Current Investigations into the Etiology and Pathogenesis of Neoplasms in California Sea Lions (Zalophus californianus)
IAAAM 1999
E.L. Buckles1; L.J. Lowenstine2; D.P. King2; J.L. Stott2; R. Garber3; T. Spraker4; T. Lipscomb5; M. Haulena6; F.M.D. Gulland6
1Veterinary Medical Teaching Hospital, University of California, Davis, CA, USA; 2Department of Pathology, Microbiology and Immunology, University of California, Davis, CA, USA; 3PathoGenesis Corporation, Seattle, WA, USA; 4Colorado State University, College of Veterinary Medicine, Fort Collins, CO, USA; 5Armed Forces Institute of Pathology, Washington, DC, USA; 6The Marine Mammal Center, Golden Gate National Recreation Area, Sausalito, CA, USA


Neoplastic diseases in free ranging populations of marine mammals were once considered to be rare. However, reports of tumors in marine mammals are increasing and in a 1983 survey of 1500 marine mammal necropsies, neoplastic lesions were found in 2.5% of animals5. Furthermore, a population of Beluga whales (Delphinapterus leucas) in a polluted section of the St. Lawrence River had a tumor incidence of 50%2. Reports of neoplasms in California sea lions (Zalophus californianus) are also becoming increasingly frequent. Ongoing collaborative investigations at the University of California, Davis and The Marine Mammal Center have documented a variety of neoplasms in stranded California sea lions and current investigations are focused on determining the cause of these neoplasms.

From 1979 to 1994, neoplasms were diagnosed in 19% of California sea lions necropsied at TMMC and UCD. The most prevalent of these neoplasms was a highly anaplastic, aggressive carcinoma presumed to be of urogenital epithelial origin. These anaplastic tumors metastasized early to regional lymph nodes, pelvic viscera and lungs. The primary tumor was either not identified or was smaller than the metastatic foci2.

Additionally, a variety of other tumors were observed including two sarcomas, a thoracic adenocarcinoma (of uncertain cell origin), a renal fibroma, an islet cell adenoma and an adrenocortical adenoma. Since the publication of this study, additional urogenital carcinomas have been identified in California sea lions as well as several benign tumors including 2 uterine leiomyomas, one islet cell tumor of the pancreas, and one teratoma of the perirenal tissues. A multicentric T-cell lymphoma and an intrathoracic squamous cell carcinoma were also diagnosed. As with the urogenital tumors, the squamous cell carcinoma was highly aggressive and the primary site was not evident.

The reasons for this apparent predisposition for aggressive neoplasms in the California sea lion are not clear. The number of reported cases could, in part, be due to over representation of the sea lions at stranding centers. However, in a survey of sea lions dying of acute domoic acid toxicity, small urogenital tumors with nodal metastases were detected in 5.7% of the animals. The finding of additional incidental benign tumors brought the incidence of neoplasia to 13.7% in this group. This suggests that the occurrence of neoplasia in sea lions may be high in the general as well as the stranded population.

The prevalence of urogenital neoplasms in California sea lions suggests that environmental factors may play a role in tumorigenesis. In other species the development of transitional cell carcinomas is closely related to exposure to environmental toxins often with viruses as cofactors7. Therefore, since 1993, our investigations into the etiology of the sea lion tumors have been focusing on environmental contaminants such as polychlorinated biphenols (PCBs)4 and viruses, especially herpesviruses. Work on herpesviruses as a co-factor was initiated in 1992 when a 1 cm diameter raised plaque was detected as an incidental finding on the penis of an adult male sea lion8. Histologically the plaque was characterized by marked acanthosis and hyperkeratosis of the squamous epithelium with ballooning degeneration of the keratinocytes, many of which contained large amphophilic to basophilic, foamy intranuclear inclusion bodies. Transmission electron microscopy demonstrated icosahedral, non-enveloped virions with size and morphology compatible with herpesviruses in the nuclei. Probable gamma herpesvirus sequences were detected by polymerase chain reaction8. Herpesviral inclusions have also been detected in a small number of urogenital tumors examined at the Armed Forces Institute of Pathology.

Herpesviruses have been implicated in epithelial tumors in a wide range of species. These include: papillomas and carcinomas in rainbow smelt (Osmerus mordax)10, papillomas in green lizard (Lecerta viridis)11, fibropapillomatosis in green sea turtles (Chelonia mydas)3, foot warts in cockatoos and macaws (Cacatua and Ara spp.)9, and cutaneous papillomas in African elephants (Loxodonta africana)6. In humans, there is also evidence that herpesviruses may play a role in the development of a variety of epithelial tumors. Epstein Barr virus (EBV) has been implicated in the development of nasopharyngeal carcinomas and EBV genomic sequences have been detected in invasive human cervical carcinomas1. Furthermore, some epidemiologic studies suggest that herpes simplex 2 virus (HSV-2) may interact with human papilloma virus (HPV) and potentiate development of cervical carcinomas. In a 1996 study cytomegalovirus, EBV, and HSV-2 sequences were detected in 11%, 34% and 9% of human bladder cancers respectively1. Thus, the development of carcinomas in the urogenital epithelium in California sea lions may well be related to infection by a transforming herpesvirus.

Ongoing collaborative investigations between the University of California, Davis and The Marine Mammal Center are underway to elucidate the histogenesis of the urogenital carcinomas, determine the role of herpesviruses in the development of urogenital carcinomas and other tumors of sea lions, describe the molecular events associated with carcinogenesis and determine molecular factors that may predispose sea lion tumors to early metastasis.


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2.  Gulland FMD, JG Trupkiewictz, TR Spraker, LJ Lowenstine. 1996. Metastatic Carcinoma of Probable Transitional Cell Origin in 66 Free-Living California Sea Lions (Zalophus californianus), 1979 to 1994. Journal of Wildlife Diseases 32 (2): 250-258.

3.  Herbst LH, ER Jacobson, R Moretti, T Brown, JP Sundberg, PA Klein. 1995. Experimental transmission of green turtle fibropapillomatosis using cell-free tumor extracts. Diseases of Aquatic Organisms 22: 1-12.

4.  Horn T, FMD Gulland, JE Stein, KL Tilbury, WL Reichert. 1999 Investigations of metastatic carcinoma and exposure to chemical contaminants in California sea lions (Zalophus californianus). In review.

5.  Howard EB, JO Britt, JG Simpson. 1983. Neoplasms in marine mammals. In: Pathobiology of Marine Mammal Diseases, Vol. II E.B. Howard (ed). CRC Press, Boca Raton, Florida. pp 95-107.

6.  Jacobson ER, JP Sundberg, JM Gaskin, GV Kollias, MK O'Banion. 1986. Cutaneous papillomas associated with herpesvirus-like infection in a herd of captive African elephants. Journal of the American Veterinary Medical Association 189 (9): 1075-1078.

7.  Koss LG. 1975. Environmental causes of carcinoma of the bladder. In: Koss, L. G. (Ed.) Tumors of the Urinary Bladder. Armed Forces Institute of Pathology, Washington D.C., Pp 76-77.

8.  Lowenstine LJ, Beckman K, Garber R, Rafet M, FMD Gulland. 1999. Herpesvirus particles and sequences associated with a penile papilloma in a California sea lion (Zalophus californianus). In progress.

9.  Lowenstine LJ, Fowler MF, Flammer K. 1983. Viral Papillomas on the Feet of Cockatoos. Proceedings of the 25th International Symposium on the Diseases of Zoo and Wild Animals. (Vienna) Akademie Verlag, Berlin pp. 85-87.

10. Morrison CM, CT Leggiadro, DJ Martell. 1996. Visualization of viruses in tumors of rainbow smelt (Osmerus mordax). Diseases of Aquatic Organisms 26: 19-23.

11. Raynaud A, M Adrian. 1976. Lesions cutanees a structure papillomateuse associees a des virus chez le Lezard vert (Lacerta viridis Laur). C.R. Academy of Science, Paris 283: 845-847.

Speaker Information
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E.L. Buckles
Veterinary Medical Teaching Hospital, University of California
Davis, CA, USA

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