Multifocal Vascular Tumors in Fowl Induced by a Newly Isolated Retrovirus1

[CANCER RESEARCH 50. 4787-479.1. August 1. I990| Multifocal Vascular Tumors in Fowl Induced by a Newly Isolated Retrovirus1

Dov Soffer,2 Nitzan Resnick-Roguel, Amiram Eldor, and Moshe Kotler Department* ojI Pathology fl). S./ and Hematology [A. Â£./,Hadassah Medical Center, and the Department of Molecular Genetics. The Hebrew t'nirersity-Hadassah Medical School f\. R-R.. M. A'./, Jerusalem 91120. Israel

ABSTRACT be induced by a UV-inactivated virus and by the viral isolated envelope glycoproteins. The morphological features of a spontaneous, multifocal vascular This report deals with the morphological features of the neoplasm of chickens are described. Histologically, the tumor was char acterized by areas consisting of freely anastomosing vascular channels vascular tumors caused by AHV and includes light microscopic, with prominent papillary appearance and lined by bland-looking endo- ultrastructural, and immunohistochemical observations. Pre thelial cells, which alternate with areas resembling cavernous heman- liminary light microscopic data were reported previously (3). gioma. Occasionally solid areas composed of plump, pleomorphic cells Morphologically the tumor most closely resembled a cavernous were also present. Although there was no clear evidence for metastatic hemangioma but also displayed prominent papillary endothelial spread, some tumors were obviously invasive. Electron microscopy and hyperplasia as seen in angiosarcoma and some features remi immunohistochemistry confirmed the endothelial nature of neoplastic niscent of KS. cells, demonstrating in particular pinocytic vesicles, well developed junctional complexes, fragmented basal lamina, occasional YYeibel-Palade MATERIALS AND METHODS bodies, and patchy factor VHI-related antigen immunoreactivity. The Animals. Fifteen clinically affected hens with spontaneous tumors overall appearance of the tumor was that of a cavernous hemangioma were selected for morphological study. The hens were killed by ether with prominent papillary endothelial hyperplasia. inhalation and underwent complete autopsy. Previously we have shown that the tumor was induced by a newly Light Microscopy. All grossly identified lesions were sampled for isolated strain of avian hemangioma retrovirus and in this study we histology. In addition, random samples were taken from grossly unaf demonstrated typical type C retrovirus particles in the tumor by electron microscopy. It is suggested that this retrovirus-induced avian tumor may fected organs including lungs, heart, liver, spleen, kidney, gastrointes tinal tract, eyes, brain, and spinal cord. Tissues were fixed by immersion serve as a useful model for the study of transformed endothelia and other in 10% buffered, neutral formalin and processed routinely. Sections vascular tumorigenesis. were stained with hematoxylin and eosin, and selected cases were also stained with Masson's trichrome. elastica-van Gieson. Masson's reticu- INTRODUCTION lin stain, and Gomori's iron stain. Immunohistochemistry. The indirect immunoperoxidase method was Retroviruses are able to induce a variety of malignant and used on formalin-fixed paraffin-embedded tissue. Selected lesions were benign diseases in vertebrates and are the causative agent of stained with the following antibodies: cytokeratin [monoclonal DPC, several forms of human cancer and other diseases including Los Angeles, CA], prediluted; epithelial membrane antigen [Sera-Lab, AIDS' (1, 2). Therefore retroviruses are being used as an Cranley Down, Sussex, United Kingdom] diluted 1:200; vimentin excellent tool for the study of human tumorigenesis and other [monoclonal (V-9); DakoPatts], diluted 1:10; factor Vlll-related antigen diseases. [DakoPatts] diluted 1:100. 1:200; and laminin [Biomakor. Rehovot, Israel] prediluted and i'lex europaeus I lectin. The same antibodies A new field strain of AHV was isolated by us from sponta neous tumors in layer hens (3). This virus belongs to the ALV (except L. europaeus) were also applied to cryostat sections of a few family and induces similar lesions in birds infected as embryos tumors and examined by immunofluorescence. or on the day of hatching (3).4 The AHV provirus was cloned Electron Microscopy. Four cutaneous lesions (from 4 different hens) were sampled for ultrastructural study. The tumors were excised under by a DNA recombination technique. Viral progenies rescued deep ether anesthesia and immersed in a phosphate-buffered mixture from quail cells transfected with viral DNA were found to be of 4% formaldehyde and 1% glutaraldehyde. Following 24 h fixation, similar to the field isolate in their molecular and biological the tumors were cut into small tissue blocks and fixed in the same characteristics. fixative for an additional 24 h. They were then washed in phosphate Avian hemangioma virus induces cytopathic effect in cultured buffer, postfixed in osmium tetroxide, and embedded in Araldite. avian and mammalian cells including bovine endothelial cells. Sections 1 ^m. thick were stained with toluidine blue, and thin sections Treatment of cultured endothelial cells with AHV leads to cell were cut from selected areas, stained with uranyl acetate and lead perturbation as defined by: (a) platelet aggregation near or on citrate, and viewed with Philips 300 and JOEL 100 XC electron the treated cells; (b) decreased prostaglandin I2 secretion; (c) microscopes. Virus Morphology. CEF were prepared from SPAFAS eggs (R. F. elevated expression of tissue factors; and (d) increased expres D.. No. 3, Norwich, CT) and grown in Dulbecco's modified Eagle's sion of interleukin 1 mRNA (4).5 All of these effects can also medium enriched with 10% tryptose phosphate and 10% heat-inacti vated fetal calf serum. AHV was isolated originally from spontaneous Received 2/16/90. 1This research was supported by Grant 1-1104-86 from BARD, the United lesions in layer hens, as described before (3). Cultures of chicken embryo States-Israel Binational Agricultural Research and Development Fund and the fibroblasts infected with AHV were processed for electron microscopy. Israel Academy of Sciences. Cultured cells were fixed overnight in a phosphate-buffered mixture of 2To whom requests for reprints should be addressed, at Department of 4% formaldehyde-1% glutaraldehyde, postfixed in 1% buffered os- Pathology. Hadassah University Hospital. Kiryat Hadassah. POB 12000, Jeru mium-tetroxide, washed, and dehydrated. The pellet was embedded in salem 91120. Israel. 3The abbreviations used are: AIDS, acquired immunodeficiency syndrome: Araldite, and thin sections stained with uranyl acetate and lead citrate AHV. avian hemangioma virus; ALV. avian leukemia virus; KS. Kaposi's sar were viewed with a JOEL electron microscope. coma; CEF. chicken embryo fibroblasts. Virus Isolation. Virus was isolated by cocultivation of the tumors 4 H. Illusimi, N. Resnick-Roguel. J. Hamburger. M. Malkinson. and M. with CEF and was further cloned by end point dilution on QT-6 cells, Kotler. A newly isolated avian hemangioma inducing retrovirus is a Rous asso ciated virus-1 variant, containing unique sequences in its tnr and I.TR. submitted as described before (3). for publication. 5 N. Resnick-Roguel. A. Eldor. H. Burstein. E. Hy-am. I. V'lodavsky. A. Panel. RESULTS M. A. Blajchman. and M. Kotler. Envelope glycoprotein of avian hemangioma retrovirus induces a thrombogenic surface on human and bovine endothelial cells. Clinical Data. During the years 1988-1989 outbreaks of J. Virol.. 64: in press. 1990. vascular tumors occurred among layer hens in several farms in 4787

Downloaded from cancerres.aacrjournals.org on September 28, 2021. © 1990 American Association for Cancer Research. RF.TROVIRUS-INDUCED VASCULAR TUMORS the Jerusalem area. The clinical features of the disease were practically identical to those reported in earlier outbreaks (3). In brief, the hens became emaciated and anemic, had dull plumage, and displayed grossly visible hemorrhagic tumors over the skin. They ceased to lay eggs and usually died 1 to 4 weeks after clinical presentation. Tumor Site and Gross Appearance. The number of lesions in each hen and their distribution are summarized in Table 1. The disease was usually multifocal, and most hens had more than one tumor. The skin was by far the most frequently involved organ (85% of the hens), followed by the muscles of the trunk Fig. 2. Overview of a typical tumor showing large vascular spaces alternating and extremities (61%), liver (31%), and other organs. It should with papillary areas. H & E. x 23. be emphasized, however, that visible skin lesions constituted a major criterion for selecting birds into the study; therefore skin lesions might have been overrepresented. There was no partic ular site of predilection in the skin, inasmuch as the tumors were evenly distributed all over the body. Grossly, the typical tumor presented as a small, well circum scribed red hemorrhagic nodule, varying in diameter from 2-3 mm to 1.5 cm (Fig. 1). Skin lesions appeared as bluish or violaceous plaques or nodules, often ulcerated and hemorrhagic. Occasionally, larger lesions measuring up to 4-6 cm in diameter were noted, which on cut sections were shown to consist of a large blood clot ensheathed by a thin fibrous pseudocapsule. In addition to vascular tumors, fresh and old hemorrhages were frequently noted in the skin, muscles, and viscera, and emacia tion was sometimes extreme, resulting in complete disappear ance of subcutaneous and mesenteric fat. HistolÃ³gica! Appearance. This histolÃ³gica! features of the various tumors were quite similar. A typical lesion was nodular and well demarcated (Fig. 2). It was surrounded by an incom-

Table 1 Distribution and number of vascular tumors in affected hens HenE485E507E508E557"E570Â°- organs00001

*Â£571Â°' (lung)2 (mesentery)00001 *E572Â°- Fig. 3. Large cavernous spaces in a skin tumor, one with organizing thrombus *E573E574E575E576E578E579Skin344222220101528Muscle210010111:20011Liver000040020400414Other(top), bordered by a vascular sponge. H & E, x 16. pÃetecollagenous pseudocapsule which formed extensions that (mesentery)01 partitioned the neoplasm into several coarse nodules. The tu (mesentery)1 mor architecture varied from area to area within the same (kidney)6Total5542102351g221059neoplasm. Large areas were composed of vascular spaces lined by neoplastic cells. Some spaces were large, dilated, filled with " Lesions examined ultrastructurally. blood, and lined by flattened, spindle cells with the general * Virus isolated from lesions. configuration of endothelial cells. The overall appearance of these regions resembled cavernous hemangioma (Fig. 3). Other regions displayed a prominent papillary appearance with freely- anastomosing vascular channels, as seen in angiosarcoma or Masson's "vÃ©gÃ©tantintravascularhemangioendothelioma" (intravascular papillary endothelial hyperplasia) (5, 6) (Fig. 4). Typically, the papillary projections consisted of a connective tissue core, with occasional hemosiderin-laden macrophages, lined by a single layer of bland-looking endothelial cells. A few tumors also contained foci of endothelial proliferation with little stromal support. Here, slit-like vascular spaces were lined by plump, slightly pleomorphic cells forming sponge-like meshwork (Fig. 5) or solid cell clusters (Fig. 6). The neoplastic cells had scant cytoplasm with indistinct cell borders and rather large, oval nuclei and inconspicuous nucleoli. Very rarely, mitotic figures were present (Fig. 7). A noteworthy feature of the neoplastic disease was the pro Gross appearance of an ulcerated skin tumor. liferation of miniature blood vessels distant to the main tumor 4788

omposed of plump cells with vesicular neuclei and small ! Â¿\3^k*'* *'* 'V*-"*S*ir/ â€¢* nucleoli. A mhotic figure iis seen right of center. H&.E,* 440.

r*Â»

Fig. 8. Proliferating miniature blood vessels in the upper dermis accompanied by a few spindle cells and sparse mononuclear inflammatory infiltrate. H & E, x 80.

Fig. 5. Details of the sponge-like meshwork shown in Fig. 3. Also shown are scar-like fibrous areas. H & E. x 70.

S'i Â»Ai.Â«' tea*. ^v

â€¢â€¢ v 9 AÂ» ' tÃ - Â» ir Fig. 6. Less-differentiated cellular area in tumor consisting of plump cells with little stromal support. H & E, x 275. Fig. 9. A lesion similar to. but presumably in a more advanced stage than, the one shown in Fig. 8. Closely packed proliferating blood vessels occupy most of (Fig. 8). The proliferating vessels were located in the upper the upper dermis. H & E. x 160. dermis and were accompanied by spindle-shaped cells and sparse mononuclear inflammatory infiltrates. While individual directly infiltrated by neoplastic cells. A few tumors, however, blood vessels were well recognizable in some lesions, in other, displayed an obvious invasive growth pattern. This was char presumably more advanced lesions, they were closely packed acterized by the ingrowth of neoplastic vascular channels into and formed a dense anastomosing meshwork of vascular chan neighboring tissues, including subcutaneous fat and striated nels (Fig. 9). muscle (Fig. 10). Similar aggressive growth was noted with In most cases, the tumor was well circumscribed and nonin- hepatic tumors. Necrosis was never encountered. vasive. Skin neoplasms were located predominantly in the der Thrombi were commonly detected within the lesions, some mis. The overlying epidermis was frequently ulcerated, but not times occupying a large segment of the tumor (Fig. 3). Occa- 4789

Fig. 10. Tumor invasion of striated muscle tissue. Neoplastic vascular channels dissect through and between individual muscle fibers. H & E. x 80. Fig. 11. Patchy weak, factor Vlll-associated antigen immunoreactivity in sionally, the whole lesion consisted of a large organized throm endothelial cells lining papillary structures in the tumor. Indirect immunoperoxidase. x 63. bus surrounded by a thick fibrous pseudocapsule which con tained small nests of proliferating neoplastic cells, hemosiderin- and lipid-laden macrophages and multinucleated foreign body giant cells. Presumably, those lesions represented "burnt out," regressed tumors which have been destroyed by a massive hemorrhage. Scar-like fibrotic areas were noted in many tumors (Fig. 5) and were probably the result of organization of a previous hemorrhage. Only grossly identifiable lesions were proved to be vascular tumors on microscopic examination. Randomly sampled tissues from grossly unaffected sites failed to show any lesions. Immunohistochemical Findings. The tumors did not stain with antibodies to cytokeratin or epithelial membrane antigen, al though these antibodies stained the normal epidermis intensely. No staining of neoplastic cells was obtained with antivimentin or with U. europaeus, presumably due to the species specificity of these antibodies. Antibody to factor Vlll-associated antigen decorated tumor cells that lined vascular channels. Although staining was patchy and weak on paraffin sections (Fig. 11), the staining and the number of positively stained cells increased considerably when cryostat sections were used. Unequivocal factor Vlll-associated antigen was rarely identified in tumor cells distant from vascular spaces. Intense immunoreactivity was noted around most tumor cells as well as around normal endothelium with laminin. Ultrastructural Findings. The cells lining well formed vascular channels and papillary projections possessed many of the fea Fig. 12. I In .IMIu. im .i appearance ot'a \ascular papilla from the area shown tures of normal endothelial cells (Fig. 12). Typically, they had in Fig. 4. Noie junclional complexes between neighboring endothelial cells thin cytoplasmic projections on the luminal surface. The cyto (encircled) and thin cytoplasmic folds on the luminal surface, x 4.300. Inset, high plasm contained small amounts of smooth and rough endo- power view of the area shown at the top to better illustrate the junctional complexes. Also seen are pinocytotic vesicles and an incomplete basal lamina plastic reticulum, free ribosomes, mitochondria, and scattered adjacent to a cell process (arrows). X 26,840. dense bodies. Many cells had cytoplasmic collections of thin and intermediate filaments (Fig. 13). Pinocytotic vesicles were frequent, commonly oriented along the plasma membrane. Oc cells. They displayed marked pinocytotic activity and had abun casionally, rod-shaped Weibel-Palade bodies (7) were also pres dant thin filaments condensed into bundles and focal densities ent (Fig. 14). The nuclei were oval, with a generally smooth (Fig. 15). Cells with ultrastructural features of fibroblasts were outline, euchromatic dispersed chromatin, and occasional intermingled among the latter cells. prominent nucleoli. Fragmented basal lamina was attached to Viral particles were frequently observed in the tumors (Fig. the abluminal surface of some cells. Usually the cells formed 16). They appeared singly or in clusters in the extracellular elaborate interdigitations with frequent junctional complexes space adjacent to the tumor cell membrane. The virions were of the zonula adherens type (Fig. 12, inset). spherical, measuring approximately 80 nm in overall diameter. Tumor cells not immediately lining vascular spaces possessed They had an electron-dense, centrally located nucleoid which many ultrastructural features in common with the neoplastic was surrounded by an inner and outer membrane (Fig. 16). endothelial cells. Some had continuous basal lamina and few Rarely, viruses with crescent-shaped nucleoid, budding from organelles which may represent pericytes. Other cells, located cytoplasmic membranes, were also noted (Fig. 17). These mor in solid differentiated regions, had features of smooth muscle phological features are characteristic of type C retroviruses (8- 4790

Fig. 15. Smooth muscle differentiation in a solid area of the tumor. The cell is surrounded by a basal lamina and contains bundles of cytoplasmic filaments, numerous pinocytotic vesicles, and focal densities, x 8,300.

Fig. 13. Details of an endothclial cell cytoplasm. There are abundant filaments, a Golgi complex, mitochondria, polyribosomes, and a few pinocytotic vesicles, x 32,000.

Fig. 16. Extracellular viral particles adjacent to a neoplastic endothelial cell. The virions have centrally located condensed nucleoid and an inner and outer membrane, typical of mature type C retrovirus. x 70,950.

DISCUSSION An outbreak of vascular neoplasms reappeared last year at several fowl farms in Israel. As in previous outbreaks (3), the tumor was induced by a newly isolated retrovirus of the ALV group, first isolated and characterized by us (3).4 This study describes the morphological features of the retrovirus-induced spontaneous, multifocal vascular tumor. The tumor occurred in various tissues and organs, most commonly in the skin. Histologically it was characterized by areas consisting of freely anastomosing channels lined by rather bland-looking endothelial cells alternating with areas resem bling cavernous hemangioma and, occasionally, less differen Fig. 14. W'eibel-Palade bodies in an endothelial cell lining a papillary structure, tiated foci composed of solid masses of plump, pleomorphic x 32,000. Inset, higher magnification of a VVeibel-Palade body demonstrating the cells. The electron microscopic and immunohistochemical find parallel striation in the "tubulated body." X 67,600. ings confirmed the vascular origin of the neoplasm and the endothelial nature of the tumor cells. These included in partic 10). Examination of CEF cultures infected with AHV revealed ular the ultrastructural demonstration of pinocytotic vesicles, abundant, mature, extracellular type C virus (Fig. 18). Rare the well developed junctions to neighboring cells, the microvil- immature type C viruses with crescent-shaped nucleoids were lous projections into the lumen, the (incomplete) basal lamina occasionally seen budding from the cell membrane (Fig. 18). and the occasional occurrence of Weibel-Palade bodies, which These particles were identical to the viral particles observed in are pathognomonic of endothelial differentiation (7, 11-14). the tumors. The immunohistochemical demonstration, in some neoplastic 4791

may be the mechanisms of neoplastic transformation used when provirus is integrated into the cell genome. Although such mechanisms could be implicated for all cell types, the prefer ential induction of vascular tumors can be explained by tissue tropism determined by the unique envelope of the AHV (1). Alternatively, tumor induction may be a result of the cytopathic effect of the virus. In order to overcome cell damage, affected cells increase their mitotic rate, and this leads to a high fre quency of somatic mutations resulting in cell transformation. The occurrence of retrovirus-induced vascular tumors in fowl brings to mind the analogy with KS, the most common malig nancy in patients with AIDS (21, 22). However, both tumors share only few morphological features. Both are multifocal Fig. 17. Immature type C retrovirus with crescent-shaped nuclcoid budding vascular tumors of endothelial cell origin (22-24) which occur from cytoplastnic membrane of a neoplastic endothelial cell, x 55.900. most frequently in the skin but which may involve other organs. A hemangioma-like pattern, as seen in the AHV-induced tu mors, is not uncommon in KS and is sometimes the predomi nant histological feature (18, 25, 26). Also, the collection of proliferating miniature blood vessels in the upper dermis of chickens, at some distance from a main dermal tumor, has some similarity to early (patch stage) KS (18, 27, 28). Occasional spontaneous regression of vascular tumor, as described in our previous study (3), has been suggested here by the presence of organized thrombi and scars in the present study. Tumor regres sion may also occur in KS (29, 30) and is sometimes related to discontinuation of immunosuppressive therapy (31-33). Epidemiological, immunological, virological, and morpho logical data suggest that KS is a viral-associated if not viral- Fig. 18. Mature type C viruses and immature type C retrovirus with crescent- induced tumor, especially in AIDS patients (20, 34, 35). There shaped nucleoid budding from cytoplasmic membrane in a culture of chicken is also some evidence suggesting a role for human immunode embryo fibroblasts infected with avian hemangioma retrovirus. x 70.950. ficiency virus 1 in KS etiology. It has been recently shown that cells, of factor VHI-related antigen provide additional evidence introduction of the tat gene of the human immunodeficiency for their endothelial origin (15, 16). virus 1 germ line of mice produces skin tumors in the transgenic Histologically, the tumor most closely resembled cavernous mice which resemble KS (36). hemangioma but also had features of well differentiated heman- We have shown recently that AHV is able to induce cyto giosarcoma. The latter included: (a) the occurrence of multiple pathic effect on cultured endothelial cells (5). Shortly after lesions; (b) the presence of freely anastomosing vascular chan infection and prior to any recognizable damage, the cells pro nels lined by endothelial cells; (c) the sponge-like appearance duce high levels of tissue factor, interleukin 1, and mitogens of less differentiated areas; (hemangiosarcoma. These in duced neoplasms in general and vascular tumorigenesis and cluded: (a) lack of obvious atypia in the cells lining the vascular transformed endothelia in particular. channels; (b) the extreme rarity of mitotic figures; (c) the lack of necrosis; and (d) evidence of tumor regression. ACKNOWLEDGMENTS Data from this study correlate with our previous studies, in which the etiological agent of the disease was defined (3).4 A The authors thank Nita Tanenhaus, Haviva Orgal, and Noemi Ron member of the ALV group was isolated from spontaneous for technical assistance and Viorica Lupo for typing the manuscript. tumors and cloned in tissue culture and by a DNA recombina tion technique. The cloned virus induced vascular neoplasms in REFERENCES fowl upon inoculation and identical virus were isolated from the induced tumors (3).4 In the present study a retrovirus was 1. Weiss. R., Teich. N.. Varmus, H., and Coffin. J. RNA Tumor Viruses, pp. 25-208. Cold Spring Harbor. NY: Cold Spring Harbor Laboratory. 198.1. isolated from several tumors and typical type C retrovirus 2. Weiss, R.. Teich, N.. Varmus. H., and Coffin, J. RNA Tumor Viruses- particles (8-10) were observed in the tumors by electron mi Supplements and Appendices, pp. 405-485. Cold Spring Harbor. NY: Cold croscopy. These particles were identical to the viruses seen in Spring Harbor Laboratory. 1985. 3. Burstein, H.. Gilead. M.. Bendhcim. V.. and Kotler. M. Viral aetiology of CEF cultures infected with AHV. haemangiosarcoma outbreaks among layer hens. Avian Pathol.. I.I: 715- We have shown previously that AHV lacks an oncogene in 726, 1984. its genome. Therefore, tumor induction by AHV could be 4. Resnick-Roguel. N., Burstein. H.. Hamburger. J.. Panel. A.. Eldor. A.. Vlodavsky, I., and Kotler. M. Cytocidal effect caused by the envelope glyco explained by at least two different mechanisms: (a) the presence protein of a newly isolated avian hemangioma inducing retrovirus. J. Virol., 63: 4325-4330. 1989. of the provirus is essential for the neoplastic transformation of 5. Kuo. T-T.. Savers, C. P., and Rosai. J. Masson's "vÃ©gÃ©tantintravascular the cell; or (b) proviral integration is not required for transfor hemangioendothelioma": a lesion often mistaken for angiosarcoma. Cancer mation. Enhancer, promotion insertion, or alternative splicing (Phila.). 38: 1227-1236. 1976. 4792

6. Clearkin, K. P., and Enzinger, F. M. Intravascular papillary endothelial vascular proliferations in skin. Am. J. Pathol.. ///: 62-77, 1983. hyperplasia. Arch. Pathol. Lab. Med., 100: 441-444. 1976. 23. RÃ¼sselJones, R.. Spaiili, J., Spry. C.. and Wilson Jones. E. Histogenesis of 7. Weibel. E. R.. and Palade. G. E. New cytoplasmic components in arterial Kaposi's sarcoma in patients with and without acquired immunodeficiency endothelia. J. Cell Biol.. 23: 101-112. 1964. syndrome (AIDS). J. Clin. Pathol.. 39: 742-749. 1986. 8. Bolognesi. D. P. Structural components of RNA viruses. Adv. Virus Res.. 24. Rutgers. J. L., Wieczorek. R.. Bonetti. F.. Kaplan. D. N.. Friedman-Kien. A. /9: 315-359, 1974. E., and Knowles. D. M. The expression of endothelial cell surface antigens by AIDS-associated Kaposi's sarcoma. Evidence for a vascular endothelial 9. Matthews. R. E. F. Classification and nomenclature of viruses. Intervirology, 12: 129-238, 1979. cell origin. Am. J. Pathol.. 122: 493-499, 1986. 10. Bouillant. A. M. P., and Becker, S. A. W. E. Ultrastructural comparison of 25. RÃ³nchese, F., and Kern, A. B. Lymphangioma-like tumors in Kaposi's oncovirinae (type C). spumavirinae and lentivirinae: three subfamilies of sarcoma. Arch. Dermatol.. 75:418-427, 1957. retroviridae found in farm animals. J. Nail. Cancer Inst., 72: 1075-1084. 26. Gauge. R. W., and Wilson Jones, E. Lymphangioma-like Kaposi's sarcoma. 1984. Br. J. Dermatol.. 100: 327-334. 1979. 11. Waldo. E. D.. Vuletin, J. C., and Kaye. G. I. The ultrastructure of vascular 27. Gottlieb, G. J.. and Ackerman. A. B. Kaposi's sarcoma: an extensively tumors: additional observations and a review of the literature. Pathol. Annu., disseminated form in young homosexual men. Hum. Pathol.. 13: 882-892, 12: 179-308. 1977. 1982. 12. Llombart-Bosch. A.. Peydro-Olaya, A., and Pellin, A. Ultrastructure of 28. Schwartz, J. L., Muhlbauer. J. E., and Steigbigel. R. T. Pre-Kaposi's sarcoma. vascular neoplasms. Pathol. Res. Pract., 174: 1-41, 1982. J. Am. Acad. Dermatol., //: 377-380, 1984. 13. Carstens, P. H. B. The Weibel-Palade body in the diagnosis of endothelial 29. Brown. S. G. The hemorrhagic type of regression in Kaposi's sarcoma. Arch. tumors. Ultrastruct. Pathol.. 2: 315-325. 1982. Dermatol.. 94: 328-340, 1966. 14. \Vick. M. R.. and Manivel, J. C. Vascular neoplasms of the skin: a current 30. Taylor. J. F.. Iversen. O. H., and Bjerkens, R. Growth kinetics of Kaposi's perspective. Adv. Dermatol., 4: 185-254, 1989. sarcoma. Br. J. Cancer. 35: 470-478. 1977. 15. Jaffe. E. A. Endothelial cells and the biology of factor VIII. N. Engl. J. Med., 31. Hardy. M. A.. Goldfarb, P., Levine, S.. Dattner, A.. Muggia, F. M., Levitt, 296.-377-383. 1979. S.. and Weinstein, E. De novo Kaposi's sarcoma in renal transplantation. 16. Burgdorf. W. C., Mukai. K., and Rosai. J. Immunohistochemical identifica Case report and brief review. Cancer (Phila.). 38: 144-148, 1976. tion of factor VIII related antigen in endothelial cells of cutaneous lesions of 32. Kleep, O.. Dahl. O., and Stenwig, J. T. Association of Kaposi's sarcoma and alleged vascular nature. Am. J. Clin. Pathol.. 75: 168-171. 1981. prior immunosuppressive therapy. A 5-year material of Kaposi's sarcoma in 17. Rosai. J.. Sumner, H. W.. Kostianovsky, M.. and Perez-Mesa. C. Angio- Norway. Cancer (Phila.), 42: 2626-2630, 1978. sarcoma of the skin. A clonicopathologic and fine structural study. Hum. 33. Bencini. P. L.. Marchesi, L., Camelli. T.. and Crosti. C. Kaposi's sarcoma in Pathol.. 7:83-109. 1976. kidney transplant recipients treated with cyclosporin. Br. J. Dermatol., 118: 18. Enzinger, F. M.. and Weiss. S. W. Malignant vascular tumors. In: Soft Tissue 709-714. 1988. tumors. Ed. 2. pp. 545-580. St. Louis: C. V. Mosby. Co.. 1988. 34. Rothman. S. Remarks on sex. age and racial distribution of Kaposi's sarcoma 19. Miyachi, Y., and Imamura. S. Very low-grade angiosarcoma. Dermatologica and on possible pathogenic factors. Acta UniÃ³ Int. Contra Cancrum, 18: (Basel), 162: 206-208, 1981. 326-329. 1962. 20. Fauci, A. S., Macher, A. M., Longo, D. L., Lane, H. C., Rook, A. H., Masur, 35. Walter, P. R.. Philippe, E., Nguemby-Mbina, C., and Chamlian. A. Kaposi's H., andCelman. E. P. Acquired immunodeficiency syndrome: epidemiologie, sarcoma. Presence of herpes-type virus particles in a tumor specimen. Hum. clinical, immunologie and therapeutic considerations. Ann. Intern. Med.. Pathol., 15: 1145-1146, 1984. 100: 92-106. 1984. 36. Vogel, J.. Hinrichs. S. H., Reynolds. R. K., Luciw, P. A., and Jay, G. The 21. Safai. B.. Johnson. K. G.. Myskowski, P. L.. Koziner. B., Yang, S. Y., HIV tat gene induces dermal lesions resembling Kaposi's sarcoma in trans- Cunningham-Rundles. S., Godbold. J. H.. and Dupont. B. The natural genie mice. Nature (Lond.). 335: 606-611. 1988. history of Kaposi's sarcoma in the acquired immunodeficiency syndrome. 37. Salahuddin. S. Z.. Nakamura. S.. Biberfeld. P.. Kaplan. M. H.. Markham. Ann. Intern. Med.. Â¡03:744-750. 1985. P. D.. Larsson. L.. and Gallo. R. Angiogenic properties of Kaposi's sarcoma 22. McNutt. N. S.. Fletcher. V.. and Conant, M. A. Early lesions of Kaposi's derived cells after long term culture in film. Science (Wash. DC). 242: 430- sarcoma in homosexual men. An ultrastructural comparison with other 433. 1988.

4793

Dov Soffer, Nitzan Resnick-Roguel, Amiram Eldor, et al.

Cancer Res 1990;50:4787-4793.

Updated version Access the most recent version of this article at: http://cancerres.aacrjournals.org/content/50/15/4787

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Subscriptions Department at [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://cancerres.aacrjournals.org/content/50/15/4787. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.