771 Q 1991 The Japanese Society of Pathology
Alveolar Soft Part Sarcoma of the Pulmonary Vein
Yutaka Tsutsumi and Yinlong Deng
Alveolar soft part sarcoma of the lung seen i n a 42-yearold female is reported. In the partial pneumonectomy specimen, there was a 3 ~ 2 . 5 c mtumor arising from the pulmonary vein at the level of the right lung hilus, with tumor thrombus formation. The transition between the tumor and venous smooth muscle layer was microscopically confirmed. At autopsy, performed 18 months after surgery, rnetastases were noted i n the left lung and brain. No primary focus was identified i n the soft tissue. The alveolus-forming clear tumor cells contained diastaseresistant periodic acid-Schiff-reactive granules. lmmunohistocherriically, granular cytoplasmic reactivities with monoclonal antibodies against pan-actin and alpha-sarcomeric actin were demonstrated, whereas other muscle markers such as desmin, alpha-smooth muscle actin, myoglobin, fast skeletal myosin, and the mm-isozyme of creatine kinase were negative. Ultrastructurally, crystallized structures were occasionally identified in the membrane-bound, electron lucent granules, which often filled the tumor cell cytoplasm. The muscle cell nature of the neoplasm i s discussed. Acta Pathol Jpn 41: 771-777, 1991. Key word*s: Alveolar soft part sarcoma, Lung, Pulmonary vein, Crystallized granule, Muscle actin
a relatively high frequency of alveolar soft part sarcoma
(1,3-5). Despite controversy concerning its histogenesis (1, 36), the myogenic, especially rhabdomyoblastic, origin of this tumor which shows peculiar histopathologic features has been proposed by several investigators, on the basis of the immunohistochemical reactivity of desmin, muscle actin, myosin, the mm-isozyme of creatine kinase, Zprotein, and beta-enolase (7-15). The formation of muscle actin-like crystals in the membrane-bound granules has been suggested to be pathognomonic of this neoplasm (16, 17). We recently experienced a case of alveolar soft part sarcoma arising from the pulmonary vein at the level of the right lung hilus. The venous branch lumina were obstructed by tumor thrombi. To the best of our knowledge, this is the first autopsy-confirmed case of alveolar soft part sarcoma of the lung. Neoplasms of pulmonary venous origin are themselves extremely rare (18-21). Clinical, histologic, immunohistochemical and electron microscopic features of the tumor are presented.
CLINICAL SUMMARY INTRODUCTION Alveolar soft part sarcoma is a rare malignant soft tissue tumor, consisting of less than 1% of all soft tissue sarcomas (1). The disease entity of this neoplasm was established by Christopherson, Foote and Stewart in 1952 (2). It occurs predominantly in the deep soft tissue of the extremities, whereas the skeletal muscles in the head and neck and other regions are also involved (1, 3-5). Females, particularly those at a young age, have Received May 7, 1991. Accepted l o r publication July 30, 1991. Department of Pathology, Tokai University School of Medicine, Isehara. Mailing address: Yutaka Tsutsumi, M.D., Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1 1, Japan.
A 42-year-old woman was admitted to Tokai University Hospital in June, 1989, with a complaint of hemoptysis during three menstrual periods. Bronchofiberscopic examination was unremarkable, and cytology yielded a diagnosis of class I. Chest X-ray and computed tomography examinations demonstrated a solitary 3 c m tumor nodule located at the hilus of the right lung (Figs. 1, 2). In July, 1989, right upper lobectomy with partial right lower lobectomy was performed. Chemotherapy (cisplatin 110 m g and vindesine sulfate 4 mg) followed. Two months after surgery, headache and left hemiparesis developed, and cranial computed tomography showed multiple brain metastases. Combined chemotherapy (cisplatin 1 5 0 mg, carboplastin 4 5 0 mg and etoposide 100 mg) was given without evident effects. Steroid administration was continued to lower the intracranial pressure for more than a year. After
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Alveolar Soft Part Sarcoma of Lung (Tsutsumi and Deng)
frequent seizure attacks, the patient died o f cerebral herniation in December, 1990. The total clinical course was 2 0 months.
PATHOLOGICAL FINDINGS OF SURGICAL SPECIMEN Gross findings A solitary 3 . 0 x 2 . 5 c m solid nodule was located in the 83 segment of the surgically resected right upper lobe. The tumor was yellowish white in color, and invaded the hilar connective tissue without forming capsules. The tumor surrounded the pulmonary venous wall and was associated with thrombotic obstruction of the lumina. As shown in Figure 3, the tumor thrombi extended to the common upper lobe branch of the right superior pulmonary vein (Vl-3). The bronchus, pulmonary artery and peripheral lung tissue were grossly isolated from the tumor. Light microscopic findings
Figure 1. A chest roentgenograph on admission. An abnormal shadow is observed near the right lung hilus (arrows).
The tumor cells exhibited a characteristic organoid, nest-forming arrangement. The tumor showed a close anatomic relationship with the pulmonary vein. Not only the venous wall but also the adventitia and lumen were involved by the tumor( ~ i4) ~. , ~ i ~ transi. t ~ l tion between the tumor cells and the venous smooth
Figure 2. Sequential computed tomograms on admission immediately above the level of the left atrium. The tumor (arrowheads) appears to be continuous to the right superior pulmonary vein (asterisk). The figure (a) represents the plane 5 m m rostra1 to the figure (b). Ao, aortic root; D, descending aorta ; R, right atrial appendage; S, superior vena cava ; PO, pulmonary outflow tract; p, lower-lobe pulmonary arteries; arrows, left superior pulmonary vein and its junction with the left at ria I appendage.
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the cytoplasm (Fig. 5b). However, PAS-positive crystalline rod inclusions were not evident by light microscopic observation. Grimelius silver staining was negative. The bronchial wall, pulmonary artery, lung parenchyma and regional lymph nodes were free of tumor growth. No heterotopic striated muscle tissue was identified in the specimen. lmmunohistochemical findings
Figure 3. Gross appearance of the surgically resected lung. At the lung h,lus, the tumor occludes the lumen of the V,-3 segment of the superior pulmonary vein (arrows). b, bronchus.
muscle layer was observed. Tumor nests of varying sizes were separated by a delicate sinusoid-like vascular stroma (Fig. 5a). The individual plump tumor cells were round or polygonal in shape, and possessed a clear and finely granulated cytoplasm. The centrally located nuclei contained dispersed chromatin and small but prominent nucleoli. Mitotic figures were infrequent, and no necrosis was seen. Periodic acid-Schiff (PAS)-positive, diastase-iresistant granular structures were identified in
The neoplastic cells in f orma lin-fixed, pa raff i n-em bedded sections revealed a granular cytoplasmic positivity o f actin, detected by the indirect immunoperoxidase technique using monoclonal antibodies against pan-actin (J LA20, Amersha m Internationa I, Amersham Bucks, England) (Fig. 5c) and alpha-sarcomeric actin (5C5, Sigma Chemical Co., St. Louis, MO, USA) (Fig. 5d). Alpha-smooth muscle actin demonstrated by a mouse monoclonal antibody (1A4, Sigma) was positive in the smooth muscle- and pericyte-like cells, but was negative in the tumor cells (Fig. 5e). Rabbit antisera and monoclonal antibodies against desmin (BioScience, Emmenbruecke, Switzerland and the clone D33, Dako Co., Carpinteria, CA, USA) and myoglobin (Dako Co., and the clone MG1, ICN Immunobiologicals, Irvine, CA, USA) failed t o identify immunoreactivity in the tumor cells. Immunoreactive fast skeletal myosin detected by a monoclonal antibody MY32 (Sigma), and the mm-isozyme of creatine kinase shown by a rabbit antiserum, Japan Tanner, Kobe, were also negative. Vimentin was
Figure 4. Low-power microscopic features of the lung tumor, showing a close topographic relationship t o the pulmonary vein. a : The transition between the tumor cells proliferating outside the venous wall and its medial layer is noted. b : The tumor cellsalso invade the venous lumen (L), with destruction of the vascular wall tissue. The elastic fibers (arrows) are labeled with Victoria blue dye (Victoria blue-HE stain). Bars=200 p m .
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Alveolar Soft Part Sarcoma of Lung (Tsutsumi and Deng)
Electron microscopic findings Fresh surgical material was fixed in 2.5% glutaraldehyde, postfixed in 1% osmic acid, and prepared for ultrathin sections after embedding in Epon 812. A number of tumor cells contained numerous membranebound vesicles and granules and round mltochondria (Fig. 6a). Some tumor cells were filled with electronlucent vesicles and/or granules while the other cells were closely packed by numerous mitochondria and fewer granules. In addition to frequent formation of myelinlike figures, crystallized material with a distinct periodicity was occasionally observed in the granules (Figs. 6 b, c). Uncrysta Ilized, elect ron-lucent granules with amorphous and fibrillar matrices were often identified. Glycogen particles were scattered in the cytoplasm. Filamentous structures were poorly developed. Hemidesmosome-like junctional complexes were found along the basal lamina.
AUTOPSY FINDINGS
Figure 5. A high-power view of the lung tumor. a : The tumor cells with plump and clear cytoplasm form distinct alveolar structures separated by a delicate vascular stroma. The centrally located nuclei possess small but prominent nucleoli. b : Diastase-resistant PAS-positive granules are seen in some tumor cells (arrowheads). c-e : The granules are immunoreactive for pan-actin (c) and alpha-sarcomeric actin (d), whereas alpha-smooth muscle actin immunoreactivity is demonstrated only in the stromal smooth muscle and pericyte-like cells(e). (a : HE, b : PAS after diastase digestion, c-e: indirect immunoperoxidase using monoclonal antibodies. Bars=20 prn).
demonstrated only in the stromal and endothelial components by a monoclonal antibody V9 (Dako Co.). Negative results obtained by monoclonal and polyclonal antibodies further included cytokera tin, carcinoembryonic antigen, epithelial membrane antigen, Leu M1, CA125, CA19-9, chromogranin A, neuron-specific enolase, lysozyme, S-100 protein, alpha 1-antitrypsin and alpha 1-antichymotrypsin.
Autopsy was performed 14 hours after death. The steroid-induced Cushing’s syndrome appearance of the face and body was evident. No local recurrence of the tumor was seen in the remaining right lung and heart. Metastases were noted in the subpleural lung tissue of the left lower lobe (two nodules less than 1 can in size) and in the frontal ( 3 c m ) and parietal (1.3cm) lobes of the right cerebral hemisphere (Fig. 7). The histologic features were identical to those of the primary lung tumor except for pronounced hemorrhagic necrosis. The brain (1,340 g) was edematous, associated with cingulate herniation. Lung abscesses with systemic microabscess formation were observed. Upon careful gross and microscopic examinations, no tumor was identified in the soft tissue, including the skeletal muscles, endocrine glands and kidneys.
DISCUSSION The myogenic origin of alveolar soft part sarcoma has been proposed, on the basis of the immunohistochemical expression of desmin, muscle actin, myosin, the mmisozyme of creatine kinase, Z-protein and beta-enolase (7-15). One of the most characteristic and pathognomonic features of this tumor is the presence of diastase-resistant PAS-positive cytoplasmic granules (l), which ultrastructurally correspond to crystallized and uncrystallized granules(1, 5, 6, 11, 12, 16, 17). In some cases, crystalloid rods can be seen by light microscopy(1-6). It has been assumed that the contents of the granules, including the crystalloid material, consist of
Acta Pathologica Japonica 41 (10): 1991
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Figure 6. Ultrastructural features of the tumor cells. a : Some tumor cells are filled with small vesicles and membrane-bound, electron-lucent granules, whereas the other cells are packed with mitochondria and fewer granules. The formation of the basal lamina is shown by the arrowheads. b, c : Crystalloid structures are identified in some of the electron lucent granules. Amorphous or fibrillar matrices of the granules are also evident (arrows). Myelin figures are often formed in the granules, suggesting their lysosomal nature. Bars indicate 2 p m (a) o r 200 nm (b, c).
Figure 7. Gross features of brain metastasis seen at autopsy (a posterior view of the cut surface). A hemorrhagic 3 c m metastatic nodule is identified in the right frontal lobe The cingulate gyrus shows right-to-left herniation
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Alveolar Soft Part Sarcoma of Lung (Tsutsumi and Deng)
actin microfilaments (16, 17). The findings that the tumor cells express skeletal muscle-specific actin (10) and beta-enolase (8) strongly suggest the rhabdomyoblastic nature of alveolar soft part sarcoma, which commonly occurs in the skeletal muscle tissue (1-6). Negative myoglobin expression has, however, been pointed out repeatedly (4,8-13, 15). To the best of our knowledge, this is the first autopsyconfirmed case of alveolar soft part sarcoma of the lung with metastases t o the contralateral lung and brain. The tumor mostly lacked the expression of the muscle markers when paraffin-embedded tissue was examined immunohistochemically, as was often so in the previous reports (4-6, 12). The granular cytoplasmic reactivity with the pan-actin and alpha-sarcomeric actin antibodies, but not with the alpha-smooth muscle actin antibody, may well support the idea that the granules of the present neoplasm contained skeletal muscle-type actin filaments. No primary tumor was found in the soft tissue a t autopsy performed 17 months after surgical removal of the lung tumor. Auerbach and Brooks listed a 38-year-old male case of alveolar soft part sarcoma of the lung in their 20-case analysis (4), but the clinicopathologic features of the respective cases were not fully presented. The gross and microscopic features indicated that the tumor in our case had arisen f r o m the pulmonary vein a t the level of the right pulmonary hilus, associated with tumor thrombus formation. Primary neoplasms of the pulmonary vessels have been documented infrequently. Most of them occurred in the trunk of the pulmonary artery(22-24). The histologic type was mostly leiomyosarcoma (22-24) occasionally with a myxosarcomatous appearance (25), while rhabdomyosarcoma of the pulmonary artery was also described (26, 27). Tumors of pulmonary venous origin are exceptionally r a r e ( l 8 - 2 1 ) , and no cases of rhabdomyosarcoma of the pulmonary vein have been reported. It should be noteworthy that the human pulmonary vein near its entry into the left atrium has an adventitial cuffing of cardiac muscle cells (28). I n rats and bats, the cardiac muscle occupies the media and extends along intrapulmonary veins f o r varying distances(29). In the present case, such cardiac muscle cells may be a candidate target of the tumorigenesis of alveolar soft part sarcoma, although no striated muscle components were demonstrated in the lung. Moreover, no cases of alveolar soft part sarcoma of the heart have been described. Aberrant skeletal muscle tissue has been observed in the bronchiolar wall and interlobular septa in cases of extralobar pulmonary sequestration and hypoplastic lung (30, 31), and they may give rise to rhabdomyosarcoma of the bronchus and lung (32, 33). So far, there have been reports of alveolar soft part
sarcoma of the smooth muscle tissue such as in the vagina (34) and uterus (35). The crystalloid structures morphologically identical t o those seen in alveolar soft part sarcoma have also been observed in the smooth muscle cell component in renal angiomyolipoma (36). Malignant tumors of smooth muscle origin often show a defective expression of desmin (37), whereas desmin is consistently expressed by rhabdomyosarcoma cells (38). The direct transition of the tumor cells to the medial smooth muscle layer of the pulmonary vein was demonstrated in the present case. From these findings, the possibility of smooth muscle cell origin of the present neoplasm should still be considered. Acknowledgements : We acknowledge the skillful technical assistance in performing immunohistochemistry and electron microscopy by Kenji Kawai, Takeshi Kawakami and Osamu Yasuda, Division of Diagnostic Pathology, Tokai University Hospital, lsehara, and in taking photomicrographs by Johbu Itoh, Cell Biology Research Laboratory, Tokai University School of Medicine, Isehara. We are also grateful to Drs. R. Yoshiyuki Osamura and Yoshiyuki Abe, Department of Pathology, Tokai University School of Medicine, Isehara, and Dr. Makio Mukai, Department of Pathology, Keio University School of Medicine, Tokyo, for their valuable advice and suggestions. Drs. Shunsuke Yamada, Jun-ichi Ogawa and Hiroshi Inoue, Department of Thoracic Surgery, Tokai University School of Medicine, Isehara, cooperatively permitted to report this case.
REFERENCES 1. Enzinger FM and Weiss SW. Alveolar soit part sar2.
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coma. In Soft Tissue Tumors, 2nd ed. C.V. Mosby, St. Louis. 1988: 929-936. Christopherson WM, Foote FW Jr, and Stewart FW. Alveolar soft part sarcomas: Structurally characteristic tumors of uncertain histogenesis. Carcer 5 : 100111, 1952. Font RL, Jurco S 111, and Zimmerman LE. Alveolar soft part sarcoma of the orbit. A clinicopathotogic analysis of 1 7 cases and a review of the literature. Hum Pathol 1 3 : 569-579, 1982. Auerbach HE and Brooks JJ. Alveolar soft part sarcoma. A clinicopathologic and immunohistochemical study. Cancer 60 : 66-73, 1987. Lieberman PH, Brennan MF, Kimmel M, et a/. Alveolar soft part sarcoma. A clinico-pathologic study of half a century. Cancer 6 3 : 1-13, 1989. Mukai M, Torikata C, Iri H, et a/. Alveolar soft-part sarcoma. A review on its histogenesis and further studies based on electron microscopy, immunohistochemistry, and biochemistry. Am J Surg Pathol 7 : 679-689, 1983. Denk H, Krepler R, Artlieb U, et a/. Proteins of intermediate filaments. An immunohistochemical and biochemical approach to the classification of soft tissue tumors. Am J Pathol 1 1 0 : 193-208, 1983. Mukai M, Torikata C, Iri H, et a/. Histogenesis of
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alveolar soft part sarcoma. An immunohistochemical and biochemical study. Am J Surg Pathol 10: 212218, 1986. Ogawa K, Nakashima Y, Yamabe H, and Hamashima Y. Alveolar soft part sarcoma, granular cell tumor, and paraganglioma. An immunohistochemical comparative study. Acta Pathol Jpn 36: 895-904, 1986. Foschini MP, Ceccarelli C, Eusebi V, Skalli 0, and Gabbiani G. Alveolar soft part sarcoma: Immunolog ica I evidence of rha bdomyo blastic differentiation. Hi:;topathology 13: 101-108, 1988. Persson S, Willems J-S, Kindblom L-G, and Angervall L. Alveolar soft part sarcoma. An immunohistochemical, cytologic and electron-microscopic study and a quantitative DNA analysis. Virchows Arch [A] 412 : 499-513, 1988. Ord6fiez NG, Ro JY, and MacKay B. Alveolar soft part sarcoma. An ultrastructural and immunocytochemical investigation of its histogenesis. Cancer 63: 17211736, 1989. Matsuno Y, Mukai K, Itabashi M, et a/. Alveolar soft part sarcoma. A clinicopathologic and immunohistochemical study of 12cases. Acta Pathol Jpn 40: 199-205, 1990. Miettinen M and Ekfors T. Alveolar soft part sarcoma. lmmunohistochemical evidence for muscle cell difierentiation. Am J Clin Pathol 93: 32-38, 1990. Yamaguchi K, Soejima J, Maeda S, and Kitamura K. Alveolar soft part sarcoma: A case report with immiinohistochemical study. Jpn J Surg 20 : 476-480, 1990. Mukai M, Torikata C, Iri H, et a/. Alveolar soft part saycoma : An elaboration of a three-dimensional configuration of the crystalloids by digital image processing. Am J Pathol 116: 398-406, 1984. Mukai M, Torikata C, and Iri H. Alveolar soft part sarcoma : An electron microscopic study especially of uncrystallized granules using a tannic acid-containing fixative. Ultrastruct Pathol 1 4 : 41-50, 1990. Kaplan S. Zur Kenntnis des primaren Geschwulste des Herzens und seiner grossen Gefasse. Z Kreislaufforsch 24: 565-571, 1932. Cumming ARR and Shillitoe AJ. Ball-valve mitral obstruction by a sarcoma of a pulmonary vein. Br Heart J 19: 287-289, 1957. Kidd BSL, Carson DJL, and Lamont ES. lntra-arterial sarcoma. Br Med J 2 : 1476-1478, 1961. Gonzalez-Campora R, Rubi-Uria J, Mara-Marin J, et a/. Pulmonary vein myxoid leiomyosarcoma. Pathol Res Pract 185: 900-904, 1989. Kevorkian J and Cento JP. Leiomyosarcoma of large arteries and veins. Surgery 73 : 390-400, 1973. Hayata T and Sat0 E. Primary leiomyosarcoma aris-
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ing in the trunk of pulmonary artery. A case report and review of literature. Acta Pathol Jpn 27: 137144, 1977. Shmookler BM, Marsh HB, and Roberts WC. Primary sarcoma of the pulmonary trunk and/or right or left main pulmonary artery. A rare cause of obstruction to right ventricular outflow. Report on two patients and analysis of 35 previously described patients. Am J Med 63: 263-272, 1977. Atari E and Okudaira M. Myxoid sarcoma arising from the pulmonary artery trunk. Acta Pathol Jpn 37: 31 5-322, 1987. Durgin B and lngleby H. Primary sarcoma of the pulmonary artery. Clinics 5 : 182-189, 1946. Goldstein B and Joubert EJ. Solid pulmonary artery. Thorax 1 9 : 322-326, 1964. Burch GE and Romney RB. Functional anatomy and throttle valve action on the pulmonary veins. Am Heart J 47 : 58-66, 1954. Sorokin SP. The respiratory system. Pulmonary circulation. In Weiss L, ed. Cell and Tissue Biology : A Textbook of Histology, 6th ed. Urban & Schwarzenberg, Baltimore, 1988 : 799-804. Aterman K and Patel S. Striated muscle in the lung. Am J Anat 128: 341-358, 1970. Remberger K and Hubner G. Rhabdomyomatous dysplasia of the lung. Virchows Arch [A] 363 : 363369, 1974. Forbes GB. Rhabdomyosarcoma of bronchus. J Pathol Bacteriol (London) 70 : 427-431, 1955. Conquest HF, Thornton JL, Massie JR, and Coxe JW Ill. Primary pulmonary rhabdomyosarcoma. Report of three cases and literature review. Ann Surg 161 : 688-692, 1965. OToole RV, Tuttle SE, Lucas JG, and Sharma HM. Alveolar soft part sarcoma of the vagina. An immunohistochemical and electron microscopic study. Int J Gynecol Pathol 4 : 258-265, 1985. Gray GF Jr, Glick AD, Kurtin PJ, and Jones HW 111. Alveolar soft part sarcoma of the uterus. Hum Pathol 17 : 297-300, 1986. Mukai M, Torikata C, Iri H, et a/. Crystalloids in angiomyolipoma. 1. A previously unnoticed phenomenon of renal angiomyolipoma occurring at a high frequency. Am J Surg Pathol (in press). Tsutsumi Y and Kubo H. lmmunohistochemistry of desmin and vimentin in smooth muscle tumors of the digestive tract. Acta Pathol Jpn 38: 455-469, 1988. Osborn M, Hill C, Altmannsberger M, and Weber K. Monoclonal antibodies to titin in conjunction with antibodies to desmin separate rhabdomyosarcomas from other tumor types. Lab Invest 55: 101-108, 1986.
Alveolar Soft Part Sarcoma of the Pulmonary Vein
Yutaka Tsutsumi and Yinlong Deng
Alveolar soft part sarcoma of the lung seen i n a 42-yearold female is reported. In the partial pneumonectomy specimen, there was a 3 ~ 2 . 5 c mtumor arising from the pulmonary vein at the level of the right lung hilus, with tumor thrombus formation. The transition between the tumor and venous smooth muscle layer was microscopically confirmed. At autopsy, performed 18 months after surgery, rnetastases were noted i n the left lung and brain. No primary focus was identified i n the soft tissue. The alveolus-forming clear tumor cells contained diastaseresistant periodic acid-Schiff-reactive granules. lmmunohistocherriically, granular cytoplasmic reactivities with monoclonal antibodies against pan-actin and alpha-sarcomeric actin were demonstrated, whereas other muscle markers such as desmin, alpha-smooth muscle actin, myoglobin, fast skeletal myosin, and the mm-isozyme of creatine kinase were negative. Ultrastructurally, crystallized structures were occasionally identified in the membrane-bound, electron lucent granules, which often filled the tumor cell cytoplasm. The muscle cell nature of the neoplasm i s discussed. Acta Pathol Jpn 41: 771-777, 1991. Key word*s: Alveolar soft part sarcoma, Lung, Pulmonary vein, Crystallized granule, Muscle actin
a relatively high frequency of alveolar soft part sarcoma
(1,3-5). Despite controversy concerning its histogenesis (1, 36), the myogenic, especially rhabdomyoblastic, origin of this tumor which shows peculiar histopathologic features has been proposed by several investigators, on the basis of the immunohistochemical reactivity of desmin, muscle actin, myosin, the mm-isozyme of creatine kinase, Zprotein, and beta-enolase (7-15). The formation of muscle actin-like crystals in the membrane-bound granules has been suggested to be pathognomonic of this neoplasm (16, 17). We recently experienced a case of alveolar soft part sarcoma arising from the pulmonary vein at the level of the right lung hilus. The venous branch lumina were obstructed by tumor thrombi. To the best of our knowledge, this is the first autopsy-confirmed case of alveolar soft part sarcoma of the lung. Neoplasms of pulmonary venous origin are themselves extremely rare (18-21). Clinical, histologic, immunohistochemical and electron microscopic features of the tumor are presented.
CLINICAL SUMMARY INTRODUCTION Alveolar soft part sarcoma is a rare malignant soft tissue tumor, consisting of less than 1% of all soft tissue sarcomas (1). The disease entity of this neoplasm was established by Christopherson, Foote and Stewart in 1952 (2). It occurs predominantly in the deep soft tissue of the extremities, whereas the skeletal muscles in the head and neck and other regions are also involved (1, 3-5). Females, particularly those at a young age, have Received May 7, 1991. Accepted l o r publication July 30, 1991. Department of Pathology, Tokai University School of Medicine, Isehara. Mailing address: Yutaka Tsutsumi, M.D., Department of Pathology, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1 1, Japan.
A 42-year-old woman was admitted to Tokai University Hospital in June, 1989, with a complaint of hemoptysis during three menstrual periods. Bronchofiberscopic examination was unremarkable, and cytology yielded a diagnosis of class I. Chest X-ray and computed tomography examinations demonstrated a solitary 3 c m tumor nodule located at the hilus of the right lung (Figs. 1, 2). In July, 1989, right upper lobectomy with partial right lower lobectomy was performed. Chemotherapy (cisplatin 110 m g and vindesine sulfate 4 mg) followed. Two months after surgery, headache and left hemiparesis developed, and cranial computed tomography showed multiple brain metastases. Combined chemotherapy (cisplatin 1 5 0 mg, carboplastin 4 5 0 mg and etoposide 100 mg) was given without evident effects. Steroid administration was continued to lower the intracranial pressure for more than a year. After
7 72
Alveolar Soft Part Sarcoma of Lung (Tsutsumi and Deng)
frequent seizure attacks, the patient died o f cerebral herniation in December, 1990. The total clinical course was 2 0 months.
PATHOLOGICAL FINDINGS OF SURGICAL SPECIMEN Gross findings A solitary 3 . 0 x 2 . 5 c m solid nodule was located in the 83 segment of the surgically resected right upper lobe. The tumor was yellowish white in color, and invaded the hilar connective tissue without forming capsules. The tumor surrounded the pulmonary venous wall and was associated with thrombotic obstruction of the lumina. As shown in Figure 3, the tumor thrombi extended to the common upper lobe branch of the right superior pulmonary vein (Vl-3). The bronchus, pulmonary artery and peripheral lung tissue were grossly isolated from the tumor. Light microscopic findings
Figure 1. A chest roentgenograph on admission. An abnormal shadow is observed near the right lung hilus (arrows).
The tumor cells exhibited a characteristic organoid, nest-forming arrangement. The tumor showed a close anatomic relationship with the pulmonary vein. Not only the venous wall but also the adventitia and lumen were involved by the tumor( ~ i4) ~. , ~ i ~ transi. t ~ l tion between the tumor cells and the venous smooth
Figure 2. Sequential computed tomograms on admission immediately above the level of the left atrium. The tumor (arrowheads) appears to be continuous to the right superior pulmonary vein (asterisk). The figure (a) represents the plane 5 m m rostra1 to the figure (b). Ao, aortic root; D, descending aorta ; R, right atrial appendage; S, superior vena cava ; PO, pulmonary outflow tract; p, lower-lobe pulmonary arteries; arrows, left superior pulmonary vein and its junction with the left at ria I appendage.
~
~
i
~
Acta Pathologica Japonica 41 (10): 1991
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the cytoplasm (Fig. 5b). However, PAS-positive crystalline rod inclusions were not evident by light microscopic observation. Grimelius silver staining was negative. The bronchial wall, pulmonary artery, lung parenchyma and regional lymph nodes were free of tumor growth. No heterotopic striated muscle tissue was identified in the specimen. lmmunohistochemical findings
Figure 3. Gross appearance of the surgically resected lung. At the lung h,lus, the tumor occludes the lumen of the V,-3 segment of the superior pulmonary vein (arrows). b, bronchus.
muscle layer was observed. Tumor nests of varying sizes were separated by a delicate sinusoid-like vascular stroma (Fig. 5a). The individual plump tumor cells were round or polygonal in shape, and possessed a clear and finely granulated cytoplasm. The centrally located nuclei contained dispersed chromatin and small but prominent nucleoli. Mitotic figures were infrequent, and no necrosis was seen. Periodic acid-Schiff (PAS)-positive, diastase-iresistant granular structures were identified in
The neoplastic cells in f orma lin-fixed, pa raff i n-em bedded sections revealed a granular cytoplasmic positivity o f actin, detected by the indirect immunoperoxidase technique using monoclonal antibodies against pan-actin (J LA20, Amersha m Internationa I, Amersham Bucks, England) (Fig. 5c) and alpha-sarcomeric actin (5C5, Sigma Chemical Co., St. Louis, MO, USA) (Fig. 5d). Alpha-smooth muscle actin demonstrated by a mouse monoclonal antibody (1A4, Sigma) was positive in the smooth muscle- and pericyte-like cells, but was negative in the tumor cells (Fig. 5e). Rabbit antisera and monoclonal antibodies against desmin (BioScience, Emmenbruecke, Switzerland and the clone D33, Dako Co., Carpinteria, CA, USA) and myoglobin (Dako Co., and the clone MG1, ICN Immunobiologicals, Irvine, CA, USA) failed t o identify immunoreactivity in the tumor cells. Immunoreactive fast skeletal myosin detected by a monoclonal antibody MY32 (Sigma), and the mm-isozyme of creatine kinase shown by a rabbit antiserum, Japan Tanner, Kobe, were also negative. Vimentin was
Figure 4. Low-power microscopic features of the lung tumor, showing a close topographic relationship t o the pulmonary vein. a : The transition between the tumor cells proliferating outside the venous wall and its medial layer is noted. b : The tumor cellsalso invade the venous lumen (L), with destruction of the vascular wall tissue. The elastic fibers (arrows) are labeled with Victoria blue dye (Victoria blue-HE stain). Bars=200 p m .
7 74
Alveolar Soft Part Sarcoma of Lung (Tsutsumi and Deng)
Electron microscopic findings Fresh surgical material was fixed in 2.5% glutaraldehyde, postfixed in 1% osmic acid, and prepared for ultrathin sections after embedding in Epon 812. A number of tumor cells contained numerous membranebound vesicles and granules and round mltochondria (Fig. 6a). Some tumor cells were filled with electronlucent vesicles and/or granules while the other cells were closely packed by numerous mitochondria and fewer granules. In addition to frequent formation of myelinlike figures, crystallized material with a distinct periodicity was occasionally observed in the granules (Figs. 6 b, c). Uncrysta Ilized, elect ron-lucent granules with amorphous and fibrillar matrices were often identified. Glycogen particles were scattered in the cytoplasm. Filamentous structures were poorly developed. Hemidesmosome-like junctional complexes were found along the basal lamina.
AUTOPSY FINDINGS
Figure 5. A high-power view of the lung tumor. a : The tumor cells with plump and clear cytoplasm form distinct alveolar structures separated by a delicate vascular stroma. The centrally located nuclei possess small but prominent nucleoli. b : Diastase-resistant PAS-positive granules are seen in some tumor cells (arrowheads). c-e : The granules are immunoreactive for pan-actin (c) and alpha-sarcomeric actin (d), whereas alpha-smooth muscle actin immunoreactivity is demonstrated only in the stromal smooth muscle and pericyte-like cells(e). (a : HE, b : PAS after diastase digestion, c-e: indirect immunoperoxidase using monoclonal antibodies. Bars=20 prn).
demonstrated only in the stromal and endothelial components by a monoclonal antibody V9 (Dako Co.). Negative results obtained by monoclonal and polyclonal antibodies further included cytokera tin, carcinoembryonic antigen, epithelial membrane antigen, Leu M1, CA125, CA19-9, chromogranin A, neuron-specific enolase, lysozyme, S-100 protein, alpha 1-antitrypsin and alpha 1-antichymotrypsin.
Autopsy was performed 14 hours after death. The steroid-induced Cushing’s syndrome appearance of the face and body was evident. No local recurrence of the tumor was seen in the remaining right lung and heart. Metastases were noted in the subpleural lung tissue of the left lower lobe (two nodules less than 1 can in size) and in the frontal ( 3 c m ) and parietal (1.3cm) lobes of the right cerebral hemisphere (Fig. 7). The histologic features were identical to those of the primary lung tumor except for pronounced hemorrhagic necrosis. The brain (1,340 g) was edematous, associated with cingulate herniation. Lung abscesses with systemic microabscess formation were observed. Upon careful gross and microscopic examinations, no tumor was identified in the soft tissue, including the skeletal muscles, endocrine glands and kidneys.
DISCUSSION The myogenic origin of alveolar soft part sarcoma has been proposed, on the basis of the immunohistochemical expression of desmin, muscle actin, myosin, the mmisozyme of creatine kinase, Z-protein and beta-enolase (7-15). One of the most characteristic and pathognomonic features of this tumor is the presence of diastase-resistant PAS-positive cytoplasmic granules (l), which ultrastructurally correspond to crystallized and uncrystallized granules(1, 5, 6, 11, 12, 16, 17). In some cases, crystalloid rods can be seen by light microscopy(1-6). It has been assumed that the contents of the granules, including the crystalloid material, consist of
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Figure 6. Ultrastructural features of the tumor cells. a : Some tumor cells are filled with small vesicles and membrane-bound, electron-lucent granules, whereas the other cells are packed with mitochondria and fewer granules. The formation of the basal lamina is shown by the arrowheads. b, c : Crystalloid structures are identified in some of the electron lucent granules. Amorphous or fibrillar matrices of the granules are also evident (arrows). Myelin figures are often formed in the granules, suggesting their lysosomal nature. Bars indicate 2 p m (a) o r 200 nm (b, c).
Figure 7. Gross features of brain metastasis seen at autopsy (a posterior view of the cut surface). A hemorrhagic 3 c m metastatic nodule is identified in the right frontal lobe The cingulate gyrus shows right-to-left herniation
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Alveolar Soft Part Sarcoma of Lung (Tsutsumi and Deng)
actin microfilaments (16, 17). The findings that the tumor cells express skeletal muscle-specific actin (10) and beta-enolase (8) strongly suggest the rhabdomyoblastic nature of alveolar soft part sarcoma, which commonly occurs in the skeletal muscle tissue (1-6). Negative myoglobin expression has, however, been pointed out repeatedly (4,8-13, 15). To the best of our knowledge, this is the first autopsyconfirmed case of alveolar soft part sarcoma of the lung with metastases t o the contralateral lung and brain. The tumor mostly lacked the expression of the muscle markers when paraffin-embedded tissue was examined immunohistochemically, as was often so in the previous reports (4-6, 12). The granular cytoplasmic reactivity with the pan-actin and alpha-sarcomeric actin antibodies, but not with the alpha-smooth muscle actin antibody, may well support the idea that the granules of the present neoplasm contained skeletal muscle-type actin filaments. No primary tumor was found in the soft tissue a t autopsy performed 17 months after surgical removal of the lung tumor. Auerbach and Brooks listed a 38-year-old male case of alveolar soft part sarcoma of the lung in their 20-case analysis (4), but the clinicopathologic features of the respective cases were not fully presented. The gross and microscopic features indicated that the tumor in our case had arisen f r o m the pulmonary vein a t the level of the right pulmonary hilus, associated with tumor thrombus formation. Primary neoplasms of the pulmonary vessels have been documented infrequently. Most of them occurred in the trunk of the pulmonary artery(22-24). The histologic type was mostly leiomyosarcoma (22-24) occasionally with a myxosarcomatous appearance (25), while rhabdomyosarcoma of the pulmonary artery was also described (26, 27). Tumors of pulmonary venous origin are exceptionally r a r e ( l 8 - 2 1 ) , and no cases of rhabdomyosarcoma of the pulmonary vein have been reported. It should be noteworthy that the human pulmonary vein near its entry into the left atrium has an adventitial cuffing of cardiac muscle cells (28). I n rats and bats, the cardiac muscle occupies the media and extends along intrapulmonary veins f o r varying distances(29). In the present case, such cardiac muscle cells may be a candidate target of the tumorigenesis of alveolar soft part sarcoma, although no striated muscle components were demonstrated in the lung. Moreover, no cases of alveolar soft part sarcoma of the heart have been described. Aberrant skeletal muscle tissue has been observed in the bronchiolar wall and interlobular septa in cases of extralobar pulmonary sequestration and hypoplastic lung (30, 31), and they may give rise to rhabdomyosarcoma of the bronchus and lung (32, 33). So far, there have been reports of alveolar soft part
sarcoma of the smooth muscle tissue such as in the vagina (34) and uterus (35). The crystalloid structures morphologically identical t o those seen in alveolar soft part sarcoma have also been observed in the smooth muscle cell component in renal angiomyolipoma (36). Malignant tumors of smooth muscle origin often show a defective expression of desmin (37), whereas desmin is consistently expressed by rhabdomyosarcoma cells (38). The direct transition of the tumor cells to the medial smooth muscle layer of the pulmonary vein was demonstrated in the present case. From these findings, the possibility of smooth muscle cell origin of the present neoplasm should still be considered. Acknowledgements : We acknowledge the skillful technical assistance in performing immunohistochemistry and electron microscopy by Kenji Kawai, Takeshi Kawakami and Osamu Yasuda, Division of Diagnostic Pathology, Tokai University Hospital, lsehara, and in taking photomicrographs by Johbu Itoh, Cell Biology Research Laboratory, Tokai University School of Medicine, Isehara. We are also grateful to Drs. R. Yoshiyuki Osamura and Yoshiyuki Abe, Department of Pathology, Tokai University School of Medicine, Isehara, and Dr. Makio Mukai, Department of Pathology, Keio University School of Medicine, Tokyo, for their valuable advice and suggestions. Drs. Shunsuke Yamada, Jun-ichi Ogawa and Hiroshi Inoue, Department of Thoracic Surgery, Tokai University School of Medicine, Isehara, cooperatively permitted to report this case.
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