presenting symptom. Only 6 patients did not present with symptoms related to the cardiorespiratory system [5, 14, 23, 37–39]. Physical examinations were recorded for 22 patients, and 21 had positive signs: 1. heart failure signs, including hepatomegaly, distention of jugular vein (“a” wave), edema (ascites) [26, 29, 31, 36, 39, 40], rales [30, 34, 41– 43], hemoptysis [19, 24, 34], tachypnea [22, 29], and visible pulsations over the precordium [27]; 2. cardiac murmurs [27, 28, 30, 39, 43, 44] or extracardiac sounds: extrasystolic sound and an S4 [14], tumor plop [39];
3. cardiac tamponade signs [45, 46] or pericardial effusion signs [5]: distant heart sounds and a weak apex beat [31], pericardial rub [47]; 4. abnormal pulse: pulsus paradoxus [48], tachycardia [30, 43, 47, 48], and abnormal blood pressure: hypertension (2 patients, aged 13 and 28 years) [26, 34] or hypotension [11].
Table 1. Clinical Symptoms of 50 Patients With Primary Cardiac Synovial Sarcoma Clinical Symptoms Cardiorespiratory symptoms Dyspneaa Chest (thoracic, sternal, retrosternal, and substernal) pain Cough (dry cough, expectoration) Edema (ascites) Palpitation Hemoptysis Cardiac tamponade symptoms Extra-cardiorespiratory symptoms Syncope Headache Abdominal distension Vomiting Nausea Vertigo Aphasia, facial droop, witnessed seizure and consciousness loss Arm weakness Nonspecific systemic symptoms Fever Fatigue (tiredness, asthenia, exercise intolerance) Weight loss Malaise Nocturnal sweating a
No. (%) (N ⫽ 50) 44 (88) 34 (68) 13 (26) 11 (22) 9 (18) 5 (10) 3 (6) 2 (4) 11 (22) 5 (10) 2 (4) 2 (4) 2 (4) 1 (2) 1 (2) 1 (2) 1 (2) 14 (28) 9 (18) 6 (12) 3 (6) 2 (4) 2 (4)
Includes shortness of breath, breathless, chest tight, tachypnea, orthopnea, respiratory distress.
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(GraphPad Software, La Jolla, CA). Two-tailed p-values of 0.05 or less were considered statistically significant.
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Laboratory Tests Laboratory findings were provided in 10 patients, of which the results were abnormal in 8 [19, 21, 29, 31, 34, 36, 41, 48] and normal in 2 [30, 39]. Elevated alanine aminotransferase and aspartate aminotransferase levels were reported in 3 patients [21, 36, 41], and elevated lactate dehydrogenase was recorded in 3 patients [31, 36, 41]. Other detection indexes appeared nonspecific, including increased C-reactive protein [19, 21, 41, 48], increased erythrocyte sedimentation rate [19, 21], increased adenosine deaminase [31], decreased serum protein [31, 34], increased blood urea nitrogen [34], and increased serum calcium (without clinical manifestation) [29].
Electrocardiogram Electrocardiogram abnormalities in 11 reported patients are summarized in Table 2. Interestingly, the 3 patients with right bundle branch block had tricuspid valve masses. Two patients with axis deviation had right-sided heart tumor masses. The low voltage was associated the pericardial tumor mass, which caused pericardial effusion. In addition, ST-T segment changes were documented in 4 patients.
Imaging Findings Chest roentgenogram findings were reported in 25 patients. In most patients, this assessment could only provide some secondary signs, of which cardiomegaly [20, 27, 30, 34, 36, 37, 40, 42, 47, 51–55] was the most common manifestation. Pulmonary congestion [17, 41, 44] and
Table 2. Electrocardiogram Abnormalities of 11 Patients With Primary Cardiac Synovial Sarcoma
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Electrocardiogram
Tumor Location
Total AV block [36]
Arose from interatrial septum near AV node, in RA and RV In RA and obstruct tricuspid valve Partly in posterior wall RV and into pericardium Arose from LA posterior septum, in LA Arose from pericardium, adhering to RV free wall Pericardium
Right axis deviation [39] ST segment changes [21] T wave inversion in V1 [41] Low voltage [31] T wave inversion in I, aVL, V4, V5 and V6 [27] T wave inversion and a right BBB [33] Right axis deviation, incomplete right BBB [49] Complete right BBB [50] Microvoltage in all leads [37] Intermittent ventricular tachycardia [43]
Attached to tricuspid annulus, in RA and RV Arose from right AV groove invading tricuspid valve, in RA Attached to root of tricuspid valve, in RA and RV Pericardium Arose from tricuspid annulus, in RA and RV
AV ⫽ atrioventricular; BBB ⫽ bundle branch block; atrium; RA ⫽ right atrium; RV ⫽ right ventricle.
LA ⫽ left
pleural effusions [30, 34, 40 – 42, 49] could also be observed. Sometimes, the roentgenogram could vaguely outline the lesion if the pericardium was involved [35, 46, 48, 56 –58]. However, it might appear completely normal in some patients [39]. Plain computed tomography (CT) or contrastenhanced CT (CECT) was one of the most practical and valuable methods to rule out the lesion, and the latter could well define the tumor size and sectional views of involved structures. Calcifications [56] and cysts [55] were occasionally observed within the mass; however, plain CT sometimes failed to determine the tumor mass [37, 44]. The tumor (a total of 13 patients were documented, in which 2 were monophasic, 9 were biphasic, and 2 without histopathology descriptions) could be slightly enhanced, heterogeneously or non-homogenously, on CECT [19, 22, 27, 29 –31, 40, 55–57, 59, 60]. Nevertheless, it was difficult to differentiate the tumor from other soft-tissue neoplasms by plain CT or CECT [29], even benign, if the tumor appeared noninvasive. There was 1 patient with pulmonary nodules that had been considered a cardiac myxoma [14]. In contrast with the CT, magnetic resonance imaging (MRI) [22, 26, 31, 37, 40, 42, 46, 51, 54, 56], with or without contrast administration, especially the cardiac MRI [47, 59], could also well confirm the presence and the extension of the tumor and might display the lesion more clearly. This device might also miss the lesion instead of only pericardial thickening [48]. Transthoracic or transesophageal echocardiography was used more widely than all of the above. It could well detect the tumor in most instances, but its value was limited when a pericardial tumor was combined with large pericardial effusion. Of the 14 patients with pericardial SS documented with echocardiography findings [22, 27, 30, 31, 37, 40, 42, 47, 48, 51, 53, 55, 60], the mass was not detected in 4 [47, 48, 53, 60]. However, it remained a sensitive and convenient strategy to detect the presence of the intracardiac tumor mass. Only 1 tumor, which attached to the mitral valve, was missed in the 20 documented nonpericardial patients [23].
Other Preoperative Diagnostic Techniques Pericardial effusion samples could be collected by therapeutic pericardiocentesis and used for cytopathologic analysis, but the results were always negative [31, 37, 40, 45, 55]. Fine-needle aspiration (biopsy or cytology) was a more sensitive and reliable technique that might lead to a more accurate diagnosis and provide an alternative method to a surgical procedure. It could be guided under CT, echocardiography, or digital subtraction angiography. Amongst the 6 cases with fine needle aspiration, two were diagnosed as SS [32, 35], two were classified as spindle tumors (one was considered as a spindle cell thymoma) [29, 58], and the other two were inconclusive [19, 27]. Transvenous biopsy was also helpful in obtaining a more preferable diagnosis [36]. Catheterization and angiography were able to evaluate the feeding vessels [31]. The 18-fluorodeoxyglucose-positron emission to-
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Synovial Sarcoma
Intracardiac Pericardiac a
Biphasic No.
Monophasic No.
16 7
13 14
The 2 test was used (p ⫽ 0.13).
mography scan showed an uptake in a marginal site of the tumor [56].
Location The accurate location was evaluated by the location from which the tumor mass arose from or adhered to as observed at the operation so that the primary site was well established. If this information was absent or poorly clarified, it was evaluated by the described position on imaging. Patients with multiple occupying lesions in which the primary location was unclear were excluded from the present study [8, 18]. A total of 58 patients were enrolled, of which 24 (affecting 41.4%) had a pericardial SS [5, 20, 22, 25, 27, 29 –31, 35, 37, 40, 42, 46 – 48, 51, 53, 55, 56, 58, 60, 61]. The second most common location was the right atrium, affecting 14 patients (24.1%) [5–7, 11, 16, 17, 24, 26, 36, 39, 44, 49, 54]. Documented locations included the left atrium in 5 (8.6%) [10, 15, 34, 41, 57], the tricuspid valve in 5 (8.6%) [14, 33, 43, 50, 52], the right ventricle in 4 (6.9%) [7, 10, 19, 21], the left ventricle in 3 (5.2%) [32, 45, 59], and the mitral valve in 3 (5.2%) [23, 28, 38].
Pathology On gross appearance, the tumor mass was often polypoid, solid, or lobulated, with a smooth or well-circumscribed external surface. It usually appeared as a bulky mass and did not diffusely infiltrate the surrounding structures, so the initiation site could be well distinguished. Most tumors have a broad base, and the tumors in 7 patients were reported to have a pedicle or stalk [17, 30, 33, 34, 39, 44, 55]. Sections through the tumor mass showed variable patterns: some have firm, glazed, or elastic consistency, or were friable with some necrotic regions; others showed cystic changes [25, 47, 55]. It could be tan-white or reddish with hemorrhage, and cream-yellow with necrosis. This was related to the histopathologic features: soft and tan when cells are rich, especially with glandular architectures, and elastic and white when abundant with fibrous stroma. Sometimes, the growth pattern of the tumor perfectly mimicked cardiac myxomas [14, 38]. Tumor dimensions were reported in 37 patients, ranging from 2 to 15 cm; of these, the mass in 12 was 10 cm or more [11, 20, 21, 24, 26, 31, 42, 47, 51, 52, 56, 61], and only 4 were less than 5 cm [7, 14, 26, 46]. To obtain and confirm the accurate histopathologic subtype, we reviewed all of the available descriptions and pathologic images. The special subtypes, such as purely glandular MSS, calcifying SS, and poorly differentiated SS, were not reported in this cohort. Those described as spindle cell tumor with lack of epithelium
differentiation, if the diagnosis was not stated, were categorized as MSS. Of the 51 reported instances with pathologic information, 24 (47.1%) were biphasic BSS and 27 (52.9%) were MSS. The histopathologic type was not associated with the tumor location (Table 3). Immunohistochemistry and genetic analysis were the most useful ancillary diagnostic methods that may help to differentiate SS from mesothelioma. The spindle cells in MSS or BSS were immunopositive for a panel of antibodies expressed with variable staining characteristics (Table 4). The distinct epithelium differentiation (glandular component, occasionally with squamous metaplasia) was positive for cytokeratin and epithelial membrane antigen. The cells forming the glandular structures frequently expressed carcino-embryonic antigen and epithelial antigen Ber-EP4 and were positive for neutral mucins, which were absent findings in most epithelial mesotheliomas. However, MSS is difficult to differentiate from sarcomatoid mesothelioma, only depending on immunohistochemistry [62]. Genetic analysis methods were documented in 23 cases, including traditional cytogenetics [20, 43, 52], reverse transcription-polymerase chain reaction [5, 23–25,
Table 4. Reported Immunohistochemical Results of the Spindle Cells Positive Variables Cytokeratin (AE1/AE3) Epithelial membrane antigen Vimentin CD99 Bcl-2 Smooth muscle actin Calretinin Cytokeratin 5/6 Calponin HBME-1 (mesothelin) CD56 LCA, intermittent filaments, catenin, synaptotagmin s-100 protein CD34, desmin Thyroid transcription factor1, carcinoembryonic antigen CD117, Melan-A, MSA, CD31, VIII-factor Myoglobin, Myo-D1, D2-40, CgA, HMB-45, AFP, Cytokeratin CAM5.2, NF, E-cadherin, WT-1, CD21/ 35, CD68, Epithelial antigen Ber-EP4 Ki-67 labelling index
Negative
Focally
Diffusely
3/22 3/22 1/21 3/11 0 11/13 6/9 3/4 3/4 1/3 1/3 0
12/22 11/22 2/21 1/11 4/15 2/13 3/9 1/4 0 2/3 0 0
7/22 8/22 18/21 7/11 11/15 0 0 0 1/4 0 2/3 1/1
17/17 12/12 3/3
0 0 0
0 0 0
2/2
0
0
1/1
0
0
20%
AFP ⫽ ␣-fetal protein; CD ⫽ cluster of differentiation; CgA ⫽ chromogranin A; HBME-1 ⫽ human bone marrow endothelial cell-1; HMB ⫽ human melanoma black; LCA ⫽ leukocyte common antigen; MSA ⫽ muscle-specific actin; NF ⫽ neurofilaments; WT-1 ⫽ Wilms tumor protein.
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Table 3. Tumor Location and Histopathologic Featuresa
Location
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29, 31, 32, 46, 47, 51, 55, 57, 58], or fluorescence in situ hybridization [5, 18, 22, 23, 26, 29, 57]. The t(X;18)(p11; q11), as the cytogenetic hallmark of SS, could be detected using traditional cytogenetics or combined binary ratiofluorescence in situ hybridization. The SYT (SS18)-SSX (SSX1 or SSX2, or both) gene fusion could be confirmed by reverse transcription-polymerase chain reaction, and the SYT break-apart signal could be confirmed using fluorescence in situ hybridization. The genetic analysis method was not mentioned in 6 patients [7, 38, 42, 59]. The X:18 chromosomal translocation was demonstrated in 29 patients.
A variety of chemotherapy regimens were documented, including doxorubicin (hydrochloride) [20, 23, 24, 29, 42, 46], ifosfamide [20, 23, 24, 27, 38, 39, 42, 46, 47], mesna [20], vincristine [39], vinorelbine [29], actinomycin [39], dacarbazine [27], gefitinib [46], cisplatin [29], cyclophosphamide [29], and corticosteroids [29], and of those, schemes based on doxorubicin and ifosfamide were selected the most. Preoperative or postoperative chemotherapy was administered in 24 patients [5, 14, 20 –24, 26, 27, 29, 32, 33, 38 – 42, 46, 47, 54, 58 – 60] and radiotherapy in 9 patients [26, 27, 29, 41, 42, 46, 47, 51, 55].
Treatment
Local recurrence and distant metastasis after the initial operation were the two most common adverse events and were documented in 11 patients [26, 27, 31, 36, 41, 45– 47, 50, 52, 57]. Nonetheless, the disease free-survival was seldom estimated because of insufficient information. Only the overall survival analysis was performed in the present review. To obtain the more accurate follow-up data, we chose the report only when it provided an accurate follow-up period, resulting in 36 patients with a mean follow-up of 21.6 months extended up to 171 months (from July 1989 to October 2003) [46]. Survival was calculated using the postoperative time. The median overall survival of the patients diagnosed antemortem was approximately 24 months. Survival rates were ap-
A macroscopically or microscopically complete resection was documented clearly in 10 patients [7, 11, 14, 17, 27, 40, 46, 50, 56]. However, some may have had distant metastasis before presentation although the primary was completely excised [14]. The most common and successful operation reported to date was conventional sternotomy and cardiopulmonary bypass. Some tumors with a broad base that showed an infiltrative growth pattern made it impossible to perform a complete resection, and usually, tumor residues or a positive margin were left. The resection was incomplete in 23 patients. One patient underwent cardiac transplantation [16, 36]. Five patients were diagnosed at autopsy [8, 20, 25, 34, 52].
Survival Analysis
Table 5. Patients’ Characteristics of Median Overall Survival Variables
Pts (No.)
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Age ⱖ 30 y ⬍30 y Location Pericardium Cardiac cavity Tumor size ⬎5 cm ⱕ5 cm Operation Complete resection Partial resection Chemotherapy Yes No Radiotherapy Yes No Chemotherapy (and/or) radiotherapy Yes No Pathology Monophasic Biphasic a
Statistically significant difference.
CI ⫽ confidence interval;
HR ⫽ hazard ratio.
21 15
Overall Survival Median (mo)
HR (95% CI)
p Value
4.435 (1.386–10.96)
0.01a
0.925 (0.328–2.594)
0.878
0.864 (0.221–3.326)
0.823
0.642 (0.196–2.206)
0.496
0.307 (0.077–0.833)
0.024a
0.469 (0.147–1.727)
0.275
0.243 (0.0498–0.599)
0.006a
1.014 (0.349–2.947)
0.98
9 Undefined
18 18
27 10
24 7
26 9
8 21
Undefined 26
16 15
27 5.5
9 22
31 Undefined
18 13
27 5
21 13
27 26
Fig 2. Kaplan-Meier survival curves of two variables found to significantly affect survival: (A) age and (B) chemotherapy. Vertical bars indicate standard error of the mean.
proximately 59.9% at 1 year and 29.9% at 5 years. To further investigate predictors of outcome, we conducted a multivariate analysis of potential prognostic factors (Table 5). Adjunctive chemotherapy and radiotherapy, as well as age, affected the overall survival pattern (Fig 2).
Comment In the present study we have re-reviewed 60 unique patients derived from 54 isolated reports. As far as we know, this is the largest PCSS cohort study to date. Our data have firstly demonstrated that PCSS has a striking male predominance and readily involves the pericardium and right atrium. Regardless of the advanced imaging, it seems that hardly any of the methods used for adjunctive detection gave a fairly accurate preoperative diagnosis. Moreover, the present study has demonstrated, for the first time, that overall survival is affected by age and chemotherapy. As noted, an interesting observation of this study was the significant sex difference in PCSS compared with counterparts found in other sites; nonetheless, it also appears different from other cardiac sarcomas, although
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there may have been a selection bias. The appropriate explanation is still unclear. Another interesting phenomenon was that the disease has a favorite onset age, at the fourth decade of life, which was similar to noncardiac counterparts. The clinical presentations are diverse. Just as with other benign or malignant cardiac tumors, the most common symptom was dyspnea, which is explained by hemodynamic changes due to the atrioventricular valve obstruction narrowing outflow tract. The pathophysiologic alteration may also lead to fibrillation, pulmonary or systematic congestion, and even cardiac tamponade. The central nervous system-related symptom in one report was attributed to embolic infarcts [38]. We consider that the thrombus originated from thrombosis induced by the tumor, rather than from the tumor fragments, because the tumor was usually not so friable. Other extracardiorespiratory manifestations may be illustrated by hemodynamic changes in the gastrointestinal circulation and by the growth of the malignancy: invasion, necrosis, or immune response. Meanwhile, hemodynamic changes may lead to heart failure signs, mechanical obstruction may cause murmurs and extracardiac sounds, and pericardial effusion could result in cardiac tamponade. Compared with benign cardiac tumors [4, 63], PCSSs more readily bear gastrointestinal and systemic symptoms and frequently pericardial effusion, and tend to have larger tumor size. These characterizations are in accord with earlier reports of cardiac malignancies [9, 10, 64]. The results of laboratory tests appeared to be nonspecific for the diagnosis. Elevated alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels may indicate injured myocardium but might also be observed in other cardiac or noncardiac malignancies. Occurrences of bundle-branch block and ST segment and T wave alteration in PCSS were more common than that in myxomas [63, 65]. The conduction block was due to the infiltrative growth pattern. The ST-T changes could be explained by injury to the endocardium and myocardium. However, other electrocardiographic changes, such as atrial hypertrophy, fibrillation, arrhythmia, and tachycardia, which are common in myxomas, were not documented in this series of reports. Despite the varieties of imaging characteristics that were summarized, the present review failed to draw a definite conclusion about how to distinguish PCSSs from other cardiac malignancies. Previous studies have made a great effort on this issue; however, no criteria or distinctions were well acknowledged. We consider CECT and MRI are helpful in differentiating vascular tumors and adipose-derived tumors. Although there are no published reports on the differential diagnosis between cardiac myxoma and PCSS, a preferable diagnosis could also been made using CECT, because myxomas often have smaller tumor size, are localized in the left atrium, and are prone to forming more vascular structures. To distinguish PCSSs from other spindle cell tumors was rather difficult, even in small biopsy specimens. However, quite a few intracardiac PCSSs showed single and local growth pattern, which has not usually been identi-
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fied in other high-grade sarcomas such as malignant fibrous histiocytoma and lymphoma. The cell origin of SS is a controversial topic, and in the present study, we still cannot explain why PCSSs favor the pericardium and right atrium. Further statistical analysis revealed pathology was not related to the location. It was sometimes difficult to differentiate PCSS from mesothelioma, especially when it occurred in the pericardium. Both could display biphasic differentiation and monophasic differentiation histomorphologically. Also, some traditional mesothelial cell biomarkers, for example, human bone marrow endothelial cell-1 and calretinin, were immunopositive for SS and vice versa. It is worth mentioning that PCSS could arise from mesothelioma [44]; therefore, we suggest all tumors resembling mesothelioma should undergo molecular cytogenetic analysis. Surgical resection was indispensable, not only for the pathology but also for the treatment, and although the tumor usually might not have been completely removed, surgical resection could partially or totally relieve the obstruction and oppression. One of the most interesting and inspiring results of this study was that adjunctive chemotherapy could significantly prolong overall patient survival, which was rarely demonstrated in other SS reports [66]. A chemotherapy scheme based on doxorubicin and ifosfamide was used most commonly. However, we note there was a bias in favor of reporting patients with unique features. In addition, age was also considered an influencing factor, which was well concurred with previous studies [67–71]. Another widely accepted view in the existing reports was that tumor size was related with overall patient survival, which was not demonstrated in the present study. In fact, we changed the cutoff value from 5 to 10 cm in an effort to reach an agreement with previous reports, but survival analysis showed differences were always not significant. Possible illustrations for this discrepancy might be: REVIEW
1. Information bias: the presented data of tumor size was derived from the pathologic examination or different imaging-detecting approaches. 2. Growth pattern: compared with their counterparts of other sites, especially in the extremities, PCSS was prone to reach a larger size before symptom onset due to the lack of surrounding tissue. 3. Statistical analysis: only the median overall survival was taken into account, not 5-year or 10-year overall survival.
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3. Wang JG, Wei ZM, Liu H, Li YJ. Primary pleomorphic liposarcoma of pericardium. Interact Cardiovasc Thorac Surg 2010;11:325–7. 4. Wang JG, Liu H, Yu WJ, Li YJ, Xin FJ. [Primary cardiac neoplasms: a clinicopathologic analysis of 81 cases]. Zhonghua Bing Li Xue Za Zhi 2012;41:808 –12. 5. Zhang PJ, Brooks JS, Goldblum JR, et al. Primary cardiac sarcomas: a clinicopathologic analysis of a series with follow-up information in 17 patients and emphasis on longterm survival. Hum Pathol 2008;39:1385–95. 6. Donsbeck AV, Ranchere D, Coindre JM, Le Gall F, Cordier JF, Loire R. Primary cardiac sarcomas: an immunohistochemical and grading study with long-term follow-up of 24 cases. Histopathology 1999;34:295–304. 7. Kim CH, Dancer JY, Coffey D, et al. Clinicopathologic study of 24 patients with primary cardiac sarcomas: a 10-year single institution experience. Hum Pathol 2008;39:933– 8. 8. McAllister HA, Fenoglio JJ. Tumors of cardiovascular system. In: Hartmann WH, Cowan WR (eds). Atlas of tumor pathology, fascicle 15. Washington, DC: Armed Forces Institute of Pathology; 1978:71– 8. 9. Neragi-Miandoab S, Kim J, Vlahakes GJ. Malignant tumours of the heart: a review of tumour type, diagnosis and therapy. Clin Oncol (R Coll Radiol) 2007;19:748 –56. 10. Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart. Cancer 1992;69:387–95. 11. Kumar N, Agarwal S, Ahuja A, Das P, Airon B, Ray R. Spectrum of cardiac tumors excluding myxoma: Experience of a tertiary center with review of the literature. Pathol Res Pract 2011;207:769 –74. 12. Perchinsky MJ, Lichtenstein SV, Tyers GF. Primary cardiac tumors: forty years’ experience with 71 patients. Cancer 1997;79:1809 –15. 13. Piazza N, Chughtai T, Toledano K, Sampalis J, Liao C, Morin JF. Primary cardiac tumours: eighteen years of surgical experience on 21 patients. Can J Cardiol 2004;20:1443– 8. 14. Bittira B, Tsang J, Huynh T, Morin JF, Huttner I. Primary right atrial synovial sarcoma manifesting as transient ischemic attacks. Ann Thorac Surg 2000;69:1949 –51. 15. Burke A, Virmani R. Tumors of the heart and great vessels. In: Rosai J, Sobin LH (eds). Atlas of tumor pathology, fascicle 16. Washington, DC: Armed Forces Institute of Pathology; 1996:1–11, 127–70. 16. Enzinger F. Soft tissue tumors: synovial sarcomas. New York: Raven Press; 1994. 17. Hannachi SS, Zargouni N, Saadi DM, Mrad K, Cammoun M, Ben RK. Primary synovial sarcoma of the heart. A clinicopathologic study of one case and review of the literature. Pathologica 2004;96:29 –34. 18. Varma T, Adegboyega P. Primary cardiac synovial sarcoma. Arch Pathol Lab Med 2012;136:454 – 8. 19. Zhang L, Qian J, Li Z, Jing H. Primary synovial sarcoma of the heart. Cardiol J 2011;18:128 –33. 20. Karn CM, Socinski MA, Fletcher JA, Corson JM, Craighead JE. Cardiac synovial sarcoma with translocation (X;18) associated with asbestos exposure. Cancer 1994;73:74 – 8. 21. Langner K, Schafer R, Muller KM, Goller T. [Synovial sarcoma of the pericardium]. Pathologe 1998;19:442– 6. 22. Cheng Y, Sheng W, Zhou X, Wang J. Pericardial synovial sarcoma, a potential for misdiagnosis: clinicopathologic and molecular cytogenetic analysis of three cases with literature review. Am J Clin Pathol 2012;137:142–9. 23. Miller DV, Deb A, Edwards WD, Zehr KJ, Oliveira AM. Primary synovial sarcoma of the mitral valve. Cardiovasc Pathol 2005;14:331–3. 24. Zhao Q, Geha AS, Devries SR, et al. Biatrial primary synovial sarcoma of the heart. J Am Soc Echocardiogr 2007;20:191–7. 25. Kodikara S. Pericardium: an exceedingly rare site for a primary biphasic synovial sarcoma. Indian J Pathol Microbiol 2012;55:227–9. 26. Koletsa T, Kotoula V, Hytiroglou P, Spanos P, Papadimitriou CS. Synovial sarcoma of the heart. Virchows Arch 2004;444: 477–9.
27. Anand AK, Khanna A, Sinha SK, Mukherjee U, Walia JS, Singh AN. Pericardial synovial sarcoma. Clin Oncol (R Coll Radiol) 2003;15:186 – 8. 28. Casselman FP, Gillinov AM, Kasirajan V, Ratliff NB, Cosgrove DR. Primary synovial sarcoma of the left heart. Ann Thorac Surg 1999;68:2329 –31. 29. Hing SN, Marshall L, Al-Saadi R, Hargrave D. Primary pericardial synovial sarcoma confirmed by molecular genetic studies: a case report. J Pediatr Hematol Oncol 2007;29: 492–5. 30. Lv X, Guo X, Chen X, et al. Primary cardiac synovial sarcoma. J Card Surg 2010;25:288 –90. 31. Oizumi S, Igarashi K, Takenaka T, et al. Primary pericardial synovial sarcoma with detection of the chimeric transcript SYT-SSX. Jpn Circ J 1999;63:330 –2. 32. Policarpio-Nicolas ML, Alasadi R, Nayar R, De Frias DV. Synovial sarcoma of the heart: Report of a case with diagnosis by endoscopic ultrasound-guided fine needle aspiration biopsy. Acta Cytol 2006;50:683– 6. 33. Provenzano SC, Con R, Jones OD, Grant PW. Synovial sarcoma of the heart. Heart Lung Circ 2006;15:278 –9. 34. Reddy RP, Snedden SS, Vauthy PA, Barnett BA, Hufford DR. An unusual cause of fatal hemoptysis in an adolescent. Pediatr Pulmonol 1994;18:264 –7. 35. Romero-Castro R, Rios-Martin JJ, Gallego-Garcia DVP, et al. Pericardial tumor diagnosed by EUS-guided FNA (with video). Gastrointest Endosc 2009;69:562–3. 36. Siebenmann R, Jenni R, Makek M, Oelz O, Turina M. Primary synovial sarcoma of the heart treated by heart transplantation. J Thorac Cardiovasc Surg 1990;99:567– 8. 37. Myers P, Konstantinidis S, Karatzas N, Milas F, Panos A. Pericardial synovial sarcoma of the heart; is it always worth operating? J Cardiovasc Surg (Torino) 2011;52:749 –51. 38. McGilbray TT, Schulz TK. Clinical picture: primary cardiac synovial sarcoma. Lancet Oncol 2003;4:283. 39. Nicholson AG, Rigby M, Lincoln C, Meller S, Fisher C. Synovial sarcoma of the heart. Histopathology 1997;30: 349 –52. 40. Moorjani N, Peebles C, Gallagher P, Tsang G. Pericardial synovial sarcoma. J Card Surg 2009;24:349 –51. 41. Fujioka M, Suehiro S, Shibata T, Kinoshita H, Wakasa K, Haba T. [Primary cardiac synovial sarcoma—a case report]. Jpn J Thorac Cardiovasc Surg 1998;46:923–7. 42. Talukder M, Joyce L, Marks R, Kaplan K. Primary cardiac synovial sarcoma. Interact Cardiovasc Thorac Surg 2010;11: 490 –2. 43. Boulmay B, Cooper G, Reith JD, Marsh R. Primary cardiac synovial sarcoma: a case report and brief review of the literature. Sarcoma 2007;2007:94797. 44. Sheffield EA, Corrin B, Addis BJ, Gelder C. Synovial sarcoma of the heart arising from a so-called mesothelioma of the atrio-ventricular node. Histopathology 1988;12:191–201. 45. Constantinou LL, Charitos CE, Lariou CM, et al. Primary synovial cardiac sarcoma: a rare cause of tamponade. Eur Heart J 1996;17:1766 – 8. 46. Van der Mieren G, Willems S, Sciot R, et al. Pericardial synovial sarcoma: 14-year survival with multimodality therapy. Ann Thorac Surg 2004;78:e41–2. 47. Akerstrom F, Santos B, Alguacil AM, Orradre JL, Lima P, Zapardiel S. Pericardial synovial sarcoma. Thorac Cardiovasc Surg 2011;59:175–7. 48. Schumann C, Kunze M, Kochs M, Hombach V, Rasche V. Pericardial synovial sarcoma mimicking pericarditis in findings of cardiac magnetic resonance imaging. Int J Cardiol 2007;118:e83– 4. 49. Mohamed AA, Al-Khaldi A, Omran AS. Primary cardiac synovial sarcoma demonstrated by 3D transesophageal echocardiogram. Eur J Echocardiogr 2011;12:409. 50. Yu L, Shi E, Gu T. Giant primary cardiac synovial sarcoma. J Card Surg 2011;26:74. 51. Al-Rajhi N, Husain S, Coupland R, McNamee C, Jha N. Primary pericardial synovial sarcoma: a case report and literature review. J Surg Oncol 1999;70:194 – 8.
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Primary cardiac synovial sarcoma is an extremely rare entity. The clinical and pathologic characteristics are still poorly understood, and prognostic factors influencing overall survival are still unknown. In the present study, all characteristics of reported patients, including sex, age, clinical presentations, laboratory tests, electrocardiogram, imaging findings, pathology, location, therapy, and
follow-up were carefully reviewed and survival analysis was performed. The present study has summarized some key features and may provide an effective consultation for the diagnosis and treatment of the tumor.
S
sarcomas. In previous case reports with literature reviews, researchers have described some clinical features, although, the characterizations, especially adjunctive diagnostic devices and treatment, remain poorly acknowledged. To the best of our knowledge, there are few large population studies of cardiac sarcomas and no accumulated knowledge of PCSS to date. We present an analysis of 60 patients with PCSS derived from 54 isolated articles in an effort to establish definite clinical, pathologic, treatment and outcome patterns of PCSS and to develop a rationale for prognostication in this disease.
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ynovial sarcoma (SS) represents only a small proportion of the soft-tissue sarcomas. In the World Health Organization classifications of cardiac tumors, SS was defined as a biphasic tumor composed of spindled and epithelioid areas, characterized by X;18 chromosomal translocations [1]. More than 80% arise in the deep soft tissue of extremities, especially around the knee, and the tumor frequently arises adjacent to joints or tendon sheaths. Histologically, SS is biphasic (BSS), characterized by epithelial and spindle cell components, or monophasic (MSS), characterized by the spindle cell component. Up to 50% of SS recur, usually within 2 years, but sometimes up to 30 years after diagnosis [2]. Quite a few large-population prognostic factor studies of SS have been published, but results have varied from report to report. Cardiac sarcomas often manifest clinical features, such as dyspnea and palpitation, that are similar to myxomas [3, 4]. Some patients may experience a long term before onset of symptoms, especially when they arise from the pericardium [3]. Therefore, these sarcomas are usually larger than their superficial counterparts. Owing to the poor understanding and indefinite conclusions for them, the correct preoperative diagnoses are always difficult to make, although varieties of examinations are performed to identify the lesion. Moreover, most cardiac sarcomas can seldom be completely removed, and are thus susceptible to recur. Despite the publication of numerous case reports and several series of cardiac sarcomas with long-term follow-up, prognostic factors are still being debated [5–7]. Primary cardiac SS (PCSS) is an extremely rare entity, which was first described in 1978 by McAllister and Fenoglio [8] in a 30-year-old woman. Since then, a series of isolated case reports have been published. An analysis of reviews shows that PCSS is calculated to account for approximately 4.2% (1 of 117 [8, 9], 2 of 75 [10], 1 of 24 [6], 1 of 14 [11], 3 of 24 [7], 2 of 17 [5], 2 of 14 [12], and 1 of 2 [13], respectively; mean, 4.2%) of the primary cardiac
Address correspondence to Mr Wang, Department of Pathology, the Affiliated Hospital of Medical College, Qingdao University, 16 Jiangsu Rd, Qingdao 266003, China; e-mail: [email protected].
© 2013 by The Society of Thoracic Surgeons Published by Elsevier Inc
(Ann Thorac Surg 2013;95:2202–9) © 2013 by The Society of Thoracic Surgeons
Material and Methods We searched PubMed using the terms “cardiac” and “synovial sarcoma,” “heart” and “synovial sarcoma.” The cases meeting the following criteria were included in the study: (1) originated from the heart chambers, myocardium, or pericardium; (2) excluded metastasis, with no history of PCSS, no SS in other location at diagnosis, or the extracardiac tumor was firmly demonstrated to be metastatic [14]; (3) article written in English, or if not, at least with an English abstract; (4) case without any descriptions was excluded [12, 13]. To expand the population size as large as possible, we also evaluated the references cited by these reports to identify any patients that might have been missed, including patients reported in previously published books. Three reports published in books [8, 15, 16] could not be accessed fully so that only available information described in literature reviewing works [17–19] was collected. A total of 60 unique patients reported in 54 isolated articles, as case reports or as original research, were selected and included in the study. All patient data, including sex, age, clinical presentations, laboratory tests, electrocardiogram, imaging findings, pathology, location, therapy, and follow-up, were collected and entered in Excel software (Microsoft Corp, Redmond, WA). Survival curves were calculated using the Kaplan-Meier method and compared with the logrank test. Data were analyzed using Prism 5.0 software 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2013.01.030
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Fig 1. Age and sex distribution (light bars, female; dark bars, male) is shown of patients with reported primary cardiac synovial sarcoma.
Results Study Population PCSS appeared to have a striking male predominance. The cohort consisted of 45 male and 15 female patients (male/female ratio was approximately 3:1). At presentation, patients were a mean age of 37.1 years (range, 13 to 70 years). The exact age was available in 58 patients (44 males and 14 females, excluding Burke and colleagues [10]), and the detailed age distribution is described in Figure 1. The medical history review appeared to be nonspecific. Amongst the 60 patients studied, only 2 had been exposed to asbestos [20, 21]. Other positive history records included 1 patient each with mediastinal teratoma [22], 3-vessel coronary artery bypass grafting [23], illicit drug and alcohol abuse [24], smoking [14], and hypertension [25]. A previous healthy or unremarkable medical history was definitely stated in 11 patients [26 –36].
Clinical Presentations Presenting complaints were provided in 50 patients. All available descriptions were carefully re-reviewed and divided mainly into three categories: cardiorespiratory symptoms (44 patients), extra-cardiorespiratory symptoms (11 patients), and nonspecific systemic symptoms (14 patients; Table 1). Dyspnea, at 68%, was by far the most common presenting symptom. Only 6 patients did not present with symptoms related to the cardiorespiratory system [5, 14, 23, 37–39]. Physical examinations were recorded for 22 patients, and 21 had positive signs: 1. heart failure signs, including hepatomegaly, distention of jugular vein (“a” wave), edema (ascites) [26, 29, 31, 36, 39, 40], rales [30, 34, 41– 43], hemoptysis [19, 24, 34], tachypnea [22, 29], and visible pulsations over the precordium [27]; 2. cardiac murmurs [27, 28, 30, 39, 43, 44] or extracardiac sounds: extrasystolic sound and an S4 [14], tumor plop [39];
3. cardiac tamponade signs [45, 46] or pericardial effusion signs [5]: distant heart sounds and a weak apex beat [31], pericardial rub [47]; 4. abnormal pulse: pulsus paradoxus [48], tachycardia [30, 43, 47, 48], and abnormal blood pressure: hypertension (2 patients, aged 13 and 28 years) [26, 34] or hypotension [11].
Table 1. Clinical Symptoms of 50 Patients With Primary Cardiac Synovial Sarcoma Clinical Symptoms Cardiorespiratory symptoms Dyspneaa Chest (thoracic, sternal, retrosternal, and substernal) pain Cough (dry cough, expectoration) Edema (ascites) Palpitation Hemoptysis Cardiac tamponade symptoms Extra-cardiorespiratory symptoms Syncope Headache Abdominal distension Vomiting Nausea Vertigo Aphasia, facial droop, witnessed seizure and consciousness loss Arm weakness Nonspecific systemic symptoms Fever Fatigue (tiredness, asthenia, exercise intolerance) Weight loss Malaise Nocturnal sweating a
No. (%) (N ⫽ 50) 44 (88) 34 (68) 13 (26) 11 (22) 9 (18) 5 (10) 3 (6) 2 (4) 11 (22) 5 (10) 2 (4) 2 (4) 2 (4) 1 (2) 1 (2) 1 (2) 1 (2) 14 (28) 9 (18) 6 (12) 3 (6) 2 (4) 2 (4)
Includes shortness of breath, breathless, chest tight, tachypnea, orthopnea, respiratory distress.
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(GraphPad Software, La Jolla, CA). Two-tailed p-values of 0.05 or less were considered statistically significant.
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Laboratory Tests Laboratory findings were provided in 10 patients, of which the results were abnormal in 8 [19, 21, 29, 31, 34, 36, 41, 48] and normal in 2 [30, 39]. Elevated alanine aminotransferase and aspartate aminotransferase levels were reported in 3 patients [21, 36, 41], and elevated lactate dehydrogenase was recorded in 3 patients [31, 36, 41]. Other detection indexes appeared nonspecific, including increased C-reactive protein [19, 21, 41, 48], increased erythrocyte sedimentation rate [19, 21], increased adenosine deaminase [31], decreased serum protein [31, 34], increased blood urea nitrogen [34], and increased serum calcium (without clinical manifestation) [29].
Electrocardiogram Electrocardiogram abnormalities in 11 reported patients are summarized in Table 2. Interestingly, the 3 patients with right bundle branch block had tricuspid valve masses. Two patients with axis deviation had right-sided heart tumor masses. The low voltage was associated the pericardial tumor mass, which caused pericardial effusion. In addition, ST-T segment changes were documented in 4 patients.
Imaging Findings Chest roentgenogram findings were reported in 25 patients. In most patients, this assessment could only provide some secondary signs, of which cardiomegaly [20, 27, 30, 34, 36, 37, 40, 42, 47, 51–55] was the most common manifestation. Pulmonary congestion [17, 41, 44] and
Table 2. Electrocardiogram Abnormalities of 11 Patients With Primary Cardiac Synovial Sarcoma
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Electrocardiogram
Tumor Location
Total AV block [36]
Arose from interatrial septum near AV node, in RA and RV In RA and obstruct tricuspid valve Partly in posterior wall RV and into pericardium Arose from LA posterior septum, in LA Arose from pericardium, adhering to RV free wall Pericardium
Right axis deviation [39] ST segment changes [21] T wave inversion in V1 [41] Low voltage [31] T wave inversion in I, aVL, V4, V5 and V6 [27] T wave inversion and a right BBB [33] Right axis deviation, incomplete right BBB [49] Complete right BBB [50] Microvoltage in all leads [37] Intermittent ventricular tachycardia [43]
Attached to tricuspid annulus, in RA and RV Arose from right AV groove invading tricuspid valve, in RA Attached to root of tricuspid valve, in RA and RV Pericardium Arose from tricuspid annulus, in RA and RV
AV ⫽ atrioventricular; BBB ⫽ bundle branch block; atrium; RA ⫽ right atrium; RV ⫽ right ventricle.
LA ⫽ left
pleural effusions [30, 34, 40 – 42, 49] could also be observed. Sometimes, the roentgenogram could vaguely outline the lesion if the pericardium was involved [35, 46, 48, 56 –58]. However, it might appear completely normal in some patients [39]. Plain computed tomography (CT) or contrastenhanced CT (CECT) was one of the most practical and valuable methods to rule out the lesion, and the latter could well define the tumor size and sectional views of involved structures. Calcifications [56] and cysts [55] were occasionally observed within the mass; however, plain CT sometimes failed to determine the tumor mass [37, 44]. The tumor (a total of 13 patients were documented, in which 2 were monophasic, 9 were biphasic, and 2 without histopathology descriptions) could be slightly enhanced, heterogeneously or non-homogenously, on CECT [19, 22, 27, 29 –31, 40, 55–57, 59, 60]. Nevertheless, it was difficult to differentiate the tumor from other soft-tissue neoplasms by plain CT or CECT [29], even benign, if the tumor appeared noninvasive. There was 1 patient with pulmonary nodules that had been considered a cardiac myxoma [14]. In contrast with the CT, magnetic resonance imaging (MRI) [22, 26, 31, 37, 40, 42, 46, 51, 54, 56], with or without contrast administration, especially the cardiac MRI [47, 59], could also well confirm the presence and the extension of the tumor and might display the lesion more clearly. This device might also miss the lesion instead of only pericardial thickening [48]. Transthoracic or transesophageal echocardiography was used more widely than all of the above. It could well detect the tumor in most instances, but its value was limited when a pericardial tumor was combined with large pericardial effusion. Of the 14 patients with pericardial SS documented with echocardiography findings [22, 27, 30, 31, 37, 40, 42, 47, 48, 51, 53, 55, 60], the mass was not detected in 4 [47, 48, 53, 60]. However, it remained a sensitive and convenient strategy to detect the presence of the intracardiac tumor mass. Only 1 tumor, which attached to the mitral valve, was missed in the 20 documented nonpericardial patients [23].
Other Preoperative Diagnostic Techniques Pericardial effusion samples could be collected by therapeutic pericardiocentesis and used for cytopathologic analysis, but the results were always negative [31, 37, 40, 45, 55]. Fine-needle aspiration (biopsy or cytology) was a more sensitive and reliable technique that might lead to a more accurate diagnosis and provide an alternative method to a surgical procedure. It could be guided under CT, echocardiography, or digital subtraction angiography. Amongst the 6 cases with fine needle aspiration, two were diagnosed as SS [32, 35], two were classified as spindle tumors (one was considered as a spindle cell thymoma) [29, 58], and the other two were inconclusive [19, 27]. Transvenous biopsy was also helpful in obtaining a more preferable diagnosis [36]. Catheterization and angiography were able to evaluate the feeding vessels [31]. The 18-fluorodeoxyglucose-positron emission to-
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Synovial Sarcoma
Intracardiac Pericardiac a
Biphasic No.
Monophasic No.
16 7
13 14
The 2 test was used (p ⫽ 0.13).
mography scan showed an uptake in a marginal site of the tumor [56].
Location The accurate location was evaluated by the location from which the tumor mass arose from or adhered to as observed at the operation so that the primary site was well established. If this information was absent or poorly clarified, it was evaluated by the described position on imaging. Patients with multiple occupying lesions in which the primary location was unclear were excluded from the present study [8, 18]. A total of 58 patients were enrolled, of which 24 (affecting 41.4%) had a pericardial SS [5, 20, 22, 25, 27, 29 –31, 35, 37, 40, 42, 46 – 48, 51, 53, 55, 56, 58, 60, 61]. The second most common location was the right atrium, affecting 14 patients (24.1%) [5–7, 11, 16, 17, 24, 26, 36, 39, 44, 49, 54]. Documented locations included the left atrium in 5 (8.6%) [10, 15, 34, 41, 57], the tricuspid valve in 5 (8.6%) [14, 33, 43, 50, 52], the right ventricle in 4 (6.9%) [7, 10, 19, 21], the left ventricle in 3 (5.2%) [32, 45, 59], and the mitral valve in 3 (5.2%) [23, 28, 38].
Pathology On gross appearance, the tumor mass was often polypoid, solid, or lobulated, with a smooth or well-circumscribed external surface. It usually appeared as a bulky mass and did not diffusely infiltrate the surrounding structures, so the initiation site could be well distinguished. Most tumors have a broad base, and the tumors in 7 patients were reported to have a pedicle or stalk [17, 30, 33, 34, 39, 44, 55]. Sections through the tumor mass showed variable patterns: some have firm, glazed, or elastic consistency, or were friable with some necrotic regions; others showed cystic changes [25, 47, 55]. It could be tan-white or reddish with hemorrhage, and cream-yellow with necrosis. This was related to the histopathologic features: soft and tan when cells are rich, especially with glandular architectures, and elastic and white when abundant with fibrous stroma. Sometimes, the growth pattern of the tumor perfectly mimicked cardiac myxomas [14, 38]. Tumor dimensions were reported in 37 patients, ranging from 2 to 15 cm; of these, the mass in 12 was 10 cm or more [11, 20, 21, 24, 26, 31, 42, 47, 51, 52, 56, 61], and only 4 were less than 5 cm [7, 14, 26, 46]. To obtain and confirm the accurate histopathologic subtype, we reviewed all of the available descriptions and pathologic images. The special subtypes, such as purely glandular MSS, calcifying SS, and poorly differentiated SS, were not reported in this cohort. Those described as spindle cell tumor with lack of epithelium
differentiation, if the diagnosis was not stated, were categorized as MSS. Of the 51 reported instances with pathologic information, 24 (47.1%) were biphasic BSS and 27 (52.9%) were MSS. The histopathologic type was not associated with the tumor location (Table 3). Immunohistochemistry and genetic analysis were the most useful ancillary diagnostic methods that may help to differentiate SS from mesothelioma. The spindle cells in MSS or BSS were immunopositive for a panel of antibodies expressed with variable staining characteristics (Table 4). The distinct epithelium differentiation (glandular component, occasionally with squamous metaplasia) was positive for cytokeratin and epithelial membrane antigen. The cells forming the glandular structures frequently expressed carcino-embryonic antigen and epithelial antigen Ber-EP4 and were positive for neutral mucins, which were absent findings in most epithelial mesotheliomas. However, MSS is difficult to differentiate from sarcomatoid mesothelioma, only depending on immunohistochemistry [62]. Genetic analysis methods were documented in 23 cases, including traditional cytogenetics [20, 43, 52], reverse transcription-polymerase chain reaction [5, 23–25,
Table 4. Reported Immunohistochemical Results of the Spindle Cells Positive Variables Cytokeratin (AE1/AE3) Epithelial membrane antigen Vimentin CD99 Bcl-2 Smooth muscle actin Calretinin Cytokeratin 5/6 Calponin HBME-1 (mesothelin) CD56 LCA, intermittent filaments, catenin, synaptotagmin s-100 protein CD34, desmin Thyroid transcription factor1, carcinoembryonic antigen CD117, Melan-A, MSA, CD31, VIII-factor Myoglobin, Myo-D1, D2-40, CgA, HMB-45, AFP, Cytokeratin CAM5.2, NF, E-cadherin, WT-1, CD21/ 35, CD68, Epithelial antigen Ber-EP4 Ki-67 labelling index
Negative
Focally
Diffusely
3/22 3/22 1/21 3/11 0 11/13 6/9 3/4 3/4 1/3 1/3 0
12/22 11/22 2/21 1/11 4/15 2/13 3/9 1/4 0 2/3 0 0
7/22 8/22 18/21 7/11 11/15 0 0 0 1/4 0 2/3 1/1
17/17 12/12 3/3
0 0 0
0 0 0
2/2
0
0
1/1
0
0
20%
AFP ⫽ ␣-fetal protein; CD ⫽ cluster of differentiation; CgA ⫽ chromogranin A; HBME-1 ⫽ human bone marrow endothelial cell-1; HMB ⫽ human melanoma black; LCA ⫽ leukocyte common antigen; MSA ⫽ muscle-specific actin; NF ⫽ neurofilaments; WT-1 ⫽ Wilms tumor protein.
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Table 3. Tumor Location and Histopathologic Featuresa
Location
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29, 31, 32, 46, 47, 51, 55, 57, 58], or fluorescence in situ hybridization [5, 18, 22, 23, 26, 29, 57]. The t(X;18)(p11; q11), as the cytogenetic hallmark of SS, could be detected using traditional cytogenetics or combined binary ratiofluorescence in situ hybridization. The SYT (SS18)-SSX (SSX1 or SSX2, or both) gene fusion could be confirmed by reverse transcription-polymerase chain reaction, and the SYT break-apart signal could be confirmed using fluorescence in situ hybridization. The genetic analysis method was not mentioned in 6 patients [7, 38, 42, 59]. The X:18 chromosomal translocation was demonstrated in 29 patients.
A variety of chemotherapy regimens were documented, including doxorubicin (hydrochloride) [20, 23, 24, 29, 42, 46], ifosfamide [20, 23, 24, 27, 38, 39, 42, 46, 47], mesna [20], vincristine [39], vinorelbine [29], actinomycin [39], dacarbazine [27], gefitinib [46], cisplatin [29], cyclophosphamide [29], and corticosteroids [29], and of those, schemes based on doxorubicin and ifosfamide were selected the most. Preoperative or postoperative chemotherapy was administered in 24 patients [5, 14, 20 –24, 26, 27, 29, 32, 33, 38 – 42, 46, 47, 54, 58 – 60] and radiotherapy in 9 patients [26, 27, 29, 41, 42, 46, 47, 51, 55].
Treatment
Local recurrence and distant metastasis after the initial operation were the two most common adverse events and were documented in 11 patients [26, 27, 31, 36, 41, 45– 47, 50, 52, 57]. Nonetheless, the disease free-survival was seldom estimated because of insufficient information. Only the overall survival analysis was performed in the present review. To obtain the more accurate follow-up data, we chose the report only when it provided an accurate follow-up period, resulting in 36 patients with a mean follow-up of 21.6 months extended up to 171 months (from July 1989 to October 2003) [46]. Survival was calculated using the postoperative time. The median overall survival of the patients diagnosed antemortem was approximately 24 months. Survival rates were ap-
A macroscopically or microscopically complete resection was documented clearly in 10 patients [7, 11, 14, 17, 27, 40, 46, 50, 56]. However, some may have had distant metastasis before presentation although the primary was completely excised [14]. The most common and successful operation reported to date was conventional sternotomy and cardiopulmonary bypass. Some tumors with a broad base that showed an infiltrative growth pattern made it impossible to perform a complete resection, and usually, tumor residues or a positive margin were left. The resection was incomplete in 23 patients. One patient underwent cardiac transplantation [16, 36]. Five patients were diagnosed at autopsy [8, 20, 25, 34, 52].
Survival Analysis
Table 5. Patients’ Characteristics of Median Overall Survival Variables
Pts (No.)
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Age ⱖ 30 y ⬍30 y Location Pericardium Cardiac cavity Tumor size ⬎5 cm ⱕ5 cm Operation Complete resection Partial resection Chemotherapy Yes No Radiotherapy Yes No Chemotherapy (and/or) radiotherapy Yes No Pathology Monophasic Biphasic a
Statistically significant difference.
CI ⫽ confidence interval;
HR ⫽ hazard ratio.
21 15
Overall Survival Median (mo)
HR (95% CI)
p Value
4.435 (1.386–10.96)
0.01a
0.925 (0.328–2.594)
0.878
0.864 (0.221–3.326)
0.823
0.642 (0.196–2.206)
0.496
0.307 (0.077–0.833)
0.024a
0.469 (0.147–1.727)
0.275
0.243 (0.0498–0.599)
0.006a
1.014 (0.349–2.947)
0.98
9 Undefined
18 18
27 10
24 7
26 9
8 21
Undefined 26
16 15
27 5.5
9 22
31 Undefined
18 13
27 5
21 13
27 26
Fig 2. Kaplan-Meier survival curves of two variables found to significantly affect survival: (A) age and (B) chemotherapy. Vertical bars indicate standard error of the mean.
proximately 59.9% at 1 year and 29.9% at 5 years. To further investigate predictors of outcome, we conducted a multivariate analysis of potential prognostic factors (Table 5). Adjunctive chemotherapy and radiotherapy, as well as age, affected the overall survival pattern (Fig 2).
Comment In the present study we have re-reviewed 60 unique patients derived from 54 isolated reports. As far as we know, this is the largest PCSS cohort study to date. Our data have firstly demonstrated that PCSS has a striking male predominance and readily involves the pericardium and right atrium. Regardless of the advanced imaging, it seems that hardly any of the methods used for adjunctive detection gave a fairly accurate preoperative diagnosis. Moreover, the present study has demonstrated, for the first time, that overall survival is affected by age and chemotherapy. As noted, an interesting observation of this study was the significant sex difference in PCSS compared with counterparts found in other sites; nonetheless, it also appears different from other cardiac sarcomas, although
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there may have been a selection bias. The appropriate explanation is still unclear. Another interesting phenomenon was that the disease has a favorite onset age, at the fourth decade of life, which was similar to noncardiac counterparts. The clinical presentations are diverse. Just as with other benign or malignant cardiac tumors, the most common symptom was dyspnea, which is explained by hemodynamic changes due to the atrioventricular valve obstruction narrowing outflow tract. The pathophysiologic alteration may also lead to fibrillation, pulmonary or systematic congestion, and even cardiac tamponade. The central nervous system-related symptom in one report was attributed to embolic infarcts [38]. We consider that the thrombus originated from thrombosis induced by the tumor, rather than from the tumor fragments, because the tumor was usually not so friable. Other extracardiorespiratory manifestations may be illustrated by hemodynamic changes in the gastrointestinal circulation and by the growth of the malignancy: invasion, necrosis, or immune response. Meanwhile, hemodynamic changes may lead to heart failure signs, mechanical obstruction may cause murmurs and extracardiac sounds, and pericardial effusion could result in cardiac tamponade. Compared with benign cardiac tumors [4, 63], PCSSs more readily bear gastrointestinal and systemic symptoms and frequently pericardial effusion, and tend to have larger tumor size. These characterizations are in accord with earlier reports of cardiac malignancies [9, 10, 64]. The results of laboratory tests appeared to be nonspecific for the diagnosis. Elevated alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels may indicate injured myocardium but might also be observed in other cardiac or noncardiac malignancies. Occurrences of bundle-branch block and ST segment and T wave alteration in PCSS were more common than that in myxomas [63, 65]. The conduction block was due to the infiltrative growth pattern. The ST-T changes could be explained by injury to the endocardium and myocardium. However, other electrocardiographic changes, such as atrial hypertrophy, fibrillation, arrhythmia, and tachycardia, which are common in myxomas, were not documented in this series of reports. Despite the varieties of imaging characteristics that were summarized, the present review failed to draw a definite conclusion about how to distinguish PCSSs from other cardiac malignancies. Previous studies have made a great effort on this issue; however, no criteria or distinctions were well acknowledged. We consider CECT and MRI are helpful in differentiating vascular tumors and adipose-derived tumors. Although there are no published reports on the differential diagnosis between cardiac myxoma and PCSS, a preferable diagnosis could also been made using CECT, because myxomas often have smaller tumor size, are localized in the left atrium, and are prone to forming more vascular structures. To distinguish PCSSs from other spindle cell tumors was rather difficult, even in small biopsy specimens. However, quite a few intracardiac PCSSs showed single and local growth pattern, which has not usually been identi-
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fied in other high-grade sarcomas such as malignant fibrous histiocytoma and lymphoma. The cell origin of SS is a controversial topic, and in the present study, we still cannot explain why PCSSs favor the pericardium and right atrium. Further statistical analysis revealed pathology was not related to the location. It was sometimes difficult to differentiate PCSS from mesothelioma, especially when it occurred in the pericardium. Both could display biphasic differentiation and monophasic differentiation histomorphologically. Also, some traditional mesothelial cell biomarkers, for example, human bone marrow endothelial cell-1 and calretinin, were immunopositive for SS and vice versa. It is worth mentioning that PCSS could arise from mesothelioma [44]; therefore, we suggest all tumors resembling mesothelioma should undergo molecular cytogenetic analysis. Surgical resection was indispensable, not only for the pathology but also for the treatment, and although the tumor usually might not have been completely removed, surgical resection could partially or totally relieve the obstruction and oppression. One of the most interesting and inspiring results of this study was that adjunctive chemotherapy could significantly prolong overall patient survival, which was rarely demonstrated in other SS reports [66]. A chemotherapy scheme based on doxorubicin and ifosfamide was used most commonly. However, we note there was a bias in favor of reporting patients with unique features. In addition, age was also considered an influencing factor, which was well concurred with previous studies [67–71]. Another widely accepted view in the existing reports was that tumor size was related with overall patient survival, which was not demonstrated in the present study. In fact, we changed the cutoff value from 5 to 10 cm in an effort to reach an agreement with previous reports, but survival analysis showed differences were always not significant. Possible illustrations for this discrepancy might be: REVIEW
1. Information bias: the presented data of tumor size was derived from the pathologic examination or different imaging-detecting approaches. 2. Growth pattern: compared with their counterparts of other sites, especially in the extremities, PCSS was prone to reach a larger size before symptom onset due to the lack of surrounding tissue. 3. Statistical analysis: only the median overall survival was taken into account, not 5-year or 10-year overall survival.
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