Dactinomycin

* Background.-Primary cardiac leiomyosarcomas are rare. Isolated reported cases and small series generally describe spindle-celled, high-grade tumors with poor shortterm survival; however, the pathologic features of many of these tumors are incompletely documented. The authors report in detail the clinicopathologic features of 2 relatively low-grade epithelioid and spindle-celled primary cardiac leiomyosarcomas.

Methods-Cases 1 and 2 were studied using standard histochemical and immunohistochemical techniques, and case 1 was examined by electron microscopy. The literature was reviewed with regard to primary cardiac leiomyosarcomas.

Results.-Both tumors showed epithelioid and spindlecelled areas. The tumor in case 1 was low grade, and the tumor in case 2 was predominately low grade with a high

grade focus. A review of 28 reported cases revealed a wide age range (mean, 43 years), equal male-to-female ratio, and a predilection for the left atrium (48%). Follow-up of reported cases with fewer than 5 mitoses per 10 high-power fields showed a mean survival of 22 months compared with a 9-month mean survival for all others.

Conclusions.-Short-term follow-up of reported cases of high-grade cardiac leiomyosarcoma suggests a poor prognosis. Long-term follow-up in our case 2, along with follow-up of reported cases that were histologically similar to our cases, suggests that cardiac leiomyosarcomas with lowgrade features or mixed low- and high-grade features also have a poor overall long-term survival, with a high rate of local recurrence and systemic spread.

(Arch Pathol Lab Med. 1999;123:782-788)

Primary cardiac tumors are rare and usually benign.1 Of malignant cardiac tumors, metastases from elsewhere are 30 to 40 times more common than primary malignancies. The most common subtypes are angiosarcoma and malignant fibrous histiocytoma, with primary cardiac leiomyosarcomas representing only 8% to 9% of all cardiac sarcomas.2 We recently diagnosed a relatively lowgrade epithelioid and spindle-celled cardiac leiomyosarcoma in a young woman. We searched our consult material and the English-language literature in an attempt to better ascertain the prognosis of this patient's tumor. The literature review revealed 28 reports of primary cardiac leiomyosarcoma; however, many of these reports were clinically oriented and included insufficient pathologic data. The search of our consult files revealed a case of a primary cardiac leiomyosarcoma in a young man that recurred locally, metastasized, and eventually killed the patient. His tumor was also epithelioid and spindle celled; however, it showed a high-grade focus and relatively lowgrade areas. In addition, one of the previously reported cases was clinically and histopathologically similar to our case 1, but limited pathologic and follow-up data were provided.3 In this report, we document in detail the histopathologic features of our cases and expand on the pathologic features and follow-up of the similar reported case.

MATERIALS AND METHODS

Case 1 was from the James Homer Wright Pathology Laboratories of the Massachusetts General Hospital and case 2 from the consultation files of one of us (C.D.M.E). For light microscopy, both specimens were formalin fixed and routinely processed. Immunohistochemical stains were performed using the avidin-biotin-peroxidase technique by a previously described method4 using commercially available antibodies (Table).

Case 1 was processed for electron microscopy. Briefly, fresh tissue was fixed in Karnovsky II solution, buffered in sodium cacodylate, and postfixed in oxmium tetroxide. The specimen was stained en bloc with urynal acetate, dehydrated in graded ethanol solutions, infiltrated with propylene oxide/epon, and embedded in 100% epon. One-micrometer-thick sections were cut, stained with toluidine blue, and examined by light microscopy. Representative areas were chosen and ultrathin sections were cut, stained with lead citrate, and examined with a Philips 301 electron microscope (Philips, Glofilampenfabrieken, Eindhoven, Netherlands).

A MEDLINE computer search using the search terms cardiac or heart and leiomyosarcoma revealed 61 references published in the English-language literature between 1966 and January 1997. Leiomyosarcomas that were metastatic to the heart or originated in the great vessels (eg, pulmonary artery) or pericardium were eliminated. The bibliographies of these articles revealed additional reported cases. In addition, cases in which the pathologic features were not described were eliminated from the literature review.

RESULTS

Case 1 was a 29-year-old woman who presented with a history of sharp, sometimes pressure-type pain in the anterior section of her chest, which she first noticed in her early 20s. The pain was sporadic and not associated with exertion or any particular activity. A magnetic resonance image revealed a 3-cm epicardial mass on the apex of the right ventricle (Figure 1). Intraoperatively, a 3.5 x 1.5-cm lobated mass extended from the cardiac apex, had a smooth overlying epicardial surface, and was not adherent to the pericardium (Figure 2). The mass was excised. Magnetic resonance imaging performed 18 months after surgery showed changes consistent with scar tissue; however, residual tumor could not be excluded with certainty. Magnetic resonance imaging performed 6 months later showed no change from the previous scan.

Histopathologic examination showed an epithelioid and spindle-celled cellular tumor that invaded into epicardial fat and myocardium and involved several surgical margins. Most of the tumor cells had distinct cell borders with minimal pleomorphism and brightly eosinophilic to clear cytoplasm (Figure 3). The nuclei were symmetrical and blunt ended, with a somewhat vesicular chromatin pattern. Some of the nuclei had a single conspicuous nucleolus, and occasional cells had multiple small nucleoli. A few cells had eosinophilic intranuclear inclusions, and multinucleated cells were occasionally seen. Most of the tumor showed 0 to 1 mitosis per 10 high-power fields (hpf); however, one area had up to 3 mitoses per 10 hpf. No necrosis was seen. The results of immunohistochemical stains are presented in the Table. Electron microscopy showed epithelioid and spindle-shaped cells arranged in groups surrounded by basal lamina and banded collagen (Figure 4). Between apposing cells were readily identifiable long, narrow junctions. The cytoplasm contained glycogen, a small amount of lipid, numerous mitochondria, and focal collections of filaments with dense bodies. There was no ultrastructural evidence of rhabdomyoblastic, fibroblastic, or endothelial differentiation.

Case 2 was a 25-year-old man who presented with loss of consciousness and atrial fibrillation. An echocardiogram revealed a mass in the atrial septum almost replacing the left atrium and partially extending into the right atrium. A 9-cm polypoid and gelatinous mass was "completely excised." Magnetic resonance imaging 11 weeks after surgery revealed a local recurrence in the atrial septum, and a total-body computed tomographic scan showed no evidence of extracardiac tumor. Chemotherapy (vinblastine sulfate, dactinomycin, ifosfamide, and doxorubicin) followed by local irradiation (40 Gy) resulted in complete remission based on magnetic resonance imaging. A 3.5cm local recurrence in the left atrium was surgically excised 5 years after the initial surgical procedure, and a 6cm polypoid jejunal mass was resected 7 months later. Chemotherapy (cisplatin and etoposide) was reinstated when the patient showed radiographic evidence of mediastinal and abdominal lymph node involvement; however, it was stopped after one cycle because of toxic effects. The patient died from brain metastases 84 months after his initial presentation.

The primary cardiac tumor was spindle celled and epithelioid. Many of the tumor cells showed distinct cell borders with mild to focally moderate pleomorphism. The spindled cells had brightly eosinophilic to clear cytoplasm, and many of the epithelioid cells had clear cytoplasm. The nuclei were blunt ended with a vesicular chromatin pattern, slightly convoluted nuclear membranes, and rare, inconspicuous nucleoli. Rarely, the spindle-celled nuclei had a more tapered appearance reminiscent of fibrosarcoma. Elsewhere in the tumor, the cells were epithelioid and markedly pleomorphic, and many cells were anchored to curvilinear vessels in a myxoid and edematous stroma in a manner suggestive of myxoid malignant fibrous histiocytoma (MFH) (Figure 5). Focal necrosis was present in the spindle-celled and MFH-like areas. The local recurrence was cytologically similar to the relatively low-grade areas of the primary tumor, with the exception of being slightly more spindle celled and having small but conspicuous nucleoli in many cells. The MFH-like areas were not seen in the local recurrence; however, only one slide was available for review. The relatively low-grade areas of the primary tumor and the local recurrence each had up to 2 mitoses per 10 hpf, whereas the MFH-like area in the primary tumor had up to 11 mitoses per 10 hpf. The jejunal metastasis was almost completely epithelioid and cytologically closely resembled the epithelioid areas of the primary tumor, with marked cellularity and pleomorphism; conspicuous, single, rarely multiple nucleoli; and up to 13 mitoses per 10 hp. The results of the immunohistochemical stains are presented in the Table.

The literature review revealed 28 additional case patients. The average age of these and the 2 current case patients was 43 years (range, 6 weeks to 69 years) and included 14 males and 16 females. The sites of involvement were as follows: left atrium (48w%), right atrium (26%), right ventricle (16%), and left ventricle (0.lo%). However, some tumors were large (average maximal diameter, 7.4 cm) and involved more than one site, making precise identification of the site of origin unreliable. In addition, the mean survival of patients with sarcomas with low mitotic counts (

COMMENT

In general, previously reported cases of primary cardiac leiomyosarcoma have consisted solely of spindled cells with moderate to marked pleomorphism (most cases were grade 3), tumor necrosis, and high mitotic activity.5-15 Some reported tumors shared some features with our cases. James and Leong16 described a 49-year-old woman with an 8.5-cm left atrial tumor who presented with atypical chest pain, underwent surgery and chemotherapy, and died 6 months after presentation. The tumor in their case was histologically similar to our cases in that it was epithelioid and spindle celled and, like the primary tumor in our case 2, showed only weak positive desmin staining. Their case, however, showed up to 10 mitoses in 1 hpf, significant pleomorphism, and necrosis.

Kennedy17 reported a 4.5-cm, incidentally found, right atrial mass in a 57-year-old woman who died 20 months after diagnosis despite undergoing chemotherapy. The tumor was epicardial based (like our case 1) and had "few" mitoses, a low cytologic grade (classified as a "probable leiomyoma" by 2 consulting pathologists), and epithelioid ("ovoid") and spindle-celled features, similar to both our cases. Unfortunately, a detailed pathologic discussion is not provided, making further comparison impossible. However, this patient was found to have high-grade, widely metastatic tumor at autopsy.

Finally, Segesser el3 all described a case that was clinically strikingly similar to our case 1. They described an 18-year-old man who presented with severe chest pain and was found to have a 7-cm lobated mass on the epicardial surface of the right atrium. A review of slides from this case (provided by Jeremiah N. Cox, MD, Geneva, Switzerland) showed a spindle-celled and epithelioid tumor that was histopathologically similar to the tumor in our case 1. The tumor was cellular, showed no necrosis, and had 0 to 1 mitosis per 10 hpf with a focus of up to 2 mitoses per 10 hpf, tumor cells that were minimally to mildly pleomorphic, eosinophilic to clear cytoplasm, and round to blunt-ended vesiculated nuclei that had small but conspicuous nucleoli. The results of their immunohistochemical stains are also presented in the Table. Follow-up on this case beyond that provided in the report by Segesser et al reveals that the patient died 24 months after diagnosis despite surgery, chemotherapy, and irradiation (Ludwig K. v. Segesser, MD, written communication).

Prognostic factors in primary cardiac leiomyosarcoma are difficult to define. Burke et al18 showed a statistically significant difference in survival between cardiac sarcomas of all types with less than 5 mitoses per 10 hpf compared with those with greater than 5 mitoses per 10 hpf. The mitotic activity in the study by Burke et al roughly correlated with survival in our review of reported cases of primary cardiac leiomyosarcoma. The mean survival of the 5 reported cases that described "rare," 3,5,19 "few," 17 or less than 5 mitoses per 10 hpf20 was 22.4 months compared with a 9.1-month mean survival for the remaining reported cases. Long-term survival, however, remains poor in patients with cardiac sarcomas of all histologic types who have a relatively low mitotic count (ie,

In addition to high mitotic activity, other reported variables that adversely affect survival for cardiac sarcomas of all histologic types include the presence of necrosis, location of tumors on the right side of the heart, and presence of metastases.18 In addition, short-term survival in patients with cardiac tumors is commonly a function of the tumor's location and is independent of histologic variables. For example, Faught et al19 described a 14-year-old boy with a minimally pleomorphic tumor that showed "rare" mitoses who died 2 months after the onset of symptoms because the tumor was large and obstructed the right atrium. We know of only 1 adult long-term survivor (>240 months) of primary cardiac leiomyosarcoma who was a patient with a 6.5-cm, endocardial-based, pedunculated, right atrial tumor that was surgically excised and that exhibited 1 mitosis per 10 hpf and a morphologic grade of 2.21 In addition, 5-year survival of a 6-week-old infant with a 4.8-cm, right atrial primary cardiac leiomyosarcoma, which was treated with incomplete surgical excision and chemotherapy and which exhibited 1 to 2 mitoses per 10 hpf and a relatively low morphologic grade, has been reported recently.22 Follow-up even beyond 5 years, however, may be necessary in low-grade primary cardiac leiomyosarcoma based on the late local recurrence and death at 84 months in our case 2.

The differential diagnosis of the tumors described herein includes rhabdomyosarcoma, fibrosarcoma, MFH, epithelioid leiomyoma, and rhabdomyoma. Rhabdomyosarcoma was considered in our cases because many of the tumor cells had brightly eosinophilic cytoplasm, which some may interpret as strap cells. In addition, well-differentiated tumor cells in case 1 infiltrated between striated cardiac myocytes, which could be misinterpreted as tumor cells with striations (Figure 6). However, neither of our tumors showed cross striations, and case 1 showed no ultrastructural evidence of striated muscle differentiation, namely ribosomal-thick filament complexes or Z-band material. The bland cytologic features in the spindle-celled components of both our tumors in addition to rare cells with tapered nuclei in case 2 might suggest fibrosarcoma. However, both our cases stained for actin filaments, case 1 contained intracytoplasmic glycogen and numerous mitochondria, and the cells in both cases showed eosinophilic cytoplasm and predominately symmetric, bluntended nuclei, all features of smooth muscle differentiation. In our case 2, MFH was considered because part of the tumor consisted of highly pleomorphic cells, many of which were anchored along blood vessels in a myxoid and edematous stroma (Figure 5, A). However, the MFH-like areas showed strong a-smooth muscle actin positivity (Figure 5, B). Of interest, MFH-like areas have been described in cases of cardiac leiomyosarcoma,2 and pleomorphic leiomyosarcoma at any site may closely mimic MFH.23 Benign tumors, including epithelioid leiomyoma or rhabdomyoma, were suggested in our case 1 because the lesion had a relatively low mitotic count, minimal pleomorphism, and no necrosis. Moderate cellularity and infiltrating margins, however, ruled out benign options in case 1. Finally, metastases enter the differential diagnosis because metastases to the heart are 30 to 40 times more common than primary cardiac malignancies.1 In particular, metastatic leiomyosarcoma from the uterus, retroperitoneum, or gastrointestinal tract must be considered in any case of cardiac leiomyosarcoma, and metastatic carcinoma was suggested in our cases because of their epithelioid appearance. The results of a metastatic workup were negative in case 1, and the presentation of the intestinal metastasis 5 years after the cardiac tumor strongly favors a cardiac primary in case 2.

In summary, we report 2 unusual cases of epithelioid and spindle-celled primary cardiac leiomyosarcoma. Our case 1 was low grade with few mitoses, whereas case 2 had a relatively low-grade area and a high-grade focus reminiscent of myxoid MFH. A literature review suggests that primary cardiac leiomyosarcomas are usually highgrade, spindle-celled tumors with poor short-term survival. Extended follow-up of our case 2 and the few reported cases of relatively low-grade cardiac leiomyosarcoma suggests that such cases have a better short-term survival, but their long-term survival remains poor.

We are extremely grateful to Ludwig K. von Segesser, MD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, and Jeremiah N. Cox, MD, Pathologie Clinique, Hopitaux Universitaires de Geneve, Geneva, Switzerland, for providing material for our review and additional follow-up on the case they reported with others.3 In addition, we are grateful to E Bryan Kennedy, MD (retired), Pittsburgh, Pa, for providing information on his reported case.17

References

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17. Kennedy FB. Primary leiomyosarcoma of the heart. Cancer. 1967;20: 2008-2012.

18. Burke AP, Cowan D, Virmani R. Primary sarcomas of the heart. Cancer. 1 992;69:387-395.

19. Faught PR, Waller BF, Hull MT. Spindle cell sarcoma of the heart in childhood: light microscopic, ultrastructural, and immunohistochemical evidence for smooth muscle, endothelial, and fibroblastic differentiation. Pediatr Pathol. 1988; 8:649-656.

20. Pucci A, Gagliardotto P Papandrea C, et al. An unusual myxoid leiomyosarcoma of the heart. Arch Pathol Lab Med. 1996;120:583-586.

21. Fine G, Raju BU. Leiomyosarcoma of the heart: a twenty year cure. Henry Ford Hosp Med J.1985;33:41-44.

22. Han P, Drachtman RA, Amenta P, Ettinger Li. Successful treatment of a primary cardiac leiomyosarcoma with ifosfamide and etoposide. J Pediat Hematol Oncol. 1996;18:314-317.

23. Fletcher CDM. Pleomorphic malignant fibrous histiocytoma: fact or fiction? A critical reappraisal based on 159 tumors diagnosed as pleomorphic sarcoma. Am J Surg Pathol. 1992;16:213-228.

Accepted for publication February 19, 1999.

From the Department of Pathology, Northwestern Memorial Hospital, Chicago, III (Dr Pins); Departments of Cardiology (Dr Ferrell), Cardiac Surgery (Dr Madsen), and Pathology (Dr Dickersin), Massachusetts General Hospital, Boston; Department of Pathology, Azienda Ospedaliera di Verona, Verona, Italy (Dr Piubello); and the Department of Pathology, Brigham and Women's Hospital, Boston, Mass (Dr Fletcher).

Reprints: Michael R. Pins, MD, Department of Pathology, Feinberg Pavilion, 7-325, 251 E Huron St, Chicago, IL 60611-2098.

Copyright College of American Pathologists Sep 1999
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