A case of primary cardiac leiomyosarcoma diagnosed at Ia?i Cardiology Center is presented. The study was made on the surgical biopsy specimen, and the diagnosis by routine morphological techniques. The gross examination revealed a large intracavitary left atrial tumor attached by a small sessile base to the left posterior atrial wall, having a smooth, white-gray surface, and a dense consistency. On the cut surface, the tumor had a whirled white appearance, with focal brown areas. The microscopic examination revealed the presence of a spindle cell tumor, forming fascicles orientated at right angles. The study revealed the morphological aspect characteristic to leiomyosarcoma. 
Key words: leiomyosarcoma, cardiac sarcomas 

INTRODUCTION 
     Sarcomas are next in frequency to myxomas among primary cardiac tumors. Extensive reviews, including those of Whorton (1949), Brukner (1955) and Somers (1968), did not enclose leiomyosarcomas (LMSs) (1). Later, Bearman (1974), O’Reilly (1975) and Thiene (1976) have reported few cases of cardiac leiomyosarcoma (LMS) and rabdomyosarcoma (1). The mean age at LMS presentation is within the fourth decade. The patients are 5 to 10 years younger than the mean age of the patients with other cardiac sarcomas. There is no apparent sex predilection. Five to 80 percent of cardiac LMSs occur in the left atrium (LA) and result in dyspnea. Other signs and symptoms include pericardial effusions, chest pain, atrial arrhythmias, and congestive heart failure. Budd-Chiari syndrome may occur in patients with right atrial LMS, and left ventricular outflow tract obstruction has been reported in a LMS of the ventricle (2). Most left atrial LMSs protrude into the cavity and thus on echocardiographic grounds can be easily mistaken with atrial myxomas (3). Histologically, LMS is composed of compact bundles of spindle cells that possess blunt-ended nuclei and are often oriented at sharp angles to one another. Characteristic features include the presence of cytoplasmic glycogen, perinuclear vacuoles, and intracellular desmin. Myxoid areas usually represent less than 25 percent of the tumor. In contrast with fibrosarcoma, pleomorphic and giant cells may be present. Zones of necrosis and mitotic figures are generally plentiful (4). The majority of cardiac LMSs arise from pulmonary vein, having origin in the smooth muscle media of pulmonary veins. However, it is likely that some LMSs originate within LA itself, because the left atrium is a preferred site of origin for most cardiac sarcomas, and because the subendocardial lining of the atrium normally contains bundles of smooth muscle cells. Their large size at the time of diagnosis makes assessment of the precise site of origin impossible in most cases (2).

MATERIAL AND METHODS 
     A 45-year-old female patient, without known cardiac history, was admitted to Iasi Cardiology Center for cardiac failure. Echocardiography revealed bilateral ventricular dilatation, more prominent on the left side, a giant left tumor atrial mass, and right pleural effusion. The tumor was removed soon after hospital admission. 
     The histological specimens were fixed in buffered 10% formalin for 12 hours, followed by routine paraffin embedding, cutting (5 mm), and hematoxylin-eosin (HE) and Van Gieson (VG) staining.
 

RESULTS 
     The patient, a woman aged 45 years, without known significant cardiovascular history, was diagnosed with giant left atrial myxoma, severe pulmonary hypertension and 3rd degree cardiac failure. At presenting symptoms were exertion dyspnea, tiredness and fatigability. The clinical examination revealed right pleural fluid, hepatomegaly, 1st degree jugular congestion, and bilateral perimaleolar edema. 
     Echocardiography showed left atrial dilatation and the presence in the left atrial cavity of a tumoral mass of 6,2 to 3,7 cm in diameter, attached to the posterolateral atrial wall by a small base and prolapsing through the mitral orifice into the left ventricle; there was also a concentric left ventricular hypertrophy, right ventricle dilatation, a small amount of pericardial effusion, and a bilateral pleural effusion, more prominent on the right side. Chest X-ray demonstrated a large mass in the left atrium, interpreted as myxoma. The tumor extended into the left ventricle through the mitral orifice. The tumor was removed one week later. 
     Macroscopically, the tumor removed from the left-side cardiac chambers was white-gray, dense and rubbery, oval in shape, and measured about 6 cm in diameter. It formed a “cast” conforming to the shape of the left atrium. The tumor had a small base of attachment to the posterolateral left atrial wall. Cross- section demonstrated a white-gray relatively homogenous cut surface, with focally brown areas. 
     Microscopically, the tumor was predominantly composed of spindle cells with pale cytoplasm and relatively oval nuclei (fig. 1) . The nuclei of these cells were elongated, blunt-ended, presenting a reduced pleomorphism (fig. 2) . Mitotic figures were rarely seen. The vascularity of the tumor was prominent showing small sized vessels intermingled with neoplastic cells. However, there were focal areas with myxomatous stroma. Such areas were estimated to occupy approximately 5-10% of the primary tumor. Interlacing bundles consisting of spindle cells with delicate collagen fibers characterized other small areas. PAS stain showed the presence of cytoplasmic glycogen (fig. 3) . The trichromic stain showed fuchsinophilic fibrils in the cytoplasm of spindle cells. The silver impregnation stain demonstrated individual cells circled by reticulin fibers (fig. 4) . Generally, neither necrosis nor hemorrhage was seen. But in some areas a small hemorrhagic infiltration between bundles of spindle shaped cells and reduced necrosis foci were evidenced.
Despite of the validation of many histologic grading systems (HGS) for STS, none have been universally accepted (8, 9). Histologic grading appears to be not only a valuable predictor of patient survival but also for selecting STS patients who could benefit from adjuvant chemotherapy. Applying this HGS in our case we could appreciate:

1. Tumor differentiation: we incorporated the studied LMS as a low grade type (G1) because the tumor exhibited an orderly fasciculated pattern, well differentiated cytologic features, absence of pleomorphism, absence or few foci of necrosis and low mitotic activity; all these features give a good prognosis of the case. According to the grade of differentiation, the tumor differentiation score was assessed as 1. In addition, the larger the amount of extracellular substance (e.g. collagen, mucoid substances) the more favorable the grade assigned. 

2. Tumor necrosis: the assessment of the extent of necrosis determines the tumoral grade, being the most important parameter for predicting the recurrence and overall patient survival. In our case there was minimal necrosis, as small foci, variably distributed, evaluated as less than 10 percent of the entire tumoral area (necrosis was not present on all slides). Taking in consideration these features, the calculated tumor necrosis score was 0. 

3. Mitotic count: the mitotic figures were counted on histological sections by using routine haematoxilin and eosin stain. We counted about 10 mitoses on 10 consecutive HPF (x 40) by selecting the most mitotically active parts of the tumor, usually located to the periphery. In our patient the mitotic score was 1. 
The histologic grading was obtained by summing the scores of the three criteria (tumor differentiation + tumor necrosis + mitotic count, that is 1+0+1). Thus the resulting score was 2, corresponding to grade 1. Finally, the diagnosis was of differentiated, histologic grade 1, cardiac LMS. 
 

DISCUSSIONS AND CONCLUSIONS
     Generally, as Virmani (3) stated, malignant fibrous histiocytoma, fibrosarcoma and LMS represent the most common left atrial malignant tumors. According to Waller (4), the malignant tumors derived from the smooth muscle are extremely rare in the heart. Referring to the frequency, Silver (5) and Burke (2) consider LMS an uncommon cardiac tumor, representing only 8 to 9 per cent of cardiac sarcomas. Silver (5) noted the mean age at presentation of 41 years, with limits between the third and fifth decade of life, while Waller (4) showed the diagnosis might be made at any age; in infants and children, cardiac sarcomas are rare and are usually undifferentiated sarcomas or rhabdomyosarcomas. There is no sex predilection for cardiac sarcomas as a group, while Olsen (1) notes that men are more frequently affected. 
     Clinically, in agreement with Virmani (3), the found symptoms and complications included dyspnea, chest pain, and pericardial effusion. The symptoms corresponding to left and right cardiac failure were also present in our patient, being secondary to the obstruction of the mitral orifice by a giant atrial tumor. Olsen (1) observed the valvular obstruction occurring rarely, and in exceptional circumstances no symptoms were experienced.
As Burke noted (2), most tumors arise in the left atrium. Virmani (3) also observed that the left atrium is the site of 50% of cardiac sarcomas, and, as in our case, they often project into the cavity, mimicking myxoma, from which are usually differentiated by multinodularity or infiltration of the atrial wall or valves, appearance undemonstrated by us. Occasionally, as Olinici (6) reported, LMSs are pedunculated, intracavitary lesions with some degree of gross myocardial infiltration. Therefore, it is evident that the distinction between a benign and malignant tumor is not always possible on gross or radiographic findings, the diagnosis being best made by echocardiography in conjunction with computed tomography. 
Macroscopically, in agreement with Burke (2), LMSs are typically sessile atrial lesions that may be grossly myxoid or mucoid. As in our case, they are typically located on the posterior atrial wall, being multiple in 30 percent of cases (3). On biopsy section we found focal brown areas, resulting in a focal variegated appearance; in the rest of the tumor, as described in the literature  (3), the tumor was relatively homogenous, white and firm.
     Microscopically, in agreement with Silver (5) and Waller (4), we found a specific architecture and cytology of the tumor. As Silver, who found that approximately 10% of cardiac sarcomas demonstrate smooth muscle cell differentiation, we found that the tumor was composed of fascicles of spindle cells that cross one another at right angles. Cytologically, the tumor cells were elongated in shape, with blunt-ended nuclei. The nuclei presented a variable pleomorfism, and mitoses were variable in number in different fields, being more numerous at the tumor periphery. Although intracellular glycogen is always present, this feature was not so prominent in our case, because of using watery formalin as fixative. According to Silver (5), in more than 50 percent of the tumors there is a focal desmin expression, but we didn’t use this staining (method). It was evident that in all the specimens from the examined lesions this tumor showed a predominance of the histopathologic features of smooth muscle tumor, but less cellular areas with a myxoid stroma were also found. As to this feature, Virmani (1) considers the focal areas of myxoid stroma common in cardiac sarcomas, especially in tumors arising in the left atrium, such as fibrosarcoma, malignant fibrous histiocytoma, and LMS. 
     This reported case is considered notable in the following two aspects. First, the clinical features of the tumor were much more characteristic for a myxoma rather than a typical LMS.  In fact, intracardiac extension was not evident in our case, while about 30 such examples have been described as infiltrative in the English literature (5). Secondly, the extensive smooth muscle differentiation was the common feature. So, this primary tumor was predominantly composed of a prototypical low-grade tumor characterized by spindle cell fascicles intersected at right angles, appearance which supported the diagnosis. We could not demonstrate by immunohistochemistry the diagnosis (positive immunoreactivity to desmin), although the usefulness of immunohistochemistry along with proper interpretation of silent morphologic features cannot be underestimated, and careful histological examination was sufficient for the diagnosis.
     As to the origin of this tumor, Symmers (7) noted that the exact histogenesis and origin of these sarcomas are unclear. LMSs are usually regarded as arising from undifferentiated mesenchymal cells in the endocardium. According to Burke (2), LMS is a malignant mesenchymal neoplasm composed of cells with structural or antigenic evidence of smooth muscle differentiation. Recently, according to the origin of the tumor, Silver (5) suggested that a certain proportion of atrial LMSs might derive from veins emptying the heart, either the venae cavae on the right or pulmonary veins on the left. Symmers (7) noted that while some sarcomas are histologically uniform, many show a mixture of differentiation patterns. But, in practice, most sarcomas consist of spindle-shaped cells with a high mitotic rate and show no particular differentiation pattern. Waller (4) stated that in these poorly differentiated examples electron microscopy is helpful in distinguishing LMSs from fibrosarcomas.
     According to Virmani (3), there is no universal grading of cardiac sarcomas. The tumors with necrosis (in our case the necrotic areas were small and focal) and those with more than 10 mitoses on HPF, in the most mitotically active area of the tumor, are considered high-grade (8, 9). In our case, less than 10 mitoses being found on HPF, the tumor was considered low-grade.
     As to survival and sites of metastases, Virmani (3) considers survival to be independent of histologic type, appreciating that mean survival for most types of cardiac sarcomas is of about 9 months. It is known that the presence of tumor necrosis and high mitotic rates are indicative of relatively poor prognosis (8, 9). Metastatic sites include lung, vertebrae, brain, lymph nodes, long bones, spleen, adrenal glands and skull. According to Symmers (7), a better survival is associated with absence of necrosis, low mitotic counts, and left-sided situation, the last feature reflecting an early diagnosis rather than a different behavior. 
     Differential diagnosis included myxoma and myofibroblastic sarcoma. Referring to differential diagnosis, Virmani (3) noted that the most common pitfall in the misdiagnosis of myxoid cardiac sarcomas is myxoma. Both lesions typically occur in the LA and are endophytic masses projecting into the atrial cavity. Comparative with myxoma, cardiac sarcomas often have multiple attachment sites, often grow within the cardiac walls, containing easily identifiable mitotic figures on histological specimens. Compared with myofibroblastic sarcomas, leiomyosarcomas have more uniform cells and may demonstrate perinuclear vacuoles, abundant fuchsinophilic cytoplasm, and intracellular glycogen.  From these, fibrosarcoma, in contrast with LMS, lacks intracytoplasmic glycogen, cellular pleomorphism, and intracytoplasmic desmin, while the nuclei of LMS are described as blunt-ended. According to AFIP members, the differentiation between pleomorphic LMS and malignant fibrous histiocytoma may be more difficult, because some cardiac LMSs have areas indistinguishable from malignant fibrous histiocytoma. 
     There is general agreement about the management of cardiac sarcoma. The treatment consists of surgical excision, and postoperative survival is measured in months.
     In agreement with Virmani (3), we can conclude that: 
- The mean age at presentation is the fourth decade, as in our case.
- Most cases occur in the left atrium, being extensions of sarcomas of pulmonary veins.
- Symptoms are usually the same as with other types of atrial tumors, including dyspnea and congestive failure.
- Prognosis is poor, survival being generally measured in months.
- LMSs resemble their extracardiac counterparts; myxoid areas are not uncommon.
- Cells form compact fascicles that are often oriented at right angles to one another; fuchsinophilic longitudinal filaments may be seen with Masson trichrome stain.
- Intracytoplasmic glycogen and perinuclear vacuoles are histological features that aid in the diagnosis.
- Approximately 50% of LMSs are desmin positive; their filaments with focal densities may be seen ultrastructurally, but dense bodies are not considered specific for LMS.
 

REFFERENCES 
1. Olsen EGJ. In: Olsen EGJ. Tumors of the Heart, published by The Macmillian Press Ltd. In 1880. pp 370-384
2. Burke, AL. Malignant Cardiac Tumors, In: Burke, AL, Virmani R, published in 1995 by AFIP, pp 77-97
3. Virmani R. Malignant Cardiac tumors. In: Virmani R, Burke A, Farb A. Atlas of Cardiovascular Pathology,  published in 2000  by W.B. Saunders Company, pg 93-95
4. Waller BF. Surgical Pathology of Cardiac Tumors. In Waller BF. Pathology of the Heart and Great Vessels, published in 1988 by Ed. Churchill Livingstone, 344-363
5. Silver MB. Tumors of the Heart. In: Silver MB, Gotlieb I, Sckoen FI.  Cardiovascular Pathology, published in 2001 by Churchill Livingstone, pp 583-592 
6. Olinici CD. Tumori cardiace maligne. In: Olinici CD, Encica; S, Scridon T. Patologia tumorala a inimii si a vaselor, published 2002 by Editura Cluj-Napoca, pp 79-122
7. Symmers WSC. Cardiac Tumors. In: Symmers WSC. The Cardiovascular System. pp 288-290.
8. Hasegawa T, Yamamoto S, Nojima T et al. Validity and Reproductibility of Histologic Diagnosis and Grading for Adult Soft-Tissue Sarcomas, published in Hum Pathol, 2002, vol. 33, No 1, pp111-115
9. Kilpatrick SE, Histologic Prognostication in Soft Tissue Sarcomas: Grading Versus Subtyping. A Comprehensive Review of the Literature with Proposed Practical Guidelines, Annals of Diagnostic Pathology, 1999, Vol 3, No 1, pp 48-61
10. Jose E. Lung disease. In: Silverberg SG. Principles and Practice of Surgical Pathology and Cytopathology. Ed. Churchill Livingstone 1997, 783-785.

...

..

.....