Metastasizing Uterine Leiomyoma

Path. Res. Pract. 192, 622-629 (1996)

Metastasizing Uterine Leiomyoma A Case with Cardiac and Pulmonary Metastasis G. Takemura1, Y. Takatsu1, K. Kaitani 1 , M. Ono1, F. Ando 2 , S. Tanada 3 , H. Niwa 3 , H. Tankawa 4 , T. Fujiwara 5 and H. Yamabe 6 Departments of 11nternal Medicine, 2Cardiovascular Surgery, 30bstetrics and Gynecology and 4Pathology, Hyogo Prefectural Amagasaki Hospital, Hyogo; 5Department of Food Science, Kyoto Women's University, Kyoto; and 6Laboratory of Anatomic Pathology, Kyoto University Hospital, Kyoto, Japan

SUMMARY A case of histologically benign cardiac and pulmonary metastases from a uterine leiomyoma in a 45-year-old woman is reported. The solitary cardiac tumor consisted of five lobules with a stalk attached to the anterior papillary muscle of the right ventricle, which occupied the right ventricular cavity and almost completely obstructed the pulmonary main trunk in the systolic cycle. Multiple small nodules were found throughout both lungs. The cardiac tumor was resected at open heart surgery and open lung biopsy of the pulmonary lesion was simultaneously performed. Both of them were histologically identical to the apparently histologically benign uterine leiomyoma which had been resected five years previously. Based on the clinical and laboratory findings, it is postulated that antegradq metastases via the venous system resulted in the cardiac metastasis from the uterine leiomyoma and the secondary pulmonary metastasis from the cardiac tumor. In contrast to the light microscopic findings, ultrastructural examination suggested the possibility of malignancy associated with the presence of immature smooth muscle cells. This is the first reported case of a so-called benign metastasizing leiomyoma occurring in the heart.

Introduction There are several quite uncommon conditions in which histologically benign leiomyomas of the uterus are associated with independent extrauterine leiomyomas. Steiner reported such a case as "metastasizing fibroleiomyoma" 15. Several similar cases have been described, but some of them were critically viewed and suggested to have been borderline or low-grade sarcomas. However, there are accepted cases of benign metastasizing leiomyoma meeting all histologic criteria 1,2,4,6-8,IJ-15,17. The most common metastatic site is the lung and/or pelvic lymph nodes. The other criti0344-0338/96/0192-0622$3.50/0

cal interpretation is that such conditions are multicentric benign leiomyomatous growths, rather than embolic metastases from benign uterine leiomyomas by way of blood or lymphatic vessels 4,6, 7, 13. We report herein a case of metastasizing leiomyoma involving the heart and lungs in which the clinical and laboratory findings suggested that the lesions were true metastases from an apparently benign uterine leiomyoma. The immunohistochemical and ultrastructural findings for the tumors are also presented. To our knowledge, no other case of cardiac involvement of a metastasizing leiomyoma has been reported to date. © 1996 by Gustav Fischer Verlag, Stuttgart

Leiomyoma Metastatic of the Heart . 623

Case Report History and Clinical Findings A 44-year-old Japanese woman was referred to our hospital by her family physician, because of exertional dyspnea and occasional faintness symptoms accompanied by a newly developed heart murumur. She had been admitted to our hospital four years previously due to a uterine leiomyoma and had undergone an abdominal supracervical hysterectomy without salpingooophorectomy. On physical examination, a long systolic ejection murmur graded 3/6, most clearly at the 2nd left sternal border, was noted. Both lungs were clear, and the chest X-ray findings were normal. She consulted us again and was admitted to our hospital eight months later because of aggrevation of the symptoms. On admission, an additional diastolic murmur graded 116 was audible at the 2nd left sternal border. The lungs were clear on ausculation. Plain X-ray of the chest, however, revealed multiple nodular densities evenly distributed throughout the lung fields without pleurisy. The computed tomogram of the chest disclosed numerous small nodules less than 10 mm in diameter distributed mainly in the middle and lower lung fields (Fig. 1). Echocardiographic examination demonstrated a large tumor-like mass in the right ventricular cavity, and turbulent flow was detected in the right ventricular outflow tract. Right ventriculogram disclosed a mobile lobulated mass occupying the right ventricular cavity. The mass protruded into and almost completely obstructed the pulmonary main trunk during cardiac systolic phase (Fig.2-a,b), when a pressure gradient of 46 mmHg was produced between the right ventricle (75/4 mmHg) and the main pulmonary artery (29/12 mmHg). Other hemodynamics were normal on both the right and left sides of the heart, and left ventriculogram revealed no abnormal findings. Coronary arteriogram disclosed no atherosclerosis, but abnormal, faint, small branches were noted arising from distal portions of the left anterior descending and right coronary arteries, which were thought to be the tumor feeding arteries. Pulmonary arteriogram showed a normal pulmonary arterial tree without any abrupt interruptions. A mass extending from the right ventricular outflow to the pulmonary main trunk was observed by magnetic resonance imaging (Fig.2-c). The blood, chemistry and inflammatory reaction test results were entirely negative for abnormal findings. Tumor markers including carcinoembryonic antigen, CA19-9, squamous cell carcinoma-associated antigen, CA1S-3 and CA12S were within normal ranges except for slight elevation of neuron-specific enolase (12.1 ngl ml: normal range, < 10.0 nglml). The blood gas and respiratory function data were normal. Examinations for abdominal organs and thyroid were negative for abnormal findings. Gynecologic examinations disclosed no mass around the remnants of the resected uterus, and only a cyst of the left ovary was de-

tected. The results of gallium tumor scintigraphy of the whole body were unremarkable. Open heart surgery was performed. The right ventricular incision revealed a white, elastic hard, fan-like shaped cardiac mass (Fig. 3). The tumor was attached by a short, narrow stalk to the anterior papillary muscle, but other portions of the tumor had no adhesion to the heart. It was resected together with the papillary muscle, and tricuspid value replacement was performed with a prosthetic valve. Numerous small white nodules less than 10 mm in diameter, some of which were biopsied, were evident over the entire surface of the both lungs. The patient recovered well after the surgery, and her symptoms of dyspnea and faintness disappeared thereafter. A permanent pacemaker was implanted, however, because postoperatively complete atrio-ventricular block developed. Pathologic Findings Cardiac tumor: The white, elastic hard cardiac tumor measured 47 x 42 x 20 mm, and the length of each of the five lobules was 47, 34, 33, 29 and 18 mm. The cut surface was also white, but also contained some small hemorrhagic areas. The border between the tumor and the papillary muscle was distinct. Histologic examination revealed a cellular tumor composed of uniform elongated cells arranged in an interlacing pattern and intermingled with rich collagen bundles (Fig.4). Many areas had the typical appearance of a leiomyoma with abundant collagen fibers. Other areas were highly cellular, consisting of closely packed, uniform spindle cells. No pleomorphism, nuclear atypia, mitotic figures, or vascular invasion was seen. At the border, the tumor was distinctly separated from the normal myocardium by loose fibrous tissue (Fig. Sa). An indirect immunoperoxidase histochemical technique was performed on the deparaffinized sections using commercially available antibodies as the primary antibody. Peroxidase-conjugated F(ab'h fragment of goat anti-mouse IgG[H + L] (Jackson Immunoresearch Laboratories, West Grove, USA) was used as the secondary antibody, and the sections were stained with diaminobenzidine tetrahydrochloride (Sigma Chemical Co., St. Louis, USA) followed by counterstaining with hematoxylin. The tumor cells were immunohistochemically positive for antibodies against human muscle actin (HHF3S, DAKO, Glostrup, Denmark), smooth muscle-specific actin (1A4, DAKO), desmin (D33, DAKO) and vimentin (V9, DAKO), but negative for antibodies against keratin (DAKO), myoglobin (Sigma), von Wille brand factor (DAKO) and melanoma (HMB4S, DAKO) (Fig. 5). Antigen retrieval was done by soaking in hot water for 10 minutes for vimentin and by treating with pronase type XIV (Sigma) for keratin and melanoma antigens. Positive immunoreactions were detected not only in the body but also, at least in part, in the surface cells of the tumor.

624 . G. Takemura et al.

Fig. 1. Chest computed tomogram on admission. There are small multiple lesions throughout the lung fields.

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Fig. 2. Antero-posterior view (a) and lateral view (b) from the right ventriculograms in systolic phase and a Tl-weighted magnetic resonance imaging of the heart (c). Arrows indicate the outline of the cardiac tumor.

Ultrastructurally, numerous spindle cells separated by collagen fibrils were seen in the central areas of the tumor (Fig. 6a). Most of the spindle cells contained closely packed, longitudinally or transversely cut myofilaments. Dense bodies were frequently observed in

Fig. 3. Gross appearance of the resected cardiac tumor. Asterisk indicate cut surfaces. The large arrow indicates the anterior papillary muscle of the right ventricle, and the small arrow indicates a portion of the smallest lobule, located behind another lobule.

the cytoplasm. The cellular membrane had pinocytotic vesicles and well developed external lamina. The cytoplasm of some cells contained distinct electron-dense round vesicles. Most nuclei were non-de script, but some had large indentations of the nuclear membrane and prominent nucleoli. Thus, the major population of the tumor cells showed findings compatible with those

Leiomyoma Metastatic of the Heart . 625

Fig. 4. Light microscopic preparations of the cardiac and pulmonary tumors (hematoxylin-eosin stain). - a: Relatively hypercellular area of the cardiac tumor is shown, consisting of closely packed, uniform spindle cells. No pleomorphism, nuclear atypia, mitotic figures or vascular invasion is seen. Original magnification, x 200. - b: Histology of the pulmonary tumor is almost identical to the cardiac tumor. Entrapped pulmonary epithelium can be seen. x 200.

of well differentiated smooth muscle cells if the grossly enlarged nucleoli are excluded (Fig. 6c). The tumor also contained a few cells « 1 %) presenting a paucity of myofilaments or focal densities, as well as abundant organellae such as rough endoplasmic reticulum and mitochondria, which seemed to be compatible with immature smooth muscle cells (Fig.6d). These cells had spindle shaped outlines, frequent pinocytotic vesicles and well established external lamina. The surface cells covering the tumor were also tumor cells containing microfibrils and were identical to those seen in the central portion (Fig.6b). Some of them appeared to be loosely attached to the tumor body, as if detaching.

Pulmonary tumors: The lung biopsy specimens contained white, spherical, variously sized (but less than 10 mm) tumors. Microscopically, they were distinctly separated from and compressed the normal lung tissue (Fig.5b). In the border of the tumor, cleft-like ducts lined by cuboidal or columnar epithelium, which were thought to be entrapped pulmonary parenchyma\ were frequently observed (Fig.4b). The histology of the tumors was almost identical to that of the cardiac tumor: there was no evidence of nuclear atypia or mitosis with abundant collagen fascicles. The reactivity to immunostaining was identical to that of the cardiac tumor (Fig. 5). Electron microscopic examination,

626 . G. Takemura et al.

again, disclosed that the majority of the cells were welldifferentiated smooth muscle cells of the same type as those found in the cardiac tumor, and that less-differentiated cells were rare.

Uterine tumor: The pathological report and the slides of the uterus resected five years beforehand were reviewed. A yellowish-white, multilobulated and welldemarcated tumor, measuring 90 x 50 x 30 mm, was located in the lateral wall of the corpus. The cut surfaces were homogeneously yellowish-white and showed no necrotic area. Histological reexamination of the slides from the tumor revealed typical benign leiomyoma without mitotic figures or nuclear atypia. The histology was basically identical to that of the cardiac tumor and of the pulmonary tumors except that it lacked the hypercellular area occasionally found in the cardiac tumor. The immunostaining reactions were compatible with those of the well-differentiated smooth muscle cells. Based on these findings, we concluded that this is a case of metastasizing leiomyoma of the uterus with cardiac and pulmonary metastasis. Follow-up of the Patient: The estrogen and progesterone receptors were examined using radioreceptor assays in the tissue of the cardiac tumor. The estrogen receptor titer was not high (7.4 fmol/mg protein: standard value, :::; 15) whereas that of progesterone receptor showed high value of 26 fmol/mg protein (standard value,:::; 10). The tumor shadows observed on the chest X-rays appeared to have increased during the followup period after the cardiac surgery. Thus, the patient underwent bilateral oophorectomy. There were no abnormal findings for the resected ovaries, except for a simple cyst of the left ovary. In addition, the administration of the superactive analogue of luteinizing hormone releasing hormone, buserelin, was started. The plasma level of estradiol (E 2 ) was low (15 pg/ml) when measured two months after oophorectomy. The patient remains well as of this writing, 20 months after the cardiac surgery.

Discussion So-called benign metastaslZlng leiomyomas of the uterus are so extremely rare that not more than 40 well-documented cases can be found in the literatures 1,2,4,6-8, 13-15, 17. The sites of metastasis organs have been mainly the lungs and lymph nodes, and we are not aware of any reports of metastasis of this lesion to the heart. Thus, to the best of our knowledge, this is the first reported case of a distant metastasis to the heart of a benign metastasizing leiomyoma. In this patient, three organs (the uterus, heart and lungs) were involved with leiomyomas. Four years after undergoing a supracervical hysterectomy, she presented dyspnea, faintness and some cardiac abnormalities, but not any pulmonary diseases. About six

months later, abnormal shadows became visible in her lungs. Because the dyspnea and faintness disappeared after the cardiac surgery, these symptoms were thought to have been due to the cardiac tumor. Thus, the course of the clinical symptoms and signs disclosed the apparent sequence of involvement of first the uterus, and then the heart, followed by the lungs. This order would coincide with antegrade progression of the lesions through the venous system. Furthermore, it may also suggest the order of the tumor growth. Pathologically, at least part of the cardiac tumor was not covered with endocardial cells, but rather with tumor cells. Moreover, some of these surface cells appeared to detach easily, suggesting the possibility of their detachment, entrance into the pulmonary arteries, and anchorage at the pulmonary capillaries. Therefore, based on both the clinical and pathological observations, it seems most likely that the cardiac tumor was a metastasis from the primary uterine leiomyoma and that the pulmonary tumors were secondary metas-

Leiomyoma Metastatic of the Heart· 627

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Fig. 6. Electron micrographs of the cardiac tumor. - a: Spindle shaped cells are separated by collagen fibrils. Well-differentiated smooth muscle cells form the majority of the cell population. Bar indicates 10 !lm. Original magnification, x 1000. - b: Surface of the cardiac tumor, at least in part, is covered with tumor cells containing myofilaments. Bar indicates 10 !lm. x 1500. Inset shows rich myofilaments in the highly magnified cytoplasm of the arrow indicated tumor cell.

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tases from the cardiac tumor arising as distant metastases following dissemination via the venous system. It is controversial whether the so-called benign metastasizing leiomyoma is a benign tumor 1, 2, 4, 8, 14, 15 or a well-differentiated leiomyosarcoma 17. We could find no histological evidence of mitotic activity in our patient. The ultrastructural examination, however, revealed that some immature smooth muscle cells were present in the tumor. Even some of the smooth muscle cells of the major population which appeared well-differentiated, showed grossly enlarged nucleoli. According to Morales et al. 10, electron microscopic findings may be of some value when the assessment of the malignancy of smooth muscle tumors is difficult by light microscopy. They found that, while the presence of well-developed and abundant structures such as myofilaments, focal densities, subplasmalemmal densities

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and pinocytotic vesicles is no assurance that a tumor is benign, the converse situation, such as a paucity or atypia of one or more of these features, is highly likely to be an indicator of malignancy, even in cases where the tumor appears benign by light microscopic examination. Thus, the ultrastructural findings in our patient do not exclude, but may suggest, the possibility of sarcoma. Another interpretation of so-called benign metastasizing leiomyoma is attractive and recently becoming more widely recognized: not metastases, but hormone-regulated multicentric leiomyomatous growth arising from uterine and/or vascular smooth muscle 6, 7, 13. This concept appears to be warranted by the evidence of examples of regression of extrauterine tumors during pregnancy8, following oophorectomy!, or in association with hormone therapy7. However,

628 . 'G. Takemura et al.

Fig. 6. c: High-power view of one of the representative tumor cells consisting the major population. The cell appears welldifferentiated smooth muscle cell except for the grossly enlarged nucleolus. Bar indicates 1 /lm. x 8000. - d: One of the rarely found immature smooth muscle cells is shown. This cell contains abundant organellae such as rough endoplasmic reticulum and mitochondria, but myofilaments and focal densities are very poor. The arrow indicates a dense body. Bar indicates 1 /lm. x 8000.

since the possibility cannot be denied of a metastatic tumor that has inherited the same character (hormone sensitivity) as the primary tumor, i. e., uterine leiomyoma, we do not think these examples are specific enough for the explanation of their etiology. Moreover, the features in our patient do not seem to coincide particularly well with this etiological interpretation, since the heart is not an organ rich in smooth muscle. The other forms of extrauterine growth of benign leiomyomas that have been reported include intravenous invasion (intravenous leiomyomatosis)9 and direct invasion of the neighboring tissues 3 • Some of those reports describe the extension of the elongated tumor body to the cardiac cavity with the stalk at-

tached to the vein or uterus ll ,16. It is obvious, however, that cases such as these cannot be categorized as a distant cardiac metastasis like the present case. Despite the benign histology of the leiomyoma cells, the metastasizing potential can bring fatal outcome to the patient. The mitosis counting, which is regarded as a standardized criteria for grading malignancy of the uterine smooth muscle tumor, is not useful for patients with benign-looking metastasizing leiomyoma as our case, and its limitations have been discussed elsewhere 5,12. Thus, new methods for differential diagnosis are needed among apparently benign leiomyomas with and without a metastasizing potential. If they are not metastases, but multicentric leiomyoma to us

Leiomyoma Metastatic of the Heart . 629

growth in the standpoint of pathogenesis, it is necessary to develop the methods for identifying specific individuals in order to anticipate the forthcoming events. Oophorectomy and anti-sex hormone therapy have been reported as effective in the treatment of metastasizing leiomyoma of the lungs as mentioned above!' 7. Our patient also underwent the bilateral oophorectomy and is presently receiving antihormone therapy under a careful follow-up. Acknowledgements Thanks are due to Mrs. Naoshi Kohrogi, Takao Komai and Ms. Kana Hatano at Hyogo Prefectural Amagasaki Hospital, and Ms. Kyoko Fuchino, Ms. Masami Nariai, Ms. Yoko Tei, Ms. Mayumi Fukata and Ms. Kyoko Miyamoto at Kyoto Women's University for their help in technical assistance. We also thank Drs. Shigehiro Ohtani, Hiroshi Sogabe and Nahoko Uemura at Hyogo Prefectural Amagasaki Hospital for their cooperation, and Dr. Hisayoshi Fujiwara at Gifu University School of Medicine for his advice.

References 1 Banner AS, Carrington CB, Emory WB, Kittle F, Leonard G, Ringus J, Taylor P, Addington WW (1981) Efficacy of oophorectomy in Iymphangioleiomyomatosis and benign metastasizing leiomyoma. N Engl J Med 305: 204-209 2 Boyce CR, Buddhdev HN (1973) Pregnancy complicated , by metastasizing leiomyoma of the uterus. Obstet Gynecol42: 252-258 3 Brewer GE (1921) Typical fibromyoma of the abdominal wall following hysterectomy. Ann Surg 74: 364-367 4 Burkhardt A, Otto HF, Kaukel E (1981) Multiple pulmonary (hamartomatous?) leiomyomas. Light and electron microscopic study. Virchows Arch (Pathol Anat) 394: 133-

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5 Donhuijsen K (1986) Mitosis counts: Reproducibility and significance in grading of malignancy. Hum Pathol 17: 1122-1125 6 Gal AA, Brooks JSJ, Pietra GG (1989) Leiomyomatous neoplasms of the lung: A clinical, histologic, and immunohistochemical study. Modern Pathol 2: 209-216 7 Hague WM, Abdulwahid NA, Jacobs HS, Craft I (1986) Use of LHRH analogue to obtain reversible castration in a patient with benign metastasizing leiomyoma. Br J Obstet Gynaecol 93: 455 -460 8 Horstmann JP, Pietra GG, Harman JA, Cole NG Jr, Grinspan S (1977) Spontaneous regression of pulmonary leiomyomas during pregnancy. Cancer 39: 314-321 9 Marshall JF, Morris DS (1959) Intravenous leiomyomatosis of the uterus and pelvis. Case report. Ann Surg 149: 126-134 10 Morales AR, Fine G, Pardo V, Horn RC (1975) The ultrastructure of smooth muscle tumors with a consideration of the possible relationship of glomangiomas, hemangiopericy, tomas and cardiac myxomas. Pathol Ann 10: 65-92 11 Norris HJ, Parmley T (1975) Mesenchymal tumors of the uterus. V. Intravenous leiomyomatosis. Cancer 36: 2164-2178 12 Silverberg SG (1976) Reproducibility of the mitosis count in the histologic diagnosis of smooth muscle tumors of the uterus. Hum Pathol 7: 451-454 13 Silverman JF, Kay S (1976) Multiple pulmonary leiomyomatous hamartomas. Report of a case with ultrastructure examination. Cancer 38: 1199-1204 14 Spiro RH, McPeak CJ (1966) On the so-called metastasizing leiomyoma. Cancer 19: 544-548 15 Steiner PE (1939) Metastasizing fibroleiomyoma of the uterus - Report of a case and review of the literature. Am J Pathol15: 89-107 16 Tierney WM, Ehrlich CE, Bailey JC, King RD, Roth LM, Wann LS (1980) Intravenous leiomyomatosis of the uterus with extension into the heart. Am J Med 69: 471-475 17 Wolff M, Silva F, Kaye F (1979) Pulmonary metastases (with admixed epithelial elements) from smooth muscle neoplasms. Report of nine cases, including three males. Am J Surg Pathol3: 325-342

Received October 9, 1995 . Accepted in revised form February 13, 1996

Key words: Metastasizing leiomyoma - Cardiac tumor - Pulmonary tumor - Uterus Yoshiki Takatsu, M.D., Department ofInternal Medicine, Hyogo Prefectural Amagasaki Hospital, 1-1-1 Higashidaimotsu-cho, Amagasaki-shi, Jiyogo 660, Japan, Tel.: 06-482-1521, Fax: 06-482-7430