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Histochemical and ultrastructural features of an unusual pulmonary carcinosarcoma
H U M A N P A T H O L O G Y ~ V O L U M E 12, NUMBER 11
November 1981
features and the distribution o f secretory material. According to their criteria, o u r case would be classified as a type A.
Acknowledgment T h e authors are grateful to Dr. Harry S. Gallager, A n d e r s o n Hospital and T u m o r Institute, for reviewing o u r material and to D r . J o h n J . Sullivan, Brisbane, Australia, for translation o f a Russian report in Voprosy Onhologii. References 1. Norris, H.J., and Taylor It. B.: Carcinoma of the breast in women less than thirty )'ears old. Cancer, 26:953-959, 1970. 2. McDivitt, W., and Stewart, W.: Breast carcinoma in children. J.A.M.A., 195:388-390, 1966. 3. Oberman, H. A., and Stepbens, J.: Carcinoma of the breast in cbildhood. Cancer, 30:470-474, 1972, 4. Lippiu, W. It., Medart, W. S., Jr., and Ramsey, S. N.: 13reast cancer in a 10-year-old girl. Surgery, 68:395-396, 1970.
HISTOCHEMICAL AND ULTRASTRUCTURAL FEATURES OF AN UNUSUAL PULMONARY CARCINOSARCOMA KENT G. ZIMMERMAN,M.D.,* RICtlARD E. SOBONYA, M.D.,~ AND CLAIRE I~,I.PAYNE, PH.D.r
An autopsy case is presented in which a pulmonary carcinosarcoma filled the left chest of a 61 year old man. The extensive pleural involvement that this neoplasm exhibited has not been reported previously. By light microscoIo' the neoplasm initially was considered a mesothelioma because of the pattern of glands and undifferentiated sarcomatous stroma. However, by electron microscopy the sarcomatous component was found to show rhabdomyoblastic differentiation. Neither histochemical stains nor electron microscolo' supported a mesothelial origin for the glandular component. Differential diagvzostic considerations of pleuropulmonary neoplasms showing rhabdomyosarcomatous differentiation are discussed. This case illustrates the importance of detailed study in order to characterize and properly classify these neoplasms. Hum Pathol 12:1046-1051, 1981. Primary pleuropulmonary neoplasms showing rhabdomyosarcomatous differentiation are quite rare. Lesions showing this feature include some carcinosarcomas and pulmonary blastomas, as well as pure rhabdomyosarcomas and rhabdomyosarcomas arising in ptdmonary malformations. Herein we report the pathologic findings in a patient with a massi,ce p l e u r o p u i m o n a r y neoplasm showing both glandular and rhabdomyosarcomatous differentiation. T h e classification ofthis neoplasm as an unusual carcinosarcoma using histochemistry and electron microscopy is presented, Accepted for publication January 27, 1981. * Resident, Department of Pathology, Arizona Health Sciences Center; Tucson, Arizona. l" Associate Professor, .Department of Pathology, Arizona Heahh Sciences Center, and Attending in Pathology, Tucson Veterans Administration Medical Center, Tucson, Arizona. Director of Electron Microgcopy Laboratory and Lecturer, Department of Pathology, Arizona Health Sciences Center, Tucson, Arizona.
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5. Byrne, M. P., Fahey, M., and Gooselaw,G.: Breast cancer with axillary metastasisin an eight and one-half-yearold girl.Cancer,31:726-728, 1973. 6. Ilartman, A. W., and Magrish, P.: Carcinomaof breast in children.Case report: six-year-old boy witb adenocarcinoma. Ann. Surg., 141:792-798, 1955. 7. Sullivan,J.J., Magee, H. R., and Donald,K.J.: Secretory (juvenile)carcinoma of the breast. Pathology,9:3-t1-346, 1977. 8. Close, M. B., and Maximov,N. G.: Carcinomaof breast in young girls. Arch. Surg., 91:386-389, 1965. 9. Ramirez,G., and Ansfield,F.J.: Carcinomaof the breast in childhood. Arch. Surg., 96:222-225, 1968. 10. Mambo, N.C., Burke, J. S., and Butler, J.J.: Primary malignant lymphomas of the breast. Cancer,39:2033-2040, 1977. 11. McDivitt,R. W.: Tumors of the Breast. In Atlas of Tumor Pathology, Second Series, Fascicle2. Washington,D.C., Armed Forces Institute of Patbology, 1968 pp. 117-132. 12. Tavassoli, F.T., and Norris, H.J.: Secretory carcinomaof the breast. Cancer, 45:2404-2413, 1980. Facuhy of Medicine Universityof Sherbrooke Sherbrooke, QuebecJ 1H 5N4 Canada (Dr. Mass6)
and tile t u m o r is compared with other neoplasms considered i n the differential diagnosis. CASE HISTORY Tile patient was a 61 year old man who had been in good heahh until nine months before his death, when he experienced the acute onset of left sided pleuritic chest pain. During the following m o n t h he began to notice progressive dyspnea and soon could not walk more than several yards withont severe shortness o f breath. A chest radiograph at this time d e m o n s t r a t e d a left p l e u r a l e f f u s i o n , a n d thoracentesis yielded 1.5 liters o f serosanguineous fluid. T h e patient was hospitalized. Repeated thoracenteses revealed several more liters o f a bloody transttdate. Bronchoscopy showed "fish mouthing" (external compression) o f the superior segment o f the left lower lobe and diffuse bronchitis. T h e r e m a i n d e r of the examination was unremarkable with no evidence of an endobronchial lesion; bronchial biopsy study yielded negative findings. Five months before he expired, radiographic examination o f the lung demonstrated a mass in the posterior aspect of the left lower hemithorax. Thoracotomy revealed t u m o r filling the left pleural space with no apparent parenchymal involvem e n t . Biopsy d e m o n s t r a t e d a n e o p l a s m consisting o f malignant glandular and stromal elements, w~ich was interpreted as being a biphasic mesothelioma. T h e r a p y was begun with 160 mg. of Adriamycin and 3 gm. of dacarbazine. Soon t h e r e a f t e r the patient began to m a n i f e s t symptoms and signs of congestive heart failure. Because of the possibility of Adriamycin induced cardiomyopathy, Adriamycin was discontinued and chemotherapy consisting of Cytoxan, vincristine, methotrexate, and 5-fluorouracil was begun. Chest radiographs then showed diffuse opacity of the left hemithorax with a mediastinal shift to the right. T h e patient expired in congestive failure. T h e patient's medical history included a 50 packyears history of smoking. He had been an electrician for 35 years but denied any direct asbestos exposure.
A U T O P S Y FINDINGS At atttopsy tile left htng was found to be compressed by a bulky nodular neoplasm (Fig. 1). T h e lung could not be dissected free from the enveloping t u m o r and the entire mass w e i g h e d 6 k i l o g r a m s . T h e l u n g seas d i s p l a c e d
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MEDICAL INTELLIGENCE
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Figure 1, I n this parasagittal section of left lung the carcinosarcoma lies posteriorly (topof illustration) and compresses the lung anteriorly, The neoplasm involves the anterior visceral pleura as well. Large bronchi (lower right) are displaced by the neoplasm,
anteriorly and was almost completely atelectatic. T h e t u m o r encroached u p o n the bronchi in the area o f the hilum. In the s u p e r i o r segment o f the left lower lobe the t u m o r involved a small bronchus n e a r the pleural surface; this represented the only parenchymal involvement by the tumor. T h e cut surface o f the t u m o r was light yellow to light gray with areas o f h e m o r r h a g e and necrosis. T h e mediastinum was shifted to the right, and tile trachea was compressed in a sagittal plane along its entire course. T h e t u m o r involved the left hilar lymph nodes, but no neoplasm was found outside the left chest. In particular, the mediastinal tissues and testes d e m o n s t r a t e d no neoplasm. Autopsy also d e m onstrated manifestations o f congestive heart failure with m o d e r a t e bilateltal pedal e d e m a and m o d e r a t e left ventricular h y p e r t r o p h y and dilatation, with chronic passive congestion o f the liver and spleen.
Light Microscopy T h e neoplasm was biphasic, consisting o f both malignant epithelial and sarcomatous c o m p o n e n t s (Fig. 2). T h e sarcomatous areas composed the majority o f the t u m o r and consisted o f cells with little cohesion, showing vesicular nuclei, p r o m i n e n t nucleoli, and variable amounts o f a slightly b a s o p h i l i c c y t o p l a s m . Focally t h e cells b e c a m e m o r e fusiform with an a b u n d a n t eosinophilic cytoplasm; in these areas occasional cells seemed to d e m o n s t r a t e cross striations within tile cytoplasm. Rarely the spindle cells took on a
"herringbone" pattern. T h e epithelial component was seen almost exclusively at the margins o f the t u m o r and consisted o f m a l i g n a n t cells f o r m i n g discrete, i r r e g u l a r l y shaped glands within the malignant stroma. In one focus tile glandular cells could be seen to merge with the surr o u n d i n g stroma. Malignant epithelial cells lining irregular clefts in a single cell layer were uncommonly seem Selected areas o f t u m o r were stained with periodic a c i d - S c h i f f (with and without diastase treatment), mucicarmine, and alcian blue stains at p H 2.5 (with and without hyaluronidase)? T h e cytoplasm o f the g l a n d u l a r areas had vacuoles containing material that was PAS positive-diastase resistant, mucicarmine positive, and alcian blue p o s i t i v e - h y a l u r o n i d a s e resistant.
Electron Microscopy A portion o f the neoplasm obtained at necropsy was fixed in 1 p e r cent g l u t a r a l d e h y d e - 4 p e r cent formald e h y d e in 0.1 M phosphate buffer, p H 7.2. z T h e tissue was postfixed in 1 per cent osmium tetroxide in 0.1 M phospilate b u f f e r , d e h y d r a t e d t h r o u g h a g r a d e d series o f ethanols, and e m b e d d e d in Spurr's epoxy, a One micron thick sections were stained with toluidine blue and examined u n d e r tile light microscope. Representative areas o f the neoplasm were thin sectioned on a Sorvall MT2-B ultramicrotome using a DuPont d i a m o n d knife. T h e ultrathin sections were m o u n t e d on uncoated 200 mesh c o p p e r grids,
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H U M A N P A T H O L O G Y - - V O L U M E 12, NUMBER 11 November 1981 stained with lead citrate and uranyl acetate, and lightly carbon coated before examination under a Hitachi HU-12 electron microscope. No cross striations could be observed in the 1 micron tlfick epoxy sections from several different random areas of tim sarcomatons portions of the neoplasm. Many cells containing typical skeletal muscle myofilaments, however, could be readily identified at the uhrastructnral level. T h e thick and thin tnyofilaments o f some ceils were aligned to form rudimentary myofibrils showing Z band differentiation (Fig. 3), but more advanced sarcomere differentiation into I, H, or M bands was not observed? T h e myofibrils, lacking A bands and arranged in a haphazard pattern in most cells, accounted for their lack o f identification in the 1 micron thick epoxy sections by !ight microscopy. Typical cell junctions most closely resembling zonula adherens (puncta adherens) were f o u n d joining the rhabdomyoblasts. Other organelles present in tire cytoplasm included short strands of rough endoplasmic reticulum, polysomes, and mitoctmndria. Glycogen and lipid droplets, although not abundant, were also readily identified. No evidence o f triad formation was observed in any o f the rhabdomyoblasts. T h e epithelial portion o f the neoplasm consisted o f cells forming glands and joined by typical junctional complexes at their luminal borders. Macula adherens and zonula adherens were abundantly present in other areas where the cells joined each other. T h e cytoplasm consisted o f medium sized, membrane bound, secretory-like vacuoles filled with a slightly electron dense secretory product (Fig.
4A). Tire apical portion o f the cells contained numerous microvilli, wtfich projected into the lumina. T h e microvilli did not appear long and sinuous in any of the profiles examined. "Intracellular" lumina, formed as a resuh o f the invagination o f tim cell surface, were a frequent finding (Fig. 4/3). DISCUSSION Tltis case is an example o f a carcinosarcoma with unusual behavioral and histologic features, which inchtde a propensity to grow along and invade the pleura, and skeletal muscle differentiation o f the sarcomatous component. T h e origin o f the neoplasm presumably was the small area o f parenchymal involvement s u r r o u n d i n g a small bronchus in the left lower lobe. Such extensive pleural involvement has not been described previously in carcinosarcoma. Rather, carcinosarcomas usually begin as polypoid endobronchiai lesions limited to the central portion o f the lung parenchyma, s-s Spencer 5 defines carcinosarcomas as biphasic neoplasms composed o f malignant squamous epithelium overlying a sarcomatous stroma. However, most investigators include lesions with either malignant glandular epithelium or a mixture o f glandular and squamons epithelium as the carcinomatous component. T h e sarcomatous component may show fibrous, osseous, or cartilaginous differentiation. A single case o f skeletal muscle differentiation has been described, a h h o u g h in this case the carcinomatous component was squamous. 6 T h e combination o f rhabdomyoblast and malignant glandular epithe-
Figure 2. Photomicrograph of a field including the malignant glandular component. The surrounding malignant stroma gives no indication of its rhabdomyosarcomatous nature. (ttematoxylin and eosin stain, x560.)
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Figure 3. Electron micrograph of a portion of the cytoplasm of a rhabdomyoblast, showing many rudimentary myofibrils arranged in a haphazard pattern. Z bands are readily observed but with no evidence of sarcomere formation. Short strands of rough endoplasmic retnculum, polysomes, and glycogen can also be seen. A portion of the nucleus is present. (Uranyl acetate and lead citrate stain, x30,000.)
lium, however, is unique to the carcinosarcoma described herein. T h e neoplasm described in this r e p o r t was thought initially to be a mesothelioma because o f the growth pattern, with extensive pleural involvement and modest invasive and metastatic behavior, and the biphasic histologic n a t u r e , namely, malignant epithelial cells lining rare cleftlike spaces with a sarconmtous stroma. However, histochemical and uhrastructural studies o f this neoplasm rule out this diagnosis. Histochemical characteristics o f the epithelial component b f mesotheliomas include a b u n d a n t glycogen (demonstrated by PA~S positivity, which is removed by diastase), often hyaluronic acid (demonstrated by alcian blue positivity, which is removed by hyaluronidase), and no mucicarmine staining material. 9-n T h e secretory product o f the neoplasm described here, however, was not consistent with that o f mesothelium. It was characterized by PAS positivity resistant to diastase, mucicarmine positivity, and alcian blue positivity that was resistant to hyaluronidase. T h u s the histochemic'al findings indicate an epithelial mucin and support an origin from bronchial epithelium for the glandular c o m p o n e n t o f this neoplasm. T h e uhrastructural characteristics o f this neoplasm also were not consistent with a m e s o t h e l i o m a . L o n g a n d s i n u o u s microvilli, typical o f
mesothelioma, were not observed in this neoplasm. T h e epithelial cells had cytoplasmic vacuoles containing material similar in a p p e a r a n c e to mucin, which corroborates the histochemical findings. Uhrastructural evidence o f rhabdomyosarcomatous differentiation, as seen in this case, also has not been r e p o r t e d in mesotheliomas.12-29~Biphasic mesotheliomas, however, can have osseous and cartilaginous foci, which may result from the differentiation o f totipotent mesothelial cells.3~ A pulmonary blastoma was considered in the differential diagnosis, since skeletal muscle differentiation has been described in this entity, a T h i s t u m o r has a characteristic a p p e a r a n c e o f well differentiated glands in a b a c k g r o u n d o f a b u n d a n t immature sarcoma, resembling fetal lung, from which it gets its name. s'a-a5 Pleural growth is n o t c h a r a c t e r istic for this neoplasm, which usually appears as a large peripheral parenchymal mass. Histologically the two components are quite distinct, with no a p p a r e n t transition from epithelial to sarcomatous components, as seen in this case. Also, in blastomas the g l a n d u l a r element is m o r e uniformly distributed t h r o u g h the neoplasm than in the present case. S k e l e t a l m u s c l e d i f f e r e n t i a t i o n in a m a l i g n a n t p l e u r o p u l m o n a r y t u m o r should include consideration o f p r i m a r y rhabdomyosarcomas o f the ludg o r the pleura.
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Figure 4. A, Electron micrograph o f the epithelial portion of the tumor. An "intracellular" microlumen, formed as a result of the invagination o f the cell surface, call be seen in one of the neoplastic epithelial cells. Numerous straight microvilli project into the microlumen. B, Electron micrograph of the epithelial portion o f the tumor. Numerous m e m b r a n e bound vacuoles filled with a'slightly electron dense, amorphous material (arrow) are present in one of the epithelial cells. (Uranyl acetate and lead citrate stain, x6,400.)
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MEDICAL Only a single report of a possible primary pleural rhabd o m y o s a r c o m a e x i s t s , b u t t h i s c a s e is n o t full}' a c c e p t e d b e c a u s e o f d i f f i c u l t y in s e p a r a t i n g it f r o m a n i n t e r c o s t a l m u s cle p r i m a r y , an T h e p r e s e n c e o f a m a l i g n a n t e p i t h e l i a l c o m p o n e n t in t h e p r e s e n t n e o p l a s m o f c o u r s e r u l e s o u t t h e diagnosis of primary rhabdomyosarcoma. Rhabdomyosarc o m a h a s a l s o b e e n d e s c r i b e d as a r i s i n g in a c o n g e n i t a l c y s t i c adenomatoid malformationY A n a s s o c i a t i o n b e t w e e n pt, lm o n a r y m a l f o r m a t i o n s a n d m a l i g n a n t n e o p l a s m s is r e c o g n i z e d , b u t t h e a b s e n c e o f a r e a s o f h a n l a r t o m a t o u s g r o w t h in the present case makes this possibility unfeasible. Neop l a s m s t h a t a r e " t e r a t o i d " in n a t u r e , s u c h as i n t r a o c n l a r m e d u l l o e p i t h e l i o m a s , c a n s h o w r h a b d o m y o b l a s t s in a s s o c i a t i o n w i t h n e o p l a s t i c e p i t h e l i a l cells, as T h e l a c k o f e c t o d e r m a l t i s s u e s in t h e p r e s e n t n e o p l a s m , h o w e v e r , w o u l d e l i m i nate a teratoma from consideration. Detailed histologic analysis of lung neoplasms conside r e d t o b e c a r c i n o s a r c o m a s c e r t a i n l y s e e m s w a r r a n t e d , in v i e w o f t h e v a r i a b i l i t y in b o t h t h e i r h i s t o l o g i c a l p a t t e r n s a n d their clinical behavior. One also might wonder how many such neoplasms with "undifferentiated" s t r o m a visible b y light microscopy might show skeletal muscle differentiation if examined by electron microscopy.
References !. Lund, L.G. (Editor): Manual of ttistologic Staining Methods of the Armed Forces Institute of Pathology. Ed. 3. New York, McGraw-tlill, Book Company, 1968. 2. McDowell, E: M.: Fixation and processing. In Trump, B. F., and Jones, R.T. (Editors): Diagnnstlc Electron Microscopy. New York, John Wiley & Sons, Inc., 1978, Vol. 1, p. 118. 3. Spurr, A. R.: A low viscosity epoxy resin embedding medium for electron microscopy. J. Uhrastruct. Res., 26:31, 1969. 4. Morales, A. R., Fine, G.. and ttorn. R. C., Jr.: Rhabdomyosarcnma: an uhrastructural appraisal. In Sommers, S.C. (Editor): Pathology Annual. New York, Appleton-Century-Crofts, 1972, p. 81. 5. Spencer, H.: Pathology of the Lung. Ed. 3. New York, Pergamon Press, 1977, Vol. 2, pp. 834-835. 6. Moore, T. C.: Carcinosarcoma of the lung. Surgery, 50:.886, 1961. 7. Ludwigsen, E.: Endobronchial carcinosarcoma. Virchows Arcl~. (Pathol. Anat.); 373:.293, 1977. 8. Stackhouse, E.M., ttarrison, E.G., and Ellis, F. tL: Primary mixed malignancies of lung: carcinosarcoma and blastoma. J. Thor. Cardiovasc. Surg., 57:385, 1969. 9. McCoughey, W . T . E . : Criteria for diagnosis of diffuse mesothelial tumors. Ann. N.Y. Acad. Sci., 132:603, 1965. 10. Kannerstein, M., Churg, J., and Wagner, D.: ttistochemistry in the diagnosis of malignant mesothelioma. Ann. Clin. Lab. Sci.,3:207, 1973. I 1. Wagner, J. C., Munday, D.E., and tlarington, J.S.: ttistochemical demonstration of hyaluronie acid in pleural mesotheliomas. J. Path. Bact., 84:73, 1962. 12. Luse, S. A., and Spjut, tl.J.: An electron microscopic siudy of a solitary pleural mesothelioma. Cancer, 17.'1546, 1964. 13. Stoebner, P., Miech, G., Sengel, A., and Witz, J. p.: Notions d'Uhrastructure pleurale. II. Les M6soth61iomes. Presse Med., 78:1403, 1970.
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14. Marcus, J. B., and Lynn, J . A . : Ultrastructural comparison o f an adenomatoid tumor, lymphangioma, hemangloma, and mesothelioma. Cancer, 25:171, 1970. 15. Kay, S., and Silverberg, S.G.: Ultrastructural studies of a malignant fibrous mesothelioma of the pleura. Arch. Path., 92:449, 1971. 16. Wang, N.-S.: Electron microscopy in the diagnosis of pleural mesotheliomas. Cancer, 31 : 1046, 1973. 17. Davis,J. M. G.: Ultrastructure of human mesotheliomas.J. Natl. Cancer Inst., 52:1715, 1974. 18. ilernandez, F.J., and Fernandez, B. B.: Localized fibrous tumors of pleura: a light and electron microscopic stud)'. Cancer, 34:1667, 1974. 19. Suzuki, Y., Churg, J., and Kannerstein, M.: Uhrastrncture of human malignant diffuse mesothelioma. Am. J. Path., 85:241, 1976. 20. Klima, M., Spjut, tl.J., and Seybold, W.D.: Diffuse malignant mesothelioma. Am. J. Clin. Path., 65:583, 1976. 21. Fenoglio, J.J., Jacobs, D. W., and McAIlister, H.A.: Uhrastructure of the mesothelioma of the atrioventricular node. Cancer, 40:72 l, 1977. 22. Osamura, R. Y.: Uhrastructure of localized fibrous mesothelioma of the pleura. Report of a case with histogenetic considerations. Cancer, 39:139, 1977. 23. Kannerstein, M., McCaughey, W. T. E., Churg, J., and Selikoff, l.J.: A critique o f the criteria for the diagnosis o f diffuse malignant mesotbelioma. Mt. SinaiJ. Med., 44:485, 1977. 24. Kannerstein, M., Churg, J., and McCaughey, W. T. E.: Asbestos and mesothelioma: a review. In Sommers, S.C. (Editor): Pathology Annual. New York, Appleton-Century-Crofts, 1978, p. 81. 25. Kawai, T., MiKata, A., ToriKata, C., Yakumaru, K., Kageyama, K., and Shimosato, Y.: Solitary (localized) pleural mesothelioma. A light- and electron-microscopic study. Am. J. Surg. Path., 2:365, 1978. 26. Sbin, M.L., and Firminger, tl. I.: Acute and chronic effects of intraperitoneal injection of two types of asbestos in rats with a study of the histopathogenesis and ultrastructure of resulting mesotheliomas. Am.J. Path., 70:.291, 1973. 27. Davis, J. M. G.: ttistogenesis and fine structure of peritoneal tumors produced in animals by injections of asbestos. J. Natl. Cancer Inst., 52:1823, 1974. 28. MacKay, B.: Personal communication, 1980. 29. MacKay, B., and Osborne, B. M.: The contribution of electron microscopy to the diagnosis of tumors. Pathobiol. Ann., 8:359-405, 1978. 30. Goldstein, B.: T~vo malignant pleural mesotheliomas with unusual histological features. Thorax, 34:375, 1979. 31. Valderrana. E., Saluja, G., Shende, A., Lanzkowski, P., and Berkman,J.: Pulmonary blastoma; report of two cases in clfildren. Am. J. Surg. Path., 2:415, 1978. 32. Spencer, tl.: Pulmonary blastomas. J. Path. Bact., 82:161, 1961. 33. McCann, N. P., Fu, Y., and Kay, S.: Pulmonary blastoma, a light and electron microscopic study. Cancer, 38:789, 1976. 34. Meinecke, R., Bauer, F., Skouras, J., and Mottu, F.: Blastomatous tumors of the respiratory tract. Cancer, 38:818, 1976. 35. Roth, J. A., and Elguezabal, A.: Pulmonary blastoma evolving into carcinosarcoma; a case study. Am. J. Surg. Path., 2:407, 1978. 36. Duhig, J. T.: Solitary rhabdomyosarcoma of the pleura; report of a case with a note on the nomenclature of pleural tumors. J. Thorac. Surg., 37:236, 1959. 37. Ueda, K., et al.: Rhabdomyosarcoma of lung arising in congenital cystic adenomatoid malformation. Cancer, 40:383, 1977. 38. Zimmerman, L. E., Font, R. L., and Andersen, S. R.: Rhabdomyosar~ comatous differentiation in malignant intraocular medulloepithellomas. Cancer, 30:817-835, 1972. Department of Pathology Arizona tteahh Sciences Center 9University of Arizona Tucson, Arizona 85724 (Dr. Zimmerman)
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features and the distribution o f secretory material. According to their criteria, o u r case would be classified as a type A.
Acknowledgment T h e authors are grateful to Dr. Harry S. Gallager, A n d e r s o n Hospital and T u m o r Institute, for reviewing o u r material and to D r . J o h n J . Sullivan, Brisbane, Australia, for translation o f a Russian report in Voprosy Onhologii. References 1. Norris, H.J., and Taylor It. B.: Carcinoma of the breast in women less than thirty )'ears old. Cancer, 26:953-959, 1970. 2. McDivitt, W., and Stewart, W.: Breast carcinoma in children. J.A.M.A., 195:388-390, 1966. 3. Oberman, H. A., and Stepbens, J.: Carcinoma of the breast in cbildhood. Cancer, 30:470-474, 1972, 4. Lippiu, W. It., Medart, W. S., Jr., and Ramsey, S. N.: 13reast cancer in a 10-year-old girl. Surgery, 68:395-396, 1970.
HISTOCHEMICAL AND ULTRASTRUCTURAL FEATURES OF AN UNUSUAL PULMONARY CARCINOSARCOMA KENT G. ZIMMERMAN,M.D.,* RICtlARD E. SOBONYA, M.D.,~ AND CLAIRE I~,I.PAYNE, PH.D.r
An autopsy case is presented in which a pulmonary carcinosarcoma filled the left chest of a 61 year old man. The extensive pleural involvement that this neoplasm exhibited has not been reported previously. By light microscoIo' the neoplasm initially was considered a mesothelioma because of the pattern of glands and undifferentiated sarcomatous stroma. However, by electron microscopy the sarcomatous component was found to show rhabdomyoblastic differentiation. Neither histochemical stains nor electron microscolo' supported a mesothelial origin for the glandular component. Differential diagvzostic considerations of pleuropulmonary neoplasms showing rhabdomyosarcomatous differentiation are discussed. This case illustrates the importance of detailed study in order to characterize and properly classify these neoplasms. Hum Pathol 12:1046-1051, 1981. Primary pleuropulmonary neoplasms showing rhabdomyosarcomatous differentiation are quite rare. Lesions showing this feature include some carcinosarcomas and pulmonary blastomas, as well as pure rhabdomyosarcomas and rhabdomyosarcomas arising in ptdmonary malformations. Herein we report the pathologic findings in a patient with a massi,ce p l e u r o p u i m o n a r y neoplasm showing both glandular and rhabdomyosarcomatous differentiation. T h e classification ofthis neoplasm as an unusual carcinosarcoma using histochemistry and electron microscopy is presented, Accepted for publication January 27, 1981. * Resident, Department of Pathology, Arizona Health Sciences Center; Tucson, Arizona. l" Associate Professor, .Department of Pathology, Arizona Heahh Sciences Center, and Attending in Pathology, Tucson Veterans Administration Medical Center, Tucson, Arizona. Director of Electron Microgcopy Laboratory and Lecturer, Department of Pathology, Arizona Health Sciences Center, Tucson, Arizona.
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5. Byrne, M. P., Fahey, M., and Gooselaw,G.: Breast cancer with axillary metastasisin an eight and one-half-yearold girl.Cancer,31:726-728, 1973. 6. Ilartman, A. W., and Magrish, P.: Carcinomaof breast in children.Case report: six-year-old boy witb adenocarcinoma. Ann. Surg., 141:792-798, 1955. 7. Sullivan,J.J., Magee, H. R., and Donald,K.J.: Secretory (juvenile)carcinoma of the breast. Pathology,9:3-t1-346, 1977. 8. Close, M. B., and Maximov,N. G.: Carcinomaof breast in young girls. Arch. Surg., 91:386-389, 1965. 9. Ramirez,G., and Ansfield,F.J.: Carcinomaof the breast in childhood. Arch. Surg., 96:222-225, 1968. 10. Mambo, N.C., Burke, J. S., and Butler, J.J.: Primary malignant lymphomas of the breast. Cancer,39:2033-2040, 1977. 11. McDivitt,R. W.: Tumors of the Breast. In Atlas of Tumor Pathology, Second Series, Fascicle2. Washington,D.C., Armed Forces Institute of Patbology, 1968 pp. 117-132. 12. Tavassoli, F.T., and Norris, H.J.: Secretory carcinomaof the breast. Cancer, 45:2404-2413, 1980. Facuhy of Medicine Universityof Sherbrooke Sherbrooke, QuebecJ 1H 5N4 Canada (Dr. Mass6)
and tile t u m o r is compared with other neoplasms considered i n the differential diagnosis. CASE HISTORY Tile patient was a 61 year old man who had been in good heahh until nine months before his death, when he experienced the acute onset of left sided pleuritic chest pain. During the following m o n t h he began to notice progressive dyspnea and soon could not walk more than several yards withont severe shortness o f breath. A chest radiograph at this time d e m o n s t r a t e d a left p l e u r a l e f f u s i o n , a n d thoracentesis yielded 1.5 liters o f serosanguineous fluid. T h e patient was hospitalized. Repeated thoracenteses revealed several more liters o f a bloody transttdate. Bronchoscopy showed "fish mouthing" (external compression) o f the superior segment o f the left lower lobe and diffuse bronchitis. T h e r e m a i n d e r of the examination was unremarkable with no evidence of an endobronchial lesion; bronchial biopsy study yielded negative findings. Five months before he expired, radiographic examination o f the lung demonstrated a mass in the posterior aspect of the left lower hemithorax. Thoracotomy revealed t u m o r filling the left pleural space with no apparent parenchymal involvem e n t . Biopsy d e m o n s t r a t e d a n e o p l a s m consisting o f malignant glandular and stromal elements, w~ich was interpreted as being a biphasic mesothelioma. T h e r a p y was begun with 160 mg. of Adriamycin and 3 gm. of dacarbazine. Soon t h e r e a f t e r the patient began to m a n i f e s t symptoms and signs of congestive heart failure. Because of the possibility of Adriamycin induced cardiomyopathy, Adriamycin was discontinued and chemotherapy consisting of Cytoxan, vincristine, methotrexate, and 5-fluorouracil was begun. Chest radiographs then showed diffuse opacity of the left hemithorax with a mediastinal shift to the right. T h e patient expired in congestive failure. T h e patient's medical history included a 50 packyears history of smoking. He had been an electrician for 35 years but denied any direct asbestos exposure.
A U T O P S Y FINDINGS At atttopsy tile left htng was found to be compressed by a bulky nodular neoplasm (Fig. 1). T h e lung could not be dissected free from the enveloping t u m o r and the entire mass w e i g h e d 6 k i l o g r a m s . T h e l u n g seas d i s p l a c e d
0046-8177181ll 10011046 $01.20 9 W. B. Saunders Company
MEDICAL INTELLIGENCE
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Figure 1, I n this parasagittal section of left lung the carcinosarcoma lies posteriorly (topof illustration) and compresses the lung anteriorly, The neoplasm involves the anterior visceral pleura as well. Large bronchi (lower right) are displaced by the neoplasm,
anteriorly and was almost completely atelectatic. T h e t u m o r encroached u p o n the bronchi in the area o f the hilum. In the s u p e r i o r segment o f the left lower lobe the t u m o r involved a small bronchus n e a r the pleural surface; this represented the only parenchymal involvement by the tumor. T h e cut surface o f the t u m o r was light yellow to light gray with areas o f h e m o r r h a g e and necrosis. T h e mediastinum was shifted to the right, and tile trachea was compressed in a sagittal plane along its entire course. T h e t u m o r involved the left hilar lymph nodes, but no neoplasm was found outside the left chest. In particular, the mediastinal tissues and testes d e m o n s t r a t e d no neoplasm. Autopsy also d e m onstrated manifestations o f congestive heart failure with m o d e r a t e bilateltal pedal e d e m a and m o d e r a t e left ventricular h y p e r t r o p h y and dilatation, with chronic passive congestion o f the liver and spleen.
Light Microscopy T h e neoplasm was biphasic, consisting o f both malignant epithelial and sarcomatous c o m p o n e n t s (Fig. 2). T h e sarcomatous areas composed the majority o f the t u m o r and consisted o f cells with little cohesion, showing vesicular nuclei, p r o m i n e n t nucleoli, and variable amounts o f a slightly b a s o p h i l i c c y t o p l a s m . Focally t h e cells b e c a m e m o r e fusiform with an a b u n d a n t eosinophilic cytoplasm; in these areas occasional cells seemed to d e m o n s t r a t e cross striations within tile cytoplasm. Rarely the spindle cells took on a
"herringbone" pattern. T h e epithelial component was seen almost exclusively at the margins o f the t u m o r and consisted o f m a l i g n a n t cells f o r m i n g discrete, i r r e g u l a r l y shaped glands within the malignant stroma. In one focus tile glandular cells could be seen to merge with the surr o u n d i n g stroma. Malignant epithelial cells lining irregular clefts in a single cell layer were uncommonly seem Selected areas o f t u m o r were stained with periodic a c i d - S c h i f f (with and without diastase treatment), mucicarmine, and alcian blue stains at p H 2.5 (with and without hyaluronidase)? T h e cytoplasm o f the g l a n d u l a r areas had vacuoles containing material that was PAS positive-diastase resistant, mucicarmine positive, and alcian blue p o s i t i v e - h y a l u r o n i d a s e resistant.
Electron Microscopy A portion o f the neoplasm obtained at necropsy was fixed in 1 p e r cent g l u t a r a l d e h y d e - 4 p e r cent formald e h y d e in 0.1 M phosphate buffer, p H 7.2. z T h e tissue was postfixed in 1 per cent osmium tetroxide in 0.1 M phospilate b u f f e r , d e h y d r a t e d t h r o u g h a g r a d e d series o f ethanols, and e m b e d d e d in Spurr's epoxy, a One micron thick sections were stained with toluidine blue and examined u n d e r tile light microscope. Representative areas o f the neoplasm were thin sectioned on a Sorvall MT2-B ultramicrotome using a DuPont d i a m o n d knife. T h e ultrathin sections were m o u n t e d on uncoated 200 mesh c o p p e r grids,
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H U M A N P A T H O L O G Y - - V O L U M E 12, NUMBER 11 November 1981 stained with lead citrate and uranyl acetate, and lightly carbon coated before examination under a Hitachi HU-12 electron microscope. No cross striations could be observed in the 1 micron tlfick epoxy sections from several different random areas of tim sarcomatons portions of the neoplasm. Many cells containing typical skeletal muscle myofilaments, however, could be readily identified at the uhrastructnral level. T h e thick and thin tnyofilaments o f some ceils were aligned to form rudimentary myofibrils showing Z band differentiation (Fig. 3), but more advanced sarcomere differentiation into I, H, or M bands was not observed? T h e myofibrils, lacking A bands and arranged in a haphazard pattern in most cells, accounted for their lack o f identification in the 1 micron thick epoxy sections by !ight microscopy. Typical cell junctions most closely resembling zonula adherens (puncta adherens) were f o u n d joining the rhabdomyoblasts. Other organelles present in tire cytoplasm included short strands of rough endoplasmic reticulum, polysomes, and mitoctmndria. Glycogen and lipid droplets, although not abundant, were also readily identified. No evidence o f triad formation was observed in any o f the rhabdomyoblasts. T h e epithelial portion o f the neoplasm consisted o f cells forming glands and joined by typical junctional complexes at their luminal borders. Macula adherens and zonula adherens were abundantly present in other areas where the cells joined each other. T h e cytoplasm consisted o f medium sized, membrane bound, secretory-like vacuoles filled with a slightly electron dense secretory product (Fig.
4A). Tire apical portion o f the cells contained numerous microvilli, wtfich projected into the lumina. T h e microvilli did not appear long and sinuous in any of the profiles examined. "Intracellular" lumina, formed as a resuh o f the invagination o f tim cell surface, were a frequent finding (Fig. 4/3). DISCUSSION Tltis case is an example o f a carcinosarcoma with unusual behavioral and histologic features, which inchtde a propensity to grow along and invade the pleura, and skeletal muscle differentiation o f the sarcomatous component. T h e origin o f the neoplasm presumably was the small area o f parenchymal involvement s u r r o u n d i n g a small bronchus in the left lower lobe. Such extensive pleural involvement has not been described previously in carcinosarcoma. Rather, carcinosarcomas usually begin as polypoid endobronchiai lesions limited to the central portion o f the lung parenchyma, s-s Spencer 5 defines carcinosarcomas as biphasic neoplasms composed o f malignant squamous epithelium overlying a sarcomatous stroma. However, most investigators include lesions with either malignant glandular epithelium or a mixture o f glandular and squamons epithelium as the carcinomatous component. T h e sarcomatous component may show fibrous, osseous, or cartilaginous differentiation. A single case o f skeletal muscle differentiation has been described, a h h o u g h in this case the carcinomatous component was squamous. 6 T h e combination o f rhabdomyoblast and malignant glandular epithe-
Figure 2. Photomicrograph of a field including the malignant glandular component. The surrounding malignant stroma gives no indication of its rhabdomyosarcomatous nature. (ttematoxylin and eosin stain, x560.)
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Figure 3. Electron micrograph of a portion of the cytoplasm of a rhabdomyoblast, showing many rudimentary myofibrils arranged in a haphazard pattern. Z bands are readily observed but with no evidence of sarcomere formation. Short strands of rough endoplasmic retnculum, polysomes, and glycogen can also be seen. A portion of the nucleus is present. (Uranyl acetate and lead citrate stain, x30,000.)
lium, however, is unique to the carcinosarcoma described herein. T h e neoplasm described in this r e p o r t was thought initially to be a mesothelioma because o f the growth pattern, with extensive pleural involvement and modest invasive and metastatic behavior, and the biphasic histologic n a t u r e , namely, malignant epithelial cells lining rare cleftlike spaces with a sarconmtous stroma. However, histochemical and uhrastructural studies o f this neoplasm rule out this diagnosis. Histochemical characteristics o f the epithelial component b f mesotheliomas include a b u n d a n t glycogen (demonstrated by PA~S positivity, which is removed by diastase), often hyaluronic acid (demonstrated by alcian blue positivity, which is removed by hyaluronidase), and no mucicarmine staining material. 9-n T h e secretory product o f the neoplasm described here, however, was not consistent with that o f mesothelium. It was characterized by PAS positivity resistant to diastase, mucicarmine positivity, and alcian blue positivity that was resistant to hyaluronidase. T h u s the histochemic'al findings indicate an epithelial mucin and support an origin from bronchial epithelium for the glandular c o m p o n e n t o f this neoplasm. T h e uhrastructural characteristics o f this neoplasm also were not consistent with a m e s o t h e l i o m a . L o n g a n d s i n u o u s microvilli, typical o f
mesothelioma, were not observed in this neoplasm. T h e epithelial cells had cytoplasmic vacuoles containing material similar in a p p e a r a n c e to mucin, which corroborates the histochemical findings. Uhrastructural evidence o f rhabdomyosarcomatous differentiation, as seen in this case, also has not been r e p o r t e d in mesotheliomas.12-29~Biphasic mesotheliomas, however, can have osseous and cartilaginous foci, which may result from the differentiation o f totipotent mesothelial cells.3~ A pulmonary blastoma was considered in the differential diagnosis, since skeletal muscle differentiation has been described in this entity, a T h i s t u m o r has a characteristic a p p e a r a n c e o f well differentiated glands in a b a c k g r o u n d o f a b u n d a n t immature sarcoma, resembling fetal lung, from which it gets its name. s'a-a5 Pleural growth is n o t c h a r a c t e r istic for this neoplasm, which usually appears as a large peripheral parenchymal mass. Histologically the two components are quite distinct, with no a p p a r e n t transition from epithelial to sarcomatous components, as seen in this case. Also, in blastomas the g l a n d u l a r element is m o r e uniformly distributed t h r o u g h the neoplasm than in the present case. S k e l e t a l m u s c l e d i f f e r e n t i a t i o n in a m a l i g n a n t p l e u r o p u l m o n a r y t u m o r should include consideration o f p r i m a r y rhabdomyosarcomas o f the ludg o r the pleura.
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Figure 4. A, Electron micrograph o f the epithelial portion of the tumor. An "intracellular" microlumen, formed as a result of the invagination o f the cell surface, call be seen in one of the neoplastic epithelial cells. Numerous straight microvilli project into the microlumen. B, Electron micrograph of the epithelial portion o f the tumor. Numerous m e m b r a n e bound vacuoles filled with a'slightly electron dense, amorphous material (arrow) are present in one of the epithelial cells. (Uranyl acetate and lead citrate stain, x6,400.)
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MEDICAL Only a single report of a possible primary pleural rhabd o m y o s a r c o m a e x i s t s , b u t t h i s c a s e is n o t full}' a c c e p t e d b e c a u s e o f d i f f i c u l t y in s e p a r a t i n g it f r o m a n i n t e r c o s t a l m u s cle p r i m a r y , an T h e p r e s e n c e o f a m a l i g n a n t e p i t h e l i a l c o m p o n e n t in t h e p r e s e n t n e o p l a s m o f c o u r s e r u l e s o u t t h e diagnosis of primary rhabdomyosarcoma. Rhabdomyosarc o m a h a s a l s o b e e n d e s c r i b e d as a r i s i n g in a c o n g e n i t a l c y s t i c adenomatoid malformationY A n a s s o c i a t i o n b e t w e e n pt, lm o n a r y m a l f o r m a t i o n s a n d m a l i g n a n t n e o p l a s m s is r e c o g n i z e d , b u t t h e a b s e n c e o f a r e a s o f h a n l a r t o m a t o u s g r o w t h in the present case makes this possibility unfeasible. Neop l a s m s t h a t a r e " t e r a t o i d " in n a t u r e , s u c h as i n t r a o c n l a r m e d u l l o e p i t h e l i o m a s , c a n s h o w r h a b d o m y o b l a s t s in a s s o c i a t i o n w i t h n e o p l a s t i c e p i t h e l i a l cells, as T h e l a c k o f e c t o d e r m a l t i s s u e s in t h e p r e s e n t n e o p l a s m , h o w e v e r , w o u l d e l i m i nate a teratoma from consideration. Detailed histologic analysis of lung neoplasms conside r e d t o b e c a r c i n o s a r c o m a s c e r t a i n l y s e e m s w a r r a n t e d , in v i e w o f t h e v a r i a b i l i t y in b o t h t h e i r h i s t o l o g i c a l p a t t e r n s a n d their clinical behavior. One also might wonder how many such neoplasms with "undifferentiated" s t r o m a visible b y light microscopy might show skeletal muscle differentiation if examined by electron microscopy.
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14. Marcus, J. B., and Lynn, J . A . : Ultrastructural comparison o f an adenomatoid tumor, lymphangioma, hemangloma, and mesothelioma. Cancer, 25:171, 1970. 15. Kay, S., and Silverberg, S.G.: Ultrastructural studies of a malignant fibrous mesothelioma of the pleura. Arch. Path., 92:449, 1971. 16. Wang, N.-S.: Electron microscopy in the diagnosis of pleural mesotheliomas. Cancer, 31 : 1046, 1973. 17. Davis,J. M. G.: Ultrastructure of human mesotheliomas.J. Natl. Cancer Inst., 52:1715, 1974. 18. ilernandez, F.J., and Fernandez, B. B.: Localized fibrous tumors of pleura: a light and electron microscopic stud)'. Cancer, 34:1667, 1974. 19. Suzuki, Y., Churg, J., and Kannerstein, M.: Uhrastrncture of human malignant diffuse mesothelioma. Am. J. Path., 85:241, 1976. 20. Klima, M., Spjut, tl.J., and Seybold, W.D.: Diffuse malignant mesothelioma. Am. J. Clin. Path., 65:583, 1976. 21. Fenoglio, J.J., Jacobs, D. W., and McAIlister, H.A.: Uhrastructure of the mesothelioma of the atrioventricular node. Cancer, 40:72 l, 1977. 22. Osamura, R. Y.: Uhrastructure of localized fibrous mesothelioma of the pleura. Report of a case with histogenetic considerations. Cancer, 39:139, 1977. 23. Kannerstein, M., McCaughey, W. T. E., Churg, J., and Selikoff, l.J.: A critique o f the criteria for the diagnosis o f diffuse malignant mesotbelioma. Mt. SinaiJ. Med., 44:485, 1977. 24. Kannerstein, M., Churg, J., and McCaughey, W. T. E.: Asbestos and mesothelioma: a review. In Sommers, S.C. (Editor): Pathology Annual. New York, Appleton-Century-Crofts, 1978, p. 81. 25. Kawai, T., MiKata, A., ToriKata, C., Yakumaru, K., Kageyama, K., and Shimosato, Y.: Solitary (localized) pleural mesothelioma. A light- and electron-microscopic study. Am. J. Surg. Path., 2:365, 1978. 26. Sbin, M.L., and Firminger, tl. I.: Acute and chronic effects of intraperitoneal injection of two types of asbestos in rats with a study of the histopathogenesis and ultrastructure of resulting mesotheliomas. Am.J. Path., 70:.291, 1973. 27. Davis, J. M. G.: ttistogenesis and fine structure of peritoneal tumors produced in animals by injections of asbestos. J. Natl. Cancer Inst., 52:1823, 1974. 28. MacKay, B.: Personal communication, 1980. 29. MacKay, B., and Osborne, B. M.: The contribution of electron microscopy to the diagnosis of tumors. Pathobiol. Ann., 8:359-405, 1978. 30. Goldstein, B.: T~vo malignant pleural mesotheliomas with unusual histological features. Thorax, 34:375, 1979. 31. Valderrana. E., Saluja, G., Shende, A., Lanzkowski, P., and Berkman,J.: Pulmonary blastoma; report of two cases in clfildren. Am. J. Surg. Path., 2:415, 1978. 32. Spencer, tl.: Pulmonary blastomas. J. Path. Bact., 82:161, 1961. 33. McCann, N. P., Fu, Y., and Kay, S.: Pulmonary blastoma, a light and electron microscopic study. Cancer, 38:789, 1976. 34. Meinecke, R., Bauer, F., Skouras, J., and Mottu, F.: Blastomatous tumors of the respiratory tract. Cancer, 38:818, 1976. 35. Roth, J. A., and Elguezabal, A.: Pulmonary blastoma evolving into carcinosarcoma; a case study. Am. J. Surg. Path., 2:407, 1978. 36. Duhig, J. T.: Solitary rhabdomyosarcoma of the pleura; report of a case with a note on the nomenclature of pleural tumors. J. Thorac. Surg., 37:236, 1959. 37. Ueda, K., et al.: Rhabdomyosarcoma of lung arising in congenital cystic adenomatoid malformation. Cancer, 40:383, 1977. 38. Zimmerman, L. E., Font, R. L., and Andersen, S. R.: Rhabdomyosar~ comatous differentiation in malignant intraocular medulloepithellomas. Cancer, 30:817-835, 1972. Department of Pathology Arizona tteahh Sciences Center 9University of Arizona Tucson, Arizona 85724 (Dr. Zimmerman)
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