The American Journal of Surgical Pathology /8(1): 107-111, 1994 Cerebral Metastasis of an Atrial Myxoma Mimicking an © 1994 Raven Press, Ltd., New York Epithelioid Hemangioendothelioma Hemamali Samaratunga, F.R.C.P.A., Jeffrey Searle, F.R.C.P.A., Diane Cominos, M.B.B.S., and Ian Le Fevre, F.R.C.P.A. A 60-year-old woman presenting with a 15-month history of Jacksonian seizures was found on computed tomogra- phy (CT) scan to have an enhancing subcortical lesion high in the left anterior parietal lobe. The excised tumor had light microscopic features similar to those of an epi- thelioid hemangioendothelioma, and immunohistochemi- cal stains confirmed its vascular nature. At surgery, the patient had no clinical or radiological (including CT body scan) evidence of any other lesion. However, 22 months after symptoms first appeared, she presented with dys- pnea and bilateral pleural effusions, and a left atrial myx- oma was detected echocardiographically. The histologic features of the resected myxoma were identical to those of the previously excised cerebral lesion, and it became apparent that the intracranial tumor was a metastasis of the atrial myxoma. This case illustrates that before a di- agnosis of visceral epithelioid hemangioendothelioma is rendered, the possibility of metastatic occult cardiac myxoma should be considered. Echocardiography is war- ranted for such patients. Key Words: Cerebral metastasis—Atrial myxoma— Epithelioid hemangioendothelioma. Am J Surg Pathol 18(1): 107-111, 1994. From the Department of Pathology, Royal Brisbane Hospital (H.S.,J.S., D.C.), and Queensland Medical Laboratory (1.L.F.), Brisbane, Queensland, Australia. Address correspondence and reprint requests to Dr. H. Samaratunga, Department of Pathology, Royal Brisbane Hospi- tal, Herston Road, Brisbane QLD 4029, Australia. Atrial myxomas are the most common primary cardiac tumors (20). However, until relatively re- cently, the biologic nature of these lesions remained uncertain. It has been proposed that myxomas were not true neoplasms but were lesions that developed in organized mural thrombi in the heart (17). Since then, their neoplastic nature has been recognized because of local recurrence (10) and metastatic po- tential (16,18). Characteristically, cardiac myxomas are polypoid masses composed of abundant myxoid stroma in which sparse numbers of stellate or poly- hedral tumour cells are seen singly, as syncytial masses, in strands, or lining single or multilayered vascular spaces (18,20). Nuclei of tumor cells show little pleomorphism, very rare mitoses, and incon- spicuous nucleoli. The cytoplasm of some tumor cells is vacuolated (18). These microscopic features are also seen in metastatic brain lesions (5,18). The myxoid stroma of these lesions contains hyaluron- idase-sensitive alcian-blue-positive material and tu- mor cells that demonstrate vascular differentiation stain positively for factor VIII-related antigen (5). These histological and immunohistochemical fea- tures are similar to those of epithelioid hemangio- endotheliomas, a rare vascular neoplasm first de- scribed by Weiss and Enzinger (22) as a soft tissue tumor with distinctive light microscopic appear- ances. Features of these tumors include the pres- ence of abundant myxoid stroma, epithelioid endo- thelial cells arranged singly or in strands with or without lumena, and evidence of vascular differen- tiation (22,23). We describe the case of a 60-year-old woman who presented with a cerebral neoplasm, the fea- tures of which were considered to be those of an epithelioid hemangioendothelioma. Twenty-two months after the onset of her neurological symp- 108 H. SAMARATUNGA ET AL. toms, a cardiac myxoma that had similar histologic features to the cerebral lesion was discovered, and the diagnosis of the cerebral tumor was revised to metastatic atrial myxoma. CASE REPORT A previously healthy female patient first pre- sented in November 1990 at the age of 59 years with a 3-month history of right-sided sensory-type Jack- sonian seizures and a 1-month history of right-sided motor-type Jacksonian seizures. Computed tomog- raphy (CT) scans revealed an enhancing subcortical lesion high in the anterior part of the parietal lobe, and a stereotactic biopsy was obtained through a burr hole. Histology revealed evidence of recent and old hemorrhage with reactive gliosis but no tu- mor. A year later, she was found to have progres- sive right-sided weakness and worsening Jackso- nian seizures. Repeat CT scans revealed that the parietal lobe lesion had enlarged slightly and ap- peared bilobed. There was evidence of edema of the surrounding cerebral parenchyma. General physical examination and investigations (including a CT body scan) showed no evidence of any other vis- ceral lesions. At craniotomy, a partly hemorrhagic pale lesion was seen within the anterior part of the left parietal lobe. It was subcortical and up to 30 mm in diameter, and it was resected in its entirety. The specimen consisted of several fragments of cream-colored, firm tissue and darkly hemorrhagic, partly brownish tissue measuring in total 20 x 15 x 10 mm. Microscopic examination revealed a myx- oid lesion containing small, solid nests and strands of polygonal, cuboidal, or elongated cells that sometimes enclosed vascular lumens containing red cells (Fig. 1). The tumor cells showed only mild nuclear pleomorphism and hyperchromasia; mitotic figures were not seen, and there was no necrosis. Blood vessels within the tumor as well as within the adjacent leptomeninges showed mural involvement by similar myxoid tissue, and lumina of affected vessels were compressed (Fig. 2). Often tumor cells contained small intracellular vacuoles that caused nuclear distortion, and some of these contained red blood cells, suggesting endothelial differentiation (Fig. 3). Where the lesion abutted cerebral paren- chyma, numerous collapsed blood vessels were sur- rounded by prominent hemosiderin-laden macro- phages. The myxoid stroma of this lesion stained strongly with alcian blue, and this positivity was prevented by pretreatment of sections with hyaluronidase, in- dicating the presence of acidic mucopolysaccha- Am J Surg Pathol, Vol. 18, No. 1, 1994 . kod Cw. » Ste se FIG. 1. Cerebral tumor. Spindled and polygonal cells arranged singly and in groups in a myxoid matrix. Some groups of tumor cells form vascular channels (arrows). ride. No intracellular or extracellular neutral mucin was seen with periodic acid-Schiff stains. Immunohistochemical stains using the peroxi- dase-antiperoxidase method were performed for cy- tokeratin, S-100 protein, glial fibrillar acidic pro- tein, and factor VIII-related antigen. Lectin histo- chemical stains for Ulex europaeus agglutinin I (UEA-I were also done. Reactions for factor VILI- related antigen and UEA-I showed a moderate de- gree of positive staining within the tumor cell cyto- plasm, with accentuation around cytoplasmic minilumens confirming the vascular nature of this neoplasm. All other reactions were negative, and the features of this neoplasm were considered those of an epithelioid hemangioendothelioma. Seven months later, the patient had wheezing and dyspnea on exertion and a cough of some weeks’ duration. She also had left-sided chest pain unrelated to ef- fort. Examination showed her to be tachypneic, and she had bibasilar crepitations, a prominent third METASTATIC ATRIAL MYXOMA 109 FIG. 2. Leptomeningeal blood vessels showing in- volvement by myxoid tumor. Lumina of these vessels are compressed, and one shows transmural extension of tumor tissue with aneurysm formation. heart sound, and a midsystolic murmur. Chest roentgenogram revealed bilateral pleural effusions and evidence of pulmonary edema. A large, pedun- culated left atrial tumor prolapsing through the mi- tral valve into the left ventricle was detected by echocardiography. A polypoid, soft hemorrhagic mass measuring 50 x 45 x 20 mm was removed from the left atrial septum. Microscopic examina- tion revealed a myxoid tumor with prominent pap- illary surface projections covered by a monolayer of polygonal and cuboidal cells. Within the myxoid stroma were similar polygonal and stellate cells that formed small, solid nests and cords (Fig. 4), some of which appeared to be canalized to form delicate vascular channels. The tumor cells showed little pleomorphism, and mitotic figures were few; some cells showed cytoplasmic vacuoles. The histologic features of this cardiac fesion were identical to those of the cerebral lesion removed previously, as were the histochemical and immuno- histochemical features of the two lesions. Hyal- uronidase-sensitive alcian-blue staining was seen in the myxoid stroma of the cardiac tumor, and reac- tions for factor VIII-related antigen and UEA-1 showed positive staining within tumor cells. All other immunohistochemical reactions were nega- tive. The patient remains well 14 months after re- moval of the cardiac myxoma. DISCUSSION The light microscopic features of the cerebral neoplasm with its epithelioid cellular characteris- tics, vasoformative nature with primitive vascular differentiation, myxoid stroma, sparse cellularity, and angiocentricity were considered those of an epi- thelioid hemangioendothelioma. Positive immuno- histochemical staining for factor VIlI-related anti- gen and lectin histochemical stains UEA-I in tumor cells confirmed its vascular nature. However, the large left atrial myxoma with iden- = © ve FIG. 3. Cerebral tumor. Myxoid stroma containing epi- thelioid cells, one of which (arrow) shows a red blood cell within a cytoplasmic vacuole. Am J Surg Pathol, Vol. 18, No. 1, 1994 110 H. SAMARATUNGA ET AL. FIG. 4. Atrial myxoma showing predominantly spin- dled cells in a myxoid matrix that contains some fibrin (F). Vasoformative features are visible in some groups of tumor cells (arrows). tical microscopic, histochemical, and immunohisto- chemical features that was discovered 7 months af- ter the neurosurgical resection made it apparent that the cerebral lesion was a metastatic deposit from the atrial myxoma. A metastasis from a pri- mary malignant cardiac myxoma in which sarcoma- tous areas were observed has been reported (21), but in the present case the atrial tumor had the typ- ical morphology of a bland paucicellular cardiac myxoma (20). Cerebral metastasis of such usual cardiac myxomas is rare, with the pathology of only five cases reported (1,9,14,15,18). In these cases, as in ours, the cerebral lesions resembled the primary cardiac tumor histologically, with the presence of abundant myxoid stroma and tumor cells singly and in strands that showed prominent vasoformative features. Epithelioid hemangioendothelioma is a relatively rare low-grade vascular neoplasm that, although first described in soft tissues (22), has since been described in lung (4), liver (8), bones (6), and in the Am J Surg Pathol, Vol. 18, No. 1, 1994 tissues of the head and neck (7), including the brain (3,11,19). Our patient had no clinical, plain x-ray, or computed tomographic evidence of a cardiac myx- oma at presentation with the cerebral lesion, indi- cating that an asymptomatic cardiac myxoma may not be detected by these radiological methods. The cerebral lesion enlarged only slightly over a !-year period (as assessed by CT scanning). Systemic em- boli occur commonly (12), but the exact metastatic potential of these lesions is unknown. Judging by the small number of reported cases, it appears to be low. The myxoid lesions present within the intrace- rebral and meningeal blood vessel walls in our case were thought initially to represent the angiocentric- ity of epithelioid hemangioendothelioma (23), but they could equally represent sites of lodgement of myxoma emboli. Burton et al. (2) described the pa- thology of such emboli in which myxoid expansion of the intima and media sometimes resulted in an- eurysms. The slow growth and relatively good prog- nosis of most cases of epithelioid hemangioendothe- lioma (23) matches the behavior of metastatic myx- omas with banal histological features in which slow growth and recurrences over some years have been reported by Seo et al. (18) and Rankin et al. (15). In the five bona fide cases of cardiac myxoma meta- static to the brain (1,9,14,15,18) the period from primary resection of myxoma to onset of neurologic symptoms varied from 10 months to 8 years. Our case is therefore unusual because the cerebral le- sion was evident 22 months before the primary car- diac tumor produced symptoms. The histologic, histochemical, and immunohisto- chemical similarities between cardiac myxomas and epithelioid hemangioendotheliomas led to the latter diagnosis of the original neurosurgical specimen. Most epithelioid hemangioendotheliomas produce factor VIII-related antigen and on electron micros- copy reveal features of endothelial differentiation (23). Intense factor VIII-related antigen positivity has been shown in tumor cells of cardiac myxomas (13). Electron microscopic features of endothelial differentiation have also been noted in these tumors (10,18). It appears that there are no definite histo- pathologic features to distinguish reliably between metastatic myxomas and epithelioid hemangioendo- theliomas. The present case illustrates that before a diagnosis of visceral epithelioid hemangioendothe- lioma is rendered, the possibility of metastatic oc- cult cardiac myxoma should be considered, and echocardiography for such patients appears war- ranted. QO Acknowledgment. We thank Dr. J.D.N. Yelland for providing clinical information and Dr. A.E.G. Tannen- METASTATIC ATRIAL MYXOMA berg for his neuropathological opinion. We also thank Karen Costello and Gail Haworth for typing the manu- script. REFERENCES . Budzilovich G, Aleksic S, Greco A, Fernandez J, Harris J, Finegold M. Malignant cardiac myxoma with cerebral me- tastasis. Surg Neurol 1979;11:461-9. . Burton C, Johnston J. Multiple cerebral aneurysms and car- diac myxoma. N Engl J Med 1970;282:35-6, . Chow LTC, Chow WH, Fong DTS. Epithelioid hemangio- endothelioma of the brain. Am J Surg Pathol 1992;16:619- 25. . Dail D, Liebow AA, Gmelich JT, et al. Intravascular, bron- chiolar and alveolar tumor of lung (IVBAT). An analysis of 20 cases of peculiar sclerosing endothelial tumour. Cancer 198355 1:452-64. . Desousa AL, Muller J, Campbell RL, Batnitzky S, Rankin L. Atrial myxoma: a review of neurological complications, metastases and recurrences. J Neurol Neurosurg Psychiatry 1978;41:1119-24. . Dorfman HD, Tsuneyoshi M, Bauer T. Epithelioid heman- gioendothelioma of bone. Lab Invest 1986;54:17A. . Ellis GL, Kratochvil FJ. Epithelioid hemangioendothelioma of the head and neck: a clinicopathologic report of 12 cases. Oral Surg Oral Med Oral Pathol 1986;61:61-8. . Ishak KG, Sesterhenn 1A, Goodman ZD, Rabin L, Stro- meyer FW. Epithelioid hemangioendothelioma of the liver: a clinicopathologic and follow up study of 32 cases. Hum Pathol 1984;15:839-52. . Kadota T, Imakita S, Mitomo M, et al. Metastatic brain tumour of atrial myxoma. Neuroradiology 1987;29:218. . Kelly M, Bhagnat AG. Ultrastructural features of a recur- rent endothelial myxoma of the left atrium. Arch Pathol 1972;93:219-26. i. 12. 18, 19, 20. 21. 22. 23. 111 Kepes JJ, Rubinstein LT, Maw G, Burdick B. Epithelioid hemangiomas (hemangioendotheliomas) of the central ner- vous system and its coverings. A report of 3 cases. J Neu- ropathol Exp Neural 1986;45:319. Markel ML, Waller BF, Armstrong WF, Cardiac myxoma. A review. Medicine (Baltimore) 1987;66:114-25. . Morales AR, Fine G, Castro A, Nadji M. Cardiac myxoma (endocardioma). Hum Pathol 1981;12:896-9. . Morimoto K, Fujita T, Wakayama A, Miyazaki Y, Kamido H, Imakita T, Mogami H. Cardiac myxoma metastatic to the brain [English abstract] No To Shinkei 1986;38:865-9. . Rankin LI, De Sauda AL. Metastatic atrial myxoma present- ing as intracranial mass. Chest 1978;74:451-2. . Read RC, White HJ, Murphy ML, Williams D, Sun CN, Flanagan WH. The malignant potentiality of left atrial myx- oma. J Thorac Cardiovasc Surg 1974;68:857-68. . Salyer WR, Page DL, Hutchins GM. The development of cardiac myxomas and papillary endocardial lesions from mu- ral thrombus. Am Heart J 1975;89:4-27. Seo IS, Warner TFCS, Colyer RA, Winkler RF. Metastasis- ing atrial myxoma. Am J Surg Pathol 1980;4:391-9. Taratuto AL, Zurbriggen G, Sevlever G, Saccoliti M. Epi- thelioid hemangioendothelioma of the central nervous sys- tem. Paediatr Neurosci 1988314:11-4. Tazelaar HD, Locke TJ, McGregor CJA. Pathology of sur- gically excised primary cardiac tumors. Mayo Clin Proc 1992;67:957-65. Todo T, Usui M, Nagashima H. Cerebral metastasis of ma- lignant cardiac myxoma. Surg Neurol 1992;37:374-9. Weiss SW, Enzinger FM. Epithelioid hemangioendothelio- ma. A vascular tumour often mistaken for carcinoma. Can- cer 1982;50:910-81. Weiss SW, Ishak KG, Dail DH, Sweet DE, Enzinger FM. Epithelioid hemangioendothelioma and related lesions. Semin Diagn Pathol 1986;3:259-87. Am J Surg Pathol, Vol. 18, No. 1, 1994