ANIMAL MODEL OF HUMAN DISEASE
Bronchiolo-Alveolar Cell Carcinoma
Animal Model: Pulmonarv Adenomatosis of Sheep, Pulmonary Carcinoma of Sheep (Jaagsiekte) Contributed by: T. A. Nobel, DMV, DTVM, and K. Perk, DMV, PdV, Department of Pathology, Kimron Veterinary Institute, Bet Dagan, and Department of Animal Science, Hebrew University, Rehovot Campus, Israel.
Bioloi Features
Pulmonary carcinoma of sheep is a spontaneous malignant disease which occurs frequently in most breeds.12 Examination of the cellular ultrastructure indicates that this tumor is derived from terminal bronchiolar epithelial cells that also form Type B alveolar epithelial cells (Type 2 pneumocytes).3'4 Although this lung tumor grows mainly by expansion, extrathoracic and intrathoracic metastases have been observed frequently.2'5'6 Due to the malignant character of the disease, the term "carcinoma of the lung" rather than "'lung adenomatosis" was recently proposed.56'7 When examining different areas of the sheep lung tumor mass, different degrees of cell differentiation and organization are seen. For example, neoplastic cells may contain glycogen granules, with or w-ithout cytosomes, which are characteristic of undifferentiated embrvonal lung epithelium. There are cells with numerous apical mucin-secretorv vesicles containing coarse granulated material, tonofibrils, and microvilli, which are characteristic of the nonciliated bronchiolar epithelium. Other tumor cells have phospholipid granules, alkaline phosphatase, cvtosomes, and microvilli characteristic of the alveolar Tvpe 2 pneumocvte (Figures 1_3). The neoplastic cells may be arranged in short rows, lavers, acinar or papillar structures, or clusters. Near tumor nodules, single or small rows of neoplastic cells (Type B) are scattered between normal alveolar epithelial cells. The cells were considered neoplastic on the basis of their morphology, peculiar arrangement, and the presence of glvcogen granules. The histologic pattern observed at the margins of tumor nodules has usually Publication sponsored by the Registry of Comparative Patholog- of the Armed Forces Institute of by Public Health Serv ice Grant RR 00301 from the Division of Research Resources. US Department of Health. Education and Welfare, under the auspices of Universities Xssociated for Research and Education in Pathology. Inc
Pathology and supported
783
784
NOBEL AND PERK
American Journal of Pathology
been described as pathognomonic. In such areas the alveoli are lined by a single laver of well-differentiated cuboidal or columnar cells. In many alveoli, papillary projections of the septum into the lumina are present. The neoplastic cells contain either abundant glvcogen and osmophilic granules, indicating Tvpe B alveolar "origin", or mucin, indicating bronchiolar "origin." Central areas of the tumor nodes contain intensely proliferating cords, sheets, or nests of anaplastic epithelial cells. The supporting stroma, in contrast to that found at the marginal areas or in small tumor nodules, is proliferative, often presenting a sarcomatous pattem consisting of interlacing bundles of fibroblastic cells (Figures 4-6). In a few cases, small tumor nodules were found to be composed of highly undifferentiated embryonal epithelial cells having a tendenev for alveolar formation. Epidemiologic and experimental evidence indicates that this neoplasm is horizontally transmitted.2'8'9 Several transmission experiments have suggested a viral etiology, although these results have not vet been unequivocally proved. Virus particles, morphologicallv and biochemically similar to RNA tumor viruses, ie, clusters of intracytoplasmic A and budding C type particles, were seen in situ. Extracts of the tumors were found to contain particles having a density of 1.15 to 1.20 g/ml and possessing the characteristics of a reverse transcriptase in association with 60-70S RNA."0 Herpes-like particles were found also in cultivated macrophages from lungs of sheep with pulmonary adenomatosis." Comaison With Human Disease
This sheep tumor is similar to human bronchioloalveolar carcinoma in that both tumors originate in the peripherv of the lung and have a tendencv to grow predominantlv within it; thev share the same histologic and ultrastruetural features. In the human cell tumor, as in the sheep carcinoma, apical mucin granules, tonofibrils and microvilli were reported '1 and neoplastic cells with cvtosomes were also found.13"l4 Thus, tumor development is similar to bronchioloalveolar embrvogenesis.15 Usefnss of Mode
This spontaneous, natural animal model may provide basic information on the cell origin of human bronchioloalveolar carcinoma; may aid in acquiring a better understanding of its pathogenesis, natural historv, epidemiology, host susceptibility; and may lead to the selection of agents for chemotherapy.
Fiure 1-Neoplastic cells contain glycogen granules, large cytoplasmic clefts, nuclear indentation. (x 4000) Figure 2-Neoplastic cells with cytosomes and microvilli. (x 3500) Fi re 3-Epithelial tumor cells contain numerous vesicles with varying amounts of mucin and microvilli. (x 7000) Figure 4-Section through lung adjacent to tumor nodules, with neoplastic cells interspersed with alveolar cells. The cells are cuboidal and contain considerable amounts of glycogen. (Periodic acid-Schiff, x 600) Figure 5-Section through margin of tumor. Neoplastic epithelial cells arranged in a papillary and acinar pattern. (H&E, x 200) Figure 6-Section through center of tumor. Neoplastic epithelial cells in a sarcomatous stroma. (H&E, x 200)
786
NOBEL AND PERK
American Journal of Pathology
Availability
This tumor is observed frequently in different breeds of sheep in manv countries. Reference5 1. jubb KVF. Kennedy PC: Pathology of Domestic Animals. New York, Academic Press, Inc., 1970, pp 268-269 2. Tustin RC: Ovine Jaagsiekte. JS Afr Med Assoc 40:3-23. 1969 :3. Perk K, Hod I, Nobel TA: Pulmonarv adenomatosis of sheep (Jaagsiekte). I. Ultrastructure of the tumor. J Natl Cancer Inst 46:525-5:3, 1971 4. Nisbet DI, Mackay JM. Smith XV. Gray EN: Ultrastructure of sheep pulmonarv adenomatosis (Jaagsiekte). J Pathol 103:157-162. 1972 5. Nobel TA. Neumann F. Klopfer U: Histological patterns of the metastases in pulmonar- adenomatosis of sheep (Jaagsiekte). I Comp Pathol 79:337-540, 1969 6. Enchev S: On the malignant (metastasizing) forms of what is know-n as pulmonary adenomatosis (Jaagsiekte) in sheep. DokI Bolg Akad Nauk 16:441-444, 1963 7. Perk K, Hod I, Presentey B. Nobel TA: Lung carcinoma of sheep (Jaagsiekte). II. Histogenesis of the tumor. J Natl Cancer Inst 47:197-205. 1971 8. Markson LM. Terlecki S: The experimental transmission of ovine pulmonary adenomatosis. Pathol Vet 1:269-288, 1964 9. Dungal N: Experiments with Jaagsiekte. Am J Pathol 22:7,37-759. 1946 10. Perk K. Michalides R. Spiegelman S. Schlom J: Biochemical and morphologic evidence for the presence of an RNA tumor virus in pulmonary carcinoma of sheep (Jaagsiekte). J Natl Cancer Inst 33:131-1.35, 1974 11. Smith WV, Mackay JM: Morphological observations on a virus associated wvith sheep pulmonar adenomatosis (Jaagsiekte). J Comp Pathol 79:421-424, 1969 12. Greenberg SD. Smith MN. Spjut HJ: Bronchiolo-alveolar carcinoma-cell of origin. Am J Clin Pathol 63:153-167, 1975 13. Coalson JJ. Mohr JA. Pirtie JK. Dee AL. Rhoades ER: Electron microscopy of neoplasms in the lung with special emphasis on the alveolar cell carcinoma. Am Rev Resp Dis 101:181-197. 1970 14. Adamson JS. Senior RNM. Merrill T: Alveolar cell carcinoma. An electron microscopic study. Am Rev Resp Dis 100:350-558. 1969 15. Sorokin SP: The cells of the lungs. Morphology of Experimental Respiratory Carcinogenesis. Edited by P Nettesheim. MG Hanna Jr. JX' Deatherage Jr. Springfield. V'irginia. AEC Symposium Series. 1970. pp 3-45
Bronchiolo-Alveolar Cell Carcinoma
Animal Model: Pulmonarv Adenomatosis of Sheep, Pulmonary Carcinoma of Sheep (Jaagsiekte) Contributed by: T. A. Nobel, DMV, DTVM, and K. Perk, DMV, PdV, Department of Pathology, Kimron Veterinary Institute, Bet Dagan, and Department of Animal Science, Hebrew University, Rehovot Campus, Israel.
Bioloi Features
Pulmonary carcinoma of sheep is a spontaneous malignant disease which occurs frequently in most breeds.12 Examination of the cellular ultrastructure indicates that this tumor is derived from terminal bronchiolar epithelial cells that also form Type B alveolar epithelial cells (Type 2 pneumocytes).3'4 Although this lung tumor grows mainly by expansion, extrathoracic and intrathoracic metastases have been observed frequently.2'5'6 Due to the malignant character of the disease, the term "carcinoma of the lung" rather than "'lung adenomatosis" was recently proposed.56'7 When examining different areas of the sheep lung tumor mass, different degrees of cell differentiation and organization are seen. For example, neoplastic cells may contain glycogen granules, with or w-ithout cytosomes, which are characteristic of undifferentiated embrvonal lung epithelium. There are cells with numerous apical mucin-secretorv vesicles containing coarse granulated material, tonofibrils, and microvilli, which are characteristic of the nonciliated bronchiolar epithelium. Other tumor cells have phospholipid granules, alkaline phosphatase, cvtosomes, and microvilli characteristic of the alveolar Tvpe 2 pneumocvte (Figures 1_3). The neoplastic cells may be arranged in short rows, lavers, acinar or papillar structures, or clusters. Near tumor nodules, single or small rows of neoplastic cells (Type B) are scattered between normal alveolar epithelial cells. The cells were considered neoplastic on the basis of their morphology, peculiar arrangement, and the presence of glvcogen granules. The histologic pattern observed at the margins of tumor nodules has usually Publication sponsored by the Registry of Comparative Patholog- of the Armed Forces Institute of by Public Health Serv ice Grant RR 00301 from the Division of Research Resources. US Department of Health. Education and Welfare, under the auspices of Universities Xssociated for Research and Education in Pathology. Inc
Pathology and supported
783
784
NOBEL AND PERK
American Journal of Pathology
been described as pathognomonic. In such areas the alveoli are lined by a single laver of well-differentiated cuboidal or columnar cells. In many alveoli, papillary projections of the septum into the lumina are present. The neoplastic cells contain either abundant glvcogen and osmophilic granules, indicating Tvpe B alveolar "origin", or mucin, indicating bronchiolar "origin." Central areas of the tumor nodes contain intensely proliferating cords, sheets, or nests of anaplastic epithelial cells. The supporting stroma, in contrast to that found at the marginal areas or in small tumor nodules, is proliferative, often presenting a sarcomatous pattem consisting of interlacing bundles of fibroblastic cells (Figures 4-6). In a few cases, small tumor nodules were found to be composed of highly undifferentiated embryonal epithelial cells having a tendenev for alveolar formation. Epidemiologic and experimental evidence indicates that this neoplasm is horizontally transmitted.2'8'9 Several transmission experiments have suggested a viral etiology, although these results have not vet been unequivocally proved. Virus particles, morphologicallv and biochemically similar to RNA tumor viruses, ie, clusters of intracytoplasmic A and budding C type particles, were seen in situ. Extracts of the tumors were found to contain particles having a density of 1.15 to 1.20 g/ml and possessing the characteristics of a reverse transcriptase in association with 60-70S RNA."0 Herpes-like particles were found also in cultivated macrophages from lungs of sheep with pulmonary adenomatosis." Comaison With Human Disease
This sheep tumor is similar to human bronchioloalveolar carcinoma in that both tumors originate in the peripherv of the lung and have a tendencv to grow predominantlv within it; thev share the same histologic and ultrastruetural features. In the human cell tumor, as in the sheep carcinoma, apical mucin granules, tonofibrils and microvilli were reported '1 and neoplastic cells with cvtosomes were also found.13"l4 Thus, tumor development is similar to bronchioloalveolar embrvogenesis.15 Usefnss of Mode
This spontaneous, natural animal model may provide basic information on the cell origin of human bronchioloalveolar carcinoma; may aid in acquiring a better understanding of its pathogenesis, natural historv, epidemiology, host susceptibility; and may lead to the selection of agents for chemotherapy.
Fiure 1-Neoplastic cells contain glycogen granules, large cytoplasmic clefts, nuclear indentation. (x 4000) Figure 2-Neoplastic cells with cytosomes and microvilli. (x 3500) Fi re 3-Epithelial tumor cells contain numerous vesicles with varying amounts of mucin and microvilli. (x 7000) Figure 4-Section through lung adjacent to tumor nodules, with neoplastic cells interspersed with alveolar cells. The cells are cuboidal and contain considerable amounts of glycogen. (Periodic acid-Schiff, x 600) Figure 5-Section through margin of tumor. Neoplastic epithelial cells arranged in a papillary and acinar pattern. (H&E, x 200) Figure 6-Section through center of tumor. Neoplastic epithelial cells in a sarcomatous stroma. (H&E, x 200)
786
NOBEL AND PERK
American Journal of Pathology
Availability
This tumor is observed frequently in different breeds of sheep in manv countries. Reference5 1. jubb KVF. Kennedy PC: Pathology of Domestic Animals. New York, Academic Press, Inc., 1970, pp 268-269 2. Tustin RC: Ovine Jaagsiekte. JS Afr Med Assoc 40:3-23. 1969 :3. Perk K, Hod I, Nobel TA: Pulmonarv adenomatosis of sheep (Jaagsiekte). I. Ultrastructure of the tumor. J Natl Cancer Inst 46:525-5:3, 1971 4. Nisbet DI, Mackay JM. Smith XV. Gray EN: Ultrastructure of sheep pulmonarv adenomatosis (Jaagsiekte). J Pathol 103:157-162. 1972 5. Nobel TA. Neumann F. Klopfer U: Histological patterns of the metastases in pulmonar- adenomatosis of sheep (Jaagsiekte). I Comp Pathol 79:337-540, 1969 6. Enchev S: On the malignant (metastasizing) forms of what is know-n as pulmonary adenomatosis (Jaagsiekte) in sheep. DokI Bolg Akad Nauk 16:441-444, 1963 7. Perk K, Hod I, Presentey B. Nobel TA: Lung carcinoma of sheep (Jaagsiekte). II. Histogenesis of the tumor. J Natl Cancer Inst 47:197-205. 1971 8. Markson LM. Terlecki S: The experimental transmission of ovine pulmonary adenomatosis. Pathol Vet 1:269-288, 1964 9. Dungal N: Experiments with Jaagsiekte. Am J Pathol 22:7,37-759. 1946 10. Perk K. Michalides R. Spiegelman S. Schlom J: Biochemical and morphologic evidence for the presence of an RNA tumor virus in pulmonary carcinoma of sheep (Jaagsiekte). J Natl Cancer Inst 33:131-1.35, 1974 11. Smith WV, Mackay JM: Morphological observations on a virus associated wvith sheep pulmonar adenomatosis (Jaagsiekte). J Comp Pathol 79:421-424, 1969 12. Greenberg SD. Smith MN. Spjut HJ: Bronchiolo-alveolar carcinoma-cell of origin. Am J Clin Pathol 63:153-167, 1975 13. Coalson JJ. Mohr JA. Pirtie JK. Dee AL. Rhoades ER: Electron microscopy of neoplasms in the lung with special emphasis on the alveolar cell carcinoma. Am Rev Resp Dis 101:181-197. 1970 14. Adamson JS. Senior RNM. Merrill T: Alveolar cell carcinoma. An electron microscopic study. Am Rev Resp Dis 100:350-558. 1969 15. Sorokin SP: The cells of the lungs. Morphology of Experimental Respiratory Carcinogenesis. Edited by P Nettesheim. MG Hanna Jr. JX' Deatherage Jr. Springfield. V'irginia. AEC Symposium Series. 1970. pp 3-45
