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Symptomatic Intracavitary (Noninvasive) Cardiac Metastasis from Low Grade Endometrial Stromal Sarcoma of the Uterus
PATHOlOGY
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Cl Urban & Fischer Verlag http://www.urbanfischer.deljournalslprp
Symptomatic Intracavitary (Noninvasive) Cardiac Metastasis from low Grade Endometrial Stromal Sarcoma of the Uterus J. Fernando Val-Bernal and Emilia Hernandez-Nieto Anatom ical Pathology Department, Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain
Summary We report a 49-year-old woman who was operated upon 33 years ago for uterine endometrial stromal sarcoma of low-grade malignancy. The patient showed obstruction of the right ventricular outflow tract. An echocardiogram and MRI showed that a mass emanating from the inferior vena cava filled the right atrium, the right ventricle , and part of the pulmonary artery. The entire intracavitary neoplasm was successfully removed and diagnosed as low-grade endometrial stromal sarcoma. To our knowledge, this is the second report of a low-grade endometrial stromal sarcoma reaching the heart via the inferior vena cava. In this case an intracavitary metastasis may be a feature indicating the progression of the endometrial stromal sarcoma. Therefore, this neoplasm should be included in the differential diagnosis of cardiac intracavitary neoplasms. Patients affected by this tumor may benefit from early identification and resection of the obstructing neoplasm. Key words: Uterus ~ Endometrial stromal sarcoma Heart ~ Metastasis ~ Intracavitary tumor
lastoma, colon adenocarcinoma, melanoma, hepatocellular carcinoma, and bronchogenic carcinoma [3, 6, 8, 21,27}. Low-grade endometrial stromal sarcoma (ESS), traditionally named endolymphatic stromal myosis, is an uncommon neoplasm that usually manifests itself as a primary tumor of the uterus. Histologically it is similar to the endometrial stroma in the proliferative phase. This tumor shows neither nuclear atypia nor polymorphism, and its mitotic count is below 10 mitosis per 10 high power fields (HPF). Tumor recurrences may appear late in life, even more than 28 years after initial treatment {I7}. They occur mainly in the pelvis, peritoneal cavity, and vagina. Metastases to the lymph
nodes, liver, lungs, bones, and brain have also been re-
ported {I5]. The patient presented here had developed a lowgrade ESS that filled the right atrium, the right ventricle, and part of the pulmonary artery via the inferior vena cava 33 years after a hysterectomy. This clinicopathologic event is extremely rare.
~
Case Report Introduction Cardiac metastatic tumors may be totally intracavitary. This is an extremely rare event, and the symptoms are usually related to right ventricular outflow obstruction. Metastatic tumors of virtually any tissue may produce such an obstruction. However, intracardiac extension is more common in renal cell carcinoma, nephrobPathol. Res. Pract 195: 7 17-72 2 (1999)
A 31-year-old woman was admitted for acute abdominal pain and a pelvic mass in August 1980. Her past medical history included a hysterectomy for uterine sarAddress for correspondence: J. Fernando Val Bernal, MD, PhD, Departamento de Anatom(a Patol6gica, Hospital Uni -
versitario Marques de Valdecilla, Avda. Valdecilla I, E 39008 Santander, Spain. Phone: ++34-9 42-20 25 99, Fax: ++34-9 42-201903. 0344-03 381991195/10-71 7 $12.0010
718 . J. F. Val-Bernal and E. Hernandez-Nieto
coma, of which neither a pathologic report nor histologic slides were available. This operation was performed in another hospital when the patient was 16 years old. She was treated with thiotepa. On surgical inspection, a twisted left ovarian tumor was found, and a bilateral salpingo-oophorectomy with left external iliac lymphadenectomy was performed. Pathologists interpreted this lesion as an adult granulosa-cell tumor with diffuse pattern of the left ovary, involving the homolateral Fallopian tube, with metastases to the two left para-aortic lymph nodes dissected. The patient, undergoing postoperative adjuvant therapy, received radiation and chemotherapy. The latter consisted of eight courses of drugs including melphalan, cisplatin, vincristine, bleomycin, and adriamycin. In March 1994, at 45 years of age, the patient underwent resection of metastatic tumor present in the left external iliac lymph node, in a 4 cm nodule within the sigma wall, and in a 3.5 cm nodule in the bladder wall. In January 1995, omentectomy and resection of the left external iliac adipose tissue revealed metastases. In November 1995, resection of the left iliac adipose tissue showed a metastatic tumor with prominent venous invasion. Radiation therapy was given postoperatively. The patient did well until March 1998, when she presented with edema of both lower limbs of three-month duration. An abdominopelvic CT-scan demonstrated a mass of the infrahepatic segment of the inferior vena cava with contrast enhancement at the periphery, a finding compatible with chronic thrombosis of the inferior vena cava. In September 1998, the patient presented with a history of dyspnea on exertion two months previously. On auscultation, a systolic ejection murmur at the pulmonary area was noticed. Another abnormality manifested in a smooth, non-tender enlargement of the liver (2 cm below the costal margin). Two-dimensional echocardiography disclosed a right atrial mass (3 x 4 cm) which moved towards the right ventricle during systole. Magnetic resonance imaging showed thrombosis occupying the left common iliac vein, the inferior vena cava, the right atrium, the right ventricle, and part of the pulmonary artery. The diameter of the azygos vein was moderately enlarged. In October 1998, abdominal and pelvic CT scans showed three space-occupying lesions affecting both lungs. The patient was operated in November 1998, at 49 years of age. At surgery, a pearly solid tumor of fIrm consistency was found and could be entirely removed. Tumor originated from the inferior vena cava above the renal vein and extended into the right atrium and right ventricle, as well as into the pulmonary artery. The neoplasm was loosely adherent to the intracardiac and intravascular walls and was compressed at the tricuspid valve. This valve was signifIcantly dilated, and an annuloplastia of the valve was performed. Pathological examination and re-evaluation of the previous specimens disclosed a low grade ESS,
probably originating from the uterus. Postoperative recovery was uneventful. The patient was discharged in good condition eleven days later. She is undergoing anastrozole treatment and has completed four courses of docetaxel. She remains well after three months of follow-up.
Pathological Findings The left ovarian tumor weighed 480 g and measured 16 x II x 4 cm. The external surface was well-circumscribed and smooth. Cross-section showed a fleshy, predominantly solid tumor with cystic areas and focal hemorrhages. The solid areas were yellow-pink in color. The homolateral Fallopian tube was completely affected by the tumor. Microscopically, the tumor showed sheets of small, round or ovoid, dark staining cells. These cells had a narrow rim of eosinophilic cytoplasm and indistinct cell boundaries. Their nuclei were round or oval, showing a regular chromatin pattern and indistinct nucleoli (Fig. IA). Nuclear grooves were absent. Cells were scant and appeared more plump with ample lipid-containing cytoplasm. Numerous small, thin-walled vessels and small arteries, occasionally presenting with a concentric arrangement of tumor cells, were a prominent feature (Fig. IB). Scattered thick bundles of hyalinized collagen were noted (Fig. IC). The mitotic index was 2 mitoses/IO HPF (with lHPF being 0.090 mm'), and the Ki67 (MIB 1) label index was 3.4 percent. Metastases were found in the two left para-aortic lymph nodes dissected. The subsequent lymphadenectomies, excision of sigma and bladder nodules, and omentectomy showed a mass that was found to be histologically similar to the ovarian neoplasm. However, in the iliac lymph node metastasis, gland-like formations were frequent (Fig. 1D). The omentum had three metastatic nodules measuring 1.9 cm, 1.0 em, and 0.3 em, respectively. The left iliac adipose tissue showed a striking venous invasion by the tumor. The multiple tumor specimens removed from the inferior vena cava, right side of the heart and pulmonary artery weighed 72.4 g and measured 12 x 8 x2.5 cm. Three of them were nodular, and the rest showed a worm-like appearance. Their lengths varied between 10.5 and 24 cm (Fig. 2). The histopathologic study showed the same morphology as did the ovarian tumor and the other metastases. The cells were ovoid and diffusely arranged in sheets. Their nuclei were oval with fIne chromatin and inconspicuous or absent nucleoli. The surface of the tumor specimens was covered by fIbrin (Fig. 3A). Vascularization was prominent (Fig. 3B). Collagen was abundant and formed thick hyalinized bundles. The mitotic index was 0.3 mitoses/1 0 HPF, and the MID 1 label index 5.3 per cent.
Tntracardiac Metastasis from Endometrial Sarcoma . 719
Fig. 1. Histologic pattern of the ovarian and lymph node metastases of the low-grade endometrial stromal sarcoma. A) Diffuse growth of oval to round cells with sparse cytoplasm, bland chromatin pattern, and uniformity of nuc1ear size. (H&E, original magnification x lOO). B) A small artery shows concentric arrangement of tumor cells (H&E. original magnification x IOO). C) Presence of hyalini zed collagen bands (H&E. original magnification x64). Dj Pseudoglandu lar pattern in the iliac lymph node metastasis (H&E, original magnification x64).
720 . J. F. Val-Bernal and E. Hernandez-Nieto
Fig. 2. Tumor casts removed from inferior vena cava, right side of the heart, and pulmonary artery.
Fig. 3. Low-grade endometrial stromal sarcoma showing a cardiac intracavitary growth. A) The surface of the tumor cast is covered by fibrin (H&E, original magnification x64). B) The tumor cells show similar morphology to that of the ovarian metastatic neoplasm. There is a prominent vascular network (H&E, original magnification x 160).
lntracardiac Metastasis from Endometrial Sarcoma, 721
All tumor deposits showed the same immunohistochemical pattern. The neoplastic cells were positive for vimentin, estrogen receptor and progesterone receptor, and negative for pancytokeratin, alpha-smooth muscle actin, desmin, S-100 protein, epithelial membrane antigen, Cml, Cm4, CD99 (HBA 71, MIC2, 013), and a1pha-inhibin. Thus, after a complete re-evaluation of the case, including the immunohistochemical findings, the diagnosis of low-grade ESS most probably originating from the uterus was rendered.
Discussion Malignant tumors spread to the heart by direct extension, hematogenous spread, lymphatic spread, and intracavitary extension [2J. A combination of these routes is possible. The cardiac lymphatic system is the most common pathway for tumors to invade the heart [19J. This neoplastic extension occurs in a retrograde fashion. Cardiac involvement caused by metastatic neoplasms is relatively unusual and commonly occurs in widely disseminated disease. In autopsy series, the incidence of cardiac deposits is approximately 15 percent for patients with cancer [I, 25J, with pericardium and epicardium being the most frequently involved sites [18,23,25 , 30, 31J. The most common tumors encountered, in decreasing order of frequency, are lung carcinoma, lymphoma, breast carcinoma, leukemia, gastric
carcinoma, melanoma, liver carcinoma, and colon ade-
nocarcinoma [I J. However, the highest percentage of cardiac involvement is reported in malignant melanoma [l4J , leukemia [28i, and malignantlymphoma [26, 29J. The majority of cardiac secondaries are clinically silent and have no functional consequences. However, these observations may hide the fact that the patients are often affected by a severe illness with widespread metastatic disease. Occasionally, tumors may grow into the right atrium from the vena cava, or enter the left atrium through pulmonary veins [7J. These intracavitary secondary tumors are rare [23J. Investigating a series of 407 autopsies with heart-affecting metastatic disease, Mukai et al. [25/ found that 6 percent of the cases showed endocardium involvement, and only seven (1.7%) had pure intracavitary growth. Most cases derive from renal cell carcinoma, nephroblastoma, colon adenocarcinoma, melanoma, hepatocellular carcinoma, or bronchial carcinoma [3, 6, 8, 21 , 27/. However, intracavitary metastases are also occasionally seen in other malignant tumors including ovarian [16/ and uterine tumors [32/. Intracavitary tumor thrombi are more prevalent in the right side [3, 8, 21 , 25, 27J. These patients, having right ventricular outflow obstruction, presented with right heart failure, dyspnea, chest pain or hypotension. Physical examination always showed a systolic ejection mur-
mur [21/. Obstruction of the right ventricular outflow tract caused by an intracavitary metastatic low-grade ESS from the uterus is extremely rare. In the English literature, only one case of tumor showing intracavitary extension to the heart has been reported [32J. Clinically, the tumor presented here is very likely to arise from the uterus. It also displays histological [4, 9, IIJ and immunohistochemical [10, 13J features of low-grade ESS. This ovarian tumor, removed 15 years after treatment for a uterine tumor, was considered metastatic. Primary ESS of the ovary is frequently associated with ovarian endometriosis [33J , which, however, was absent in our case. Metastatic ESS involving the ovary may resemble a diffuse granular cell tumor [33J. There may be some confusion, especially when the presence of a uterine tumor is not known [33J. In our case, ovarian granulosa cell tumor can be definitively ruled out histologically and immunohistochemically. Histologically, the neoplasm resembles the stroma of the proliferative phase endometrium. Inhibin or CD99 positivity are useful in the diagnosis and confirmation of late metastases originating from granulosa cell tumor [12, 22, 24/. A uterine tumor resembling ovarian sex-cord tumor metastatic to the ovary can also be excluded [20/. We describe the second case of a low-grade ESS invading the heart by direct intravenous extension with successful excision. However, in contrast to the case reported by Vargas-Barron et al. [32J , intracavitary metastasis appeared late in life of our patient, as long as 33 years after initial therapy. The differential diagnosis includes benign uterine leiomyomatosis [2, 32/ and leiomyosarcoma [32J with intravenous extension to the heart. To avoid misdiagnoses, one should be familiar with the histologic features of these tumors and use immunohistochemistry for muscular markers. Low-grade ESS usually occurs as a primary tumor of the uterus. However, ESSs occasionally arise in the vagina, ovary, fallopian tube, pelvic or abdominal cavity, and retroperitoneum [5J. Low-grade ESS is characterized by slow growth leading to a large tumor size at the time of diagnosis. These tumors, which tend to recur or metastasize later in life, are often of low grade malignancy, and the course pursued by the tumor is usually very indolent. Intervals of up to 22 years have been reported between resection of the primary tumor and its first recurrence [l7J. Chang et al. [4i concluded that tumor stage and mitotic index at the time of diagnosis are independent predictors of both survival and relapse.
References I. Abraham KP, Reddy V, Gattuso P (1990) Neoplasms
metastatic to the heart: review of 3314 consecutive autop-
sies. Am J Cardiovasc Patho13: 195-198
722 . 1. F. Val-Bernal and E. Hernandez-Nieto 2. Burke A, Vinnani R (1996) Tumors of the heart and great vessels. Atlas of tumor pathology, third series, Anned Forces Institute of Pathology, Washington DC 3. Chan HSL, Sonley Ml, Moes CAF, Daneman A, Smith CR, Martin Dl (1985) Primary and secondary tumors of childhood involving the heart, pericardium, and great vessels. A report of 75 cases and review of the literature.
Cancer 56: 825- 836 4. Chang KL, Crabtree GS, Lim-Tan SK, Kempson RL, Hendrickson MR (1990) Primary uterine endometrial stromal neoplasms. A clinicopathologic study of 117 cases. Am 1 Surg Pathol14: 415- 438 5. Chang KL, Crabtree GS, Lim-Tan SK, Kempson RL, Hendrickson MR (1993) Primary extrauterine endometrial stroma neoplasms: a clinicopathologic study of 20 cases and a review of the literature. Int J Gynecol Pathal 12: 282-296 6. Choh IH, Gurney R, Shenoy SS, et al (1981) Renal-cell carcinoma: removal of intracardiac extension with aid of
7. 8. 9. 10.
cardiopulmonary bypass. NY State 1 Med 81: 929- 932 Ciafone RA, Galle JS, Chawla SK (1980) Carcinoma of the lung invading the left atrium. Conn Med 44: 773- 776 Cleveland DC, Westaby S, Karp RB (1983) Treatment of intra-atrial cardiac tumors. lAMA 249: 2799- 2802 Evans HL (1982) Endometrial stromal sarcoma and poorly differentiated endometrial sarcoma. Cancer 50: 21702182 Farhood AI, Abrams 1 (1991) Immunohistochemistry of endometrial stromal sarcoma. Hum Pathol22: 224- 230
11. Fekete PS, Vellios F (1984) The clinical and histologic spectrum of endometrial stromal neoplasms: a report of
41 cases. Int 1 Gynecol Patho13: 198- 212 12. Flemming P, Wellmann A, Maschek H, Lang H, Georgii A (1995) Monoclonal antibodies against inliibin represent key markers of adult granulosa cell tumors of the ovary even in their metastases. A report of three cases with late metastases, being previously misinterpreted as hemangioperieytoma. Am J Surg Pathol19: 927- 933
13. Franquemont OW, Frierson lr HF, Mills SE (1991) An immunohistochemical study of nonnal endometrial stroma and endometrial stromal neoplasms. Evidence for smooth muscle differentiation. Am J Surg Pathol 15:
861- 870 14. Glancy DL, Roberts WC (1968) The heart in malignant melanoma: a study of 70 autopsy cases. Am J Cardiol 21: 555-571 IS. Gloor E, Schnyder P, Cikes M, Hofstetter J, Cordey R, Bumier F, Knobel P (1982) Endolymphatic stromal myosis. Surgical and honnonal treatment of extensive abdominal recurrence 20 years after hysterectomy. Cancer 50: 1888- 1893
16. Griffith DNW, Myers A (1978) Obstruction of right ven-
tricular outflow tract by solitary ovarian metastasis. Br
Heart 1 40: 700- 702 17. Hunter WC, Nohlgren JE, Lancefie1d SM (1956) Stromal endometriosis or endometrial sarcoma. A reevaluation of old and new cases, with special reference to duration re-
currences, and metastases. Am 1 Obst Gynec 72: 10721088 18. Klatt EC, Heitz DR (1990) Cardiac metastases. Cancer 65: 1456- 1459 19. Kline IK (1972) Cardiac lymphatic involvement by metastatic tumor. Cancer 29: 799- 808 20. Krishnamurthy S, lungbluth AA, Busam Kl, Rosai 1 (1988) Uterine tumors resembling ovarian sex-cord tumors have an immunophenotype consistent with true sex-
cord differentiation. Am J Surg Pathol22: 1078- 1082 21. Labib SB, Schick EC Jr, Isner JM (1992) Obstruction of right ventricular outflow tract caused by intracavitary metastatic disease: analysis of 14 cases. J Am CoIl Cardi0119: 1664- 1668
22. Loo KT, Leung AKF, Chan JKC (1995) Immunohisto-
chemical staining of ovarian granulosa cell tumors with
MIC2 antibody. Histopathology 27: 388- 390 23. MacGee W (1991) Metastatic and invasive tumours involving the heart in a geriatric popUlation: a necropsy
study. Virchows Archiv A Pathol Anat 419: 183- 189 24. MeCluggage WG, Maxwell P, Sloan 1M (1997) Immunohistochemical staining of ovarian granulosa cell tumors
with monoclonal antibody against inhibin. Hum Pathol 28: 1034- 1038 25. Mukai K, Shinkai T, Tominaga K, Shimosato Y (1988) The incidence of secondary tumors of the heart and pericardium: a IO-year study. Jpn J Clin Oncol 18: 195- 201 26. Petersen CD, Robinson WA, Kurnick IE (1976) Involvement of the heart and pericardium in malignant lym-
phomas. Am J Med Sci 272: 161- 165 27. Poole GV Jr, Meredith lW, Breyer RH, Mills SA (1983) Surgical implications in malignant cardiac disease. Ann Thoracic Surg 36: 484- 49 I 28. Roberts WC, Bodey GP, Wertlake PT (1968) The heart in acute leukemia: a study of 420 autopsy cases. Am J Car-
diol21: 388-412 29. Roberts WC, Glancy DL, Devita VT Jr (1968) Heart in malignant lymphoma (Hodgkin~s disease, lymphosarcoma, reticulum cell sarcoma and mycosis fungoides): a
study of 196 autopsy cases. Am 1 Cardiol22: 85- 107 30. Skhvatsabaja LV (1986) Secondary malignant lesions of the heart and pericardium in neoplastic disease. Oncology 43: 103-106
31. Smith C (1986) Tumors of the heart. Arch Pathol Lab Med 110: 371- 374 32. Vargas-Barron J, Keirns C, Bartagan-Garcia R, BeltranOrtega A, Rotberg T, Santana-Gonzalez A, Salazar-Davila E (1990) Intracardiac extension of malignant uterine tumors. Echocardiographic detection and successful sur-
gical resection. 1 Thorae Cardiovasc Surg 99: 1099- 1103 33. Young RH, Scully RE (1990) Sarcomas metastatic to the ovary: a report of 21 cases. Int J Gynecol Pathol 9:231252 Received: March I, 1999 Accepted in revised version: May 31, 1999
RESEARCH AND PRAcnCE
Cl Urban & Fischer Verlag http://www.urbanfischer.deljournalslprp
Symptomatic Intracavitary (Noninvasive) Cardiac Metastasis from low Grade Endometrial Stromal Sarcoma of the Uterus J. Fernando Val-Bernal and Emilia Hernandez-Nieto Anatom ical Pathology Department, Marques de Valdecilla University Hospital, Medical Faculty, University of Cantabria, Santander, Spain
Summary We report a 49-year-old woman who was operated upon 33 years ago for uterine endometrial stromal sarcoma of low-grade malignancy. The patient showed obstruction of the right ventricular outflow tract. An echocardiogram and MRI showed that a mass emanating from the inferior vena cava filled the right atrium, the right ventricle , and part of the pulmonary artery. The entire intracavitary neoplasm was successfully removed and diagnosed as low-grade endometrial stromal sarcoma. To our knowledge, this is the second report of a low-grade endometrial stromal sarcoma reaching the heart via the inferior vena cava. In this case an intracavitary metastasis may be a feature indicating the progression of the endometrial stromal sarcoma. Therefore, this neoplasm should be included in the differential diagnosis of cardiac intracavitary neoplasms. Patients affected by this tumor may benefit from early identification and resection of the obstructing neoplasm. Key words: Uterus ~ Endometrial stromal sarcoma Heart ~ Metastasis ~ Intracavitary tumor
lastoma, colon adenocarcinoma, melanoma, hepatocellular carcinoma, and bronchogenic carcinoma [3, 6, 8, 21,27}. Low-grade endometrial stromal sarcoma (ESS), traditionally named endolymphatic stromal myosis, is an uncommon neoplasm that usually manifests itself as a primary tumor of the uterus. Histologically it is similar to the endometrial stroma in the proliferative phase. This tumor shows neither nuclear atypia nor polymorphism, and its mitotic count is below 10 mitosis per 10 high power fields (HPF). Tumor recurrences may appear late in life, even more than 28 years after initial treatment {I7}. They occur mainly in the pelvis, peritoneal cavity, and vagina. Metastases to the lymph
nodes, liver, lungs, bones, and brain have also been re-
ported {I5]. The patient presented here had developed a lowgrade ESS that filled the right atrium, the right ventricle, and part of the pulmonary artery via the inferior vena cava 33 years after a hysterectomy. This clinicopathologic event is extremely rare.
~
Case Report Introduction Cardiac metastatic tumors may be totally intracavitary. This is an extremely rare event, and the symptoms are usually related to right ventricular outflow obstruction. Metastatic tumors of virtually any tissue may produce such an obstruction. However, intracardiac extension is more common in renal cell carcinoma, nephrobPathol. Res. Pract 195: 7 17-72 2 (1999)
A 31-year-old woman was admitted for acute abdominal pain and a pelvic mass in August 1980. Her past medical history included a hysterectomy for uterine sarAddress for correspondence: J. Fernando Val Bernal, MD, PhD, Departamento de Anatom(a Patol6gica, Hospital Uni -
versitario Marques de Valdecilla, Avda. Valdecilla I, E 39008 Santander, Spain. Phone: ++34-9 42-20 25 99, Fax: ++34-9 42-201903. 0344-03 381991195/10-71 7 $12.0010
718 . J. F. Val-Bernal and E. Hernandez-Nieto
coma, of which neither a pathologic report nor histologic slides were available. This operation was performed in another hospital when the patient was 16 years old. She was treated with thiotepa. On surgical inspection, a twisted left ovarian tumor was found, and a bilateral salpingo-oophorectomy with left external iliac lymphadenectomy was performed. Pathologists interpreted this lesion as an adult granulosa-cell tumor with diffuse pattern of the left ovary, involving the homolateral Fallopian tube, with metastases to the two left para-aortic lymph nodes dissected. The patient, undergoing postoperative adjuvant therapy, received radiation and chemotherapy. The latter consisted of eight courses of drugs including melphalan, cisplatin, vincristine, bleomycin, and adriamycin. In March 1994, at 45 years of age, the patient underwent resection of metastatic tumor present in the left external iliac lymph node, in a 4 cm nodule within the sigma wall, and in a 3.5 cm nodule in the bladder wall. In January 1995, omentectomy and resection of the left external iliac adipose tissue revealed metastases. In November 1995, resection of the left iliac adipose tissue showed a metastatic tumor with prominent venous invasion. Radiation therapy was given postoperatively. The patient did well until March 1998, when she presented with edema of both lower limbs of three-month duration. An abdominopelvic CT-scan demonstrated a mass of the infrahepatic segment of the inferior vena cava with contrast enhancement at the periphery, a finding compatible with chronic thrombosis of the inferior vena cava. In September 1998, the patient presented with a history of dyspnea on exertion two months previously. On auscultation, a systolic ejection murmur at the pulmonary area was noticed. Another abnormality manifested in a smooth, non-tender enlargement of the liver (2 cm below the costal margin). Two-dimensional echocardiography disclosed a right atrial mass (3 x 4 cm) which moved towards the right ventricle during systole. Magnetic resonance imaging showed thrombosis occupying the left common iliac vein, the inferior vena cava, the right atrium, the right ventricle, and part of the pulmonary artery. The diameter of the azygos vein was moderately enlarged. In October 1998, abdominal and pelvic CT scans showed three space-occupying lesions affecting both lungs. The patient was operated in November 1998, at 49 years of age. At surgery, a pearly solid tumor of fIrm consistency was found and could be entirely removed. Tumor originated from the inferior vena cava above the renal vein and extended into the right atrium and right ventricle, as well as into the pulmonary artery. The neoplasm was loosely adherent to the intracardiac and intravascular walls and was compressed at the tricuspid valve. This valve was signifIcantly dilated, and an annuloplastia of the valve was performed. Pathological examination and re-evaluation of the previous specimens disclosed a low grade ESS,
probably originating from the uterus. Postoperative recovery was uneventful. The patient was discharged in good condition eleven days later. She is undergoing anastrozole treatment and has completed four courses of docetaxel. She remains well after three months of follow-up.
Pathological Findings The left ovarian tumor weighed 480 g and measured 16 x II x 4 cm. The external surface was well-circumscribed and smooth. Cross-section showed a fleshy, predominantly solid tumor with cystic areas and focal hemorrhages. The solid areas were yellow-pink in color. The homolateral Fallopian tube was completely affected by the tumor. Microscopically, the tumor showed sheets of small, round or ovoid, dark staining cells. These cells had a narrow rim of eosinophilic cytoplasm and indistinct cell boundaries. Their nuclei were round or oval, showing a regular chromatin pattern and indistinct nucleoli (Fig. IA). Nuclear grooves were absent. Cells were scant and appeared more plump with ample lipid-containing cytoplasm. Numerous small, thin-walled vessels and small arteries, occasionally presenting with a concentric arrangement of tumor cells, were a prominent feature (Fig. IB). Scattered thick bundles of hyalinized collagen were noted (Fig. IC). The mitotic index was 2 mitoses/IO HPF (with lHPF being 0.090 mm'), and the Ki67 (MIB 1) label index was 3.4 percent. Metastases were found in the two left para-aortic lymph nodes dissected. The subsequent lymphadenectomies, excision of sigma and bladder nodules, and omentectomy showed a mass that was found to be histologically similar to the ovarian neoplasm. However, in the iliac lymph node metastasis, gland-like formations were frequent (Fig. 1D). The omentum had three metastatic nodules measuring 1.9 cm, 1.0 em, and 0.3 em, respectively. The left iliac adipose tissue showed a striking venous invasion by the tumor. The multiple tumor specimens removed from the inferior vena cava, right side of the heart and pulmonary artery weighed 72.4 g and measured 12 x 8 x2.5 cm. Three of them were nodular, and the rest showed a worm-like appearance. Their lengths varied between 10.5 and 24 cm (Fig. 2). The histopathologic study showed the same morphology as did the ovarian tumor and the other metastases. The cells were ovoid and diffusely arranged in sheets. Their nuclei were oval with fIne chromatin and inconspicuous or absent nucleoli. The surface of the tumor specimens was covered by fIbrin (Fig. 3A). Vascularization was prominent (Fig. 3B). Collagen was abundant and formed thick hyalinized bundles. The mitotic index was 0.3 mitoses/1 0 HPF, and the MID 1 label index 5.3 per cent.
Tntracardiac Metastasis from Endometrial Sarcoma . 719
Fig. 1. Histologic pattern of the ovarian and lymph node metastases of the low-grade endometrial stromal sarcoma. A) Diffuse growth of oval to round cells with sparse cytoplasm, bland chromatin pattern, and uniformity of nuc1ear size. (H&E, original magnification x lOO). B) A small artery shows concentric arrangement of tumor cells (H&E. original magnification x IOO). C) Presence of hyalini zed collagen bands (H&E. original magnification x64). Dj Pseudoglandu lar pattern in the iliac lymph node metastasis (H&E, original magnification x64).
720 . J. F. Val-Bernal and E. Hernandez-Nieto
Fig. 2. Tumor casts removed from inferior vena cava, right side of the heart, and pulmonary artery.
Fig. 3. Low-grade endometrial stromal sarcoma showing a cardiac intracavitary growth. A) The surface of the tumor cast is covered by fibrin (H&E, original magnification x64). B) The tumor cells show similar morphology to that of the ovarian metastatic neoplasm. There is a prominent vascular network (H&E, original magnification x 160).
lntracardiac Metastasis from Endometrial Sarcoma, 721
All tumor deposits showed the same immunohistochemical pattern. The neoplastic cells were positive for vimentin, estrogen receptor and progesterone receptor, and negative for pancytokeratin, alpha-smooth muscle actin, desmin, S-100 protein, epithelial membrane antigen, Cml, Cm4, CD99 (HBA 71, MIC2, 013), and a1pha-inhibin. Thus, after a complete re-evaluation of the case, including the immunohistochemical findings, the diagnosis of low-grade ESS most probably originating from the uterus was rendered.
Discussion Malignant tumors spread to the heart by direct extension, hematogenous spread, lymphatic spread, and intracavitary extension [2J. A combination of these routes is possible. The cardiac lymphatic system is the most common pathway for tumors to invade the heart [19J. This neoplastic extension occurs in a retrograde fashion. Cardiac involvement caused by metastatic neoplasms is relatively unusual and commonly occurs in widely disseminated disease. In autopsy series, the incidence of cardiac deposits is approximately 15 percent for patients with cancer [I, 25J, with pericardium and epicardium being the most frequently involved sites [18,23,25 , 30, 31J. The most common tumors encountered, in decreasing order of frequency, are lung carcinoma, lymphoma, breast carcinoma, leukemia, gastric
carcinoma, melanoma, liver carcinoma, and colon ade-
nocarcinoma [I J. However, the highest percentage of cardiac involvement is reported in malignant melanoma [l4J , leukemia [28i, and malignantlymphoma [26, 29J. The majority of cardiac secondaries are clinically silent and have no functional consequences. However, these observations may hide the fact that the patients are often affected by a severe illness with widespread metastatic disease. Occasionally, tumors may grow into the right atrium from the vena cava, or enter the left atrium through pulmonary veins [7J. These intracavitary secondary tumors are rare [23J. Investigating a series of 407 autopsies with heart-affecting metastatic disease, Mukai et al. [25/ found that 6 percent of the cases showed endocardium involvement, and only seven (1.7%) had pure intracavitary growth. Most cases derive from renal cell carcinoma, nephroblastoma, colon adenocarcinoma, melanoma, hepatocellular carcinoma, or bronchial carcinoma [3, 6, 8, 21 , 27/. However, intracavitary metastases are also occasionally seen in other malignant tumors including ovarian [16/ and uterine tumors [32/. Intracavitary tumor thrombi are more prevalent in the right side [3, 8, 21 , 25, 27J. These patients, having right ventricular outflow obstruction, presented with right heart failure, dyspnea, chest pain or hypotension. Physical examination always showed a systolic ejection mur-
mur [21/. Obstruction of the right ventricular outflow tract caused by an intracavitary metastatic low-grade ESS from the uterus is extremely rare. In the English literature, only one case of tumor showing intracavitary extension to the heart has been reported [32J. Clinically, the tumor presented here is very likely to arise from the uterus. It also displays histological [4, 9, IIJ and immunohistochemical [10, 13J features of low-grade ESS. This ovarian tumor, removed 15 years after treatment for a uterine tumor, was considered metastatic. Primary ESS of the ovary is frequently associated with ovarian endometriosis [33J , which, however, was absent in our case. Metastatic ESS involving the ovary may resemble a diffuse granular cell tumor [33J. There may be some confusion, especially when the presence of a uterine tumor is not known [33J. In our case, ovarian granulosa cell tumor can be definitively ruled out histologically and immunohistochemically. Histologically, the neoplasm resembles the stroma of the proliferative phase endometrium. Inhibin or CD99 positivity are useful in the diagnosis and confirmation of late metastases originating from granulosa cell tumor [12, 22, 24/. A uterine tumor resembling ovarian sex-cord tumor metastatic to the ovary can also be excluded [20/. We describe the second case of a low-grade ESS invading the heart by direct intravenous extension with successful excision. However, in contrast to the case reported by Vargas-Barron et al. [32J , intracavitary metastasis appeared late in life of our patient, as long as 33 years after initial therapy. The differential diagnosis includes benign uterine leiomyomatosis [2, 32/ and leiomyosarcoma [32J with intravenous extension to the heart. To avoid misdiagnoses, one should be familiar with the histologic features of these tumors and use immunohistochemistry for muscular markers. Low-grade ESS usually occurs as a primary tumor of the uterus. However, ESSs occasionally arise in the vagina, ovary, fallopian tube, pelvic or abdominal cavity, and retroperitoneum [5J. Low-grade ESS is characterized by slow growth leading to a large tumor size at the time of diagnosis. These tumors, which tend to recur or metastasize later in life, are often of low grade malignancy, and the course pursued by the tumor is usually very indolent. Intervals of up to 22 years have been reported between resection of the primary tumor and its first recurrence [l7J. Chang et al. [4i concluded that tumor stage and mitotic index at the time of diagnosis are independent predictors of both survival and relapse.
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